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WO2023244713A1 - Dérivés de quinazoline, compositions et procédés associés - Google Patents

Dérivés de quinazoline, compositions et procédés associés Download PDF

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Publication number
WO2023244713A1
WO2023244713A1 PCT/US2023/025372 US2023025372W WO2023244713A1 WO 2023244713 A1 WO2023244713 A1 WO 2023244713A1 US 2023025372 W US2023025372 W US 2023025372W WO 2023244713 A1 WO2023244713 A1 WO 2023244713A1
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Prior art keywords
compound
substituted
unsubstituted
nrr
mmol
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Hongbo Deng
Tao Liu
Minghong HAO
Upul K. Bandarage
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Ensem Therapeutics Inc
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Ensem Therapeutics Inc
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    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel quinazoline derivatives that are shown to be potent and selective inhibitors of KRas, in particular KRas (G12D). The invention also provides pharmaceutical compositions comprising compounds of the invention and methods for treating diseases and disorders associated with or related to KRas activities, such as various types of cancer.
  • KRAS Philadelphia rat sarcoma virus
  • KRas a gene that provides instructions for making a protein called KRas, a part of the RAS/MAPK pathway.
  • the protein relays signal from outside the cell to the cell's nucleus instructing the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate).
  • KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP -bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, such as cellular proliferation.
  • GDP-bound inactive
  • GTP -bound active
  • the role of activated KRas in malignancy was first observed over thirty years ago. (Santos et al. 1984 Science 223:661-664; Alamgeer et al. 2013 Current Opin Pharmcol.1394-401)
  • KRas mutation occurs in nearly 30% of human cancers. For example, mutations of KRas are observed in pancreatic ductal adenocarcinomas, colon and rectal carcinomas, and nonsmall cell lung carcinomas. Mutations often occur in the glycine residue of KRas at position 12 with KRas(Gl 2D) being the most prevalent and oncogenic variant.
  • KRas(Gl 2D) mutation has been shown to be present in about 25% of all pancreatic ductal adenocarcinoma patients, about 13% of all colorectal carcinoma patients, about 10% of all rectal carcinoma patients, about 4% of all non-small cell lung carcinoma patients and about 1.7% of all small cell lung carcinoma patients (The AACR Project GENIE Consortium, 2017 Cancer Discovery 7(8): 818-831, Dataset Version 4).
  • KRas inhibitors in particular, inhibitors of KRas mutants, especially KRas(G12D), that are safe and effective in treating diseases and conditions associated with aberrant expression of KRAS, such as various types of cancer (e.g., ductal cancer, colorectal cancer, rectal cancer, cell lung cancer).
  • various types of cancer e.g., ductal cancer, colorectal cancer, rectal cancer, cell lung cancer.
  • the invention provides novel quinazoline derivatives as KRas inhibitors, in particular KRas (G12D) inhibitors, which have been shown to exhibit favorable potency and selectivity profiles over known KRas inhibitors. These novel compounds selectively target, bind to, inhibit and/or modulates the activity of KRas.
  • the compound is also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treating various diseases and disorders associated with or related to KRas activities, such as various types of cancer.
  • the invention generally relates to a compound having the structural Formula (I):
  • R 1 is XR 11 or NR 12 R 13 , wherein X is O, S or absent, R 11 is (CH2)iR 14 , and z is an integer selected from 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6), wherein (CHi); is optionally substituted;
  • R 2 is an unsubstituted or substituted 6- to 10-membered (e.g., 6-, 7-, 8-, 9- or 10- membered) unsaturated monocyclic or bicyclic ring, comprising 0-5 e.g., 0, 1, 2, 3, 4 or 5) heteroatoms selected from N, O and S;
  • R 3 is L-R 3 , wherein
  • L is a single bond or NR(CH2)k, wherein k is an integer selected from 0-3 (e.g., 0, 1, 2 or 3);
  • R 3 is an unsubstituted or substituted, 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8- , 9- or 10-membered) saturated or unsaturated monocyclic, bicyclic or bridged ring moiety that comprises 0-5 (e.g., 0, 1, 2, 3, 4 or 5) heteroatoms selected from N, O and S; each of R 4 and R 5 is independently selected from the group consisting of H, halogen, CN, OH, unsubstituted or substituted Ci-4 alkyl, unsubstituted or substituted Ci-4 alkoxy, NO2, NRR’, C(O)NRR’, NRC(O)R”, C(O)R”, OC(O)R”, C(O)OR, unsubstituted or substituted 3- to 8- membered (e.g., 3-, 4-, 5-, 6-, 7- or 8-membered) carbocycle, and unsubstituted or substituted 3- to 8-member
  • R is H, unsubstituted or substituted C1-4 alkoxy, unsubstituted or substituted C1.4 alkyl, or unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5- or 6-membered) carbocyclic ring.
  • the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.
  • the invention generally relates to a method for inhibiting KRas(G12D) activity in a cell, comprising contacting the cell with a compound disclosed herein.
  • the invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.
  • “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited.
  • consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents.
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
  • administering encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein.
  • the term “co-administer” refers to the presence of two pharmacological agents in a subject’s body (e.g., in the blood) at the same time.
  • the two pharmacological agents can be administered concurrently or sequentially.
  • the terms "effective amount” or “therapeutically effective amount” refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to achieve the intended application including, but not limited to, disease treatment, as illustrated below.
  • the amount is that is sufficient to negatively modulate or inhibit the activity of KRas (G12D). In some embodiments, the amount is that effective for reduction or amelioration of a symptom to stop or reversion of progression of a disease or disorder such as cancer. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer.
  • the therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. Such amount may be administered as a single dosage or according to a regimen. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration.
  • the specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • KRas(G12D) or “KRas G12D” are used interchangeably and refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
  • the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Glyl2Asp.
  • an “inhibitor” of “KRas(G12D)” or “KRas G12D” refers to a compound of the invention capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12D.
  • a “KRas G12D-associated” disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation.
  • KRas G12D-associated diseases or disorders include various KRas G12D-associated cancer types.
  • the term “contacting” refers to the bringing together of indicated moieties in vitro or in vivo.
  • “contacting” a KRas G12D with a compound disclosed herein includes the administration of the compound to a subject having KRas G12D, as well as, for example, introducing the compound into a sample containing a cellular or purified preparation containing the KRas G12D.
  • a cell in which inhibition of KRas G12D activity is desired is contacted with an effective amount of a compound disclosed herein or pharmaceutically acceptable form thereof to negatively modulate the activity of KRas G12D.
