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WO2025240742A1 - Protein degraders of kras g12d mutant - Google Patents

Protein degraders of kras g12d mutant

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Publication number
WO2025240742A1
WO2025240742A1 PCT/US2025/029560 US2025029560W WO2025240742A1 WO 2025240742 A1 WO2025240742 A1 WO 2025240742A1 US 2025029560 W US2025029560 W US 2025029560W WO 2025240742 A1 WO2025240742 A1 WO 2025240742A1
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WIPO (PCT)
Prior art keywords
int
compound
pharmaceutically acceptable
mmol
acceptable salt
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PCT/US2025/029560
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French (fr)
Inventor
Ping LAN
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Publication of WO2025240742A1 publication Critical patent/WO2025240742A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the KRAS gene belongs to the RAS family, is one of the common gene mutations in human cancers and encodes a small GTPase.
  • RAS proteins are membrane-associated guanine nucleotide-binding proteins which function as molecular switches.
  • RAS proteins function as components of signaling pathways transmitting signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation.
  • RAS proteins cycle between an inactive GDP-bound state and an active GTP-bound state.
  • the KRAS gene is involved in the kinase signaling pathway that controls gene transcription, thereby regulating cell growth and differentiation.
  • KRAS protein transitions between an inactive and an active state - when KRAS binds to Guanosine Diphosphate (GDP), it is in the inactive state; when it binds to Guanosine Triphosphate (GTP), it is in the active state and can activate downstream signaling pathways.
  • GDP Guanosine Diphosphate
  • GTP Guanosine Triphosphate
  • KRAS in most cells is inactivated and when activated, downstream signaling pathways that can be activated include the MAPK signaling pathway, the PI3K signaling pathway, and the Ral-GEFs signaling pathway. These signaling pathways play an important role in promoting cell survival, proliferation and cytokine release, thereby affecting tumorigenesis and progression.
  • KRAS gene mutations occur in nearly 90% of pancreatic cancers, about 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of Lung cancers (mostly Non-Small Cell Lung Cancer, NSCLC). It also appears in cancer types such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and 145021.608066 (2500.PC) breast cancer. That is, in many of the cancers described above, there is a high proportion of KRAS gene mutations.
  • KRAS missense mutations occur in codon 12, resulting in glycine to other amino acids, for example, exchange of glycine for an aspartate at residue 12 of RAS (the G12D mutation).
  • G12C, G12D and G12R are the most common KRAS mutations in patients, e.g., KRAS G12D and KRAS G12V mutations, both found in about 90% of pancreatic cancers, and KRAS G12D is the most common KRAS mutation in colon cancer.
  • Targeted protein degraders are heterobifunctional molecules containing two small molecule binding moieties, joined together by a linker.
  • One of the small molecule components is designed to bind with high affinity to a target protein in the cell and the other can bind with high affinity to an E3 ligase.
  • the TPD selectively binds to the target protein of interest.
  • the TPD then recruits a specific E3 ligase to the target protein to form a ternary complex with both the target protein and the E3 ligase held in close proximity.
  • the E3 ligase then recruits an E2 conjugating enzyme to the ternary complex.
  • E2 is then able to ubiquitinate the target protein, labelling an available lysine residue on the protein, and then dissociates from the ternary complex.
  • E3 can then recruit additional E2 molecules resulting in poly-ubiquitination of the target protein, labelling the target protein for potential degradation by the cell’s proteasome activity.
  • a TPD is then able to dissociate from the target protein and initiate another catalytic cycle.
  • the poly-ubiquitinated target protein is then recognized and degraded by the proteasome.
  • Embodiments of the present disclosure fulfill this need and provide further related advantages.
  • SUMMARY OF THE DISCLOSURE The present disclosure provides small molecule protein degraders which modulate mutant KRAS proteins and may be valuable pharmaceutically active compounds for the 145021.608066 (2500.PC) treatment of cancer.
  • the compounds of the disclosure can modulate the KRAS activity and thereby affect the signaling pathway which regulates cell growth, differentiation, and proliferation associated with oncological disorders.
  • the compounds of the disclosure can modulate the KRAS (G12D) protein.
  • the disclosure furthermore provides processes for preparing compounds of the disclosure, methods for using such compounds to treat oncological disorders, and pharmaceutical compositions which comprise compounds of the disclosure.
  • the present disclosure provides a compound having structural Formula (I), or a pharmaceutically acceptable salt thereof, as shown above, wherein: Rb1 is H, C 1 -C 3 alkyl, cyano, C 1 -C 4 alkylcyano, or fluoro; R b2 is fluoro; M L is selected from the group consisting of: 145021.608066 (2500.PC) C M is (i) a 5- to 6-membered heterocyclylene containing one heteroatom selected from the group consisting of N, O, and S; (ii) a 3- to 6-membered monocyclic or a 5- to 8-membered bridged bicyclic cycloalkyl; wherein C M is unsubstituted or substituted by 1 to 2 substituents independently s elected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalky
  • Y is unsubstituted or substituted phenyl, naphthyl, pyridyl, indazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, or isoquinolinyl.
  • Y is naphthyl or indazolyl, wherein Y is substituted by 1 to 3 R Y substituents independently selected from the group consisting of halo, hydroxy, amino, C 1 - C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, C 2 -C 4 alkynyl, and cyano.
  • Y is selected from the group consisting of: [0023] In an embodiment, Y is selected from the group consisting of: 145021.608066 (2500.PC) [0024] In an embodiment, Y is selected from the group consisting of: [0025] In an embodiment, R 1 is tert-butyl or isopropyl. [0026] In an embodiment, R 2 is H or methyl. [0027] In an embodiment, R 2 is H. [0029] In an embodiment, each R 3 is H. [0030] In specific embodiments, the present disclosure provides a compound as described in any one of Examples 1-15 as set forth below, or a pharmaceutically acceptable salt thereof.
  • 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. 145021.608066 (2500.PC) Definitions [0032] 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. [0033] 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.
  • 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 oxygen atom to the central carbon atom, and a single-bonded alkyl group to the central carbon atom.
  • the acyl group can be a C 2 acyl, i.e., acetyl or a C 3 acyl, i.e., proprionyl.
  • 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.
  • Alk 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 C 1 -C 6 alkyl means an alkyl group having one (i.e., methyl) up to 6 carbon atoms (i.e., hexyl).
  • linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3- 7 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.
  • 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.
  • Alkylthio means an alkyl group linked to a sulfur.
  • “Fluoroalkylthio” means an alkylthio that is mono-or multiple-fluoro-substituted.
  • Alkoxy and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxygen.
  • Alkoxyalkyl means an alkoxy group linked to an alkyl group. The bond to the parent moiety is through a carbon atom of the alkyl component. 145021.608066 (2500.PC)
  • “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.
  • 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.
  • 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.
  • 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.
  • the bicyclic or tricyclic rings may be aryl rings, heterocyclic rings, cycloalkyl rings, etc.
  • Cyano means a N ⁇ C- group. The bond to the parent group is through the carbon atom.
  • 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.
  • suitable cyanoalkyl groups include cyanomethyl and 3-cyanopropyl.
  • 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.
  • cycloalkyl examples 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.
  • 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(CH 3 ) 2 or -N(CH 3 )(CH 2 CH 3 ).
  • “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.
  • “Fluoroalkoxy” includes mono- substituted as well as multiple fluoro-substituted “alkoxy” groups as previously defined. 145021.608066 (2500.PC) [0050] “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). [0051] “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.
  • heteroaryl groups include pyrazolyl, oxadiazolonyl, pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.
  • Heterocyclyl or “heterocyclic ring” means a partially aromatic, non-aromatic, or aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17 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.
  • heterocyclyl root name means that at least a nitrogen, oxygen, phosphorus or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • the heterocyclyl can contain N, S, S(O), S(O) 2 and/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.
  • spirocyclic heterocyclyl means a heterocyclyl having at least two rings sharing only a single atom.
  • Heterocyclylene means a divalent hydrocarbon group radical derived from a heterocyclyl or heterocyclic ring. In contrast to heterocyclyl or heterocyclic ring, two single bonds exist and each single bond attaches to a different parent group.
  • heterocyclylene examples include azetidinylene, pyrrolidinylene, and piperidinylene.
  • “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 145021.608066 (2500.PC) 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.
  • 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.
  • “Hydroxy” means a HO- group in which the bond to the parent moiety is through the oxygen atom.
  • “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. [0057] When any variable (e.g., R x ) 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 may also be used to determine the absolute stereochemistry.
  • 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. 145021.608066 (2500.PC) [0063]
  • 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 fractional 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.
  • the compounds of Formula (I) which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.
  • 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.
  • 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).
  • 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.
  • 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.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, 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 145021.608066 (2500.PC) 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.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of Formula (I) is 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.
  • organic non-toxic bases from which salts can be formed 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.
  • a compound of Formula (I) 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.
  • 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 145021.608066 (2500.PC) 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.
  • 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.
  • some of the compounds of Formula (I) may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate.
  • 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.
  • 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.
  • terapéuticaally 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.
  • therapeutically effective amount means an amount of a compound of Formula (I) that alleviates at least one clinical symptom in a human patient.
  • 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) [0073] 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.
  • 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).
  • 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
  • compositions may be administered in a single dose or may be divided into multiple doses.
  • Pharmaceutical Compositions [0075]
  • 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.
  • 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 145021.608066 (2500.PC) need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition.
  • 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.
  • the present disclosure therefore also provides the compounds of Formula (I) and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for modulating 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.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts inhibit the KRAS-G12C, KRAS- G12D, KRAS-G12V, and/or KRAS-G13D proteins.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. 145021.608066 (2500.PC)
  • 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.
  • 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 one 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.
  • Suitable carriers for the preparation of solutions 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.
  • 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.
  • 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.
  • the present application provides a method of modulating RAS-mediated cell signaling comprising contacting a cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Modulation 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 binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream 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.
  • the present application also provides methods of using the compounds of the disclosure (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 (e.g., cancer), and in some embodiments the KRAS G12D mutant.
  • a method of degrading a KRAS G12D protein in a cell comprising administering a therapeutically effective amount a compound of the disclosure (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, resulting in degradation of the KRAS G12D protein in the cell.
  • a method of inhibiting a KRAS G12D protein in a cell comprising administering a therapeutically effective amount of a compound of the disclosure (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, resulting in inhibition of the KRAS G12D protein in the cell.
  • a method for treatment of cancer comprising administering a therapeutically effective amount a compound of the disclosure (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.
  • the cancer is mediated by a KRAS mutation, e.g., the KRAS G12D mutation.
  • the cancer is pancreatic cancer, colorectal cancer or lung cancer.
  • the cancer is gall bladder cancer, thyroid cancer, or bile duct cancer.
  • 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 G12D mutation) and if the subject is determined to have the KRAS mutation, then administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof.
  • KRAS mutation e.g., KRAS G12D mutation
  • the disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis.
  • another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a compound of Formula (I).
  • 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 the disclosure (e.g., in the form of a pharmaceutical composition) to a subject in need of treatment of a hematological malignancy.
  • malignancies include, but are not limited to leukemias and lymphomas.
  • 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.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • CML chronic myelogenous leukemia
  • AoL acute monocytic leukemia
  • the compounds are useful for treatment of lymphomas such as Hodgkins lymphoma or non-Hodgkins lymphoma.
  • the compounds are useful for treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglubunemia
  • Determining whether a tumor or cancer comprises a KRAS mutation 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 protein.
  • the sequences of wild- type human KRAS are known in the art.
  • Methods for detecting a mutation in a KRAS nucleotide sequence are also known by those of skill in the art.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MASA mutant allele-specific PCR amplification
  • direct sequencing primer extension reactions
  • electrophoresis oligonucleotide ligation assays
  • hybridization assays TaqMan assays
  • SNP genotyping assays high resolution melting 145021.608066 (2500.PC) assays and microarray analyses.
  • samples are evaluated for KRAS mutations (e.g., the KRAS G12D mutation) by real-time PCR.
  • KRAS mutations e.g., the KRAS G12D mutation
  • real-time PCR fluorescent probes specific for the KRAS mutation are used. When a mutation is present, the probe binds and fluorescence is detected.
  • the KRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS gene.
  • tissue samples can be assessed for determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12D mutation).
  • the sample is taken from a subject having a tumor or cancer.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample.
  • the sample is a formalin- fixed paraffin-embedded sample.
  • the sample is a circulating tumor cell (CTC) sample.
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • 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.
  • 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 lymphom
  • 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)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • 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.
  • the lung cancer is a non-small cell lung carcinoma (NSCLC), for example, adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma.
  • NSCLC non-small cell lung carcinoma
  • 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.
  • the present disclosure also provides methods of modulating a mutant KRAS protein activity (e.g., activity resulting from the KRAS G12D mutation) by contacting the protein 145021.608066 (2500.PC) with an effective amount of a compound of the disclosure. Modulation can be inhibiting or activating protein activity, or degrading targeted polypeptides or proteins.
  • the present disclosure provides methods of inhibiting protein activity or degrading the mutant KRAS protein by contacting the mutant KRAS protein (e.g., KRAS G12D mutant) with an effective amount of a compound of the disclosure in solution.
  • the present disclosure provides methods of inhibiting the mutant KRAS protein activity or degrading the mutant KRAS protein by contacting a cell, tissue, or organ that expresses the protein of interest.
  • the disclosure provides methods of inhibiting protein activity or degrading targeted polypeptides or proteins 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 the disclosure.
  • 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.
  • any suitable additional active agent or agents 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.
  • the compounds of Formula (I) (or pharmaceutically acceptable salts thereof) can be administered in combination with radiation therapy, hormone therapy, surgery or immunotherapy.
  • 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.
  • 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, 145021.608066 (2500.PC) to provide a synergistic or additive therapeutic effect.
  • such therapy includes radiation treatment to provide a synergistic or additive therapeutic effect.
  • additional active agents i.e., additional anti-cancer agents
  • 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.
  • 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).
  • 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”.
  • HGF hepatocyte growth factor
  • 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).
  • 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 GI
  • the additional anti-cancer agent(s) is a chemotherapeutic agent.
  • chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, anti-metabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.
  • 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.
  • 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
  • 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, triethylenethiophospha
  • 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; 145021.608066 (2500.PC) broxuridine;
  • Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
  • Non-limiting examples of enzymes include asparaginase and pegaspargase.
  • 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.
  • Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.
  • Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.
  • 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; esperamicin
  • the additional anti-cancer agent(s) is a hormonal and/or anti- hormonal agent (i.e., hormone therapy).
  • 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
  • the additional anti-cancer agent(s) is an immunotherapeutic agent (i.e., immunotherapy).
  • immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.
  • Non-limiting examples of biological response modifiers 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.
  • interferon alfa/interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa
  • 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).
  • 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, mo
  • 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 bootszelimab, and anti-OX40 agents.
  • 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 bootszelimab, and anti-OX40 agents
  • 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.
  • 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.
  • 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.
  • HDAC histone deacetylase
  • MMP matrix-metalloproteinase
  • 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.
  • 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.
  • HDAC histone deacetylase
  • Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.
  • Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors include abemaciclib, alvocidib, palbociclib, and ribociclib.
  • 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-l ⁇ inhibitors such as PX 478; HIF-2 ⁇ inhibitors such as belzutifan and the HIF-2 ⁇ 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); AD
  • MMP matrix-metall
  • MMP inhibitors include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830.
  • WO 96/33172 examples include 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.
  • 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).
  • 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).
  • Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, 145021.608066 (2500.PC) pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAPTM.
  • 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), CV2
  • 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.
  • 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.
  • IMDs immunomodulatory imides
  • Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib. 145021.608066 (2500.PC)
  • Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.
  • Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK- 8353, SCH772984, ravoxertinib, ulixertinib, and an ERKi as described in WO 2017/068412.
  • 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; wortmann
  • 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.
  • 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.
  • 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 145021.608066 (2500.PC) 5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO 94/02136, WO 95/16691, WO 96/41807, WO
  • Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.
  • Non-limiting examples of SHP2 inhibitors include SHP2 inhibitors described in WO 2019/167000 and WO 2020/022323.
  • 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 ocfos
  • 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.
  • 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.
  • brachytherapy 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.
  • 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.
  • the radionuclide(s) can be embodied in a gel or radioactive microspheres.
  • 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.
  • 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.
  • 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-administered 145021.608066 (2500.PC) with other agents as described above.
  • 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.
  • a compound of Formula (I) can be administered just followed by and any of the agents described above, or vice versa.
  • 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.
  • 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.
  • kits include syringes, boxes, and bags.
  • 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.
  • 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 the 145021.608066 (2500.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.
  • 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.
  • CSA (1R)-(-)- camphorsulfonic acid
  • Davis reagent 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine
  • DAST diethylaminosulfur trifluoride
  • DCE 1,2-dichloroethane
  • DCM dichloromethane
  • DHP 3,4-dihydro-2H-pyran
  • DMA N,N- dimethylacetamide
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • dppf 1,1'-bis(diphenylphosphino)ferrocene
  • EDC 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • equiv eq.
  • ESI electrospray ionization
  • Et ethyl
  • EtOAc ethyl acetate
  • EtOH ethanol
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • h hr.
  • HATU hexafluorophosphate azabenzotriazole tetramethyl uranium
  • HMDS hexamethydisilazane
  • HPLC high pressure liquid chromatography
  • Int intermediate
  • i-Pr isopropyl
  • ISCO in situ chemical oxidation
  • KHMDS potassium bis(trimethylsilyl)amide
  • LAH lithium aluminum hydride
  • LCMS liquid chromatography-mass spectrometry
  • min minute
  • LDA lithium diisopropylamide
  • LiHMDS Lithium bis(trimethylsilyl)amide
  • M Molar
  • Me methyl
  • MeCN acetonitrile
  • MeOH methanol
  • MO methoxy
  • Ms methylsulfonyl
  • MS mass
  • 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.
  • Peak 1 refers to the first eluting compound, e.g., first eluting stereoisomer, under the specified conditions.
  • Step B 4-bromo-5-iodo-6-methyl- indazole (Int-1B) [00155] To a solution of 2-bromo-6-fluoro- 4-methylbenzaldehyde (Int-1A) (18.7 g, 54.5 mmol) in DMSO (200 mL) was added hydrazine (19.84 mL, 327 mmol, 85% aqueous solution) at 20 °C under N 2 atmosphere. The reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 x 400 145021.608066 (2500.PC) mL).
  • Step C 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 1C)
  • Int-1B 4-bromo-5-iodo-6-methyl-1H-indazole
  • THF 200 mL
  • 4-methylbenzenesulfonic acid 1.584 g, 9.20 mmol
  • DHP 8.41 mL, 92 mmol
  • Step D 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl- indazole (Int-1D)
  • Int-1C 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole
  • Step E 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carbaldehyde (Int-1E) [00161] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H- indazole (Int-1D) (4.5 g, 12.89 mmol) in THF (50 mL) and water (50 mL) was added sodium periodate (11.03 g, 51.6 mmol), 2,6-lutidine (2.76 g, 25.8 mmol), and potassium osmate(VI) dihydrate (0.475 g, 1.289 mmol) at 25 °C, and the mixture was stirred at 50 °C 145021.608066 (2500.PC) for 2 h.
  • Step F 4-bromo-5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-1F) [00163] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carbaldehyde (Int-1E) (3 g, 9.28 mmol) in DCM (30 mL) was added DAST (6.13 mL, 46.4 mmol) at -78 °C under N 2 atmosphere, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was added dropwise to aq.
  • Step G (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)boronic acid (Int-1)
  • Int-1F 4-bromo-5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole
  • n-butyllithium 1.6 M in hexanes, 0.725 mL, 1.160 mmol
  • Step B 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B) 145021.608066 (2500.PC) [00170] 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A) (100 g, 0.317 mol) was dissolved in DMF (1.50 L).
  • Step C 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (Int-2C)
  • 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B) (100 g, 0.382 mol) was dissolved in 2-MeTHF (500 mL). The reaction mixture was cooled down to -65 °C.
  • Step D 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (Int-2D)
  • 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (Int-2C) (100 g, 0.351 mol) was dissolved in 2-MeTHF (800 mL).
  • Step E 4-bromo-6-methyl-1- -5-(trifluoromethyl)-1H- indazole (Int-2E)
  • Step E 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (Int-2D) was dissolved in DCM (240 mL) and MeCN (240 mL).
  • DHP (21.7 g, 0.258 mol) and TsOH ⁇ H 2 O (8.18 g, 0.043 mol) were added to the mixture at 20 °C.
  • the reaction mixture was stirred for 12 h at 25 °C. Water (200 mL) was added to the product mixture.
  • Step F (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)boronic acid (Int-2) [00178] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazole (Int-2E) (1.2 g, 3.30 mmol) in MeOH (15 mL) was added tetrahydroxydiboron (1.185 g, 13.22 mmol), TEA (1.382 mL, 9.91 mmol), and cataCXium A Pd G2 (0.110 g, 0.165 mmol).
  • Step A Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (Int-3A) [00181] To a solution of ethyl 1H-pyrazole-4-carboxylate (13.75 g, 98 mmol) in DCM (100 mL) at 0 °C was added N,N-diisopropylethylamine (25.4 g, 196 mmol).
  • Step B N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxamide 3B)
  • ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (Int-3A) (20 g, 74.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.82 g, 111 mmol) in dry THF (350 mL) was added iPrMgBr (77 mL, 222 mmol, 2.9 M in 2-methyltetrahydrofuran) at 0 °C.
  • Step C 3,4-dibromothiophene-2-carbaldehyde (Int-3C) [00185] To the solution of 3,4-dibromothiophene (12.38 g, 51.2 mmol) in THF (120 mL) was added LDA (102 mL, 102 mmol, 1M in THF) at -78 °C and the reaction mixture was stirred at -78 °C for 2 h. DMF (4.73 mL, 61.4 mmol) was added dropwise to the reaction mixture, warmed to 25 °C, and stirred for 1 h.
  • LDA 102 mL, 102 mmol, 1M in THF
  • Step D 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N-methyl-1- ((2-(trimethylsilyl)ethoxy)methyl)- pyrazole-4-carboxamide (Int-3D)
  • N- N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-3B) (6.20 g, 21.7 mmol) in THF (150 mL) was added LDA (22.81 mL, 22.81 mmol, 1M in THF) at -78 °C under N 2 atmosphere and the reaction was stirred at -78 °C for 0.5 h.3,4-dibromothiophene-2-carbaldehyde (Int-3C) (8.80 g, 32.6 mmol) in THF (10 mL) was added at -78
  • Step E 5-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1H-pyrazole- 4-carboxamide
  • Int-3E To a solution of 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3D) (7.38 g, 13.29 mmol) in DCM (18 mL) was added triethylsilane (36.5 mL, 229 mmol) and TFA 145021.608066 (2500.PC) (18.25 mL, 237 mmol) at 25 °C.
  • Step F 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F) [00191] To a solution of 5-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1H- pyrazole-4-carboxamide (Int-3E) (4.85 g, 11.9 mmol) in DCM (50 mL) was added N,N- diisopropylethylamine (3.06 g, 23.7 mmol), and the mixture was stirred at 0 °C for 15 min.
  • Step G 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4- a stirred solution of 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F) (2 g, 3.71 mmol) in THF (20 mL) was added dropwise isopropylmagnesium chloride lithium chloride complex (5.70 mL, 7.42 mmol, 1.3M in THF) at 0 °C.
  • Step H 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-ol (Int-3H)
  • ethynyltriisopropylsilane 425 mg, 2.329 mmol
  • copper(I) iodide 29.6 mg, 0.155 mmol
  • triphenylphosphine 40.7 mg, 0.155 mmol
  • bis(triphenylphosphine)palladium(II) dichloride 54.5 mg, 0.0
  • Step I 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-yl trifluoromethanesulfonate (Int-3I)
  • To a solution of 5-((triisopropylsilyl)ethynyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-ol (Int-3H) (442 mg, 0.883 mmol) in DCM (8 mL) under N 2 atmosphere was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min.
  • Step J (5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-yl)boronic acid (Int-3)
  • Step B 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-6- carbaldehyde (Int-4B)
  • Int-4A 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]
  • Step C 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int-4C)
  • Int-4C Two reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane]-6-carbaldehyde (Int-4B) (80.0 g, 266 mmol) was dissolved in DMSO (133 mL) and N 2 H 4 •H 2 O (204 g, 3.99 mol) was added to the mixture at room temperature.
  • Step D 4-bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D)
  • Step D 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane]
  • Int- 4C (100 g, 339 mmol) was dissolved in acetone (1.00 L) and H 2 O (200 mL) at room temperature. Then, HCl (200 mL, 6M in H 2 O) was added to the mixture at room temperature. The reaction was heated to 60 °C for 0.5 h.
  • Step E 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydrocyclopenta[f]indazol- 5(1H)-one (Int-4)
  • Step E 4-bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D) (75.0 g, 299 mmol) was dissolved in toluene (1350 mL) at 20 o C and DHP(100 g, 1.19 mol) and CSA (6.94 g, 29.9 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 100 o C and stirred for 3 h.
  • Step B 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5B)
  • Step B 4-bromo-5-methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (2.5 g, 7.50 mmol) (Int-5A) was dissolved in EtOAc (50.0 145021.608066 (2500.PC) ml) and rhodium (3.09 g, 1.500 mmol) was added.
  • Step C 4-bromo-5-methyl-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5C)
  • Int-5C 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (2.46 g, 7.34 mmol) (Int-5B) was taken up in isopropyl alcohol (24.46 ml) and 4N HCl in 1,4-dioxane (12.23 ml) was added. Reaction stirred at 45 °C overnight, then quenched with sat.
  • Step D 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole 5D)
  • 4-bromo-5-methyl- [f]indazole (570 mg, 2.270 mmol) (Int-5C) and p-toluenesulfonic acid monohydrate (130 mg, 0.681 mmol) were taken up in THF (7566 ⁇ l).
  • DHP (828 ⁇ l, 9.08 mmol
  • Step E (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int-5) [00221] To a solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (1.19 g, 3.55 mmol) in MeOH (17.75 ml) was added TEA (1.979 ml, 14.20 mmol), tetrahydroxydiboron (0.477 g, 5.32 mmol) and CataCXium A Pd G2 (0.237 g, 0.355 mmol) at 20 °C under N 2 atmosphere, the mixture was stirred at 50 °C for 1 hour.
  • TEA 1.979 ml, 14.20 mmol
  • tetrahydroxydiboron
  • Step B 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B) 145021.608066 (2500.PC) [00226] To a solution of 5-((2-bromo-4-fluorophenyl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6A) (20.0 g, 40.9 mmol) in DCM (56 mL) was added triethylsilane (118 mL, 737 mmol) and TFA (56.8 mL, 737 mmol), and the mixture was stirred at 60 °C for 3 h.
