Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch for central growth signaling pathways. In response to extracellular signals, Ras is converted from a GDP-bound (Ras GDP ) to a GTP-bound (Ras GTP ) state, as catalyzed by guanine nucleotide exchange factors (GEFs), notably the SOS1 protein. Active Ras GTP mediates its diverse growth- stimulating functions through its direct interactions with effectors including Raf, PI3K, and Ral guanine nucleotide dissociation stimulator.
• GEFs guanine nucleotide exchange factors
• Ras The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP to terminate Ras signaling.
• the Ras GTPase activity can be further accelerated by its interactions with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.
• GAPs GTPase-activating proteins
• Mutant Ras has a reduced GTPase activity, which prolongs its activated state, thereby promoting Ras-dependent signaling and cancer cell survival or growth. Mutation in Ras that affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer.
• a pharmaceutical composition comprising a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.
• a method of treating a cancer comprising a KRas mutation comprising administering to a patient having such cancer, a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.
• a method for regulating activity of a KRas mutant protein the method comprising reacting the mutant protein with a compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.
• a method for inhibiting proliferation of a cell population comprising contacting the cell population with a compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.
• a method for inhibiting tumor metastasis comprising administering to an individual in need thereof a therapeutically effective amount of the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein or a pharmaceutical composition as described herein to a subject in need thereof.
• FIG. 1 shows the pharmacokinetic profile of compounds 6, 7, 81, and 194, and comparator compound.
• such compounds and compositions are inhibitors or modulators of mutant G12D KRas as provided herein.
• the compounds and compositions described herein are useful in treating diseases and disorders mediated by mutant KRas, including KRas G12D mutations.
• alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one example, the alkyl radical is one to eighteen carbon atoms (C 1-18 ). In other examples, the alkyl radical is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , or C 1-3 .
• alkyl groups include methyl (Me, –CH 3 ), ethyl (Et, –CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, – CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, –CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, –CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, –CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, –CH(CH 3 )CH 2 CH 3 ), 2- methyl-2-propyl (t-Bu, t-butyl, –C(CH 3 )3), 1-pentyl (n-pentyl, –CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (–CH(CH 3 )CH 2 CH 2 CH 2 CH
• alkylidene radical is C 1-3 , C 1-2 , or C1.
• alkenyl refers to linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond and includes radicals having "cis" and "trans” orientations, or alternatively, "E” and "Z” orientations.
• the alkenyl radical is two to eighteen carbon atoms (C 2-18 ).
• the alkenyl radical is C 2-12 , C 2-10 , C 2-8 , C 2-6 , or C 2-3 .
• alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon, triple bond.
• the alkynyl radical is two to eighteen carbon atoms (C 2-18 ).
• the alkynyl radical is C 2-12 , C 2-10 , C 2-8 , C 2-6 , or C 2-3 . Examples include, but are not limited to, ethynyl (–CoCH), prop-1-ynyl (–CoCCH 3 ), prop-2-ynyl (propargyl, –CH 2 CoCH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.
• alkylene refers to a saturated, branched, or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
• the divalent alkylene group is one to eighteen carbon atoms (C1-18).
• the divalent alkylene group is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , or C 1-3 .
• Example alkylene groups include methylene (– CH 2 –), 1,1-ethyl (–CH(CH 3 )–), (1,2-ethyl (–CH 2 CH 2 —), 1,1-propyl (–CH(CH 2 CH 3 )–), 2,2-propyl (–C(CH 3 ) 2 –), 1,2-propyl (–CH(CH 3 )CH 2 –), 1,3-propyl (–CH 2 CH 2 CH 2 —), 1,1-dimethyleth-1,2-yl (–C(CH 3 ) 2 CH 2 –), 1,4-butyl (–CH 2 CH 2 CH 2 CH 2 —), and the like.
• cycloalkyl refers to a saturated hydrocarbon ring group. Cycloalkyl encompasses mono-, bi-, tricyclic, spiro and bridged, saturated ring systems. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C 3-12 ). In other examples, cycloalkyl is C 3-4 , C 3-5 , C 3-7 , C 3-8 , C 3-10 , or C 5-10 . In other examples, the cycloalkyl group, as a monocycle, is C 3-4 , C 3-8 , C 3-6 , or C 5-6 . In another example, the cycloalkyl group, as a bicycle, is C 7 -C 12 .
• the cycloalkyl group is C 5-12 .
• monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
• Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
• Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
• Examples of spirocycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.
• heterocyclic group refers to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule.
• heterocyclyl includes 3-10 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen.
• heterocyclyl includes 4-10 or 5-10 ring atoms.
• heterocyclyl includes 1 to 4 heteroatoms.
• heterocyclyl includes 1 to 3 heteroatoms.
• heterocyclyl includes 3- to 7-membered monocycles having 1- 2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen.
• heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen.
• heterocyclyl includes 3-membered monocycles.
• heterocyclyl includes 4-membered monocycles.
• heterocyclyl includes 5-6 membered monocycles.
• a heterocycloalkyl includes at least one nitrogen.
• the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO 2 ), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR 4 ] + Cl-, [NR 4 ] + OH-).
• Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2- dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thio
• a heterocyclylgroup or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group.
• carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an aze
• the heterocyclyl group or heteroaryl group is N-attached.
• nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3- pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
• Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).
• haloalkyl refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl.
• a substituted haloalkyl refers to a haloalkyl having a moiety other than a halogen.
• An unsubstituted haloalkyl refers to a haloalkyl substituted with no moiety other than hydrogen or halogen as described herein.
• a wavy line “ ” that intersects a bond in a chemical structure indicate the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.
• divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise.
• R 1 –R 2 –R 3 if the group R 2 is described as –CH 2 C(O)–, then it is understood that this group can be bonded both as R 1 –CH 2 C(O)–R 3 , and as R 1 –C(O)CH 2 –R 3 , unless specified otherwise.
• pharmaceutically acceptable refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
• Compounds described herein may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts.
• “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesul
• base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
• Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
• basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethyla
• a salt is selected from a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furo
• a “sterile” formulation is aseptic or free from all living microorganisms and their spores.
• stereoisomers refer to compounds that have identical chemical constitution but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers and the like.
• chiral refers to molecules that have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
• diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC. [0047] The term “enantiomers” refers to two stereoisomers of a compound that are non- superimposable mirror images of one another.
• atropisomers refers to two conformers resulting from hindered rotation about a single bond where the steric strain barrier to rotation can be high enough to allow for the isolation of each conformer.
• Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
• the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
• the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
• a compound prefixed with (+) or d is dextrorotatory.
• these stereoisomers are identical except that they are mirror images of one another.
• a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
• a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
• the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
• the term “tautomer” or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
• proton tautomers also known as prototropic tautomers
• Valence tautomers include interconversions by reorganization of some of the bonding electrons.
• Certain compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms.
• a “solvate” refers to an association or complex of one or more solvent molecules and a compound described herein. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
• Certain compounds described herein can exist in multiple crystalline or amorphous forms. In general, all physical forms are contemplated herein.
• the term "hydrate” refers to the complex where the solvent molecule is water.
• the compounds and pharmaceutically acceptable salts thereof described herein also embrace isotopically-labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated herein, and their uses.
• Exemplary isotopes that can be incorporated into compounds and pharmaceutically acceptable salts thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I.
• Certain isotopically-labeled compounds or pharmaceutical acceptable salts thereof described herein are useful in compound and/or substrate tissue distribution assays.
• Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
• Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
• Isotopically labeled compounds or pharmaceutical acceptable salts thereof described herein can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• Compounds and pharmaceutically acceptable salts thereof described herein may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof.
• the syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods.
• enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art.
• Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are contemplated herein.
• all stereoisomers are contemplated and included.
• stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.
• a “subject,” “individual,” or “patient” is a vertebrate and are used interchangeably herein.
• the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.
• a mammal is a human.
• the patient is typically in need thereof.
• the terms “inhibiting” and “reducing,” or any variation of these terms includes any measurable decrease or complete inhibition to achieve a desired result.
• treatment refers to clinical intervention designed to alter the natural course of the patient or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
• a patient is successfully “treated” if one or more symptoms associated with a cancer described herein are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of patients.
• the term “delaying progression” of a disease refers to deferring, hindering, slowing, retarding, stabilizing, and/or postponing development of a cancer described herein. This delay can be of varying lengths of time, depending on the history of the cancer and/or patient being treated.
• a “mutant KRas mediated disease” and the like refer to a disease described herein (e.g., a cancer described herein) having symptoms or requiring treatment as set forth herein that is/are wholly or partly associated with, a result of, a function of, or otherwise correlated to mutant KRas activity as described herein.
• the mutant KRas is KRas G12D .
• An “effective amount” or “therapeutically effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a cancer described herein.
• An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to elicit a desired response in the patient.
• An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
• Beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, delaying the onset of the disease (including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease), decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
• an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow or stop) tumor metastasis; inhibiting (i.e., slow or stop) tumor growth; and/or relieving one or more of the symptoms associated with the disorder.
• An effective amount can be administered in one or more administrations.
• Co-administration includes simultaneous administration in separate compositions, administration at different times (i.e., sequential administration) in separate compositions, or administration in a composition in which both agents are present.
• packet insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
• antagonist and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as a mutant form of KRas.
• the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.
• agonist refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide.
• cancer specifically interact with (e.g., bind to) the target
• compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
• cancer and “cancerous”, “neoplasm”, and “tumor” and related terms are used interchangeably herein and refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
• a “tumor” comprises one or more cancerous cells.
• cancers include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) and lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung.
• squamous cell cancer e.g., epithelial squamous cell cancer
• lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung.
• NSCLC non-small cell lung cancer
• cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, diffuse large B-Cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin's, and associated metastases.
• DLBCL diffuse large B-Cell lymphoma
• neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocytosis, myelofibrosis, such as primary myelofibrosis, and chronic myelogenous leukemia (CML).
• a "chemotherapeutic agent” is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders. Examples of chemotherapeutic agents are well- known in the art. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, as well as combinations of two or more of them.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• Exemplary isotopes that can be incorporated into compounds and pharmaceutically acceptable salts thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
• Isotopically-labeled compounds can be useful in compound or substrate tissue distribution assays.
• Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
• one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
• Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
• Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0068] It is specifically contemplated that any limitation discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein.
• any compound and pharmaceutically acceptable salts thereof described herein or composition described herein may be used in any method provided herein, and any method provided herein may be used to produce or to utilize any compound and pharmaceutically acceptable salts thereof described herein or composition described herein.
• the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.
• Compounds described herein may have stereochemistry depicted as follows: It is understood that all three stereochemical depictions above are equivalent as set forth herein.
• a compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is R 7A -substituted phenyl or R 7A -substituted pyridinyl; each R 7A is independently halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl; L 1 is R L1 -substituted or unsubstituted C1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C3-4 cyclo
• each R 4 is hydrogen. In another embodiment, one R 4 is hydrogen and one R 4 is methyl. In another embodiment, one R 4 is hydrogen and one R 4 is CF3.
• R 1 is R 7 -substituted or unsubstituted naphthyl, R 7 -substituted or unsubstituted isoquinolinyl, R 7 -substituted or unsubstituted indazolyl, R 7 -substituted or unsubstituted indanyl, or R 7 -substituted or unsubstituted benzothiazolyl.
• R 1 is R 7 -substituted or unsubstituted naphthyl, R 7 -substituted or unsubstituted isoquinolinyl, or R 7 - substituted or unsubstituted indazolyl. In another embodiment, R 1 is R 7 -substituted or unsubstituted naphthyl. In another embodiment, R 1 is R 7 -substituted or unsubstituted isoquinolinyl. In another embodiment, R 1 is R 7A -substituted phenyl or R 7A -substituted pyridinyl.
• R 1 is R 7 -substituted naphthyl. In one such embodiment, R 1 is R 7 -substituted isoquinolinyl and each R 4 is hydrogen. In another embodiment, R 1 is R 7 -substituted naphthyl, R 7 - substituted isoquinolinyl, R 7 -substituted indazolyl, R 7 -substituted indanyl, R 7 -substituted benzothiazolyl, or R 7A -substituted phenyl. In such embodiments, each R 4 is hydrogen or one R 4 is hydrogen and one R 4 is methyl.
• each R 7A is independently halogen, CN, NH 2 , N(Me) 2 , R 7B - substituted or unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl.
• each R 7A is independently halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.
• at least one R 7A is NH 2 .
• each R 7 is independently halogen, OH, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, unsubstituted C 1-3 alkynyl, unsubstituted C 1-3 alkoxy, or unsubstituted C 1- 3 haloalkyl.
• each R 7 is independently halogen, OH, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 alkynyl. In still another embodiment, at least one R 7 is NH 2 . In another embodiment, at least one R 7 is OH. [0078] In one embodiment, R 1 is: wherein X 1 is N or CR 7C . [0079] In one such embodiment, X 1 is N or CF and each R 7A is independently hydrogen, halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.
• each R 7A is independently hydrogen, Cl, methyl, ethyl, or CF3, where no more than one R 7A is hydrogen.
• at least one R 7A is NH 2 .
• each R 7A is independently halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.
• one R 7A is cyclopropyl.
• one R 7A is cyclopropyl and is para to the amino group.
• one R 7A is cyclopropyl and is meta to the amino group.
• X 1 is N.
• X 1 is CR 7C .
• R 7C is hydrogen or halogen.
• X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is formula wherein X 1 is N or CR 7C and R 7C is hydrogen or halogen; each R 7A is independently halogen, CN, NH 2 , N(Me) 2 , R 7B -substituted or unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo, or C 1-3 alkyl; L 1 is R L1 -substit
• X 1 is N and R 7A is hydrogen, halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.
• R 7A is unsubstituted C 1-3 haloalkyl (e.g. CF3).
• R 1 comprises the moiety of formula (E1); [0082] In another embodiment is a compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is of formula each R 7A is independently halogen, CN, NH 2 , N(Me) 2 , R 7B -substituted or unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo, or C 1-3 alkyl; L 1 is R L1 -substituted or unsubstituted C1-4 alkylene; R
• each R 7A is independently hydrogen, Cl, methyl, or CF 3 . In another such embodiment, each R 7A is independently hydrogen, methyl, or CF 3 . [0084] In one embodiment, where R 1 is a moiety of formula (E) and X 1 is N, R 1 is: , or . [0085] In another embodiment, R 1 comprises the moiety of formula (E2); or wherein each R 7A is independently hydrogen, halogen, unsubstituted C 1-3 alkyl or unsubstituted C 1-3 haloalkyl. In one such embodiment, no more than one R 7A is hydrogen. In another such embodiment, R 7A is not hydrogen.
• At least one R 7A is halogen. In one embodiment of the moieties (E2) and (E3), at least one R 7A is unsubstituted C1-3 haloalkyl (e.g., CF3, CHF 2 , CF 2 CF3, CHCF3, or CH 2 CF3).
• X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is (E2) or (E3) or ; each R 7A is independently hydrogen, halogen, unsubstituted C 1-3 alkyl or unsubstituted C 1-3 haloalkyl; L 1 is R L1 -substituted or unsubstituted C 1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C 3-4 cycloalkyl; R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising
• R 1 is: or .
• R 1 is a compound of formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2;
• L 1 is R L1 -substituted or unsubstituted C 1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C 3-4 cycloalkyl;
• R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O;
• R 9 is independently halogen, CN, OH, OCF3, OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3 alkyl, R 10 -substituted or unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, R 10 -substituted or unsubstituted C 1-3 alkylidene, or R 10 -substituted or unsubstituted C
• R 1 is: .
• R 1 is a compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is ; L 1 is R L1 -substituted or unsubstituted C 1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C3-4 cycloalkyl; R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; R 9 is independently halogen, CN, OH, OCF 3
• R 1 is: or , or a stereoisomer thereof, wherein t is 0, 1, 2, or 3. In one embodiment, t is 1 or 2. In another embodiment, t is 3. In one embodiment of the compounds described herein, R 1 is not a formula of F, F1, F2, F3, F4, or F5 and is a monocylic ring. [0093] In another embodiment, R 1 is a moiety of formula (F), (F1), (F 2 ), or (F3), wherein t is 0, 1, 2, or 3. In one embodiment, t is 1 or 2. In another embodiment, t is 3. [0094] In one embodiment, R 1 is: or a stereoisomer thereof, wherein R 7 is as described herein.
• R 1 is: or or a stereoisomer thereof.
• R 1 is: or , or a stereoisomer thereof, wherein t is 0, 1, 2, or 3. In one embodiment, t is 1 or 2.
• R 7 is halogen, NH 2 , OH, C 1-3 alkyl, or C 2-3 alkynyl.
• R 2 is R 9 -substituted or unsubstituted 4- 10 membered heterocycle comprising one or more heteroatoms selected from N or O.
• R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more nitrogen heteroatoms. In another embodiment, R 2 is R 9 - substituted or unsubstituted 5-8 membered heterocycle comprising at least one nitrogen heteroatom.
• each R 9 is independently halogen, CN, OH, OCF3, OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3 alkyl, R 10 -substituted or unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, R 10 -substituted or unsubstituted C 1-3 alkylidene, or R 10 - substituted or unsubstituted C 3-4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle.
• each R 9 is independently halogen, CN, OH, OCF 3 , OCHF 2 , or OCH 2 F. In another such embodiment, each R 9 is independently halogen, CN, OH, OCF3, OCHF 2 , OCH 2 F,R 10 -substituted or unsubstituted C 1-3 alkyl, R 10 -substituted or unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, or R 10 -substituted or unsubstituted C 1-3 alkylidene.
