WO2022093820A1 - Composés de morpholine substitués - Google Patents

Composés de morpholine substitués Download PDF

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Publication number
WO2022093820A1
WO2022093820A1 PCT/US2021/056651 US2021056651W WO2022093820A1 WO 2022093820 A1 WO2022093820 A1 WO 2022093820A1 US 2021056651 W US2021056651 W US 2021056651W WO 2022093820 A1 WO2022093820 A1 WO 2022093820A1
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WIPO (PCT)
Prior art keywords
pyrazin
methylmorpholino
dihydropyrazolo
cancer
mmol
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PCT/US2021/056651
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English (en)
Inventor
Snahel PATEL
Michael Siu
Shumei Wang
Huifen Chen
Dennis X. HU
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Genentech, Inc.
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Publication of WO2022093820A1 publication Critical patent/WO2022093820A1/fr

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

Definitions

  • Vascular protein sorting 34 is a phosphoinositide 3-kinase that plays an important role in regulating autophagy, endosomal trafficking, and phagocytosis (Bilanges et al., Nat Rev Mol Cell Biol 20, 515–534 (2019)).
  • Vps34 inhibitors with potent and selective properties.
  • pyrazolopiperazinone inhibitors of Vps34 kinase activity which are potent and selective.
  • each R A is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C5cycloalkyl, or C 3 - C5halocycloalky, each of which is independently unsubstituted or substituted with one or more R 1 ; wherein each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkoxy, phenyl, or -OH; two R A on the same carbon atom or adjacent carbon atoms, together with the atom or atoms to which they are attached, independently may form C 3 -C 6 cycloalkyl, each of which is independently unsubstituted or substituted with one or more substituent
  • a pharmaceutical composition comprising a compound of Formula (A), or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method for treating a hyperproliferative disorder in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as provided herein.
  • a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof for use in treating a hyperproliferative disorder in a subject in need thereof.
  • each R A is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C5cycloalkyl, or C 3 - C5halocycloalky, each of which is independently unsubstituted or substituted with one or more R 1 ; wherein each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkoxy, phenyl, or -OH; two R A on the same carbon atom or adjacent carbon
  • p is 1, 2, or 3. In certain embodiments, p is 1 or 2. In some embodiments, p is 1. In other embodiments, p is 2. In still further embodiments, p is 3.
  • each R A is independently: C 3 -C 5 cycloalkyl, unsubstituted or substituted with one to four substituents independently selected from the group consisting of C 1 -C 6 alkyl and phenyl; C 1 -C 6 alkyl, unsubstituted or substituted with one to five substituents independently selected from the group consisting of -OH, phenyl, and C 1 -C 3 alkoxy; or C 1 -C 6 haloalkyl, unsubstituted or substituted with one to five substituents independently selected from the group consisting of -OH, phenyl, and C 1 -C 3 alkoxy; and two R A together with the atom or atoms to which they are attached may form C 5 -C 6 - cycloalkyl or C5-C 6 -halocycloalkyl, unsubsti
  • each R A is independently methyl, trifluoromethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl; and two R A attached to the same atom may form cyclopropyl; and two R A attached to adjacent atoms may form cyclopentyl.
  • p is 1 to 3. In other embodiments, p is 1 or 2.
  • p is 2, 3, or 4; two R A are attached to the same atom and form C5- C 6 -cycloalkyl; and the remaining R A , if present, are independently: C 3 -C 5 cycloalkyl, unsubstituted or substituted with one to four substituents independently selected from the group consisting of C 1 -C 6 alkyl and phenyl; C 1 -C 6 alkyl, unsubstituted or substituted with one to five substituents independently selected from the group consisting of -OH, phenyl, and C 1 -C 3 alkoxy; or C 1 -C 6 haloalkyl, unsubstituted or substituted with one to five substituents independently selected from the group consisting of -OH, phenyl, and C 1 -C 3 alkoxy.
  • the compound of formula (A) or formula (B) is a compound of formula (B): or a solvate or pharmaceutically acceptable salt thereof, wherein: each R A is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 5 cycloalkyl, or C 3 - C 5 halocycloalky, each of which is independently unsubstituted or substituted with one or more R 1 ; wherein each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkoxy, phenyl, or -OH.
  • the compound of formula (A) is a compound of formula (C): or a solvate or pharmaceutically acceptable salt thereof, wherein: each R A is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 5 cycloalkyl, or C 3 - C 5 halocycloalky, each of which is independently unsubstituted or substituted with one or more R 1 ; wherein each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkoxy, phenyl, or -OH.
  • each R A is independently unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 haloalkyl, or unsubstituted C 3 -C5cycloalkyl.
  • at least one R A is C 1 -C 6 alkyl, unsubstituted or substituted with one to three substituents independently selected from halo, -OH, and C 1 -C 6 alkoxy. In certain embodiments, at least one R A is C 3 -C5cycloalkyl.
  • each R A attached to the same atom form cyclopropyl.
  • each R A is independently methyl, trifluoromethyl, isopropyl, tertbutyl, cyclopropyl, cyclobutyl, or cyclopentyl; or two R A attached to the same atom form a cyclopropyl.
  • each R A is independently methyl, ethyl, propyl, butyl, ethyl substituted with -OH, propyl substituted with -OH, methyl substituted with -OCH3, ethyl substituted with -OCH3, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, trifluoroethyl, or pentafluoroethyl.
