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WO2025235872A1 - Hétérocycles en tant qu'inhibiteurs d'egfr - Google Patents

Hétérocycles en tant qu'inhibiteurs d'egfr

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Publication number
WO2025235872A1
WO2025235872A1 PCT/US2025/028620 US2025028620W WO2025235872A1 WO 2025235872 A1 WO2025235872 A1 WO 2025235872A1 US 2025028620 W US2025028620 W US 2025028620W WO 2025235872 A1 WO2025235872 A1 WO 2025235872A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/028620
Other languages
English (en)
Inventor
Nicholas BOYLES
Suresh Eknath Kurhade
Shelby ELLERY
Mee Yoo Shelley
Andreas Verras
Jiayi Xu
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Schroedinger Inc
Original Assignee
Schroedinger Inc
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Filing date
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Application filed by Schroedinger Inc filed Critical Schroedinger Inc
Publication of WO2025235872A1 publication Critical patent/WO2025235872A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • EGFR Upon binding of extracellular protein ligands, such as EGF and EGF family members, EGFR undergoes a conformational change, leading to homo or heterodimerization, stimulation of its intrinsic tyrosine kinase activity, autophosphorylation of several tyrosine residues in its intracellular domain, and signal transduction of MAPK/ERK, AKT, and JNK pathways. Ultimately, induction of these pathways can lead to DNA synthesis, cell proliferation, and cell migration (Normano et al., Gene 366(1):2-16 (2006)).
  • extracellular protein ligands such as EGF and EGF family members
  • Osimertinib a third-generation EGFR inhibitor, overcomes T790M-driven resistance while maintaining efficacy against del19 or L858R driver mutations (Mok et al., N Engl J Med 376:629-640 (2017)).
  • osimertinib has several notable characteristics: 1) greater selectivity for mutants over WT EGFR; 2) lower rates and severity of gastrointestinal and dermatological toxicities; and 3) efficacy against brain metastases owing to CNS exposure.
  • First generation EGFR compounds retain activity against the C797S mutation in the absence of T790M and have been combined with osimertinib to treat patients who develop T790M and C797S mutations in trans after sequential treatment with first generation and third generation inhibitors (Arunalananda et al., J Thorac Oncol 12(11):1728-1732 (2017)).
  • first generation EGFR compounds exhibit poor CNS penetrance, enabling the development of CNS metastases, and only achieve modest selectivity over WT EGFR, which limits their tolerability and utility in combination with other agents.
  • Zorifertinib which has activity against mutant EGFR and can penetrate the blood brain barrier, is under evaluation in patients with advanced EGFR mutation positive NSCLC with CNS metastasis.
  • this compound achieves only modest ( ⁇ 10-fold) mutant EGFR selectivity and has demonstrated high rates of gastrointestinal and skin toxicities associated with inhibition of WT EGFR (Yang et al., Oncotarget.7:78985-78993 (2016); Ahn et al., Lancet Respir Med 5(11):891-902 (2017)).
  • brain penetrant compounds that are active against EGFR activating mutations (Del-19 or L858R), spare EGFR WT, and retain activity in the presence of the C797S mutation.
  • a pharmaceutical composition including a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a method of inhibiting mammalian cell proliferation, in vitro or in vivo including contacting a cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of treating cancer in a subject in need of such treatment including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1).
  • EGFR epidermal growth factor receptor
  • ERBB1 epidermal growth factor receptor
  • These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human).
  • This range may be integral or continuous between and including the end values.
  • the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units.
  • the range “from 1 to 3 ⁇ M (micromolar),” which is intended to include 1 ⁇ M, 3 ⁇ M, and everything in between to any number of significant figures (e.g., 1.255 ⁇ M, 2.1 ⁇ M, 2.9999 ⁇ M, etc.).
  • the term “compounds of the invention” refers to the compounds of formula (I), and all of the embodiments thereof (e.g., formulas (I-A), (I-B), etc.), as described herein, and to the compounds identified in Table A.
  • the term “compound,” when referring to the compounds of the invention, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules.
  • the term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules.
  • the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.
  • alkenyl as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms.
  • the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkenyl.”
  • Alkenyl can include any number of carbons, such as C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , and C 20 , and so on up to 20 carbon atoms.
  • Alkenyl groups can have any suitable number of Attorney Docket No.94019-421949 (P30890-WO-PCT) double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
  • Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.
  • alkyl as used herein, alone or in combination, (sometimes abbreviated Alk) refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl may comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.
  • Alkyl can include any number of carbons, such as C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 .
  • C 16 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc.
  • Alkyl groups can be substituted or unsubstituted.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (–CH 2 –). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as –CH 3 , Me, or just a single bond terminating with no end group substitution.
  • alkoxy as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined above.
  • Alkoxy groups may have the general formula: alkyl-O-.
  • alkyl group alkoxy groups can have any suitable number of carbon atoms.
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, and the like.
  • the alkoxy groups can be further optionally substituted as defined herein.
  • halo or “halogen” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and Attorney Docket No.94019-421949 (P30890-WO-PCT) dichloropropyl.
  • Haloalkylene refers to a haloalkyl group attached at two or more positions.
  • cycloalkyl refers to a saturated or partially unsaturated mono- or bicyclic carbon group having 3 to 10 carbon atoms, such as C 3 -C 10 cycloalkyl groups and C 3 -C 6 cycloalkyl groups. Bicyclic cycloalkyl groups include fused, spiro, and bridged ring systems.
  • Non-limiting examples of cycloalkyl groups include phenyl, 2,3-dihydro-1H-indene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and spiro[2.5]octyl.
  • heterocyclyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system, having 3 to 10 ring atoms, that is not aromatic, having at least one heteroatom within the ring selected from N, O and S.
  • Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems.
  • the heterocyclyl group may be denoted as, for example, a “5 to 10-membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom.
  • Heterocyclyl groups can, for example, have 1, 2, 3, or more, heteroatoms.
  • a heterocyclyl group has one or two independently selected heteroatoms.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo- systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
  • the heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen.
  • heterocyclyl groups include, but are not limited to azepanyl, 1,3-dioxolane, 1,4-dioxolanyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, qui
  • aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • exemplary aryls are hydrocarbon ring system radical comprising hydrogen and 6 to 10 carbon atoms and at least one aromatic ring; hydrocarbon ring system radical comprising hydrogen and 9 to 12 carbon atoms and at least one Attorney Docket No.94019-421949 (P30890-WO-PCT) aromatic ring; hydrocarbon ring system radical comprising hydrogen and 12 to 15 carbon atoms and at least one aromatic ring; or hydrocarbon ring system radical comprising hydrogen and 15 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • heteroaryl refers to a 5- to 10-membered mono- or bicyclic group wherein at least one ring in the system is aromatic; and wherein one or more carbon atoms in at least one ring in the system is/are replaced with an heteroatom independently selected from N, O, and S.
  • heteroaryl groups include furanyl, furazanyl, thiofuranyl, benzothiophenyl, phthalazinyl, pyrrolyl, oxazolyl, benzoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, indolyl, indazole, pyrazolyl, benzopyrazolyl, isoxazolyl, benzoisoxazole, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, pteridinyl, quinolinyl, isoquino
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • spirocycle refers to a direct attachment of a ring, including for example a carbocycle, heterocycle, aromatic and heteroaromatic ring, to a single carbon atom of the rest of the molecule, where the carbon at the point of attachment is part of the ring.
  • Spirocyclic moieties include, for example, spirocyclic cycloalkyls (e.g., cyclobutane, cyclopentane, cyclohexane, etc.), spirocyclic dioxane, spirocyclic dioxolane, spirocyclic methylpyrrolidin-2-one, spyrocyclic 3-methyl-4,5-dihydroisoxazole, and spirocyclic tetrahydrofuran.
  • cyano as used herein, alone or in combination, refers to –CN.
  • any one of the positions that is understood to have a hydrogen may also exist or understood to be isotopically enriched.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that Attorney Docket No.94019-421949 (P30890-WO-PCT) atom.
  • Obtaining 100% deuteration at any relevant site of a compound in an amount of milligram or greater can be difficult. Therefore, it is understood that some percentage of hydrogen may still be present, even though a deuterium atom is specifically shown in a chemical structure.
  • a chemical structure contains a “D”
  • the compound represented by the structure is deuterium-enriched at the site represented by “D.”
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least 50.1% incorporation of deuterium).
  • a benzene ring may be optionally exist as –C 6 D 5 , –C 6 DH 4 , –C 6 D 2 H 3 , –C 6 D 3 H 2 , and –C 6 D 4 H.
  • a cyclohexyl group may optionally exist as –C 6 D 11 .
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • optionally substituted means the anteceding group or groups may be substituted or unsubstituted. Groups constituting optional substitution may themselves be optionally substituted. For example, where an alkyl group is embraced by an optional substitution, that alkyl group itself may also be optionally substituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: alkyl, alkenyl, alkynyl, alkanoyl, heteroalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, lower perhaloalkyl, perhaloalkoxy, cycloalkyl, phenyl, aryl, aryloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, alkylcarbonyl, carboxyester, carboxamido, cyano, hydrogen, halogen, hydroxy, amino, alkylamino, arylamino, amido, sulfonamido, thioamido, nitro, thiol, alkylthio, haloalkyl
  • Particular subsets of optional substitution include, without limitation: (1) alkyl, halo, and alkoxy; (2) alkyl and halo; (3) alkyl and alkoxy; (4) alkyl, aryl, and heteroaryl; (5) halo and alkoxy; and (6) hydroxyl, alkyl, halo, alkoxy, and cyano.
  • an optional substitution includes a heteroatom-hydrogen bond (—NH-, SH, OH)
  • further optional substitution of the heteroatom hydrogen is contemplated and includes, without limitation optional substitution with alkyl, acyl, alkoxymethyl, alkoxyethyl, arylsulfonyl, alkyl sulfonyl, arylsulfoximinyl, alkylsulfoximinyl, any of Attorney Docket No.94019-421949 (P30890-WO-PCT) which are further optionally substituted.
  • Optionally substituted may include any of the chemical functional groups defined hereinabove and throughout this disclosure. Two optional substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., –CH 2 CH 3 ), fully substituted (e.g., –CF 2 CF 3 ), monosubstituted (e.g., –CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., –CH 2 CF 3 ).
  • the various optional substitutions need not be the same and any combination of optional substituent groups may be combined.
  • a carbon chain may be substituted with an alkyl group, a halo group, and an alkoxy group. Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed.
  • substituents are qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.” [0042] Asymmetric centers, axial asymmetry (non-interchanging rotamers), or the like may exist in the compounds of the various embodiments disclosed herein. Such chirality may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom or the relevant axis.
  • embodiments encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, d-isomers and l-isomers, and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the various embodiments disclosed herein may exist as geometric isomers.
  • the various embodiments disclosed herein includes all cis, trans, syn, anti,
  • E
  • Z
  • compounds may exist as tautomers, including keto-enol tautomers; all tautomeric isomers are embraced by the embodiments disclosed herein.
  • the compounds of the various embodiments disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, Attorney Docket No.94019-421949 (P30890-WO-PCT) and the like.
  • solvated forms are considered equivalent to the unsolvated forms for the purposes of the various embodiments disclosed herein.
  • Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound of the invention, includes all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes.
  • Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • any reference to a compound of formula (I) in connection with the invention should be understood to include the tautomers, racemates, and stereoisomers (e.g.atropisomers, enantiomers, diastereomers, etc. and mixtures of any of the foregoing) thereof, if any.
  • the invention relates to pharmaceutically acceptable salts, solvates, hydrates, polymorphs, physiologically functional derivatives (e.g. deuterated forms), metabolites, and/or prodrugs of a compound of formula (I).
  • the compounds disclosed herein can exist as pharmaceutically acceptable salts, including acid addition salts.
  • Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.
  • Pharmaceutical Salts Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). It is understood that each of the compounds Attorney Docket No.94019-421949 (P30890-WO-PCT) disclosed herein, and each embodiment of the compounds set forth herein, include pharmaceutically acceptable salts of such compounds.
  • the compounds of the invention include pharmaceutically acceptable salts thereof.
  • the compounds of the invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of the invention and/or for separating enantiomers of compounds of the invention.
  • the compounds of the invention or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
  • compounds of the invention and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compounds of the invention include the compounds of Examples 1-91 and stereoisomers and pharmaceutically acceptable salts and solvates thereof.
  • the compounds of Examples 1-91 are in the free base form.
  • the compounds of Examples 1-91 are in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl
  • basic groups in the compounds of the various embodiments disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Salts can also be formed by coordination of the compounds with an alkali metal or alkaline Attorney Docket No.94019-421949 (P30890-WO-PCT) earth ion.
  • the various embodiments disclosed herein contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • the term “prodrug” refers to a compound that is made active in vivo through chemical reaction in vivo thereby releasing an active compound.
  • Compounds disclosed herein can be modified to exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Additionally, prodrugs can be converted to the active compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the active compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug is a compound which is administered as an ester (the “prodrug”), which is then metabolically hydrolyzed to the carboxylic acid, as the active entity. Additional examples include peptidyl derivatives of a compound.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions that are suitable for use in contact with the tissues of subjects without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • test compounds to act as inhibitors of EGFR may be demonstrated by the biological assays described herein. Values for inhibiting the activity of EGFR are shown in Tables 21 and 22.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
  • cancer is to be understood in a most general sense as a disease characterized by inappropriate cellular proliferation, migration, apoptosis or angiogenesis, preferably by inappropriate cellular proliferation.
  • Inappropriate cell proliferation means cellular proliferation resulting from inappropriate cell growth, from excessive cell division, from cell division at an accelerated rate and/or Attorney Docket No.94019-421949 (P30890-WO-PCT) from inappropriate cell survival.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., but not limited to, humans), including leukemia, lymphomas, carcinomas and sarcomas.
  • the phrase “effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat an EGFR pathway-associated disease or disorder, such as an EGFR-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of a compound of the invention, or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • an EGFR pathway-associated disease or disorder includes proliferative diseases (e.g., cancer or benign neoplasm), inflammatory diseases (e.g., fibrosis), and/or neurodegenerative diseases (e.g. Alzheimer disease).
  • proliferative diseases e.g., cancer or benign neoplasm
  • inflammatory diseases e.g., fibrosis
  • neurodegenerative diseases e.g. Alzheimer disease
  • inflammatory disease refers to a disease caused by, resulting from, or resulting in inflammation.
  • inflammatory disease may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, per
  • An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.
  • the inflammatory disorder is fibrosis, and the fibrosis is idiopathic pulmonary fibrosis, liver cirrhosis, cystic fibrosis, systemic sclerosis, progressive kidney disease, or cardiovascular fibrosis.
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • a therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for inhibition of an EGFR protein or gene.
  • a therapeutically effective amount is an amount sufficient for treating a proliferative disease.
  • the expression “patient” and/or “subject” relates to a human or non-human mammalian patient (e.g., mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and/or primates) suffering from cancer and thus in need of such treatment, preferably the patient is a human person.
  • patient and/or “subject” should be understood to include such cancer patients carrying tumors with wild-type EGF receptor as well as pre-selected cancer patients with tumors harboring activating EGFR mutations. These can be located in the tyrosine kinase domain of the EGF receptor such as for instance the L858R or L861 point mutations in the activation loop (exon 21), or in-frame deletion/insertion mutations in the ELREA sequence (exon 19), or substitutions in G719 situated in the nucleotide binding loop (exon 18).
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the term “inhibit” or “inhibition” in the context of proteins refers to a reduction in the activity of the tyrosine kinase. In some embodiments, the term refers to a reduction of the level of activity of EGFR to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity.
  • the term refers to a reduction of the level of EGFR activity to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of tyrosine kinase activity.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the proliferation of cells.