• each R 9 is independently R 10 -substituted or unsubstituted C 1-3 alkyl, R 10 -substituted or unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, or R 10 -substituted or unsubstituted C 1-3 alkylidene.
• each R 9 is independently halogen, R 10 -substituted or unsubstituted C3-4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle.
• two R 9 together form a R 10 -substituted or unsubstituted C3-5 cycloalkyl or a R 10 -substituted or unsubstituted C3-5 heterocycle comprising one or more oxygen atoms.
• two R 9 together form an unsubstituted cyclopropyl moiety.
• two R 9 together form an unsubstituted oxetanyl or azetidinyl.
• two R 9 together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons. In one such embodiment, the bridge comprises one carbon atom.
• the bridge comprises 2 carbon atoms.
• R 9 is halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene.
• R 2 is or a stereoisomer thereof, wherein, R 9 is halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene r is an integer of 0-12; j is 1, 2, or 3; and k is 1 or 2.
• R 2 is a moiety of formula: or a stereoisomer thereof, wherein R 9 is independently halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene; each R 10 is independently hydrogen or halogen; and r is 1 or 2.
• R 2 is a moiety of formula: or , or a stereoisomer thereof.
• R 2 is a moiety of formula: or or a stereoisomer thereof.
• R 2 is a moiety of formula: or or a stereoisomer thereof, wherein R 9 and r are as described herein. In one such embodiment, r is 1 or 2.
• each R 9 is independently halogen or R 10 -substituted or unsubstituted C 1-3 alkyl.
• R 2 is a moiety of formula: or , or a stereoisomer thereof.
• R 2 is , or a stereoisomer thereof, wherein R 9 is independently halogen, oxo, or unsubstituted C 1-3 alkyl; and r is 1 or 2.
• R 2 is , or a stereoisomer thereof.
• R 2 is [0111]
• R 2 is or a stereoisomer thereof, herein X 2 is CR 9 or O.
• X 2 is O. In one such embodiment, X 2 is O and r is 0. [0113] In another embodiment, R 2 is or a stereoisomer thereof, [0114] In one embodiment, R 2 is a moiety of formula (D), where X 3 is CR 9 , wherein R 9 is as described herein. In one such embodiment, X 3 is CH 2 or CF 2 . In another such embodiment, R 2 is a moiety of formula (D) or (D1) and X 3 is O. In one embodiment, R 2 is a moiety of formula (D), X 3 is O and R 9 is unsubstituted C 1-3 alkyl or halogen.
• R 2 is a moiety of formula (D)
• X 3 is NR 9
• R 9 is oxo or unsubstituted C 1-3 alkyl.
• R 2 is , or a stereoisomer thereof.
• r is 0 or 1.
• L 1 is methylene.
• R 2 is as described herein and L 1 is methylene.
• L 1 is R L1 -substituted or unsubstituted C2-3 alkylene. In one such embodiment, L 1 is unsubstituted C2-3 alkylene.
• L 1 is R L1 - substituted C 2-3 alkylene, where two R L1 together form an unsubstituted C 3-4 cycloalkyl. In one such embodiment, L 1 has the formula: . [0117] In one embodiment of the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, R 3 is halogen. In another embodiment, R 3 is -CN.
• each R 5 is independently halogen, oxo, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl. In one such embodiment, each R 5 is independently unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl. In some embodiments, p is 0 or 1. [0119] In another embodiment, two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N.
• two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons. In one such embodiment, the bridge comprises 1 or 2 carbon atoms. In another such embodiment, the bridge comprises 1 carbon atom. In another such embodiment, the bridge comprises 2 carbon atoms. [0120] In one embodiment, two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 . In one embodiment, the bridge comprises an O heteroatom. In another embodiment, the bridge comprises NR 11 where R 11 is hydrogen or methyl. [0121] In some embodiments, Ring A is a 6 membered ring (i.e., where m and n are both 1).
• Ring A is a 7-membered ring where m is 2 and n is 1. In another embodiment, Ring A is a 7-membered ring where m is 1 and n is 2.
• X is NR 6 , where R 6 is as described herein. [0122] In one embodiment, R 6 is hydrogen or R 6A -substituted or unsubstituted C 1-3 alkyl. In one embodiment, R 6 is R 6A -substituted or unsubstituted C 1-3 alkyl. In one embodiment, R 6 is hydrogen. In one embodiment, R 6 is methyl.
• R 6 is R 6A -substituted or unsubstituted C 1-6 alkyl, R 6A -substituted or unsubstituted C 1-6 haloalkyl, R 6A -substituted or unsubstituted C 1-6 alkenyl; R 6A -substituted or unsubstituted C 1-6 alkynyl.
• R 6A is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle.
• R 6A is halogen, CN, OH, OMe, OEt, OCF 3 , SO 2 Me, unsubstituted C 1-3 alkyl, or 4-membered heterocycle.
• each R 6B is independently C 1-3 alkyl or C 1-3 haloalkyl. In one such embodiment, R 6B is independently C 1-3 alkyl.
• R 6B is independently C 1-3 alkyl.
• the compound of formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises formula (IId-1), wherein R 2 , R 3 , R 4 , R 5 , R 7A , X, X 1 , and p are as described herein.
• the compound of formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises formula (IId-2), wherein R 2 , R 3 , R 4 , R 5 , R 7A , X, and p are as described herein.
• the compound of formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises formula (IId-3), wherein R 2 , R 3 , R 4 , R 5 , R 7A , X, and p are as described herein.
• the compound of formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises formula (IId-4), wherein R 2 , R 3 , R 4 , R 5 , R 7A , X, and p are as described herein.
• the compound of formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises formula (IId-5), wherein R 2 , R 3 , R 4 , R 5 , X, and p are as described herein [0134]
• X is NH or N(CH 3 ).
• R 1 is a moiety of formula for (E), (E1), (E2), (E3), (F), (F1), (F 2 ), (F3), (F4), or (F5) as described herein.
• R 2 is a moiety of formula (A), (A-1), (A-2), (A-3), (A-4), (B), (C), (D), or (D1) as described herein.
• R 2 comprises a moiety of formula: or or a stereoisomer thereof.
• the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein comprises formula (IId) as described herein.
• the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein comprises formula (IId-1), (IId-2), (IId-3), (IId-4), or (IId-5), as described herein.
• R 2 comprises a moiety of formula: , or .
• the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein comprises formula (IId) as described herein.
• the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein comprises formula (IId-1), (IId-2), (IId- 3), (IId-4), or (IId-5), as described herein.
• the compound of formula (I) as described herein has formula: or , or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, and p are as described herein.
• X is N R 6 , where R 6 is hydrogen or R 6A -substituted or unsubstituted C 1-3 alkyl.
• [0140] in one embodiment is a compound selected from compounds 1-36, 38-45, 47-62, 64- 108, 110-146, and 149-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• In one embodiment is a compound selected from compounds 126-146 and 149-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• In one embodiment is a compound selected from compounds 6, 15, 24, 26, 29, 31-32, 57-59, 61-62, 64-66, 75-76, 91, 96, 104, 106, 111, 113, 118-124, 126-146, 149-156, 158-175, 181, 183, 186, 190-192, 195, 200, 204, 224-225, 228-229, 232-239, 241, 244-250, 255, 258-259, and 263 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• In one embodiment is a compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 57-58, 60-62, 64-77, 90-97, 100-102, 104, 108, 111, 113, 115, 118-146, 149-175, 181- 183, 186-187, 190, 195, 200, 204, 224-232, 234-239, 241, 244-250, 255, 258-259, and 263 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• In one embodiment is a compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 57-62, 64-72, 74, 76, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• In one embodiment is a compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 42-45, 47-48, 52, 57-58, 60-78, 84-88, 90-97, 100-104, 106, 108, 111-113, 115, 118-146, 149-175, 177-178, 181-183, 185-187, 189-192, 194-195, 197-200, 203-232, 234-250, and 252- 291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• In one embodiment is a compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 42-45, 47-48, 52, 57-62, 64-72, 74, 76, 84-88, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• [0148] is a compound selected from compounds 42-45, 47-48, and 52 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Synthesis of Compounds [0150] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein of the present disclosure can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.
• the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2 nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol.1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W.
• Synthetic chemistry transformations and protecting group methodologies useful in synthesizing compounds described herein and necessary reagents and intermediates include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
• Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein described herein can be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.
• Libraries of compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein of the formulae described herein can be prepared by a combinatorial split and mix approach or by multiple parallel syntheses using, for example, either solution phase or solid phase chemistry.
• a compound library comprising at least 2 compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.
• the Examples provide exemplary methods for preparing compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.
• Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein described herein.
• specific starting materials and reagents are depicted and discussed in the Examples, other starting materials and reagents can be substituted to provide a variety of derivatives and/or reaction conditions.
• many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry.
• reaction products from one another and/or from starting materials.
• the desired products of each step or series of steps are separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
• Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
• Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
• reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
• the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like. Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. [0157] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as by chromatography and/or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein described herein can be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated by use of a chiral HPLC column.
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
• converting e.g., hydrolyzing
• a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302).
• Racemic mixtures of chiral compounds or pharmaceutically acceptable salts thereof described herein can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
• diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
• the diastereomeric salts can be induced to separate by fractional crystallization or ionic chromatography.
• the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994, p.322).
• Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
• a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.
• Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
• the chemical reactions described herein may be readily adapted to prepare other compounds and pharmaceutically acceptable salts thereof described herein.
• the synthesis of non-exemplified compounds and pharmaceutically acceptable salts thereof described herein may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions.
• other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds and pharmaceutically acceptable salts thereof described herein.
• compositions comprising compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients.
• Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein as described herein can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
• a pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein as described herein and one or more pharmaceutically acceptable excipients.
• a typical formulation is prepared by mixing a compound or pharmaceutically acceptable salt thereof as described herein and an excipient.
• Suitable carriers, diluents and excipients include, but are not limited to, materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
• the particular excipient used will depend upon the means and purpose for which the compound or pharmaceutically acceptable salt thereof as described herein is being applied.
• Solvents are generally selected based on solvents recognized as safe (GRAS) to be administered to a mammal.
• GRAS solvents recognized as safe
• safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
• Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.
• the formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• the formulations can be prepared using conventional dissolution and mixing procedures.
• the bulk drug substance i.e., compound or pharmaceutically acceptable salt thereof as described herein or stabilized form thereof (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.
• the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein as described herein is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
• the pharmaceutical composition (or formulation) for application can be packaged in a variety of ways depending upon the method used for administering the drug.
• an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
• suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
• the container can also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
• the container has deposited thereon a label that describes the contents of the container. The label can also include appropriate warnings.
• Pharmaceutical formulations of the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein can be prepared for various routes and types of administration.
• a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof having the desired degree of purity can optionally be mixed with one or more pharmaceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16 th edition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution.
• Formulation can be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
• physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
• the pH of the formulation depends mainly on the particular use and the concentration of compound, but can range from about 3 to about 8.
• formulation in an acetate buffer at pH 5 can be a suitable embodiment.
• the pharmaceutical composition ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.
• the pharmaceutical compositions described herein can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
• the effective amount of the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, or treat the hyperproliferative disorder.
• the initial pharmaceutically effective amount of the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof administered parenterally per dose will be in the range of about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
• a pharmaceutical composition described herein comprises an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein in an amount of about: 1mg-10mg; 10mg-25mg; 20mg-50mg; 50mg-75mg; 70mg-100mg;100mg-150mg; 100mg-200mg; 100mg- 500mg; 200mg-500mg; 250mg-500mg; 500mg-1000mg; or 750mg-1000mg.
• Acceptable pharmaceutically acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, argin
• the active pharmaceutical ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
• colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
• macroemulsions for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
• Sustained-release preparations of compounds or pharmaceutically acceptable salts thereof as described herein may be prepared.
• sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound or pharmaceutically acceptable salt thereof as described herein , which matrices are in the form of shaped articles, e.g., films, or microcapsules.
• sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (US 3773919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT ⁇ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.
• the formulations include those suitable for the administration routes detailed herein.
• the formulations can conveniently be presented in unit dosage form and can be prepared by any methods. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
• Formulations of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of such compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
• Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
• the tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
• Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use.
• Formulations of compounds or pharmaceutically acceptable salts thereof as described herein intended for oral use can be prepared according to any method for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
• excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.
• inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
• granulating and disintegrating agents such as maize starch, or alginic acid
• binding agents such as starch, ge
• the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% W/W.
• the active ingredients can be employed with either a paraffinic or a water-miscible ointment base.
• the active ingredients can be formulated in a cream with an oil-in-water cream base.
• the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
• the topical formulations can desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
• the oily phase of the emulsions of compositions provided herein can be constituted from known ingredients in a known manner.
• the phase can comprise merely an emulsifier, it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
• a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
• the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
• Emulsifiers and emulsion stabilizers suitable for use in the formulation of described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
• Aqueous suspensions comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein can contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
• a suspending agent such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl
• the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
• preservatives such as ethyl or n-propyl p-hydroxybenzoate
• coloring agents such as a coloring agent
• flavoring agents such as sucrose or saccharin.
• sweetening agents such as sucrose or saccharin.
• the pharmaceutical compositions of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
• This suspension can be formulated using suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder.
• a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol or prepared as a lyophilized powder.
• acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile fixed oils can conventionally be employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid can likewise be used in the preparation of injectables.
• a time-release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight:weight(w/w)).
• the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
• an aqueous solution intended for intravenous infusion can contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
• Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
• Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
• the active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5%w/w.
• Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• Formulations for rectal administration can be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
• Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
• Suitable formulations include aqueous or oily solutions of the active ingredient.
• Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below.
• Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers considered to be appropriate.
• the formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
• sterile liquid carrier for example water
• Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
• Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
• the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof are formulated as a prodrug.
• prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized, or cleaved under biological conditions to provide the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• a prodrug as defined herein includes derivatives comprising one or more moieties that modulate or improve one or more physical, physiological or pharmaceutical property such as, but not limited to, solubility, permeability, uptake, biodistribution, metabolic stability, onset of action or some other druglike property, and is transformed to the bioactive or more biologically active substance as provided herein.
• a prodrug herein has no biological activity until release of the compound or pharmaceutically acceptable salt thereof.
• Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous (IV), intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.
• a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein is administered orally or by IV.
• the compounds can be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation. It will be appreciated that the preferred route can vary with for example the condition of the recipient.
• the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is administered orally, it can be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient.
• the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is administered parenterally, it can be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.
• a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients.
• compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are administered as pharmaceutical compositions capable of being administered to a subject orally or parenterally.
• the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein can be formulated for topical or parenteral use where the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is dissolved or otherwise suspended in a solution suitable for injections, suspensions, syrups, creams, ointments, gels, sprays, solutions and emulsions.
• Oral administration can promote patient compliance in taking the compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy.
• Oral pharmaceutical compositions comprising a compound described herein include, but are not limited to, tablets (e.g., coated, non-coated and chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric coated capsules, and sustained release capsules). Tablets can be prepared by direct compression, by wet granulation, or by dry granulation.
• Oral pharmaceutical compositions comprising a compound described herein can be formulated for delayed or prolonged release.
• a dose to treat human patients can range from about 10 mg to about 1000 mg of a compound described herein.
• a typical dose can be about 100 mg to about 300 mg of the compound.
• a dose can be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound.
• Administration as used herein refers to the frequency of dosing and not, for example, the number of individual units a patient described herein must take for a dose.
• a patient may take two or more dosage units (e.g., two or more pills/tablets/capsules) QD.
• toxicity factors can influence the dosage and administration regimen.
• the pill, capsule, or tablet can be ingested daily or less frequently for a specified period of time.
• the regimen can be repeated for a number of cycles of therapy.
• Methods of Treating and Uses [0191]
• the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as Ras inhibitors.
• the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as KRas inhibitors.
• the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as NRas inhibitors.
• the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as HRas inhibitors.
• the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as G12D Ras inhibitors, and as G12D KRas inhibitors.
• Provided herein are methods of contacting a cell, such as an ex vivo cell, with a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, to inhibit Ras activity (e.g., KRas activity) in the cell.
• the activity is mutant G12D KRas activity.
• methods of treating a cancer comprising a KRas mutation comprising administering to a patient having such cancer, an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.
• the KRas mutation is a KRas G12D mutation.
• the methods further comprise testing a sample (e.g., as set forth herein) from the patient before administration of a compound of pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRas G12D mutation.
• a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition described herein is administered to the patient after the patient sample is determined to be positive for (e.g., the presence of) a KRas G12D mutation.
• the methods of treating a cancer described herein relate to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS- related cancers (e.g.
• lymphoma and Kaposi's sarcoma anal cancer, appendix cancer, astrocytomas, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing
• the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
• the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer.
• the cancer is pancreatic cancer, lung cancer, or colon cancer.
• the lung cancer can be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC).
• the cancer is colorectal cancer.
• the cancer is pancreatic cancer.
• the cancer is lung adenocarcinoma.
• the methods provided herein can also comprise testing a sample from the patient before administration of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRas G12D mutation.
• a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRas G12D mutation.
• a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein is not administered unless a patient sample comprises a KRas G12D mutation.
• the cancer is pancreatic cancer, lung cancer, or colorectal cancer.
• the cancer is tissue agnostic (comprises a KRas G12D mutation).
• the pancreatic cancer, lung cancer, or colorectal cancer comprises a KRas G12D mutation.
• Further provided herein are methods of treating lung cancer comprising a KRas G12D mutation in a patient having such a lung cancer.
• the lung cancer is non-small cell lung carcinoma (NSCLC).