  • a compound disclosed herein or pharmaceutically acceptable form thereof to negatively modulate the activity of KRas G12D.
  • the methods disclosed herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to achieve the desired negative modulation of KRas G12D.
  • the ability of compounds to bind KRas G12D may be monitored in vitro using methods known in the art.
  • the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D activity using methods known in the art.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, - COOH, -CH 2 CN, -O-C 1 -C 6 alkyl, C 1 -C 6 alkyl, -OC 1 -C 6 alkenyl, -OC 1 -C 6 alkynyl, -C 1 -C 6 alkenyl, -C 1 -C 6 alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -OC(O)OCi- C 6 alkyl, NH 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 , -NHC(
  • a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds.
  • a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds.
  • a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19 Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • the salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, tri methyl amine, diethylamine, tri ethyl amine, tri propyl amine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable ester.
  • pharmaceutically acceptable ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein.
  • Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids.
  • esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates.
  • the esters can be formed with a hydroxy or carboxylic acid group of the parent compound.
  • the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate).
  • solvate refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate".
  • solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g, hydrolysis in blood).
  • hydrolysis e.g, hydrolysis in blood
  • a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound.
  • exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam).
  • a discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage
  • pharmaceutically acceptable excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydrox
  • wetting agents such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • the term “subject” refers to any animal ( ⁇ ?. ., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated with a compound disclosed herein and/or according to a herein disclosed method.
  • the subject has been identified or diagnosed as having a cancer having a KRas G12D mutation.
  • the subject has a cancer that is positive for a KRas G12D mutation.
  • the subject is suspected of having a KRas G12D gene-associated cancer.
  • an assay is used to determine whether the subject has KRas G12D mutation using a sample (e.g., a biological sample or a biopsy sample (e , a paraffin-embedded biopsy sample) from a subject
  • a sample e.g., a biological sample or a biopsy sample (e , a paraffin-embedded biopsy sample) from a subject
  • a sample e.g., a biological sample or a biopsy sample (e , a paraffin-embedded biopsy sample) from a subject
  • a sample e.g., a biological sample or a biopsy sample (e , a paraffin-embedded biopsy sample) from a subject
  • Various techniques may be employed, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time
  • treatment refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred.
  • Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology.
  • Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder.
  • the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease.
  • reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • the term "therapeutic effect” refers to a therapeutic benefit and/or a prophylactic benefit as described herein.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.
  • Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.
  • an “isolated” or “substantially isolated” molecule is one that has been manipulated to exist in a higher concentration than in nature or has been removed from its native environment.
  • a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed.
  • RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules.
  • Isolated nucleic acid molecules further include synthetically produced molecules.
  • vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”
  • the term “purified” when used in reference to a molecule it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was produced, found or synthesized.
  • Naturally associated molecules include proteins, nucleic acids, lipids and sugars but generally do not include water, buffers, and reagents added to maintain the integrity or facilitate the purification of the molecule being purified.
  • a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.
  • Ci-4 alkyl is intended to encompass, Ci, C2, C3, C4, C1-3, C1-2, C2-4, C3-4 and C2-3 alkyl groups.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e. ., C1-10 alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • alkyl can be a Ci-6 alkyl group.
  • alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms.
  • Representative saturated straight chain alkyls include, but are not limited to, -methyl, - ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3- methylbutyl, 2-m ethylpentyl, 3 -methylpentyl, 4-m ethylpentyl, 2-methylhexyl, 3 -methylhexyl, 4- methylhexyl, 5 -methylhexyl, 2,3 -di
  • alkyl is attached to the parent molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfona
  • a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.
  • aromatic refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, H, halogen, -O-C 1 -C 6 alkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkenyl, -OC 1 -C 6 alkynyl, -C 1 -C 6 alkenyl, -C 1 -C 6 alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -OC(O)OC 1 - C 6 alkyl, NH 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 , -S(O) 2 -C 1 -C 6 alkyl, -S(O)NHC 1 -C 6 alkyl, and S(O)N(CI-C6 alkyl) 2 .
  • the substituents can themselves be optionally substituted.
  • the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring.
  • Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • heteroaryl or “hetero-aromatic” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S.
  • heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl
  • Heteroaryl also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.
  • Heteroaryl groups may be substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZiZ2)carbonyl.
  • substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkyl
  • NZ1Z2 means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom.
  • Zi and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl.
  • Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.
  • alkoxy refers to an -O-alkyl radical
  • cycloalkyl and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl” if the carbocycle contains at least one double bond, or "cycloalkynyl” if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl).
  • a numerical range such as “3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms” means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms.
  • the term "cycloalkyl” also includes bridged and spiro-fused cyclic structures containing no heteroatoms.
  • the term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups.
  • Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like.
  • cycloalkyl can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical.
  • Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like.
  • C3-7 carbocyclyl groups include norbomyl (C7).
  • Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl (C?), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1 ]heptanyl, bicyclo[2.2.2]octanyl, and the like.
  • C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like.
  • a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, s
  • cycloalkenyl and “cycloalkynyl” mirror the above description of “cycloalkyl” wherein the prefix “alk” is replaced with “alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are as described herein.
  • a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms.
  • a cycloalkynyl group can have 5 to 13 ring atoms.
  • heterocycloalkyl refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, S, P or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups.
  • heterocycloalkyl examples include 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl- tetrahydrofuran-3-yl, 3 -carboxy -morpholin-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl.
  • heterocycle refers to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered spirocyclic or tricyclic ring systems, which have at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent.
  • heteroatom selected from the group consisting of N, O, and S
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted.
  • heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononany
  • the invention is based in part on the discovery of KRas inhibitors, in particular KRas (G12D) inhibitors, that selectively target, bind to, inhibit or modulate the activity of KRas.
  • KRas inhibitors in particular KRas (G12D) inhibitors
  • the novel compounds exhibit favorable potency and selectivity as well as pharmacokinetics profiles suitable for development into an orally administered therapeutic agent for treating diseases and disorders associated with or related to KRas activities, such as various types of cancer.