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • the invention relates to a compound of formula (I): , or a pharmaceutically Ring A is a 5- to 10- Z is N or CR 8 ; R 1 is selected from halo, C1-C3 alkyl, C1-C3 alkoxy, –NH-(C1-C3 alkylene)-(R9), C C R 10 , and –O-(C 1 -C 3 alkylene)-R 11 ; R 2 is phenyl or 5- to 10-membered heteroaryl wherein the phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1-3 substituents each independently selected from: halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy; R 3 is H, C 1 -C 3 alkyl, or –(C 1 -C 3 alkyl, or –(C 1 -C 3 alkyl
  • the compounds of the invention comprise multiple variable groups (e.g., Ring A, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n, m, etc.).
  • variable groups e.g., Ring A, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n, m, etc.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ⁇ C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • the compounds of the invention include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein.
  • Enantiomers are defined as one of a pair of molecular entities which are mirror images of each other and non-superimposable. The absolute configuration of enantiomers are designated R or S based on the Cahn-Ingold-Prelog priority rules.
  • Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers not related as mirror images.
  • Tautomers are defined as two or more compounds that differ by the position of a single hydrogen atom. Typically, compounds that demonstrate tautomerism readily interconvert between the Attorney Docket No.94019-421949 (P30890-WO-PCT) two or more tautomeric forms.
  • tautomerism examples include, but are not limited to, the keto and enol forms of ketone-containing compounds, the amide and imidic acid forms of compounds containing an amide bond, as well as the hydroxypyridine and pyridone forms of compounds containing a hydroxy-substituted pyridine ring.
  • a non-bold, straight bond attached to a stereocenter of a compound such as in , denotes that the configuration of the The compound may have any configuration, or a mixture of configurations, at the stereocenter.
  • any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element.
  • an atom is not specifically designated as a particular isotope in any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.
  • stable when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay.
  • Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).
  • H refers to hydrogen and includes any stable isotope of hydrogen, namely 1 H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.
  • protium As used herein, “ 1 H” refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position with at least the natural abundance concentration of protium. [0075] As used herein, “D,” “d,” and “ 2 H” refer to deuterium. Attorney Docket No.94019-421949 (P30890-WO-PCT) [0076] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the natural abundance isotopic composition of the specified element.
  • the compounds of the invention, and pharmaceutically acceptable salts thereof include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts).
  • isotope-labeled compounds and salts include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P, respectively.
  • the isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments.
  • the isotope-labeled compounds and salts are deuterium ( 2 H)-labeled.
  • Deuterium ( 2 H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non- 2 H-labeled compounds.
  • deuterium ( 2 H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention.
  • the isotope-labeled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the Examples and the related description, replacing a non-isotope-labeled reactant by a readily available isotope-labeled reactant.
  • the deuterium ( 2 H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction.
  • the concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio Attorney Docket No.94019-421949 (P30890-WO-PCT) between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.
  • the isotopic enrichment factor is at least 3500 ( ⁇ 52.5% deuterium incorporation), at least 4000 ( ⁇ 60% deuterium incorporation), at least 4500 ( ⁇ 67.5% deuterium incorporation), at least 5000 ( ⁇ 75% deuterium incorporation), at least 5500 ( ⁇ 82.5% deuterium incorporation), at least 6000 ( ⁇ 90% deuterium incorporation), at least 6333.3 ( ⁇ 95% deuterium incorporation), at least 6466.7 ( ⁇ 97% deuterium incorporation), at least 6600 ( ⁇ 99% deuterium incorporation), or at least 6633.3 ( ⁇ 99.5% deuterium incorporation).
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from furo[3,2-d]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyridinyl, pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, thieno[2,3-d]pyrimidinyl, and thieno[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is furo[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 1H-pyrazolo[3,4-b]pyridine. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrimidinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 1H-pyrrolo[3,2-b]pyridinyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is thieno[2,3-d]pyrimidinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is thieno[3,2-d]pyrimidinyl. [0083] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from halo, C 1 -C 3 alkoxy, –NH-(C1-C3 alkylene)-(R9), C C R 10 , and –O-(C 1 -C 3 alkylene)-R 11 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 Attorney Docket No.94019-421949 (P30890-WO-PCT) is halo.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 3 alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-(C 1 -C 3 alkylene)-(R 9 ). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –O-(C 1 -C 3 alkylene)-R 11 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from F, –OCH 3 , –NHCH 2 -R 9 , C C R10 , and –OCH2-R11.
  • R 1 is selected from F, –OCH 3 , –NHCH 2 -R 9 , C C R10 , and –OCH2-R11.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is F.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NHCH 2 -R 9 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 2 -R 11 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is a 5-membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-(C 1 -C 3 alkylene)-(R 9 ) and R 9 is a 5-membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-(C 1 -C 3 alkylene)-(R 9 ) and R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-(C 1 -C 3 alkylene)-(R 9 ) and R 9 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-CH 2 -(R 9 ) and R 9 is a 5-membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from Attorney Docket No.94019-421949 (P30890-WO-PCT) halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-CH 2 -(R 9 ) and R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-CH 2 -(R 9 ) and R 9 is unsubstituted tetrahydrofuranyl [0087]
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a C 5 cycloalkyl and a 5-membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is C 5 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from cyclopentyl and pyrazolyl, wherein the cyclopentyl or pyrazolyl is optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is cyclopentyl optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is unsubstituted cyclopentyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is pyrazolyl optionally substituted with 1 –CH 3 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is pyrazolyl substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is selected from a C 5 cycloalkyl and a 5-membered heterocyclyl, wherein the cycloalkyl and heteroaryl are optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is C5 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), Attorney Docket No.94019-421949 (P30890-WO-PCT) or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is a 5-membered heterocyclyl, wherein the heteroaryl is optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R 10 is selected from cyclopentyl and pyrazolyl, wherein the cyclopentyl or pyrazolyl is optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is cyclopentyl optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is unsubstituted cyclopentyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is pyrazolyl optionally substituted with 1 –CH 3 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is pyrazolyl substituted with 1 –CH3.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is a 5-membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –O-(C 1 -C 3 alkylene)-R 11 and R 11 is a 5-membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –O-(C 1 -C 3 alkylene)-R 11 and R 11 is tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –O-CH 2 -R 11 and R 11 is a 5-membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –O-CH 2 -R 11 and R 11 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and Attorney Docket No.94019-421949 (P30890-WO-PCT) C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is –O-CH 2 -R 11 and R 11 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from F, , .
  • the invention relates to a , or a salt thereof, wherein .
  • the invention relates to a compound of formula (I), or a salt thereof, wherein R 1 is .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein .
  • the invention relates to a compound of formula (I), acceptable salt thereof, .
  • invention relates to a compound of formula (I), or a N a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring .
  • the invention relates to a compound of formula (I), or a Attorney Docket No.94019-421949 (P30890-WO-PCT) N salt thereof, wherein Ring A .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein .
  • the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein embodiments, the invention relates to a compound of formula (I), or a thereof, wherein Ring A .
  • the invention relates to a compound of Attorney Docket No.94019-421949 (P30890-WO-PCT) formula (I), or a pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein .
  • the invention relates to a or a pharmaceutically acceptable salt thereof, wherein Z is N.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR 8 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR 8 , and R 8 is selected from H and C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR 8 , and R 8 is H.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR 8 , and R 8 is C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR 8 , and R 8 is selected from H and –CH 3 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR 8 , and R 8 is –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from benzothiazolyl, indolyl, phenyl, pyridinyl, and thiophenyl, each of which are optionally substituted with 1-3 substituents each Attorney Docket No.94019-421949 (P30890-WO-PCT) independently selected from: halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from benzothiazolyl, indolyl, phenyl, pyridinyl, and thiophenyl, each of which are optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • R 2 is benzothiazolyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is indolyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is pyridinyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophenyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected , salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I), or acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula Attorney Docket No.94019-421949 (P30890-WO-PCT) (I), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I), or a salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, in other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R 2 is .
  • the invention relates to a compound of formula (I), or a F Cl pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), salt thereof, wherein R 2 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), or a 2 salt thereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R 2 is .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is H or C 1 -C 3 alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1 -C 3 alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is H or –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from H, D, and C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 4 is C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from H, D, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 4 is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 4 is D. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 4 is –CH 3 . [0098] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from H, D, and C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 5 is C 1 -C 3 alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from H, D, and –CH 3 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 5 is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 5 is D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R 5 is –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the carbon atom to which they are attached, form a cyclobutyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 is selected from H, D, and C 1 -C 3 alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 is C 1 -C 3 alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 is selected from H, D, and –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 is D. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 is –CH 3 . [0101] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 5 is selected from H, D, and C 1 -C 3 alkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 5 is C 1 -C 3 alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 5 is selected from H, D, and –CH 3 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 5 is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 5 is D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 5 is –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 2.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 4 and R 5 , together with the carbon atom to which they are attached, form a cyclobutyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 2, each R 4 is H, and each R 5 is H.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, D, –CH 3 , and –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is H. In other embodiments, the invention relates to a compound of formula (I), Attorney Docket No.94019-421949 (P30890-WO-PCT) or a pharmaceutically acceptable salt thereof, wherein R 6 is D. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is –CH 3 . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, D, –CH 3 , and –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is H.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a 5- to 6-membered heterocyclyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a cyclobutyl, cyclopentyl, or tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a cyclobutyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a cyclopentyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a tetrahydrofuranyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl and R 7 is selected from H, D, –CH 3 , and –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they Attorney Docket No.94019-421949 (P30890-WO-PCT) are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl and R 7 is H.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl and R 7 is D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl and R 7 is –CH 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl and R 7 is –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I-A): , or a pharmaceutically acceptable Ring A is a 5- to 10-
  • R 1 is halo,–NH-(C1-C3 alkylene)-(R9), or C C R 10
  • R 2 is phenyl or 5- to 10-membered heteroaryl wherein the phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1-3 substituents each independently selected from: halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy
  • R 3 is H or C 1 -C 3 alkyl
  • R 4 is H, D, or C 1 -C 3 alkyl
  • R 5 is H, D, or C 1 -C 3 alkyl; or R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl
  • R 6 is H, D, C 1 -C 3 alkyl
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 1H-pyrazolo[3,4-b]pyridine, 1H-pyrrolo[3,2-b]pyridinyl, pyridinyl, pyrimidinyl, thieno[2,3-d]pyrimidinyl, and thieno[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is 1H-pyrazolo[3,4-b]pyridine.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is 1H-pyrrolo[3,2-b]pyridinyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrimidinyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is thieno[2,3-d]pyrimidinyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is thieno[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 0.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 1.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from F,–NHCH2-R9, and C C R 10 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is F.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NHCH 2 -R 9 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R1 is C C R10.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 9 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-(C 1 -C 3 alkylene)-(R 9 ) and R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NH-(C 1 -C 3 alkenylene)-R 9 and R 9 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NHCH 2 -R 9 and R 9 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is –NHCH 2 -R 9 and R 9 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from cyclopentyl and pyrazolyl, wherein the cyclopentyl or pyrazolyl is optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 10 is cyclopentyl optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 10 is pyrazolyl optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I-A), or a p harmaceutically acceptable salt thereof, wherein R1 is C C R10 and R10 is selected from cyclopentyl and pyrazolyl, wherein the cyclopentyl or pyrazolyl is optionally substituted with 1 –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt t hereof, wherein R1 is C C R10 and R10 is cyclopentyl optionally substituted with 1 –CH3.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt t hereof, wherein R1 is C C R10 and R10 is pyrazolyl optionally substituted with 1 –CH3.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from , .
  • the invention relates to a compound of formula (I-A), or a salt thereof, wherein R 1 is F.
  • the invention relates to Attorney Docket No.94019-421949 (P30890-WO-PCT) a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 1 is .
  • the invention relates to a compound of formula (I-A), or a acceptable salt thereof, wherein R 1 is .
  • the invention relates to a compound of formula (I-A), or a acceptable salt thereof, wherein R 1 is .
  • the invention relates to a compound of formula (I-A), or a N pharmaceutically acceptable salt thereof, wherein Ring A is selected , .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I-A), or a acceptable salt thereof, wherein Ring A is .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I-A), or salt thereof, wherein Attorney Docket No.94019-421949 (P30890-WO-PCT) other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of acceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein .
  • the invention relates to a compound of formula (I-A), or a acceptable salt thereof, wherein Ring A is .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein embodiments, the invention relates to a compound of formula (I-A), or salt thereof, wherein .
  • R 2 is selected from benzothiazolyl, indolyl, phenyl, pyridinyl, and thiophenyl, each of which are optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is benzothiazolyl Attorney Docket No.94019-421949 (P30890-WO-PCT) optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is indolyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is pyridinyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophenyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-A), or a , , .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-A), or a acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is . In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 . In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 . In other Attorney Docket No.94019-421949 (P30890-WO-PCT) embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, .
  • the invention relates to a compound of formula (I-A), or a salt thereof, wherein F Cl other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-A), or acceptable salt thereof, wherein other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-A), or acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 3 is –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4 is H, D, or –CH 3 .
  • the Attorney Docket No.94019-421949 (P30890-WO-PCT) invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4 is D.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4 is –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, D, or –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 is H. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 is D. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 is –CH 3 . [0123] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the carbon atom to which they are attached, form a cyclobutyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, D, –CH 3 , and –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 6 is D.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 6 is –CH 3 . In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 6 is –CH 2 OCH 3 . [0125] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, D, –CH 3 , and –CH 2 OCH 3 . In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is H.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is D. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 3 . In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl or 5- to 6-membered heterocyclyl.
  • the Attorney Docket No.94019-421949 (P30890-WO-PCT) invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a C 4 -C 6 cycloalkyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a 5- to 6-membered heterocyclyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a cyclobutyl, cyclopentyl, or tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a cyclobutyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a cyclopentyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the carbon atoms to which they are attached, form a tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, D, –CH 3 , and –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is H.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is D.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 3 .
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 2 OCH 3 .
  • the invention relates to a compound of formula (I-B): , or a pharmaceutically acceptable Ring A is a 5- to 10-membered heteroaryl; R 1 is halo, C 1 -C 3 alkoxy, or –O-(C 1 -C 3 alkylene)-R 11 ; R 2 is phenyl or 5- to 10-membered heteroaryl wherein the phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1-3 substituents each independently selected from: halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy; Attorney Docket No.94019-421949 (P30890-WO-PCT) R 4 is H; R 5 is H; or R 4 and R 5 , together with the carbon
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from furo[3,2-d]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridine, pyridinyl, thieno[2,3-d]pyrimidinyl, and thieno[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is furo[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is 1H-pyrazolo[3,4-b]pyridine. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is thieno[2,3-d]pyrimidinyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is thieno[3,2-d]pyrimidinyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 0. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 1. [0131] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is F, –OCH 3 , or –OCH 2 -R 11 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is F. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 3 . In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 2 -R 11 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 11 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 11 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 2 -R 11 and R 11 is tetrahydrofuranyl optionally substituted with 1-3 substituents each independently selected from halo, oxo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 2 -R 11 and R 11 is unsubstituted tetrahydrofuranyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is F, –OCH 3 , or .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is F.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is –OCH 3 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 1 is .
  • the invention relates to a compound of formula (I-B), or a N , salt thereof, wherein Ring A .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt Attorney Docket No.94019-421949 (P30890-WO-PCT) thereof, wherein .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein
  • the invention relates to a compound of formula (I- acceptable salt thereof, wherein Ring A is .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is . In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I-B), or acceptable salt thereof, wherein . embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H and –CH 3 . In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 8 is H.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 8 is –CH 3 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, pyridinyl, and thiophenyl, each of which are optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-B), or a Attorney Docket No.94019-421949 (P30890-WO-PCT) pharmaceutically acceptable salt thereof, wherein R 2 is phenyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2 is pyridinyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophenyl optionally substituted with 1-2 substituents each independently selected from: F, Cl, and –CH 3 .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected , F Cl .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2 .