• NSCLC non-small cell lung carcinoma
• SCLC squamous-cell lung carcinoma
• lung cancer is adenocarcinoma, NSCLC, or SCLC.
• the lung cancer is small cell lung carcinoma.
• the lung cancer is glandular tumors, carcinoid tumors or undifferentiated carcinomas.
• the lung cancer can be stage I or II lung cancer.
• the lung cancer is stage III or IV lung cancer.
• the methods provided herein include administration of the compound as a 1L therapy.
• Still further provided herein are methods of treating pancreatic cancer comprising a KRas G12D mutation in a patient having such pancreatic cancer.
• a method (M2) of pancreatic lung cancer comprising a KRas G12D mutation in a patient having pancreatic cancer comprising administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the patient has been previously treated with radiation and one or more chemotherapy agents.
• the pancreatic cancer is stage 0, I, or II.
• the pancreatic cancer is stage III or stage IV.
• Still further provided herein are methods of treating colon cancer comprising a KRasG12D mutation in a patient having such colon cancer.
• a method (M3) of treating colon cancer comprising a KRas G12D mutation in a patient having, the method comprising administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein to the patient.
• the colon cancer is stage I or II. In another embodiment, the colon cancer is stage III or stage IV.
• the method further comprises: (a) determining the absence or presence of a KRas G12D mutation in a sample taken from a patient with a suspected diagnosed cancer; and (b) administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• a KRas G12D mutation in a sample taken from a patient with a suspected diagnosed cancer
• administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the method comprises: (a) determining the absence or presence of a KRas G12D mutation in a sample taken from a patient with a suspected diagnosed cancer; and (b) administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the patient is diagnosed with a cancer described herein.
• the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy.
• the sample is taken before administration of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein and after administration of another chemotherapeutic agent.
• the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein is administered as provided herein (e.g. orally or IV).
• the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof can be for the therapeutic treatment of a cancer comprising a Kras G12D mutation.
• a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof for the therapeutic and/or prophylactic treatment of a cancer comprising a KRas G12D mutation.
• the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12D mutation.
• Still further provided herein are uses of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting tumor metastasis.
• methods for inhibiting tumor metastasis comprising administering to a patient having a tumor a therapeutically effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the inhibition is of a tumor comprising a KRas G12D mutation.
• inhibiting tumor metastasis in a patient described herein results in reduction of tumor size.
• inhibiting tumor metastasis in a patient described herein results in stabilizing (e.g. no further growth) of tumor size. In another embodiment, inhibiting tumor metastasis in a patient described herein results in remission of the cancer and/or its symptoms.
• methods for inhibiting proliferation of a cell population comprising contacting the cell population with a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the cell population is in a human patient.
• the cell population comprises a KRas G12D mutation.
• KRas inhibited is KRas G12D .
• inhibiting KRas results in decreased tumor size.
• inhibiting KRas results in remission of the cancer and/or its symptoms.
• the mutant protein comprises a KRas G12D mutation.
• the activity of KRas is decreased after contacting with a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the downregulation of activity of the KRas mutant protein treats a cancer described herein in a patient described herein.
• the downregulation of activity of the KRas mutant protein results in decreased tumor size.
• the downregulation of activity of the KRas mutant protein results in remission of a cancer described herein and/or its symptoms.
• the methods provided herein comprise inhibiting Kras G12D activity in a cell by contacting said cell with an amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRas G12D in said cell.
• the methods provided herein comprise inhibiting KRas G12D activity in a tissue by contacting said tissue with an amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRas G12D in said tissue.
• the methods provided herein comprise inhibiting KRas G12D activity in a patient described herein by contacting said patient with an amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRas G12D in said patient.
• a labeled KRas G12D mutant protein comprising reacting a KRas G12D mutant protein with a labeled compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein to result in the labeled KRas G12D mutant protein.
• the label is an imaging agent.
• the labeled KRas G12D can be used to detect the absence or presence of G12D mutant KRas in a patient sample, thereby detecting the presence or absence of a cancer mediated by mutant KRas.
• Still further provided herein are methods of inhibiting Ras-mediated cell signaling.
• the methods comprise contacting a cell with an effective amount of one or more compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof disclosed herein thereof.
• Inhibition of Ras-mediated signal transduction can be assessed and demonstrated by a wide variety of ways known in the art.
• Non-limiting examples include a showing of (a) a decrease in GTPase activity of Ras; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream in the Ras pathway, such as a decrease in pMEK level; and/or (e) a decrease in binding of Ras complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.
• KRas mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments are directed to administration of a disclosed compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition) as described herein to a patient in need of treatment of a hematological malignancy.
• Such malignancies include but are not limited to leukemias and lymphomas.
• the presently disclosed compounds can be used for treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and/ or other leukemias.
• ALL acute lymphoblastic leukemia
• AML acute myelogenous leukemia
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• CML chronic myelogenous leukemia
• AoL acute monocytic leukemia
• the compounds or a pharmaceutically acceptable salt thereof described herein are useful for treatment of lymphomas such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.
• Determining whether a tumor or cancer comprises a KRas G12D mutation can be undertaken by assessing the nucleotide sequence encoding the KRas protein, by assessing the amino acid sequence of the KRas protein, or by assessing the characteristics of a putative KRas mutant protein.
• the sequence of wild-type human KRas e.g., Accession No. NP203524. is known in the art.
• Methods for detecting a mutation in a KRas nucleotide sequence are known by those of skill in the art.
• PCR-RFLP polymerase chain reaction- restriction fragment length polymorphism
• PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
• MASA mutant allele-specific PCR amplification
• direct sequencing primer extension reactions
• electrophoresis oligonucleotide ligation assays
• hybridization assays TaqMan assays
• SNP genotyping assays high resolution melting assays and microarray analyses.
• samples are evaluated for G12d KRas mutations by real-time PCR.
• Methods for determining whether a tumor or cancer comprises a KRas G12D mutation can use a variety of samples.
• the sample is taken from a subject having a tumor or cancer.
• the sample is a fresh tumor/cancer sample.
• the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. [0218] Further provided herein are uses of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection (e.g. IV administration). In some embodiments, the cancer is comprises a KRas G12D mutation.
• the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
• the cancer is lung cancer, colorectal cancer, or pancreatic cancer.
• the cancer is colorectal cancer.
• the cancer is pancreatic cancer.
• the cancer is lung adenocarcinoma.
• the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein.
• the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound or a pharmaceutically acceptable salt thereof described herein such that they do not adversely affect each other.
• the combination therapy may provide "synergy” and prove “synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
• the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
• Combination therapies herein comprise the administration of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, and the use of at least one other treatment method.
• the amounts of the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
• the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin- like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan, or such as etoposide, or such as doxorubicin), a taxane (such as anti-microtubule agents including paclitaxel and docetaxel), an anti-metabolite agent (such as 5-FU or such as gemcitabine), or an alkylating agent (such as cisplatin or such as cyclophosphamide), or a
• the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as Erlotinib or such as Afatinib.
• EGFR epidermal growth factor receptor
• the additional therapeutic agent is gefitinib, osimertinib, or dacomitinib.
• the additional therapeutic agent is a monoclonal antibody such as cetuximab (Erbitux) or panitumumab (Vectibix).
• the GFR inhibitor is a dual or pan- HER inhibitor.
• the additional therapeutic agent is a phosphatidylinositol-3- kinase (PI3K) inhibitor, such as GDC-0077, GDC-0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib).
• PI3K phosphatidylinositol-3- kinase
• GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4- methanesulfonyl-piperazin- 1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine or a salt thereof (e.g., bismesylate salt).
• the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor.
• IGF1R insulin-like growth factor receptor
• the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541.
• the additional therapeutic agent is IGOSI-906 (Linsitinib), BMS-754807, or in other embodiments the additional therapeutic agent is a neutralizing monoclonal antibody specific to IGF1R such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (robatumumab).
• the additional therapeutic agent is a Janus kinase (JAK) inhibitor.
• the additional therapeutic agent is CYT387, GLPG0634, Baricitinib, Lestaurtinib, momelotinib, Pacritinib, Ruxolitinib, or TG101348.
• the additional therapeutic agent is an anti-glypican 3 antibody.
• the anti-glypican 3 antibody is codrituzumab.
• the additional therapeutic agent is an antibody drug conjugate (ADC).
• the ADC is polatuzumab vedotin, RG7986, RG7882, RG6109, or RO7172369.
• the additional therapeutic agent is an MDM2 antagonist.
• the MDM2 antagonist is idasanutlin.
• the additional therapeutic agent is an agonistic antibody against CD40.
• the agonistic antibody against CD40 is selicrelumab (RG7876).
• the additional therapeutic agent is a bispecific antibody.
• the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP- DR5), RG6160, RG6026, ERY974, or anti-HER2/CD3.
• the additional therapeutic agent is a targeted immunocytokine.
• the targeted immunocytokine is RG7813 or RG7461.
• the additional therapeutic agent is an antibody targeting colony stimulating factor-1 receptor (CSF-1R).
• the CSF-1R antibody is emactuzumab.
• the additional therapeutic agent is a personalized cancer vaccine.
• the personalized cancer vaccine is RG6180.
• the additional therapeutic agent is an inhibitor of BET (bromodomain and extraterminal family) proteins (BRD2/3/4/T). In some embodiments, the BET inhibitor is RG6146. [0235] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A). [0236] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, giredestrant).
• BET bromodomain and extraterminal family proteins
• the additional therapeutic agent is an MET kinase inhibitor, such as Crizotinib, tivantinib, AMG337, cabozantinib, or foretinib.
• the additional therapeutic agent is a neutralizing monoclonal antibody to MET such as onartuzumab.
• the additional therapeutic agent is a SRC family non-receptor tyrosine kinase inhibitor.
• the additional therapeutic agent is an inhibitor of the subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors in this respect include Dasatinib.
• the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor.
• the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, COTELLIC® (cobimetinib), PD0325901, or RO5126766.
• the MEK inhibitor is GSK-1120212, also known as trametinib.
• the additional therapeutic agent is an extracellular-signal- regulated kinase (ERK) inhibitor.
• the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.
• the protein kinase inhibitor is taselisib, ipatasertib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, Afatinib, Axitinib, Atezolizumab, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunit
• the additional therapeutic agent is a topoisomerase inhibitor.
• the topoisomerase inhibitor is Irinotecan.
• the additional therapeutic agent is a taxane. Exemplary taxanes include Taxol and Docetaxel.
• other chemotherapeutics are presently known in the art and can be used in combination with the compounds and pharmaceutically acceptable salts thereof described herein.
• the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
• chemotherapeutic agents include cytotoxic agents, and non-peptide small molecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents.
• Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methyl melamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmus
• paclitaxel TAXOL TM , Bristol-Myers Squibb Oncology, Princeton, N.J.
• docetaxel TAXOTERE TM , Rhone-Poulenc Rorer, Antony, France
• retinoic acid esperamicins
• capecitabine ecitabine
• pharmaceutically acceptable salts, acids or derivatives of any of the above TAXOL TM , Bristol-Myers Squibb Oncology, Princeton, N.J.
• chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4- hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;
• the compounds or pharmaceutical acceptable salts thereof or pharmaceutical composition as described herein can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, VenclextaTM, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3- Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Bir
• the compound and the additional therapeutic agent are co-administered. In other embodiments, the compound and the additional therapeutic agent are separately administered.
• the compound and the additional therapeutic agent are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound and any of the additional therapeutic agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound and any of the additional therapeutic agents described herein can be simultaneously administered, wherein both the agents are present in separate formulations.
• the compound can be administered just followed by any of the additional therapeutic agents described herein, or vice versa.
• the compound and any of the additional therapeutic agents described herein are administered a few minutes apart, or a few hours apart, or a few days apart.
• kit articles of manufacture, or "kit", containing materials useful for the treatment of a cancer provided herein.
• the kit comprises a container comprising compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.
• the kit may further comprise a label or package insert on or associated with the container.
• Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
• the container may be formed from a variety of materials such as glass or plastic.
• the container may hold a compound or a pharmaceutically acceptable salt thereof described herein or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
• At least one active agent in the composition is a compound or a pharmaceutically acceptable salt thereof described herein.
• the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
• BWFI bacteriostatic water for injection
• phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution or dextrose solution.
• BWFI bacteriostatic water for injection
• phosphate-buffered saline such as bacteriostatic water for injection
• Ringer's solution or dextrose solution such as a commercial and user standpoint
• the kits are suitable for the delivery of solid oral forms of a compound or a pharmaceutically acceptable salt thereof described herein, such as tablets or capsules.
• Embodiment 1 A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is R 7 -substituted or unsubstituted naphthyl, R 7 -substituted or unsubstituted isoquinolinyl, R 7 -substituted or unsubstituted indazolyl, R 7 -substituted or unsubstituted indanyl, R 7 - substituted or unsubstituted benzothiazolyl, R 7A
• Embodiment 1 A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is formula (E), wherein X 1 is N or CR 7C and R 7C is hydrogen or halogen; each R 7A is independently halogen, CN, NH2, N(Me)2, R 7B -substituted or unsubstituted C1-3 alkyl, unsubstituted C1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo, or C1-3 alkyl; L 1 is R L1 -substituted or unsubstituted C1-4 alkylene; R L1 is halogen
• Embodiment 2 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 1, wherein X 1 is CR 7C and R 7C is hydrogen or halogen.
• Embodiment 3 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 1, wherein X 1 is N.
• Embodiment 5 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 4, wherein no more than one R 7A is hydrogen.
• Embodiment 6. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 4, wherein R 7A is not hydrogen.
• Embodiment 7. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 4, wherein at least one R 7A is halogen.
• Embodiment 10 A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is R 7A -substituted phenyl or R 7A -substituted pyridinyl; each R 7A is independently halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl; L 1 is R L1 -substituted or unsubstituted C1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C3-4 cycloalkyl; R 2 is
• Embodiment 11 A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2;
• L 1 is R L1 -substituted or unsubstituted C1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C3-4 cycloalkyl;
• R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O;
• R 9 is independently halogen, CN, OH, OCF3, OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3 alkyl, R 10 -substituted or unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, R 10 - substituted or unsubstituted C 1-3 alkylidene, or R 10 -substituted or unsubstituted C3-4 cycl
• Embodiment 12 A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is of formula (E1); each R 7A is independently halogen, CN, NH 2 , N(Me) 2 , R 7B -substituted or unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo, or C 1-3 alkyl; L 1 is R L1 -substituted or unsubstituted C 1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl
• Embodiment 13 A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together make a 6- or 7-membered ring Ring A; p is 0, 1, or 2; R 1 is ; L 1 is R L1 -substituted or unsubstituted C1-4 alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl, or wherein two R L1 together form an unsubstituted C3-4 cycloalkyl; R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; R 9 is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -sub
• Embodiment 14 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-13, wherein each R 4 is hydrogen.
• Embodiment 15. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-13, wherein one R 4 is hydrogen and one R 4 is methyl.
• Embodiment 16 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-13, wherein R 4 is hydrogen and one R 4 is -CF 3 .
• Embodiment 18 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-3 and 12, wherein each R 7A is independently halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.
• Embodiment 18 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-3, 10, 12, and 14-17, wherein at least one R 7A is NH 2 .
• Embodiment 19 Embodiment 19.
• Embodiment 20 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-18, wherein L 1 is methylene.
• Embodiment 20 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-18, wherein L 1 is R L1 - substituted or unsubstituted C2-3 alkylene.
• Embodiment 21 Embodiment 21.
• Embodiment 23 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is a moiety of formula (B), or a stereoisomer thereof, wherein R 9 is independently halogen or unsubstituted C 1-3 alkyl; and r is 1 or 2.
• Embodiment 23 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is: or , or a stereoisomer thereof.
• Embodiment 24 Embodiment 24.
• Embodiment 25 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is: or , or a stereoisomer thereof, wherein R 9 is independently halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene; each R 10 is independently hydrogen or halogen; and r is 1 or 2.
• Embodiment 25 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is: or , or a stereoisomer thereof.
• Embodiment 26 Embodiment 26.
• Embodiment 27 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is a moiety of formula (C) or a stereoisomer thereof, wherein X 2 is CR 9 or O.
• Embodiment 27 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is a moiety of formula (D) or (D1) or a stereoisomer thereof, wherein X 3 is CR 9 , NR 9 , or O.
• Embodiment 28 Embodiment 28.
• Embodiment 29 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is: or , or a stereoisomer thereof.
• Embodiment 29 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-20, wherein R 2 is: .
• Embodiment 30 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-29, wherein R 3 is halogen.
• Embodiment 31 Embodiment 31.
• Embodiment 32 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 31, wherein the bridge comprises 2 carbon atoms.
• Embodiment 33 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 31, the bridge comprises 1 carbon atom.
• Embodiment 34 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 31, the bridge comprises 1 carbon atom.
• Embodiment 35 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 34, wherein R 6 is hydrogen or R 6A - substituted or unsubstituted C 1-3 alkyl.
• Embodiment 36 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 34, wherein R 6 is R 6A -substituted or unsubstituted C 1-3 alkyl.
• Embodiment 37 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 34-36, wherein R 6A is halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1-3 alkyl, or 4-membered heterocycle.
• Embodiment 38 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of embodiment 34, wherein R 6 is hydrogen.
• Embodiment 39 Embodiment 39.
• Embodiment 40 The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-13, wherein the compound of formula (I) comprises formula (IIa), (IIb), (IIc), or (IId), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 41 Embodiment 41.