  • the invention generally relates to a compound having the structural Formula (I):
  • R 1 is XR 11 or NR 12 R 13 , wherein X is O, S or absent, R 11 is (CH2)iR 14 , and z is an integer selected from 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6), wherein (CHi); is optionally substituted;
  • R 2 is an unsubstituted or substituted 6- to 10-membered (e.g., 6-, 7-, 8-, 9- or 10- membered) unsaturated monocyclic or bicyclic ring, comprising 0-5 e.g., 0, 1, 2, 3, 4 or 5) heteroatoms selected from N, O and S;
  • R 3 is L-R 3 , wherein
  • L is a single bond or NR(CH2)k, wherein k is an integer selected from 0-3 (e.g., 0, 1, 2 or 3);
  • R 3 is an unsubstituted or substituted, 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8- , 9- or 10-membered) saturated or unsaturated monocyclic, bicyclic or bridged ring moiety that comprises 0-5 (e.g., 0, 1, 2, 3, 4 or 5) heteroatoms selected from N, O and S; each of R 4 and R 5 is independently selected from the group consisting of H, halogen, CN, OH, unsubstituted or substituted Ci-4 alkyl, unsubstituted or substituted Ci-4 alkoxy, NO2, NRR’, C(O)NRR’, NRC(O)R”, C(O)R”, OC(O)R”, C(O)OR, unsubstituted or substituted 3- to 8- membered (e.g., 6-, 7- or 8-membered) carbocycle, and unsubstituted or substituted 3- to 8- membered (e.g
  • R is H, unsubstituted or substituted C1-4 alkoxy, unsubstituted or substituted C1.4 alkyl, or unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5- or 6-membered) carbocyclic ring. [0061] In certain embodiments, at least one of R 4 and R 5 is not H.
  • one of R 4 and R 5 is H and the other is not H.
  • neither R 4 nor R 5 is H.
  • At least one of R 4 and R 5 is not H.
  • R 4 is halogen, CN, OH, unsubstituted or substituted C1-4 alkyl, unsubstituted or substituted C1-4 alkoxy, NO2, NRR’, C(O)NRR’, NRC(O)R”, C(O)R”, OC(O)R” or C(O)OR.
  • R 5 is halogen, CN, OH, unsubstituted or substituted C1-4 alkyl, unsubstituted or substituted C1-4 alkoxy, NO2, NRR’, C(O)NRR’, NRC(O)R”, C(O)R”, OC(O)R” or C(O)OR.
  • R 5 is an unsubstituted or substituted 3- to 8-membered (e.g., 3-, 4-, 5-, 6-, 7- or 8-membered) carbocycle.
  • R 5 is an unsubstituted or substituted 3- to 8-membered (e.g., 3-, 4-, 5-, 6-, 7- or 8-membered) heterocycle.
  • R 4 is H and R 5 is an unsubstituted or substituted 3- to 6- membered (e.g., 3-, 4-, 5- or 6-membered) carbocycle.
  • R 4 is H and R 5 is an unsubstituted or substituted 4- to 7- membered (e.g., 4-, 5-, 6- or 7-membered) heterocycle.
  • one of R 4 and R 5 is a halogen and the other is selected from halogen, CN, methyl and ethyl.
  • one of R 4 and R 5 is a halogen and the other is selected from OH, OCH 3 , C(O)NH 2 and C(O)NHCH 3 .
  • one of R 4 and R 5 is halogen, CN, methyl and ethyl and the other is an unsubstituted or substituted 3- to 8-membered (e.g, 3-, 4-, 5-, 6-, 7- or 8-membered) carbocycle.
  • one of R 4 and R 5 is halogen, CN, methyl and ethyl and the other is an unsubstituted or substituted 3- to 8-membered (e.g., 3-, 4-, 5-, 6-, 7- or 8-membered) heterocycle.
  • one of R 4 and R 5 is unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • one of R 4 and R 5 is unsubstituted or substituted tetrahydrofuran, tetrahydropyran, cyclic sulfone, cyclic sulfonamide, cyclic amide, cyclic carbamate, azetidine, pyrrolidine, piperidine, pyrazole, imidazole, 1, 3 -oxazole, 1,2-oxazole, 1,3- thiazole, 1, 2,4-triazole, 1,2, 3 -triazole, 1. 3,4-oxadiazole, 1,3,4-thiadiazole, furan, pyridine, pyrimidine, pyridazine, pyrazine, or triazine.
  • R 1 is X(CH 2 )iR 14 , wherein X is O.
  • R 14 is a C3-6 carbocyclic ring substituted with 0-5 (e. ., 0, 1,
  • R 15 is independently selected from D, halo, C1-3 alkyl optionally substituted with one or more of halo, OH, NRR’, CN, CONRR’ or SO 2 NRR’.
  • z is 1.
  • R 14 is C3-4 cycloalkyl ring substituted with 0-5 (e.g., 0, 1, 2,
  • R 1 has the structure: wherein R x is OH, halo, NRR’, CN, CONRR’ or SO 2 NRR’.
  • R 15 is F, m is 0, 1 or 2, and R x is CH 2 OH.
  • R 1 has the structure: wherein R x is OH, halo, NRR’, CN, CONRR’ or SO2NRR’.
  • R 15 is F
  • m is 0, 1 or 2
  • CH2OH is H
  • R 1 is NR 12 R 13 .
  • X is absent and R 1 is (CH2)iR 14 .
  • R 14 is NRR’ .
  • R 14 comprises one or more of amino, amide, sulfonamide, and carboxylic ester groups.
  • R 14 is a mono- or bicyclic, unsubstituted or substituted C4-10 heterocyclic ring.
  • R 14 is a bicyclic, unsubstituted or substituted Ce-io heterocyclic ring.
  • R 14 has the structure of: wherein
  • Ring E is a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) unsubstituted or substituted monocyclic or bicyclic carbocyclic of heterocyclic ring;
  • W is O, S, N, NR, C(O), S(O) 2 , NHC(O), C(O)NH, OC(O), C(O)O, S(O) 2 NH, or NHS(O) 2 ;
  • R 13 is as defined herein.
  • R 1 is X(CH2);R 14 , wherein X is S.
  • R 1 is NR 12 R 13 .
  • R 1 has the structure of: wherein each of Ring C and Ring D is a 4- to 7-memebered heterocyclic ring;
  • R 19 is selected from the group consisting of: H, Ci-6 alkyl, and Ci-g alkoxy; each of g, p and q is independently 0, 1, 2 or 3, provided that if one of f and p is 0, the other is not 0 and if one of g and g is 0, the other is not 0; and each of m and n is independently 0, 1, 2 or 3.
  • each of T 1 and T 2 is CR 17 R 18 , each of g,p and q is 1, with R 1 having the structure of:
  • n is 1
  • R 16 is F.
  • X is O.
  • i is 1.
  • X is absent and R 1 is (CH2)iR 14 .
  • R 14 is NRR’.
  • R 14 comprises one or more of amino, amide, sulfonamide, and carboxylic ester groups.