  • the invention relates to a compound of formula (I-B), or a 2 salt thereof, wherein R is .
  • the invention relates to a compound of formula (I-B), or a F pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I- acceptable salt thereof, wherein R 2 is . In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2 . [0138] In some embodiments, the invention of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is H.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , together with the carbon atom to which they are attached, form a cyclobutyl.
  • the invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound selected from Table A, i.e., the compound in non-salt form.
  • Table A Exemplary Compounds of the Invention.
  • Compound Name 3-phenyl-2-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one - Attorney Docket No.94019-421949 (P30890-WO-PCT)
  • Attorney Docket No.94019-421949 Compound Name 3-(4-chlorophenyl)-2-(thieno[3,2-d]pyrimidin-4-yl)-6,7
  • the invention relates to a compound selected from Table B, i.e., the compound in non-salt form.
  • Table B Additional Compounds of the Invention Compound Name 3-phenyl-2-(pyridin-4-yl)-67-dihydropyrazolo[15-a]pyrazin-4(5H)-one - Attorney Docket No.94019-421949 (P30890-WO-PCT) Compound Name (5aR,8aR)-3-(4-chlorophenyl)-2-(3-fluoropyridin-4-yl)-5,5a,6,7,8,8a-hexahydro-4H-cyclopenta[e]pyrazolo[1,5- - - e - Attorney Docket No.94019-421949 (P30890-WO-PCT) Compound Name 8-(4-chlorophenyl)-7-(3-fluoropyridin-4-yl)-3,
  • the invention relates to a comound selected from Examples 1 to 461, i.e. the compound in non-salt form.
  • the invention relates to a compound selected from Table A, Table B, or Examples 1 to 91, or a pharmaceutically acceptable salt thererof.
  • the invention relates to a compound selected from Table A, Table B, or Examples 1 to 91, i.e. the compound in non-salt form.
  • the invention relates to radiolabeled analogs of the compounds of the invention.
  • the term “radiolabeled analogs of the compounds of the invention” refers to compounds that are identical to the compounds of the invention, as described herein, including all embodiments thereof, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the invention.
  • the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include 3 H, 14 C, 32 P, 35 S, 18 F, 36 Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M.
  • the radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays.
  • assays such as substrate tissue distribution assays.
  • tritium ( 3 H)- and/or carbon-14 ( 14 C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R 4 , R 5 , R 6 , or R 7 is D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least two of R 4 , R 5 , R 6 , or R 7 are D. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least three of R 4 , R 5 , R 6 , or R 7 are D. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each of R 4 , R 5 , R 6 , or R 7 is D. [0150] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is D. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is D. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is D. [0151] In another aspect, the invention relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable Attorney Docket No.94019-421949 (P30890-WO-PCT) carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to methods of inhibiting EGFR and methods of treating or lessening the severity of various diseases and disorders, including various cancers, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the invention.
  • the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention. IV. MODES OF ADMINISTRATION A.
  • compositions which comprise one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients.
  • the carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • a pharmaceutical composition including a compound of of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Attorney Docket No.94019-421949 (P30890-WO-PCT) excipient.
  • compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of the invention, or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • the pharmaceutical compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition including, for example, a compound of the invention and a pharmaceutically acceptable carrier and/or excipient.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophiles for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • a pharmaceutically acceptable carrier including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • Attorney Docket No.94019-421949 (P30890-WO-PCT) [0161]
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol; ( 11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; ( 12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents and published applications cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which Attorney Docket No.94019-421949 (P30890-WO-PCT) produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Formulations of the compounds disclosed herein suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
  • capsules including sprinkle capsules and gelatin capsules
  • cachets pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth)
  • lyophile powder
  • Solid dosage forms for oral administration may include the active ingredient mixed with one or more pharmaceutically acceptable earners, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as.
  • glycerol for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; ( 50) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents.
  • compositions may also include buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), and/or surface- active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions such as dragees, capsules, pills and granules, may be prepared with coatings and shells, such as enteric coatings Attorney Docket No.94019-421949 (P30890-WO-PCT) and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredients) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbon s and volatile unsubstituted hydrocarbons, such as butane and propane.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof) the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • Combination Therapies [0181] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with one or more additional therapeutic agent.
  • the additional therapeutic agent includes an anti-cancer agent.
  • the anti-cancer agent may be a chemotherapeutic, radiation, or surgical removal of the cancer.
  • the multiple therapeutic agents (at least one of which is a compound of the various embodiments disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • the one or more additional therapies or therapeutic agents are independently selected from: secondary EGFR inhibitors (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, and olmutinib), ErbB2/Her2 inhibitors (e.g., afatinib, lapatinib, trastuzumab, and pertuzumab), ALK inhibitors (e.g., crizotinib, alectinib, entrectinib, brigatinib), ROS1 inhibitors (e.g., crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib), MEK inhibitors (e.g., trametinib, cobimetinib, binimetinib, selumetini
  • secondary EGFR inhibitors
  • Epidermal growth factor receptor (EGFR) inhibitors such as osimertinib (AZD9291, merelectinib, TAGRISSO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA®, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITA®, HM61713, BI-1482694), naquotinib (ASP8273), creartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992
  • the additional EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.
  • the invention relates to a method of treating any of the diseases or disorders disclosed herein in a subject, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, Attorney Docket No.94019-421949 (P30890-WO-PCT) pharmaceutically acceptable salt, or pharmaceutical composition.
  • the one or more additional therapeutic agents includes osimertinib (AZD9291, merelectinib, TAGRISSO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA®, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITA®, HM61713, BI-1482694), naquotinib (ASP8273), creartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF
  • the one or more additional therapeutic agent includes osimertinib (AZD9291, merelectinib, TAGRISSO®). In yet other aspects, the one or more additional therapeutic agent includes erlotinib (TARCEVA®). In yet other aspects, the one or more additional therapeutic agent includes gefitinib (IRESSA®). In yet other aspects, the one or more additional therapeutic agent includes cetuximab (ERBITUX®). In yet other aspects, the one or more additional therapeutic agent includes necitumumab (PORTRAZZA®, IMC-11F8). In yet other aspects, the one or more additional therapeutic agent includes neratinib (HKI-272, NERLYNX®).
  • the one or more additional therapeutic agent includes lapatinib (TYKERB®). In yet other aspects, the one or more additional therapeutic agent includes panitumumab (ABX-EGF, VECTIBIX®). In yet other aspects, the one or more additional therapeutic agent includes vandetanib (CAPRELSA®). In yet other aspects, the one or more additional therapeutic agent includes rociletinib (CO-1686). In yet other aspects, the one or more additional therapeutic agent includes olmutinib (OLITA®, HM61713, BI-1482694). In yet other aspects, the one or more additional therapeutic agent includes naquotinib (ASP8273).
  • the one or more additional therapeutic agent includes toartinib (EGF816, NVS-816). In yet other aspects, the one or more additional therapeutic agent includes PF-06747775, icotinib (BPI-2009H). In yet other aspects, the one or more additional Attorney Docket No.94019-421949 (P30890-WO-PCT) therapeutic agent includes afatinib (BIBW 2992, GILOTRIF®). In yet other aspects, the one or more additional therapeutic agent includes dacomitinib (PF-00299804, PF-804, PF-299, PF-299804). In yet other aspects, the one or more additional therapeutic agent includes avitinib (AC0010).
  • the one or more additional therapeutic agent includes AC0010MA EAI045. In yet other aspects, the one or more additional therapeutic agent includes matuzumab (EMD-7200). In yet other aspects, the one or more additional therapeutic agent includes nimotuzumab (h-R3, BIOMAb EGFR®). In yet other aspects, the one or more additional therapeutic agent includes zalutumab. In yet other aspects, the one or more additional therapeutic agent includes MDX447. In yet other aspects, the one or more additional therapeutic agent includes depatuxizumab (humanized mAb 806, ABT-806). In yet other aspects, the one or more additional therapeutic agent includes depatuxizumab mafodotin (ABT-414).
  • the one or more additional therapeutic agent includes ABT-806. In yet other aspects, the one or more additional therapeutic agent includes mAb 806. In yet other aspects, the one or more additional therapeutic agent includes canertinib (CI-1033). In yet other aspects, the one or more additional therapeutic agent includes shikonin. In yet other aspects, the one or more additional therapeutic agent includes one or more shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, ⁇ , ⁇ -dimethylacrylshikonin and acetylalkannin). In yet other aspects, the one or more additional therapeutic agent includes poziotinib (NOV120101, HM781-36B).
  • the one or more additional therapeutic agent includes AV-412. In yet other aspects, the one or more additional therapeutic agent includes ibrutinib. In yet other aspects, the one or more additional therapeutic agent includes WZ4002. In yet other aspects, the one or more additional therapeutic agent includes brigatinib (AP26113, ALUNBRIG®). In yet other aspects, the one or more additional therapeutic agent includes pelitinib (EKB-569). In yet other aspects, the one or more additional therapeutic agent includes tarloxotinib (TH-4000, PR610). In yet other aspects, the one or more additional therapeutic agent includes BPI-15086. In yet other aspects, the one or more additional therapeutic agent includes Hemay022. In yet other aspects, the one or more additional therapeutic agent includes ZN-e4.
  • the one or more additional therapeutic agent includes tesevatinib (KD019, XL647). In yet other aspects, the one or more additional therapeutic agent includes YH25448. In yet other aspects, the one or more additional therapeutic agent includes epitinib (HMPL-813). In yet other aspects, the one or more additional therapeutic agent includes CK-101. In yet other aspects, the one or more additional therapeutic agent includes MM-151. In yet other aspects, the one or more additional therapeutic agent includes AZD3759. In yet other aspects, the one or more additional therapeutic agent includes ZD6474. In yet other aspects, the one or more additional therapeutic agent includes PF-06459988.
  • the one or more additional therapeutic agent includes varlintinib (ASLAN001, ARRY-334543). In yet other aspects, the one or more additional therapeutic agent includes AP32788. In yet other aspects, the one or more Attorney Docket No.94019-421949 (P30890-WO-PCT) additional therapeutic agent includes HLX07. In yet other aspects, the one or more additional therapeutic agent includes D-0316. In yet other aspects, the one or more additional therapeutic agent includes AEE788. In yet other aspects, the one or more additional therapeutic agent includes HS-10296. In yet other aspects, the one or more additional therapeutic agent includes avitinib. In yet other aspects, the one or more additional therapeutic agent includes GW572016.
  • the one or more additional therapeutic agent includes pyrotinib (SHR1258). In yet other aspects, the one or more additional therapeutic agent includes SCT200. In yet other aspects, the one or more additional therapeutic agent includes CPGJ602. In yet other aspects, the one or more additional therapeutic agent includes Sym004. In yet other aspects, the one or more additional therapeutic agent includes MAb-425. In yet other aspects, the one or more additional therapeutic agent includes Modotuximab (TAB-H49). In yet other aspects, the one or more additional therapeutic agent includes futuximab (992 DS). In yet other aspects, the one or more additional therapeutic agent includes zalutumumab. In yet other aspects, the one or more additional therapeutic agent includes KL-140.
  • the one or more additional therapeutic agent includes RO5083945. In yet other aspects, the one or more additional therapeutic agent includes IMGN289. In yet other aspects, the one or more additional therapeutic agent includes JNJ-61186372. In yet other aspects, the one or more additional therapeutic agent includes LY3164530. In yet other aspects, the one or more additional therapeutic agent includes Sym013. In yet other aspects, the one or more additional therapeutic agent includes AMG 595. In yet other aspects, the one or more additional therapeutic agent includes BDTX-189. In yet other aspects, the one or more additional therapeutic agent includes avatinib. In yet other aspects, the one or more additional therapeutic agent includes Disruptin. In yet other aspects, the one or more additional therapeutic agent includes CL-387785.
  • the one or more additional therapeutic agent includes EGFRBi-Armed Autologous T Cells. In yet other aspects, the one or more additional therapeutic agent includes EGFR CAR-T Therapy.
  • Human Epidermal Growth Factor Receptor 2 (HER2 receptor) also known as Neu, ErbB-2, CD340, or p185
  • trastuzumab e.g., TRAZIMERATM, HERCEPTIN®
  • pertuzumab e.g., PERJETA®
  • trastuzumab emtansine T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®
  • neratinib e.g., NERLYNX®
  • dacomitinib e.g., VIZIMPRO®
  • afatinib GILOTRIF®
  • tucatinib e.g
  • the FGFR inhibitor is selected from infigratinib, AZD4547, erdafitinib (JNJ-42756493), nintedanib dovitinib, ponatinib, and TAS120.
  • the ALK inhibitor is selected from alectinib, crizotinib (XALKORI®), ceritinib, AP26113, ASP3026, TSR-011, PF-06463922, X-396, and CEP-37440.
  • the ROS1 inhibitor is selected from crizotinib (XALKORI®), ceritinib, lorlatinib, brigatinib, cabozantinib, and repotrectinib.
  • the mTOR inhibitor is selecte from everolimus, tacrolimus rapamycin, perifosine, and temsirolimus.
  • the Trk inhibitor is selected from larotrectinib, lestaurtinib, and entrectinib.
  • the RET inhibitors is selected from sunitinib (Sutent®), selpercatinib (RETEVMO®), vandetanib (Caprelsa®), motesanib (AMG706), sorafenib, regorafenib, and danusertib.
  • the MET inhibitor is selected from capmatinib, tepotinib, savolitinib, crizotinib, cabozantinib, tivantinib, bozitinib, merestinib, glesatinib, sitravatinib, onartuzumab, and emibetuzumab.
  • the AXL inhibitor is selected from sitravatinib, bemcentinib, dubermatinib, DS-1205, SLC-391, INCB081776, ONO-7475, and BA3011.
  • the Shp2 inhibitor is selected from TNO155, BBP-398, JAB-3068, RMC-4360, and RLY-1971.
  • the RAF inhibitor is a BRAF inhibitor, such as vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), encorafenib (BRAFTOVI®), BMS-908662, sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, and LXH254.
  • BRAF inhibitor such as vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), encorafenib (BRAFTOVI®), BMS-908662, sorafenib, LGX818, PLX3603, RAF265, RO5185426, G
  • the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPA®, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib
  • the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine, API-1, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, GSK2141795, ONC201, tricirbine, A674563, and AT78
  • the MEK inhibitor is selected from trametinib (MEKINIST®), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), and hypothemycin.
  • the ERK inhibitor is selected from FRI-20 (ON-01060), VTX-11e, 25- OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-Oxozeaenol, 5-iodotubercidin, GDC0994, and ONC201.
  • the PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.
  • LYNPARZA® olaparib
  • rucaparib rucaparib
  • niraparib niraparib
  • veliparib BGB-290 (pamiparib)
  • the RAS inhibitor is MRTX849, LY3499446, JNJ-74699157, AMG 510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.
  • the PDK-1 inhibitor is selected from GSK 2334470, JX06, SNS-510, and AR-12.
  • the BET inhibitor is selected from GSK1210151A, GSK525762, OTX-015, TEN-010, CPI-203, CPI-0610, olinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, and MS645.
  • the MCL-1 inhibitor is AZD5991.
  • the Bcl-2 protein family inhibitor is selected from ABT-263, Tetrocarcin A, Antimycin, Gossypol (( ⁇ )BL-193), obatoclax, HA14-1, oblimersen (Genasense®); ( ⁇ )-Gossypol acetic acid (AT-101); ABT-737, and navitoclax.