• Embodiment 42 A compound selected from compounds 1-36, 38-45, 47-62, 64-108, 110-146, and 149-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 43 A compound selected from compounds 1-36, 38-45, 47-62, 64-108, 110-146, and 149-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 44 A compound selected from compounds 126-146 and 149-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 45 A compound selected from compounds 126-146 and 149-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 47 Embodiment 47.
• Embodiment 49 Embodiment 49.
• Embodiment 51 A compound selected from compounds 112, 205-218, 242-243, 252- 254, 261-262, and 264-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 52 A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-51, and one or more pharmaceutically acceptable excipients.
• Embodiment 53 Embodiment 53.
• a method of treating cancer comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-51, or a pharmaceutical composition of embodiment 52.
• Embodiment 54 The method of embodiment 53, wherein the cancer is characterized as comprising a KRas mutation.
• Embodiment 55 The method of embodiment 54, wherein the KRas mutation corresponds to a KRas G12D mutation.
• Embodiment 56 The method of any one of embodiments 53-55, further comprising testing a sample from the patient before administration for the absence or presence of a KRas G12D mutation.
• Embodiment 57 The method of embodiment 56, wherein the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRas G12D mutation.
• Embodiment 58 The method of any one of embodiments 53-57, wherein the cancer is tissue agnostic.
• Embodiment 59 The method of any one of embodiments 53-57, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.
• Embodiment 60 The method of embodiment 59, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.
• Embodiment 61 The method of embodiment 59, wherein the cancer is pancreatic cancer.
• Embodiment 62 The method of embodiment 59, wherein the cancer is colorectal cancer.
• Embodiment 63 The method of any one of embodiments 53-62, further comprising administering at least one additional therapeutic agent.
• Embodiment 64 Embodiment 64.
• the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an anti-metabolite agent, or an alkylating agent.
• EGFR epidermal growth factor receptor
• PI3K phosphatidylinositol kinase
• IGF1R insulin-like growth factor receptor
• JK Janus kinase
• MEK mitogen-activated protein kinase
• ERK extracellular-signal-regulated kinase
• Embodiment 66 Use of a compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRas G12D mutation.
• Embodiment 67 Use of a compound according to any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.
• Embodiment 68 Use of a compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRas G12D mutation.
• Embodiment 69 A compound according to any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, for the therapeutic and/or prophylactic treatment of a cancer comprising a KRas G12D mutation.
• Embodiment 70 Use of a compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, for the therapeutic and/or prophylactic treatment of a cancer comprising a KRas G12D mutation.
• Embodiment 71 A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.
• Embodiment 72 A method of embodiment 71, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.
• Embodiment 73 A method of embodiment 71, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.
• a method for inhibiting tumor metastasis comprising administering to an individual in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.
• Embodiment 74 A compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in regulating activity of a KRas mutant protein.
• Embodiment 75 A compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting proliferation of a cell population.
• Embodiment 76 The compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt for use of embodiment 75, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.
• Embodiment 77 A compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.
• Embodiment 78 Use of a compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for regulating activity of a KRas mutant protein.
• Embodiment 79 Use of a compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting proliferation of a cell population.
• Embodiment 80 The use of embodiment 79, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.
• Embodiment 81 Use of a compound of any one of embodiments 1-51, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis. Examples [0331] The following Examples are presented by way of illustration, not limitation.
• Step 2 tert-Butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3-fluoro-4-pyridyl)carbamate
• a solution of 2,6-dichloro-3-fluoropyridin-4-amine (4.82 g, 26.6 mmol) in THF 100mL was added NaHMDS (53.1 mL, 2M in THF) at 0°C.
• the resulting solution was stirred for 30 min at 0°C.
• Boc 2 O 29.0 g, 133 mmol
• THF 450 mL
• Step 3 tert-Butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate
• tert-butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3- fluoro-4-pyridyl)carbamate 9.11 g, 23.9 mmol
• LDA 41.9 mL, 1M in THF
• the resulting solution was stirred for 0.5 h at -78°C.
• the reaction was quenched with aq. NH 4 Cl and extracted with EtOAc (300 mL*2).
• Step 4 4-Amino-2,6-dichloro-5-fluoronicotinic acid
• LC-MS: (ESI, m/z): [M+H] + 225.
• Step 2 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one
• Ch3ONa 320 mg, 5.93 mmol
• CH 3 I 842 mg, 5.93 mmol
• Step 1 tert-Butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [0349] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (50.0 g, 236 mmol) in DMF (800 mL) was added K 2 CO 3 (65.1 g, 472 mmol) and BnBr (60.1g, 353.53 mmol). Stirred at rt for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc.
• Step 2 3-(tert-Butyl) 2-methyl (1R,2S,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3- dicarboxylate and 3-(tert-Butyl) 2-methyl (1R,2R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane- 2,3-dicarboxylate [0351] Under N 2 , to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (23.0 g, 76.06 mmol) and TMEDA (17.7 g, 152.59 mmol) in diethyl ether (500 mL) was added dropwise s-BuLi (117 mL, 1.3 M in hexane) at -78°C, and the mixture was stirred at - 78°C
• Step 3 tert-Butyl (1R,2S,5S)-8-benzyl-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate
• 3-(tert-butyl) 2-methyl (1R,2S,5S)-8-benzyl-3,8- diazabicyclo[3.2.1]octane-2,3-dicarboxylate 20.0g, 55.5mmol, faster peak of previous operation
• THF 300 mL
• LiAlH 4 (4.20g, 111mmol
• Step 4 (6S,9R,9aS)-10-Benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3- one [0355] Under nitrogen, to a solution of tert-butyl 8-benzyl-4-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (5.1 g, 15.34 mmol) in THF (100 mL) was added NaH (1.35 g, 33.75 mmol, 60% in mineral oil) at 0°C.
• Step 5 (6S,9R,9aS)-Hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one
• 6S,9R,9aS A mixture of (6S,9R,9aS)-10-Benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4- a]azepin-3-one (10.0 g, 38.7 mmol) and Pd/C (3.0 g, 10% dry ) in methyl alcohol (200 mL) was stirred under an atmosphere of hydrogen at room temperature for 2 hours at room temperature. The catalyst was filtered off.
• Step 7 tert-Butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
• Step 2 (1S,6S,9R,9aS)-10-Benzyl-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4- a]azepin-3-one
• tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3- carboxylate 7.0 g, 23.1mmol
• TMEDA 5.38 g, 46.3mmol
• diethyl ether 70 mL
• s-BuLi 35.6 mL, 46.3mmol, 1.3 M in hexane
• Step 3 (1S,6S,9R,9aS)-1-Methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin- 3-one
• (1S,6S,9R,9aS)-10-Benzyl-1-methylhexahydro-1H,3H-6,9- epiminooxazolo[3,4-a]azepin-3-one (1.00 g, 3.67 mmol) (the compound a of previous step) and Pd/C (500 mg, 10%) in methyl alcohol (15 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen gas.
• Step 4 tert-Butyl (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9- epiminooxazolo[3,4-a]azepine-10-carboxylate [0370] A solution of (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4- a]azepin-3-one (658 mg, 3.61 mmol), (Boc) 2 O (1.18 g, 5.41 mmol) and DIPEA (1.4 g, 10.8 mmol) in dichloromethane (10 mL) was stirred for 30 min at room temperature.
• Step 5 tert-Butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
• Step 2 Ethyl (7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate [0377] Under nitrogen, to a solution of ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (1.22 g, 5.68 mmol) in tetrahydrofuran (100 mL) was added NaBH 4 (70.3 mg, 1.85 mmol) at 0 °C. The mixture was stirred for 30 mins at 0 °C. The reaction was quenched with water and concentrated under vacuum.
• Step 3 Ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate and Ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate [0379] Under nitrogen, to a solution of ethyl (7aS)-2-hydroxy-5-oxotetrahydro-1H- pyrrolizine-7a(5H)-carboxylate (809 mg, 3.80 mmol) was added DAST (923 mg, 5.74 mmol, dissolved in 20 mL DCM) at -15 °C.
• Step 4 ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
• ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H- pyrrolizine-7a(5H)-carboxylate 310 mg, 1.44 mmol
• LiAlH 4 3.1 mL, 1M in THF
• Step 2 tert -Butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14- carboxylate [0406] To a solution of tert -butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 2.15 mmol) in DCM (10 mL) was added DIPEA (4.16 g, 32.3 mmol) and BO
• Step 2 tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8- ab]heptalene-14-carboxylate [0415] To a solution of tert-butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.
• Step 1 4-Amino-2,6-dichloro-5-fluoronicotinamide
• Step 2 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one
• a solution of 4-amino-2,6-dichloro-5-fluoronicotinamide (1.51 g, 6.74 mmol) in triethoxymethane (30 mL) was stirred at 150°C for 3 hours. Then the mixture was concentrated under vacuum. The residue was triturated with EtOAc/petroleum ether (1:1, 10 mL). The solid was collected by filtration to afford the title compound (1.04 g, crude) as a yellow solid which was used for next step without further purification.
• Step 3 tert-Butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0430] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (624 mg, 2.58 mmol, intermediate 3) in DMF (6 mL) was added NaH (134 mg, 3.35 mmol, 60% in mineral oil) at 0°C.
• Step 4 tert-Butyl (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa- 3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate [0432] Under nitrogen, a solution of tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (452 mg, 1.03 mmol), BOP-Cl (1.05 g, 4.12 mmol) and DIPEA (1.99 g, 15.5 mmol) in DCM (10mL) was stirred for
• Step 2 tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro- 5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate [0437] To a solution of tert-butyl (1R,2R,5S)-2-((S)-1-((7-chloro-8-fluoro-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (476 mg, 1.05 mmol) in DCM (20mL) was added DIPEA (2.03 g, 15.71 mmol) and BOPCl (1.
• Step 2 6-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole
• a solution of 77-bromo-6-fluoro-1-methyl-1H-indazole 150 mg, 0.660 mmol
• Pin 2 B 2 836 mg, 3.29 mmol
• Pd(dppf)Cl 48.2 mg, 0.0700 mmol
• KOAc 258 mg, 2.63 mmol
• Step 2 6-(Allylsulfonyl)-N, N-bis(4-methoxybenzyl)-4-methyl-5- (trifluoromethyl)pyridin-2 amine
• 6-allylsulfanyl-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5- (trifluoromethyl)pyridin-2-amine 5.05 g, 10.3 mmol
• mCPBA (14.3 g, 82.7 mmol
• Step 2 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate
• Step 2 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate
• Step 3 ((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane
• a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3.01 g, 6.32 mmol)
• Pin 2 B 2 (3.22 g, 12.7 mmol)
• Pd(dppf)Cl 2 (486 mg, 0.630 mmol)
• KOAc (1.24 g, 12.7 mmol) in 1,4-Dioxane (12 mL) was stirred at 110°C overnight.
• Step 2 2-Fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline
• Step 2 2-Fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline
• Step 3 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)aniline
• Step 3 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)aniline
• Step 4 (5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)boronic acid
• 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3- methyl-4-(trifluoromethyl)aniline (2.40 g, 4.68 mmol) and triisopropyl borate (1.60 mL, 6.91mmol) in THF (35 mL) was added n-BuLi (2.2 mL, 2.5 M in THF) at -78°C. The resulting solution was stirred for 1h at -78°C.
• Step 2 5-Bromo-2-fluoro-4-iodo-N, N-bis(4-methoxybenzyl)aniline
• acetic acid 150 mL
• the reaction was quenched with aq. Na 2 S 2 O 3 (15 mL), diluted with EtOAc (300 mL) and washed with water (250 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 3 5-Bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline
• Step 3 5-Bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline
• Step 4 2-fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-4-(trifluoromethyl)aniline
• 5-bromo-2-fluoro-N, N-bis[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)aniline 321 mg, 0.640 mmol
• Pin 2 B 2 (327 mg, 1.29 mmol)
• Pd(dppf)Cl 2 99.1 mg, 0.131 mmol
• KOAc 189 mg, 1.93 mmol
• Step 2 N-(5-Fluoronaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine
• N-(5-bromonaphthalen-1-yl)-1,1,1-trimethyl-N- (trimethylsilyl)silanamine 87.2 g, 238 mmol
• n-BuLi 148 mL, 2.5 M in n-hexane
• N-Fluoro-N-(phenylsulfonyl) benzenesulfonamide (121 g, 382 mmol) was added at this temperature.
• the reaction mixture was warmed naturally to room temperature and stirred at this temperature for 1 h.
• the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (500 mL*3).
• the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
• the residue was purified by flash chromatography on silica gel (gradient: 100% petroleum ether) to afford 45.1 g (62.1%) of the title compound as a light red syrup.
• LC-MS: (ESI, m/z): [M+H] + 203.
• Step 3 5-Fluoronaphthalen-1-amine
• N-(5-Fluoronaphthalen-1-yl)-1,1,1-trimethyl-N- (trimethylsilyl)silanamine 45.1 g, 148 mmol
• MeOH 300 mL
• aqueous HCl 40 mL, 1 M
• the resulting residue was purified by reverse phase chromatography (gradient: 0–65 % acetonitrile in water (0.1% TFA)) to afford 23.4 g (98.4% yield) of the title compound as a brown solid.
• Step 4 2,4-Dibromo-5-fluoronaphthalen-1-amine
• a solution of 5-fluoronaphthalen-1-amine (10.0 g, 62.0 mmol) in HOAc (100 mL) was added a solution of bromine (21.4 g, 134 mmol) in HOAc (100 mL) at 0°C. Then the mixture was stirred at 70°C for 3 h. Cooled to room temperature. The solid was collected by fltration and washed with HOAc (300 mL). Then the solid was suspended in aqueous NaOH (15%, 200 mL) and stirred for 20 min.
• Step 5 5-Bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole
• Step 6 4-Bromo-5-fluoronaphthalen-2-ol
• EtOH 150 mL
• THF 75 mL
• NaBH 4 3.15 g, 82.9 mmol
• the mixture was stirred at room temperature for 1.5 h and quenched with NaHSO 4 (125 mL, 10% in water).
• NaHSO 4 125 mL, 10% in water
• a majority of EtOH was stripped off under vacuum.
• the residual reaction mixture was extracted with EtOAc (3*150 mL).
• Step 7 1-Bromo-8-fluoro-3-(methoxymethoxy)naphthalene
• Step 8 2-(8-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [0500] Under nitrogen, a solution of 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene (5.1 g, 17.9 mmol), Pin 2 B 2 (11.4 g, 44.9 mmol), Pd(dppf)Cl 2 (1.38 g, 1.80 mmol) and KOAc (5.28 g, 53.8 mmol) in 1,4-dioxane (100 mL) was stired at 110°C for 4 h. Cooled to room temperature.
• Step 2 Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-1-yl)ethynyl)silane
• a solution of 3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.12 g, 2.17mmol)
• Pin 2 B 2 (1.65 g, 6.50 mmol)
• Pd(dppf)Cl 2 (166.7 mg, 0.22 mmol)
• KOAc (745 mg, 7.59 mmol) in toluene (11 mL) was stirred at 110°C overnight.
• Step 2 2-(8-Ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane
• 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.41 g, 3.87mmol)
• Pin 2 B 2 (2.95 g, 11.6 mmol
• Pd(dppf)Cl 2 (298 mg, 0.390 mmol)
• KOAc 949 mg, 9.67 mmol
• Step 2 3-Bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline
• NIS 1-(4-methoxyphenyl)methyl]-5-methyl-aniline
• TsOH 96.0 mg, 0.560 mmol
• Step 3 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline
• Step 3 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline
• Step 4 N,N-Bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl) aniline
• a solution of 3-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-4- (trifluoromethyl)aniline 100 mg, 0.2mmol
• Pin 2 B 2 (153.6 mg, 0.600 mmol
• PdCl 2 (dppf) (15.0 mg, 0.0200 mmol)
• KOAc 59.3 mg, 0.610 mmol
• Step 2 5-Bromo-2,3-difluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline
• a solution of 5-bromo-2,3-difluoro-N,N-bis[(4-methoxyphenyl)methyl]aniline (900 mg, 2.01 mmol) and NIS (676 mg, 3.02 mmol) in acetic acid (10 mL) was stirred at room temperature for 2 hours. Then the mixture was concentrated under vacuum.
• Step 3 5-Bromo-2,3-difluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline
• 5-bromo-2,3-difluoro-4-iodo-N,N-bis[(4- methoxyphenyl)methyl]aniline 900 mg, 1.57 mmol
• methyl 2,2-difluoro-2- (fluorosulfonyl)acetate 900 mg, 1.57 mmol
• DMA 9 mL
• CuI 300 mg, 1.57 mmol
• Step 4 2,3-Difluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)aniline
• 5-bromo-2,3-difluoro-N,N-bis[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)aniline 500 mg, 0.970 mmol
• Pin 2 B 2 (739 mg, 2.91 mmol
• PdCl 2 (dppf) (71.0 mg, 0.100 mmol)
• KOAc 285 mg, 2.91 mmol
• Step 2 3-Bromo-5-fluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline
• Step 2 3-Bromo-5-fluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline
• Step 3 3-Fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-4-(trifluoromethyl)aniline
• a solution of 3-bromo-5-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)aniline 129 mg, 0.260 mmol
• PdCl 2 (dppf) (19.0 mg, 0.0300 mmol)
• KOAc (76.0 mg, 0.780 mmol
• Pin 2 B 2 198 mg, 0.780 mmol
• Step 2 tert-Butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate
• 3-bromo-2,6-difluoro-5-methyl-benzoic acid (2.00 g, 7.97 mmol)
• diphenyl azidophosphate (3.28 g, 11.9 mmol)
• triethylamine (1.62 g, 16.0 mmol)
• 2-methyl- 2-propanol 50 mL
• Step 3 3-Bromo-2,6-difluoro-5-methylaniline
• a solution of tert-butyl N-(3-bromo-2,6-difluoro-5-methyl-phenyl) carbamate (2.00 g, 6.21 mmol) and HCl (30 mL, 4 mol/L in dioxane) in dichloromethane (30 mL) was stirred for 5 h at room temperature. Then the mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO 3 (aq.) and EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
• Step 4 2,6-Difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• DME 1,2-dimethoxyethane
• Step 2 Methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-2-carboxylate [0549] To a solution of 1-(tert-Butyl) 2-methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine- 1,2-dicarboxylate (1.26 g, 3.87 mmol) in dichloromethane (10 mL) was added TFA (5 mL). The resulting solution was stirred at room temperature for 30 min. Solvent was evaporated under vacuum to yield 2 g (crude) of the title compound as a yellow oil which was used for next step without further purification.