  • Step C 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6C)
  • Int-6C 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazole-4-carboxamide
  • Step D 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4- one (Int-6D)
  • Int-6D 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4- one
  • Step E 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1,9- dihydro-4H-benzo[f]indazol-4-one (Int-6E) 145021.608066 (2500.PC) [00232] To a solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H- benzo[f]indazol-4-one (Int-6D) (6.50 g, 22.7 mmol) in dioxane (120 mL) was added (bromoethynyl)triisopropylsilane (17.8 g, 68.1 mmol), potassium acetate (7.8 g, 79 mmol), and dichloro(p-cymene)ruthenium(II) dimer (6.95 g, 11.4
  • Step F 6-fluoro-1-((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F)
  • Int-6F A solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)- 1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6E) (5.50 g, 11.8 mmol) and N,N- diisopropylethylamine (12.4 mL, 70.7 mmol) in DCM (60 mL) was added Tf 2 O (5.97 mL, 35.4 mmol) at -40 °C, and the reaction mixture was stirred for 15 min.
  • Step G 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)- [f]indazole (Int-6)
  • dichlorobis(triphenylphosphine)palladium(II) (0.760 g, 1.08 mmol) was added at 25°C and the mixture was stirred at 80 °C for 24 h under N 2 atmosphere. The mixture cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure.
  • Step B 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B)
  • Int-7A A mixture of 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A) (8.91 g, 38.5 mmol), iron (10.8 g, 193 mmol), and NH 4 Cl (10.3 g, 193 mmol) in EtOH (120 mL) and water (20 mL) was vigorously stirred at 70 °C for 1 h.
  • Step C 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-7C) 145021.608066 (2500.PC) [00243] To a solution of 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B) (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 room temperature, sat. aq. NaHCO 3 and EtOAc were added to the reaction mixture.
  • Step D 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D)
  • Int-7C 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine
  • nitrosyl tetrafluoroborate 380 mg, 3.25 mmol
  • 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.
  • Step E 4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-7E)
  • Int-7E 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D) (920 mg), (1R)-(-)-camphor-10-sulfonic acid (60 mg, 0.26 mmol), and DHP (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 room temperature and sat. aq.
  • Step F 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol- 5-yl)cyclopropan-1-ol (Int-7F)
  • KOH (1.25 mL, 2.50 mmol, 2N in H 2 O) was added to a solution of 4-chloro-5- iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-7E) (430 mg, 0.999 mmol), 2,2'-cyclopropylidenebis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (740 mg, 2.52 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (100 mg, 0.195 mmol) in
  • Step G 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G)
  • DAST 0.035 mL, 0.265 mmol
  • Step H (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-7)
  • the mixture of 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G) 34 mg, 0.094 mmol
  • tetrahydroxydiboron 40 mg, 0.45 mmol
  • cataCXium A Pd G3 (6.0 mg, 0.0082 mmol) and TEA (0.080 ml, 0.57 mmol) in MeOH (1 mL) was stirred at room temperature for 60 hours.
  • Step B 6-chloro-5-nitro-1H-indazole (Int-8B)
  • Int-8A 4-chloro-2-fluoro-5-nitrobenzaldehyde
  • hydrazine hydrate (161 mL, 2.82 mol)
  • the reaction mixture was stirred at 100 °C for 15 h.
  • the reaction mixture was cooled and quenched with ice water (2 L).
  • the mixture was filtered and the filtered cake was washed with water (2 x 300 mL), dried in vacuum to give 6-chloro-5-nitro-1H- indazole (Int-8B).
  • Step C 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-8C) [00260] To a solution of 6-chloro-5-nitro-1H-indazole (Int-8B) (92 g, 0.47 mol) in THF (1.0 L) were added DHP (85 mL, 0.93 mol) and p-toluenesulfonic acid (8.0 g, 47 mmol) at 25 °C under N 2 atmosphere.
  • Step D 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int-8D)
  • Int-8D 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine
  • Step E 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 8E)
  • Int- 8D 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine
  • NBS 56.5 g, 318 mmol
  • Step F 4-bromo-6-chloro-1H-indazol-5-amine (Int-8F)
  • Int-8E 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- amine
  • Step G 4-bromo-6-chloro-5-iodo- indazole (Int-8G)
  • HCl 10 g, 35 mmol
  • 6M aq. HCl 100 mL
  • sodium nitrite 2.9 g, 42 mmol
  • Step H 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8H)
  • Int-8G 4-bromo-6-chloro-5-iodo-1H-indazole
  • THF 300 mL
  • 4-methylbenzenesulfonic acid 1.5 g, 9.0 mmol
  • DHP 16 mL, 180 mmol
  • Step I 1-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropan-1-ol (Int-8I) 145021.608066 (2500.PC)
  • Step II 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-8H) (0.2019 g, 0.457 mmol) was added to a vial with a stir bar and the headspace swept with N 2 .
  • Methylmagnesium chloride (123 ⁇ L, 0.368 mmol, 3 M in THF) was added to the reaction followed by the contents of the first reaction flask containing 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole, both dropwise via syringe.
  • the reaction was allowed to warm to room temperature overnight. Sat. aq. Na2CO3 (50 mL), H2O (500 mL), brine (25 mL), and EtOAc (100 mL) were added and the layers were separated.
  • Step J 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (Int-8J)
  • DAST 90 ⁇ L, 0.681 mmol
  • 1-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-8I) 111.6 mg, 0.300 mmol
  • DCM 2.5 mL
  • the mixture was stirred at -78 °C for 50 min.
  • Step K (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-8) [00276] CataCXium A Pd G2 (24 mg, 0.036 mmol), hypodiboric acid (56.4 mg, 0.629 mmol), and TEA (110 ⁇ L, 0.789 mmol) in MeOH (2000 ⁇ l) were added to a vial containing 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8J) (78.4 mg, 0.210 mmol).
  • Step B 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B)
  • Copper iodide (612 mg, 3.21 mmol) and tert-butyl nitrite (0.395 ml, 3.32 mmol) were added to a stirred solution of 4-bromo-6-(trifluoromethyl)-1H-indazol-5-amine (Int- 9A) (300 mg, 1.07 mmol) in MeCN (25 mL) at room temperature. The mixture was warmed to 70°C and stirred for 30 min. After cooling, the mixture was partitioned between EtOAc and sat. aq. NaHCO 3 .
  • Step C 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-9C) 145021.608066 (2500.PC) [00283] A mixture of 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B) (320 mg, 0.81 mmol), DHP (0.15 mL, 1.61 mmol), (1R)-(-)-camphor-10-sulfonic acid (24 mg, 0.11 mmol) in toluene (10 mL) was stirred at 70 °C for 3 h.
  • Step D 4-bromo-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazole (Int-9D)
  • Step E (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- indazol-4-yl)boronic acid (Int-9)
  • CataCXium A Pd G3 (12 mg, 0.017 mmol) was added to a stirred mixture of 4- bromo-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int- 9D) (66 mg, 0.17 mmol), triethylamine (0.095 mL, 0.68 mmol), and tetrahydroxydiboron (31 mg, 0.34 mmol) in MeOH (3.4 mL) at room temperature.
  • Step B (2- fluoropyridin-4-yl)methanol (Int-11B) [00294] Twelve were set up in parallel. To each reactor was charged EtOH (2.3 L), methyl 2-chloro-3-fluoroisonicotinate (Int-11A) (235 g, 1.2 mol), and CaCl2 (206 g, 1.8 mol). The reactor was degassed and purged with N2 three times and cooled to 0 ⁇ 10 °C. 145021.608066 (2500.PC) NaBH 4 (93.0 g, 2.4 mol) was added at 0 ⁇ 10 o C and stirred for 1 hr. The mixture was warmed to 20 ⁇ 25 °C and stirred for 12 h.
  • EtOH 2.3 L
  • methyl 2-chloro-3-fluoroisonicotinate Int-11A
  • CaCl2 206 g, 1.8 mol
  • Step C 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-11C)
  • 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-11B) (200 g, 1.2 mol).
  • PBr 3 (402 g, 1.5 mol) was charged into the reactor vessel at 0 °C. The vessel was warmed to 25 °C 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 reactor was warmed to 100 °C and stirred at 145021.608066 (2500.PC) 100 °C for 1 h.
  • NaOH (1 L, 5.00 mol, 5 M in H 2 O) was added and the mixture was stirred at 100 °C for 10 h.
  • the reaction was cooled to room temperature 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 H 2 O (5.0 L), and oven-dried at 50 °C for 12 h to give 2-amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-11E).
  • Step F 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F)
  • DMSO 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide
  • Int-11E 2- amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile
  • K 2 CO 3 92.0 g, 0.60 mol
  • H 2 O 2 (615 g, 5.4 mol, 30 wt%) was added slowly into the reactor in portions over 4 hr. The reaction mixture was stirred at 25 °C for 6 hr.
  • Step G 8-chloro-2-mercaptopyrido ol (Int- 11G)
  • EtOH 0.5 L
  • KOH 52.0 g, 0.90 mol
  • CS 2 70.0 g, 0.9 mol
  • Step J Tert-butyl (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) [00310] To a stirred mixture of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidine (Int-11I) (170 mg, 0.56 mmol) and N,N-diisopropylethylamine (300 ⁇ L, 1.69 mmol) in DMF (5 mL) was added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (119 mg, 0.56 mmol) at 0 °C
  • Step K Tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-11K) [00312] To a stirring solution of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (200 mg, 2.52 mmol) in DCM (2.5 mL) was added mCPBA (580 mg, 2.52mmol, 75 wt%) at 0
  • Step L Tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L)
  • Tert-butyl (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (500 mg, 1.046 mmol) was dissolved in DCM (10 ml).
  • Step B Tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-12) [00319] To a stirred solution of tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-12) [00319] To a stirred solution of tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)
  • the resulting mixture was stirred at r.t. for 1 h, diluted with DCM, and quenched by addition of 1:1 Na 2 S 2 O 3 (1 N in water)/sat. NaHCO 3 .
  • the organic layer was separated, and the aqueous layer was extracted with DCM twice.
  • Step B Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13B) [00324] To a solution of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octtane-8-carboxylate (Int-13B) [00324] To a solution of tert-butyl (1R,5S)
  • Step C Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) [00326] Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.
  • Step B Tert-butyl (1R,5S)-3-(2-(methylsulfonyl)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl) d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- [00334] To a solution of tert-butyl (1R,5S)-3-(2-(methylthio)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5
  • Step B Tert-butyl (1R,5S)-3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-17B) [00342] To a mixture of tert-butyl (1R,5S)-3-(8-(6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyri
  • Step C Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17C) [00344] To a mixture of tert-butyl (1R,5S)-3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)- 1H-benzo[f]indazol-4-yl)-2-(methylthio)pyr
  • Step D Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17) [00346] To a solution of tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H
  • Step B Tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19) [00354] To a solution of tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4',3'
  • Step B Tert-butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20) [00359] Tert-Butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl
  • Step B Tert-butyl (1R,5S)-3-(2-(((S)-1-(((tert-butyldimethylsilyl)oxy)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- 145021.608066 (2500.PC) (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21B) [00364] A solution of tert-butyl (1R,5S)-3-(2-hydroxy-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)
  • Step C Tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21C) [00366] A solution of tert-butyl (1R,5S)-3-(2-(((S)-1-(((tert- butyldimethylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (t)
  • Step D Tert-butyl (1R,5S)-3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 145021.608066 (2500.PC) 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) [00368] A solution of tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-8-(
  • Step A Benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int-22A) 145021.608066 (2500.PC) [00371] In a 100 mL round bottom flask, 3-(hydroxymethyl)-3-methylpiperidin-1-ium chloride (1500 mg, 9.05 mmol) was dissolved in DCM (22.6 ml). To above solution was added TEA (5048 ⁇ L, 36.2 mmol, 4 eq), followed by CbzCl (4527 ⁇ L, 13.58 mmol, 1.5 eq). The reaction was stirred at r.t.
  • Step B Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl) d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- [00373] In a 40 mL vial, tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-
  • Step C Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22) [00375] Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydr
  • Step B Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylazetidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23) [00380] Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylazetidin-3- yl)methoxy)-8-(6-methyl-1-(
  • Step B (R)-2-Amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1-ol (Int-25B)
  • Step B To a stirred solution of tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (260 mg, 0.80 mmol) (Int-25A) in DCM (2.6 mL) was added HCl (4 M in dioxane, 1.4 mL, 5.6 mmol).
  • Step C Tert-Butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)- 2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)carbamate (Int-25C) [00390] To a stirred solution of (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan- 1-ol (100 mg, 0.37 mmol) (Int-25B) and (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4- hydroxypyrrolidine-2-carboxylic acid (150 mg, 0.45 mmol) in DMF (1.2 mL) was added DIPEA (200 ⁇ L,
  • Step D (2S,4R)-1-(L-Valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-25) [00392] To a stirred solution of tert-butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)carbamate (180 mg, 0.34 mmol) (Int-25C) in DCM (1.1
  • Step A 4-(4-methylthiazol-5-yl)benzonitrile (Int-28A) [00400] To a solution of 4-bromobenzonitrile (20 g, 110 mmol) in DMA (280 mL) was added 4-methylthiazole (21.79 g, 220 mmol), Pd(OAc) 2 (0.247 g, 1.099 mmol) and Potassium carbonate (21.57 g, 220 mmol) at 25 °C under N 2 atmosphere.
  • Step B (4-(4-methylthiazol-5-yl)phenyl)methanamine (Int-28B)
  • Step B (4-(4-methylthiazol-5-yl)phenyl)methanamine (Int-28B)
  • Step C Tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C)
  • Step C Tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C)
  • 4-(4-methylthiazol-5-yl)phenyl)methanamine 2.4 g, 11.75 mmol
  • (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.99 g, 12.92 mmol)
  • 1H-benzo[d][1,2,3]triazol-1-ol 1.905 g, 14.10 mmol
  • DIEA (6.16 mL, 35.2
  • Step D (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide
  • Step D The compound of tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (8 g, 19.16 mmol) (Int-28C) was added to HCl (4.79 mL, 19.16 mmol) (4 M in Dioxane) at 25 °C. The mixture was stirred at 25 °C for 30 min.
  • Step E (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-28) [00408] To a solution of (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (6 g, 18.90 mmol) (Int-28D) in DCM (60 mL) was added 2,6-Lutidine (33.0 mL, 284 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (30.0 g, 113 mmol)) at 25 °C under N 2 atmosphere.
  • Step B 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (Int-29B) [00413] To a solution of 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole (9.3 g, 50.8 mmol) (Int-29A) in THF (90 mL) was added dropwise KHMDS (76 mL, 76 mmol, 1 M in THF) at -66 °C under nitrogen atmosphere, and the reaction mixture was stirred at -66 °C for 0.5 h.
  • KHMDS 76 mL, 76 mmol, 1 M in THF
  • reaction mixture was then bubbled carbon dioxide at -66° C for 1 h., and the mixture was stirred at 10 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed.
  • Step C Methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (Int- 29C) 145021.608066 (2500.PC) [00415] To a solution of 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (4 g, 17.60 mmol) (Int-29B) in a mixture of EtOAc (40 mL) and MeOH (40 mL) was added (trimethylsilyl)diazomethane (44 mL, 88 mmol) at 0 °C.
  • Step D Methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate (Int-29D) [00417] To a solution of methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (3.6 g, 14.92 mmol) (Int-29C) in DMF (40 mL) was added potassium tert-butoxide (1.842 g, 16.41 mmol) and 2-iodopropane (2.79 g, 16.41 mmol) at 0 °C under N 2 atmosphere.
  • Step E 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoic acid (Int-29E) [00419] To a solution of methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate (800 mg, 2.82 mmol) (Int-29D) in MeOH (8 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (592 mg, 14.12 mmol) at 10 °C. The mixture was stirred at 10 °C for 3 h.
  • Step F (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-((tetrahydro- 2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide (Int-29F) 145021.608066 (2500.PC) [00421] To a solution of 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoic acid (368 mg, 1.367 mmol) (Int-29E) in DMF (4 mL) was added PyBOP (853 mg, 1.640 mmol), (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-
  • Step G (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
  • (Int-29G) [00423] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3- ((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (669 mg, 0.980 mmol) (Int-29F) in MeOH (7 mL) was added PPTS (738 mg, 2.94 mmol) at 15 °
  • Step H (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29-a & Int-29-b)
  • Step B Methyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (Int-32B) [00435] To a stirred mixture of methyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4- hydroxypyrrolidine-2-carboxylate (3 g, 8.71 mmol) (Int-32A) in DCM (14 mL) was added hydrochloride in 1,4-dioxane (30 mL, 4 M, 120 mmol) at room temperature. The resulting 145021.608066 (2500.PC) mixture was stirred for 2 h.
  • Step C Methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine- 2-carboxylate (Int-32C) [00437] To a stirred mixture of methyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2- carboxylate hydrochloride (3 g, 12.28 mmol) (Int-32B) in DMF (30 mL) were added 1H- imidazole-1-sulfonyl azide hydrochloride (3.09 g, 14.74 mmol) and aqueous potassium bicarbonate (3 M, 20.47 mL, 61.4 mmol) at room temperature.
  • Step D (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2- carboxylic acid 32D)
  • Step D (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2- carboxylic acid 32D)
  • methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylate (1.45 g, 5.36 mmol) (Int-32C) in methanol (27 mL) was added LiOH (6.71 mL, 26.8 mmol) at room temperature.
  • the resulting mixture was stirred for 2 h.
  • the reaction mixture was quenched by aq.
  • Step E (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-32) [00441] To a stirred mixture of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid (700 mg, 2.73 mmol) (Int-32D) in DMF (8 mL) were added HATU (1428 mg, 3.76 mmol), (R)-2-amino-2-(4-(4-methylthiazol-5- yl)phenyl)ethan-1-ol (800 mg, 3.41 mmol) and DIEA (2.385 mL, 13.66 mmol) at 0 °C.
  • Step B Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (Int-38B) [00459] A solution of oxalyl chloride (14.79 mL, 175 mmol) in DCM (400 mL) was cooled to -78 °C, and a solution of DMSO (24.81 mL, 350 mmol) in DCM (100 mL) was added dropwise. The mixture was stirred at -78 °C for 15 min.
  • Step C Methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (Int-38C) 145021.608066 (2500.PC) [00461] To a solution of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (17.6 g, 114 mmol) (Int-38B) in MeOH (360 mL) was added K 2 CO 3 (47.3 g, 342 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (32.9 g, 171 mmol) at 25 °C The mixture was stirred at 25 °C for 16 h.
  • Step D (3-ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-38) [00463] To a solution of methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (7.6 g, 50.6 mmol) (Int-38C) in THF (80 mL) was added LAH (20.24 mL, 50.6 mmol) (2.5 M in THF) at 0 °C, and the mixture was stirred at 0 °C for 1 h.
  • Example 1 (2S,4R)-1-((2S)-2-(7-((3R and 3S)-3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-(difluoromethyl)-6-methyl-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-1)
  • Step A Tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step B Tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00471] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)
  • the resulting mixture was stirred at r.t. for 2 h, at which point a second portion of mCPBA (70 wt%, 266 mg, 1.54 mmol) was added.
  • the resulting mixture was stirred at RT for 2 h, at which point a third portion of mCPBA (70 wt%, 266 mg, 1.54 mmol) was added.
  • the resulting mixture was stirred at r.t. for 1 h, diluted with DCM, and quenched by addition of 1:1 Na 2 S 2 O 3 (1 N in water)/sat’d NaHCO3.
  • the organic layer was separated, and the aqueous layer was extracted with DCM twice.
  • Step C Tert-Butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(((R and S)-1-(7-methoxy-7-oxoheptyl)-3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00473] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro- 2H-pyran-2-yl
  • Step D 7-((3R and 3S)-3-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3- methylpiperidin-1-yl)heptanoic acid [00475] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-
  • Step E Tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-((R and S)-(1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol- 5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7- oxoheptyl)-3-methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl
  • tert-butyl 3- (8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((R and S)-1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)- 3-methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- 145021.608066
  • Step F (2S,4R)-1-((2S)-2-(7-((3R and 3S)-3-(((4-(3,8-Diazabicyclo[3.2.1]octan-3- yl)-8-(5-(difluoromethyl)-6-methyl-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-1) [00479] To a stirred solution of
  • Example 2 (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-2)
  • Step A Tert-butyl (1R,5S)-3-(2-((1-(7-methoxy-7-oxoheptyl)-3-methylpiperidin- 3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00482] To a solution of tert-butyl (1R,5S)-3-(2-(methylsulfinyl)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethoxy-7-oxoheptyl)-3-methylpipe
  • Step B 7-(3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2- 145021.608066 (2500.PC) f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin- 1-yl)heptanoic acid [00484] To a solution of tert-butyl (1R,5S)-3-(2-((1-(7-methoxy-7-oxoheptyl)
  • Step C Tert-butyl (1R,5S)-3-(2-((1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-7-oxoheptyl)-3-methylpiperidin-3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,
  • Step D (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [00488] A mixture of tert-butyl (1R,5S)-3-(
  • Step E (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-2) [00490] To a solution of (2S,4R)-1-((2S)-2-(7-(3-(((4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-2)
  • Ex-3 in the table below was synthesized via a similar route as described in the above synthesis of Ex-2 by making the appropriate substitutions.
  • 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. E x.
  • Step B Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00496] To a solution of tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3- methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyr
  • reaction mixture was warmed to r.t. and stirred for 30 min. Upon completion by LCMS, water was added and the mixture was extracted with DCM (2x, 10.0 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated under vacuum.
  • Step C Tert-butyl (1R,5S)-3-(2-((3-methyl-1-(pent-4-yn-1-yl)piperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00498] Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)me
  • Step D Tert-butyl ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl) - dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)propyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl) pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00500] To a solution of tert-butyl (1R,5S)-3-(2-((3-methyl-1-(pent)
  • Step E (2S,4R)-1-((2S)-2-(4-(3-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-4) 145021.608066 (2500.PC) [00502] Tert-butyl (1R,5S)-2-(4-(3-(3-(((4-((1R,
  • Example 5 (2S,4R)-1-((2S)-2-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)cyclohexane-1-carboxamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-5) 145021.608066 (2500.PC) [00504] Step A: butyl (1R,5S)-3-(2-((1-((4-(methoxycarbonyl)cycl
  • Step B 4-((3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- 145021.608066 (2500.PC) yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)methyl)cyclohexane-1-carboxylic acid [00507] Crude tert-butyl (1R,5S)-3-(2-((1-((4-((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8
  • Step C Tert-butyl (1R,5S)-3-(2-((1-((4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)cyclohexyl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimi
  • Step D (2S,4R)-1-((2S)-2-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)cyclohexane-1-carboxamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrol
  • Ex-6 and Ex 7 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-5 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. 145021.608066 (2500.PC) E x.
  • Step B Tert-butyl (1R,5S)-3-(2-((1-(4-(1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)butyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-
  • Step C (2S,4R)-1-((2S)-2-(4-(4-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)butyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide
  • Ex-9 to Ex-11 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-8 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. E x.
  • Step B (2S,4R)-1-((2S)-2-(4-(3-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)- 4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3- 1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)- 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-12) [00525] A solution of tert-butyl (1R,5
  • Ex-13 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-12 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. E x.