  • the Bcr/Abl kinase inhibitor is selected from imatinib (Gleevec®), inilotinib, nilotinib (Tasigna®), dasatinib (BMS-345825), bosutinib (SKI-606), ponatinib (AP24534), bafetinib (INNO406), danusertib (PHA-739358), AT9283, saracatinib (AZD0530), and PF-03814735.
  • the checkpoint inhibitor is selected from ipilimumab (YERVOY®), pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), IMP701 (LAG525), CPI-444, MBG453, enoblituzumab, JNJ-61610588, and indoximod. See, e.g., Marin-Acevedo, et. al., J Hematol Oncol.11: 39 (2016).
  • the other immunotherapy is an antibody therapy (e.g., a monoclonal antibody).
  • the antibody therapy is selected from bevacizumab (MvastiTM, Avastin®), trastuzumab (Herceptin®), rituximab (MabTheraTM, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (LartruvoTM), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®
  • the other chemotherapeutic agents are selected from an anthracycline, an alkylating agent, a taxane, a platinum-based agent, eribulin (HALAVEN TM ), a farnesyl transferase inhibitor, a topoisomerase inhibitor, a DNA synthesis inhibitor, and cytotoxic agents.
  • the taxane is selected from paclitaxel, docetaxel, cabazitaxel, abraxane, and taxotere.
  • the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.
  • the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • the farnesyl transferase inhibitor is selected from lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.
  • the topoisomerase inhibitor is a topoisomerase I inhibitor (e.g., irinotecan (Camptosar®), topotecan (Hycamtin®), and 7-Ethyl-10-hydroxycampothecin (SN38)) or a topoisomerase II inhibitor (e.g., etoposide (Toposar®, VePesid®, and Etopophos®), teniposide (VM-26, Vumon®), and tafluposide.
  • a topoisomerase I inhibitor e.g., irinotecan (Camptosar®), topotecan (Hycamtin®), and 7-Ethyl-10-hydroxycampothecin (SN38)
  • a topoisomerase II inhibitor e.g., etoposide (Toposar®, VePesid®, and Etopophos®
  • VM-26 teniposide
  • Vumon®
  • the DNA synthesis inhibitor is selected from capecitabine (Xeloda®), gemcitabine hydrochloride (Gemzar®), nelarabine (Arranon® and Atriance®), and sapacitabine.
  • the alkylating agent is selected from temozolomide (Temodar® and Temodal®), dactinomycin (also known as actinomycin-D, Cosmegen®), melphalan (Alkeran®), altretamine (Hexalen®), carmustine (BiCNU®), bendamustine (Treanda®), busulfan (Busulfex® and Myleran®), lomustine (CeeNU®), chlorambucil (Leukeran®), cyclophosphamide (Cytoxan® and Neosar®), dacarbazine (DTIC-Dome®), altretamine (Hexalen®), ifosfamide (Ifex®), prednumustine, procarbazine (Matulane®), mechlorethamine (Mustargen®), streptozocin (Zanosar®), and thiotepa (Thioplex®).
  • temozolomide Temodar
  • the cytotoxic agent is selected from bleomycin, cytarabine, dacarbazine, methotrexate, mitomycin C, pemetrexed, and vincristine.
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses.
  • a pharmaceutical combination for treating a cancer in a subject in need thereof which includes (a) a compound of the invention, or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of the invention, or pharmaceutically acceptable salt thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition including such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product including such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a subject in need thereof.
  • additional therapeutic agent e.g., any of the exemplary additional therapeutic agents described herein or known in the art
  • the cancer is an EGFR pathway-associated cancer.
  • pharmaceutical combination refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), are both administered to a subject simultaneously in the form of a single composition or dosage.
  • non-fixed combination means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.
  • additional therapeutic agent e.g., chemotherapeutic agent
  • cocktail therapies e.g., the administration of three or more active ingredients.
  • compositions including a compound of the invention or a pharmaceutically acceptable salt can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of the invention or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient.
  • compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient. [0225] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. [0226]
  • the daily dosage of the compound of the invention or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein.
  • compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein.
  • the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein.
  • the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein.
  • Pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose. [0227] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art.
  • the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of Attorney Docket No.94019-421949 (P30890-WO-PCT) the preparation, the condition to be treated, and the advancement of the disease condition.
  • factors associated with the particular subject being treated including subject response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages.
  • the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg.
  • the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg.
  • such administration can be once-daily or twice-daily (BID) administration.
  • BID twice-daily
  • kits useful for example, in the treatment of EGFR pathway-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition including an effective amount of a compound provided herein.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • kits for treating cancer (e.g., an EGFR-associated cancer) in a subject in need of such treatment.
  • the method includes administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • a cancer is an EGFR-associated cancer.
  • a cancer is associated with a dysregulation of an EGFR pathway gene, an EGFR pathway protein, or expression or activity or level of any of the same.
  • Attorney Docket No.94019-421949 (P30890-WO-PCT) [0233]
  • an EGFR pathway-associated cancer e.g., an EGFR-associated cancer
  • a RAS-associated cancer e.g., an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, a NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, a FGFR1-associated cancer, FGFR2-associated cancer, FGFR3-associated cancer, a IGF1 R-associated cancer, a INSR-associated cancer, a ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a
  • the method includes a) detecting a dysregulation of an EGFR pathway gene, an EGFR pathway protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • a subject with cancer e.g., a cancer associated with a dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same
  • administering to the subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof including administering to the subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • EGFR-associated cancer refers to cancers associated with or having a dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same, as described herein).
  • Examples of an EGFR-associated cancer include, but are not limited to cancers of the head and neck, breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and squamous lung cancer), ovaries, gastrointestinal cancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer, glioma, glioblastoma, gynecological carcinomas, and prostate cancer.
  • lung e.g., NSCLC, adenocarcinoma and squamous lung cancer
  • ovaries e.g., gastrointestinal cancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer, glioma, glioblastoma, gynecological carcinomas, and prostate cancer.
  • gastrointestinal cancers gastric, colon, pancreatic
  • renal cell cancer e.g., glioma, glioblastoma, gynecological carcinomas, and prostate cancer.
  • the phrase “dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same” refers to a genetic mutation that results in the expression of a mutation in an EGFR gene that results in the expression of an EGFR protein that includes a deletion of at least one amino acid as compared to a wild type EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with one or more point mutations as compared to a wild type EGFR Attorney Docket No.94019-421949 (P30890-WO-PCT) protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with at least one inserted amino acid as compared to a wild type EGFR protein, a gene duplication that results in an increased level of EGFR protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of EGFR protein
  • the subject has been identified or diagnosed as having an EGFR-associated cancer.
  • a method for treating cancer in a subject in need thereof including: (a) determining that the cancer is associated with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same; and (b) administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • methods for treating an EGFR-associated cancer in a subject in need of such treatment are provided herein.
  • the method includes a) detecting a dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the method includes: (a) detecting an EGFR-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a small molecule or an immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • EGFR is a transmembrane protein tyrosine kinase of the ErbB receptor family.
  • a growth factor ligand e.g., epidermal growth factor (EGF)
  • the receptor can homodimerize with an additional EGFR molecule, or it may heterodimerize with another family member (e.g., ErbB2 (HER2), ErbB3 (HER3), or ErbB4 (HER4)).
  • EGFR inhibitors are capable of decreasing both the mitogen-activated protein kinase (MAPK) and PI3K/AKT protein kinase pathways (Phuchareon et al., Proc Natl Acad Sci USA 112(29):E3855-63 (2015)).
  • the MAPK pathway is involved in the regulation of cell growth, survival, and differentiation, and elevated level of MAPK expression have been detected in a variety of human tumors and may be associated with invasive, metastatic and angiogenic activities of tumor cells.
  • the EGFR pathway-associated cancer is a MAPK-associated cancer, a Pi3K associated cancer and/or an AKT-associated cancer.
  • a method of treating an EGFR pathway-associated disease or disorder in a subject in need of such treatment including administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the EGFR pathway-associated disease or disorder is an EGFR-associated cancer.
  • the EGFR pathway-associated cancer is a MAPK-associated cancer, a Pi3K associated cancer and/or an AKT-associated cancer.
  • the method includes: administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.
  • the subject is determined to have a cancer associated with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a small molecule or an immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of an EGFR gene, an Attorney Docket No.94019-421949 (P30890-WO-PCT) EGFR protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a small molecule or immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy.
  • the subject is a subject suspected of having an EGFR-associated cancer, a subject presenting with one or more symptoms of an EGFR-associated cancer, or a subject having an elevated risk of developing an EGFR-associated cancer.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy.
  • any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. [0247] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • the subject can be a subject whose tumors have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • the subject is suspected of having an EGFR-associated cancer.
  • provided herein are methods for treating an EGFR-associated cancer in a subject in need of such treatment.
  • the method includes a) detecting a dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same includes one or more EGFR protein point mutations/insertions/deletions.
  • the cancer with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the tumor with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • Also provided are methods of treating a subject that include administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same.
  • the method also includes administering to a subject determined to have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the method includes determining that a subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject.
  • the method also includes administering to a subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the cancer is a solid tumor (e.g., solid tumors that are EGFR-associated cancers).
  • solid tumors include, but are not limited to, thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer (e.g., non-small cell lung cancer, small-cell lung carcinoma, bronchial adenoma, and pleuropulmonary blastoma), pancreatic cancer, pancreatic ductal carcinoma, biliary tract cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ), stomach cancer, small intestinal cancer, colon cancer, colorectal cancer, peritoneal cancer, ovarian cancer, uterine cancer, liver cancer, endometrial cancer, prostate cancer (including benign prostatic hyperplasia), testicular cancer, bladder cancer, urinary tract cancer, cervical cancer, head and neck cancer, brain cancer (e.g., glioblastoma, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastom
  • the cancer is thyroid cancer. In other embodiments, the cancer is papillary thyroid carcinoma. In other embodiments, the cancer is medullary thyroid carcinoma. In other embodiments, the cancer is lung cancer. In other embodiments, the cancer is non-small cell lung cancer. In other embodiments, the cancer is EGFR-associated non-small cell lung cancer. In other embodiments, the cancer is EGFR-mutated non-small cell lung cancer. In other embodiments, the cancer is small-cell lung carcinoma. In other embodiments, the cancer is bronchial adenoma. In other embodiments, the cancer is pleuropulmonary blastoma. In other embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is pancreatic ductal carcinoma.
  • the cancer is biliary tract cancer. In other embodiments, the cancer is breast cancer. In other embodiments, the cancer is invasive ductal carcinoma. In other embodiments, the cancer is invasive lobular carcinoma. In other embodiments, the cancer is ductal carcinoma in situ. In other embodiments, the cancer is and lobular carcinoma in situ. In other embodiments, the cancer is stomach cancer. In other embodiments, the cancer is small intestinal cancer. In other embodiments, the cancer is colon cancer. In other embodiments, the cancer is colorectal cancer. In other embodiments, the cancer is peritoneal cancer. In other embodiments, the cancer is ovarian cancer. In other embodiments, the cancer is uterine cancer. In other embodiments, the cancer is liver cancer.
  • the cancer is endometrial cancer. In other embodiments, the cancer is prostate cancer. In other embodiments, the cancer is benign prostatic hyperplasia. In other embodiments, the cancer is testicular cancer. In other embodiments, the cancer is bladder cancer. In other embodiments, the cancer is urinary tract cancer. In other embodiments, the cancer is cervical cancer. In other embodiments, the cancer is head and neck cancer. In other embodiments, the cancer is brain cancer. In other embodiments, the cancer is glioblastoma. In other embodiments, the cancer is brain stem and hypophtalmic glioma. In other embodiments, the cancer is cerebellar and cerebral astrocytoma. In other embodiments, the cancer is medulloblastoma.
  • the cancer is ependymoma. In other embodiments, the cancer is, squamous cell carcinoma. In other embodiments, the cancer is melanoma. [0253] In some embodiments, the invention relates to a method of treating non-small cell lung cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the invention relates to a method of treating EGFR-associated non-small cell lung cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the invention relates to a method of treating EGFR-mutated non-small cell lung cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the invention relates to a method of treating non-small cell lung cancer in a subject, the method including administering to the subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the invention relates to a method of treating EGFR-associated non-small cell lung cancer in a subject, the method including administering to the subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the invention relates to a method of treating EGFR-mutated non-small cell lung cancer in a subject, the method including administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the subject is a human.
  • a method for treating a subject diagnosed with or identified as having an EGFR-associated cancer e.g., any of the exemplary EGFR-associated cancers disclosed herein, including administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the compound of the invention is selected from Examples 1-91, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Dysregulation of an EGFR pathway protein, an EGFR pathway gene, or the expression or activity or level of any (e.g., one or more) of the same can contribute to tumorigenesis.
  • EGFRvIII a specific deletion-mutation in the EGFR gene
  • Activation of EGFR stimulated signaling pathways promote multiple processes that are potentially cancer-promoting, e.g., proliferation, angiogenesis, cell motility and invasion, decreased apoptosis and induction of drug resistance.
  • Increased Attorney Docket No.94019-421949 (P30890-WO-PCT) EGFR expression is frequently linked to advanced disease, metastases and poor prognosis.
  • increased EGFR expression has been shown to correlate with a high metastatic rate, poor tumor differentiation and increased tumor proliferation.
  • Cancers associated with mutations of the EGFR gene and/or protein are often associated with poor prognosis. Lung caner patients harboring EGFR mutations frequently develop progressive cancer while receiving therapy.
  • a secondary EGFR mutation, T790M can render some EGFR inhibitors ineffective.
  • the EGFR T790M mutation is found in approximately 50% of tumors from patients that acquire resistance to gefitinib or erlotinib. This secondary genetic alteration occurs in the “gatekeeper” residue and in an analogous position to other secondary resistance alleles in diseases treated with kinase inhibitors, e.g., T315I in ABL in imatinib resistant chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • the predominant oncogenic EGFR mutations (L858R and ex19del) account for about 90% of EGFR NSCLC.
  • EGFR Exon 20 insertion mutations (Ex20ins) were described to account for 4-10% of all EGFR mutations in patients, the third largest EGFR mutant patient population behind the classic (L858R and ex19del) EGFR mutations.
  • Somatic mutations in lung cancer identified to date include point mutations in which a single amino acid residue is altered in the expressed protein (e.g.
  • the EGFR-associated cancer is linked to an EGFR mutation, including, but not limited to L858R, C797S, E746-A750 deletions, T790M, G719S, G719C, G719A, L861Q, and any combination thereof.
  • the EGFR gene and/or protein has developed a resistance to inhibition with a previous tyrosine kinase inhibitor (e.g., gefitinib, erlotinib and/or lapatinib).
  • a previous tyrosine kinase inhibitor e.g., gefitinib, erlotinib and/or lapatinib.
  • the compounds provided herein are selective EGFR inhibitors.
  • the term “selective EGFR inhibitor” means a compound which selectively inhibits certain mutant EGFR kinases over wild-type EGFR and the kinome. Said another way, a selective EGFR inhibitor has no or low activity against wild-type EGFR and the kinome.
  • a selective EGFR inhibitor’s inhibitory activity against certain mutant EGFR kinases is more potent in terms of IC50 value (i.e., a nanomolar IC 50 value) when compared with its inhibitory activity against wild-type EGFR and many other kinases. Potency can be measured using known biochemical assays.
  • the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting the EGFR pathway (e.g., EGFR, MAPK, and/or AKT or a combination thereof) activity in the brain and/or other CNS structures.
  • CNS central nervous system
  • the compounds provided herein are capable of Attorney Docket No.94019-421949 (P30890-WO-PCT) crossing the blood brain barrier in an effective amount.