• Step 1 Ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate & Ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate
• Step 2 Ethyl (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'- pyrrolizine]-7a'(5'H)-carboxylate
• a solution of ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate 200 mg, 0.960 mmol
• NaI 7. mg, 0.480 mmol
• THF 5 mL
• TMSCF 3 476 mg, 3.35 mmol
• the resulting solution was stirred for 2.5 h at 65 °C.
• the solution was diluted with DCM, washed with sodium thiosulfate solution and dried over with Na 2 SO 4 .
• the organic layer was concentrated under vacuum.
• the residue was purified by flash chromatography on silica gel (gradient: 0%-35% ethyl acetate/petroleum ether) to afford the faster peak 95.0 mg (38.3% yield) and (gradient: 35%-90% ethyl acetate /petroleum ether) to afford the slower peak 108 mg (43.6% yield) as a yellow solid.
• Step 2 ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]- 7a'(5'H)-yl)methanol
• ethyl (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate 95.0 mg, 0.370 mmol, the faster peak of previous step) in THF (2.5 mL) was added LiAlH 4 (1.1 mL, 1 M in THF).
• Step 2 (1-Benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans) [0565] To an ice-cooled solution of diethyl trans-1-benzylpyrrolidine-2,5-dicarboxylate (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) under nitrogen was added LiAlH 4 (716 mg, 18.8 mmol) in several portions. The reaction was warmed to room temperature. After 2 h, the mixture was quenched with Na 2 SO 4 •10H 2 O. The solid was filtered, and the filtrate was concentrated under vacuum.
• Step 4 1-(2,5-Bis(hydroxymethyl)pyrrolidin-1-yl)-2-bromoethan-1-one (mixture of trans) [0569] To an ice-cooled solution of pyrrolidine-2,5-diyldimethanol (355 mg, 2.71 mmol) and N-methyl morpholine (410 mg, 4.06 mmol) in tetrahydrofuran (10 mL) was added 2-bromoacetyl bromide (539 mg, 2.67 mmol). After 1 h, the reaction was concentrated under vacuum.
• Step 5 6-(Hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (mixture of trans)
• Step 6 (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans) [0573]
• tetrahydrofuran 5 mL
• 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin- 4(3H)-one 60.0 mg, 0.350 mmol
• the reaction was cooled to room temperature and quenched with Na 2 SO 4 •10H 2 O.
• Step 2 (1-Benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans) [0578] To an ice-cooled solution of diethyl trans-1-benzylpyrrolidine-2,5-dicarboxylate (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) under nitrogen was added LiAlH 4 (716 mg, 18.8 mmol) in several portions. The reaction was warmed to room temperature. After 2 h, the mixture was quenched with Na 2 SO 4 •10H 2 O. The solid was filtered, and the filtrate was concentrated under vacuum.
• Step 3 Pyrrolidine-2,5-diyldimethanol (mixture of trans)
• a solution of (1-benzylpyrrolidine-2,5-diyl)dimethanol (0.60 g, 2.7 mmol) and Pd / C (180 mg, 10% w/w) in methanol (10 mL) was stirred at room temperature for 2 h.
• the catalyst was filtered, and the filtrate was concentrated to afford 405 mg (crude) of the title compound as a light yellow oil.
• LC-MS: (ESI, m/z): [M+H] + 132.1. The crude product was used without further purification.
• Step 4 (6R,8aR)-6-(Hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)- one & (6S,8aS)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one [0582] To a solution of pyrrolidine-2,5-diyldimethanol (7.9 g, 60.305 mmol) in IPA (300.0 mL) was added potassium trimethylsilanolate (16.98 g, 132.671 mmol) at 0 °C.
• Step 5 ((6S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol
• 6S,8aS 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1- c][1,4]oxazin-4(3H)-one
• the resulting solution warmed to 60 °C for 2 h.
• Step 2 (2'-Cyano-[1,1'-biphenyl]-4-yl)methyl methanesulfonate
• 2-[4-(hydroxymethyl)phenyl]benzonitrile (235 mg, 1.12 mmol)] and N,N-diisopropylethylamine (0.58 mL, 3.36 mmol) in dichloromethane (10 mL) was added methanesulfonicanhydride (254 mg, 1.46 mmol) at 0°C under nitrogen.
• the resulting solution was stirred for 2 h at room temperature, diluted with CH 2 Cl 2 and washed with brine.
• Step 3 4'-((((2R,7aS)-7a-((Trityloxy)methyl)hexahydro-1H-pyrrolizin-2- yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile
• (2R,8S)-8-(trityloxymethyl)-1,2,3,5,6,7- hexahydropyrrolizin-2-ol 448 mg, 1.12 mmol
• NaH 269 mg, 6.73 mmol, 60% in mineral oil
• reaction mixture was diluted with DCM, washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-100% EtOAc/petroleum ether) to afford 800 mg of the title compound as a colorless oil.
• the two enantiomers were separated by Prep-SFC with the following conditions: (Column: CHIRALPAK IG, 3*25cm, 5 ⁇ m ; Mobile Phase A:CO2, Mobile Phase B:IPA(0.5% 2M NH 3 -MeOH); Flow rate:70 mL/min; Gradient:30% B; Column Temperature: 35 °C; Back Pressure: 100 bar; 215 nm; RT1:6.86; RT2:7.89; Injection Volumn:1.5 ml; Number Of Runs:20) to yield 330 mg of faster peak and 340 mg slower peak as a white oil. The faster peak is the desired isomer.
• Step 2 Benzyl (1R,5R)-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate [0604] A solution of 3-benzyl 6-(tert-butyl) (1S,5R)-3,6-diazabicyclo[3.2.2]nonane-3,6- dicarboxylate (10.0 g, 27.7 mmol) in dichloromethane (60mL) and 4 M HCl/dioxane (20 mL) was stirred at room temperature for 2 h.
• Step 3 Benzyl (1R,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate [0606] A solution of benzyl (1R,5R)-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (11.4 g, 43.7 mmol), benzyl bromide (8.99 g, 52.5 mmol) and DIPEA (11.3 g, 87.5 mmol) in N,N- dimethylformamide (50 mL) was stirred at 80°C for 3 hours.
• Step 6 3-(tert-Butyl) 2-methyl (1R,2S,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane- 2,3-dicarboxylate
• tert-butyl (1R,5R)-6-benzyl-3,6- diazabicyclo[3.2.2]nonane-3-carboxylate 6.09 g, 19.2mmol
• TMEDA 2.72 g, 23.4mmol
• diethyl ether 46 mL
• s-BuLi 18.8 mL, 1.3 M in hexanes
• Step 8 (6R,9R,9aS)-11-Benzylhexahydro-1H,3H-6,9-(epiminomethano)oxazolo[3,4- a]azepin-3-one
• tert-butyl (1R,2S,5R)-6-benzyl-2-(hydroxymethyl)-3,6- diazabicyclo[3.2.2]nonane-3-carboxylate 480 mg, 1.39 mmol
• NaH (112 mg, 2.82 mmol, 60% in mineral oil
• Step 9 tert-Butyl (6R,9R,9aS)-3-oxohexahydro-1H,3H-6,9- (epiminomethano)oxazolo[3,4-a]azepine-11-carboxylate [0618] Under H 2 (3atm), a mixture of (6R,9R,9aS)-11-benzylhexahydro-1H,3H-6,9- (epiminomethano)oxazolo[3,4-a]azepin-3-one (330 mg, 1.20 mmol), 10% Pd/C (99.0 mg, dry) and Boc2O (530 mg, 2.45 mmol) in methyl alcohol (70 mL) was stirred at room temperature for 1 hour.
• Step 10 tert-Butyl (1R,2S,5R)-2-(hydroxymethyl)-3,6-diazabicyclo[3.2.2]nonane-6- carboxylate
• Step 2 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol
• MOMBr 6.70 g, 54.0 mmol
• Step 3 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate
• 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-ol) and N-(4-chlorophenyl)-1,1,1- trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide 5.85 g, 14.9 mmol
• THF 50 mL
• Step 4 ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane
• a solution of 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.51 g, 2.81 mmol)
• Pin 2 B 2 (1.43 g, 5.62 mmol)
• Pd(dppf)Cl 2 216 mg, 0.280 mmol
• KOAc 826 mg, 8.43 mmol
• Step 1 2-Chloro-3-fluoro-5-iodopyridin-4-amine
• 2-chloro-3-fluoropyridin-4-amine (20.0 g, 136 mmol) and NIS (37.0 g, 164 mmol) in CH 3 CN (260 mL) was added p-toluene sulfonic acid monohydrate (1.30 g, 6.83 mmol). The solution was stirred at 70 °C for 16 hours. The solvent was evaporated under vacuum.
• Step 2 Ethyl 4-amino-6-chloro-5-fluoronicotinate
• 2-chloro-3-fluoro-5-iodopyridin-4-amine (15.0 g, 55.1 mmol) in EtOH (260 mL) was added Pd(PPh 3 ) 2 Cl 2 (3.87 g, 5.51 mmol) and Et 3 N (20.1 g, 199 mmol) at room temperature.
• Pd(PPh 3 ) 2 Cl 2 3.87 g, 5.51 mmol
• Et 3 N 20.1 g, 199 mmol
• Step 3 Ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate
• trichloroacetyl isocyanate (10.3 mL, 86.3 mmol) at 25 °C.
• the resulting solution was stirred for 20 min at 25 °C.
• the mixture was concentrated under vacuum.
• the residue was washed with MTBE (250 mL).
• Step 5 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine
• a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (7.01 g, 32.5 mmol) and DIPEA (21.0 g, 162.8 mmol) in POCl 3 (70 mL) was stirred for 2 h at 100 °C.
• the mixture was added slowly to ice water, maintaining the system at ⁇ 10 °C.
• the solids were collected by filtration and washed with water (300 mL). The solid was dried under vacuum to afford 6.20 g (crude) of the title compound as a red brown solid.
• Step 3 Ethyl 4-amino-2,5,6-trichloronicotinate
• a mixture of 2,3,6-trichloro-5-iodo-pyridin-4-amine (8.0 g, 24.7 mmol), Pd(PPh3) 2 Cl 2 (1.74 g, 2.47 mmol) and triethylamine (7.51 g, 74.2 mmol) in ethanol (80 mL) was stirred for 48h at 80 °C. The resulting mixture was concentrated under vacuum.
• Step 4 4-Amino-2,5,6-trichloronicotinic acid [0657] To a solution of ethyl 4-amino-2,5,6-trichloro-pyridine-3-carboxylate (3.0g, 11.3mmol) in EtOH (20 mL) was added NaOH (890 mg, 22.3 mmol) and water (60 mL). The resulting mixture was stirred for 2h at room temperature.
• Step 5 4-Amino-2,5,6-trichloronicotinamide
• a solution of 4-amino-2,5,6-trichloro-pyridine-3-carboxylic acid (300 mg, 1.24 mmol), NH 4 Cl (332 mg, 6.21 mmol), HATU (709 mg, 1.86 mmol) and DIPEA (1.6 g, 12.4 mmol) in N,N-dimethylacetamide (5 mL) was stirred at room temperature for 1 hour. The resulting solution was diluted with EtOAc (8 mL), washed with water. The separated organic layer was concentrated under vacuum.
• Step 2 tert-Butyl (5S,5aS,6S,9R)-1,2-dichloro-5-methyl-5a,6,7,8,9,10-hexahydro-5H- 4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate [0666] Under nitrogen, a solution of tert-butyl rac-(1S,2S,5R)-2-[rac-(1S)-1-[(7,8-dichloro-4- oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 0.04 mmol), BOPCl (32.5 mg, 0.130 mmol) and DIPEA (32.9 mg, 0.260 mmol) in dichlor
• Step 2 tert-Butyl (5aR,6S,9R)-2-chloro-1-fluoro-4-methyl-12-(methylthio)- 4,5,5a,6,7,8,9,10-octahydro-3,4,10a,11,13,14-hexaaza-6,9-methanonaphtho[1,8-ab]heptalene-14- carboxylate [0671] To a solution of tert-butyl (1S,2R,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)(methyl)amino)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2.16 g, 4.33 mmol) in dichloromethane (20 mL) were added BOPCl (4.41 g, 17.3
• Step 3 tert-Butyl (5aR,6S,9R)-2-chloro-1-fluoro-4-methyl-12-(methylsulfonyl)- 4,5,5a,6,7,8,9,10-octahydro-3,4,10a,11,13,14-hexaaza-6,9-methanonaphtho[1,8-ab]heptalene-14- carboxylate [0673] To a solution of tert-butyl (5aR,6S,9R)-2-chloro-1-fluoro-4-methyl-12-(methylthio)- 4,5,5a,6,7,8,9,10-octahydro-3,4,10a,11,13,14-hexaaza-6,9-methanonaphtho[1,8-ab]heptalene-14- carboxylate (1.70 g, 3.53 mmol) in EtOAc (20 mL) was added m-CPBA (1.83
• Step 2 (S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and (S,E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol [0678] Under nitrogen, to a solution of ethyl (S,Z/E)-2-(fluoromethylene)-5-oxotetrahydro- 1H-pyrrolizine-7a(5H)-carboxylate (60.0 mg, 0.260 mmol) in tetrahydrofuran (5 mL) was added DIBAL-H (2.64 mL, 2.64 mmol) at 0 °C.
• Step 2 3-Bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline
• NIS 1-(4-methoxyphenyl)methyl]-5-methyl-aniline
• TsOH 96.0 mg, 0.560 mmol
• Step 3 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline
• Step 3 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline
• Step 4 (5-(Bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)boronic acid
• Step 4 (5-(Bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)boronic acid
• Step 2 N,N-Bis(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)aniline
• Step 2 N,N-Bis(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)aniline
• Pin 2 B 2 3.22 g, 12.7 mmol
• KOAc (1.24 g, 12.7 mmol
• Pd(dppf)Cl 2 0.620 g, 0.850 mmol
• Step 2 1-(4-(Bis(4-methoxybenzyl)amino)-2-bromo-5-fluorophenyl)ethan-1-one
• DMF dimethyl methoxyethyl
• concentrated hydrochloric acid 2.0 mL, 36%) at room temperature. The solution was stirred at room temperature for 1 hour. The solution was concentrated under vacuum.
• Step 3 5-Bromo-4-(1,1-difluoroethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)aniline
• a solution of 1-(4-(bis(4-methoxybenzyl)amino)-2-bromo-5- fluorophenyl)ethan-1-one 970 mg, 2.05 mmol
• BAST 5.0 mL
• the reaction was cooled to room temperature, quenched with aqueous NaHCO 3 solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 4 4-(1,1-Difluoroethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [0707] Under nitrogen, a solution of 5-bromo-4-(1,1-difluoroethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)aniline (415 mg, 0.840 mmol), PdCl 2 (dppf) (122 mg, 0.170 mmol), Pin 2 B 2 (640 mg, 2.52 mmol) and KOAc (247 mg, 2.52 mmol) in 1,4-Dioxane (3 mL) was stirred for 16 hours at 110°C.
• Step 2 3-Bromo-4-chloro-5-methylaniline
• Step 3 4-Chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• 3-bromo-4-chloro-5-methylaniline 600 mg, 2.72 mmol
• 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.07 g, 8.16 mmol)
• 1,4- dioxane 10 mL
• Pd(dppf)Cl 2 199 mg, 0.270 mmol
• KOAc 800 mg, 8.16 mmol
• Step 2 5-Bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline
• NIS 4-(4-methoxybenzyl)-3-methylaniline
• Step 3 4-(Bis(4-methoxybenzyl)amino)-6-bromo-3-fluoro-2-methylbenzaldehyde
• i-PrMgCl 6-(Bis(4-methoxybenzyl)amino-6-bromo-3-fluoro-2-methylbenzaldehyde
• Step 4 5-Bromo-4-(difluoromethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)-3- methylaniline
• Step 5 4-(Difluoromethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• a solution of 5-bromo-4-(difluoromethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)-3-methylaniline (647 mg, 1.31 mmol), PdCl 2 (dppf) (180 mg, 0.230 mmol), Pin 2 B 2 (998 mg, 3.93 mmol) and KOAc (385 mg, 3.92 mmol) in 1,4-dioxane (15 mL) was stirred at 90°C for 5 hours.
• Step 2 2-(4-(Bis(4-methoxybenzyl)amino)-6-bromo-3-fluoro-2- methylphenyl)acetaldehyde
• Step 2 2-(4-(Bis(4-methoxybenzyl)amino)-6-bromo-3-fluoro-2- methylphenyl)acetaldehyde
• Step 3 5-Bromo-4-(2,2-difluoroethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)-3- methylaniline
• 2-(4-(bis(4-methoxybenzyl)amino)-6-bromo-3-fluoro- 2-methylphenyl)acetaldehyde 500 mg, 1.03 mmol
• DAST 3.20 mL, 26.2 mmol
• the solution was stirred at room temperature for 3 hours.