  • R 14 is a mono- or bicyclic, unsubstituted or substituted C4-10 heterocyclic ring. In certain embodiments, R 14 is a monocyclic, unsubstituted or substituted C4-7 heterocyclic ring. In certain embodiments, R 14 is a bicyclic, unsubstituted or substituted Ce-io heterocyclic ring.
  • R 14 include:
  • R 13 and R 16 are as defined herein.
  • R 2 is an unsubstituted or substituted 6- to 10-membered (e.g., 5-, 6-, 7-, 8-, 9- or 10-membered) unsaturated bicyclic ring, comprising 0-5 (e.g., 0, 1, 2, 3, 4 or 5) heteroatoms selected from N, O and S.
  • R 2 has the structure of: wherein
  • Ring A is a 6-membered aryl or heteroaryl ring with 0-2 N atoms
  • R 2 is: wherein each of Z 1 and Z 2 is independently selected from CH and N.
  • each of Z 1 and Z 2 is CH.
  • Z 1 is CH and Z 2 is N.
  • Z 1 is Z and Z 2 is CH.
  • each of Z 1 and Z 2 is N.
  • R 2 is: wherein each of Z 1 and Z 2 is independently selected from CH and N; and each of Z 3 , Z 4 and Z 5 is independently selected from CR”, N, NR, O or S, provided that Ring B remains an aromatic ring, wherein R is H or a Ci-4 alkyl.
  • each of Z 1 and Z 2 is CH.
  • Z 1 is CH and Z 2 is N.
  • Z 1 is Z and Z 2 is CH.
  • each of Z 1 and Z 2 is N.
  • each of Z 3 , Z 4 and Z 5 is not a heteroatom.
  • at least one of Z 3 , Z 4 and Z 5 is a heteroatom.
  • R 2 groups include: wherein R 21 and R 22 are as defined herein.
  • R 2 include:
  • R 3 is an unsubstituted or substituted, saturated or unsaturated bicyclic or bridged ring moiety that comprises at least one N atom.
  • L is a single bond.
  • R 3 is: wherein
  • Y 1 is N or CR
  • Y 2 is (CH 2 )j, NR or CH 2 OCH 2 ;
  • Y 3 is NR, CR”, O or S; each R 31 is independently selected from the group consisting of halogen, OH, NRR’, C(O)NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6 alkoxy, NRC(O)R”, NRC(O)NRR’, C(O)R”, and C(O)OR, S(O) 2 NRR’, NRS(O) 2 R and NRS(O) 2 NRR’; each j is independently 0, 1, 2 or 3; and m is 0, 1, 2 or 3.
  • j is 2. In certain embodiments, j is 1. In certain embodiments, is 0. [00127] In certain embodiments, m is 2 Tn certain embodiments, m is 1 . Tn certain embodiments, m is 0.
  • Y 3 is NR.
  • Y 3 is CR”.
  • Y 3 is O.
  • Y 3 is S.
  • j is 2.
  • R 3 is:
  • Y 3 is NR.
  • Y 3 is CR”.
  • R 3 include:
  • R, R’ and m are as defined herein.
  • m is 0.
  • m is 1.
  • L is a single bond and R 3 is an unsubstituted or substituted, 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered) saturated or unsaturated monocyclic that comprises 0-3 (e.g., 0, 1, 2 or 3) heteroatoms selected from N, O and S.
  • R 3 is an unsubstituted or substituted, 6-membered saturated or unsaturated monocyclic that comprises 1-3 heteroatoms selected from N, O and S.
  • R 3 has the structure: wherein
  • Ring G is a 5- to 7-membered ( ⁇ ?.g., 5-, 6- or 7-membered) heterocyclic ring with 1-3 heteroatoms selected from N, O and S; each R 32 is independently selected from the group consisting of halogen, OH, NRR’, C(O)NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6 alkoxy,
  • NRC(O)R NRC(O)NRR’, C(O)R”, and C(O)OR, S(O) 2 NRR’, NRS(O) 2 R and NRS(O) 2 NRR’; and m is 0, 1, 2 or 3.
  • Ring G is 6-membered.
  • R 3 is an unsubstituted or substituted, 10- to 12-membered (e.g., 10-, 11- or 12-membered) saturated or unsaturated bicyclic that comprises 1-5 (e.g., 1, 2, 3, 4 or 5) heteroatoms selected from N, O and S.
  • Rings F and H together form a hetero-bicyclic ring; each R 32 is independently selected from the group consisting of halogen, OH, NRR’, C(O)NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6 alkoxy, NRC(O)R”, NRC(O)NRR’, C(O)R”, and C(O)OR, S(O) 2 NRR’, NRS(O) 2 R and NRS(O) 2 NRR’; and m is 0, 1, 2 or 3.
  • Ring F is 7-membered and Ring H is 5-membered.
  • L is NR(CH2)k and R 3 is NR(CH2)kR 3 .
  • k is 0.
  • k is 1.
  • R 3 is an unsubstituted or substituted, 3- to 6-membered (e.g., 3-, 4-, 5-, 6-membered) monocyclic ring moiety that comprises 0-3 (e.g., 0, 1, 2 or 3) heteroatoms selected from N, O and S.
  • R 3 has the structure: wherein
  • Ring J is a 5- to 7-membered (e.g., 5-, 6- or 7-membered) carbocyclic or heterocyclic ring with 0-3 (e.g., 0, 1 , 2 or 3) heteroatoms selected from N, O and S; each R 32 is independently selected from the group consisting of halogen, OH, NRR’, C(O)NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6 alkoxy, NRC(O)R”, NRC(O)NRR’, C(O)R”, and C(O)OR, S(O) 2 NRR’, NRS(O) 2 R and NRS(O) 2 NRR’; and m is 0, 1, 2 or 3.
  • each R 32 is independently selected from the group consisting of halogen, OH, NRR’, C(O)NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6
  • Ring J is 6-membered.
  • the compound has the structural formula:
  • the compound has the structural formula: wherein
  • Ring K is a C3-4 cycloalkyl
  • R x is OH, halo, NRR’, CN, CONRR’ or SO 2 NRR’; and m is 0, 1, 2 or 3.
  • the compound has the structural formula: wherein
  • each R 32 is independently selected from the group consisting of halogen, OH, NRR’, C(O)NRR’, unsubstituted or substituted C1-6 alkyl, and unsubstituted or substituted C1-6 alkoxy, NRC(O)R”, NRC(O)NRR’, C(O)R”, and C(O)OR, S(O) 2 NRR’, NRS(O) 2 R and NRS(O) 2 NRR’; and m is 0, 1, 2 or 3.