  • treatment of a subject with cancer e.g., an EGFR pathway-associated cancer such as an EGFR-associated brain or CNS cancer
  • administration e.g., oral administration
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, the tumors listed in Louis, D.N. et al., Acta Neuropathol 131(6), 803-820 (June 2016)).
  • the brain tumor is a primary brain tumor.
  • the subject has previously been treated with another anticancer agent, e.g., another EGFR pathway inhibitor (e.g., a compound that is not a compound of the invention), or an inhibitor of another tumorgenic pathway gene or protein (e.g., Ras (e.g., KRas, HRas, and/or NRas), ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof).
  • another anticancer agent e.g., another EGFR pathway inhibitor
  • an inhibitor of another tumorgenic pathway gene or protein e.g., Ras (e.
  • the brain tumor is a metastatic brain tumor.
  • assays known in the art.
  • Such assays include BBB models such as the transwell system, the hollow fiber (dynamic in vitro BBB) model, other microfluidic BBB systems, the BBB spheroid platform, and other cell aggregate-based BBB models. See, e.g., Cho et al. Nat Commun. 2017; 8: 15623; Bagchi, et al. Drug Des Devel Ther. 2019; 13: 3591–3605; Gastfriend, et al. Curr Opin Biomed Eng. 2018 Mar; 5: 6–12; and Wang et al.
  • the compounds described herein are fluorescently labeled, and the fluorescent label can be detected using microscopy (e.g., confocal microscopy).
  • microscopy e.g., confocal microscopy
  • the ability of the compound to penetrate the surface barrier of the model can be represented by the fluorescence intensity at a given depth below the surface.
  • the fluorescent label is non-fluorescent until it permeates live cells and is hydrolyzed by intracellular esterases to produce a fluorescent compound that is retained in the cell and can be quantified with a spectrophotometer.
  • Non-limiting examples of fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared IRDye® CW-800 (LICOR #929-71012), far-red IRDye® 650 (LICOR #929-70020), sodium fluorescein (Na-F), lucifer yellow (LY), 5’carboxyfluorescein, and calcein-acetoxymethylester (calcein-AM).
  • the BBB model e.g., the tissue or cell aggregate
  • a compound described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analyses).
  • the ability of a compound described herein to cross Attorney Docket No.94019-421949 (P30890-WO-PCT) the BBB through a transcellular transport system can be demonstrated by assays known in the art. See, e.g., Wang, et al. Drug Deliv. 2019; 26(1): 551–565.
  • assays to determine if compounds can be effluxed by the P-glycoprotein (Pgp) include monolayer efflux assays in which movement of compounds through Pgp is quantified by measuring movement of digoxin, a model Pgp substrate (see, e.g., Doan et al.2002. J Pharmacol Exp Ther. 303(3):1029-1037).
  • Alternative in vivo assays to identify compounds that pass through the blood-brain barriers include phage-based systems (see, e.g., Peng et al.2019. ChemRxiv. Preprint doi.org/10.26434/chemrxiv.8242871.v1).
  • binding of the compounds described herein to brain tissue is quantified.
  • a brain tissue binding assay can be performed using equilibrium dialysis, and the fraction of a compound described herein unbound to brain tissue can be detected using LC-MS/MS (Cyprotex: Brain Tissue Binding Assay www.cyprotex.com/admepk/protein_binding/brain-tissue-binding/).
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., having an EGFR-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having an EGFR-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • an assay used to determine whether the subject has a dysregulation of an EGFR gene, or an EGFR protein, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or Attorney Docket No.94019-421949 (P30890-WO-PCT) antigen-binding fragment thereof.
  • Assays can utilize other detection methods known in the art for detecting dysregulation of an EGFR gene, an EGFR protein, or expression or activity or levels of any of the same.
  • the sample is a biological sample or a biopsy sample (e.g., a paraffin- embedded biopsy sample) from the subject.
  • the subject is a subject suspected of having an EGFR-associated cancer, a subject having one or more symptoms of an EGFR-associated cancer, and/or a subject that has an increased risk of developing an EGFR-associated cancer).
  • Activation of EGFR triggers multiple cascades of signal transduction pathways.
  • EGFR contains at least six autophosphorylation sites that serve as docking nodes for a multitude of intracellular signaling molecules including adapter proteins and other enzymes. Therefore, rather than regulating a single linear pathway, activation of EGFR modulates entire networks of cellular signal transduction cascades. These signals affect both cell cycle progression/proliferation and apoptosis.
  • MAPK mitogen activated protein kinase
  • Akt Akt pathways
  • MAPK pathway EGFR activates the small GTP binding protein Ras to transfer cell growth signals through the Raf-MEK-ERK cascade, culminating in the regulation of transcription factors important for cell cycle progression.
  • the MAPK network involves at least twelve cloned highly conserved, proline-directed serine-threonine kinases which, when activated by cell stresses (e.g., oxidative stress, DNA damage, heat or osmotic shock, ultraviolet irradiation, ischemia-reperfusion), exogenous agents (e.g., anisomycin, Na arsenite, lipopolysaccharide, LPS) or pro-inflammatory cytokines, TNF- ⁇ and IL-1 ⁇ , can phosphorylate and activate other kinases or nuclear proteins such as transcription factors in either the cytoplasm or the nucleus.
  • cell stresses e.g., oxidative stress, DNA damage, heat or osmotic shock, ultraviolet irradiation, ischemia-reperfusion
  • exogenous agents e.g., anisomycin, Na arsenite, lipopolysaccharide, LPS
  • pro-inflammatory cytokines TNF- ⁇ and IL-1 ⁇
  • the activation of the MAPK pathway may play an central role in: (1) production of proinflammatory cytokines such as IL-1 ⁇ , TNF- ⁇ and IL-6; (2) induction of enzymes such as COX-2, which controls connective tissue remodeling in pathological condition; (3) expression of an intracellular enzyme such as iNOS, which regulates oxidation; (4) induction of adherent proteins such as VCAM-1 and many other inflammatory related molecules.
  • the MAPK pathway may play a regulatory role in the proliferation and differentiation of cells of the immune system.
  • Deviation from the strict control of MAPK signaling pathways has been implicated in the development of a variety of diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple types of cancers (Kim et al., Biochim Biophys Acta 1802(4):396-405 (2010)).
  • Another aspect of the present application relates to a method of treating a MAPK-associated disease or disorder in a subject, including administering to a subject identified or diagnosed as having a MAPK-associated disease or disorder an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject.
  • MAPK-associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of a gene in a MAPK pathway, a protein in a MAPK pathway, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a gene in a MAPK pathway, a protein in a MAPK pathway, or the expression or activity or level of any of the same, as described herein).
  • Non-limiting examples of a MAPK-associated diseases or disorders include, for example, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis) as well as hyperproliferativedisorders (e.g., cancer).
  • EGFR can activate PI3K (through homodimers or heterodimers with HER3) to initiate signals through the PDK1-Akt pathway.
  • Akt can positively regulate anti-apoptotic factors within the cell to promote cell survival.
  • Akt can activate the protein kinase mTOR (mammalian target of rapamycin) to promote cell growth and proliferation.
  • mTOR is a major regulator of cell growth and proliferation in response to both growth factors and cellular nutrients.
  • AKT-associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of a gene in a AKT pathway, a protein in a AKT pathway, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a gene in a AKT pathway, a protein in a AKT pathway, or the expression or activity or level of any of the same, as described herein).
  • Non-limiting examples of a AKT-associated diseases or disorders include, for example, AKT-associated diseases or disorders, such as hyperproliferative disorders including lymphomas, melanomas, prostate cancer, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, thyroid cancer, and colorectal cancer; cancer metastasis; as well as inflammatory disorders, including diabetes, and schizophrenia.
  • AKT-associated diseases or disorders such as hyperproliferative disorders including lymphomas, melanomas, prostate cancer, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, thyroid cancer, and colorectal cancer; cancer metastasis; as well as inflammatory disorders, including diabetes, and schizophrenia.
  • the present invention also provides methods for the treatment of disorders associated with aberrant mitogen extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
  • Effective amounts of compounds of the present invention can be used to treat such disorders.
  • Attorney Docket No.94019-421949 P30890-WO-PCT
  • the phrase "aberrant kinase activity" or "aberrant tyrosine kinase activity” includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over- expression of the gene or polypeptide; gene amplification; mutations which produce constitutively-active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.
  • a method for inhibiting EGFR activity in a mammalian cell including contacting the mammalian cell with a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method includes administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject having a mammalian cell having EGFR activity.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is any cancer as described herein.
  • the mammalian cancer cell is an EGFR pathway-associated cancer cell (e.g., an EGFR-associated cancer).
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” an EGFR protein with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having an EGFR protein, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the EGFR protein.
  • Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo.
  • the method includes contacting a mammalian cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • Combination Treatments [0280]
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer.
  • compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as Ras pathway inhibitors, kinase inhibitors, signal transduction inhibitors, and/or monoclonal antibodies.
  • chemotherapeutic agents such as Ras pathway inhibitors, kinase inhibitors, signal transduction inhibitors, and/or monoclonal antibodies.
  • a surgery may be open surgery or minimally invasive surgery.
  • a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered one or more doses of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof for a period of time and under one or more rounds of radiation therapy.
  • the treatment with one or more doses of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • the one or more additional therapies or therapeutic agents are independently selected from those therapeutic agents described supra.
  • the compound of the invention and the one or more additional therapies or therapeutic agents are both administered to a subject simultaneously in the form of a single composition or dosage. Alternatively, the compound of the invention and the one or more additional therapies or therapeutic agents are both administered to a subject sequentially with variable intervening time limits.
  • a method of treating a cancer including administering to a subject in need thereof a pharmaceutical combination for treating cancer which includes (a) a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (b) an additional therapeutic agent, wherein the compound of the invention and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the compound of the invention, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.
  • the compound of the invention, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages.
  • the compound of the invention, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly effective amounts, e.g., in daily or intermittently dosages.
  • the compound of the invention, or pharmaceutically acceptable salt thereof, and the Attorney Docket No.94019-421949 (P30890-WO-PCT) additional therapeutic agent are administered simultaneously as a combined dosage.
  • the cancer is an EGFR pathway-associated cancer (e.g., an EGFR-associated cancer).
  • the method includes administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • Such methods can be used in the treatment of one or more of the cancers described herein. See, e.g., US Publication No. 2013/0029925; International Publication No. WO 2014/083567; and US Patent No.8,568,998.
  • the cancer is an EGFR pathway-associated cancer (e.g., an EGFR- associated cancer).
  • the compound of the invention, or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent, such as those described herein.
  • a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer and/or inhibiting metastasis associated with a particular cancer.
  • metastasis is an art known term and means the formation of an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject, where the additional tumor includes the same or similar cancer cells as the primary tumor.
  • Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having an EGFR-associated cancer that include: selecting, identifying, or diagnosing a subject as having an EGFR-associated cancer, and administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having an EGFR-associated cancer. Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having an EGFR-associated cancer that includes administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject having an EGFR-associated cancer.
  • the decrease in the risk of developing a metastasis or an additional metastasis in a subject having an EGFR-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same EGFR-associated cancer that has received no treatment or a different treatment.
  • the additional therapeutic agent is selected from any of the therapeutic agents identified herein.
  • the subject has been administered one or more doses of a compound of the invention, or a pharmaceutically acceptable salt thereof, prior to administration of the pharmaceutical composition.
  • risk of developing a metastasis means the risk that a subject having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor.
  • additional tumor e.g., a solid tumor
  • the phrase “risk of developing additional metastases” means the risk that a subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors include the same or similar cancer cells as the primary tumor.
  • Methods for reducing the risk of developing additional metastasis are described herein.
  • Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use [0290]
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in inhibiting EGFR.
  • Compounds of the invention, pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions thereof are also useful for treating an EGFR-associated cancer.
  • a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of cancer is also provided herein.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating cancer.
  • the cancer is an EGFR-associated cancer.
  • the cancer is associated with a dysregulation of an EGFR pathway gene, an EGFR pathway protein, or expression or activity or level of any of the same.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating an EGFR pathway-associated cancer.
  • the EGFR pathway-associated cancer is selected from a RAS-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, a NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, a FGFR1-associated cancer, FGFR2-associated cancer, FGFR3-associated cancer, a IGF1 R-associated Attorney Docket No.94019-421949 (P30890-WO-PCT) cancer, a INSR-associated cancer, a ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, a SHP2-associated cancer, a
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating a cancer associated with a dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating an EGFR-associated cancer in a subject.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating an EGFR pathway-associated disease or disorder in a subject.
  • the EGFR pathway-associated disease or disorder is an EGFR-associated cancer.
  • the EGFR pathway-associated cancer is a MAPK-associated cancer, a Pi3K associated cancer and/or an AKT-associated cancer.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating cancer in a subject, wherein the subject is determined to have a cancer associated with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have an EGFR-associated cancer through the use of a regulatory agency-approved test or assay for identifying dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • a compound of the invention for use in treating an EGFR-associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, Attorney Docket No.94019-421949 (P30890-WO-PCT) where the presence of a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, identifies that the subject has an EGFR-associated cancer.
  • an assay e.g., an in vitro assay
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating a subject diagnosed with or identified as having an EGFR-associated cancer.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating non-small cell lung cancer in a subject in need thereof.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating EGFR-associated non-small cell lung cancer in a subject in need thereof.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating EGFR-mutated non-small cell lung cancer in a subject in need thereof.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating non-small cell lung cancer in a subject.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating EGFR-associated non-small cell lung cancer in a subject.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating EGFR-mutated non-small cell lung cancer in a subject.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating one or more gliomas.
  • the one or more gliomas is selected from glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas.
  • the brain tumor is a primary brain tumor.
  • the subject has previously been treated with another anticancer agent, e.g., another EGFR pathway inhibitor (e.g., a compound that is not a compound of the invention), or an inhibitor of another tumorgenic pathway gene or protein (e.g., Ras (e.g., KRas, HRas, and/or NRas), ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof).
  • another anticancer agent e.g., another EGFR pathway inhibitor
  • an inhibitor of another tumorgenic pathway gene or protein e.g., Ras (e.
  • the brain tumor is a metastatic brain tumor.
  • Attorney Docket No.94019-421949 P30890-WO-PCT
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating a MAPK-associated disease or disorder in a subject.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating an AKT-associated disease or disorder in a subject.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating disorders associated with aberrant mitogen extracellular kinase activity.
  • the disorder is selected from stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in inhibiting mammalian cell proliferation, in vitro or in vivo.
  • the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition.
  • the additional therapeutic agent is selected from the agents described herein.
  • Manufacture of Medicaments provides the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting EGFR.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating cancer.
  • the cancer is an EGFR-associated cancer.
  • the cancer is associated with a dysregulation of an EGFR pathway gene, an EGFR pathway protein, or expression or activity or level of any of the same.
  • Attorney Docket No.94019-421949 (P30890-WO-PCT) [0312]
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating an EGFR pathway-associated cancer.
  • the EGFR pathway-associated cancer is selected from a RAS-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, a NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, a FGFR1-associated cancer, FGFR2-associated cancer, FGFR3-associated cancer, a IGF1 R-associated cancer, a INSR-associated cancer, a ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, a SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a cancer associated with a dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating an EGFR-associated cancer in a subject.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating an EGFR pathway-associated disease or disorder in a subject.
  • the EGFR pathway-associated disease or disorder is an EGFR-associated cancer.
  • the EGFR pathway-associated cancer is a MAPK-associated cancer, a Pi3K associated cancer and/or an AKT-associated cancer.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating cancer in a subject, wherein the subject is determined to have a cancer associated with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same.