• the reaction was quenched with aqueous NaHCO 3 solution and extracted with DCM.
• Step 4 4-(2,2-Difluoroethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• a solution of 5-bromo-4-(2,2-difluoroethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)-3-methylaniline 518 mg, 1.02 mmol
• PdCl 2 (dppf) 140 mg, 0.180 mmol
• Pin 2 B 2 (712 mg, 2.80 mmol
• KOAc 300 mg, 3.07 mmol
• Step 2 5-Bromo-4-chloro-2-fluoro-3-methylaniline
• Step 3 4-Chloro-2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
• 5-bromo-4-chloro-2-fluoro-3-methylaniline (277 mg, 1.16 mmol)
• Pin 2 B 2 (594 mg, 2.34 mmol)
• KOAc (229 mg, 2.34 mmol)
• PdCl 2 (dppf) 85.4 mg, 0.120 mmol
• the reaction system was cooled to room temperature. The solid was filtered off and washed with EtOAc.
• Step 2 7,8-Difluoronaphthalen-1-ol
• a solution of 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (6.01 g, 33.3 mmol) and HCl (38.8 mL, 12 M) in EtOH (60 mL) was stirred at 80 °C for 3 h.
• the EtOH was concentrated under vacuum.
• the residue was adjusted pH to 7 with NaOH solid and extracted with EtOAc.
• the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under vacuum.
• the crude product was slurried with petroleum ether at room temperature for 1 h.
• Step 3 1,2-Difluoro-8-(methoxymethoxy)naphthalene
• DIPEA 1,2-Difluoro-8-(methoxymethoxy)naphthalene
• Step 4 2-(5,6-Difluoro-4-(methoxymethoxy)naphthalen-2-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane [0752] Under nitrogen, to a solution of 1,2-difluoro-8-(methoxymethoxy)naphthalene (1.01 g, 4.46 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.43 g, 11.2 mmol) in THF (12 mL) was added (Ir(OMe)(cod)) 2 (292 mg, 0.450 mmol) and dtbbpy (144 mg, 0.540 mmol).
• Step 5 5,6-Difluoro-4-(methoxymethoxy)naphthalen-2-ol
• 2-(5,6-difluoro-4-(methoxymethoxy)naphthalen-2-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (8.41 g, 9.60 mmol) in THF (85 mL) was added HOAc (95 mL) and H 2 O 2 (8.8 mL, 30% in H 2 O) at 0 °C. The mixture was stirred at room temperature for 1 h.
• the reaction solution was diluted with saturated NaHSO 3 aqueous and extracted with EtOAc.
• Step 6 5,6-Difluoro-4-(methoxymethoxy)naphthalen-2-yl acetate
• Et3N 415 mg, 4.11 mmol
• DMAP 25.1 mg, 0.210 mmol
• acetyl chloride 320 mg, 4.08 mmol
• Step 7 5,6-Difluoro-4-hydroxynaphthalen-2-yl acetate
• HCl 2 mL, 4 M in 1,4-dioxane
• the solution was stirred at 0 °C for 0.5 h.
• the solution diluted with saturated water NaHCO 3 and extracted with ethyl acetate.
• Step 8 5,6-Difluoro-4-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl acetate
• DIPEA 407 mg, 3.15 mmol
• Tf2O 356 mg, 1.26 mmol
• Step 9 7,8-Difluoro-3-hydroxynaphthalen-1-yl trifluoromethanesulfonate
• 56-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl acetate 120 mg, 0.320 mmol
• H 2 O 0.5 mL
• LiOH 9.4 mg, 0.390 mmol
• the solution was stirred at 0 °C for 1 h.
• the solution was adjusted pH to 6 with AcOH.
• the solution was diluted with water and extracted with ethyl acetate.
• Step 10 7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate
• DIPEA 124 mg, 0.960 mmol
• MOMBr 80.1 mg, 0.640 mmol
• Step 11 2-(7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane [0766] Under nitrogen, a solution of 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (90.1 mg, 0.240 mmol), Pin 2 B 2 (122.9 mg, 0.4800 mmol), Pd(dppf)Cl 2 (18.6 mg, 0.0200 mmol) and KOAc (119 mg, 1.21 mmol) in DMF (1.5 mL) was stirred at 80 °C overnight.
• Step 2 4-Bromo-6-nitro-2,3-dihydro-1H-indene [0771] To a solution of 5-nitro-2,3-dihydro-1H-indene (300 mg, 1.84 mmol) in sulfuric acid (3 mL) and water (3 mL) was added NBS (327 mg, 1.84 mmol) at room temperature. The solution was stirred at room temperature for 1 hour.
• Step 3 7-Bromo-2,3-dihydro-1H-inden-5-amine
• a mixture of 4-bromo-6-nitro-2,3-dihydro-1H-indene (350 mg, 1.45 mmol), NH 4 Cl (781 mg, 14.6 mmol) and iron powder (409 mg, 7.30 mmol) in water (1.5 mL) and EtOAc (3.5 mL) was stirred at 80 °C for 2 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-6% EtOAc in petroleum ether) to afford the title compound (300 mg, 63.6% yield) as a yellow solid.
• Step 2 6-(Allylthio)-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine
• 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)pyridin-2-amine 500 mg, 1.04 mmol
• K 2 CO 3 287 mg, 2.08 mmol
• prop-2-ene-1-thiol (0.41 mL, 5.19 mmol).
• the resulting mixture was stirred for overnight at 50 °C.
• the resulting mixture was diluted with water, extracted with EtOAc.
• Step 3 6-(Allylsulfonyl)-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2- amine
• 6-allylsulfanyl-N,N-bis[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)pyridin-2-amine 165 mg, 0.35 mmol
• dichloromethane 5 mL
• m- CPBA 240 mg, 1.39 mmol
• Step 2 6-Bromo-3-fluoro-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine
• 6-bromo-3-fluoro-5-iodo-pyridin-2-amine 100 mg, 0.320 mmol
• N,N-dimethylformamide 2 mL
• NaH 50.5 mg, 1.26 mmol, 60% suspension in oil
• PMBCl 98.8 mg, 0.63 mmol
• Step 3 6-((2R,5aS,6R,9R)-3-Chloro-1-fluoro-13-(((S,Z)-2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-15-(3-fluoropropyl)- 5a,6,7,8,9,10-hexahydro-5H-9,6-(epiminomethano)azepino[2',1':3,4][1,4]oxazepino[5,6,7- de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [0791] Under nitrogen, to a solution of 6-bromo-3-fluoro-5-iodo-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (2.0 g, 3.59 mmol) in N,N-dimethylformamide (20 m
• Step 4 6-(Allylthio)-3-fluoro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2- amine
• 6-bromo-3-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)pyridin-2-amine 500 mg, 1.00 mmol
• isopropylmagnesium chloride lithium chloride (1 mL, 1.3 mmol
• allyl disulfide 146 mg, 1.00 mmol
• Step 5 6-(Allylsulfonyl)-3-fluoro-N,N-bis(4-methoxybenzyl)-5- (trifluoromethyl)pyridin-2-amine
• 6-allylsulfanyl-3-fluoro-N,N-bis[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)pyridin-2-amine 50.0 mg, 0.10 mmol
• dichloromethane 2 mL
• m-CPBA 52.6 mg, 0.30 mmol
• Step 3 1-(Allylthio)-3-methoxyisoquinoline
• the crude product was purified by reverse phase chromatography (gradient: 0-100 % acetonitrile in water (0.05% TFA) to afford 180 mg (75.6% yield) of the title compound as a yellow oil.
• Step 2 2-(Allylthio)-4-methyl-3-(trifluoromethyl)pyridine
• a solution of prop-2-ene-1-thiol (1.95 mL, 24.5 mmol), K 2 CO 3 (1.35 g, 9.81 mmol) and 2-chloro-4-methyl-3-(trifluoromethyl)pyridine (956 mg, 4.89 mmol) in N,N- dimethylformamide (10 mL) was stirred at room temperature overnight.
• the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 1 Methyl 2-(3-chloro-2-cyanophenyl)-2-cyanoacetate
• a solution of 2-chloro-6-fluorobenzonitrile (5.00 g, 32.1 mmol), K 2 CO 3 (8.87 g, 64.3 mmol) and methyl 2-cyanoacetate (3.69 mL, 41.8 mmol) in dimethyl sulfoxide (50 mL) was stirred at 50 °C for 6 hours. The solution was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 2 2-Chloro-6-(cyanomethyl)benzonitrile
• HCl 6.0 mL, 36.0 mmol, 6 M in water
• the reaction system was stirred at 70 °C overnight.
• the solution was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 4 1-Bromo-8-chloro-N,N-bis(4-methoxybenzyl)isoquinolin-3-amine
• N,N- dimethylacetamide 8 mL
• NaH 223 mg, 5.83 mmol, 60% suspension in oil
• PMBCl 804 mg, 5.13 mmol
• the reaction mixture was quenched with water.
• the filtrate was concentrated under reduced pressure. The residual was diluted with water, extracted with EtOAc.
• Step 5 8-Chloro-N,N-bis(4-methoxybenzyl)-1-(trimethylstannyl)isoquinolin-3-amine
• a solution of 1-bromo-8-chloro-N,N-bis(4-methoxybenzyl)isoquinolin- 3-amine (60.0 mg, 0.120 mmol), Sn 2 Me 6 (128 mg, 0.390 mmol) and Pd(PPh3)4 (13.9 mg, 0.0100 mmol) in toluene (1 mL) was stirred at 100 °C overnight. The solution was cooled to room temperature, diluted with water and extracted with DCM.
• reaction mixture was diluted with DCM and washed with water.
• organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
• the residue was purified by flash chromatography on silica gel (gradient: 0-100% EtOAc/petroleum ether) to afford 800 mg of the title compound as a colorless oil.
• the two enantiomers were separated by Prep-SFC with the following conditions: (Column: CHIRALPAK IG, 3*25cm, 5 ⁇ m ; Mobile Phase A:CO 2 , Mobile Phase B:IPA(0.5% 2 M NH 3 -MeOH); Flow rate:70 mL/min; Gradient:30% B; Column Temperature: 35 °C; Back Pressure: 100 bar; 215 nm; RT1:6.86; RT2:7.89; Injection Volumn:1.5 ml; Number Of Runs:20) to yield 330 mg of faster peak and 340 mg slower peak as a white oil. The faster peak is the desired isomer.
• Step 2 5-Bromo-4-chloro-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methylaniline
• Step 3 (5-(Bis(4-methoxybenzyl)amino)-2-chloro-4-fluoro-3-methylphenyl)boronic acid
• 5-bromo-4-chloro-2-fluoro-N,N-bis[(4- methoxyphenyl)methyl]-3-methyl-aniline 500 mg, 1.04 mmol
• triisopropyl borate 985 mg, 5.24 mmol
• n-BuLi 2.5 M in Hex
• Step 2 4-Bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine
• a solution of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine (2.10 g, 4.91 mmol) and NIS (1.11 g, 4.91 mmol) in acetic acid (20mL) was stirred at room temperature for 30 min. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 3 4-Bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2- amine
• 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6- methylpyridin-2-amine (2.58 g, 4.66 mmol)
• methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 5.94 mL, 46.6 mmol
• CuI 8.86 g, 46.6 mmol
• Step 4 (6-(Bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4- yl)boronic acid
• 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5- (trifluoromethyl)pyridin-2-amine (1.83 g, 3.69 mmol) and triisopropyl borate (1.28 mL, 5.54 mmol) in tetrahydrofuran (20 mL) was added a solution of n-BuLi (2.77 mL, 1.6 M in hexane) at -78 °C, and the mixture was stirred at -78 °C for 1 hour.
• Step 1 5-Bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline
• Step 2 4-(Bis(4-methoxybenzyl)amino)-6-bromo-3-fluoro-2-methylbenzaldehyde
• i-PrMgCl 4-(Bis(4-methoxybenzyl)amino)-6-bromo-3-fluoro-2-methylbenzaldehyde
• Step 3 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4-(2,2,2- trifluoroethyl)aniline
• Step 4 2-Fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(2,2,2-trifluoroethyl)aniline
• a solution of 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4- (2,2,2-trifluoroethyl)aniline 510 mg, 0.970 mmol
• PdCl 2 (dppf) 149 mg, 0.190 mmol
• Pin 2 B 2 (738 mg, 2.91 mmol
• KOAc 286 mg, 2.91 mmol
• Step 1 3-Bromo-4-iodo-5-(trifluoromethyl)aniline and 3-bromo-2-iodo-5- (trifluoromethyl)aniline
• a solution of 3-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.17 mmol) and NIS (937 mg, 4.17 mmol) in acetic acid (10 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
• Step 2 3-Bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)aniline
• Step 2 3-Bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)aniline
• Step 3 3-Bromo-N,N-bis(4-methoxybenzyl)-4,5-bis(trifluoromethyl)aniline
• a solution of 3-bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5- (trifluoromethyl)aniline 200 mg, 0.330 mmol
• methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 0.42 mL, 3.30 mmol
• CuI (627 mg, 3.30 mmol) in N,N-dimethylacetamide (3mL) was stirred at 80 °C for 1 hour.
• the solution was cooled to room temperature.
• Step 4 (5-(Bis(4-methoxybenzyl)amino)-2,3-bis(trifluoromethyl)phenyl)boronic acid
• 3-bromo-N,N-bis(4-methoxybenzyl)-4,5- bis(trifluoromethyl)aniline 95.0 mg, 0.170 mmol
• triisopropyl borate 0.06 mL, 0.260 mmol
• n-BuLi 0.13 mL, 1.6 M in hexane
• Step 2 4-(tert-Butyl)-N,N-bis(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline
• a mixture of 3-bromo-4-(tert-butyl)-N,N-bis(4-methoxybenzyl)aniline (280 mg, 0.598 mmol), Pin 2 B 2 (228 mg, 0.898 mmol), Pd(dppf)Cl 2 (44.0 mg, 0.0600 mmol) and KOAc (117 mg, 1.19 mmol) in 1,4-dioxane (5 mL) was stirred at 90°C overnight.
• Step 2 3-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• 5-bromo-3-chloro-2-fluoroaniline 200 mg, 0.890 mmol
• Pin 2 B 2 339 mg, 1.34 mmol
• Pd(dppf)Cl 2 65.2 mg, 0.0900 mmol
• KOAc 175 mg, 1.78 mmol
• 1,2-dimethoxyethane 8 mL
• Step 3 1-(Allylthio)-3-methoxyisoquinoline
• K 2 CO 3 (285 mg, 2.07 mmol)
• allyl mercaptan (0.39 mL, 4.85 mmol).
• the resulting solution was stirred at 25°C overnight.
• the residue was purified by reverse phase flash chromatography on a pre-packed C18 column (gradient: 0-100% CH 3 CN in water (0.05% TFA)) to yield 200 mg (83.7% yield) the title compound as a yellow solid.
• the resulting solution was stirred at 0°C for 2 hours and at room temperature for 1 hour.
• the solution was cooled to 0°C and NaH (1.04 g, 26.0 mmol, 60% in mineral oil) was added.
• the solution was stirred at 40°C for 5 hours.
• the reaction was quenched with aqueous NH 4 Cl solution, and the mixture was extracted with EtOAc.
• the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
• the residue was purified by flash chromatography on silica gel (gradient: 0-70% EtOAc in petroleum ether) to afford 871 mg (47% yield) of the title compound as a yellow oil.
• Step 2 Methyl (3S)-7-oxooctahydroindolizine-3-carboxylate [0894] Under nitrogen, to a solution of methyl but-3-yn-1-yl-L-prolinate (3.41 g, 18.8 mmol) and 4 ⁇ MS (10 g) in dichloromethane (100 mL) was added m-CPBA (4.35 g, 21.4 mmol) at 0°C. The solution was stirred at 0°C for 2 hours.
• Step 3 ((3S)-7,7-Difluorooctahydroindolizin-3-yl)methanol and ((3S)-7-Fluoro- 1,2,3,5,6,8a-hexahydroindolizin-3-yl)methanol & ((3S)-7-fluoro-1,2,3,5,6,8a- hexahydroindolizin-3-yl)methanol [0896] Under nitrogen, to a solution of methyl (3S)-7-oxooctahydroindolizine-3-carboxylate (1.73 g, 8.77 mmol) in dichloromethane (30 mL) was added DAST (3.0 mL, 24.4 mmol) at -5°C.
• Step 4 ((3S)-7,7-Difluorooctahydroindolizin-3-yl)methanol and ((3S)-7-Fluoro- 1,2,3,5,6,8a-hexahydroindolizin-3-yl)methanol [0898] Under nitrogen, to a solution of the mixture of methyl (3S)-7,7- difluorooctahydroindolizine-3-carboxylate and methyl (3S)-7-fluoro-1,2,3,5,6,8a- hexahydroindolizine-3-carboxylate (90.2 mg, 0.410 mmol) in tetrahydrofuran (5 mL) was added LiAlH 4 (0.84 mL, 0.84 mmol, 1 M in THF) at 0°C.
• Step 2 (6R,7aS)-7a-((Benzyloxy)methyl)-6-fluorohexahydro-3H-pyrrolizin-3-one
• 6R,7aS 6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolizin-3-one
• NaH 50% dispersion in mineral oil, 340 mg, 8.50 mmol
• benzyl bromide (1.16 g, 6.80 mmol) in tetrahydrofuran (10mL) was added at 0°C, and the mixture was stirred at room temperature for 6 hours.