  • the compound has the structural formula:
  • R 3 is an unsubstituted or substituted, 3- to 6-membered (e.g., 3-, 4-, 5-, 6-membered) monocyclic ring moiety that comprises 0-3 (e.g., 0, 1, 2 or 3) heteroatoms selected from N, O and S; and k is 0, 1 or 2.
  • a compound of the invention is selected from Table 1.
  • a pro-drug comprises an ester, a carbonate and/or a carbamate moiety.
  • R 2 and R 3 in formula (I) comprises an ester, a carbonate and/or a carbamate moiety.
  • ester, carbonate and carbamate moi eties are selected from:
  • ester, carbonate and carbamate moi eties are selected from:
  • a compound of invention has one or more deuterium atoms in place of hydrogen. In certain embodiments, a compound of invention has one deuterium atom in place of a hydrogen atom.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the pharmaceutical composition is suitable for oral administration.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the unit dosage form is in the form of a tablet or capsule.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch).
  • Other formulations may conveniently be presented in unit dosage form, e g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary, shaping the product.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid,
  • binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example, paraffin
  • absorption accelerators as for example
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvent
  • the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.
  • the invention generally relates to a method for inhibiting KRas(G12D) activity in a cell, comprising contacting the cell with a compound disclosed herein.
  • the invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.
  • diseases or disorders that may be treated or reduced by compositions or methods of the invention include, but are not limited to, tumors, cancers, autoimmune diseases, macroglob id in emi a, and the like.
  • the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.
  • cancers targeted in the present invention include, but are not particularly Limited to, head and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer, and rectal cancer), etc.), lung cancer (e.g., non- small-cell lung cancer, small-cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcoma (e.g., osteosarcoma, and soft-tissue sar
  • digestive organ cancer
  • squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.
  • adenocarcinoma is a cancer of prostate, small intestine, endometrium, uterine cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.
  • tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer leukemia or uterine cancer.
  • the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and a hematologic malignancy.
  • a subject suffering from any of the disease selected from the above does not have to have KRAS G12D mutant protein. In certain embodiments, a subject suffering from any of the disease selected from the above has KRAS G12D mutant protein.
  • the subject has a mutation of KRAS, HRAS and/or NRAS.
  • the amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound and the discretion of the prescribing physician. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.
  • Any appropriate route of administration can be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalational, buccal, intraperintoneal, rectal, intrapleural, and intrathecal administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may 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 may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions of pharmaceutically active ingredients are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein.
  • Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein).
  • a useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may 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 may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3 -butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention. [00199] Methods of treatment disclosed herein ay be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.
  • Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds, e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • FDA U.S. Food and Drug Administration
  • CFR Code of Federal Regulations
  • a compound of the invention may be administered in combination with endocrine therapy, e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.
  • endocrine therapy e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.
  • a compound of the invention may be administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine.
  • a compound of the invention may be administered in combination with an anti-HER2 agent, e.g., trastuzumab or pertuzumab.
  • the method disclosed herein is in combination with one or more of immune check point blockade, co-signaling of T cells, and tumor targeting antibody therapies.
  • the method further comprises administering a chemotherapeutic agent to the subject.
  • the method further comprises administering a radiotherapy to the subject. In certain embodiments, the method further comprises administering a targeted therapy to the subject. In certain embodiments, the method further comprises administering an immunotherapy to the subject. In certain embodiments, the method further comprises administering hormonal therapy to the subject.
  • chemotherapeutic agent refers to a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU1 1248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, e
  • NAVELBTNE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
  • Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincris), mito
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cisand Zra/rs-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.
  • Isotopically-labeled compounds are also within the scope of the present disclosure.
  • an “isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which 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.
  • isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • the compounds may be useful in drug and/or substrate tissue distribution assays.
  • Tritiated ( 3 H) and carbon- 14 ( 14 C) labeled compounds are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.
  • substitution of normally abundant hydrogen ( 1 H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and/or excretion (ADME) properties, creating drugs with improved efficacy, safety, and/or tolerability. Benefits may also be obtained from replacement of normally abundant 12 C with 13 C. (See, WO 2007/005643, WO 2007/005644, WO 2007/016361, and WO 2007/016431.)
  • Stereoisomers e.g., cis and trans isomers
  • optical isomers of a presently disclosed compound e.g., R and S enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. Tn certain embodiments, the compounds of the present invention are more than 99% pure.
  • Solvates and polymorphs of the compounds of the invention are also contemplated herein.
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
  • compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions can also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily and more usually 1 to 300 mg/kg body weight.
  • the dose, from 0.0001 to 300 mg/kg body, may be given twice a day.
  • AIBN a,a'-Azoisobyronitrile
  • BINAP 2,2'-Bis(diphenylphosphino)-l,r-binaphthyl
  • BOP Bis(2-oxo-3-oxazolidinyl)phosphine
  • CAN Ceric ammonium nitrate cataCXium
  • Pd G3 mesylate [(di(l-adamantyl)-n-butylphosphine)-2-
  • CPhos 2-Dicyclohexylphosphino-2',6'-bis(jV,7V-dimethylamino)biphenyl
  • DIBAL Diisobutylaluminium hydride
  • DIPEA Diisopropylethylamine
  • DMPU l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pirimidone
  • EDC l-Ethyl-3-(3-dimethylaminopropy)carbodiimide
  • EDCI l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochloride
  • HMDS Hexamethyldisilazane
  • HMPA Hexamethylphosphoramide
  • HOAt 7-Aza-l-hydroxybenzotriazole
  • HOBt 1 -Hydroxybenzotriazole
  • KHMDS Potassium bis(trimethylsilyl)amide
  • LAH Lithium aluminium hydride
  • LHMDS Lithium bis(trimethylsilyl)amide
  • MCPBA meta-chloroperoxybenzoic acid
  • NBS N-Bromosuccinimide
  • NCS N-Chlorosuccinimide
  • NIS N-Iodosuccinimide
  • NMM N-Methylmorpholine
  • NMO N-Methylmorpholine-N-oxide
  • Ns p-Nitrophenyl sulphonyl
  • Pd(dppf)Q2 [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium
  • Pd(PPh3)4 tetrakis(triphenylphosphine)palladium
  • PCC Pyridinium chlorochromate
  • PPTS Pyridinium p-toluensulphonate
  • n-Pr n-Propyl
  • Red-Al® Sodium bis(2-methoxyethoxy)aluminium hydride
  • RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl
  • TBDPS tert-Butyldiphenylsilyl
  • TBHP tert-Butylhydroperoxyde
  • TBS tert-Butyl di methyl silyl
  • Tf2O Trifluoromethanesulfonyl anhydride
  • TfOH Trifluoromethanesulfonic acid
  • TIPS Triisopropylsilyl
  • TMEDA N,N,N',N'-Tetramethylethylendiamine
  • TPAP Tetra-n-propylammonium perruthenate
  • Tr Trityl, triphenylmethyl
  • Trt Trityl, triphenylmethyl
  • Ts p-Toluenesulphonyl
  • p-TsOH p-Toluenesulphonic acid
  • UV ultraviolet
  • Scheme 1 illustrates one procedure for preparing the compounds of disclosure using metal-catalyzed reaction to prepare the substituted quinazoline.