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have an EGFR-associated cancer through the use of a regulatory agency- approved test or assay for identifying dysregulation of an EGFR gene, an EGFR protein, or expression or Attorney Docket No.94019-421949 (P30890-WO-PCT) activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating an EGFR-associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, where the presence of a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, identifies that the subject has an EGFR-associated cancer.
  • an assay e.g., an in vitro assay
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a subject diagnosed with or identified as having an EGFR-associated cancer.
  • the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating non-small cell lung cancer in a subject in need thereof.
  • the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating EGFR-associated non-small cell lung cancer in a subject in need thereof.
  • the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating EGFR-mutated non-small cell lung cancer in a subject in need thereof.
  • the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating non-small cell lung cancer in a subject.
  • the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating EGFR-associated non-small cell lung cancer in a subject.
  • the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating EGFR-mutated non-small cell lung cancer in a subject.
  • Attorney Docket No.94019-421949 P30890-WO-PCT
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating one or more gliomas.
  • the one or more gliomas is selected from glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas.
  • the brain tumor is a primary brain tumor.
  • the subject has previously been treated with another anticancer agent, e.g., another EGFR pathway inhibitor (e.g., a compound that is not a compound of the invention), or an inhibitor of another tumorgenic pathway gene or protein (e.g., Ras (e.g., KRas, HRas, and/or NRas), ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof).
  • another anticancer agent e.g., another EGFR pathway inhibitor
  • an inhibitor of another tumorgenic pathway gene or protein e.g., Ras (e.
  • the brain tumor is a metastatic brain tumor.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a MAPK-associated disease or disorder in a subject.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating an AKT-associated disease or disorder in a subject.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating disorders associated with aberrant mitogen extracellular kinase activity.
  • the disorder is selected from stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting mammalian cell proliferation, in vitro or in vivo.
  • a compound of the invention for the manufacture of a medicament for treating an EGFR-associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same where the presence of dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same, identifies that the subject has an EGFR-associated cancer.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • the additional therapeutic agent is selected from the agents described herein.
  • the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups.
  • Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006).
  • the compounds of the invention can be prepared by one or more of the processes outlined in General Synthetic Schemes 1-3, below.
  • the reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the Attorney Docket No.94019-421949 (P30890-WO-PCT) temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley- Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Step-2 ethyl 3-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1-3) [0340] Hydrazine hydrate (2.3 mL) was added dropwise to an ice-cold solution of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate (1-2) (3 g) in AcOH (10 mL) and stirred at RT for 16 h. The reaction mixture was diluted with ice-cold water, neutralized with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the title compound (1-3) which was used as such in the next step without further purification.
  • Step-3 ethyl 4-bromo-3-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1-4) [0341] A solution of ethyl 3-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1-3) (2.8 g) in DCM was treated with NBS (2.5 g) at RT. The reaction mixture was stirred at RT for 16 h, evaporated, triturated with diethyl ether, and filtered to afford the title compound (1-4).
  • Step-4 ethyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(pyridin-4-yl)-1H-pyrazole-5- carboxylate (1-5) [0342] To a mixture of ethyl 4-bromo-3-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (1-4) (2.8 g) and tert-butyl (2-hydroxyethyl) carbamate (2.3 g) in THF (40 mL) were added PPh 3 (3.72 g) and DIAD (2.5 g) at RT.
  • Step-5 3-bromo-2-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Int-1) [0343] An ice cold solution of ethyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(pyridin-4- yl)-1H-pyrazole-5-carboxylate (1-5) (3.5 g) in DCM was treated with TFA (10 mL). The reaction mixture was stirred at RT for 24 h and concentrated under reduced pressure, diluted with DCM and neutralized with saturated aqueous NaHCO 3 solution.
  • Step-3 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (4-4)
  • the RM was stirred at RT for 3 h then evaporated Attorney Docket No.94019-421949 (P30890-WO-PCT) diluted with ice-water. The precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (4-4) which was used in the next step without further purification and characterization.
  • Step-4 2-(3-fluoropyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (4-5)
  • Step-5 3-bromo-2-(3-fluoro-4-pyridyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one one (Int-4) [0350] To a stirred solution of 2-(3-fluoropyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (4-5) (1 g) in AcOH (30 mL) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (1.8 g) at RT.
  • Step-2 3-(5-chlorothiophen-2-yl)-2-(3-fluoropyridin-4-yl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (Int-9) [0354] A mixture of (9-1) (2.1 g), (5-chloro-2-thienyl)boronic acid (1.6 g) and K 3 PO 4 (3.1 g) in 1,4- dioxane:water (4:1 ratio) was purged with argon for 10 min and treated with X-phosPd G 2 (383 mg) at RT.
  • Step-2 2-bromo-3-iodo-5-(4-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Int-10) [0356] NaH (60–65% suspension in oil) (96 mg) was treated with an ice-cold solution of 2-bromo-3- iodo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (10-1) (0.55 g) in DMF and stirred for 30 min, then treated with 4-methoxybenzyl chloride (0.38 g) in DMF.
  • Step-2 (3-(cyclopentylethynyl)pyridin-4-yl)boronic acid (Int-12) [0359] A mixture of 4-bromo-3-(cyclopentylethynyl)pyridine (12-2) (0.37 g) and bis(pinacolato)diboron (563 mg) in 1,4-dioxane were added Pd 2 (dba) 3 .CHCl 3 (153 mg) and KOAc (436 mg) at RT. The RM was purged with argon for 10 min, sealed and heated at 80°C for 2 h, cooled to RT, diluted with water, and extracted using EtOAc.
  • Step-2 methyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-chloro-1H-pyrrole-2-carboxylate (14-3) [0362] A mixture of methyl 4-bromo-3-chloro-1H-pyrrole-2-carboxylate (14-2) (45 g), tert-butyl (2- hydroxyethyl) carbamate (45.6 g) and PPh 3 (99 g) in THF was treated with DIAD (76 g) at RT.
  • Step-3 ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-chloro-4-(pyridin-4-yl)-1H-pyrrole-2-carboxylate (14-4)
  • a mixture of stirred solution of methyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-3- chloro-1H-pyrrole-2-carboxylate (14-3) 5 g
  • pyridin-4-ylboronic acid 2.4 g
  • Na 2 CO 3 4.16 g
  • 1,4-dioxane:water (4:1 ratio was purged under a stream of argon for 10 min after which tetrakis (0.7 g) was added.
  • Step-4 8-chloro-7-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Int-14) [0364]
  • An ice-cold solution of (14-4) (22 g) in DCM was treated with TFA (100 mL).
  • the RM stirred at RT for 24 h, evaporated, diluted with saturated aqueous NaHCO 3 solution, and extracted with DCM.
  • the combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the residue (15 g) was diluted with MeOH, treated with CS 2 CO 3 (8.7 g), and stirred for 24 h at RT.
  • Step-2 methyl 3-bromo-1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-4-iodo-1H-pyrrole-2- carboxylate (15-3)
  • NIS 2.9 g
  • the RM was stirred at RT for 32 h, diluted with water, and extracted using EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the RM was stirred at RT for 4 h, evaporated, diluted with saturated aqueous NaHCO 3 solution, and extracted with DCM. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue (3.2 g, crude) was taken up in MeOH and treated with Cs 2 CO 3 (1.26 g) at RT. The RM was stirred for 16 h, concentrated, and residue was purified by column chromatography on silica gel (5% methanol in DCM) to afford the title compound (15-4).
  • Step-5 8'-bromo-2'-(4-methoxybenzyl)-7'-(pyridin-4-yl)-4'H-spiro[cyclobutane-1,3'-pyrrolo[1,2- a]pyrazin]-1'(2'H)-one (Int-15) [0369] A solution of 8-bromo-7-iodo-2-[(4-methoxyphenyl)methyl]spiro[4H-pyrrolo[1,2-a]pyrazine- 3,1'-cyclobutane]-1-one (15-5) (2 g) and pyridin-4-ylboronic acid (0.73 g) were combined in 1,4-dioxane in a sealed tube and treated with K 2 CO 3 (1.6 g) in water.
  • the RM was purged under a stream of argon for 10 min, and Pd(dppf)Cl 2 .DCM (0.32 g) was added. The tube was sealed and the mixture stirred at 70 °C for 24 h. The RM was cooled to RT, and the mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 , evaporated, and the residue was purified by column chromatography on silica gel (2% methanol in DCM) to obtain the title compound (Int-15).
  • Step-2 methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-iodo-1H-pyrrole-2-carboxylate (16-2) [0371] NIS (0.65 g) was added to a stirred solution of methyl 3-bromo-1-(2-((tert- butoxycarbonyl)amino)ethyl)-1H-pyrrole-2-carboxylate (16-1) (1 g) in DMF at RT. The RM was stirred 16 h, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step-3 methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(3-methoxypyridin-4-yl)-1H-pyrrole- 2-carboxylate (16-3) [0372] To a stirred solution of methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-iodo-1H- pyrrole-2-carboxylate (16-2) (5 g) in 1,4-dioxane:water (4:1 ratio) were added (3-methoxy-4- pyridyl)boronic acid (1.6 g) and Na 2 CO 3 (3.4 g).
  • the RM was purged under a stream of argon for 10 min before Pd(dppf)Cl 2 .DCM (0.86 g) was added and the RM was heated at 110 °C for 24 h.
  • the RM was Attorney Docket No.94019-421949 (P30890-WO-PCT) cooled to RT, diluted with water and extracted using EtOAc. The combined organic layer was dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1% methanol in DCM) to afford the title compound (16-3).
  • Step-4 methyl 1-(2-aminoethyl)-3-bromo-4-(3-methoxypyridin-4-yl)-1H-pyrrole-2-carboxylate (16-4) [0373] An ice-cold solution of 3-bromo-1-[2-(tert-butoxycarbonylamino)ethyl]-4-(3-methoxy-4- pyridyl)pyrrole-2-carboxylate (2.5 g) (16-3) in DCM was treated with TFA (10 ml).
  • the RM was stirred at RT for 6 h, concentrated, neutralized with saturated aqueous NaHCO 3 solution, and extracted using DCM. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the title compound (16-4) which was used in the next step without further purification and characterization.
  • Step-5 8-bromo-7-(3-methoxypyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (16-5) [0374] To a stirred solution of methyl 1-(2-aminoethyl)-3-bromo-4-(3-methoxypyridin-4-yl)-1H- pyrrole-2-carboxylate (16-4) (1.9 g) in methanol was added Cs 2 CO 3 (1.7 g). The RM was stirred at RT for 6 h, concentrated, diluted with water, and extracted using DCM. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-6 8-bromo-2-(4-methoxybenzyl)-7-(3-methoxypyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin- 1(2H)-one (Int-16) [0375] NaH (60-65% suspension in oil) (90 mg) was added to an ice-cold solution of 8-bromo-7-(3- methoxypyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (16-5) (1.3 g) in DMF and the RM was stirred for another 20 min before the addition of 4-methoxybenzyl chloride (0.95 g).
  • Step-2 7-bromo-8-chloro-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (18-2) [0378] To a stirred solution of methyl 1-(2-aminoethyl)-4-bromo-3-chloro-1H-pyrrole-2-carboxylate (18-1) (15 g) in MeOH was added Cs 2 CO 3 (8.6 g) at RT.
  • Step-3 7-bromo-8-chloro-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (18-3)
  • NaH 60% in mineral oil
  • 2.2 g was added in portions to an ice-cold solution of 7-bromo-8- chloro-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (18-2) (9 g) in DMF and stirred for another 30 min, followed by addition of 4-methoxybenzyl chloride (8.5 g).
  • the RM was stirred at RT for 2 h, quenched with ice-cold water, and extracted using EtOAc.
  • Step-4 8-chloro-7-(3-fluoropyridin-4-yl)-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)- one (Int-18) [0380]
  • 7-bromo-8-chloro-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2- a]pyrazin-1(2H)-one (18-3) (1.3 g) in 1,4-dioxane:water (4:1 ratio) were added K 3 PO 4 (1.5 g) and (3- fluoropyridin-4-yl)boronic acid (0.6 g) at RT.
  • the RM was purged under a stream of argon for 15 min, and then treated with X-Phos PdG 2 (0.28 g). The RM was stirred at 100 °C for 3 h, cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (2% methanol in DCM) to afford the title compound (Int-18). MS (ESI + ): m/z 386.22 [M+H] +
  • Step-2 methyl 3-(3-fluoropyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (19-2) [0382] To a solution of methyl 3-bromo-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrazole-5- carboxylate (19-1) (1 g) in 1,2-dimethoxyethane: water (4:1 ratio) were added (3-fluoro-4-pyridyl)boronic acid (1.3 g) and K 3 PO 4 (1.3 g) at RT. The RM was purged under a stream of argon, treated with PdCl 2 (dppf) .
  • Step-7 (R)-3-bromo-2-(3-fluoropyridin-4-yl)-7-(methoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (Int-19) [0387] Prepared using a similar method described for the synthesis of (18-2). MS (ESI + ): m/z 355.25 [M( 79 Br)+H] + , 357.20 [M( 81 Br)+H] + . [0388] The Int-20 from Table 3 was prepared using methods similar to those described for the synthesis of Int-19 by using the corresponding substituted Boc-protected aminoethanol reagent. [0389] Table 3. Int. No.
  • Step-3 methyl 1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-3-(thieno[2,3-d]pyrimidin-4-yl)- 1H-pyrazole-5-carboxylate (21-3) [0392] Prepared using a similar method described for the synthesis of (Int-15). MS (ESI + ): m/z 344.21 [M-100] + .
  • Step-4 Methyl 1-((1-aminocyclobutyl)methyl)-3-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazole-5- carboxylate (21-4) [0393] Prepared using a similar method described for the synthesis of (18-1). MS (ESI + ): m/z 344.20 [M+H] + .
  • Step-6 3'-bromo-2'-(thieno[2,3-d]pyrimidin-4-yl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazin]- 4'(5'H)-one (Int-21) [0395] To a stirred solution of 2'-(thieno[2,3-d]pyrimidin-4-yl)-7'H-spiro[cyclobutane-1,6'- pyrazolo[1,5-a]pyrazin]-4'(5'H)-one (21-5) (1.2 g) in DMF (15 mL) was added NBS (2.1 g) at RT, stirred at 70 °C for 16 h.
  • Step-2 methyl 3-(thieno[3,2-d] pyrimidin-4-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrazole-5- carboxylate (22-2) [0397] To a stirred solution of 4-chlorothieno[3,2-d] pyrimidine (4 g) and 5-(methoxycarbonyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)boronic acid (22-1) (9.1 g) in 1,4-dioxane:water (4:1 ratio) was added K 3 PO 4 (14.9 g) at RT.
  • the RM was degassed under a stream of argon for 10 min., Attorney Docket No.94019-421949 (P30890-WO-PCT) followed by addition of XPhos-PdG2 (0.9 g) and stirred at 100 °C for 3 h.
  • the RM was cooled to RT and filtered through celite-bed, washed with EtOAc. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5% EtOAc in hexane) to afford the title compound (22-2).
  • Step-3 methyl 3-(thieno[3,2-d] pyrimidin-4-yl)-1H-pyrazole-5-carboxylate (Int-22) [0398] TFA (19.6 mL) was added to an ice-cold solution of methyl 3-(thieno[3,2-d] pyrimidin-4-yl)- 1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrazole-5-carboxylate (22-2) (5 g) in DCM and stirred at RT for 12 h then evaporated to dryness.