• Step 3 (2R,7aS)-7a-((Benzyloxy)methyl)-2-fluoro-5-methylenehexahydro-1H- pyrrolizine
• 6R,7aS)-7a-((benzyloxy)methyl)-6-fluorohexahydro- 3H-pyrrolizin-3-one (298 mg, 1.13 mmol) in tetrahydrofuran (10mL) was added Tebbe reagent (0.5M solution in toluene, 6.60 mL, 3.30 mmol) dropwise over a period of 30 minutes at -40°C. The temperature was warmed to room temperature, and the mixture was stirred for 2 hours.
• Step 4 ((2R,7aS)-2-Fluoro-5-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (single unknown stereoisomer) [0907] Under hydrogen, to a solution of (2R,7aS)-7a-((benzyloxy)methyl)-2-fluoro-5- methylenehexahydro-1H-pyrrolizine (261 mg, 1.00 mmol) in methanol (10mL) were added 10%Pd/C (106 mg, wet) and 20%Pd(OH) 2 /C (140 mg) at room temperature. The solution was stirred at 50°C for 2 hours. The resulting mixture was filtered.
• Step 2 Diethyl 1-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)pyrrolidine-2,5- dicarboxylate (mixture of trans isomers) [0912] To a solution of diethyl pyrrolidine-2,5-dicarboxylate (mixture of trans isomers, 300mg, 1.39mmol) in dichloromethane (10mL) was added a solution of tert-butyl methyl(2- oxoethyl)carbamate (1.21g, 6.99mmol) in dichloromethane (2mL) at 0°C, and the mixture was stirred for 30 minutes.
• Step 3 Ethyl 2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate (mixture of trans isomers) [0914] To a solution of diethyl 1-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)pyrrolidine- 2,5-dicarboxylate (mixture of trans isomers, 438 mg, 1.18 mmol) in ethyl acetate (5mL) was added hydrogen chloride (4M solution in ethyl acetate, 6mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum.
• Step 4 6-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (mixture of trans isomers)
• Step 4 6-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (mixture of trans isomers)
• ethyl 2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazine- 6-carboxylate mixture of trans isomers, 134 mg, 0.592 mmol
• LiBH 4 (64.5mg, 2.96mmol
• Step 2 (1-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2-yl)methanol (mixture of trans isomers)
• TBDMSCl 896 mg, 3.26 mmol
• DIPEA 841 mg, 6.52 mmol
• Step 3 1-(1-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2-yl)-N- methylmethanamine (mixture of trans isomers) [0923] Under nitrogen, to a solution of (1-benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)pyrrolidin-2-yl)methanol (mixture of trans isomers, 370 mg, 0.806 mmol) and DIPEA (208 mg, 1.61 mmol) in dichloromethane (3 mL) was added trifluoromethanesulfonic anhydride (364 mg, 1.29 mmol) at -78°C.
• Step 4 tert-Butyl ((1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2- yl)methyl)(methyl)carbamate (mixture of trans isomers) [0925] To a solution of 1-(1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2-yl)- N-methylmethanamine (mixture of trans isomers, 612 mg, 1.30 mmol) and DIPEA (201 mg, 1.56 mmol) in dichloromethane (5mL) was added Boc 2 O (311mg, 1.43mmol) at 0°C.
• Step 5 tert-Butyl ((5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2- yl)methyl)(methyl)carbamate (mixture of trans isomers)
• tert-butyl ((1-benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)pyrrolidin-2-yl)methyl)(methyl)carbamate(mixture of trans isomers, 290 mg, 0.507 mmol) in methanol (10mL) were added 10%Pd/C (54.0 mg) and 20%Pd(OH) 2 /C (71.0mg) at room temperature.
• Step 6 Methyl 2-(2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(((tert- butyldiphenylsilyl)oxy)methyl)pyrrolidin-1-yl)acetate (mixture of trans isomers) [0929] To a mixture of tert-butyl ((5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2- yl)methyl)(methyl)carbamate (mixture of trans isomers, 200 mg, 0.415 mmol) and K 2 CO 3 (170 mg, 1.23 mmol) in acetonitrile (10mL) was added methyl 2-bromoacetate (100 mg, 0.654 mmol) at room temperature.
• Step 7 6-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylhexahydropyrrolo[1,2- a]pyrazin-3(4H)-one (mixture of trans isomers)
• Step 7 To a solution of methyl 2-(2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(((tert- butyldiphenylsilyl)oxy)methyl)pyrrolidin-1-yl)acetate (mixture of trans isomers, 185 mg, 0.334 mmol) in ethyl acetate (5 mL) was added hydrogen chloride (6 mL, 4 M solution in ethyl acetate) at 0°C.
• Step 8 6-(hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one (mixture of trans isomers)
• a solution of 6-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylhexahydropyrrolo[1,2- a]pyrazin-3(4H)-one (mixture of trans isomers, 100 mg, 0.237 mmol) and hydrogen chloride (1 mL, 4 M solution in methanol) in methanol (10 mL) was stirred at 60°C for 2 hours. The solvent was concentrated under vacuum to afford the title compound (mixture of trans isomers, 35.0 mg, crude) as a colorless solid.
• Step 2 (6S,8aS)-6-(Hydroxymethyl)-3,3-dimethyltetrahydro-1H-pyrrolo[2,1- c][1,4]oxazin-4(3H)-one
• Step 2 (6S,8aS)-6-(Hydroxymethyl)-3,3-dimethyltetrahydro-1H-pyrrolo[2,1- c][1,4]oxazin-4(3H)-one
• Step 3 ((6S,8aS)-3,3-Dimethylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol
• 6S,8aS 6-(hydroxymethyl)-3,3-dimethyltetrahydro- 1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one
• tetrahydrofuran (1mL) was added a solution of LiAlH 4 in THF (0.29 mL, 2.5 M in THF) at 0 °C.
• Step 2 Methyl 2-(2-fluoroethyl) pyrrolidine-2-carboxylate HCl salt
• HCl 4-methyl 2-(2-fluoroethyl) pyrrolidine-1,2-dicarboxylate
• Step 3 Methyl 2-(2-fluoroethyl)-1-methylpyrrolidine-2-carboxylate [0947] A solution of methyl 2-(2-fluoroethyl) pyrrolidine-2-carboxylate HCl salt (560 mg, 2.65 mmol), (HCHO)n (676 mg, 22.5 mmol) and NaOAc (440 mg, 5.37 mmol) in dichloromethane (10 mL) and methanol (5 mL) was stirred at room temperature for 2 hours. Then NaBH(OAc)3 (1.13 g, 5.33 mmol) was added. The solution was stirred at room temperature for 16 hours. The solution was concentrated under vacuum.
• Step 4 (2-(2-Fluoroethyl)-1-methylpyrrolidin-2-yl)methanol
• Step 2 (R)-(1-((3-Methylmorpholino) methyl) cyclopropyl) methanol
• ethyl (R)-1-((3-methylmorpholino) methyl) cyclopropane-1-carboxylate (1.80 g, crude) in THF (20 mL) was added LiAlH 4 (600 mg, 15.8 mmol) in portions at 0 °C , and the mixture was stirred for 1 hour at room temperature. The reaction was quenched with Na 2 SO 4 .10H 2 O and filtrated. The filtrate was concentrated under reduced pressure to afford the title compound (714 mg, crude) as a yellow oil.
• Step 2 1-(tert-Butyl) 2-ethyl 5-(difluoromethyl)-1H-pyrrole-1,2-dicarboxylate
• ethyl 5-(difluoromethyl)-1H-pyrrole-2-carboxylate 5.00 g, 26.3 mmol
• DMAP 650 mg, 5.30 mmol
• DIPEA 10.2 g, 79.0 mmol
• dichloromethane 300 mL
• (Boc) 2 O 46.2 g, 212 mmol
• dichloromethane 200 mL
• Step 3 1-(tert-Butyl) 2-ethyl 5-(difluoromethyl) pyrrolidine-1,2-dicarboxylate
• a solution of 1-(tert-butyl) 2-ethyl 5-(difluoromethyl)-1H- pyrrole-1,2-dicarboxylate 5.40 g, 18.7 mmol
• 10%Pd/C 2.45 g
• ethanol 100 mL
• Step 5 Ethyl 3-(difluoromethyl) tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate [0967] To a solution of 1-(tert-butyl) 2-ethyl 2-(3-chloropropyl)-5-(difluoromethyl) pyrrolidine-1,2-dicarboxylate (2.54 g, 6.88 mmol) in HFIP (100 mL) was added 2,2,2- trifluoroacetic acid (5 mL) at room temperature, and the mixture was stirred for 3 hours. The solvent was concentrated under vacuum.
• Step 6 (3-(Difluoromethyl) tetrahydro-1H-pyrrolizin-7a(5H)-yl) methanol
• ethyl 3-(difluoromethyl) tetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate 3.20 g, crude
• LiAlH 4 779 mg, 20.5 mmol
• Step 2 (1-Benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl) methanol (mixture of trans isomers)
• TBDPSCl (1-Benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl) methanol
• Step 3 1-(1-Benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl)-N- methylmethanamine (mixture of trans isomers)
• Step 3 1-(1-Benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl)-N- methylmethanamine (mixture of trans isomers)
• a solution of (1-benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl) methanol (370 mg, 0.806 mmol) and DIPEA (208 mg,1.61 mmol) in dichloromethane (3 mL) was added trifluoromethanesulfonic anhydride (364 mg, 1.29 mmol) at - 78 °C, and the mixture was stirred for 15 minutes.
• Step 4 tert-Butyl ((1-benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl) methyl) (methyl)carbamate (mixture of trans isomers) [0978] To a solution of 1-(1-benzyl-5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl)- N-methylmethanamine (300 mg, 0.634 mmol) and DIPEA (98.2 mg, 0.761 mmol) in dichloromethane (5 mL) was added (Boc) 2 O (152 mg, 0.697 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours.
• dichloromethane 5 mL
• Step 5 tert-Butyl ((5-(((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl) methyl) (methyl) carbamate (mixture of trans isomers) [0980] Under hydrogen (1atm), to a solution of tert-butyl ((1-benzyl-5-(((tert- butyldiphenylsilyl) oxy) methyl) pyrrolidin-2-yl) methyl) (methyl) carbamate (270 mg, 0.471 mmol) in methanol (10 mL) was added 10%Pd/C (49.9 mg) and 20%Pd(OH) 2 /C (contain 61.7% water, 87.9 mg) at room temperature.
• Step 6 Methyl 2-(2-(((tert-butoxycarbonyl) (methyl) amino) methyl)-5-(((tert- butyldiphenylsilyl) oxy) methyl) pyrrolidin-1-yl) acetate (mixture of trans isomers)
• Step 7 6-(((tert-Butyldiphenylsilyl) oxy) methyl)-2-methylhexahydropyrrolo[1,2-a] pyrazin-3(4H)-one (mixture of trans isomers)
• Step 7 To a solution of methyl 2-(2-(((tert-butoxycarbonyl) (methyl) amino) methyl)-5-(((tert- butyldiphenylsilyl) oxy) methyl) pyrrolidin-1-yl) acetate (185 mg, 0.334 mmol) in dioxane (5 mL) was added hydrogen chloride (4M solution in ethyl acetate, 6 mL) at 0 °C, and the mixture was stirred for 2 hours at room temperature.
• Step 8 6-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a] pyrazin-3(4H)-one (mixture of trans isomers)
• 6-(((tert-butyldiphenylsilyl) oxy) methyl)-2- methylhexahydropyrrolo[1,2-a] pyrazin-3(4H)-one 100 mg, 0.237 mmol
• hydrogen chloride (4M solution in methanol, 1 mL, 4.00 mmol
• Step 2 Diethyl 2-allyl-2-aminomalonate
• TFA diethyl 2-allyl-2-((tert-butoxycarbonyl) amino) malonate
• Step 3 Diethyl 2-allyl-2-(methylamino)malonate
• Step 5 6-Allyl-N,2,2,3,3,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine [0997] To a solution of 2-allyl-2-(methylamino) propane-1,3-diol (491 mg, 3.38 mmol) and triethylamine (1.71 g, 16.9 mmol) in dichloromethane (10 mL) was added tert- butylchlorodimethylsilane (1.52 g, 10.1 mmol) at 0 °C. The resulting solution was stirred for 2 h at room temperature.
• Step 6 4-Bromo-2,2-bis(((tert-butyldimethylsilyl) oxy) methyl)-1-methylpyrrolidine
• 6-allyl-N,2,2,3,3,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6- amine 760 mg, 2.03 mmol
• 1-bromopyrrolidine-2,5-dione 361 mg, 2.04 mmol
• Step 7 (4-Bromo-1-methylpyrrolidine-2,2-diyl) dimethanol [1001] To a mixture of 4-bromo-2,2-bis(((tert-butyldimethylsilyl) oxy) methyl)-1- methylpyrrolidine (240 mg, 0.530 mmol) in methanol methyl alcohol (2.00 mL) and tetrahydrofuran (2.00 mL) was added HCl (6.00 mL, 4 M in water). The resulting solution was stirred for overnight at room temperature. Solvent was evaporated under vacuum to afford 200 mg (crude) of the title compound as a yellow oil.
• Step 8 (5-Methyl-2-oxa-5-azabicyclo [2.2.1] heptan-4-yl) methanol [1003] Under nitrogen, to a solution of (4-bromo-1-methylpyrrolidine-2,2-diyl) dimethanol (200 mg, 0.890 mmol) in N,N-dimethylformamide (5 mL) was added NaH (71.4 mg, 1.79 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with sat. NH 4 Cl aqueous.
• Step 2 Diethyl 1-(2-((tert-butoxycarbonyl) (methyl)amino) ethyl) pyrrolidine-2,5- dicarboxylate (mixture of trans isomers) [1008] To a solution of diethyl pyrrolidine-2,5-dicarboxylate (300 mg, 1.39 mmol) in dichloromethane (10 mL) was added a solution of tert-butyl methyl(2-oxoethyl)carbamate (1.21 g, 6.99 mmol) in dichloromethane (2 mL) at 0°C, and the mixture was stirred for 30 minutes.
• Step 3 Ethyl 2-methyl-1-oxooctahydropyrrolo[1,2-a] pyrazine-6-carboxylate (mixture of trans isomers) [1010] To a solution of diethyl 1-(2-((tert-butoxycarbonyl) (methyl) amino) ethyl) pyrrolidine- 2,5-dicarboxylate (438 mg, 1.18 mmol) in ethyl acetate (5 mL) was added hydrogen chloride (4M solution in ethyl acetate, 6 mL) at 0 °C, and the mixture was stirred for 2 hours at room temperature. The solvent was concentrated under vacuum.
• Step 4 6-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a] pyrazin-1(2H)-one (mixture of trans isomers)
• ethyl 2-methyl-1-oxooctahydropyrrolo[1,2-a] pyrazine-6-carboxylate 134 mg, 0.592 mmol
• LiBH 4 64.5 mg, 2.96 mmol
• the reaction was quenched with Na 2 SO 4 .10H 2 O.
• Step 2 Methyl (3S)-7-oxooctahydroindolizine-3-carboxylate [1017] Under nitrogen, to a solution of methyl but-3-yn-1-yl-L-prolinate (9.48 g, 52.3 mmol) and 4 ⁇ MS (10 g) in dichloromethane (300 mL) was added m-CPBA (12.9 g, 63.3 mmol) at 0°C. The solution was stirred at 0°C for 2 hours. Then the solution was cooled to -78°C, a solution of PPh3AuNTf2 (1.95 g, 2.64 mmol) in DCM was added at -78°C.
• Step 3 Methyl (3S)-7-cyanooctahydroindolizine-3-carboxylate (two isomers) [1019] Under nitrogen, to a solution of methyl (3S)-7-oxooctahydroindolizine-3-carboxylate (2.01 g, 10.2 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (3.3 g, 16.9 mmol) in 1,2-dimethoxyethane (100 mL) and methanol (0.4 mL) was added t-BuOK (1 M in THF, 25 mL) at 0°C. The solution was stirred at room temperature for 3 hours.
• Step 4 (3S)-3-(Hydroxymethyl) octahydroindolizine-7-carbonitrile (two isomers) [1021] Under nitrogen, to a solution of methyl (3S)-7-cyanooctahydroindolizine-3-carboxylate (500 mg, 2.4 mmol) (isomer 1of last step) in tetrahydrofuran (14 mL) was added LiBH 4 (2 M in THF, 2.5 mL) at 0°C. The solution was stirred at room temperature for 16 hours. The reaction was quenched by EtOAc.
• Step 5 (3S)-3-(Hydroxymethyl) octahydroindolizine-7-carboxylic acid (two isomers)
• a solution of (3S)-3-(hydroxymethyl) octahydroindolizine-7-carbonitrile (181 mg, 1 mmol) (isomer 1 of last step) in hydrochloric acid (6 mL, 12M) was stirred at 80°C for 2 hours. The solution was concentrated under vacuum to afford 270 mg (crude) of the title compound (isomer 1) as a brown oil.
• LC-MS: (ESI, m/z): [M+H] + 200.
• Step 6 Benzoic (3S)-3-((benzoyloxy)methyl) octahydroindolizine-7-carboxylic anhydride (two isomers) [1027] To a solution of (3S)-3-(hydroxymethyl) octahydroindolizine-7-carboxylic acid (271 mg, crude) (isomer 1 of last step) in dichloromethane (8 mL) were added DIPEA (1.19 g, 9.22 mmol) and benzoyl chloride (585 mg, 4.16 mmol) at 0°C. The solution was stirred at room temperature for 16 hours. The solution was quenched by water, extracted with DCM.