  • Step B (2S,4R)-1-((2R)-2-(3-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5-yl)- 3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine

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Abstract

Compounds or their pharmaceutically acceptable salts can modulate the G12D mutant 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 disclosed herein 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

145021.608066 (2500.PC) PROTEIN DEGRADERS OF KRAS G12D MUTANT CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims benefit of U.S. Provisional Application No.63/648,063, filed May 15, 2024, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] The present disclosure relates to certain compounds and pharmaceutically acceptable salts thereof that modulate the G12D mutant of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treatment of cancer. The present application also relates to pharmaceutical compositions containing such compounds as well as methods of using the compounds for treating cancer. BACKGROUND [0003] The KRAS gene belongs to the RAS family, is one of the common gene mutations in human cancers and encodes a small GTPase. RAS proteins are membrane-associated guanine nucleotide-binding proteins which function as molecular switches. RAS proteins function as components of signaling pathways transmitting signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation. RAS proteins cycle between an inactive GDP-bound state and an active GTP-bound state. The KRAS gene is involved in the kinase signaling pathway that controls gene transcription, thereby regulating cell growth and differentiation. Within the cell, KRAS protein transitions between an inactive and an active state - when KRAS binds to Guanosine Diphosphate (GDP), it is in the inactive state; when it binds to Guanosine Triphosphate (GTP), it is in the active state and can activate downstream signaling pathways. KRAS in most cells is inactivated and when activated, downstream signaling pathways that can be activated include the MAPK signaling pathway, the PI3K signaling pathway, and the Ral-GEFs signaling pathway. These signaling pathways play an important role in promoting cell survival, proliferation and cytokine release, thereby affecting tumorigenesis and progression. [0004] In human cancers, KRAS gene mutations occur in nearly 90% of pancreatic cancers, about 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of Lung cancers (mostly Non-Small Cell Lung Cancer, NSCLC). It also appears in cancer types such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and 145021.608066 (2500.PC) breast cancer. That is, in many of the cancers described above, there is a high proportion of KRAS gene mutations. Most KRAS missense mutations occur in codon 12, resulting in glycine to other amino acids, for example, exchange of glycine for an aspartate at residue 12 of RAS (the G12D mutation). Depending on the particular mutation present, G12C, G12D and G12R are the most common KRAS mutations in patients, e.g., KRAS G12D and KRAS G12V mutations, both found in about 90% of pancreatic cancers, and KRAS G12D is the most common KRAS mutation in colon cancer. [0005] Currently in relation to KRAS G12D, in the case of anticancer drugs, small molecules traditionally inhibit the activity of target protein by targeted binding to induce cancer cell apoptosis, but target proteins in tumor cells often recover their activity and acquire drug resistance through overexpression of the target protein or incorporation of a new mutation in the target protein. [0006] Targeted protein degraders (TPDs) are heterobifunctional molecules containing two small molecule binding moieties, joined together by a linker. One of the small molecule components is designed to bind with high affinity to a target protein in the cell and the other can bind with high affinity to an E3 ligase. In the cell, the TPD selectively binds to the target protein of interest. The TPD then recruits a specific E3 ligase to the target protein to form a ternary complex with both the target protein and the E3 ligase held in close proximity. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex. E2 is then able to ubiquitinate the target protein, labelling an available lysine residue on the protein, and then dissociates from the ternary complex. E3 can then recruit additional E2 molecules resulting in poly-ubiquitination of the target protein, labelling the target protein for potential degradation by the cell’s proteasome activity. A TPD is then able to dissociate from the target protein and initiate another catalytic cycle. The poly-ubiquitinated target protein is then recognized and degraded by the proteasome. [0007] Accordingly, while progress has been made in this field, there remains a need in the art for small molecules that enable targeted degradation therapy for KRAS G12D mutation- related diseases or disorders. Embodiments of the present disclosure fulfill this need and provide further related advantages. SUMMARY OF THE DISCLOSURE [0008] The present disclosure provides small molecule protein degraders which modulate mutant KRAS proteins and may be valuable pharmaceutically active compounds for the 145021.608066 (2500.PC) treatment of cancer. The compounds of the disclosure, including compounds of Formula (I): and their pharmaceutically acceptable salts, can modulate the KRAS activity and thereby affect the signaling pathway which regulates cell growth, differentiation, and proliferation associated with oncological disorders. In certain embodiments, the compounds of the disclosure can modulate the KRAS (G12D) protein. The disclosure furthermore provides processes for preparing compounds of the disclosure, methods for using such compounds to treat oncological disorders, and pharmaceutical compositions which comprise compounds of the disclosure. DETAILED DESCRIPTION OF THE INVENTION Compounds of the Disclosure [0009] In one embodiment, the present disclosure provides a compound having structural Formula (I), or a pharmaceutically acceptable salt thereof, as shown above, wherein: Rb1 is H, C 1 -C 3 alkyl, cyano, C 1 -C 4 alkylcyano, or fluoro; R b2 is fluoro; M L is selected from the group consisting of: 145021.608066 (2500.PC) C M is (i) a 5- to 6-membered heterocyclylene containing one heteroatom selected from the group consisting of N, O, and S; (ii) a 3- to 6-membered monocyclic or a 5- to 8-membered bridged bicyclic cycloalkyl; wherein CM is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, and C 1 -C 3 alkoxy; Ld ifs selected from the group consisting of -CH2- and -O-; L e is selected from the group consisting of: R5 is H or C 1 -C 3 alkyl; X e , X f , X g , and X h are independently selected from the group consisting of C, C(H), C(R Le ), N, O, and S; wherein at least one of X e , X f , X g , and X h is C, C(H), or C(R Le ); each RLe substituent is independently selected from the group consisting of halo, C1-C3 alkyl, C 1 -C 3 fluoroalkyl, and C 1 -C 3 alkoxy; R1 is C 1 -C 6 alkyl, -CH 2 -C1, C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; wherein C1 is C 3 -C 7 cycloalkyl; R2 is H, C 1 -C 6 alkyl, or -CH 2 OH; each R3 is independently H, fluoro, C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl; 145021.608066 (2500.PC) X a , X b , X c and X d are independently selected from the group consisting of C(H), C(R 4 ), N, N(R 4 ), S and O; wherein at least one of X a , X b , X c and X d is C(H) or C(R 4 ); X i is C or N; R4 is halo, C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl; W A is S, O, or N(R W1 ); RW1 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 fluorocycloalkyl; Ring A is a saturated 5- to 8-membered N-containing monocyclic heterocyclyl or a saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl, wherein the saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl contains at least one further N atom in addition to the illustrated N atom; RA is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C1-C3 alkoxy, C1- C3 alkoxy(C 1 -C 3 )alkyl, halo, C 1 -C 3 fluoroalkyl, hydroxy, C 1 -C 3 hydroxyalkyl, CF 3- C(H)(OH)-, C(H)(F 2 )-C(H)(OH)-, cyano, and C 1 -C 3 cyanoalkyl; Y is a 5- to 6-membered mono- or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (ii) a 12- to 14-membered tricyclic heterocyclyl, where at least 2 of the rings of the 12- to 14-membered tricyclic heterocyclyl are aromatic, the third ring is unsaturated or aromatic, wherein the 12- to 14-membered tricyclic heterocyclyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; or (iii) phenyl or naphthyl; wherein Y is unsubstituted or substituted by 1 to 4 RY substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 3 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, C 2- C 3 acyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 fluoroalkylthio, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino and cyano; or alternatively, 2 RY substituents, together with the carbon atom to which both are attached, form a 3- to 5-membered saturated carbocyclic ring; subscript i is 0, 1, or 2; subscript j is 1, 2, 3, 4, 5, 6, or 7; 145021.608066 (2500.PC) subscript m is 0, 1, 2, or 3; subscript n is 0, 1, 2, or 3; subscript p is 1, 2, or 3: subscript r is 1, 2, 3, 4, 5, or 6; subscript t is 0 or 1; and subscript u is 0 or 1; [0010] In an embodiment, [0011] In an embodiment, ML is selected from the group consisting of: [0013] In an embodiment, p is 1 or 3. [0014] In an embodiment, is piperidinyl or cyclohexyl. 145021.608066 (2500.PC) [0019] In an embodiment, Y is unsubstituted or substituted phenyl, naphthyl, pyridyl, indazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, or isoquinolinyl. [0020] In an embodiment, Y is naphthyl or indazolyl, wherein Y is substituted by 1 to 3 RY substituents independently selected from the group consisting of halo, hydroxy, amino, C1- C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, C 2 -C 4 alkynyl, and cyano. [0021] In an embodiment, Y is selected from the group consisting of: [0023] In an embodiment, Y is selected from the group consisting of: 145021.608066 (2500.PC) [0024] In an embodiment, Y is selected from the group consisting of: [0025] In an embodiment, R 1 is tert-butyl or isopropyl. [0026] In an embodiment, R 2 is H or methyl. [0027] In an embodiment, R 2 is H. [0029] In an embodiment, each R 3 is H. [0030] In specific embodiments, the present disclosure provides a compound as described in any one of Examples 1-15 as set forth below, or a pharmaceutically acceptable salt thereof. [0031] 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. 145021.608066 (2500.PC) Definitions [0032] 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. [0033] 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. [0034] “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 oxygen atom to the central carbon atom, and a single-bonded alkyl group to the central carbon atom. In some embodiments, for example, the acyl group can be a C2 acyl, i.e., acetyl or a C3 acyl, i.e., proprionyl. [0035] “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. [0036] “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-C6 alkyl 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. [0037] “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. [0038] “Alkylthio” means an alkyl group linked to a sulfur. “Fluoroalkylthio” means an alkylthio that is mono-or multiple-fluoro-substituted. [0039] “Alkoxy” and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxygen. [0040] “Alkoxyalkyl” means an alkoxy group linked to an alkyl group. The bond to the parent moiety is through a carbon atom of the alkyl component. 145021.608066 (2500.PC) [0041] “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. [0042] “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. [0043] “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. [0044] “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. [0045] “Cyano” means a N≡C- group. The bond to the parent group is through the carbon atom. [0046] “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. [0047] “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. [0048] “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). [0049] “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. “Fluoroalkoxy” includes mono- substituted as well as multiple fluoro-substituted “alkoxy” groups as previously defined. 145021.608066 (2500.PC) [0050] “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). [0051] “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. [0052] “Heterocyclyl” or “heterocyclic ring” means a partially aromatic, non-aromatic, or aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17 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)2 and/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. [0053] “Heterocyclylene” means a divalent hydrocarbon group radical derived from a heterocyclyl or heterocyclic ring. In contrast to heterocyclyl or heterocyclic ring, two single bonds exist and each single bond attaches to a different parent group. Non-limiting examples of a heterocyclylene include azetidinylene, pyrrolidinylene, and piperidinylene. [0054] “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 145021.608066 (2500.PC) 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. [0055] “Hydroxy” means a HO- group in which the bond to the parent moiety is through the oxygen atom. [0056] “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. [0057] 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). [0058] 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. [0059] 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 145021.608066 (2500.PC) 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. [0060] The wavy line , as used herein, indicates a point of attachment to the rest of the compound. [0061] 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. [0062] 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. 145021.608066 (2500.PC) [0063] 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 fractional 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. [0064] The compounds of Formula (I) which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers. [0065] 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). [0066] 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. [0067] 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 145021.608066 (2500.PC) 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. [0068] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of Formula (I) is 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 be formed 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. [0069] 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 145021.608066 (2500.PC) 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. [0070] 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 compounds 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. [0071] 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. [0072] 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) [0073] 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 145021.608066 (2500.PC) 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. [0074] 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 a 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 [0075] 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 145021.608066 (2500.PC) 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. [0076] The present disclosure therefore also provides the compounds of Formula (I) and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for modulating 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. [0077] 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. [0078] 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. [0079] 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. [0080] 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. 145021.608066 (2500.PC) [0081] 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 one 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. [0082] 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. [0083] 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. 145021.608066 (2500.PC) Methods of Using the Compounds of Formula (I) [0084] The present application provides a method of modulating RAS-mediated cell signaling comprising contacting a cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Modulation 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 binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream 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. [0085] The present application also provides methods of using the compounds of the disclosure (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 (e.g., cancer), and in some embodiments the KRAS G12D mutant. [0086] In some embodiments, a method of degrading a KRAS G12D protein in a cell is provided, comprising administering a therapeutically effective amount a compound of the disclosure (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, resulting in degradation of the KRAS G12D protein in the cell. [0087] In some embodiments, a method of inhibiting a KRAS G12D protein in a cell is provided, comprising administering a therapeutically effective amount of a compound of the disclosure (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, resulting in inhibition of the KRAS G12D protein in the cell. [0088] In some embodiments, a method for treatment of cancer is provided, the method comprising administering a therapeutically effective amount a compound of the disclosure (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 G12D mutation. 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. 145021.608066 (2500.PC) [0089] 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 G12D mutation) and if the subject is determined to have the KRAS mutation, then administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof. [0090] The disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a compound of Formula (I). [0091] 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 the disclosure (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 Hodgkins lymphoma or non-Hodgkins 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. [0092] Determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12D mutation) 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 protein. The sequences of wild- type human KRAS are known in the art. [0093] Methods for detecting a mutation in a 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 145021.608066 (2500.PC) assays and microarray analyses. In some embodiments, samples are evaluated for KRAS mutations (e.g., the KRAS G12D mutation) 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 is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS gene. [0094] Methods for detecting a mutation in a KRAS protein (e.g., the KRAS G12D mutation) are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. [0095] A number of tissue samples can be assessed for determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12D mutation). 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. [0096] 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, 145021.608066 (2500.PC) gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, 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)). [0097] 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. [0098] The present disclosure also provides methods of modulating a mutant KRAS protein activity (e.g., activity resulting from the KRAS G12D mutation) by contacting the protein 145021.608066 (2500.PC) with an effective amount of a compound of the disclosure. Modulation can be inhibiting or activating protein activity, or degrading targeted polypeptides or proteins. In some embodiments, the present disclosure provides methods of inhibiting protein activity or degrading the mutant KRAS protein by contacting the mutant KRAS protein (e.g., KRAS G12D mutant) with an effective amount of a compound of the disclosure in solution. In some embodiments, the present disclosure provides methods of inhibiting the mutant KRAS protein activity or degrading the mutant KRAS protein by contacting a cell, tissue, or organ that expresses the protein of interest. In some embodiments, the disclosure provides methods of inhibiting protein activity or degrading targeted polypeptides or proteins 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 the disclosure. Combination Therapies [0099] 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. [00100] 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, 145021.608066 (2500.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. [00101] 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. [00102] 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”. [00103] 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, 145021.608066 (2500.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. [00104] 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. [00105] 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. [00106] 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. [00107] 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; 145021.608066 (2500.PC) broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine. [00108] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate. [00109] Non-limiting examples of enzymes include asparaginase and pegaspargase. [00110] 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. [00111] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin. [00112] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa. [00113] 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. [00114] 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; 145021.608066 (2500.PC) lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin. [00115] 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. [00116] 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. [00117] 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). [00118] 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. [00119] 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. 145021.608066 (2500.PC) [00120] 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. [00121] 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. [00122] 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. [00123] 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. [00124] 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. 145021.608066 (2500.PC) [00125] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat. [00126] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib. [00127] Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and ribociclib. [00128] 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. [00129] 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). [00130] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, 145021.608066 (2500.PC) pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™. [00131] 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. [00132] 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. [00133] Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib. 145021.608066 (2500.PC) [00134] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib. [00135] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK- 8353, SCH772984, ravoxertinib, ulixertinib, and an ERKi as described in WO 2017/068412. [00136] 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. [00137] 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. [00138] 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 145021.608066 (2500.PC) 5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO 94/02136, WO 95/16691, WO 96/41807, WO 96/41807 and US 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05/016252). [00139] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. [00140] Non-limiting examples of SHP2 inhibitors include SHP2 inhibitors described in WO 2019/167000 and WO 2020/022323. [00141] 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. 145021.608066 (2500.PC) [00142] 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. [00143] 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. [00144] 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. [00145] 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-administered 145021.608066 (2500.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. [00146] 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. [00147] 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 the 145021.608066 (2500.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 [00148] 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-." [00149] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated: 2-MeTHF = 2- methyltetrahydrofuran; Ac = acetyl; AcOH = acetic acid; Am = amyl; tAm = tert-amyl; 145021.608066 (2500.PC) tAmOH = tert-amyl alcohol; aq. = aqueous; atm = atmosphere; BBA = B2(OH)4 = tetrahydroxydiboron; Boc = tert-butyloxycarbonyl; BOP = benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate; B2pin2 = bis(pinacolato)diboron; Bu = butyl; tBu = tert-butyl; tBuO = tert-butoxide; 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); Cbz = benzyl formyl; conc. = concentrated; CSA = (1R)-(-)- camphorsulfonic acid; Davis reagent = 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine; DAST = diethylaminosulfur trifluoride; DCE = 1,2-dichloroethane; DCM = dichloromethane; DHP = 3,4-dihydro-2H-pyran; DIEA = DIPEA = N,N-diisopropylethylamine; DMA = N,N- dimethylacetamide; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC = 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide; equiv = eq. = equivalent(s); ESI = electrospray ionization; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; GDP = guanosine diphosphate; GTP = guanosine triphosphate; h = hr. = hour; HATU = hexafluorophosphate azabenzotriazole tetramethyl uranium; HMDS = hexamethydisilazane; HPLC = high pressure liquid chromatography; Int = intermediate; i-Pr = isopropyl; IPA = i-PrOH = isopropyl alcohol; ISCO = in situ chemical oxidation; KHMDS = potassium bis(trimethylsilyl)amide; LAH = lithium aluminum hydride; LCMS = liquid chromatography-mass spectrometry; min = minute; LDA = lithium diisopropylamide; LiHMDS = Lithium bis(trimethylsilyl)amide; M = Molar; mCPBA = 3- chlorobenzoperoxoic acid = m-chloroperoxybenzoic acid; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MO = methoxy; Ms = methylsulfonyl; MS = mass spectrometry; N = Normal; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMR = nuclear magnetic resonance; Pet. ether = petroleum ether; Ph = phenyl; pin = pinacolato; POCl3 = phosphorus(V) oxide chloride; PPTS = pyridinium p-toluenesulfonate; PyAOP = 7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; PyBOP = benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; rac = racemic; RPLC = reverse phase liquid chromatography; r.t. = room temperature; sat. = saturated; SEM = (2-methoxyethyl)trimethylsilane; SEMCl = (2- (chloromethoxy)ethyl)trimethylsilane; SFC = supercritical fluid chromatography; SPhos Pd G3 = (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate; TBS = tert-butyl(dimethyl)silyl; TEA = Et3N = triethylamine; Tf = trifluoromethanesulfonyl; TfO = trifluoromethanesulfonate; Tf2O = 145021.608066 (2500.PC) trifluoromethanesulfonic anhydride; TFA = trifluoroacetic acid; THF = tetrahydrofuran; THP = tetrahydropyran; TIPS = triisopropypsilyl; TIPSCCBr = (bromoethynyl)triisopropylsilane; TLC = thin layer chromatography; TMP= 2,2,6,6- tetramethylpiperidine; TMS = trimethylsilyl; TMSCN = Trimethylsilyl cyanide; TsOH = p- toluenesulfonic acid = 4-methylbenzenesulfonic acid; UPLC = ultra-performance liquid chromatography; VCD = vibrational circular dichroism; v, v/v = volume, volume to volume; w, w/w = weight, weight to weight, XPhos Pd G2 = chloro(2- dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II); XPhos Pd G4 = (SP-4-3)-[dicyclohexyl[2′,4′,6′-tris(1- methylethyl)[1,1′-biphenyl]-2-yl]phosphine](methanesulfonato-κO)[2′-(methylamino- κN)[1,1′-biphenyl]-2-yl-κC]palladium; μm = micrometer. EXAMPLES [00150] 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. 