  • Step-2 methyl 1-(2-aminoethyl)-3-(thieno[3,2-d] pyrimidin-4-yl)-1H-pyrazole-5-carboxylate (24-2) [0402] To a stirred solution of methyl 1-(2-((tert-butoxycarbonyl) amino) ethyl)-3-(thieno[3,2-d] pyrimidin-4-yl)-1H-pyrazole-5-carboxylate (24-1) (1 g) in DCM was added TFA (5 mL) at 0 °C and stirred at RT for 3 h. The RM was diluted with DCM and basified with 10% aq. ammonia (pH ⁇ 8-9).
  • Step-3 2-(thieno[3,2-d] pyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one (24-3) [0403] To a stirred solution of methyl 1-(2-aminoethyl)-3-(thieno[3,2-d] pyrimidin-4-yl)-1H- pyrazole-5-carboxylate (24-2) (0.8 g) in methanol was added Cs 2 CO 3 (3.2 g) at RT and the RM was stirred for 3 h. The RM was then concentrated under reduced pressure, diluted with ice-water and the solid obtained was collected by filtration and dried under vacuum to afford the title compound (24-3).
  • Step-3 (S)-6-methyl-2-(thieno[2,3-d]pyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (26-3) [0409] Prepared using a similar method described for the synthesis of (24-3). MS (ESI + ): m/z 286.17 [M+H] + .
  • Step-4 (S)-3-bromo-6-methyl-2-(thieno[2,3-d]pyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (Int-26) [0410] Prepared using a similar method described for the synthesis of (Int-24). MS (ESI + ): m/z 364.08 [M( 79 Br)+H] + , 366.08 [M( 81 Br)+H] + .
  • Step-3 2-bromo-5a,6,8,8a-tetrahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazin-4(5H)-one (36-3) [0415] Prepared using a similar method described for the synthesis of (24-3). MS (ESI + ): m/z 258.22 [M( 79 Br)+H] + , 260.22 [M( 81 Br)+H] + .
  • Step-4 2-(3-fluoropyridin-4-yl)-5a,6,8,8a-tetrahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazin-4(5H)-one (36-4) [0416] Prepared using a similar method described for the synthesis of (22-3). MS (ESI + ): m/z 275.12 [M+H] + .
  • Step-5 3-bromo-2-(3-fluoropyridin-4-yl)-5a,6,8,8a-tetrahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazin-4(5H)- one (Int-36) [0417]
  • a stirred solution of 2-(3-fluoropyridin-4-yl)-5a,6,8,8a-tetrahydrofuro[3,4-e]pyrazolo[1,5- a]pyrazin-4(5H)-one (36-4) (0.4 g) in AcOH (5 mL) was treated with 1,3-dibromo-5,5-dimethylhydantoin (0.6 g) at RT, and the RM was stirred at 70 °C for 5 h.
  • the RM was degassed under a stream of argon, treated with Pd2(dba) 3 (0.2 g) and stirred at 100 °C for 2 h, cooled to RT, diluted with water and extracted with ethyl acetate. Organic layer was dried over Na 2 SO 4 , filtered, and evaporated to afford the title compound (38-1). The crude product was used in the next step without further purification and characterization.
  • Step-2 8-chloro-7-(thieno[3,2-d]pyrimidin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Int-38) [0421] To a stirred solution of 8-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (38-1) (1.0 g) and 4-chlorothieno[3,2-d]pyrimidine (0.6 g) in Attorney Docket No.94019-421949 (P30890-WO-PCT) 1,4-dioxane:water (4:1 ratio) was added Na 2 CO 3 (0.7 g).
  • the RM was degassed under a stream of argon, treated with Pd(dppf)Cl 2.
  • DCM 0.1 g
  • the RM was cooled to RT, diluted with water and extracted using EtOAc.
  • the combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the residue was purified by column chromatography on silica gel (2% methanol in DCM) to afford the title compound (Int-42).
  • Step-2 Methyl(S)-1-(1-amino-3-hydroxypropan-2-yl)-3-bromo-1H-pyrazole-5-carboxylate (44-2) [0432] Prepared using a similar method described for the synthesis of (24-2) which was used in the next step without further purification.
  • Step-3 (S)-2-bromo-7-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (44-3) [0433] Prepared using a similar method described for the synthesis of (24-3).
  • Step-4 (S)-2-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (44-4)
  • (S)-2-bromo-7-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (44-3) 1.0 g
  • TBS-Cl 0. g
  • imidazole 0.8 g
  • DMAP 0.1 g
  • Step-5 (S)-2-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-methoxybenzyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (44-5) [0435] Prepared using a similar method described for the synthesis of (18-3).
  • Step-6 (S)-2-bromo-7-(hydroxymethyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (44-6) [0436] To a stirred solution of (S)-2-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4- methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (44-5) (1.5 g) in THF was added 1M TBAF (1.6 g) at 0 o C and stirred at RT for 3 h.
  • Step-7 (S)-2-bromo-5-(4-methoxybenzyl)-7-(methoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (44-7) [0437] To a stirred solution of (S)-2-bromo-7-(hydroxymethyl)-5-(4-methoxybenzyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (44-6) (1.0 g) in DMF was added NaH (0.2 g) at 0 °C, stirred for 30 min, and treated with treated with methyl iodide (0.6 g) and stirred at RT for 1 h.
  • Step-8 (S)-2-(3-fluoropyridin-4-yl)-5-(4-methoxybenzyl)-7-(methoxymethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (44-8) [0438] Prepared using a similar method described for the synthesis of (22-3).
  • the RM was stirred at 100 °C for 3 h.
  • the RM was cooled to RT and filtered to afford the title compound (Int-45) as a mixture of crude boric acid and ester in dioxane, which was directly used in the next step without further purification.
  • Step-2 2-bromo-7,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (46-2) [0443] To a stirred solution of methyl 3-bromo-1-(1-((tert-butoxycarbonyl)amino)-2-methylpropan- 2-yl)-1H-pyrazole-5-carboxylate (46-1) (6.8 g) in 1,4-dioxane was added 2M HCl (45 mL) at RT and the RM was then stirred at 80 °C for 2 h. The RM was then cooled to RT and concentrated under reduced pressure.
  • Step-3 2-bromo-3-iodo-7,7-dimethyl-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one (46-3)
  • 2-bromo-7,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (46-2) (3.7 g) in ACN (148 mL) were added iodine (3.85 g) and CAN (8.31 g) at RT.
  • the RM was stirred at 80 °C for 5 h, cooled to RT, concentrated and diluted with water and extracted with EtOAc.
  • Step-5 2-bromo-3-(5-chlorothiophen-2-yl)-5-(4-methoxybenzyl)-7,7-dimethyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (Int-46) [0446] Prepared using a similar method described for the synthesis of (Int-42).
  • Example 1 3-phenyl-2-(pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [0447] 4(5H)- one (Int-1) (100 mg) and phenylboronic acid (62 mg) in 1,4-dioxane:water (4:1 ratio) was added K 2 CO 3 (140 mg) at RT. The RM was purged under a stream of argon for 10 min and Pd(dppf)Cl 2 (13 mg) was added. The RM was stirred at 80 °C for 24 h, diluted with water and extracted using EtOAc.
  • the RM was heated at 120 °C for 48 h, cooled to RT, diluted with water and extracted using EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1.2% methanol in DCM) to afford the title compound (20).
  • Example 21 (R)-3-(5-chlorothiophen-2-yl)-2-(3-(((tetrahydrofuran-2-yl)methyl)amino)pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Step-1 (R)-3-(5-chlorothiophen-2-yl)-5-(4-methoxybenzyl)-2-(3-(((tetrahydrofuran-2- yl)methyl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Example 21.1 [0454] To a stirred solution of 3-(5-chloro-2-thienyl)-2-(3-fluoro-4-pyridyl)-5-[(4- methoxyphenyl)methyl]-6,7-dihydropyrazolo
  • Step-2 (R)-3-(5-chlorothiophen-2-yl)-5-(4-methoxybenzyl)-2-(3-(((tetrahydrofuran-2- yl)methyl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Example-21) [0455] TfOH (2 mL) was added to an ice-cold solution of 3-(5-chloro-2-thienyl)-5-[(4- methoxyphenyl)methyl]-2-[3-[[(2R)-tetrahydrofuran-2-yl]methylamino]-4-pyridyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-4-one (21.1) (120 mg) in DCM.
  • the RM was stirred at RT for 3 h, diluted with saturated aqueous NaHCO 3 solution, and extracted using DCM. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography on silica gel (2% methanol in DCM) to afford the title compound (21).
  • Example 22 (S)-3-(5-chlorothiophen-2-yl)-2-(3-(((tetrahydrofuran-2-yl)methyl)amino)pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one changing coupling partner, (S)-(tetrahydrofuran-2-yl)methanamine.
  • Example 23 2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(thiophen-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one 4(5H)-one (Example-23.1) [0458] To a stirred solution of 2-bromo-3-iodo-5-[(4-methoxyphenyl)methyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-4-one (0.831 g) (Int-10), K 2 CO 3 (2.0 M in H 2 O, 2.7 mL) and Pd(dppf)Cl 2 .DCM (0.15 mg) in 1,4-dioxane was added (5-chloro-2-thienyl) boronic acid (290 mg) at RT in three courses over the course of the reaction
  • the RM was purged under argon for 10 min and stirred at 100 °C for 2 h, cooled to RT, diluted with H 2 O and extracted using EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (50% EtOAc in hexane) (23.1). MS (ESI + ): m/z 451.90 [M+H] + .
  • Step-2 5-(4-methoxybenzyl)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(thiophen-2-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Example-23.2 [0459] To a stirred solution of 2-bromo-3-(5-chloro-2-thienyl)-5-[(4-methoxyphenyl)methyl]-6,7- dihydropyrazolo[1,5-a]pyrazin-4-one (0.350 g) (23.1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazolo[3,4-b]pyridine (0.28 g) in 1,4-dioxane:water (4:1 ratio) was added K 2 CO 3 (0.27 g) and Pd(dppf)Cl 2 .DCM
  • the RM was purged with argon for 10 min, and heated at 110 °C temperature for 16 h, cooled to RT, diluted with water and extracted using EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography on silica gel (1.2% methanol in DCM) to afford the title compound (23.2) MS (ESI + ): m/z 457.37 [M+H] + .
  • the RM was diluted with ice-cold water, neutralised with saturated aqueous NaHCO 3 solution (pH ⁇ 7–8), and extracted using DCM.
  • the combined organic layer was Attorney Docket No.94019-421949 (P30890-WO-PCT) washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude residue was purified by reverse phase preparative HPLC (0.1% HCOOH in water and ACN as a mobile phase) to afford the title compound (Example-23).
  • Example-24 2-(3-(cyclopentylethynyl)pyridin-4-yl)-3-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one Step-1:3- -one (Ex-24.1) [0461] To a stirred solution of 2-bromo-3-chloro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (200 mg) (Int-11) and [3-(2-cyclopentylethynyl)-4-pyridyl]boronic acid (206 mg) in 1,4-dioxane:water (4:1 ratio) was added tetrakis Pd(0) (92 mg) and Na 2 CO 3 (169 mg) at RT.
  • the RM was purged with argon for 10 min and heated at 100 °C for 16 h, cooled to RT, diluted with water and extracted using DCM. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography on silica gel (1.5% methanol in DCM) to afford the title compound (Ex-24.1). MS (ESI + ): m/z 341.28 [M+H] + .
  • Step-2 2-(3-(cyclopentylethynyl)pyridin-4-yl)-3-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Example-24) [0462] To a stirred solution of 3-chloro-2-[3-(2-cyclopentylethynyl)-4-pyridyl]-6,7-dihydro-5H- pyrazolo[1,5-a]pyrazin-4-one (24.1) (60 mg) and phenylboronic acid (64 mg) in 1,4-dioxane:water (4:1 ratio) was added Pd(dppf)Cl 2 .DCM (14 mg) and Na 2 CO 3 (55 mg) at RT.
  • the RM was purged under a stream of argon for 10 min, and heated at 100°C 16 h, cooled to RT, diluted with water, and extracted using EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude residue which was purified by column chromatography on silica gel (1.7% methanol in DCM ) to afford the title compound (Example-24).
  • Example-25 2-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)-3-phenyl-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one (3- ( 2 as a coupling counterparts.
  • Example-26 8-phenyl-7-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one [0465] To a stirred solution of 8-chloro-7-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Int-14) (100 mg) and phenylboronic acid (74 mg) in 1,4-dioxane:water (4:1 ratio) was added K 3 PO 4 (257 mg) at RT. The RM was purged under a stream of argon for 10 min, after which X-Phos PdG 2 (15 mg) was added.
  • the RM was purged under a stream of argon for 10 min and stirred at 100 °C for 16 h.
  • the RM was cooled RT, diluted with ice-cold water, and extracted using EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc in hexane) to afford the title compound (Ex- 31.1).
  • Step-2 8'-(5-chlorothiophen-2-yl)-7'-(pyridin-4-yl)-4'H-spiro[cyclobutane-1,3'-pyrrolo[1,2-a]pyrazin]- 1'(2'H)-one (Example-31) [0469] TfOH was added to an ice cold solution of 8-(5-chloro-2-thienyl)-2-[(4- methoxyphenyl)methyl]-7-(4-pyridyl)spiro[4H-pyrrolo[1,2-a]pyrazine-3,1'-cyclobutane]-1-one (Ex- 31.1) (120 mg) in DCM and allowed to warm to RT and stirred for 5 h.
  • the RM was diluted with DCM, neutralized to pH ⁇ 7 using saturated aqueous NaHCO 3 solution and extracted. The combined organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (1.8% methanol in DCM) to afford the title compound (Example-31).
  • Step-2 8-(5-chlorothiophen-2-yl)-7-(3-methoxypyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)- one (Example-32) [0471] TFA (0.5 mL) was added to an ice-cold solution of 8-(5-chloro-2-thienyl)-2-[(4- methoxyphenyl)methyl]-7-(3-methoxy-4-pyridyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1-one (Ex-32.1) (0.70 g) in DCM and stirred at RT for 24 h.
  • Example 34 (R)-8-(5-chlorothiophen-2-yl)-7-(3-((tetrahydrofuran-2-yl)methoxy)pyridin-4-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Ex-34.1) [0474] The Tsunoda reagent (507 mg) was added to an ice-cold solution of 8-bromo-7-(3-hydroxy-4- pyridyl)-2-[(4-methoxyphenyl)methyl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1-one (Int-17) (300 mg) and [(2R)-tetrahydrofuran-2-yl]methanol (214 mg) in toluene.
  • Step-2 (R)-8-(5-chlorothiophen-2-yl)-2-(4-methoxybenzyl)-7-(3-((tetrahydrofuran-2 yl)methoxy)pyridin- 4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Ex-34.2) [0475] To a stirred solution of 8-bromo-2-[(4-methoxyphenyl)methyl]-7-[3-[[(2R)-tetrahydrofuran- 2-yl]methoxy]-4-pyridyl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1-one (Ex-34.1) (180 mg) in THF:water (4:1 ratio) were added (5-chloro-2-thienyl)boronic acid (171 mg) and K 3 PO 4 (223 mg) at RT.
  • the RM was purged under a stream of argon for 10 min, followed by addition of X-phos PdG 2 (27 mg) and the RM was stirred at 100 °C for 16 h.
  • the RM was cooled to RT, diluted with water, and extracted by EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , concentrated under Attorney Docket No.94019-421949 (P30890-WO-PCT) reduced pressure and the residue was purified by column chromatography on silica gel (60% EtOAc in hexane) to afford the title compound (Ex-34.2).
  • Step-3 (R)-8-(5-chlorothiophen-2-yl)-7-(3-((tetrahydrofuran-2-yl)methoxy)pyridin-4-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Example-34)
  • TfOH 0.6 mL
  • the RM was diluted with DCM, neutralized using saturated aqueous NaHCO 3 solution, and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure and the crude residue was purified by column chromatography using on silica gel (2.5% methanol in DCM) to afford the title compound (Example-34).