• Step 7 ((3S)-7-(Dimethylcarbamoyl) octahydroindolizin-3-yl)methyl benzoate (four isomers) [1030] A mixture of benzoic (3S)-3-((benzoyloxy)methyl) octahydroindolizine-7-carboxylic anhydride (810 mg, crude) (isomer 1 of last step) and dimethylamine (2 M in THF, 12 mL) was stirred at room temperature for 4 hours. The solution was concentrated under vacuum.
• Step 8 (3S)-3-(Hydroxymethyl)-N,N-dimethyloctahydroindolizine-7-carboxamide (four isomers) [1033] To a solution of ((3S)-7-(dimethylcarbamoyl) octahydroindolizin-3-yl)methyl benzoate (65.1 mg, 0.200 mmol) (isomer 1 of last step) in ethanol (1.5 mL) was added a solution of NaOH (24.8 mg, 0.620 mmol) in water (0.5 mL). The solution was stirred at room temperature for 2 hours.
• Step 2 Triethyl pyrrolidine-2,2,3-tricarboxylate & Triethyl pyrrolidine-2,2,4- tricarboxylate ( ⁇ 3:1 mixture)
• a solution of diethyl 2-aminomalonate (20.0 g, 114 mmol), ethyl acrylate (11.4 g, 114 mmol) and polyformaldehyde (3.42 g, 38.0 mmol) in toluene (500 mL) was stirred overnight at 110 °C. The solvent was concentrated under vacuum.
• Step 3 Triethyl 1-methylpyrrolidine-2,2,3-tricarboxylate
• Step 4 (1-Methylpyrrolidine-2,2,3-triyl) trimethanol
• a solution of triethyl 1-methylpyrrolidine-2,2,3-tricarboxylate (9.00 g, 30.0 mmol) in tetrahydrofuran (200 mL) was added LiAlH 4 (2M solution in tetrahydrofuran, 30 mL) dropwise at 0 °C, and the mixture was stirred for 2 hours at room temperature. The reaction was quenched with Na 2 SO 4 .10H 2 O. After filtration, the filtrate was collected and concentrated under vacuum to afford the title compound (5.10 g, crude) as a yellow oil.
• Step 2 tert-Butyl (S)-3-((R)-3-(benzyloxy)-2-(tosyloxy) propoxy) pyrrolidine-1- carboxylate
• Et 3 N 2.84g, 28.0 mmol
• TsCl 1.75g, 9.18 mmol
• 4-DMAP 4-DMAP
• Step 3 (R)-1-(Benzyloxy)-3-(((S)-pyrrolidin-3-yl)oxy)propan-2-yl 4- methylbenzenesulfonate (TFA salt)
• TFA salt methylbenzenesulfonate
• Step 5 ((2R,5S)-4-Oxa-1-azabicyclo [3.2.1] octan-2-yl) methanol
• a solution of ((2R,5S)-2-((benzyloxy)methyl)-4-oxa-1- azabicyclo [3.2.1] octane (139mg, 0.600mmol) and 10% Pd/C (180mg) in methyl alcohol (4mL) was stirred at room temperature overnight. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford the title compound (51mg crude) as a white oil.
• Step 2 2-(((2S,3S)-2-(Methoxycarbonyl) pyrrolidin-3-yl) oxy) acetic acid
• acetonitrile 3 mL
• HCl / 1,4- dioxane 1 mL, 4 mol/L
• Step 3 2-(((2S,3S)-1-(tert-Butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidin-3- yl)oxy)acetic acid
• 2-(((2S,3S)-2-(methoxycarbonyl) pyrrolidin-3-yl)oxy)acetic acid (261 mg, 1.28 mmol) in DCM (2 mL) was added DIPEA (1.30 g, 10.1 mmol) and (Boc) 2 O (837 mg, 3.84 mmol). The solution was stirred at room temperature for 1 hour.
• Step 4 1-(tert-Butyl) 2-methyl (2S,3S)-3-(2-hydroxyethoxy) pyrrolidine-1,2- dicarboxylate
• 2-(((2S,3S)-1-(tert-butoxycarbonyl)-2- (methoxycarbonyl) pyrrolidin-3-yl) oxy) acetic acid (262 mg, 0.860 mmol) in THF (3 mL) was added BH 3 (1.6 mL, 1M in THF) at 0°C.
• the resulting solution was stirred for 3 hours at 0°C.
• the reaction was quenched with MeOH.
• Step 6 Methyl (2S,3S)-3-(2-(tosyloxy) ethoxy) pyrrolidine-2-carboxylate
• acetonitrile 4.5 mL
• HCl / 1,4-dioxane 1.5 mL, 4 mol/L
• Step 7 Methyl (5S,8S)-4-oxa-1-azabicyclo [3.2.1] octane-8-carboxylate [1072] To a solution of methyl (2S,3S)-3-(2-(tosyloxy) ethoxy) pyrrolidine-2-carboxylate (103 mg, 0.300 mmol) in acetonitrile (5 mL) was added K 2 CO 3 (227 mg, 1.64 mmol), and the mixture was stirred at 70°C for 3 hours.
• Step 1 Ethyl 1-(3-(1,3-dioxoisoindolin-2-yl) propyl)-2-oxocyclopentane-1-carboxylate [1077] To a solution of ethyl 2-oxocyclopentane-1-carboxylate (10.0 g, 64.1 mmol) in tetrahydrofuran (50 mL) and DMF (50 mL) was added NaH (60% dispersion in mineral oil, 3.08 g, 76.9 mmol) in 3 portions at 0 °C, and the mixture was stirred for 30 minutes.
• Step 2 Ethyl 2,3,4,5,6,7-hexahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate
• ethyl 1-(3-(1,3-dioxoisoindolin-2-yl) propyl)-2-oxocyclopentane-1- carboxylate (13.5 g, 39.2 mmol) in ethanol (200 mL) was added hydrazine hydrate (80%, 7.2 mL) at room temperature, and the mixture was stirred for 1 hour at 80 °C. The mixture was cooled to room temperature and the solid was filtered.
• Step 4 (1-Methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl) methanol
• ethyl 1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (1.50 g, 7.08 mmol) in tetrahydrofuran (20 mL) was added LiAlH 4 (2M solution in tetrahydrofuran, 7.1 mL) dropwise at 0 °C, and the mixture was stirred for 1 hour at room temperature. The reaction was quenched with Na 2 SO 4 .10H 2 O.
• Step 2 Ethyl 2-((benzyloxy) methyl) pyrrolidine-2-carboxylate
• Step 4 Ethyl 2-((benzyloxy)methyl)-1-(2-(methylamino) ethyl) pyrrolidine-2- carboxylate
• a solution of ethyl 2-(benzyloxymethyl)-1-[2-[tert-butoxycarbonyl(methyl) amino]ethyl]pyrrolidine-2-carboxylate (100mg, 0.24mmol) in aqueous HCl (1M) in EtOAc solution (1.5mL) and dichloromethane (3mL) was stirred at 25 °C for 4 hours. The resulting mixture was concentrated under reduced pressure to afford 50mg (crude) of the title compound as a yellow solid.
• Step 6 8a-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a] pyrazin-1(2H)-one
• Step 6 8a-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a] pyrazin-1(2H)-one
• Pd/C 10%, 20.0 mg
• Step 2 1-(tert-Butyl) 2-methyl 2-(3-chloropropyl)-3,4-dihydroxypyrrolidine-1,2- dicarboxylate
• Step 3 Methyl 2-(3-chloropropyl)-3,4-dihydroxypyrrolidine-2-carboxylate
• LC-MS: (ESI, m/z): [M+H] + 238.
• Step 4 Methyl 1,2-dihydroxytetrahydro-1H-pyrrolizine-7a(5H)-carboxylate
• a solution of methyl 2-(3-chloropropyl)-3,4-dihydroxypyrrolidine-2-carboxylate (8.26 g, 34.8 mmol) and K 2 CO 3 (14.2 g, 103 mmol) in acetonitrile (60 mL) was stirred at room temperature for 1.5 hours. The solvent was concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-70% ACN in water (0.05% NH 4 HCO 3 )) to yield 13.0 g (crude) as a yellow solid.
• Step 7 (1,2-Difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methyl benzoate [1111] To a solution of (1,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methanol (1.19 g, 6.72 mmol) and Et 3 N (1.36 g, 13.5 mmol) in DCM (12mL) was added benzoyl chloride (1.42 g, 10.1 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum.
• the isomer 1 and isomer 2 were separated by Chiral-Prep-HPLC (conditions: Column: CHIRAL ART Cellulose-SC, 2*25 cm,5um; Mobile Phase A: – (0.5 % 2 M NH 3 -MeOH) -- –C, Mobile Phase B: IPA--HPLC; Flow rate:20 mL/min; Gradient:30 B to 30 B in 15 min; 220/254 nm; RT1:8.505; RT2:10.259) to afford 229 mg of isomer 1 as a colorless syrup (single cis isomer, complete configuration not determined) and 223 mg of isomer 2 as a colorless syrup (single cis isomer, complete configuration not determined).
• the isomer 3 and isomer 4 were separated by Chiral-Prep-HPLC (conditions: Column: LUX 5 um Cellulose-2, 2.12*25 cm; Mobile Phase A:–x (0.5% 2 M NH 3 -MeOH) -- H–, Mobile Phase B: EtOH--HPLC; Flow rate:20 mL/min; Gradient:5 B to 5 B in 15 min; 220/254 nm; R T1 :9.533; RT2:13.438) to afford 117 mg of isomer 3 as a colorless syrup (single trans isomer, the exact structure is not sure) and 108 mg of isomer 4 as a colorless syrup (single trans isomer, the exact structure is not sure).
• Step 8 (1,2-Difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methanol
• Step 2 (2-(2,2-Difluoroethyl)-1-methylpyrrolidin-2-yl)methanol
• 1-(tert-butyl) 2-methyl 2-(2,2-difluoroethyl)pyrrolidine-1,2- dicarboxylate (1.50 g, 5.11 mmol) in tetrahydrofuran (15 mL) was added LiAlH 4 (389 mg, 10.3 mmol) in portions at 0 °C, and the mixture was stirred for 2 hours at 60 °C. The reaction was quenched with Na 2 SO 4 .10H 2 O. The reaction mixture was diluted with water and extracted with ethyl acetate.
• Step 2 1-(tert-Butyl) 2-methyl (2S,4R)-4-(2-hydroxyethoxy)pyrrolidine-1,2- dicarboxylate
• a suspension of Pd/C (1.68 g, 10%) and 1-(tert-butyl) 2- methyl (2S,4R)-4-(2-(benzyloxy)ethoxy)pyrrolidine-1,2-dicarboxylate (6.70 g, 17.7 mmol) in MeOH (700 mL) was stirred at room temperature for 2 days. The solution was filtered and the filtrate was concentrated under vacuum to afford 4.89 g (crude) of the title compound as a yellow oil.
• Step 4 tert-Butyl (2S,4R)-2-(hydroxymethyl)-4-(2-(tosyloxy)ethoxy)pyrrolidine-1- carboxylate
• a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-(2- (tosyloxy)ethoxy)pyrrolidine-1,2-dicarboxylate 9.46 g, 21.3 mmol) in THF (100 mL) was added LiAlH 4 (8.54 mL, 2.5 M in THF ) at 0 °C. The result solution was stirred at 0 °C for 30 min.
• Step 5 tert-Butyl (2S,4R)-2-((benzoyloxy)methyl)-4-(2-(tosyloxy)ethoxy)pyrrolidine- 1-carboxylate
• tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(2- (tosyloxy)ethoxy)pyrrolidine-1-carboxylate 7.50 g, 18.1 mmol
• Et3N 48 g, 54.2 mmol
• benzoyl chloride (3.82 g, 27.2 mmol) at 0 oC.
• the result solution was stirred at room temperature for 3 h.
• Step 6 ((2S,4R)-4-(2-(Tosyloxy)ethoxy)pyrrolidin-2-yl)methyl benzoate [1137]
• LC-MS: (ESI, m/z): [M+H] + 420.
• Step 7 ((1R,5R,7S)-4-Oxa-1-azabicyclo[3.2.1]octan-7-yl)methyl benzoate [1139] To a solution of ((2S,4R)-4-(2-(tosyloxy)ethoxy)pyrrolidin-2-yl)methyl benzoate (9.40 g, 22.4 mmol) in DMA (285 mL) was added K 2 CO 3 (21.7 g, 157 mmol). The solution was stirred at 40 °C for overnight. After filtrated, the solution was concentrated under vacuum.
• Step 8 ((1R,5R)-4-Oxa-1-azabicyclo[3.2.1]octan-7-yl)methanol
• ((1R,5R,7S)-4-Oxa-1-azabicyclo[3.2.1]octan-7- yl)methyl benzoate 500 mg, 2.02 mmol
• LiAlH 4 3.04 mL, 1 M in THF
• the result solution was stirred at room temperature for 1 h.
• the solution was quenched with Na 2 SO 4 .10H 2 O at 0 °C and filtrated.
• Step 2 tert-Butyl (4R)-4-fluoro-2-(3-hydroxypropyl) pyrrolidine-1-carboxylate
• tert-butyl (4R)-2-(3-(benzyloxy) propyl)-4- fluoropyrrolidine-1-carboxylate 2.60 g, 7.71 mmol
• MeOH 25 mL
• Pd / C 801 mg, 10 %
• the resulting solution was stirred overnight at room temperature. After filtration, the filtrate was concentrated under vacuum to afford 2.01 g (crude) of the title compound as a yellow oil.
• Step 4 tert- Butyl (4R)-2-(but-3-en-1-yl)-4-fluoropyrrolidine-1-carboxylate
• t-BuOK 9.53 mL, 1 M in THF
• tert-butyl (4R)-4-fluoro-2-(3-oxopropyl) pyrrolidine- 1-carboxylate 934 mg, 3.81 mmol) in THF (8 mL) was added at 0 °C.
• Step 5 tert-Butyl (4R)-4-fluoro-2-(2-(oxiran-2-yl)ethyl)pyrrolidine-1-carboxylate
• m-CPBA 959 mg, 5.54 mmol
• Step 6 ((6R)-6-Fluorohexahydro-1H-pyrrolizin-3-yl) methanol
• LC-MS: (ESI, m/z): [M+H] + 160.
• Step 7 ((6R)-6-Fluorohexahydro-1H-pyrrolizin-3-yl)methyl benzoate [1156] To a solution of ((6R)-6-fluorohexahydro-1H-pyrrolizin-3-yl)methanol (200 mg, 1.26 mmol) and Et 3 N (381 mg, 3.77 mmol) in DCM (3 mL) was added BzCl (213 mg, 1.51 mmol) at 0 °C. The solution was stirred at room temperature for 1.5 h. The solution was concentrated under vacuum.
• Step 8 ((6R)-6-Fluorohexahydro-1H-pyrrolizin-3-yl)methanol
• ((6R)-6-fluorohexahydro-1H-pyrrolizin-3-yl)methyl benzoate (35.1 mg, 0.130 mmol) (the faster peak from last step) in THF (1.5 mL) was added LiAlH 4 (0.2 mL, 1 M in THF) at 0 °C.
• the solution was stirred at room temperature for 1 h.
• the mixture was quenched by Na 2 SO 4 .10H 2 O and filtrated.
• Step 2 tert-Butyl 4,4-difluoro-2-(3-hydroxypropyl) pyrrolidine-1-carboxylate
• a solution of tert-butyl 2-(3-benzyloxypropyl)-4,4-difluoro- pyrrolidine-1-carboxylate (1.9g, 5.35mmol) in methanol (10mL) was added 10% Pd/C (200 mg) at 25 °C. The resulting solution was stirred at room temperature for 24 hours. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product 1.09g.
• LC-MS: (ESI, m/z): [M+H] + 266.
• Step 3 tert-Butyl 4,4-difluoro-2-(3-oxopropyl) pyrrolidine-1-carboxylate
• DMSO dichloromethane
• oxalyl chloride 2M in DCM, 11.3mL, 22.6mmol
• the tert- butyl 4,4-difluoro-2-(3-hydroxypropyl) pyrrolidine-1-carboxylate 1.2g, 4.52mmol
• CH 2 Cl 2 5mL
• Step 4 3-(4,4-Difluoropyrrolidin-2-yl)propanal
• TMSI 380mg, 1.9mmol
• the resulting solution was stirred at room temperature for 2 hours.
• the resulting mixture was concentrated under reduced pressure.
• the crude product 53mg was used for the next step without further purification.
• LC-MS: (ESI, m/z): [M+H] + 164.
• Step 6 Methyl 6,6-difluorohexahydro-1H-pyrrolizine-3-carboxylate
• a solution of 6,6-difluorohexahydro-1H-pyrrolizine-3-carbonitrile (150mg, 0.87mmol) in hydrochloric acid solution (2mL) and methanol (2mL) was stirred at 40 °C for 18 hours. The resulting mixture was concentrated under reduced pressure to afford the crude product 129mg.
• LC-MS: (ESI, m/z): [M+H] + 206.
• Step 7 (6,6-Difluorohexahydro-1H-pyrrolizin-3-yl) methanol
• Step 2 2-((6S,8aS)-4-Oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)acetonitrile
• [1178] To a solution of [rac-(6S,8aS)-4-oxo-6,7,8,8a-tetrahydro-1H-pyrrolo[2,1- c][1,4]oxazin-6-yl]methyl 4-methylbenzenesulfonate (50.0mg, 0.15mmol), TBAF (161mg, 0.61mmol) in acetonitrile (3mL) was added TMSCN (91mg, 0.92mmol) at 0 °C.

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