145021.608066 (2500.PC) Intermediate Syntheses: [00151] Intermediate 1: (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-1) [00152] Step A: 2-bromo-6-fluoro-3-iodo-4-methylbenzaldehyde (Int-1A) [00153] To a solution of diisopropylamine (15 mL, 106 mmol) in THF (45 ml) was added n-butyllithium (40 mL, 100 mmol, 2.5 M in hexanes) at -78 °C, and the mixture was stirred at -78 °C for 30 min to give LDA. To a solution of 1-bromo-5-fluoro-2-iodo-3- methylbenzene (Int-1A) (24 g, 76 mmol) in THF (45 ml) was added LDA (91 mL, 91 mmol, 1 M in THF) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 0.5 h, charged with ethyl formate (6.21 g, 84 mmol), and the resulting mixture was stirred at -78 °C for 15 min. The mixture was slowly poured into sat. aq. NH4Cl (200 mL) and extracted with EtOAc (3 x 400 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc in petroleum ether) to give 2-bromo-6-fluoro-3-iodo-4- methylbenzaldehyde (Int-1A).1H NMR (400MHz, CDCl3) δ 10.16 - 10.02 (m, 1H), 7.05 (d, J=11.0 Hz, 1H), 2.56 (s, 3H). [00154] Step B: 4-bromo-5-iodo-6-methyl- indazole (Int-1B) [00155] To a solution of 2-bromo-6-fluoro- 4-methylbenzaldehyde (Int-1A) (18.7 g, 54.5 mmol) in DMSO (200 mL) was added hydrazine (19.84 mL, 327 mmol, 85% aqueous solution) at 20 °C under N2 atmosphere. The reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 x 400 145021.608066 (2500.PC) mL). The organic layer was washed with sat. aq. NaCl (2 x 50 mL), dried over sodium sulfate, filtered, and the solvent was concentrated in vacuo to give 4-bromo-5-iodo-6- methyl-1H-indazole (Int-1B), which was used directly in the next step without further purification. MS (ESI): m/z (M+H)+ 337, 339. [00156] Step C: 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 1C) [00157] To a solution of 4-bromo-5-iodo-6-methyl-1H-indazole (Int-1B) (15.5 g, 46.0 mmol) in THF (200 mL) was added 4-methylbenzenesulfonic acid (1.584 g, 9.20 mmol) and DHP (8.41 mL, 92 mmol) at 20 °C, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (0 to 15% EtOAc in petroleum ether). The collected solid was diluted with MeOH (50 mL), and the resulting mixture was stirred for 5 min and then filtered. The solid was collected and dried in vacuum to give 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (Int-1C). MS (ESI): m/z (M+H)+ 421, 423.1H NMR (400MHz, CDCl3) δ 7.84 (s, 1H), 7.44 - 7.35 (m, 1H), 5.58 (dd, J=2.7, 9.1 Hz, 1H), 4.00 - 3.85 (m, 1H), 3.73 - 3.59 (m, 1H), 2.67 - 2.58 (m, 3H), 2.52 - 2.36 (m, 1H), 2.16 - 1.93 (m, 2H), 1.76 - 1.51 (m, 3H). [00158] Step D: 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl- indazole (Int-1D) [00159] To a solution of 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-1C) (6 g, 14.25 mmol) in t-amyl alcohol (60 ml) and water (20 mL) was added potassium vinyltrifluoroborate (2.481 g, 18.52 mmol), Cs2CO3 (13.93 g, 42.7 mmol), and Pd(PPh3)4 (0.823 g, 0.712 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (200 x 3 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (0 to 15% EtOAc in petroleum ether) to give 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl- 1H-indazole (Int-1D). MS (ESI): m/z (M+H)+ 321, 323. [00160] Step E: 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carbaldehyde (Int-1E) [00161] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H- indazole (Int-1D) (4.5 g, 12.89 mmol) in THF (50 mL) and water (50 mL) was added sodium periodate (11.03 g, 51.6 mmol), 2,6-lutidine (2.76 g, 25.8 mmol), and potassium osmate(VI) dihydrate (0.475 g, 1.289 mmol) at 25 °C, and the mixture was stirred at 50 °C 145021.608066 (2500.PC) for 2 h. The reaction mixture was quenched with sat. aq. Na2SO3 (20 mL), and the mixture was extracted with EtOAc (3x 200 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 4-bromo- 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (Int-1E). MS (ESI): m/z (M+H)+ 323, 325.1H NMR (400MHz, CDCl3) δ 10.62 - 10.44 (m, 1H), 8.09 (s, 1H), 7.30 (s, 1H), 5.62 (dd, J=2.8, 9.1 Hz, 1H), 4.02 - 3.85 (m, 1H), 3.69 (ddd, J=3.0, 10.0, 11.6 Hz, 1H), 2.66 (d, J=0.7 Hz, 3H), 2.51 - 2.34 (m, 1H), 2.17 - 1.92 (m, 2H), 1.78 - 1.56 (m, 3H). [00162] Step F: 4-bromo-5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-1F) [00163] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carbaldehyde (Int-1E) (3 g, 9.28 mmol) in DCM (30 mL) was added DAST (6.13 mL, 46.4 mmol) at -78 °C under N2 atmosphere, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was added dropwise to aq. NaHCO3 (50 mL), and the mixture was extracted with EtOAc (3 x 120 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 4-bromo-5-(difluoromethyl)-6- methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-1F). MS (ESI): m/z (M+H)+ 345, 347.1H NMR (400MHz, CDCl3) δ 7.96 (s, 1H), 7.45 - 7.06 (m, 2H), 5.61 (dd, J=2.8, 9.1 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.72 - 3.60 (m, 1H), 2.62 (s, 3H), 2.51 - 2.38 (m, 1H), 2.14 - 1.95 (m, 2H), 1.77 - 1.54 (m, 3H). [00164] Step G: (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)boronic acid (Int-1) [00165] To a solution of 4-bromo-5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole (Int-1F) (0.308 g, 0.892 mmol) in THF (8 mL) was added n-butyllithium (1.6 M in hexanes, 0.725 mL, 1.160 mmol) at -78 °C. The resulting mixture was stirred at this temperature for 30 min. Then, triisopropyl borate (618 μL, 2.68 mmol) was added via syringe. The mixture was stirred at -78 °C for 10 min. The mixture was quenched with sat. aq. NH4Cl (2 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. (5-(difluoromethyl)-6-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-1) was obtained and used directly in subsequent step(s) without further purification. MS (ESI): [M+H]+ m/z: 311. 145021.608066 (2500.PC) [00166] Intermediate 2: (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazol-4-yl)boronic acid (Int-2) [00167] Step A: 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A) [00168] 2-bromo-4-fluoro-6-methylaniline (200 g, 0.983 mol) was dissolved in MeCN (800 mL). The resulting mixture was cooled down to 0 °C. Concentrated HCl (12 M, 245 mL) was added into the reaction mixture while maintaining the reaction temperature at 0 °C. A solution of NaNO2 (81.1 g, 1.18 mol eq) in water (400 mL) was added dropwise into the reaction mixture maintaining the reaction temperature at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C. Then a solution of KI (195 g, 1.18 mol) in water (400 mL) was added dropwise into the reaction mixture at 0 °C. The resulting mixture was warmed up to room temperature and stirred for 12 h at 20 °C. This reaction was repeated in one additional batch using the above conditions. The two batches of reactions were combined. The product mixture was adjusted to pH 8-9 by aq. NaOH and the aqueous phase was extracted with EtOAc (2.00 L × 2). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by column chromatography (SiO2, Petroleum ether : Ethyl acetate = 1 : 0 to 0 : 1) to give 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A). 1H NMR (400 MHz, CDCl3) δ 7.27 - 7.22 (m, 1H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 2.56 (s, 3H) [00169] Step B: 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B) 145021.608066 (2500.PC) [00170] 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A) (100 g, 0.317 mol) was dissolved in DMF (1.50 L). To this mixture were added CuI (514 g, 2.70 mol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (518 g, 2.70 mol) at 25 °C. The reaction mixture was heated and stirred for 12 h at 60 °C. This reaction was repeated in 3 additional batches using the above conditions. The four batches of reactions were combined and quenched with water (24 L). The mixture was extracted with petroleum ether (8.00 L × 2). The combined organic layers were washed with brine (4 L × 2) and dried over Na2SO4. The dried solution was filtered and the filtrate was concentrated in vacuo to give a crude material containing 1- bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B), which was used directly in the next step without further purification. [00171] Step C: 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (Int-2C) [00172] 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B) (100 g, 0.382 mol) was dissolved in 2-MeTHF (500 mL). The reaction mixture was cooled down to -65 °C. A 2 M solution of LDA (213 mL, 426 mmol) was added into the mixture at -65 °C. The reaction mixture was stirred for 0.5 h at -65 °C. To this mixture was added dropwise DMF (31.2 g, 0.420 mol) at -65 °C. The reaction mixture was stirred for 2 h at -65 °C. This reaction was repeated in 2 additional batches using the above conditions. The three batches of reactions were combined. The reaction mixture pH was adjusted to 3-4 by using 1 M HCl and the aqueous phase was extracted with 2-MeTHF (500 mL × 2). The organic phase was dried over Na2SO4, filtered, and concentrated to give 2-bromo-6-fluoro-4-methyl-3- (trifluoromethyl)benzaldehyde (Int-2C), which was used directly in the next step without further purification. [00173] Step D: 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (Int-2D) [00174] 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (Int-2C) (100 g, 0.351 mol) was dissolved in 2-MeTHF (800 mL). To this mixture was added N2H4·H2O (53.7 g, 1.05 mol) at 25 °C. The mixture was heated and stirred for 2 h at 60 °C. The product mixture was quenched with water (400 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The dried solution was filtered and the filtrate was concentrated in vacuo to give the residue. This reaction was repeated in 2 additional batches using the above conditions. The three batches of reactions were combined. The residue obtained was triturated with DCM (100 mL) at 15 °C for 2 h. The solid was collected by filtration to give 4-bromo-6-methyl-5- (trifluoromethyl)-1H-indazole (Int-2D). 1H NMR (400 MHz, CDCl3) δ 10.61 - 10.20 (m, 1H), 8.20 (d, J = 0.8 Hz, 1H), 7.34 (d, J = 0.6 Hz, 1H), 2.67 - 2.63 (m, 3H). 145021.608066 (2500.PC) [00175] Step E: 4-bromo-6-methyl-1- -5-(trifluoromethyl)-1H- indazole (Int-2E) [00176] 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (Int-2D) (60.0 g, 0.215 mol) was dissolved in DCM (240 mL) and MeCN (240 mL). DHP (21.7 g, 0.258 mol) and TsOH·H2O (8.18 g, 0.043 mol) were added to the mixture at 20 °C. The reaction mixture was stirred for 12 h at 25 °C. Water (200 mL) was added to the product mixture. The resulting mixture was extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The dried solution was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1) to give 4- bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (Int-2E). 1H NMR (400 MHz, CDCl3- d) δ 8.12 (s, 1H), 7.44 (s, 1H), 5.69 (dd, J = 3, 9 Hz, 1H), 4.09 - 3.94 (m, 1H), 3.81 - 3.69 (m, 1H), 2.69 - 2.63 (m, 3H), 2.56 - 2.43 (m, 1H), 2.19 - 2.14 (m, 1H), 2.12 - 2.04 (m, 1H), 1.87 - 1.73 (m, 2H), 1.71 - 1.63 (m, 1H). [00177] Step F: (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)boronic acid (Int-2) [00178] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazole (Int-2E) (1.2 g, 3.30 mmol) in MeOH (15 mL) was added tetrahydroxydiboron (1.185 g, 13.22 mmol), TEA (1.382 mL, 9.91 mmol), and cataCXium A Pd G2 (0.110 g, 0.165 mmol). The mixture was stirred at r.t. for 16 h under N2 atmosphere. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-20% EE (EtOAc:EtOH=3:1) / petroleum ether) to give (6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-2). MS (ESI) [M+H]+: m/z 329. [00179] Intermediate 3: (5-((triisopropylsilyl)ethynyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-yl)boronic acid (Int-3) 145021.608066 (2500.PC) [00180] Step A: Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (Int-3A) [00181] To a solution of ethyl 1H-pyrazole-4-carboxylate (13.75 g, 98 mmol) in DCM (100 mL) at 0 °C was added N,N-diisopropylethylamine (25.4 g, 196 mmol). The mixture was stirred for 15 min, then (2-(chloromethoxy)ethyl)trimethylsilane (24.54 g, 147 mmol) was added slowly. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with water (50 mL) and extracted with DCM (3 x 200 mL). The combined organic layer was dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether) to give ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-4-carboxylate (Int-3A). MS (ESI) [M+H]+: m/z 271. [00182] Step B: N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxamide 3B) [00183] To a of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (Int-3A) (20 g, 74.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.82 g, 111 mmol) in dry THF (350 mL) was added iPrMgBr (77 mL, 222 mmol, 2.9 M in 2-methyltetrahydrofuran) at 0 °C. The mixture was warmed to 25 °C and stirred 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 the filtrate was evaporated 145021.608066 (2500.PC) under reduced pressure to give the crude product. The crude product 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-3B). MS (ESI) [M+H]+: m/z 286. [00184] Step C: 3,4-dibromothiophene-2-carbaldehyde (Int-3C) [00185] To the solution of 3,4-dibromothiophene (12.38 g, 51.2 mmol) in THF (120 mL) was added LDA (102 mL, 102 mmol, 1M in THF) at -78 °C and the reaction mixture was stirred at -78 °C for 2 h. DMF (4.73 mL, 61.4 mmol) was added dropwise to the reaction mixture, warmed to 25 °C, and stirred for 1 h. The mixture was quenched with aqueous NH4Cl (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give 3,4-dibromothiophene-2-carbaldehyde (Int-3C).1H NMR (400 MHz, CDCl3) δ: 9.96 (d, J=1.4 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H). [00186] Step D: 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N-methyl-1- ((2-(trimethylsilyl)ethoxy)methyl)- pyrazole-4-carboxamide (Int-3D) [00187] To a stirred solution of N- N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-3B) (6.20 g, 21.7 mmol) in THF (150 mL) was added LDA (22.81 mL, 22.81 mmol, 1M in THF) at -78 °C under N2 atmosphere and the reaction was stirred at -78 °C for 0.5 h.3,4-dibromothiophene-2-carbaldehyde (Int-3C) (8.80 g, 32.6 mmol) in THF (10 mL) was added at -78 °C and the reaction was warmed 25 °C and stirred for 16 h. The mixture was quenched with sat. aq. NH4Cl (40 mL) and extracted with EtOAc (3 x 200 mL). The organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3D).1H NMR (400 MHz, CDCl3) δ: 8.04 (s, 1H), 7.28 (s, 1H), 6.39 (s, 1H), 5.56 (d, J=8.1 Hz, 2H), 3.70 (s, 3H), 3.39- 3.55 (m, 2H), 3.37 (s, 3H), 0.60-0.92 (m, 2H), -0.05 (s, 9H). [00188] Step E: 5-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1H-pyrazole- 4-carboxamide (Int-3E) [00189] To a solution of 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3D) (7.38 g, 13.29 mmol) in DCM (18 mL) was added triethylsilane (36.5 mL, 229 mmol) and TFA 145021.608066 (2500.PC) (18.25 mL, 237 mmol) at 25 °C. The mixture was warmed to 60 °C and stirred for 5 h. After 5 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (50 mL) and adjusted to pH ~8 with sat. aq. NaHCO3. The layers were separated and the organic layer was washed with brine (2 x 30 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 100% EtOAc in petroleum ether) to give 5-((3,4-dibromothiophen-2- yl)methyl)-N-methoxy-N-methyl-1H-pyrazole-4-carboxamide (Int-3E).1H NMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.25 (s, 1H), 4.63 (s, 2H), 3.69 (s, 3H), 3.36 (s, 3H). [00190] Step F: 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F) [00191] To a solution of 5-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1H- pyrazole-4-carboxamide (Int-3E) (4.85 g, 11.9 mmol) in DCM (50 mL) was added N,N- diisopropylethylamine (3.06 g, 23.7 mmol), and the mixture was stirred at 0 °C for 15 min. (2-(chloromethoxy)ethyl)trimethylsilane (2.96 g, 17.78 mmol) was added slowly at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was quenched with H2O (10 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 100% EtOAc in petroleum ether) to give 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F). MS (ESI) [M+H]+: m/z 538. [00192] Step G: 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4- a stirred solution of 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F) (2 g, 3.71 mmol) in THF (20 mL) was added dropwise isopropylmagnesium chloride lithium chloride complex (5.70 mL, 7.42 mmol, 1.3M in THF) at 0 °C. The reaction was warmed to 25 °C and stirred for 16 h under N2 atmosphere. The mixture was quenched with sat. aq. NH4Cl (15 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether) to give 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-ol (Int-3G). MS (ESI) [M+H]+: m/z 399. 145021.608066 (2500.PC) [00194] Step H: 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-ol (Int-3H) [00195] To a solution of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2- f]indazol-4-ol (Int-3G) (620 mg, 1.552 mmol) in TEA (15 mL) was added ethynyltriisopropylsilane (425 mg, 2.329 mmol), copper(I) iodide (29.6 mg, 0.155 mmol), triphenylphosphine (40.7 mg, 0.155 mmol), and bis(triphenylphosphine)palladium(II) dichloride (54.5 mg, 0.078 mmol) at 25 °C under N2 atmosphere. The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was cooled and evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 10% EtOAc in petroleum ether) to give 5-((triisopropylsilyl)ethynyl)- 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-ol (Int-3H). MS (ESI) 501. [00196] Step I: 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-yl trifluoromethanesulfonate (Int-3I) [00197] To a solution of 5-((triisopropylsilyl)ethynyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-ol (Int-3H) (442 mg, 0.883 mmol) in DCM (8 mL) under N2 atmosphere was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. Trifluoromethanesulfonic anhydride (0.224 mL, 1.324 mmol) was added to the above mixture. The reaction was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was warmed to room temperature and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (petroleum ether/EtOAc = 10/1) to give 5- ((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4- yl trifluoromethanesulfonate (Int-3I). MS (ESI) [M+H]+: m/z 633. [00198] Step J: (5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-yl)boronic acid (Int-3) [00199] To a solution of 5-((triisopropylsilyl)ethynyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-yl trifluoromethanesulfonate (Int- 3I) (424 mg, 0.670 mmol) in MeOH/THF (5 mL, 3:1 v/v) was added hypodiboric acid (360 mg, 4.02 mmol) and CataCXium A Pd G2 (44.8 mg, 0.067 mmol) and TEA (339 mg, 3.35 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether) to give (5- 145021.608066 (2500.PC) ((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4- yl)boronic acid (Int-3). MS (ESI) [M+H]+: m/z 529. [00200] Intermediate 4: 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7- [00201] Step A: 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane] (Int-4A) [00202] Five reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydro-1H-inden-1-one (60.0 g, 262 mmol) was dissolved in toluene (2.58 L) at room temperature. Then, ethylene glycol (325 g, 5.24 mol) and TsOH•H2O (9.97 g, 52.4 mmol) were added to the mixture at room temperature. A Dean-Stark trap was added to the reactor and the reaction was heated to 140 °C for 19 h. The five reactions were cooled to room temperature, combined, and partitioned between EtOAc (3 x 2.50 L) and sat. aq. NaHCO3 (3.00 L). The organic phase was washed with water (3 x 2.50 L) and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1 to 1/1) to give 7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane] (Int-4A).1H NMR (400MHz, CDCl3) δ 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 1.2 Hz, 1H), 4.32-4.36 (m, 2H), 4.09-4.11 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H). [00203] Step B: 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-6- carbaldehyde (Int-4B) [00204] Two reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane] (Int-4A) (80.0 g, 293 mmol) was dissolved in THF(1.60 L) at room temperature. The reaction was cooled to -78 °C and LDA (220 mL, 440 mmol, 2M in THF) was added. The reaction was stirred at -78 °C for 1 h. Then, DMF (85.7 g, 1.17 mol) was added to the mixture and the reaction was stirred at -78 °C for 0.5 h. The two reactions were combined and quenched with sat. aq. NH4Cl (3.00 L). The reaction mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were 145021.608066 (2500.PC) washed with brine (1.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was triturated with MTBE (500 mL) for 30 min to give 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-6-carbaldehyde (Int-4B).1H NMR (400MHz, CDCl3) δ 10.43 (s, 1H), 7.01 (d, J = 10.0 Hz, 1H), 4.34-4.36 (m, 2H), 4.10-4.14 (m, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H). [00205] Step C: 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int-4C) [00206] Two reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane]-6-carbaldehyde (Int-4B) (80.0 g, 266 mmol) was dissolved in DMSO (133 mL) and N2H4•H2O (204 g, 3.99 mol) was added to the mixture at room temperature. The reaction was heated to 120 °C for 1.5 h. The two reaction mixtures were combined and quenched with water (1.0 L). The reaction mixture was extracted with EtOAc (2 x 500 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1 to 0/1) to give 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int- 4C).1H NMR (400MHz, DMSO-d6) δ 13.25 (s, 1H), 8.02 (s, 1H), 7.37 (s, 1H), 4.24 (t, J = 3.6 Hz, 2H), 4.03 (t, J = 3.6 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H). [00207] Step D: 4-bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D) [00208] 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int- 4C) (100 g, 339 mmol) was dissolved in acetone (1.00 L) and H2O (200 mL) at room temperature. Then, HCl (200 mL, 6M in H2O) was added to the mixture at room temperature. The reaction was heated to 60 °C for 0.5 h. After 0.5 h, the reaction was cooled to room temperature and the pH was adjusted to ~7-8 with sat. aq. NaHCO3. The precipitated solid was collected by filtration, washed with water, and dried to give 4-bromo- 6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D).1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.23 (s, 1H), 7.58 (s, 1H), 3.15 (t, J = 6.8 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H). [00209] Step E: 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydrocyclopenta[f]indazol- 5(1H)-one (Int-4) [00210] 4-bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D) (75.0 g, 299 mmol) was dissolved in toluene (1350 mL) at 20 oC and DHP(100 g, 1.19 mol) and CSA (6.94 g, 29.9 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 100 oC and stirred for 3 h. The reaction was quenched with sat. aq. NH4Cl (2.0 L) and the organic layer was separated. The aqueous phase was extracted with DCM (2 x 0.5 L) and 145021.608066 (2500.PC) the combined organic layers were washed with brine (0.5 L), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude residue was triturated with a mixture of MTBE and petroleum ether (3:2, 500 mL) at 25 oC for 30 mins to give 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4). 1H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 7.53 (s, 1H), 5.72 (dd, J = 9.2, 3.2 Hz, 1H), 4.00-4.03 (m, 1H), 3.76-3.77 (m, 1H), 3.20-3.23 (m, 2H), 2.81-2.85 (m, 2H), 2.49-2.53 (m, 1H), 2.08-2.18 (m, 2H), 1.70-1.78 (m, 3H). [00211] Intermediate 5: (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int-5) [00212] Step A: 4-bromo-5-methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5A) [00213] To a solution of methyltriphenylphosphonium bromide (6.39 g, 17.90 mmol) in THF (59.7 ml) was added potassium tert-butoxide (1 M) (17.90 ml, 17.90 mmol) at 25 °C and was stirred for 30 min.4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7- dihydrocyclopenta[f]indazol-5(1H)-one (3 g, 8.95 mmol) (Int-4) was added as a mixture in THF (5 mL) at 0 °C and was stirred at 25 °C for 1 h. The mixture was quenched with sat. NaHCO3 (50 mL, aq.), and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (0-15% EtOAc in hex) to give 4-bromo-5- methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5A). [M+H]+ Found: 333, 335. [00214] Step B: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5B) [00215] 4-bromo-5-methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (2.5 g, 7.50 mmol) (Int-5A) was dissolved in EtOAc (50.0 145021.608066 (2500.PC) ml) and rhodium (3.09 g, 1.500 mmol) was added. Mixture was bubbled through with H2 for 10 minutes and heated at 50 °C under H2 balloon for 1 h. The reaction was cooled, degassed with bubbling N2, and filtered through a pad of CELITE®. The filtrate was concentrated and purified by silica gel column chromatography (0-50% EtOAc in hex) to give 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5B). [M+H]+ Found: 335, 337. [00216] Step C: 4-bromo-5-methyl-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5C) [00217] 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (2.46 g, 7.34 mmol) (Int-5B) was taken up in isopropyl alcohol (24.46 ml) and 4N HCl in 1,4-dioxane (12.23 ml) was added. Reaction stirred at 45 °C overnight, then quenched with sat. NaHCO3, extracted with DCM (3x), dried over Na2SO4 and concentrated under reduced pressure. Purified using SFC chromatography (OD-H 21x150 mm, 1:1 MeOH:MeCN) to give 4-bromo-5-methyl-1,5,6,7- tetrahydrocyclopenta[f]indazole (peak 1; Rt = 3 minutes) (Int-5C) and 4-bromo-5-methyl- 1,5,6,7-tetrahydrocyclopenta[f]indazole (peak 2; Rt = 4 minutes) (Int-5C). [M+H]+ Found: 251, 253. [00218] Step D: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole 5D) [00219] 4-bromo-5-methyl- [f]indazole (570 mg, 2.270 mmol) (Int-5C) and p-toluenesulfonic acid monohydrate (130 mg, 0.681 mmol) were taken up in THF (7566 μl). DHP (828 μl, 9.08 mmol) was added and reaction stirred at 25 °C overnight. The mixture was quenched with NaHCO3, extracted with DCM, concentrated under reduced pressure, then purified by silica gel column chromatography (0-100% EtOAc in hex) to give 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5D). [M+H]+ Found: 335, 337. [00220] Step E: (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int-5) [00221] To a solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (1.19 g, 3.55 mmol) in MeOH (17.75 ml) was added TEA (1.979 ml, 14.20 mmol), tetrahydroxydiboron (0.477 g, 5.32 mmol) and CataCXium A Pd G2 (0.237 g, 0.355 mmol) at 20 °C under N 2 atmosphere, the mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue purified directly by silica gel column chromatography (0-50% 3:1 EtOAc:EtOH in hex) to 145021.608066 (2500.PC) give (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4- yl)boronic acid (Int-5). [M+H]+ Found: 301. [00222] Intermediate 6: 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6) [00223] Step A: 5-((2-bromo-4-fluorophenyl)(hydroxy)methyl)-N-methoxy-N-methyl-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6A) [00224] To a stirred solution of N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (24.7 g, 87.0 mmol) in THF (50 mL) was added LDA (95 mL, 95 mmol, 1 M in THF) at -78 °C under N2, and the reaction was stirred at -78 °C for 1 h. Then 2-bromo-4-fluorobenzaldehyde (16 g, 79 mmol) was added at -78 °C and the reaction was stirred at -78 °C for 1 h. The mixture was warmed to room temperature and concentrated in vacuum. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 500 mL). The organic layers were washed with sat. brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (0 to 25% EtOAc in petroleum ether) to give 5-((2-bromo-4- fluorophenyl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-6A). MS (ESI) [M+H]+: m/z 488, 490. [00225] Step B: 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B) 145021.608066 (2500.PC) [00226] To a solution of 5-((2-bromo-4-fluorophenyl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6A) (20.0 g, 40.9 mmol) in DCM (56 mL) was added triethylsilane (118 mL, 737 mmol) and TFA (56.8 mL, 737 mmol), and the mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (400 mL). The reaction mixture was basified with sat. aq. NaHCO3 to pH~8. The organic layer was washed with brine (2 x 30 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 15% ethyl acetate in petroleum ether) to give 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B). MS (ESI) [M+H]+: m/z 342, 344. [00227] Step C: 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6C) [00228] To a solution of 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B) (7.50 g, 21.9 mmol) in THF (80 mL) was added 4- methylbenzenesulfonic acid (0.377 g, 2.19 mmol) and DHP (4.01 mL, 43.8 mmol) at 25 °C, and the mixture was stirred for 2 h. The mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (petroleum ether/EtOAc = 2/1) to give 5-(2- bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4- carboxamide (Int-6C). MS (ESI) [M+H]+: m/z 426, 428. [00229] Step D: 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4- one (Int-6D) [00230] To a stirred solution of 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6C) (22 g, 51.6 mmol) in THF (220 mL) was added n-BuLi (31 mL, 77 mmol, 2.5 M in hexane) dropwise over 30 min at - 78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. The reaction mixture was poured into sat. aq. NH4Cl (200 mL) and diluted with EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash silica gel chromatography (0 to 22% THF in petroleum ether) to give 6-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6D). MS (ESI) [M+H]+: m/z 287. [00231] Step E: 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1,9- dihydro-4H-benzo[f]indazol-4-one (Int-6E) 145021.608066 (2500.PC) [00232] To a solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H- benzo[f]indazol-4-one (Int-6D) (6.50 g, 22.7 mmol) in dioxane (120 mL) was added (bromoethynyl)triisopropylsilane (17.8 g, 68.1 mmol), potassium acetate (7.8 g, 79 mmol), and dichloro(p-cymene)ruthenium(II) dimer (6.95 g, 11.4 mmol) at 25 °C under N2. The mixture was stirred at 100 °C for 3 h. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (2% ethyl acetate in DCM) to give 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6E). MS (ESI) [M+H]+: m/z 467. [00233] Step F: 6-fluoro-1-((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F) [00234] A solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)- 1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6E) (5.50 g, 11.8 mmol) and N,N- diisopropylethylamine (12.4 mL, 70.7 mmol) in DCM (60 mL) was added Tf2O (5.97 mL, 35.4 mmol) at -40 °C, and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated in vacuo at 30 °C and the residue was purified by flash silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F).1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.50 (s, 1H), 8.04 (dd, J = 5.36, 9.18 Hz, 1H), 7.55 (t, J = 8.64 Hz, 1H), 1.17-1.24 (m, 21H). [00235] Step G: 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)- [f]indazole (Int-6) [00236] A solution of 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2- (3.14 g, 13.9 mmol), potassium acetate (1.37 g, 13.9 mmol), 6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F) (3.00 g, 4.64 mmol), trans-bis(triphenylphosphine)palladium dichloride (326 mg, 464 μmol) in dioxane (30 mL) was stirred for 10 min at 25 °C. Then, dichlorobis(triphenylphosphine)palladium(II) (0.760 g, 1.08 mmol) was added at 25°C and the mixture was stirred at 80 °C for 24 h under N2 atmosphere. The mixture cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with MeCN (70 mL), filtered, and the solid was dried under reduced pressure to give 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6). MS (ESI): m/z (M+H)+ 611.1H 145021.608066 (2500.PC) NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 8.33 (s, 1H), 7.92 (dd, 1H, J=5.7, 9.2 Hz), 7.37 (t, 1H, J=8.7 Hz), 3.86 (s, 4H), 1.14 (s, 21H), 1.07 (s, 6H). [00237] Intermediate 7: (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- [00238] Step A: 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A) [00239] To a solution of 6-(trifluoromethyl)-1H-indazole (7.4 g, 40 mmol) in H2SO4 (100 mL, conc. aq.) at 0 °C, was slowly added KNO3 (4.5 g, 44 mmol). The reaction mixture was warmed up to room temperature. After stirring for 3 h at room temperature, it was poured into crushed ice. The precipitated solid was collected by filtration and washed with water to give 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A). MS (ESI) [M+H]+: m/z 232. [00240] Step B: 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B) [00241] A mixture of 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A) (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 diluted with EtOAc (200 mL), filtered by glass fiber membrane filter, and washed with EtOAc. The filtrate was concentrated under reduced pressure and sat. aq. NaHCO3 and EtOAc were added. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B). MS (ESI) [M+H]+: m/z 202. [00242] Step C: 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-7C) 145021.608066 (2500.PC) [00243] To a solution of 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B) (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 room temperature, sat. aq. NaHCO3 and 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-7C). MS (ESI) [M+H]+: m/z 236. [00244] Step D: 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D) [00245] To a solution of 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-7C) (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. NaHCO3 and Na2S2O3 solution, dried over Na2SO4, and concentrated to give 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D). MS (ESI) [M+H]+: m/z 347. [00246] Step E: 4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-7E) [00247] A mixture of 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D) (920 mg), (1R)-(-)-camphor-10-sulfonic acid (60 mg, 0.26 mmol), and DHP (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 room temperature 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-7E). MS (ESI) [M+H]+: m/z 431. [00248] Step F: 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol- 5-yl)cyclopropan-1-ol (Int-7F) [00249] KOH (1.25 mL, 2.50 mmol, 2N in H2O) was added to a solution of 4-chloro-5- iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-7E) (430 mg, 0.999 mmol), 2,2'-cyclopropylidenebis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (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, 2N in H2O) were added. 145021.608066 (2500.PC) H2O2 (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 CHCl3 and 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 give 1-(4-chloro-1- (tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-7F). MS (ESI) [M+H]+: m/z 361. [00250] Step G: 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G) [00251] DAST (0.035 mL, 0.265 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-7F) (43 mg, 0.12 mmol) in DCM (3 mL) at -78 °C. After stirring at -78 °C for 30 min, sat. aq. NaHCO3 and 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-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-7G). MS (ESI) [M+H]+: m/z 363. [00252] Step H: (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-7) [00253] The mixture of 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G) (34 mg, 0.094 mmol), tetrahydroxydiboron (40 mg, 0.45 mmol), cataCXium A Pd G3 (6.0 mg, 0.0082 mmol) and TEA (0.080 ml, 0.57 mmol) in MeOH (1 mL) was stirred at room temperature for 60 hours. 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. 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-7). MS (ESI) [M+H]+: m/z 373. [00254] Intermediate 8: (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)boronic acid (Int-8) 145021.608066 (2500.PC) [00255] Step A: 4-chloro-2-fluoro-5-nitrobenzaldehyde (Int-8A) [00256] To a solution of 4-chloro-2-fluorobenzaldehyde (58 g, 370 mmol) in conc. H2SO4 (500 mL) was added potassium nitrate (47 g, 470 mmol) at 0 °C. Then the reaction was stirred at 25 °C for 1 h. The reaction 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-8A). 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). [00257] Step B: 6-chloro-5-nitro-1H-indazole (Int-8B) [00258] To a solution of 4-chloro-2-fluoro-5-nitrobenzaldehyde (Int-8A) (67.0 g, 329 mmol) in DMF (1.00 L) were added hydrazine hydrate (161 mL, 2.82 mol) at 25 °C under N2 atmosphere. The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was cooled and quenched with ice water (2 L). The mixture was filtered and the filtered cake was washed with water (2 x 300 mL), dried in vacuum to give 6-chloro-5-nitro-1H- indazole (Int-8B). MS (ESI) [M+H]+: m/z 198. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H). 145021.608066 (2500.PC) [00259] Step C: 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-8C) [00260] To a solution of 6-chloro-5-nitro-1H-indazole (Int-8B) (92 g, 0.47 mol) in THF (1.0 L) were added DHP (85 mL, 0.93 mol) and p-toluenesulfonic acid (8.0 g, 47 mmol) at 25 °C under N2 atmosphere. The reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was cooled and evaporated under reduced pressure to give a crude product. The crude 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-8C). MS (ESI) [M+H]+: m/z 282.1H 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). [00261] Step D: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int-8D) [00262] To a solution of 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8C) (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 stirred at 70 °C for 15 h. The reaction mixture was cooled, diluted with EtOAc (200 mL), filtered, and the solvent was concentrated in vacuo. The residue was then dissolved in EtOAc (3 x 300 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a crude product. The crude 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-8D). 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). [00263] Step E: 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 8E) [00264] To a solution of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 8D) (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 solvent was evaporated under reduced pressure to give the crude product. The crude 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)- 145021.608066 (2500.PC) 1H-indazol-5-amine (Int-8E). MS (ESI) [M+H]+: m/z 330, 332.1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.59 (s, 1H), 5.61 (dd, J=9.0, 2.7 Hz, 1H), 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). [00265] Step F: 4-bromo-6-chloro-1H-indazol-5-amine (Int-8F) [00266] To a solution of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- amine (Int-8E) (30 g, 90 mmol) was added 4N 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-8F) isolated as an HCl salt. MS (ESI) [M+H]+: m/z 246, 248. [00267] Step G: 4-bromo-6-chloro-5-iodo- indazole (Int-8G) [00268] To a solution of 4-bromo-6- indazol-5-amine (Int-8F), HCl (10 g, 35 mmol) in 6M aq. HCl (100 mL) was added a solution of sodium nitrite (2.9 g, 42 mmol) in water (20 mL) dropwise at -5 °C and stirred for 5 min. Then a solution of KI (23 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 solvent was evaporated under reduced pressure to give 4-bromo-6-chloro-5-iodo-1H-indazole (Int-8G). MS (ESI) [M+H]+: m/z 357, 359. 1H NMR (400 MHz, DMSO-d6) δ 13.62 (br s, 1H), 8.00 (s, 1H), 7.88 (d, J=0.8 Hz, 1H). [00269] Step H: 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8H) [00270] To a solution of 4-bromo-6-chloro-5-iodo-1H-indazole (Int-8G) (32 g, 90 mmol) in THF (300 mL) were added 4-methylbenzenesulfonic acid (1.5 g, 9.0 mmol) and DHP (16 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 to give a crude product. The crude 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- 8H). 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). [00271] Step I: 1-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropan-1-ol (Int-8I) 145021.608066 (2500.PC) [00272] 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-8H) (0.2019 g, 0.457 mmol) was added to a vial with a stir bar and the headspace swept with N2. 2-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 50 mL round bottom flask with a stir bar was charged with 1- (phenylsulfonyl)cyclopropan-1-ol (80 mg, 0.387 mmol) and placed under N2.2-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 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole, both dropwise via syringe. The reaction was allowed to warm to room temperature 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. The crude residue was purified via silica gel chromatography (0 to 40% EtOAc in hexanes) to give 1-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-8I). MS (ESI): [M+H]+ m/z 371. [00273] Step J: 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (Int-8J) [00274] DAST (90 μL, 0.681 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-8I) (111.6 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. NaHCO3 and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatograpy (0 to 40% EtOAc in hexane) to give 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (Int-8J). MS (ESI): [M+H]+ m/z 373, 375. [00275] Step K: (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-8) [00276] CataCXium A Pd G2 (24 mg, 0.036 mmol), hypodiboric acid (56.4 mg, 0.629 mmol), and TEA (110 μL, 0.789 mmol) in MeOH (2000 μl) were added to a vial containing 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8J) (78.4 mg, 0.210 mmol). The mixture was evacuated and backfilled with N2 (3x). The mixture was stirred at 50 °C for 2 h. The mixture was diluted with water and extracted with 145021.608066 (2500.PC) EtOAc (3x) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-8). MS (ESI): [M+H]+ m/z 339. [00277] Intermediate 9: (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazol-4-yl)boronic acid (Int-9) [00278] Step A: 4-bromo-6-(trifluoromethyl)-1H-indazol-5-amine (Int-9A) [00279] NBS (880 mg, 5.0 mmol) was added to a stirred solution of 6-(trifluoromethyl)- 1H-indazol-5-amine (1.0 g, 5.0 mmol) in MeCN (25 mL) at room temperature. After 10 min, the mixture was partitioned between EtOAc and sat. aq. NaHCO3. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified via silica gel chromatography (0 to 20% EtOAc in hexane) to give 4-bromo-6- (trifluoromethyl)-1H-indazol-5-amine (Int-9A). MS (ESI) [M+H]+: m/z 280. [00280] Step B: 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B) [00281] Copper iodide (612 mg, 3.21 mmol) and tert-butyl nitrite (0.395 ml, 3.32 mmol) were added to a stirred solution of 4-bromo-6-(trifluoromethyl)-1H-indazol-5-amine (Int- 9A) (300 mg, 1.07 mmol) in MeCN (25 mL) at room temperature. The mixture was warmed to 70°C and stirred for 30 min. After cooling, the mixture was partitioned between EtOAc and sat. aq. NaHCO3. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified via silica gel chromatography (0 to 20% EtOAc in hexane) to give 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B). MS (ESI) [M+H]+: m/z 391. [00282] Step C: 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-9C) 145021.608066 (2500.PC) [00283] A mixture of 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B) (320 mg, 0.81 mmol), DHP (0.15 mL, 1.61 mmol), (1R)-(-)-camphor-10-sulfonic acid (24 mg, 0.11 mmol) in toluene (10 mL) was stirred at 70 °C for 3 h. After cooling to room temperature, the mixture was partitioned between EtOAc and aqueous sat. aq. NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via silica gel chromatography (0 to 10% EtOAc in hexane) to give 4- bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-9C). MS (ESI) [M+H]+: m/z 475. [00284] Step D: 4-bromo-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazole (Int-9D) [00285] A mixture of 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazole (Int-9C) (170 mg, 0.358 mmol), cyclopropylboronic acid (31 mg, 0.36 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.071 mmol), sodium carbonate (1.07 mL, 1.07 mmol, 1 M in H2O) in 2-MeTHF (3.6 mL) was evacuated and backfilled with N2 (3x). The mixture was stirred at 100 °C under N2 for 8 h. Additional cyclopropylboronic acid (15 mg, 0.18 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.036 mmol) were added to the mixture and stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via silica gel chromatography (0 to 10% EtOAc in hexane) to give 4-bromo-5-cyclopropyl-1-(tetrahydro- 2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-9D). MS (ESI) [M+H]+: m/z 389. [00286] Step E: (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- indazol-4-yl)boronic acid (Int-9) [00287] CataCXium A Pd G3 (12 mg, 0.017 mmol) was added to a stirred mixture of 4- bromo-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int- 9D) (66 mg, 0.17 mmol), triethylamine (0.095 mL, 0.68 mmol), and tetrahydroxydiboron (31 mg, 0.34 mmol) in MeOH (3.4 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was filtered through a pad of CELITE®, washed with MeOH and the filtrate was concentrated. The residue was purified via silica gel chromatography (10 to 50% EtOAc in hexanes) to give (5-cyclopropyl-1-(tetrahydro-2H- pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-9). MS (ESI) [M+H]+: m/z 355. 145021.608066 (2500.PC) [00288] Intermediate 10: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (Int-10) [00289] To a solution of 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (15 g, 28.1 mmol) in dioxane (150 mL) was added bis(pinacolato)diboron (13.32 g, 52.5 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.053 g, 2.81 mmol), and potassium acetate (6.88 g, 70.1 mmol). The reaction was stirred at 110 °C under N2 for 15 h. The mixture was concentrated and the residue was purified by flash silica gel chromatography (petroleum ether) to give ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (Int-10). NMR (400MHz, CDCl3) δ 7.69 - 7.64 (m, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.23 (t, J=8.8 Hz, 1H), 5.29 - 5.26 (m, 2H), 3.51 (s, 3H), 1.44 (s, 12H), 1.18 - 1.14 (m, 21H). [00290] Intermediate 11J, 11K, 11L: Tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J), tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-11K) & tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate 11L) 145021.608066 (2500.PC) [00291] Step A: Methyl 2-chloro-3-fluoroisonicotinate (Int-11A) [00292] 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, 0.40 mol). The mixture was heated to 75 °C and stirred for 12 h. The contents of the eight reactors were combined and concentrated to remove the volatiles. The pH of the resulting residue was adjusted to ~7 using aq. Na2CO3 and the mixture was extracted with EtOAc (20 L × 2). The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to give methyl 2-chloro-3-fluoroisonicotinate (Int-11A), which was used directly in the next step without further purification. [00293] Step B: (2- fluoropyridin-4-yl)methanol (Int-11B) [00294] Twelve were set up in parallel. To each reactor was charged EtOH (2.3 L), methyl 2-chloro-3-fluoroisonicotinate (Int-11A) (235 g, 1.2 mol), and CaCl2 (206 g, 1.8 mol). The reactor was degassed and purged with N2 three times and cooled to 0~10 ℃. 145021.608066 (2500.PC) NaBH4 (93.0 g, 2.4 mol) was added at 0~10 oC and stirred for 1 hr. The mixture was warmed to 20~25 ℃ and stirred for 12 h. The contents of the twelve reactors were combined and the mixture was slowly poured into ice water (5.0 V) under N2 atmosphere. The mixture was 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-11B).1H NMR (400 MHz, CDCl3) δ 2.91 (s, 1 H), 4.85 (s, 2H), 7.45 - 7.46 (t, J = 4.0 Hz, 1 H), 8.17 - 8.18 (d, J = 4.0 Hz, 1H). [00295] Step C: 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-11C) [00296] 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-11B) (200 g, 1.2 mol). PBr3 (402 g, 1.5 mol) was charged into the reactor vessel at 0 ℃. The vessel was warmed to 25 ℃ 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 separate. The aqueous solution was extracted with DCM (2 x 20 L). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduce pressure to give 4- (bromomethyl)-2-chloro-3-fluoropyridine (Int-11C). MS (ESI) m/z 224. [00297] Step D: 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-11D) [00298] Eight reactors were set up in parallel. To each reactor was charged MeCN (2.3 L), 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-11C) (230 g, 1.0 mol), TMSCN (1.01 kg, 10 mol), and LiOH (51 g, 1.2 mol). The mixture was stirred at 0 ℃ for 4 h and then warmed to 25 ℃ and stirred for 8 h. The contents of the eight reactors were combined and concentrated to remove the volatiles. The mixture was diluted with EtOAc (25 L) and H2O (10 L) and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 L) and the combined organic layers were dried with Na2SO4, filtered, and concentrated in vacuo to give 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-11D). MS (ESI) [M+H]+: m/z 171. [00299] Step E: 2-amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-11E) [00300] 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-11D) (170 g, 1.00 mol). The reactor was degassed and purged with N2 three times. Potassium tert-butoxide (123 g, 1.1 mol) was added in batches at 25 ℃ over 30 min. The mixture was stirred at 25 ℃ for 30 min. After 30 min, ethoxycarbonyl isothiocyanate (143 g, 1.1 mol) was added at 25 ℃. The mixture was stirred at 25 ℃ for 30 min. The reactor was warmed to 100 ℃ and stirred at 145021.608066 (2500.PC) 100 ℃ for 1 h. NaOH (1 L, 5.00 mol, 5 M in H2O) was added and the mixture was stirred at 100 ℃ for 10 h. The reaction was cooled to room temperature and the contents of the 12 reactors were combined for workup. The reaction was poured into ice water (10 V) and stirred at 0 ℃ for 30 min. The resulting solid was filtered, washed with H2O (5.0 L), and oven-dried at 50 ℃ for 12 h to give 2-amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-11E). MS (ESI) [M+H]+: m/z 210. [00301] Step F: 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F) [00302] 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-11E) (70.0 g, 0.3 mol), and K2CO3 (92.0 g, 0.60 mol). H2O2 (615 g, 5.4 mol, 30 wt%) was added slowly into the reactor in portions over 4 hr. The reaction mixture was stirred at 25 ℃ for 6 hr. The contents of the six reactors were combined, and the resulting mixture was poured into 10% aq. Na2SO3 at 15- 25 ℃. The mixture was stirred at 0 ℃ 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 ℃ for 12 h to give 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F). 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). [00303] Step G: 8-chloro-2-mercaptopyrido ol (Int- 11G) [00304] Five reactors were set up in parallel. To each reactor was charged EtOH (0.5 L) and KOH (52.0 g, 0.90 mol), and the mixture was stirred at 25 ℃ for 0.5 h. CS2 (70.0 g, 0.9 mol) was added at 25 ℃ and the mixture was stirred at 25 ℃ for 0.5 h. H2O (0.5 L) was added followed by 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F) (70.0 g, 0.3 mol). The mixture was heated to 110 ℃ and stirred for 12 h. The contents of the five reactors were combined. The volatiles were removed under reduced pressure and the pH was adjusted to ~3 with aq. HCl. The mixture was stirred at 0 ℃ for 1 h, filtered, and washed with H2O (5.0 L). The resulting solid was triturated with EtOH (10 V) at 25 ℃ for 8 h and dried in an oven at 40 ℃ for 12 hr to give 8-chloro-2- mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11G). MS (ESI) m/z 270. [00305] Step H: 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int- 11H) [00306] 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-11G) 145021.608066 (2500.PC) (135 g, 0.50 mol), and KOH (56.0 g, 1.0 mol). The mixture was stirred at 0 ℃ for 0.5 h. MeI (85.0 g, 0.60 mol) was added at 0 ℃ and the mixture was stirred for 1.5 h. The contents of the two reactors were combined. The volatiles were removed under reduced pressure and the pH was adjusted to ~3 with aq. HCl. The mixture was stirred at 0 ℃ for 1 h, filtered, and washed with H2O (5.0 L). The resulting solid was triturated with EtOH (10 V) at 25 ℃ for 8 h and then dried in an oven at 40 ℃ for 12 h to give 8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11H). MS (ESI) [M+H]+: m/z 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). [00307] Step I: 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int- 11I) [00308] 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- 11H) (55.0 g, 0.20 mol). The reaction mixture was stirred at 120 ℃ for 5 h. The contents of the three reactors were combined. The resulting mixture was concentrated under reduced pressure and the residue was triturated with EtOH (10 V) at 25 ℃ for 8 h. The resulting solid was dried in an oven at 40 ℃ for 12 hr to give 4,8-dichloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int-11I). MS (ESI) [M+H]+: m/z 302. 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). [00309] Step J: Tert-butyl (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) [00310] To a stirred mixture of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidine (Int-11I) (170 mg, 0.56 mmol) and N,N-diisopropylethylamine (300 μL, 1.69 mmol) in DMF (5 mL) was added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (119 mg, 0.56 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with EtOAc and water and the layers were separated. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (30 to 50% EtOAc in hexane) to give tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J). MS (ESI) [M+H]+: m/z 478. 1H NMR (400 MHz, CDCl3) δ = 8.43 (d, J = 5.5 Hz, 1H), 7.47 (d, J = 5.5 Hz, 1H), 4.48 - 4.21 (m, 3H), 4.18 - 3.99 (m, 1H), 3.84 - 3.38 (m, 2H), 2.65 (s, 3H), 1.96 - 1.84 (m, 2H), 1.82 - 1.63 (m, 2H), 1.55 (s, 9H). 145021.608066 (2500.PC) [00311] Step K: Tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-11K) [00312] To a stirring solution of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (200 mg, 2.52 mmol) in DCM (2.5 mL) was added mCPBA (580 mg, 2.52mmol, 75 wt%) at 0 °C. The mixture was quenched with sat. aq. NaHCO3 and the mixture was extracted with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via silica gel chromatography (60 to 100% EtOAc in hexane) to give tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-11K). MS (ESI) [M+H]+: m/z 494.1H NMR (400 MHz, CDCl3) δ = 8.52 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 4.62 - 4.28 (m, 3H), 4.23 - 4.02 (m, 1H), 3.93 - 3.47 (m, 2H), 3.01 (s, 3H), 1.96 - 1.87 (m, 2H), 1.83 - 1.61 (m, 2H), 1.56 (s, 9H). [00313] Step L: Tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L) [00314] Tert-butyl (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (500 mg, 1.046 mmol) was dissolved in DCM (10 ml). The solution was cooled to 0 °C. To above solution was added mCPBA (469 mg, 2.092 mmol) at 0 °C. The reaction was stirred at zero degree for 1 h. Cold DCM was added to the reaction mixture, followed by washing with sat aqueous NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (ISCO, 40 g), eluted with 0-100% EtOAc/Hex to give tert-butyl (1R,5S)-3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L) (430mg, 0.843 mmol, 81 % yield) as white solid. ESI-MS m/z calc’d for C21H24ClN5O4S2: 510.0, found [M+H]+: 510.3. [00315] Intermediate 12: Tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-12) 145021.608066 (2500.PC) [00316] Step A: Tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-12A) [00317] To a stirred solution of tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (254 mg, 0.531 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (184 mg, 0.584 mmol), XPhos Pd G4 (46 mg, 0.053 mmol) in dioxane (4 mL) was added K3PO4 (2 M in water, 0.797 mL, 1.59 mmol) and the biphasic mixture was heated to 110 °C overnight, cooled to r.t., and then diluted with EtOAc, and quenched by addition of sat. NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 0-25% EtOAc/DCM) to give tert-butyl 3-(8-(3- (methoxymethoxy)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-12A). ESI-MS m/z calc’d for C33H36N5O4S2 [M+H]+: 630; found: 630. [00318] Step B: Tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-12) [00319] To a stirred solution of tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-12A) (206 mg, 0.328 mmol) in DCM (5 mL) was added mCPBA (70 wt%, 170 mg, 0.690 mmol). The resulting mixture was stirred at r.t. for 1 h, diluted with DCM, and quenched by addition of 1:1 Na2S2O3 (1 N in water)/sat. NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM twice. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl 3-(8-(3- 145021.608066 (2500.PC) (methoxymethoxy)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-12), which was used directly in the next step without further purification. ESI m/z calc’d for C33H36N5O6S2 [M+H]+: 662; found: 662. [00320] Intermediate 13: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) [00321] Step A: Tert-butyl (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13A) [00322] To a solution of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidine (2 g, 6.62 mmol) in isopropyl alcohol (10 mL) was added tert-butyl (1R,5S)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.475 g, 6.95 mmol) and K2CO3 (1.829 g, 13.24 mmol). The reaction was stirred at 80 °C for 5 h. LCMS showed the reaction was finished. The reaction was cooled to room temperature and poured into ice water (30 mL). Yellow solid was precipitated. The mixture was filtered. The filtered cake was washed with H2O (30 mL), IPA (30 mL) and EtOAc (30 mL). The filtered cake was collected and concentrated in vacuo to give tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-13A). MS (ESI) [M+H]+: m/z 478.2. 145021.608066 (2500.PC) [00323] Step B: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13B) [00324] To a solution of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.5 g, 1.046 mmol) (Int-13A) in toluene (10 mL) was added (6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-2) (0.515 g, 1.569 mmol), SPhos Pd G3 (0.408 g, 0.523 mmol) and K2CO3 (1.569 mL, 3.14 mmol) (2 M in H2O) in the glove box. The reaction was stirred at 50 °C for 16 h. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL) and extracted with EtOAc (3 * 20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give crude product. The crude was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 0~35% THF/Pet. ether gradient @ 40 mL/min, dry loaded) to give tert-butyl (1R,5S)-3-(8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-13B). MS (ESI) [M+H]+: m/z 726.3. [00325] Step C: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) [00326] Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 1.653 mmol) (Int-13B) was taken up in CHCl3 (16.5 ml) and 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.48 g, 1.82 mmol) was added. The reaction was stirred at 25 °C. The reaction was concentrated in vacuo and purified by silica gel column chromatography (0 to 100% (3:1 EtOAc :EtOH) in hexane ) to give tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)- 1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-13). MS (ESI) [M+H]+: m/z 742.1H NMR (499 MHz, DMSO) δ 8.83 (t, J = 5.1 Hz, 1H), 8.05 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.56 (s, 1H), 5.97 (d, J = 9.7 Hz, 1H), 4.45 – 4.34 (m, 1H), 4.28 (d, J = 22.5 Hz, 2H), 4.21 – 4.12 (m, 1H), 3.97 – 3.89 (m, 1H), 3.86 – 3.77 (m, 2H), 3.73 – 3.64 (m, 1H), 2.94 – 2.88 (m, 3H), 2.72 (s, 3H), 2.44 – 2.33 (m, 1H), 2.07 – 2.01 (m, 2H), 1.81 – 1.70 (m, 3H), 1.70 – 1.63 (m, 1H), 1.63 – 1.57 (m, 2H), 1.54 – 1.51 (m, 1H), 1.50 (s, 9H). 