  • Step-2 8-(4-chlorophenyl)-7-(3-fluoropyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Example-36) [0480] TfOH (0.3 mL) was added to an ice-cold solution of 8-(4-chlorophenyl)-7-(3-fluoro-4- pyridyl)-2-[(4-methoxyphenyl)methyl]-3,4-dihydropyrrolo[1,2-a] pyrazin-1-one (Ex-36.1) (80 mg) in DCM and allowed to warm at RT and stirred 16 h.
  • Example 37 3-phenyl-2-(thieno[2,3-d]pyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [1,5- a]pyrazin-4-one (Int-30) (40 mg) in 1,4-dioxane:water (4:1 ratio) were added phenylboronic acid (42 mg) and K 2 CO 3 (40 mg). The RM was degassed under a stream of argon, treated with Pd(dppf)Cl 2 .DCM (9 mg) and stirred at 100 °C for 16 h.
  • Example-66 3-(4-chlorophenyl)-2-(3-fluoropyridin-4-yl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (cis racemic), - -2- 4- - Step-1: 3-(4-chlorophenyl)-2-(3-fluoropyridin-4-yl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (Ex-66-1) [0488] Prepared using a similar method described for the synthesis of (22-2).
  • Example-69 3-phenyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one a]pyrazin-4(5H)-one (Ex-69.1) [0494] Prepared using similar methods to those described for the synthesis of (Example-37), MS (ESI + ): m/z 451.39 [M+H] + .
  • Step-2 3-phenyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Int-69) [0495] Prepared using similar methods to those described for the synthesis of (44-9) .
  • Example-70 8-phenyl-7-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one
  • Step-1 2-(4-methoxybenzyl)-8-phenyl-7-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3,4-dihydropyrrolo[1,2- a]pyrazin-1(2H)-one (Ex-70.1) [0496] Prepared using similar methods to those described for the synthesis of (Example-22-2) .
  • Step-4 8-phenyl-7-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Example-70) [0497] Prepared using similar methods to those described for the synthesis of (44-9).
  • Example 71 listed in Table 16 was prepared using methods similar to those described for the synthesis of Example 70 using the corresponding boronic acid. [0499] Table 16.
  • Examples 77–82 listed in Table 18 were prepared using methods similar to those described for the synthesis of Example 75 and 76.
  • Int. Int No IUPAC Name Structure used Anal tical Data H .9 4 .3 9 , 0 Attorney Docket No.94019-421949 (P30890-WO-PCT)
  • Int. Int No. IUPAC Name Structure used Analytical Data H .9 4 .3 9 , 0 H , 7 m, z, 0
  • Step-2 5'-(4-methoxybenzyl)-3'-phenyl-2'-(pyrimidin-4-yl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5- a]pyrazin]-4'(5'H)-one (Ex-83.2) [0512]
  • 2'-acetyl-5'-(4-methoxybenzyl)-3'-phenyl-7'H-spiro[cyclobutane-1,6'- pyrazolo[1,5-a]pyrazin]-4'(5'H)-one (83.1) (0.2 g) in toluene (2 mL) were added ZnCl 2 (0.1 g), NH 4 OAc (0.3 g) and triethyl orthoformate (2.4 g) at RT.
  • Step-3 3-phenyl-2-pyrimidin-4-yl-spiro[5,7-dihydropyrazolo[1,5-a]pyrazine-6,1'-cyclobutane]-4-one (Example-83) [0513] Prepared using similar methods to those described for the synthesis of (44-9).
  • Example-85 (S)-8-(methoxymethyl)-3-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a][1,4]diazepin-4-one and - - - Attorney Docket No.94019-421949 (P30890-WO-PCT)
  • Step-1 di-tert-butyl but-3-en-1-yliminodicarbonate (Ex-85.2) [0514]
  • K 2 CO 3 (31.8 g)
  • 4-bromobut-1-ene 31 g
  • the RM was stirred at RT for 16 h, evaporated, diluted with ice cold water and extracted using ethyl acetate. The combined organic layer was washed with brine solution dried over anhydrous Na 2 SO 4, evaporated under reduced pressure to afford the title compound (Ex-85.2). The crude was used for the next step without further purification and characterization.
  • Step-2 di-tert-butyl (3,4-dihydroxybutyl)iminodicarbonate (Ex-85.3) [0515] To a stirred solution of di-tert-butyl but-3-en-1-yliminodicarbonate (85.2) (25 g) in t-BuOH and acetone were added NMO (4.3 g) and OsO 4 (23.4 g) at 0 °C, stirred at RT for 16 h. The RM was diluted with ice cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-3 di-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-3-hydroxybutyl)iminodicarbonate (Ex-85.4) [0516] Prepared using similar methods to those described for the synthesis of (44-4) which was used for the next step without further purification.
  • Step-4 methyl 3-bromo-1-(9-(tert-butoxycarbonyl)-2,2,3,3,12,12-hexamethyl-10-oxo-4,11-dioxa-9-aza- 3-silatridecan-6-yl)-1H-pyrazole-5-carboxylate (Ex-85.5) [0517] To a stirred solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (4.1) (2.3 g) in THF were added di-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-3-hydroxybutyl)iminodicarbonate (85.4) (4.7 g), PPh 3 (11.8 g), and DIAD (4.6 g) at RT, stirred at 70 °C for 12 h.
  • Step-5 methyl 1-(4-amino-1-hydroxybutan-2-yl)-3-bromo-1H-pyrazole-5-carboxylate (Ex-85.6) [0518] To a stirred solution of methyl 3-bromo-1-(9-(tert-butoxycarbonyl)-2,2,3,3,12,12- hexamethyl-10-oxo-4,11-dioxa-9-aza-3-silatridecan-6-yl)-1H-pyrazole-5-carboxylate (85.5) (5 g) in THF and water was added TFA (25 mL) at RT and stirred for 4 h, evaporated under reduced pressure to afford the title compound (Ex-85.6).
  • Step-7 2-bromo-8-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-4-one (Ex-85.8) [0520] Prepared using similar methods to those described for the synthesis of (44-4), MS (ESI + ): m/z 374.24 [M( 79 Br)+H] + , 376.24 ([M( 81 Br)+H] + .
  • Step-8 2-bromo-8-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H- pyrazolo[1,5-a][1,4]diazepin-4-one (Ex-85.9) [0521] Prepared using similar methods to those described for the synthesis of (18-3), MS (ESI + ): m/z 494.20 [M( 79 Br)+H] + , 496.24 ([M( 81 Br)+H] + .
  • Step-9 2-bromo-8-(hydroxymethyl)-5-[(4-methoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5- a][1,4]diazepin-4-one (Ex-85.10) [0522] Prepared using similar methods to those described for the synthesis of (44-6). MS (ESI): m/z 380.30 [M( 79 Br)+H] + , 382.20 [M( 81 Br)+H] + .
  • Step-10 2-bromo-5-(4-methoxybenzyl)-8-(methoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-4-one (Ex-85.11) [0523] To a stirred solution of 2-bromo-8-(hydroxymethyl)-5-(4-methoxybenzyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepin-4-one (85.10) (0.6 g) in DMF was added NaH (0.1 g) at 0 °C and stirred the RM for 15 min, treated with methyl iodide (0.2 g), stirred at RT for 3 h.
  • Step-11 5-(4-methoxybenzyl)-8-(methoxymethyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-4-one (Ex-85.12) [0524] Prepared using a similar method described for the synthesis of (Example-37).
  • Step-14 8-(methoxymethyl)-3-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-4-one (Ex-85.15) [0527] Prepared using a similar method described for the synthesis of (Example-37).
  • Step-2 5-benzyl-2-bromo-5a,6,7,7a-tetrahydrocyclobuta[e]pyrazolo[1,5-a]pyrazin-4(5H)-one (Ex-87.2) [0534]
  • benzyl amine (7.9 g) and acetic acid (4.4 g) at RT stirred for 4 h.
  • the RM was cooled to 0 °C and NaBH 4 (4.2 g) was added in portions and stirred for 16 h at RT, diluted with water and extracted using EtOAc.
  • Step-4 2-(3-fluoropyridin-4-yl)-5a,6,7,7a-tetrahydrocyclobuta[e]pyrazolo[1,5-a]pyrazin-4(5H)-one (Ex-87.4)
  • TFA 0.3 mL
  • Step-5 3-bromo-2-(3-fluoropyridin-4-yl)-5a,6,7,7a-tetrahydrocyclobuta[e]pyrazolo[1,5-a]pyrazin-4(5H)- one (Ex-87.5) [0537] Prepared using a similar method described for the synthesis of (Int-24). MS (ESI + ): m/z 337.05 [M( 79 Br)+H] + and 339.05 [M( 81 Br)+H] + .
  • Step-6 3-(4-chlorophenyl)-2-(3-fluoropyridin-4-yl)-5a,6,7,7a-tetrahydrocyclobuta[e]pyrazolo[1,5- a]pyrazin-4(5H)-one (Ex-87.6) [0538] Prepared using a similar method described for the synthesis of (Example-37). MS (ESI + ): m/z 369.34 [M+H] + .
  • Step-7 (5aR,7aS)-3-(4-chlorophenyl)-2-(3-fluoropyridin-4-yl)-5a,6,7,7a- tetrahydrocyclobuta[e]pyrazolo[1,5-a]pyrazin-4(5H)-one (Example-87) and (5aS,7aR)-3-(4- chlorophenyl)-2-(3-fluoropyridin-4-yl)-5a,6,7,7a-tetrahydrocyclobuta[e]pyrazolo[1,5-a]pyrazin-4(5H)- one (Example-88) [0539] Racemic compound (Ex-87.6) was separated by chiral SFC to afford the title compound.
  • Step-2 3-(5-chlorothiophen-2-yl)-5-(4-methoxybenzyl)-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Ex-89.2) [0544] Prepared using a similar method described for the synthesis of (Int-38). MS (ESI + ): m/z 490.10 [M+H] + .
  • Step-3 3-(5-chlorothiophen-2-yl)-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (Example-89) [0545] To a stirred solution of 3-(5-chloro-2-thienyl)-5-[(4-methoxyphenyl)methyl]-2-(1H- pyrrolo[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one (Ex-89.2) (160 mg) in TFA (3.2 mL) was stirred at 80 °C for 16h.
  • Example 90 3-(5-chlorothiophen-2-yl)-7,7-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Step-1 3-(5-chlorothiophen-2-yl)-5-(4-methoxybenzyl)-7,7-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Ex-90.1) [0546] Prepared using a similar method described for the synthesis of (Example-11).
  • Step-2 3-(5-chlorothiophen-2-yl)-7,7-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Example-90) [0547] A stirred solution of 3-(5-chlorothiophen-2-yl)-5-(4-methoxybenzyl)-7,7-dimethyl-2-(1H- pyrrolo[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Ex-90.1) (0.15 g) in TFA (3 mL) and H 2 O (0.5 mL) was stirred at 100 °C for 72 h.
  • Example-91 3-(5-chlorothiophen-2-yl)-7,7-dimethyl-2-(thieno[3,2-d]pyrimidin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Step- [0548] To a stirred solution of 4-chlorothieno[3,2-d]pyrimidine (Ex-91.1) (5 g) and prop-2-ene-1- thiol (4.7 g) in acetone (100 mL) was added K 2 CO 3 (12 g) under N 2 . The RM was stirred at 60 °C for 16 h.
  • the RM was stirred at this temperature for 3 h, then extra m-CPBA was added in two lots (1.38 g and 0.47 g) at 0 °C with 2 h in between.
  • the RM was then quenched with aqueous Na 2 S 2 O 3 solution.
  • the heterogeneous solution was filtered and the filtrate was collected, concentrated under reduced pressure, and diluted with EtOAc.
  • the combined organic layer was washed by NaS 2 O 3 solution, NaHCO 3 solution and brine solution, dried over Na 2 SO 4 , concentrated and the crude residue was purified by column chromatography on silica gel (20% ethyl acetate in hexane) to afford the title compound (Ex-91.3).
  • Step-4 3-(5-chlorothiophen-2-yl)-7,7-dimethyl-2-(thieno[3,2-d]pyrimidin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (Example-91) [0551] Prepared using a similar method described for the synthesis of (Example-90).
  • BIOLOGICAL ASSAYS Biochemical EGFR Inhibition Assays [0552] The kinase activity of the EGFR variants were determined using a real-time fluorescent peptide sensor of kinase activity as described previously (Zhai et al., Biochemistry 59(14):1428-1441 (2020), which is hereby incorporated by reference in its entirety). IC50s were determined by measuring the fluorescence at varying concentrations of the compounds.
  • Assays were performed in the following reaction conditions: 52 mM HEPES pH 7.5, 1.1 mM DTT, 0.011% Brij-35, 5% glycerol, 0.2 mg/ml BSA, 250 ⁇ M MnCl2, 0.52 mM EGTA, 10 mM MgCl2, 1% DMSO, 15 ⁇ M AQT0734 (AssayQuant Technologies).
  • 1 mM ATP was used, otherwise, ATP concentrations were as stated in Table 2.
  • Enzymes and compounds were first pre-incubated for 30 minutes at 37°C to equilibrate before starting the kinase reaction. Assays were performed in duplicate with several biological repeats.
  • Target engagement assays to measure pEGFR were used to measure cellular activity of the EGFR inhibitor compounds.
  • the commercially available AlphaLISA SureFire Ultra p-EGFR (Tyr1068) assay kit (PerkinElmber ALSU-PEGFR-A50K) was used according to the manufacturer's instructions. Briefly, 40 uL of Ba/F3 EGFR L858R/C797S, PC-9, or A431 cells were seeded in 384 well plates (Corning 3764) diluted in their culture medium (see table 3 for cell number and culture medium for each cell line).
  • Plates were covered and placed in a 37°C, 5% CO 2 incubator overnight. Cells were treated with 40 nL of compounds in DMSO in a 3-fold, 10-point serial dilution and incubated for 2 hours. Plates were centrifuged at room temperature for 10 minutes at 3,000 rpm and 40 uL of medium was removed using an apricot liquid handler.10 uL of 1x lysis buffer was added to each well and plates were shaken at 600 rpm for 1 hour.5 uL of AlphaLISA acceptor mix was added to each well and plates were shaken at 350 rpm for 1 hour in the dark.5 uL of donor mix was added to each well, plates were mixed on a shaker, and plates were sealed and wrapped in aluminum foil and incubated overnight at room temperature.18.5 uL of the mixture was transferred to a white optiplate 384 well plate (PerkinElmer 6007290) using an apricot liquid handler, and the plates were read on an Envision plate reader using standard AlphaLISA settings.
  • Table 20 Cell Number and Culture Medium Cell Line Culture Medium Cells/Well Attorney Docket No.94019-421949 (P30890-WO-PCT)
  • Table 21 the EGFR LR/CS and EGFR Del19 K i ranges are as follows: A: K i ⁇ 10 nM; B: 10 nM ⁇ K i ⁇ 100 nM; C: K i > 100 nM.
  • a value of “NA” indicates that no K i value was available for the compound and does not necessarily indicate that the compound is inactive in the referenced assay.
  • Table 21 Table 21.

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Abstract

La présente invention concerne des composés inhibiteurs d'EGFR de formule (I), tels que définis dans la description, et des sels pharmaceutiquement acceptables de ceux-ci. La présente invention concerne également une composition pharmaceutique comprenant un composé de formule (I), et des sels pharmaceutiquement acceptables de celui-ci, et des procédés d'utilisation des composés et des compositions pour inhiber certaines interactions protéine-protéine, et pour traiter le cancer.
PCT/US2025/028620 2024-05-10 2025-05-09 Hétérocycles en tant qu'inhibiteurs d'egfr Pending WO2025235872A1 (fr)

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