  • Displacement of 4-chloro group of 1,3 -di substituted quinazoline with a protected piperazine or amine provides 2-chloro-4-amine- substituted quinazoline intermediate.
  • the second chloro group was displaced with an appropriate alcohol to fetch an ether substituted quinazoline intermediate.
  • This intermediate could be utilized in two different ways to prepare the final target compounds.
  • the first method is to install bromine atom at C7 position after deprotonation with strong base such as BuLi or LDA.
  • Pd-catalyzed Suzuki reaction will be applied to couple a suitable aryl boronic acid or ester followed by the deprotection of all the protecting group to yield the final product.
  • the second method is to apply a zincate to deprotonate C7 to form an aromatic zinc reagent, then couple with an appropriate aryl halide to form C7-aryl substituted quinazolines. Final deprotection yields the desired target compounds.
  • Scheme 2 illustrates the other procedure for preparing the compounds of disclosure by using C7 brominated amino benzoic acid as starting material.
  • 2-Amino benzoic acid reacts with chlorosulfonyl isocyanate and provides 2-thiol-3 -hydroxyl quinazoline. After methylation of thiol, 4-hydroxyl group was transformed to 4-chloride. Displacement of 4-chloro group with a protected piperazine or amine provides 4-amine-2 -thiol quinazoline intermediate. Then some functional group transformation can be carried out at C6 and more reactive C5-fluoro was displaced with an appropriate alcohol or other nucleophile. This intermediate was coupled to aryl boronic acid or ester by Pd-catalyzed Suzuki reaction followed by the deprotection of all the protecting group to yield the final target compounds.
  • Step 1 Synthesis of l,5-difluoro-2-methyl-4-nitrobenzene
  • Step 2 Synthesis of 2,4-difluoro-5-methylaniline [00234] A mixture of l,5-difluoro-2-methyl-4-nitrobenzene (5.0 g, 28.9 mmol) and Pd/C (10%, 1.7 g) in MeOH (50 mL) was hydrogenated with a balloon of hydrogen at room temperature for 3 h. HPLC showed the reaction was completed. The mixture was filtered and concentrated to give crude product, 2,4-difluoro-5-methylaniline (3.1 g, 75.6%) as a gray solid, which was used for next step without further purification.
  • Step 7 Synthesis of 2,4-dichloro-6,8-difluoro-5-methylquinazoline [00239] A solution of 6,8-difluoro-5-methylquinazoline-2,4-diol (456 mg, 2.2 mmol, 1.0 eq) in POCL (4.5 mL) was added DIEA (1.1 g, 8.6 mmol, 4.0 eq) and stirred at 90 °C for 3 h under nitrogen atmosphere.
  • DIEA 1.1 g, 8.6 mmol, 4.0 eq
  • Step 1 Synthesis of tert-butyl (3-bromo-2-fluoro-5-methylphenyl) carbamate
  • Step 1 Synthesis of l,5-difluoro-2-methoxy-4-nitrobenzene
  • Step 7 Synthesis of 7-bromo-5,8-difluoro-6-iodo-2-(methylthio)quinazolin-4-ol
  • a solution of 7-bromo-5,8-difluoro-6-iodo-2-mercaptoquinazolin-4-ol 5.5 g, 13.15 mmol, 1.0 eq
  • 1% NaOH 80 mL
  • Mel 1.87 g, 13.15 mmol, 1.0 eq
  • MeOH 60 mL
  • the reaction mixture was stirred at room temperature for 1 h.
  • the aqueous phase was acidified with 2 N HC1.
  • Step 8 Synthesis of 7-bromo-4-chloro-5,8-difluoro-6-iodo-2-(methylthio)quinazoline
  • Step 1 Synthesis of l-(benzyloxy)-2,4-difluoro-5-nitrobenzene
  • Step 3 Synthesis of 3-bromo-l,4-difluoro-2-methoxy-5-nitrobenzene [00277] To a solution of 2-bromo-3,6-difluoro-4-nitrophenol (4.5 g, 17.72 mmol, 1.0 eq) in Acetone (45 mL) was added NaHCCh (4.5 g, 53.15 mmol, 3 eq) and Me2SO4 (4.5 g, 35.44 mmol, 2 eq). The reaction mixture was stirred at 50 °C for 15 h. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3).
  • Step 6 Synthesis of methyl 2-amino-4-bromo-3,6-difluoro-5-methoxybenzoate
  • Step 8 Synthesis of 7-bromo-2,4-dichloro-5,8-difluoro-6-methoxyquinazoline
  • Step 1 Synthesis of l-(tert-butoxy)-3-chloro-7-fluoroisoquinoline
  • Step 2 Synthesis of l-(tert-butoxy)-7-fluoro-N, N-bis(4-methoxybenzyl)isoquinolin-3-amine
  • Step 4 Synthesis of 3-(bis(4-methoxybenzyl)amino)-7-fluoro-8-((triisopropylsilyl) ethynyl)isoquinolin-l-ol
  • Step 1 Synthesis of tert-butyl 2-(isopropylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
  • Step 2 Synthesis of N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carboxamide
  • Step 1 Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol
  • Step 2 Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diyl bis(trifluoromethanesulfonate) [00291 ] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l ,3-diol (1 .2 g, 3.3 mmol, 1.0 eq) in DCM (20 mL) was added TfzO (3.77 g, 13.3 mmol, 4.0 eq) and DIEA (2.6 g, 20.0 mmol, 6.0 eq) at 0 °C.
  • Step 3 Synthesis of 3-(difluoromethyl)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl trifluoromethanesulfonate
  • Step 1 Synthesis of l-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene
  • Step 4 Synthesis of 4-bromo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)- 1H -indazole
  • Step 3 Synthesis of 2-amino-6-chloro-3,5-difluorobenzoic acid [00299] To a solution of 4-chloro-5,7-difluoroindoline-2, 3-dione (10.0 g, 45.97 mmol, 1 .0 eq) in NaOH (2 mol/L aqueous solution, 400 mL) was added dropwise H2O2 (30 mL, 37% aqueous solution) at 0 °C. The reaction mixture was stirred at room temperature for 15 h.