145021.608066 (2500.PC) [00327] Intermediate 14: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) [00328] Step A: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) [00329] To a solution of tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13B) (450 mg, 0.620 mmol) in DCM (6 mL) was added mCPBA (378 mg, 1.860 mmol), and the reaction was stirred at 25 °C for 1 h. LCMS showed that the reaction was completed. The mixture was diluted with DCM (10 mL), quenched with sat. Na2SO3 (aq., 5 mL), sat. NaHCO3 (aq., 5 mL) and stirred for 30 min. The mixture was extracted with DCM (10 mL x 3). The combined organic layer was washed with sat. NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude was purified by flash silica gel chromatography (ISCO®; 4 g Agela® Silica Flash Column, Eluent of 0~35% THF/Pet. ether gradient @ 40 mL/min, dry loaded) to give tert- butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol- 4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-14). MS (ESI) [M+H]+: m/z 758.2. [00330] Intermediate 15: Tert-butyl (1R,5S)-3-(2-(methylsulfonyl)-8-(5- ((triisopropylsilyl) ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-15) 145021.608066 (2500.PC) [00331] Step A: Tert-butyl (1R,5S)-3-(2-(methylthio)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-15A) [00332] To a solution of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (160 mg, 0.335 mmol) in toluene (2.5 mL) was added (5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)boronic acid (212 mg, 0.402 mmol), potassium carbonate (0.502 mL, 1.004 mmol) (2 M in water) and SPhos Pd G3 (131 mg, 0.167 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 h under N2 atmosphere. LCMS showed the reaction was finished. The mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether : ethyl acetate = 2 : 1) to give tert-butyl (1R,5S)-3- (2-(methylthio)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-15A). MS (ESI) [M+H]+: m/z 926.3. [00333] Step B: Tert-butyl (1R,5S)-3-(2-(methylsulfonyl)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl) d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- [00334] To a solution of tert-butyl (1R,5S)-3-(2-(methylthio)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- 145021.608066 (2500.PC) carboxylate (300 mg, 0.324 mmol) (Int-15A) in DCM (5 mL) was added mCPBA (145 mg, 0.712 mmol, 85%) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was filtered and the filtered cake was washed with DCM (3 mL), the filtrate was quenched with Na2SO3 (aq, 5 mL) and NaHCO3 (5 mL). The mixture was stirred for 20 min, and extracted with DCM (20 mL x 3). The combined organic layer was washed with NaHCO3 (2 mL), brine (3 mL), dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure give the crude product. The residue was purified by preparative TLC (SiO2, petroleum ether : ethyl acetate =1 : 1) to give tert-butyl (1R,5S)-3-(2- (methylsulfonyl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-15). MS (ESI) [M+H]+: m/z 958.3. [00335] Intermediate 16: Tert-butyl (1R,5S)-3-(2-(methylsulfinyl)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-16) [00336] Step A: Tert-butyl (1R,5S)-3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-16) [00337] To a solution of tert-butyl (1R,5S)-3-(2-(methylthio)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (641 mg, 0.692 mmol) in DCM (7 mL) was added 3-phenyl-2-(phenylsulfonyl)- 1,2-oxaziridine (651 mg, 2.491 mmol) at 20 °C under N2 atmosphere. The mixture was 145021.608066 (2500.PC) stirred at 20 °C for 2 h. TLC (SiO2; petroleum ether:ethyl acetate = 1:2) showed the reaction is complete. The mixture was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc/Pet. ether gradient @ 40 mL/min) to give tert-butyl (1R,5S)-3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-16). MS (ESI) [M+H]+: m/z 942.5. [00338] Intermediate 17: Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 5-((triisopropylsilyl) -1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl) thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17) [00339] Step A: Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17A) [00340] To a mixture of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (4.8 g, 10.04 mmol) and 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6- fluoro-1-((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6) (7.97 g, 13.05 mmol), SPhos Pd G3 (3.92 g, 5.02 mmol) in Toluene (120 mL) was added K2CO3 (20.08 mL, 40.2 mmol) (2 M in H2O) at 25 °C, and the mixture was stirred at 50 °C for 2 h under N2 atmosphere. LCMS showed the starting material was consumed and the desired MS was found. The mixture was diluted with EtOAc (200 mL), and the mixture 145021.608066 (2500.PC) was washed with H2O (15 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 20% THF in petroleum ether gradient @ 40 mL/min) to give tert-butyl (1R,5S)-3-(8-(6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17A). MS (ESI) [M+H]+: m/z 940.2. [00341] Step B: Tert-butyl (1R,5S)-3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-17B) [00342] To a mixture of tert-butyl (1R,5S)-3-(8-(6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (3 g, 3.19 mmol) (Int-17A) in DCM (10 mL) was added ammonia (25 mL, 175 mmol) (7 M in MeOH) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS that showed the starting material was consumed and desired MS was found. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 20% THF in petroleum ether gradient @ 40 mL/min) to give tert-butyl (1R,5S)-3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17B). MS (ESI) [M+H]+: m/z 808.3. [00343] Step C: Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17C) [00344] To a mixture of tert-butyl (1R,5S)-3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)- 1H-benzo[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 2.97 mmol) (Int-17B) in DCM (30 mL) was added 4-methylbenzenesulfonic acid (0.153 g, 0.891 mmol) and DHP (0.815 mL, 8.91 mmol) at 25 °C, and the mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was concentrated in vacuum, the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 20% ethyl acetate in petroleum ether gradient 145021.608066 (2500.PC) @ 40 mL/min) to give tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17C). MS (ESI) [M+H]+: m/z 892.6. [00345] Step D: Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17) [00346] To a solution of tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.8 g, 2.017 mmol) (Int-17C) in DCM (30 mL) was added 3-phenyl-2- (phenylsulfonyl)-1,2-oxaziridine (1.318 g, 5.04 mmol) at 25 °C, and the mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was concentrated in vacuo at 35 °C, and the residue was purified by silica gel chromatography (glass column, 40 g silica gel (100-200Å), Pet. ether/THF=1/1, dry loading) to give tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H- pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17). MS (ESI) [M+H]+: m/z 908.5. 1H NMR (400MHz, CD3OD) δ 8.83 – 8.80 (m, 1H), 8.52 (d, J=3.8 Hz, 1H), 8.37 - 8.24 (m, 1H), 8.07 (br t, J=6.0 Hz, 1H), 7.54 - 7.14 (m, 2H), 6.01 (br t, J=8.9 Hz, 1H), 5.18 - 4.97 (m, 1H), 4.45 (br s, 1H), 4.39 - 4.28 (m, 1H), 4.22 (br t, J=12.3 Hz, 1H), 4.15 - 3.96 (m, 2H), 3.96 - 3.84 (m, 1H), 3.56 (br d, J=12.5 Hz, 1H), 3.10 - 2.94 (m, 3H), 2.61 - 2.31 (m, 1H), 2.22 - 1.67 (m, 9H), 1.62 - 1.54 (m, 9H), 0.86 (br d, J=6.9 Hz, 9H), 0.75 - 0.56 (m, 12H). [00347] Intermediate 18: Tert-butyl -3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 5-((triisopropylsilyl)ethynyl)-1H- 4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18) 145021.608066 (2500.PC) [00348] Step A: Tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18) [00349] To a solution of tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (85 mg, 0.095 mmol) in DCM (3 mL) was added mCPBA (58.0 mg, 0.286 mmol) (85% w/w) at 0 °C, and the mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was directly purified by preparative TLC plate (SiO2, Pet. ether/EtOAc=1/1) to give tert-butyl (1R,5S)-3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18). MS (ESI) [M+H]+: m/z 924.6. [00350] Intermediate 19: Tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19) 145021.608066 (2500.PC) [00351] Step A: Tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19A) [00352] To a solution of tert-butyl (1R,5S)-3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (200 mg, 0.418 mmol) in toluene (2 mL) was added ((8-(5,5- dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane (209 mg, 0.418 mmol) SPhos Pd G3 (98 mg, 0.126 mmol) and K2CO3 (1.046 mL, 2.092 mmol) (2 M in water) under N2 atmosphere. The reaction mixture was stirred at 60 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 19% ethyl acetate in petroleum ether gradient @ 20 mL/min) to give tert-butyl (1R,5S)-3-(8-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-19A). MS (ESI) [M+H]+: m/z 828.4. [00353] Step B: Tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19) [00354] To a solution of tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (141 mg, 0.126 mmol) (Int- 19A) in CH2Cl2 (2 mL) was added mCPBA (61.4 mg, 0.302 mmol, wt 85 %) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was quenched with sat. aq. Na2SO3 (2 mL) and sat. aq. NaHCO3 (2 mL), extracted with CH2Cl2 (3 x 2 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude tert-butyl (1R,5S)-3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19). MS (ESI) [M+H]+: m/z 860.4. [00355] Intermediate 20: Tert-butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2- yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)-2- 145021.608066 (2500.PC) (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-20) [00356] Step A: Tert-butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20A) [00357] Tert-Butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (69 mg, 0.144 mmol), (5-methyl- 1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int- 5)(60.7 mg, 0.202 mmol), SPhos Pd G3 (17 mg, 0.022 mmol) and potassium phosphate, tribasic (92 mg, 0.433 mmol) were added to a vial. THF (1299 μl) and water (144 μl) were added through the septum and the resulting mixture was degassed and backfilled with nitrogen (3x) and was stirred at 60 °C overnight. The reaction mixture was diluted with DCM and water and was extracted with DCM (2x). The combined organic fractions were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in hex) to give tert-butyl (1R,5S)-3-(8-(5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-20A). MS (ESI) [M+H]+ Found: 698. [00358] Step B: Tert-butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20) [00359] Tert-Butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (88.5 mg, 0.127 mmol) (Int-20A) was taken up in CHCl3 (1268 μl) and 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (39.8 mg, 0.152 mmol) was added. Reaction stirred at 25 °C for 4 hours and was directly purified by silica gel column chromatography (0-100% 3:1 EtOAc:EtOH in hex) to give tert-butyl (1R,5S)-3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- 145021.608066 (2500.PC) d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20). MS (ESI) [M+H]+ Found: 714. [00360] Intermediate 21: Tert-butyl (1R,5S)-3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- [00361] Step A. Tert-butyl (1R,5S)-3-(2-hydroxy-8-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21A) [00362] A solution of tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) (498 mg, 0.671 mmol) in THF (6.7 ml) was cooled to 0 °C and then treated with 1 N NaOH (3356 μl, 3.36 mmol). After ~30-45min the reaction was complete. The crude reaction was then partitioned between EtOAc and water and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give crude tert-butyl (1R,5S)-3-(2-hydroxy- 8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-21A) which was used without further purification in the next step. MS (ESI) [M+H]+ m/z 696. [00363] Step B: Tert-butyl (1R,5S)-3-(2-(((S)-1-(((tert-butyldimethylsilyl)oxy)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- 145021.608066 (2500.PC) (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21B) [00364] A solution of tert-butyl (1R,5S)-3-(2-hydroxy-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (474 mg, 0.68 mmol) (Int-21A) and (R)-(1- (((tert-butyldimethylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methyl 4- nitrobenzenesulfonate (447 mg, 1.022 mmol) in acetonitrile (6813 μl) was treated with Cs2CO3 (444 mg, 1.36 mmol) at 50 °C. After ~3.5 h the reaction was cooled, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Redisep Gold Flash Column, eluent of 20-100% EtOAc/Hexanes gradient) to give tert-butyl (1R,5S)-3-(2-(((S)-1-(((tert-butyldimethylsilyl)oxy)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21B). MS (ESI) [M+H]+ m/z 930. [00365] Step C: Tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21C) [00366] A solution of tert-butyl (1R,5S)-3-(2-(((S)-1-(((tert- butyldimethylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (495 mg, 0.53 mmol) (Int- 21B) in THF (3.5 ml) and treated wtih TBAF (2.1 ml, 2.1 mmol) at r.t. After ~30min the reaction was partitioned between EtOAc and sat. ammonium chloride. The organic layer was washed with water, brine and then dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Redisep Gold Flash Column, eluent of 20-100% [3:1 EtOAc/EtOH]/Hexanes gradient) to give tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methoxy)-8- (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-21C). MS (ESI) [M+H]+ m/z 816. [00367] Step D: Tert-butyl (1R,5S)-3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 145021.608066 (2500.PC) 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) [00368] A solution of tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (338 mg, 0.414 mmol) (Int-21C), and triethylamine (87 μl, 0.621 mmol) in DCM (4143 μl) was cooled to 0 °C and then treated with a solution of Ms-Cl (40.4 μl, 0.518 mmol) in DCM (75 μl) The reaction was allowed to stir at 0 °C and was deemed complete in 10 minutes. The reaction was partitioned between DCM and sat. sodium bicarbonate solution, the organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Redisep Gold Flash Column, eluent of 10-100% [3:1 EtOAc/EtOH]/Hexanes gradient) to give tert-butyl (1R,5S)-3-(2- (((S)-2,2-difluoro-1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-21). MS (ESI) [M+H]+ m/z 894. [00370] Step A: Benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int-22A) 145021.608066 (2500.PC) [00371] In a 100 mL round bottom flask, 3-(hydroxymethyl)-3-methylpiperidin-1-ium chloride (1500 mg, 9.05 mmol) was dissolved in DCM (22.6 ml). To above solution was added TEA (5048 μL, 36.2 mmol, 4 eq), followed by CbzCl (4527 μL, 13.58 mmol, 1.5 eq). The reaction was stirred at r.t. for 1 h, quenched with water (5 ml), extracted with DCM (20 ml x 3). The organic layer was dried over MgSO4, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 120 g column, eluted with 0-100% EtOAc/Hex in 30 min). Fractions containing desired product were combined and concentrated to give benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int- 22A). ESI-MS m/z calc’d for C15H21NO3: 263.337, found [M+Na]+: 286.3. [00372] Step B: Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl) d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- [00373] In a 40 mL vial, tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (200 mg, 0.264 mmol) and benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int-22A) (141 mg, 0.528 mmol, 2 eq.) were dissolved in THF (2639 μL). The solution was cooled to zero degree, added NaH (63.3 mg, 1.583 mmol). The reaction was let stirred at zero degree for 1.5 h, quenched with NaHCO3 (1 mL), and extracted with DCM (5 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM). Fractions containing desired product were combined and concentrated to give tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-22B). ESI-MS m/z calc’d for C49H55F3N8O6S: 941.084, found [M+H]+: 942.8. [00374] Step C: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22) [00375] Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- 145021.608066 (2500.PC) carboxylate (Int-22B) (124 mg, 0.132 mmol) was dissolved in DCM (22 ml). To above solution was added TEA (55.1 μL, 0.395 mmol), triethylsilane (421 μl, 2.64 mmol) and palladium(II) chloride (35.0 mg, 0.198 mmol). The reaction was stirred under N2 for 16 h, then quenched with addition of MeOH (5 ml) and stirred at room temperature for 10 min. To above solution was added TEA (1 ml). The crude was filtered and concentrated, purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM) to give tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22). ESI-MS m/z calc’d for C41H49F3N8O4S: 806.950, found [M+H]+: 807.4. [00376] Intermediate 23: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylazetidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23) [00377] Step A: Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylazetidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23A) [00378] In a 40 mL vial, tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (200 mg, 0.264 mmol) and benzyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (124 mg, 0.528 mmol, 2 eq.) were dissolved in THF (2639 μL). The solution was cooled to zero degree, added NaH (63.3 mg, 1.583 mmol). The reaction was let stirred at zero deg for 1.5 h, quenched with NaHCO3 (1 mL), extracted with DCM (5 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM). Fractions 145021.608066 (2500.PC) containing desired product were combined and concentrated to give tert-butyl (1R,5S)-3-(2- ((1-((benzyloxy)carbonyl)-3-methylazetidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-23A). ESI-MS m/z calc’d for C47H51F3N8O6S: 913.03, found [M+H]+: 913.4. [00379] Step B: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylazetidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23) [00380] Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylazetidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23A) (240 mg) was dissolved in CH2Cl2 (2629 μL). To above solution was added TEA (110 μL, 0.789 mmol), triethylsilane (630 μL, 3.94 mmol) and palladium(II) chloride(55.9 mg, 0.315 mmol). The mixture was stirred under N2 for 2 h. UPLC-MS indicated formation of desired product. To above mixture was added MeOH (5 ml) and stirred at r.t. for 10 min, then added TEA (1 ml), filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM). Fractions containing desired product were combined and concentrated to give tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)- 1H-indazol-4-yl)-2-((3-methylazetidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-23). ESI-MS m/z calc’d for C39H45F3N8O4S: 778.896, found [M+H]+: 779.5. [00381] Intermediate 24: Tert-butyl (1R,5S)-3-(2-hydroxy-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-24) 145021.608066 (2500.PC) [00382] Step A: Tert-butyl (1R,5S)-3-(2-hydroxy-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-24) [00383] LiOH solution (1.6 mL, 1 M) was added to tert-butyl (1R,5S)-3-(8-(5-ethynyl-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-16) (300mg,0.32mmol) in THF (1.6mL) dropwise. The mixture was stirred at 25oC for overnight. The mixture was neutralized with 0.5 N HCl to pH7, extracted with EtOAc (3x10mL). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated to generate product tert-butyl (1R,5S)-3-(2-hydroxy-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-24). ESI-MS m/z calc’d for C46H61N7O4S2Si2 [M+H]+: 897; found: 897. [00384] Intermediate 25: (2S,4R)-1-(L-Valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-25) 145021.608066 (2500.PC) [00385] Step A: Tert-Butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (Int-25A) [00386] To a stirred solution of 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (420 mg, 1.9 mmol), tert-butyl (R)-(1-(4-bromophenyl)-2- hydroxyethyl)carbamate (300 mg, 0.95 mmol) and XPhos Pd G2 (75 mg, 0.095 mmol) in dioxane (4.3 mL) and water (0.43 mL) was added Cs2CO3 (1.0 M in water, 1.9 mL, 1.9 mmol). The resulting mixture was heated to 80 °C for 1 h, cooled to RT, filtered through a pad of MgSO4/silica gel (rinsing with EtOAc), and concentrated in vacuo. The residue was purified by flash chromatography (silical gel, 0-100% EtOAc/hexanes) to give tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamate (Int-25A). ESI-MS m/z calc’d for C18H26N3O3 [M+H]+: 332; found: 332. [00387] Step B: (R)-2-Amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1-ol (Int-25B) [00388] To a stirred solution of tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (260 mg, 0.80 mmol) (Int-25A) in DCM (2.6 mL) was added HCl (4 M in dioxane, 1.4 mL, 5.6 mmol). The resulting mixture was stirred at RT for 30 min and then concentrated in vacuo to give (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethan-1-ol (Int-25B), which was used directly in the next step without further purification. ESI-MS m/z calc’d for C13H18N3O [M+H]+: 232; found: 232. [00389] Step C: Tert-Butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)- 2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)carbamate (Int-25C) [00390] To a stirred solution of (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan- 1-ol (100 mg, 0.37 mmol) (Int-25B) and (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4- hydroxypyrrolidine-2-carboxylic acid (150 mg, 0.45 mmol) in DMF (1.2 mL) was added DIPEA (200 μL, 1.1 mmol), followed by HATU (190 mg, 0.49 mmol). The resulting mixture was stirred at RT for 15 min, quenched by addition of sat. NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was 145021.608066 (2500.PC) purified by flash chromatography (silica gel, 0-15% MeOH/DCM) to give tert-butyl ((S)-1- ((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4- hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (Int-25C). ESI-MS m/z calc’d for C28H42N5O6 [M+H]+: 544; found: 544 [00391] Step D: (2S,4R)-1-(L-Valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-25) [00392] To a stirred solution of tert-butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)carbamate (180 mg, 0.34 mmol) (Int-25C) in DCM (1.1 mL) was added HCl (4 M in dioxane, 590 uL, 2.4 mmol). The resulting mixture was stirred at RT for 1 h and then concentrated in vacuo to give (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-25). ESI-MS m/z calc’d for C23H34N5O4 [M+H]+: 444; found: 444.1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 7.9 Hz, 1H), 8.11 (s, 3H), 7.51 (d, J = 1.8 Hz, 1H), 7.42 (s, 3H), 6.33 (d, J = 1.8 Hz, 1H), 4.87 (q, J = 6.2 Hz, 1H), 4.60 (t, J = 8.3 Hz, 1H), 4.34 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.05 – 4.00 (m, 1H), 3.75 – 3.58 (m, 3H), 3.54 (dd, J = 10.8, 3.9 Hz, 1H), 2.13 (tt, J = 12.2, 6.2 Hz, 2H), 1.79 (ddd, J = 13.1, 9.0, 4.3 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). [00393] The compound in the table below was synthesized via a similar route as described in the above synthesis of Int-25 by making the appropriate substitutions using the appropriate boronic acid. 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. Int. Structure Compound Name ESI-MS m/z (2S,4R)-1-(L-valyl)-4-hydroxy- N-((R)-2-hydroxy-1-(4-(4- Calc’d for [M+H]+ Int-26 methylthiazol-5- : 447; found: 447 yl)phenyl)ethyl)pyrrolidine-2- carboxamide [00394] Int-26: 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 4.3 Hz, 3H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 4.85 (q, J = 6.2 145021.608066 (2500.PC) Hz, 1H), 4.59 (t, J = 8.3 Hz, 1H), 4.34 (s, 1H), 4.03 (t, J = 5.3 Hz, 1H), 3.75 – 3.58 (m, 3H), 3.56 – 3.45 (m, 1H), 2.48 (s, 3H), 2.14 (dt, J = 14.1, 7.2 Hz, 2H), 1.78 (ddd, J = 13.0, 9.0, 4.3 Hz, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H). [00395] Intermediate 27: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 27) [00396] Step A: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 27) [00397] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.7 g, 3.95 mmol) in DCM (20 mL) was added 1H-imidazole (0.403 g, 5.92 mmol) and tert-butylchlorodimethylsilane (0.893 g, 5.92 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was diluted with water (5 mL) and extracted with DCM (40 mL * 3). The combined organic layer was dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®, 40 g Agela Flash Column, DCM:MeOH=10:1, 30 min, 30 mL/min, dry loaded) to give (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-27). m/z 545.4. [00398] Intermediate 28: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide (Int-28) 145021.608066 (2500.PC) [00399] Step A: 4-(4-methylthiazol-5-yl)benzonitrile (Int-28A) [00400] To a solution of 4-bromobenzonitrile (20 g, 110 mmol) in DMA (280 mL) was added 4-methylthiazole (21.79 g, 220 mmol), Pd(OAc)2 (0.247 g, 1.099 mmol) and Potassium carbonate (21.57 g, 220 mmol) at 25 °C under N2 atmosphere. The mixture was stirred at 149 °C for 2 h. LCMS showed the starting material was consumed and desired peak was formed. The mixture was cooled, diluted with EtOAc (500 mL), washed with H2O (60 mL x 3), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 75 mL/min) to give 4-(4-methylthiazol-5- yl)benzonitrile (Int-28A). MS (ESI) [M+H]+: m/z 200.9. [00401] Step B: (4-(4-methylthiazol-5-yl)phenyl)methanamine (Int-28B) [00402] To a solution of 4-(4-methylthiazol-5-yl)benzonitrile (8.5 g, 42.4 mmol) (Int-28A) and cobalt(II) chloride (8.27 g, 63.7 mmol) in MeOH (90 mL) was added sodium tetrahydroborate (9.76 g, 424 mmol) portionwise (~0.5 h) and the mixture was stirred at 0 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was quenched with acetone (100 mL) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g Agela® Silica Flash Column (basified by TEA), Eluent of 0~5% DCM/MeOH gradient @ 70 mL/min, dry loaded) to give (4-(4-methylthiazol-5-yl)phenyl)methanamine (Int-28B). MS (ESI) [M+H]+: m/z 205.1. [00403] Step C: Tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C) [00404] To a stirred solution of (4-(4-methylthiazol-5-yl)phenyl)methanamine (2.4 g, 11.75 mmol) (Int-28B) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.99 g, 12.92 mmol) in DMF (35 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (1.905 g, 14.10 mmol), DIEA (6.16 mL, 35.2 mmol) and EDC (3.38 g, 17.62 mmol), and the mixture was stirred at 30 °C for 2h. LCMS showed the starting material was consumed 145021.608066 (2500.PC) and desired MS was found. The reaction mixture was extracted with EtOAc (60 mL * 3). The combined organic layer was washed with H2O (30 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash silica gel chromatography (ISCO®, 20 g Agela Flash Column, Pet. ether/THF=1/2) to give tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.41 - 7.31 (m, 4H), 4.48 (br s, 3H), 3.56 - 3.45 (m, 2H), 3.37 - 3.15 (m, 2H), 3.01 - 2.86 (m, 1H), 2.50 (s, 3H), 2.23 - 2.03 (m, 1H), 1.51 - 1.29 (m, 9H). [00405] Step D: (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28D) [00406] The compound of tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (8 g, 19.16 mmol) (Int-28C) was added to HCl (4.79 mL, 19.16 mmol) (4 M in Dioxane) at 25 °C. The mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and desired MS was found. The mixture was concentrated in vacuum and the residue was azeotropy with toluene (40 mL * 2) to give (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28D). MS (ESI) [M+H]+: m/z 318.5. [00407] Step E: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-28) [00408] To a solution of (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (6 g, 18.90 mmol) (Int-28D) in DCM (60 mL) was added 2,6-Lutidine (33.0 mL, 284 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (30.0 g, 113 mmol)) at 25 °C under N2 atmosphere. The mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and the desired MS was found. The mixture was concentrated under reduced pressure, purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0%-50% of EE (EtOAc:EtOH=3:1): petroleum ether gradient @ 70 mL/min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28). MS (ESI) [M+H]+: m/z 432.2. [00409] Intermediate 29-a & 29-b: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3- hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-29-a & 29-b) 145021.608066 (2500.PC) [00410] Step A: 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole (Int-29A) [00411] To a solution of 5-methylisoxazol-3-ol (5 g, 50.5 mmol) in DCM (50 mL) was added DHP (7 mL, 77 mmol) and PPTS (1.268 g, 5.05 mmol) at 20 °C, the mixture was stirred at 20 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with DCM (50 mL), washed with H2O (20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 60 mL/min) to give 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole (Int- 183.8. [00412] Step B: 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (Int-29B) [00413] To a solution of 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole (9.3 g, 50.8 mmol) (Int-29A) in THF (90 mL) was added dropwise KHMDS (76 mL, 76 mmol, 1 M in THF) at -66 °C under nitrogen atmosphere, and the reaction mixture was stirred at -66 °C for 0.5 h. Then to the reaction mixture was then bubbled carbon dioxide at -66° C for 1 h., and the mixture was stirred at 10 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The reaction mixture was quenched by saturated ammonium chloride aqueous solution (120 mL) and extracted with ethyl acetate (100 mL) two times. The aqueous layer was adjusted by aqueous hydrochloric acid solution (1 M) until pH 3 at 0 °C, extracted with DCM/ IPA (v/v = 5:1, 250 mL, six times). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (Int-29B). MS (ESI) [M+H]+: m/z 228.2. [00414] Step C: Methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (Int- 29C) 145021.608066 (2500.PC) [00415] To a solution of 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (4 g, 17.60 mmol) (Int-29B) in a mixture of EtOAc (40 mL) and MeOH (40 mL) was added (trimethylsilyl)diazomethane (44 mL, 88 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC (SiO2; petroleum ether: ethyl acetate = 1:1) showed a new spot was observed. The mixture was quenched with saturated NH4Cl solution (30 mL), extracted with EtOAc (2 x 50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 40% ethyl acetate in petroleum ether gradient @ 40 mL/min) to give methyl 2-(3-((tetrahydro-2H- pyran-2-yl)oxy)isoxazol-5-yl)acetate (Int-29C). MS (ESI) [M+H]+: m/z 242.2. [00416] Step D: Methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate (Int-29D) [00417] To a solution of methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (3.6 g, 14.92 mmol) (Int-29C) in DMF (40 mL) was added potassium tert-butoxide (1.842 g, 16.41 mmol) and 2-iodopropane (2.79 g, 16.41 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 10 °C for 3 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with EtOAc (150 mL), washed with saturated NH4Cl solution (30 mL), H2O (2 x 30 mL) and brine (40 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoate (Int-29D). MS (ESI) [M+H]+: m/z 284.2. [00418] Step E: 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoic acid (Int-29E) [00419] To a solution of methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate (800 mg, 2.82 mmol) (Int-29D) in MeOH (8 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (592 mg, 14.12 mmol) at 10 °C. The mixture was stirred at 10 °C for 3 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was acidified with aq. HCl (1 M) until pH 3, extracted with DCM/iPrOH (v/v=5:1, 3 x 20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product 3-methyl-2-(3-((tetrahydro- 2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoic acid (Int-29E). MS (ESI) [M+H]+: m/z 270.2. [00420] Step F: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-((tetrahydro- 2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide (Int-29F) 145021.608066 (2500.PC) [00421] To a solution of 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoic acid (368 mg, 1.367 mmol) (Int-29E) in DMF (4 mL) was added PyBOP (853 mg, 1.640 mmol), (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-28) (708 mg, 1.640 mmol) and DIEA (0.716 mL, 4.10 mmol) at 11 °C. The mixture was stirred at 11 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with EtOAc (30 mL), washed with water (2 x 7 mL) and brine (8 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5% MeOH in DCM gradient @ 30 mL/min) to give (2S,4R)-4- ((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29F). MS (ESI) [M+H]+: m/z 683.3. [00422] Step G: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29G) [00423] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3- ((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (669 mg, 0.980 mmol) (Int-29F) in MeOH (7 mL) was added PPTS (738 mg, 2.94 mmol) at 15 °C. The mixture was stirred at 50 °C for 15 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was cooled, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5% MeOH in DCM gradient @ 30 mL/min) to give racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29G). MS (ESI) [M+H]+: m/z 599.3. [00424] Step H: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29-a & Int-29-b) [00425] The racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5- yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (280 mg, 0.468 mmol) (Int-29G) was separated by SFC (Column: Daicel Chiralcel OD (250 mm * 30 mm, 10 um); Condition: CO2- MeOH (0.1% NH3·H2O); Begin B--End B: 20--20; Gradient Time (min): 10; 100% B Hold Time (min): 10; FlowRate (mL/min): 70) to give 145021.608066 (2500.PC) (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29-a, the first eluting isomer from SFC) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5- yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 29-b, the second eluting isomer from SFC). MS (ESI) [M+H]+: m/z 599.2. [00426] Intermediate 30: (2S,4R)-1-(L-valyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-2- ((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide [00427] At 0 °C, to a solution of (2S,4R)-1-(L-valyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (15 mg, 1 eq.) and imidazole (9.2 mg, 4 eq.) in DCM (0.4mL) was added TBS-Cl(15.3 mg, 3 eq.), and the resulting mixture was allowed to stir at ambient temperature for 48 h. The reaction mixture was diluted with DCM and washed twice with water and once with brine. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluted with Hex/(EtOAc/EtOH 3:1) 10-100, to give desired product (2S,4R)-1-(L-valyl)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-30). ESI-MS m/z calc’d for C35H61N5O4Si2 [M+H]+: 672; found: 672. [00428] Intermediate 31: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-31) 145021.608066 (2500.PC) [00429] Step A: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-31) [00430] To a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (2 g, 4.28 mmol) in DMF (40 mL) were added 1H-imidazole-1-sulfonyl azide hydrochloride (1.077 g, 5.14 mmol) and potassium bicarbonate (3 M in water) (7.14 mL, 21.41 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (400 mL) and washed with water (300 mL × 2), brine (300 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combi-flash with the following: Column: AQ-C18 Column, 220 g, 60 Å, 40-60 μm; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 80 mL / min; 0% B to 100% B in 25 min; Detector: UV 254 / 210 nm. The product-containing fractions were combined, roto-evaporated in vacuo to give (2S,4R)-1-((S)-2-azido-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-31). MS ESI calculated for C22H28N6O3S [M + H]+ 457.19 found 457.10. 1H NMR (300 MHz, CD3OD) δ 8.88 (s, 1H), 7.57 - 7.29 (m, 4H), 4.73 - 4.56 (m, 1H), 4.56 - 4.25 (m, 3H), 4.03 (s, 1H), 3.86 - 3.62 (m, 2H), 2.48 (s, 3H), 2.33 - 2.16 (m, 1H), 2.16 - 2.05 (m, 1H), 1.12 - 0.96 (m, 9H). [00431] Intermediate 32: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2- hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-32) 145021.608066 (2500.PC) [00432] Step A: Methyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine- 2-carboxylate (Int-32A) [00433] To a stirred mixture of (tert-butoxycarbonyl)-L-valine (2 g, 9.21 mmol) in DMF (20 mL) were added HATU (3.85 g, 10.13 mmol), methyl (2S,4R)-4-hydroxypyrrolidine-2- carboxylate (1.336 g, 9.21 mmol) and DIEA (6.43 mL, 36.8 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (220 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give methyl (2S,4R)-1-((tert-butoxycarbonyl)- L-valyl)-4-hydroxypyrrolidine-2-carboxylate (3 g, 8.71 mmol, 95% yield) (Int-32A) as a white solid. MS ESI calculated for C16H28N2O6 [M - C4H8 + H]+ 289.19 found 289.05. 1H NMR: (400 MHz, CDCl3) δ 5.33 - 5.14 (m, 1H), 4.75 - 4.61 (m, 1H), 4.52 (s, 1H), 4.20 - 3.94 (m, 2H), 3.72 (s, 4H), 2.79 (s, 1H), 2.43 - 2.26 (m, 1H), 2.04 - 1.93 (m, 2H), 1.41 (s, 9H), 1.05 - 0.89 (m, 6H). [00434] Step B: Methyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (Int-32B) [00435] To a stirred mixture of methyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4- hydroxypyrrolidine-2-carboxylate (3 g, 8.71 mmol) (Int-32A) in DCM (14 mL) was added hydrochloride in 1,4-dioxane (30 mL, 4 M, 120 mmol) at room temperature. The resulting 145021.608066 (2500.PC) mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was washed by hexane to give methyl (2S,4R)-1-(L-valyl)-4- hydroxypyrrolidine-2-carboxylate hydrochloride (3 g, 10.69 mmol, 99% yield) (Int-32B), a white solid. MS ESI calculated for C11H20N2O4 [M + H]+ 245.14, found 245.10. [00436] Step C: Methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine- 2-carboxylate (Int-32C) [00437] To a stirred mixture of methyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2- carboxylate hydrochloride (3 g, 12.28 mmol) (Int-32B) in DMF (30 mL) were added 1H- imidazole-1-sulfonyl azide hydrochloride (3.09 g, 14.74 mmol) and aqueous potassium bicarbonate (3 M, 20.47 mL, 61.4 mmol) at room temperature. The resulting mixture was stirred for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched by water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (220 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give methyl (2S,4R)-1-((S)-2-azido-3- methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (1.45 g, 5.36 mmol, 43.7% yield) (Int-32C) as a white solid. MS ESI calculated for C16H28N2O6 [M + H]+ 271.13 found 271.05.1H NMR: (300 MHz, DMSO-d6) δ 5.24 (s, 1H), 4.46 - 4.27 (m, 2H), 3.81 (d, J = 8.1 Hz, 1H), 3.62 (s, 3H), 3.60 - 3.55 (m, 2H), 2.26 - 1.97 (m, 2H), 1.96 - 1.83 (m, 1H), 1.07 - 0.91 (m, 6H). [00438] Step D: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2- carboxylic acid 32D) [00439] To a mixture of methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylate (1.45 g, 5.36 mmol) (Int-32C) in methanol (27 mL) was added LiOH (6.71 mL, 26.8 mmol) at room temperature. The resulting mixture was stirred for 2 h. The reaction mixture was quenched by aq. HCl (1 M, 20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic fractions were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine- 2-carboxylic acid (900 mg, 3.51 mmol, 65.5% yield) (Int-32D) as a white solid. MS ESI calculated for C10H16N4O4 [M + H]+ 257.12, found 257.10.1H NMR: (400 MHz, DMSO- 145021.608066 (2500.PC) d6) δ 5.21 (d, J = 3.6 Hz, 1H), 4.39 - 4.25 (m, 2H), 3.79 (d, J = 8.0 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.34 (s, 1H), 2.21 - 2.02 (m, 2H), 1.95 - 1.84 (m, 1H), 1.06 - 0.92 (m, 6H). [00440] Step E: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-32) [00441] To a stirred mixture of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid (700 mg, 2.73 mmol) (Int-32D) in DMF (8 mL) were added HATU (1428 mg, 3.76 mmol), (R)-2-amino-2-(4-(4-methylthiazol-5- yl)phenyl)ethan-1-ol (800 mg, 3.41 mmol) and DIEA (2.385 mL, 13.66 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (120 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)- 4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (1.1 g, 2.328 mmol, 68.2% yield) (Int-32) as a white solid. MS ESI calculated for C22H28N6O4S [M + H]+ 473.19 found 473.00.1H NMR: (300 MHz, CD3OD) δ 8.88 (s, 1H), 7.57 - 7.28 (m, 4H), 5.02 (t, J = 6.0 Hz, 1H), 4.67 (t, J = 8.4 Hz, 1H), 4.55 - 4.39 (m, 1H), 3.82 (d, J = 6.0 Hz, 2H), 3.76 - 3.64 (m, 3H), 2.48 (s, 3H), 2.31 - 2.13 (m, 2H), 2.03 - 1.88 (m, 1H), 1.19 - 0.91 (m, 6H). [00442] Intermediate 33: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl- 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) 145021.608066 (2500.PC) [00443] Step A: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) [00444] To a stirred mixture of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid (950 mg, 3.71 mmol) in DMF (9.5 mL) were added HATU (1551 mg, 4.08 mmol), (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1- ol (857 mg, 3.71 mmol) and DIEA (2.59 mL, 14.83 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (120 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl- 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (1 g, 2.130 mmol, 57.4% yield) (Int-33) as a white solid. MS ESI calculated for C23H31N7O4 [M + H]+ 470.24, found 470.00.1H NMR: (400 MHz, CD3OD) δ 7.61 - 7.30 (m, 5H), 6.31 (m, 1H), 5.13 - 4.97 (m, 1H), 4.76 - 4.60 (m, 1H), 4.51 - 4.37 (m, 1H), 4.29 - 4.06 (m, 2H), 3.83 (m, 2H), 3.78 - 3.63 (m, 3H), 2.33 - 2.13 (m, 2H), 2.02 - 1.90 (m, 1H), 1.44 - 1.26 (m, 3H), 1.16 - 0.92 (m, 6H). [00445] Intermediate 34: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 34) [00446] Step A: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 34) [00447] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (6.0 g, 11.01 mmol) (Int-27) in MeCN (60 mL) and water (30 mL) was added 1H-imidazole-1- 145021.608066 (2500.PC) sulfonyl azide hydrochloride (2.77 g, 13.22 mmol), copper(II) sulfate pentahydrate (0.275 g, 1.101 mmol) and TEA (4.60 mL, 33.0 mmol) at 25 °C under N2 atmosphere. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was extracted with EtOAc (100 mL * 2). The combined organic layer was dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5% MeOH in DCM gradient @ 30 mL/min) to give (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-34). MS (ESI) [M+H]+: m/z 571.4. [00448] Intermediate 35: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-35) [00449] Step A: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-35) [00450] At 0 °C, to a solution of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((S)-1-(4-(1- ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (50 mg, 0.1 mmol) and 1H-imidazole (29mg, 0.43 mmol) in DCM (1.06 mL) was added TBSCl (48.1 mg, 0.319 mmol) and the resulting mixture was allowed to stir 48 h at 25oC. The reaction mixture was diluted with DCM and washed twice with water and once with brine. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (eluted with Hex/(EtOAc/EtOH 3:1) (0-100%) to give titled product (2S,4R)-1- ((S)-2-azido-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-2-((tert- butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Int-35). ESI-MS m/z calc’d for C35H59N7O4Si2 [M+H]+: 698; found: 698. 145021.608066 (2500.PC) [00451] The compound in the table below was synthesized via a similar route as described in the above synthesis of Int-35 by making the appropriate substitutions. 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. Int. Structure Compound Name ESI-MS m/z (2S,4R)-1-((S)-2-azido-3- methylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N- Calc’d for Int- ((R)-2-((tert- [M+H]+: 36 butyldimethylsilyl)oxy)-1-(4- 701; found: (4-methylthiazol-5- 701 yl)phenyl)ethyl)pyrrolidine- 2-carboxamide [00452] Intermediate 37: Methyl 7-(3-(hydroxymethyl)-3-methylpiperidin-1- yl)heptanoate (Int-37) [00453] Step A: methyl 7-(3-(hydroxymethyl)-3-methylpiperidin-1-yl)heptanoate (Int-37) [00454] To a solution of (3-methylpiperidin-3-yl)methanol hydrochloride (1 g, 6.04 mmol) in MeCN (10 mL) was added K2CO3 (3.34 g, 24.15 mmol) and methyl 7-bromoheptanoate (2.020 g, 9.05 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 h. LCMS showed starting material was consumed and desired MS was formed. The reaction solution was concentrated under reduced pressure to give the crude product. The crude was purified by flash silica gel chromatography (ISCO®; 20 g Agela® Silica Flash Column, Eluent of 0~50% EE (EtOAc/ EtOH= 3:1)/ Pet. ether gradient @ 40 mL/min, dry loaded) to give methyl 7-(3-(hydroxymethyl)-3-methylpiperidin-1-yl)heptanoate (Int-37). MS (ESI) [M+H]+: m/z 272.2. [00455] Intermediate 38: (3-ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-38) 145021.608066 (2500.PC) [00456] Step A: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-38A) [00457] To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (23 g, 135 mmol) in THF (230 mL) was added BH3·DMS (20.27 mL, 203 mmol) (10 M) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 16 h. TLC (SiO2, Pet. ether:EtOAc=2:1) showed the starting material was consumed and a new spot was formed. The reaction mixture was quenched with MeOH (58 mL) at 0 °C. Then the mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 220 g Agela Flash Column, Pet. ether/EtOAc=1/1) to give methyl 3- (hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-38A). 1H NMR (400MHz, CDCl3) δ 3.61 (s, 3H), 3.57 (br s, 2H), 1.93 (s, 6H). [00458] Step B: Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (Int-38B) [00459] A solution of oxalyl chloride (14.79 mL, 175 mmol) in DCM (400 mL) was cooled to -78 °C, and a solution of DMSO (24.81 mL, 350 mmol) in DCM (100 mL) was added dropwise. The mixture was stirred at -78 °C for 15 min. Then a solution of methyl 3- (hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (21g, 134 mmol) (Int-38A) in DCM (80 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min. Then TEA (94 mL, 672 mmol) was added dropwise, and the mixture was stirred at -78 °C for another 30 min. TLC (SiO2, Pet. ether/EtOAc = 1/1) showed the starting material was consumed and a new spot was formed. The mixture was warmed to room temperature, then H2O (100 mL) was added. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (400 mL). The combined organic layer was washed with NaHCO3 (1 M aq.200 mL), and saturated aq. NaCl (200 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to give methyl 3-formylbicyclo[1.1.1]pentane-1- carboxylate (Int-38B). 1H NMR (400 MHz, CDCl3) δ 9.42-9.64 (m, 1H), 3.64 (s, 3H), 2.25 (s, 6H). [00460] Step C: Methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (Int-38C) 145021.608066 (2500.PC) [00461] To a solution of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (17.6 g, 114 mmol) (Int-38B) in MeOH (360 mL) was added K2CO3 (47.3 g, 342 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (32.9 g, 171 mmol) at 25 °C The mixture was stirred at 25 °C for 16 h. TLC (SiO2, Pet. ether/EtOAc = 1/1) showed the starting material was consumed and a new spot was formed. The solvent was evaporated under reduced pressure, and the residue was diluted with water (30 mL), and then extracted with EtOAc (3 * 500 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~10% EtOAc/Pet. ether gradient @ 60 mL/min) to give methyl 3-ethynylbicyclo[1.1.1]pentane-1- carboxylate (Int-38C). 1H NMR (400 MHz, CDCl3) 3.60 (s, 3H), 2.26 (s, 6H), 1.98 (s, 1H). [00462] Step D: (3-ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-38) [00463] To a solution of methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (7.6 g, 50.6 mmol) (Int-38C) in THF (80 mL) was added LAH (20.24 mL, 50.6 mmol) (2.5 M in THF) at 0 °C, and the mixture was stirred at 0 °C for 1 h. TLC (SiO2, Pet. ether/EtOAc = 5/1) showed the starting material was consumed and a new spot was formed. The reaction mixture was quenched with Na2SO4·10H2O (60 g) and water (8 mL), and the resulting mixture was diluted with EtOAc (500 mL). Then the mixture was filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc/Pet. ether gradient @ 60 mL/min) to give (3- ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-38). 1H NMR (400 MHz, CDCl3) δ 3.61 (br d, J=4.65 Hz, 2H), 2.14 (s, 1H), 2.04 (s, 6H). [00464] Intermediate 39: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2-(4-(3-((3- (hydroxymethyl)-3-methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-39) 145021.608066 (2500.PC) [00465] Step A: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2-(4-(3-((3- (hydroxymethyl)-3-methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-39) [00466] To a solution of (3-(1-((S)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (300 mg, 0.389 mmol) in DMF (5 mL) was added (3-methylpiperidin-3-yl)methanol hydrochloride (97 mg, 0.584 mmol), sodium iodide (58.3 mg, 0.389 mmol) and K2CO3 (269 mg, 1.945 mmol) at 30 °C. The mixture was stirred at 80 °C for 3 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was diluted with water (2 mL), extracted with EtOAc (3 x 20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Agela® Silica Flash Column, Eluent of 40% EtOAc/Pet. ether @ 30 mL/min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2- (4-(3-((3-(hydroxymethyl)-3-methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-39). MS (ESI) [M+H]+: m/z 804.3. Example Syntheses [00467] Example 1: (2S,4R)-1-((2S)-2-(7-((3R and 3S)-3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-(difluoromethyl)-6-methyl-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-1)
145021.608066 (2500.PC) [00468] Step A: Tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. [00469] To a stirred solution of tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (2.00 g, 4.18 mmol), (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-1) (2.00 g, 6.46 mmol), XPhos Pd G4 (360 mg, 0.418 mmol) in dioxane (35 mL) was added K3PO4 (2 M in water, 6.50 mL, 13.0 mmol) and the biphasic mixture was heated to 110 °C overnight, cooled to RT, and then diluted with EtOAc, and quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 0-40% EtOAc/DCM) to give tert-butyl 3-(8- (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2.51 g). ESI-MS m/z calc’d for C35H40F2N7O3S2 [M+H]+: 708; found: 708. 145021.608066 (2500.PC) [00470] Step B: Tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00471] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (363 mg, 0.513 mmol) in DCM (15 mL) was added mCPBA (70 wt%, 266 mg, 1.54 mmol). The resulting mixture was stirred at r.t. for 2 h, at which point a second portion of mCPBA (70 wt%, 266 mg, 1.54 mmol) was added. The resulting mixture was stirred at RT for 2 h, at which point a third portion of mCPBA (70 wt%, 266 mg, 1.54 mmol) was added. The resulting mixture was stirred at r.t. for 1 h, diluted with DCM, and quenched by addition of 1:1 Na2S2O3 (1 N in water)/sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM twice. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step without further purification. ESI m/z calc’d for C35H40F2N7O5S2 [M+H]+: 740; found: 740. [00472] Step C: Tert-Butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(((R and S)-1-(7-methoxy-7-oxoheptyl)-3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00473] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.055 mmol) and methyl 7-(3-(hydroxymethyl)-3-methylpiperidin-1-yl)heptanoate (Int-37) (32.5 mg, 0.120 mmol) in THF (1 mL) at 0 °C was added LiHMDS (1 M in PhMe, 0.22 mL, 0.22 mmol) dropwise. The resulting mixture was stirred for 15 min, quenched by addition of sat. NaHCO3, diluted with EtOAc, and warmed to RT. The organic layer was separated, passed through a phase separator, and concentrated in vacuo to give tert-butyl 3-(8-(5- (difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((R and S)-1- (7-methoxy-7-oxoheptyl)-3-methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step without further purification. ESI m/z calc’d for C49H66F2N8O6S [(M+2H)/2]2+: 466; found: 466. 145021.608066 (2500.PC) [00474] Step D: 7-((3R and 3S)-3-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3- methylpiperidin-1-yl)heptanoic acid [00475] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((R and S)-1-(7-methoxy-7-oxoheptyl)-3- methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate in dioxane (1 mL) was added LiOH (1 N in water, 0.45 mL, 0.45 mmol). The resulting mixture was heated to 50 °C for 15 min, cooled to RT, and quenched by addition of 1 N HCl until pH < 4. The organic layer was separated, and the aqueous layer was extracted with DCM twice. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to give 7-((3R and 3S)-3-(((4-(8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-(difluoromethyl)-6-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanoic acid, which was used directly in the next step without further purification. ESI m/z calc’d for C48H64F2N8O6S [(M+2H)/2]2+: 459; found: 459. [00476] Step E: Tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-((R and S)-(1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol- 5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7- oxoheptyl)-3-methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00477] To a stirred solution of 7-((3R and 3S)-3-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3,2,1]octan-3-yl)-8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3- methylpiperidin-1-yl)heptanoic acid, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (24 mg, 0.055 mmol), PyAOP (29 mg, 0.055 mmol) in DMF (1 mL) was added DIPEA (48 uL, 0.28 mmol). The resulting mixture was stirred at RT overnight and then purified by reverse- phase preparative HPLC (C18, MeCN/water with 0.05% TFA modifier) to give tert-butyl 3- (8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((R and S)-1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)- 3-methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- 145021.608066 (2500.PC) diazabicyclo[3.2.1]octane-8-carboxylate (23.0 mg). ESI-MS m/z calc’d for C70H92F2N12O8S2 [(M+2H)/2]2+: 665; found: 665. [00478] Step F: (2S,4R)-1-((2S)-2-(7-((3R and 3S)-3-(((4-(3,8-Diazabicyclo[3.2.1]octan-3- yl)-8-(5-(difluoromethyl)-6-methyl-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-1) [00479] To a stirred solution of tert-butyl 3-(8-(5-(difluoromethyl)-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((R and S)-1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-7-oxoheptyl)-3-methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3,2,1]octane-8-carboxylate (23 mg, 0.016 mmol) in DCE (2.3 mL) was added TFA (0.30 mL, 3.9 mmol). The resulting mixture was stirred at r.t. for 30 min at which point a second portion of TFA (0.30 mL, 3.9 mmol) was added. The resulting mixture was stirred at RT for 30 min, concentrated in vacuo, and then purified by reverse-phase preparative HPLC (C18, MeCN/water with 0.05% TFA modifier) to give (2S,4R)-1-((2S)-2-(7-((3R and 3S)-3-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- (difluoromethyl)-6-methyl-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (12.3 mg). ESI m/z calc’d for C60H76F2N12O5S2 [(M+2H)/2]2+: 573; found: 573. [00480] Example 2: (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-2)
145021.608066 (2500.PC) [00481] Step A: Tert-butyl (1R,5S)-3-(2-((1-(7-methoxy-7-oxoheptyl)-3-methylpiperidin- 3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00482] To a solution of tert-butyl (1R,5S)-3-(2-(methylsulfinyl)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-16) (100 mg, 0.106 mmol) and methyl 7-(3-(hydroxymethyl)-3- methylpiperidin-1-yl)heptanoate (Int-37) (34.6 mg, 0.127 mmol) in MeCN (1.5 mL) was added 2,2,6,6-tetramethylpiperidine (150 mg, 1.061 mmol) at 25 °C. Then the mixture was stirred at 100 °C for 48 h. (Note: The lid was not tightly closed, MeCN was evaporated in about 30 min). LCMS showed starting material was consumed and the desired MS was found. The organic layer was washed with water (2 mL x 2) and extracted with EtOAc (20 mL x 3), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by preparative TLC (SiO2, DCM:MeOH=15:1) to give tert-butyl (1R,5S)-3-(2-((1-(7-methoxy-7-oxoheptyl)-3- methylpiperidin-3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]+: m/z 575.9. [00483] Step B: 7-(3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2- 145021.608066 (2500.PC) f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin- 1-yl)heptanoic acid [00484] To a solution of tert-butyl (1R,5S)-3-(2-((1-(7-methoxy-7-oxoheptyl)-3- methylpiperidin-3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (74 mg, 0.064 mmol) in THF:MeOH:H2O=1:1:1 (1 mL) was added lithium hydroxide monohydrate (13.50 mg, 0.322 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was concentrated in vacuo and the residue was diluted with EtOAc (3 mL). The reaction mixture was adjusted pH to 5~6 with aq. HCl (1 M in H2O). The organic layer was separated and washed with brine (0.5 mL x 2), dried with Na2SO4, filtered and concentrated in vacuo to give the crude product 7-(3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)heptanoic acid. MS (ESI) [M/2+H]+: m/z 568.8. [00485] Step C: Tert-butyl (1R,5S)-3-(2-((1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-7-oxoheptyl)-3-methylpiperidin-3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00486] To a solution of 7-(3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanoic acid (73.1 mg, 0.064 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (33.3 mg, 0.077 mmol) and PyBOP (50.2 mg, 0.097 mmol) in DMF (1 mL) was added DIEA (0.034 mL, 0.193 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was quenched with water (0.5 mL), and then extracted with EtOAc (10 mL * 2). The combined organic layer was dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The crude was purified by prep-TLC (SiO2, DCM/MeOH=20:1) to give tert-butyl (1R,5S)-3-(2-((1-(7-(((S)-1-((2S,4R)-4-hydroxy-2- 145021.608066 (2500.PC) ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-7-oxoheptyl)-3-methylpiperidin-3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]+: m/z 775.0. [00487] Step D: (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [00488] A mixture of tert-butyl (1R,5S)-3-(2-((1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-7-oxoheptyl)-3-methylpiperidin-3-yl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (120 mg, 0.078 mmol) and TFA (0.3 mL) in DCM (0.9 mL) was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was concentrated in vacuo and the mixture was adjusted to pH 8 with NH3 (7 M in MeOH). The mixture was diluted with water (1 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (0.5 mL x 2), dried with Na2SO4, filtered and concentrated in vacuo to give (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]+: m/z 659.3. [00489] Step E: (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-2) [00490] To a solution of (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (102 mg, 0.077 mmol) in DMF (1 mL) was added CsF (118 mg, 0.774 mmol) at 25 °C under N2 atmosphere. The mixture was stirred at 25 °C for 145021.608066 (2500.PC) 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was diluted with water (1 mL) and extracted with EtOAc (10 mL x 3). The organic layer was dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Column: Boston Green ODS 150 * 30 mm * 5 um; Condition: water (0.2% FA)-MeCN; Begin B-- End B: 22--42; Gradient Time (min): 10; 100% B Hold Time (min): 2; FlowRate (mL/min): 25) to give (2S,4R)-1-((2S)-2-(7-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-2). MS (ESI) [M/2+H]+: m/z 581.5. 1H NMR (400MHz, CD3OD) δ 8.81-8.91 (m, 1H), 8.70 (br d, J=5.5 Hz, 1H), 8.26 (br d, J=4.9 Hz, 1H), 7.84 (br d, J=5.6 Hz, 1H), 7.77-7.82 (m, 2H), 7.40-7.48 (m, 2H), 7.35-7.40 (m, 2H), 4.60 (s, 1H), 4.54-4.57 (m, 1H), 4.49-4.53 (m, 1H), 4.48 (br s, 1H), 4.32- 4.42 (m, 3H), 4.29 (br d, J=10.6 Hz, 1H), 4.24 (br d, J=13.5 Hz, 1H), 3.86-3.91 (m, 1H), 3.78 (br dd, J=10.8, 4.0 Hz, 3H), 3.69 (br d, J=19.3 Hz, 3H), 2.86-2.93 (m, 1H), 2.82 (br d, J=3.0 Hz, 1H), 2.73-2.80 (m, 1H), 2.63 (br d, J=16.9 Hz, 3H), 2.42-2.47 (m, 3H), 2.17-2.22 (m, 3H), 2.03 (br s, 1H), 1.80 (br d, J=15.9 Hz, 6H), 1.55 (br s, 4H), 1.33 (br s, 6H), 1.09- 1.14 (m, 3H), 1.00 (br d, J=3.5 Hz, 9H). [00491] Ex-3 in the table below was synthesized via a similar route as described in the above synthesis of Ex-2 by making the appropriate substitutions. 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. Ex. Structure Name ESI-MS m/z (2S,4R)-1-((2S)-2-(7-(3-(((4- ((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5- calc’d luoromethyl)-1H- [M+ + (trif H] : Ex-3 indazol-4- 1163.4; yl)pyrido[4',3':4,5]thieno[2,3 found: -d]pyrimidin-2- 1163.6 yl)oxy)methyl)-3- methylpiperidin-1- yl)heptanamido)-3,3- 145021.608066 (2500.PC) dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide [00492] Example 4: (2S,4R)-1-((2S)-2-(4-(3-(3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)propyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-4) [00493] Step A: Tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00494] To a solution of tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (341 mg, 0.450 mmol), benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (213 mg, 0.810 mmol) in THF (5624 μl) at r.t. was added NaH (90 mg, 2.250 mmol). The reaction mixture was stirred at the same temperature for 1 h. Upon completion by LCMS, the reaction mixture was quenched with water and extracted with EtOAc (3x, 20.0 mL). The combined organic 145021.608066 (2500.PC) layers were dried over Na 2 SO 4 , filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-70% EtOAc/hexanes) to give tert-butyl (1R,5S)-3- (2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (262 mg) as a colorless oil. MS m/z calc’d for C49H55F3N8O6S [M+H]+: 941; found: 941. [00495] Step B: Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00496] To a solution of tert-butyl (1R,5S)-3-(2-((1-((benzyloxy)carbonyl)-3- methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (262 mg, 0.278 mmol) in DCM (2784 μL) at 0 °C was added TEA (155 μL, 1.114 mmol), triethylsilane (356 μL, 2.227 mmol) followed by palladium(II) chloride (49.4 mg, 0.278 mmol). The reaction mixture was warmed to r.t. and stirred for 30 min. Upon completion by LCMS, water was added and the mixture was extracted with DCM (2x, 10.0 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-50% 3 : 1 EtOAc : EtOH mixture/hexanes) to give tert-butyl (1R,5S)-3- (8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-((3- methylpiperidin-3-yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg) as a colorless oil. MS m/z calc’d for 807; found: 807. [00497] Step C: Tert-butyl (1R,5S)-3-(2-((3-methyl-1-(pent-4-yn-1-yl)piperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00498] Tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (50.0 mg, 0.062 mmol) in acetonitrile (413 μl) was added 5-bromopent-1-yne (18.22 mg, 0.124 mmol) followed by K2CO3 (25.7 mg, 0.186 mmol). The reaction mixture was stirred at 80 °C overnight and allowed to cool to r.t. before being filtered through a pad 145021.608066 (2500.PC) of celite to remove solids. The filtrate was then concentrated under vacuum. The crude residue was purified by silica gel chromatography (0-50% 3 : 1 EtOAc : EtOH/hexanes) to give tert-butyl (1R,5S)-3-(2-((3-methyl-1-(pent-4-yn-1-yl)piperidin-3-yl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (39.0 mg) as a pale-orange oil. MS m/z calc’d for C46H55F3N8O4S [(M+H)/2]+: 437; found: 437. [00499] Step D: Tert-butyl ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl) - dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)propyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl) pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00500] To a solution of tert-butyl (1R,5S)-3-(2-((3-methyl-1-(pent-4-yn-1-yl)piperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (39.0 mg, 0.045 mmol) in DCM (1489 μL) was added (2S,4R)-1-((S)-2-azido- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-31) (28.6 mg, 0.063 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (33.3 mg, 0.089 mmol) and DIPEA (46.8 μL, 0.268 mmol) at r.t. The reaction mixture was stirred at the same temperature overnight before being diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC (Waters XBridge C18, MeCN/H2O with pH 10 NH4OH modifier) and lyophilized to give tert-butyl (1R,5S)-3-(2-((1-(3-(1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4- yl)propyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (15.0 mg) as a white powder. MS m/z calc’d for 1329; found: 1329. [00501] Step E: (2S,4R)-1-((2S)-2-(4-(3-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-4) 145021.608066 (2500.PC) [00502] Tert-butyl (1R,5S)-3-(2-((1-(3-(1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)propyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.0 mg, 0.011 mmol) in DCM (1000 μL) was added TFA (200 μL, 2.60 mmol), and the reaction mixture was stirred at r.t. for 1 h before diluted with 3 : 1 CHCl3 : iPrOH mixture. The mixture was washed with sat aqueous NaHCO 3 . The aqueous layer was extracted with the same CHCl 3 /iPrOH mixture (3x). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC (Waters XBridge C18 column, MeCN/H2O with pH 10 NH4OH modifier) and lyophilized to give (2S,4R)-1-((2S)-2-(4-(3- (3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H- indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)propyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-4) (11.0 mg) as a white powder. MS m/z calc’d for C58H67F3N14O4S2 [(M+H)]+: 1145; found: 1145.1H NMR (500 MHz, CD3OD) δ 8.83 (d, J = 4.6 Hz, 1H), 8.66 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 7.3 Hz, 1H), 7.75 (s, 1H), 7.71 (t, J = 5.9 Hz, 1H), 7.51 (d, J = 6.8 Hz, 2H), 7.48 – 7.42 (m, 1H),7.38 (dd, J = 8.2, 1.8 Hz, 2H), 5.51 (d, J = 1.9 Hz, 1H), 4.65 – 4.57 (m, 2H), 4.56 – 4.46 (m, 2H), 4.41 – 4.31 (m, 3H), 4.16 (s, 1H), 3.96 – 3.90 (m, 1H), 3.85 – 3.79 (m, 1H), 3.74 – 3.64 (m, 3H),3.52 (s, 2H), 2.78 – 2.67 (m, 6H), 2.57 (s, 1H), 2.45 (dd, J = 12.8, 3.5 Hz, 3H), 2.26 (dd, J = 13.3, 7.7 Hz, 3H), 2.17 – 2.10 (m, 1H), 1.90 (d, J = 14.4 Hz, 1H), 1.81 (s, 2H), 1.71 (s, 5H), 1.63 (s, 1H),1.29 (d, J = 21.1 Hz, 2H), 1.11 (s, 3H), 1.06 (d, J = 6.8 Hz, 9H). [00503] Example 5: (2S,4R)-1-((2S)-2-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)cyclohexane-1-carboxamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-5) 145021.608066 (2500.PC) [00504] Step A: butyl (1R,5S)-3-(2-((1-((4-(methoxycarbonyl)cyclohexyl)methyl)-3- methylpiperidin- -8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00505] In a 5 mL vial, tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22) (7.6 mg, 9.42 μmol) and methyl 4-(bromomethyl)cyclohexane-1- carboxylate (3.54 mg, 0.015 mmol, 1.6 eq.) were dissolved in acetonitrile (1000 μl). To above solution was added K2CO3 (5.21 mg, 0.038 mmol, 4 eq.). The mixture was stirred at 80 °C for 18 h, the solvent was removed. The crude was extracted with DCM (1 mL x 3) and washed with brine (1 mL). The organic layer was dried over MgSO4, filtered and concentrated to give a crude intermediate, tert-butyl (1R,5S)-3-(2-((1-((4- (methoxycarbonyl)cyclohexyl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was directly used in the next step without further purification. ESI-MS m/z calc’d for C50H63F3N8O6S: 961.59, found [M+H]+: 961.6. [00506] Step B: 4-((3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- 145021.608066 (2500.PC) yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)methyl)cyclohexane-1-carboxylic acid [00507] Crude tert-butyl (1R,5S)-3-(2-((1-((4-(methoxycarbonyl)cyclohexyl)methyl)-3- methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate was dissolved in THF/MeOH/1 M NaOH (200 μL/100 μL/100 μL) and stirred at r.t. overnight. The crude was neutralized to pH<4, extracted with DCM (1 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated. The crude 4-((3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)cyclohexane-1-carboxylic acid was used directly in the next step without further purification. ESI-MS m/z calc’d for C49H61F3N8O6S: 947.132, found [M+H]+: 947.6. [00508] Step C: Tert-butyl (1R,5S)-3-(2-((1-((4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)cyclohexyl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00509] In a 20 mL vial, intermediate 4-((3-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)cyclohexane-1-carboxylic acid (12.34 mg, 0.013 mmol) with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (8.52 mg, 0.020 mmol), HATU (10.03 mg, 0.026 mmol) were dissolved in MeCN (1 ml). To above mixture was added DIPEA (18.44 μL, 0.106 mmol). The reaction was stirred at r.t. for 18 h. The crude was purified by RPLC (eluted with 0-100% MeCN/water in 18 min). Fractions containing desired pdt were combined and lyophilized to give, tert-butyl (1R,5S)-3-(2-((1-((4-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)carbamoyl)cyclohexyl)methyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. ESI-MS m/z calc’d for C71H89F3N12O8S2: 1359.684, found [M+H]+: 1359.7. 145021.608066 (2500.PC) [00510] Step D: (2S,4R)-1-((2S)-2-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)cyclohexane-1-carboxamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-5) [00511] Tert-butyl (1R,5S)-3-(2-((1-((4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)cyclohexyl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13.1 mg, 9.72 μmol) was dissolved in DCM/TFA (200 μl/ 200 μl). The reaction was stirred at room temperature for 1 hr. Solvent was removed. The crude was neutralized with Hunig base/DCM (1% 2 ml) and concentrated. The crude was purified under basic condition Gilson (on a 19X100 mm, Waters XBridge C18 column, 5μ particle size, linear gradient 30% MeCN/H2O to 100% MeCN/H2O buffering with pH 10 ammonium hydroxide @ flow rate 20 mL/min over 15 min) and lyophilized to give (2S,4R)-1-((2S)-2-(4-((3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)methyl)cyclohexane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. ESI-MS m/z calc’d for C61H73F3N12O5S2: 1175.449, found [M+H]+: 1175.7.1H NMR (500 MHz, Methanol-d4) δ 8.89 (s, 1H), 8.72 – 8.66 (m, 1H), 7.75 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 – 7.32 (m, 6H), 7.30 (d, J = 6.2 Hz, 1H), 4.63 – 4.51 (m, 7H), 4.38 (d, J = 16.0 Hz, 2H), 3.82 (d, J = 11.1 Hz, 1H), 3.78 – 3.70 (m, 7H), 3.63 – 3.57 (m, 2H), 2.75 (s, 3H), 2.68 (s, 2H), 2.49 (s, 3H), 2.21 (d, J = 15.1 Hz, 1H), 2.11 (s, 1H), 1.41 – 1.29 (m, 12H), 1.03 (d, J = 13.1 Hz, 8H), 0.97 (s, 1H), 0.92 (d, J = 7.4 Hz, 2H), 0.12 (s, 1H). [00512] Ex-6 and Ex 7 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-5 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. 145021.608066 (2500.PC) Ex. Structure Name ESI-MS m/z (2S,4R)-1-((2S)-2-(3-((3- (((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5- (trifluoromethyl)-1H- indazol-4- yl)pyrido[4',3':4,5]thieno[2,3 calc’d -d]pyrimidin-2- [M+Na]+ : Ex-6 yl)oxy)methyl)-3- 1197; found: methylpiperidin-1- 1197.6 yl)methyl)cyclohexane-1- carboxamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide (2S,4R)-1-((2S)-2-(7-(3-(((4- ((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5- (trifluoromethyl)-1H- indazol-4- yl)pyrido[4',3':4,5]thieno[2,3 calc’d -d]pyrimidin-2- [M+H]+ : Ex-7 yl)oxy)methyl)-3- 1136; found: methylazetidin-1- 1136.5 yl)heptanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide [00513] Example 8: (2S,4R)-1-((2S)-2-(4-(4-(3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)butyl)- 145021.608066 (2500.PC) 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-8) [00514] Step A: Tert-butyl (1R,5S)-3-(2-((1-(hex-5-yn-1-yl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00515] In a 5 mL vial, tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22) (7.6 mg, 9.42 μmol) and 6-iodohex-1-yne (3.54 mg, 0.015 mmlol, 1.6 eq) were dissolved in acetonitrile (1000 μl). To above solution was added K2CO3 (5.21 mg, 0.038 mmol, 4 eq). The mixture was stirred at 80 °C for 18 h. The solvent was removed. The crude was extraction with DCM (1 mLx3), wash with brine (1 ml). The organic layer was dried over MgSO4, filtered and concentrated to give a crude intermediate, tert-butyl (1R,5S)-3-(2-((1-(hex-5-yn-1-yl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step without further purification. ESI-MS m/z calc’d for C47H57F3N8O4S: 887.080, found [M + H]+: 887.7. [00516] Step B: Tert-butyl (1R,5S)-3-(2-((1-(4-(1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)butyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00517] In a 20 mL vial, tert-butyl (1R,5S)-3-(2-((1-(hex-5-yn-1-yl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- 145021.608066 (2500.PC) yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (10 mg, 0.011 mmol) and (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-31) (7.72 mg, 0.017 mmol) were dissolved in CH2Cl2 (376 μL). To above solution was added tetrakis(acetonitrile)copper(I) hexafluorophosphate (8.40 mg, 0.023 mmol) and DIPEA (11.81 μL, 0.068 mmol). The reaction was stirred at room temperature for 18 h. The reaction was concentrated and dissolved in DMF (1 ml), purified by RPLC (ISCO C18 Gold column 15 g, eluted with 0-100% MeCN/water with 0.05% TFA). The fractions containing desired product were combined and lyophilized to give tert-butyl (1R,5S)-3-(2-((1-(4-(1- ((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)butyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. ESI-MS m/z calc’d for C69H85F3N14O7S2: 1343.645, found [M/2+H]+:627.7. [00518] Step C: (2S,4R)-1-((2S)-2-(4-(4-(3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)butyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-8) [00519] Tert-butyl (1R,5S)-3-(2-((1-(4-(1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H- 1,2,3-triazol-4-yl)butyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13.1 mg, 9.72 μmol) was dissolved in DCM/TFA (200 μl/ 200 μl). The reaction was stirred at room temperature for 1 hr. Solvent was removed. The crude was neutralized with Hunig base/DCM (1% 2 ml) and concentrated. The crude was purified by HTP under basic condition Gilson (on a 19X100 mm, Waters XBridge C18 column, 5μ particle size, linear gradient 30% MeCN/H2O to 100% MeCN/H2O buffering with pH 10 ammonium hydroxide @ flow rate 20 mL/min over 15 min) and lyophilized to give (2S,4R)-1-((2S)-2-(4-(4-(3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)butyl)- 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide. ESI-MS m/z calc’d for C59H69F3N14O4S2: 1159.410, 145021.608066 (2500.PC) found [M+H]+: 1160.6.1H NMR (500 MHz, Methanol-d4) δ 8.88 (d, J = 3.1 Hz, 1H), 8.68 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 15.8 Hz, 1H), 7.83 – 7.73 (m, 2H), 7.53 – 7.42 (m, 4H), 7.39 – 7.34 (m, 2H), 5.50 (d, J = 4.0 Hz, 1H), 4.62 – 4.51 (m, 3H), 4.40 (d, J = 15.6 Hz, 2H), 3.83 – 3.70 (m, 4H), 3.63 – 3.56 (m, 2H), 2.74 (s, 2H), 2.72 – 2.64 (m, 2H), 2.48 (d, J = 7.7 Hz, 3H), 2.21 (dd, J = 15.0, 7.3 Hz, 1H), 1.78 (s, 2H), 1.40 – 1.29 (m, 9H), 1.10 – 1.00 (m, 9H), 0.92 (t, J = 6.9 Hz, 1H), 0.12 (s, 1H). [00520] Ex-9 to Ex-11 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-8 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. Ex. Structure Name ESI-MS m/z (2S,4R)-1-((2S)-2-(4-(6-(3- (((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5- (trifluoromethyl)-1H-indazol- H N 4- calc’d N yl)pyrido[4',3':4,5]thieno[2,3- [M+Na]+ : Ex-9 N N O O N NH N HN S N O N d]pyrimidin-2-yl)oxy)methyl)- 1160; found: CF N N S N N OH 3-methylpiperidin-1-yl)hexyl)- 1160.6 1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide (2S,4R)-1-((2S)-2-(4-(2-(3- (((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5- calc’d (trifluoromethyl)-1H- + Ex- indazol- [M+H] : 4- 1131.3; 10 yl)pyrido[4',3':4,5]thieno[2,3- found: d]pyrimidin-2-yl)oxy)methyl)- 1131.7 3-methylpiperidin-1-yl)ethyl)- 1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy- 145021.608066 (2500.PC) N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide (2S,4R)-1-((2S)-2-(4-(6-(3- (((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5- (trifluoromethyl)-1H-indazol- calc’d 4- - [ + Ex M+H] : yl)pyrido[4',3':4,5]thieno[2,3- 1159.4; 11 d]pyrimidin-2-yl)oxy)methyl)- found: 3-methylazetidin-1-yl)hexyl)- 1159.7 1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide [00521] Example 12: (2S,4R)-1-((2S)-2-(4-(3-((3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)- 4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3- 1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-12) - - methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- 145021.608066 (2500.PC) (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00523] To a solution of tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (80 mg, 0.106 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2-(4-(3-((3-(hydroxymethyl)-3- methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-39) (102 mg, 0.127 mmol) in THF (3 mL) was added sodium hydride (12.67 mg, 0.528 mmol) (60% in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed the starting material was consumed and the desired MS was found. The reaction mixture was quenched with water (1.0 mL), then extracted with EtOAc (10 mL * 2). The organic layer was dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, DCM/MeOH=10/1) to give tert-butyl (1R,5S)-3-(2-((1-((3-(1-((S)-1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl)-3- methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]+: m/z 1481.7. [00524] Step B: (2S,4R)-1-((2S)-2-(4-(3-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)- 4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3- 1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)- 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-12) [00525] A solution of tert-butyl (1R,5S)-3-(2-((1-((3-(1-((S)-1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl)-3- methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (46 mg, 0.031 mmol) in TFA (0.5 mL) was stirred at 25 °C for 15 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure. Then the crude was basified with aq. NaHCO3 (0.5 mL), and extracted with DCM (5 mL * 2). The combined organic 145021.608066 (2500.PC) layer was dried with Na2SO4, filtered and the solvent was removed under reduced pressure to give crude product, which was purified by pre-HPLC (Column YMC-Actus Triart C18 150 * 30 mm * 5 um Condition water (0.04 % NH3H2O+10 mM NH4HCO3)-MeCN Begin B 80 End B 100 Gradient Time (min) 11100 % B Hold Time 3 Flow Rate (mL/min) 25 Injections 1) to give (2S,4R)-1-((2S)-2-(4-(3-((3-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-12). MS (ESI) [M+H]+: m/z 1183.5. 1H NMR (400MHz, CD3OD) δ 8.71-8.81 (m, 1H), 8.51-8.59 (m, 1H), 7.90-7.93 (m, 1H), 7.61-7.68 (m, 2H), 7.31-7.43 (m, 5H), 5.39 (d, J=10.73 Hz, 1H), 4.17-4.59 (m, 9H), 4.08 (br d, J=11.92 Hz, 1H), 3.82 (dd, J=3.52, 10.91 Hz, 1H), 3.51-3.70 (m, 3H), 3.42 (br s, 2H), 2.62 (br s, 3H), 2.52 (br s, 1H), 2.34-2.39 (m, 4H), 2.26-2.31 (m, 1H), 2.10-2.20 (m, 2H), 1.91-1.98 (m, 7H), 1.60 (br s, 5H), 1.23 (br d, J=10.13 Hz, 2H), 1.14 (br s, 1H), 0.88-0.97 (m, 12H). [00526] Ex-13 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-12 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. Ex. Structure Name ESI-MS m/z (2S,4R)-1-((2S)-2-(4-(3-((3- (((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-6-fluoro-1H- benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3- calc’d Ex- d]pyrimidin-2- [M+H]+ : 13 yl)oxy)methyl)-3- 1193.5; found: methylpiperidin-1- 1193.5 yl)methyl)bicyclo[1.1.1]penta n-1-yl)-1H-1,2,3-triazol-1-yl)- 3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- 145021.608066 (2500.PC) yl)benzyl)pyrrolidine-2- carboxamide diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1- yl)methyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Ex-14) [00528] Step A: Tert-butyl (1R,5S)-3-(2-((1-((1-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)piperidin-4-yl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00529] To a solution of tert-butyl (1R,5S)-3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22) (55 mg, 0.068 mmol) and (2S,4R)-1-((R)-2-(3-(4-formylpiperidin-1- yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (36.7 mg, 0.068 mmol) in DCM (0.5 mL) at room temperature was added sodium triacetoxyborohydride in MeOH (1 M, 0.679 mL, 0.679 mmol) followed by AcOH (0.01 mL) and the mixture was stirred at RT for 3 hrs. The mixture was quenched at room temperature with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic fractions were, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (Isco 4 g, eluting with DCM/MeOH 99:1 to DCM/MeOH 60:40) to give, in order of elution, tert-butyl (1R,5S)-3-(2-((1-((1-(5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol- 145021.608066 (2500.PC) 5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3- yl)piperidin-4-yl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. ESI-MS m/z calc’d for C72H88F3N13O8S2 [(M+H)]+: 1388; found: 1388. [00530] Step B: (2S,4R)-1-((2R)-2-(3-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5-yl)- 3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide (Ex-14) [00531] To a solution of tert-butyl (1R,5S)-3-(2-((1-((1-(5-((R)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)isoxazol-3-yl)piperidin-4-yl)methyl)-3-methylpiperidin-3-yl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (13 mg, 9.39 μmol) in DCM (0.5 ml) at room temperature was added TFA (0.014 ml, 0.188 mmol) and the mixture was stirred at r.t. for 2h. The solution was then diluted with 3:1 CHCl 3 :iPrOH mixture and was washed with saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 /iPrOH mixture (3x). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN/water with 7 ml NH4OH modifier) and lyophilized to give (2S,4R)-1-((2R)-2-(3-(4-((3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-1-yl)methyl)piperidin-1-yl)isoxazol-5-yl)- 3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide (Ex-14).1H NMR (500 MHz, CD3OD) 8.89 (d, 1H), 8.71 (dd, 1H), 7.85 (dd, 1H), 7.75 (s, 1H), 7.5-7.44 (m, 5H), 6.01 (s, 1 H), 5.97 (s, 1 H), 5.06 (d, 1H), 4.53 (t, 1H), 4.32-4.29 (m, 3H), 4.24 (d, 1H), 3.88-3.83 (m, 1H), 3.77-3.69 (m, 2H), 3.66-3.58 (m, 4H), 3.53-3.42 (m, 2H), 2.82-2.57 (m, 6H), 2.51-2.48 (m, 6H), 2.40-2.30 (m, 2H), 2.2-2.11 (m, 4H), 2.01-1.93 (m, 2H), 1.85-1.77 (m, 4H), 1.59-1.52 (m, 4H), 1.32-1.23 (m, 2H), 1.1-1.04 (m, 10H), 0.93-0.84 (m, 6H). ESI-MS m/z calc’d for C62H72F3N13O5S2 [(M+H)]+: 1200; found: 1200. 145021.608066 (2500.PC) [00532] Ex-15 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-14 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. ESI-MS Ex. Structure Name m/z H (2S,4R)-1-((2R)-2-(3-(2-(3-(((4- N ((1R,5S)-3,8- N diazabicyclo[3.2.1]octan-3-yl)- F F N F N 8-(6-methyl-5-(trifluoromethyl)- S N O 1H-indazol-4- calc’d N yl)pyrido[4',3':4,5]thieno[2,3- Ex- N N [M+H]+ : H d]pyrimidin-2-yl)oxy)methyl)-3- 15 O OH 1147; methylpiperidin-1- N O N found: 1147 yl)ethoxy)isoxazol-5-yl)-3- O HN O methylbutanoyl)-4-hydroxy-N- S ((S)-1-(4-(4-methylthiazol-5- N yl)phenyl)ethyl)pyrrolidine-2- carboxamide Assays [00532] HiBiT Potency Data [00533] ASPC-1 KRASG12D-HiBiT protein degradation assay: A frozen vial of ASPC-1 KRASG12D N-terminal HiBiT tagged cell line was thawed and cultured in RPMI1640 media supplemented with 10% heat inactive fetal bovine serum, 2 mM GlutaMax, and 100U/mL Penicillin-Streptomycin for 7 days. Media was changed on day 4. On the day of the assay, cells were washed with 1x PBS and dissociated with 0.25mg/ml Trypsin/EDTA. Cells were resuspended in culture media and 20 μL of cell suspension were plated in 384 W culture plate at 10,000 cells per well. Cells were incubated in 37ºC, 5% CO2 with 95% relative humidity incubator for 16-24 h. Cells were treated with compounds and incubated for an additional 24 h. Equal volume of premixed HiBiT detection reagent containing HiBiT Lytic buffer, 1% of LgBiT Protein and 2% of HiBiT Lytic Substrate was added to the plate. Plates were shaken on a shaker setting 400 rpm for 20 min at room temperature 145021.608066 (2500.PC) with protection from light. Luminescence was read on EnVision® Multilabel Reader. The results of this assay are presented in the table below. Example # KRAS_G12D_HIBIT_24h_EC50 (nM) 1 1381 2 110.4 3 416.5 4 300.2 5 4545 6 1720 7 5820 8 216.8 9 320.4 10 371.6 11 5144 12 3212 13 131.1 14 479.4 15 711.3

Claims

145021.608066 (2500.PC) We claim: 1. A compound of Formula (I) wherein: Rb1 is H, C 1 -C 3 alkyl, cyano, C 1 -C 4 alkylcyano, or fluoro; R b2 is fluoro; M L is selected from the group consisting of: C M is (i) a 5- to 6-membered heterocyclylene containing one heteroatom selected from the group consisting of N, O, and S; (ii) a 3- to 6-membered monocyclic or a 5- to 8-membered bridged bicyclic cycloalkyl; wherein CM is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, and C 1 -C 3 alkoxy; Ld ifs selected from the group consisting of -CH2- and -O-;
145021.608066 (2500.PC) L e is selected from the group consisting of: R5 is H or C 1 -C 3 alkyl; X e , X f , X g , and X h are independently selected from the group consisting of C, C(H), C(R Le ), N, O, and S; wherein at least one of X e , X f , X g , and X h is C, C(H), or C(R Le ); each RLe substituent is independently selected from the group consisting of halo, C1-C3 alkyl, C 1 -C 3 fluoroalkyl, and C 1 -C 3 alkoxy; R1 is C 1 -C 6 alkyl, -CH 2 -C1, C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; wherein C1 is C 3 -C 7 cycloalkyl; R2 is H, C 1 -C 6 alkyl, or -CH 2 OH; each R3 is independently H, fluoro, C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl; X a , X b , X c and X d are independently selected from the group consisting of C(H), C(R 4 ), N, N(R 4 ), S and O; wherein at least one of X a , X b , X c and X d is C(H) or C(R 4 ); X i is C or N; R4 is halo, C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl; W A is S, O, or N(R W1 ); RW1 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 fluorocycloalkyl; Ring A is a saturated 5- to 8-membered N-containing monocyclic heterocyclyl or a saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl, wherein the saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl contains at least one further N atom in addition to the illustrated N atom;
145021.608066 (2500.PC) RA is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C1-C3 alkoxy, C1- C3 alkoxy(C 1 -C 3 )alkyl, halo, C 1 -C 3 fluoroalkyl, hydroxy, C 1 -C 3 hydroxyalkyl, CF 3- C(H)(OH)-, C(H)(F 2 )-C(H)(OH)-, cyano, and C 1 -C 3 cyanoalkyl; Y is (i) a 5- to 6-membered mono- or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (ii) a 12- to 14-membered tricyclic heterocyclyl, where at least 2 of the rings of the 12- to 14-membered tricyclic heterocyclyl are aromatic, the third ring is unsaturated or aromatic, wherein the 12- to 14-membered tricyclic heterocyclyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; or (iii) phenyl or naphthyl; wherein Y is unsubstituted or substituted by 1 to 4 RY substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 3 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, C 2- C 3 acyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 fluoroalkylthio, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino and cyano; or alternatively, 2 RY substituents, together with the carbon atom to which both are attached, form a 3- to 5-membered saturated carbocyclic ring; subscript i is 0, 1, or 2; subscript j is 1, 2, 3, 4, 5, 6, or 7; subscript m is 0, 1, 2, or 3; subscript n is 0, 1, 2, or 3; subscript p is 1, 2, or 3: subscript r is 1, 2, 3, 4, 5, or 6; subscript t is 0 or 1; and subscript u is 0 or 1; or a pharmaceutically acceptable salt thereof. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein .
145021.608066 (2500.PC) 3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein M L is selected from the group consisting of: . 4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein 5. The compound of claim 4 or the pharmaceutically acceptable salt thereof, wherein p is 1 or 3. 6 The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein C M is piperidinyl or cyclohexyl. 7. The compound of claim 6 or the pharmaceutically acceptable salt thereof, wherein M L is selected from the group consisting of:
145021.608066 (2500.PC) 8. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Le . 9. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein W A is S. 10. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Ring A is wherein subscript n is 0, 1, or 2. 11. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is unsubstituted or substituted phenyl, naphthyl, pyridyl, indazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, or isoquinolinyl. 12. The compound of claim 11 or the pharmaceutically acceptable salt thereof, wherein Y is naphthyl or indazolyl, wherein Y is substituted by 1 to 3 RY substituents independently selected from the group consisting of halo, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, C 2 -C 4 alkynyl, and cyano. 13. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:
145021.608066 (2500.PC) 3, or 4. 14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y wherein subscript s is 0, 1, 2, or 3. 15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y wherein subscript s is 0, 1, 2 or 3. 16. The compound of claim 15 or the pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:
145021.608066 (2500.PC) 17. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R1 is tert-butyl or isopropyl. 18. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R2 is H or methyl. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R2 is H. 20. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein 21. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein each R 3 is H. 22. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Example Nos.1-15. 23. A pharmaceutical composition comprising the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
145021.608066 (2500.PC) 24. A pharmaceutical composition comprising the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier. 25. A method of degrading KRAS G12D protein in a cell, comprising administering the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, resulting in degradation of the KRAS G12D protein in the cell. 26. A method of treating cancer comprising administering a therapeutically effective amount of the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment. 27. The method of claim 26, further comprising administering an additional active agent to the subject. 28. The compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, in therapy. 29. The compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, for treating cancer. 30. The compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer. 31. The compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent for treating cancer.
145021.608066 (2500.PC) 32. The compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer. 33. A pharmaceutical composition comprising the compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, for treating cancer. 34. A pharmaceutical composition comprising the compound of any one of claims 1-22 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 1-22, or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for treating cancer.
PCT/US2025/029560 2024-05-15 2025-05-15 Protein degraders of kras g12d mutant Pending WO2025240742A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150246934A1 (en) * 2012-09-12 2015-09-03 Trius Therapeutics Inc. Tricyclic gyrase inhibitors
WO2022148421A1 (en) * 2021-01-08 2022-07-14 Beigene, Ltd. Bridged compounds as kras g12d inhibitor and degrader and the use thereof
WO2022266206A1 (en) * 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023193085A1 (en) * 2022-04-06 2023-10-12 RISEN (SUZHOU) PHARMA TECH Co.,Ltd. Bifunctional compounds and pharmaceutical uses thereof
WO2024103010A1 (en) * 2022-11-11 2024-05-16 Merck Sharp & Dohme Llc Small molecule inhibitors of kras proteins

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150246934A1 (en) * 2012-09-12 2015-09-03 Trius Therapeutics Inc. Tricyclic gyrase inhibitors
WO2022148421A1 (en) * 2021-01-08 2022-07-14 Beigene, Ltd. Bridged compounds as kras g12d inhibitor and degrader and the use thereof
WO2022266206A1 (en) * 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023193085A1 (en) * 2022-04-06 2023-10-12 RISEN (SUZHOU) PHARMA TECH Co.,Ltd. Bifunctional compounds and pharmaceutical uses thereof
WO2024103010A1 (en) * 2022-11-11 2024-05-16 Merck Sharp & Dohme Llc Small molecule inhibitors of kras proteins

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