  • Step 1 Synthesis of tert-butyl l-(methoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • Step 2 Synthesis of tert-butyl l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • Step 1 Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-
  • Step 2 Synthesis of ((6-(difluoromethoxy)-2-fluoro-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane
  • Step 1 Synthesis of tert-butyl l-methyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 Synthesis of tert-butyl l-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 1 Synthesis of tert-butyl 2-(isopropylcarbamoyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-
  • Step 3 Synthesis of 4-bromo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)- lH-indazole-3-carbonitrile
  • Step 1 Synthesis of ethyl (S)-2-(fluoromethylene)-5-oxotetrahydro-lH-pyrrolizine-7a(5H)- carboxylate [00313] To a solution of 2-((fluoromethyl)sulfonyl) pyridine (4.6 g, 26.3 mmol, 1.1 eq) in THF (260 mL) under nitrogen was added KHMDS (31 mL, 30.77 mmol, 1.3 eq) at -78 °C.
  • Step 1 Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-l-carboxylate
  • Step 2 Synthesis of tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- methoxypyrrolidine-l-carboxylate [00316] To a solution of tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-l - carboxylate (35.0 g, 151.3 mmol, 1.0 eq) in DCM (350 mL) was added Imidazole (15.5 g, 227.0 mmol, 1.5 eq) and TBSC1 (27.4 g, 181.6 mmol, 1.2 eq) in portions at 0 °C. The reaction was stirred at room temperature for 15 h under N2.
  • Step 3 Synthesis of tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyanopyrrolidine-l-carboxylate
  • Step 4 Synthesis of l-(tert-butyl) 2-methyl (5S)-5-(hydroxymethyl)pyrrolidine-l,2- dicarboxylate [00318] To a solution of tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyanopyrrolidine-1 -carboxylate (20.0 g, 58.7 mmol, 1.0 eq) in MeOH (200 mL) was added K2CO3 (20.3 g, 146.8 mmol, 2.5 eq). The reaction was stirred at room temperature for 3 h under N2. The reaction mixture was adjusted pH ⁇ 2 with 10% HC1 aqueous solution.
  • Step 5 Synthesis of l-(tert-butyl) 2-methyl (5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl) pyrrolidine -1,2-dicarboxylate
  • Step 6 Synthesis of l-(tert-butyl) 2-methyl (2S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2-(2-(chloromethyl)allyl)pyrrolidine-l,2-dicarboxylate [00320] To a solution of 1 -(tert-butyl) 2-methyl (5S)-5-(((tert- butyldiphenylsilyl)oxy)methyl)pyrrolidine-l,2-dicarboxylate (10.0 g, 20.1 mmol, 1.0 eq) in THF (100 mL) was added HMPA (18.0 g, 100.5 mmol, 5.0 eq) and LDA (2M) (20.1 mL, 40.2 mmol, 2.0 eq) dropwise at -78 °C.
  • Step 7 Synthesis of methyl (5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylene tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate
  • Step 8 Synthesis of ((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylene tetra hydro-lH-pyrrolizin-7a(5H)-yl)methanol
  • the reaction mixture was stirred at 100 °C for 2 h under N2.
  • the reaction mixture was partitioned between EtOAc (40 mL) and H2O (40 mL). The layers were separated. The aqueous layer was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated to a crude.
  • Step 2 Synthesis of N-(6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-
  • Step 1 Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diyl bis(trifluoromethanesulfonate)
  • Step 2 Synthesis of ethyl 2-(6-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)acetate
  • Step 3 Synthesis of ethyl 2-(6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)acetate
  • Step 1 Synthesis of ethyl (S)-2-(difluoromethylene)-5-oxotetrahydro-lH-pyrrolizine-
  • Step 2 Synthesis of (S)-(2-(difluoromethylene)tetrahydro-lH-pyirolizin-7a(5H)- yl)methanol
  • Step 1 Synthesis of tert-butyl 3-(2-chloro-5,6,8-trifluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 Synthesis of tert-butyl 3-(5,6,8-trifluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 Synthesis of tert-butyl 3-(7-bromo-5,6,8-trifluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate
  • Step 4 Synthesis of tert-butyl 3-(5,6,8-trifluoro-7-(8-fluoro-3- (methoxymethoxy)naphthalen -1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy) quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 Synthesis of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,6,8-trifluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl) methoxy)quinazolin-7-yl)-5-fluoronaphthalen-2- ol
  • Step 2 Synthesis of tert-butyl 3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo [3.2.1]octane-8- carboxylate
  • Step 3 Synthesis of tert-butyl 3-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo [3.2.1]octane-8- carboxylate
  • Step 4 Synthesis of tert-butyl 3-(6,8-difluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 Synthesis of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-7-yl)-5- fluoronaphthalen-2-ol [00339] A solution of tert-butyl 3-(6,8-difluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.17 mmol,
  • the precipitate formed was collected by fdtration, washed with DCM (3 mL). The solid was partitioned between EtOAc (10 mL) and aqueous NaHCCL (5 mL). The layers were separated. The aqueous layer was extracted with EtOAc (5 mL x 3).
  • Step 1 Synthesis of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodo-5-methylquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 Synthesis of tert-butyl 3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-6-iodo-5-methylquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate
  • the reaction mixture was stirred at room temperature for 3 h.
  • the mixture was partitioned between EtOAc (20 mL) and water (5 mL), the layers were separated.
  • the aqueous layer was extracted with EtOAc (20 mL x 3).
  • the combined organic layers were washed with H2O (10 mL), brine (10 mL), dried over Na2SO 4 and evaporated to dryness.
  • Step 3 Synthesis of tert-butyl 3-(7-bromo-6-cyano-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate
  • the reaction mixture was stirred at 100 °C for 12 h.
  • the mixture was partitioned between EtOAc (20 mL) and water (5 mL).
  • the aqueous layer was extracted with EtOAc (20 mL x 3).
  • the combined organic layers were washed with H2O (10 mL), brine (10 mL), dried over Na2SO 4 and evaporated to dryness.
  • Step 4 Synthesis of tert-butyl 3-(6-cyano-8-fluoro-7-(8-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00343] To a solution of tert-butyl 3-(7-bromo-6-cyano-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.06 m
  • Step 5 Synthesis of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3- hydroxynaphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl) methoxy)-5-methylquinazoline-6-carbonitrile
  • the crude product was purified by Prep-HPLC (acetonitrile with 0.1% FA in water, 30% to 40%) to give the desired product, 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8- fluoro-3-hydroxynaphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methylquinazoline-6-carbonitrile(3.8 mg, 46.9%) as a white solid.
  • Step 1 Synthesis of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoro-5-methyl quinazolin-4-yl)-
  • Step 2 Synthesis of tert-butyl 3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diaza bicyclo [3.2.1] octane-8-carboxylate
  • Step 3 Synthesis of tert-butyl 3-(6-chloro-8-fluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl) methoxy)-5- methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 Synthesis of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methylquinazolin-7-yl)-5- fluoronaphthalen-2-ol [00348] A solution of tert-butyl 3-(6-chloro-8-fluoro-7-(8-fluoro-3-
  • Step 1 Synthesis of tert-butyl 3-(2-chloro-6,8-difluoro-5-methoxyquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 Synthesis of tert-butyl 3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxyquinazolin-4-yl)-3,8-diazabicyclo [3.2.1]octane-8- carboxylate
  • Step 3 Synthesis of tert-butyl 3-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • Step 4 Synthesis of tert-butyl 3-(6,8-difluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 Synthesis of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxyquinazolin-7-yl)-5- fluoronaphthalen-2-ol
  • the precipitate formed was collected by filtration and washed with DCM.
  • the solid was partitioned between EtOAc (10 mL) and aqueous NaHCCh (5 mL). The layers were separated. The aqueous layer was extracted with EtOAc (5 mL x 3).
  • Example 6 (included in Example 11 and 12)
  • Step 1 Synthesis of tert-butyl 3-(7-bromo-5,8-difluoro-6-iodo-2-(methylthio)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 Synthesis of tert-butyl 3-(7-bromo-6-cyano-5,8-difluoro-2-(methylthio)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 Synthesis of tert-butyl 3-(6-cyano-5,8-difluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • the reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere.
  • the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3).
  • the organic phase was washed with brine (20 mL), dried with JSfeSCL, filtered and concentrated to give residue.
  • Step 4 Synthesis of tert-butyl 3-(6-cyano-5,8-difluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-2-(methylsulfonyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00357] To a solution of tert-butyl 3-(6-cyano-5,8-difluoro-7-(8-fluoro-3- (m ethoxymethoxy )naphthalen-l-yl)-2-(methylthio)quinazolin-4-yl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.53 mmol, 1.0 eq) in DCM (6.00mL) was added m-CPBA (309 mg, 1.34 mmol, 2.5 eq, 75%) at
  • Step 5 Synthesis of tert-butyl 3-(6-cyano-5,8-difluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy) quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 6 Synthesis of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluoro-7-(8-fluoro-3- hydroxynaphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl) methoxy)quinazoline-6-carbonitrile
  • Step 2 Synthesis of tert-butyl-3-(7-bromo-8-fluoro-6-iodo-5-methoxy-2-(methylthio) quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 Synthesis of tert-butyl-3-(7-bromo-6-cyano-8-fluoro-5-methoxy-2-(methylthio) quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 Synthesis of tert-butyl 3-(6-cyano-8-fluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-5-methoxy-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • the reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere.
  • the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3).
  • the organic phase was washed with brine (20 mL), dried with Na2SO 4 , filtered and concentrated to give residue.
  • Step 6 Synthesis of tert-butyl 3-(6-cyano-8-fluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxyquinazolin-4-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate
  • Step 7 Synthesis of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3- hydroxynaphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxyquinazoline-6-carbonitrile formate (1: 1)
  • Step 1 Synthesis of tert-butyl 3-(6-carbamoyl-8-fluoro-7-(8-fluoro-3-(methoxymethoxy) naphthalen-l-yl)-2-(((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxyquinazolin-4-yl)-3 ,8-diazabicyclo [3.2.1] octane-8-carboxylate
  • Step 2 Synthesis of (R)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3- hydroxynaphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxyquinazoline-6-carboxamide formate (1: 1) and (S)-4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fhioro-7-(8-fhioro-3-hydroxynaphthalen-l-yl)-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxyquinazoline-6- carboxamide formate (1: 1)
  • Step 1 Synthesis of tert-butyl 3-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-

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Abstract

L'invention concerne de nouveaux dérivés de quinazoline, substitués en position C4 par une fraction de noyau hétérocyclique azoté monocyclique, bicyclique ou ponté de 3 à 10 chaînons, non substituée ou substituée, qui sont représentés comme étant puissants et des inhibiteurs sélectifs de KRas, en particulier de KRas (G12D), des compositions pharmaceutiques de ceux-ci et des procédés de traitement de maladies et de troubles associés à ou liés à des activités de KRas, tels que divers types de cancer.
PCT/US2023/025372 2022-06-16 2023-06-15 Dérivés de quinazoline, compositions et procédés associés Ceased WO2023244713A1 (fr)

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Cited By (9)

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WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2024215862A3 (fr) * 2023-04-12 2025-02-06 Board Of Regents, The University Of Texas System Composés hétérocycliques en tant qu'inhibiteurs de nras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025214341A1 (fr) * 2024-04-08 2025-10-16 江苏恒瑞医药股份有限公司 Composé dihydrofuro[3,4-f]quinazoline, son procédé de préparation et son utilisation en médecine
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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US20100234324A1 (en) * 2007-07-13 2010-09-16 Merck Patent Gesellschaft Mit Beschrankter Haftung Quinazolinamide derivatives
US20210188869A1 (en) * 2013-10-10 2021-06-24 Araxes Pharma Llc Inhibitors of kras g12c
WO2022002102A1 (fr) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Composés de quinazoline, leurs procédés de préparation et leurs utilisations
WO2022232331A1 (fr) * 2021-04-29 2022-11-03 Amgen Inc. Composés hétérocycliques et procédés d'utilisation

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US20100234324A1 (en) * 2007-07-13 2010-09-16 Merck Patent Gesellschaft Mit Beschrankter Haftung Quinazolinamide derivatives
US20210188869A1 (en) * 2013-10-10 2021-06-24 Araxes Pharma Llc Inhibitors of kras g12c
WO2022002102A1 (fr) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Composés de quinazoline, leurs procédés de préparation et leurs utilisations
WO2022232331A1 (fr) * 2021-04-29 2022-11-03 Amgen Inc. Composés hétérocycliques et procédés d'utilisation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024215862A3 (fr) * 2023-04-12 2025-02-06 Board Of Regents, The University Of Texas System Composés hétérocycliques en tant qu'inhibiteurs de nras
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025214341A1 (fr) * 2024-04-08 2025-10-16 江苏恒瑞医药股份有限公司 Composé dihydrofuro[3,4-f]quinazoline, son procédé de préparation et son utilisation en médecine
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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