  • the compound is selected from Table 1, or is a solvate or pharmaceutically acceptable salt thereof: Table 1 [0020] Additional representative compounds of the present disclosure are listed in Table 2. It should be understood that individual enantiomers and diastereomers are included in the table below by Compound Name, and their corresponding structures can be readily determined therefrom.
  • the enantiomers or diastereomers are identified by their respective properties, for example, retention times on a chiral HPLC or its biological activities (e.g., as described further in the Examples), and the absolute stereo configurations of one or more chiral centers are arbitrarily assigned (e.g., stereochemistry of all chiral centers is arbitrarily assigned, or stereochemistry of one chiral center is known and remaining chiral centers arbitrarily assigned, etc.).
  • the compound is selected from Table 1, or is a solvate or pharmaceutically acceptable salt thereof:
  • the scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the subject matter disclosed herein includes combinations and subsets of the particular groups defined herein. [0022] The subject matter disclosed herein also includes isotopically-labelled forms of the compounds described herein, such as wherein 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 examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 123 I, and 125 I.
  • substituents such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the present disclosure.
  • substituted refers to the replacement of a hydrogen atom in a given structure with a specified substituent. In some embodiments, more than one hydrogen atom is replaced with a specified substituent. Combinations of substituents envisioned by the present disclosure are typically those that result in the formation of stable or chemically feasible compounds.
  • the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.
  • the articles “a” and “an” as used in this disclosure may refer to one or more than one (e.g., to at least one) of the grammatical object of the article.
  • an element may mean one element or more than one element.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, if not otherwise described, alkyl comprises 1 to 6 carbon atoms (C 1 -C 6 alkyl), or 1 to 4 carbon atoms (C 1 -C4alkyl). Examples of alkyl groups may include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3- hexyl, and 3-methyl pentyl.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • butyl can include n-butyl, sec-butyl, isobutyl and t-butyl
  • propyl can include n-propyl and isopropyl.
  • Alkoxy refers to an -O-alkyl group. If not otherwise described, alkoxy comprises 1 to 6 carbon atoms (C 1 -C 6 alkoxy), or 1 to 4 carbon atoms (C 1 -C 4 alkoxy). Examples of alkoxy groups include methoxy, ethoxy, and propoxy.
  • Haloalkyl refers to an alkyl group substituted with one or more halo, which may be selected independently.
  • haloalkyl includes alkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo.
  • Haloalkyl may include, for example, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CHFCl, -CHFCH3, - CH2Br, and -CH2CHFCH2CH2Br, and the like.
  • Haloalkoxy refers to an -O-alkyl group wherein the alkyl is substituted with one or more halo, which may be selected independently.
  • Cycloalkyl refers to a monocyclic saturated hydrocarbon. In some embodiments, unless otherwise described, cycloalkyl comprises, 3 to 8 carbon atoms (C 3 - C 8 cycloalkyl), 3 to 6 carbon atoms (C 3 -C 6 cycloalkyl), or 3 to 5 carbon atoms (C 3 -C 4 cycloalkyl).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • “Halocycloalkyl”, as used herein, refers to a cycloalkyl group substituted with one or more independently selected halogens.
  • a “patient” or “subject” may encompass both mammals and non-mammals.
  • mammals may include, but are not limited to, any member of the class Mammalia: humans; non- human primates such as chimpanzees, monkeys, baboons, or rhesus monkeys, as well as other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; companion animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs; and the like.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • “Patient” or “subject” may include both human and animals. In some embodiments, the patient or subject is a human.
  • an effective amount or “therapeutically effective amount” refers to an amount of a compound (or tautomer, solvate, or pharmaceutically acceptable salt thereof) or pharmaceutical composition sufficient to produce a desired therapeutic outcome, such as reducing the severity of duration of, stabilizing the severity of, or eliminating one or more signs, symptoms, or causes of a disorder.
  • beneficial or desired results may include, for example, decreasing one or more symptoms resulting from the disorder (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disorder, increasing the quality of life of those suffering from the disorder, decreasing the dose of other medications required to treat the disorder, enhancing effect of another medication, delaying the progression of the disorder, and/or prolonging survival of patients.
  • excipient refers to an inert or inactive substance that may be used in the production of a drug or pharmaceutical composition, such as a tablet containing a compound as described herein (or tautomer or pharmaceutically acceptable salt) as an active ingredient.
  • a drug or pharmaceutical composition such as a tablet containing a compound as described herein (or tautomer or pharmaceutically acceptable salt) as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a diluent, filler or extender, binder, disintegrant, humectant, coating, emulsifier or dispersing agent, compression/encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Binders may include, e.g., carbomers, povidone, xanthan gum, etc.; coatings may include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include e.g.
  • disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.
  • creams or lotions include, e.g., maltodextrin, carrageenans, etc.
  • lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.
  • materials for chewable tablets include, e.g.
  • suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.
  • sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.
  • wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
  • the term “excipient” encompasses pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable salts” includes salts which are generally safe and not biologically or otherwise undesirable, and includes those which are acceptable for veterinary use as well as human pharmaceutical use. Such salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base (e.g., if the compound of formula (A), (B), or (C) is a free acid), or treatment of the free base with an inorganic or organic acid (e.g., if the compound of formula (A), (B), or (C) is a free base).
  • Suitable pharmaceutically acceptable salts may include, for example, those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like. They may also include, for example, those derived from organic acids (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, or salicylic acid), a pyranosidyl acid (such as glucuronic acid or galacturonic acid), an alpha hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), or the like.
  • inorganic acids
  • Suitable pharmaceutically acceptable sals may also include, for example, those derived from organic bases (such as an amine, e.g., a primary, secondary or tertiary amine), an alkali metal hydroxide, or alkaline earth metal hydroxide, or the like.
  • Suitable salts include, but are not limited to, organic salts derived from amino acids (such as glycine or arginine); ammonia; primary, secondary, and tertiary amines; cyclic amines (such as piperidine, morpholine, and piperazine); and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, or lithium (such as derived from inorganic bases such as sodium carbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, aluminum hydroxide, and the like).
  • Numerical ranges, as used herein, may include sequential integers.
  • a range expressed as “from 0 to 5” would include 0, 1, 2, 3, 4 and 5.
  • the term “unsubstituted” may mean that the specified group bears no substituents beyond the moiety recited (e.g., where valency is satisfied by hydrogen).
  • the disclosure is directed to compounds as described herein and solvates and pharmaceutically acceptable salts thereof.
  • the use of the terms “pharmaceutically acceptable salt” and “solvate” is intended to equally apply to the solvates, pharmaceutically acceptable salts, rotamers, or racemates of the disclosed compounds.
  • the compounds of formula (A), (B), or (C), or solvates or pharmaceutically acceptable salts thereof includes pharmaceutically acceptable salts of solvates of the compounds of formula (A), (B), or (C).
  • Compounds of the disclosure may exist as solvates.
  • the term “solvate” may refer to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates.
  • Hydrates may include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the terms “treat” or “treatment” are meant to indicate a postponement of development of one or more disorders; preventing the development of one or more disorders; and/or reducing severity of one or more symptoms of a disorder that will or are expected to develop.
  • these terms may include ameliorating one or more existing disorder symptoms; preventing one or more additional symptoms; ameliorating or preventing the underlying causes of one or more symptoms; inhibiting the disorder, e.g., arresting the development of the disorder; relieving the disorder; causing regression of the disorder; relieving a symptom caused by the disorder; or stopping or alleviating the symptoms of the disorder.
  • the term “about,” when referring to a value is meant to encompass variations of, for example, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of the range and any other stated or intervening value in that stated range, is encompassed within the invention.
  • compositions comprising a compound of formula (A) (including compounds of formula (B) or (C)) or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs,” M. E.
  • a pharmaceutical composition comprising combining one or more disclosed compounds (e.g., of formula (A), (B), or (C)) or solvate or pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients.
  • Pharmaceutical compositions may be prepared, for example, according to conventional dissolution, mixing, granulating, or coating methods, or combinations thereof.
  • Such pharmaceutically acceptable excipients may include, for example, sugars (e.g., lactose, glucose, sucrose); starches (e.g., corn starch, potato starch); cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate); powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil); glycols (e.g., propylene glycol); polyethylene glycols (PEG); esters (e.g., ethyl oleate, ethyl laurate); agar; buffering agents (e.g., magnesium hydroxide, aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethy
  • Preservatives and antioxidants can also be present in the pharmaceutical composition, according to the judgment of the formulator.
  • the disclosed pharmaceutical compositions can be in solid, semi-solid, or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • These modes may include systemic or local administration such as oral, nasal, parenteral (as by intravenous (both bolus and infusion), intramuscular, or subcutaneous injection), transdermal, vaginal, buccal, rectal, or topical (as by powders, ointments, or drops) administration modes. These modes may also include intracisternally, intraperitoneally, as an oral or nasal spray, or as a liquid aerosol or dry powder pharmaceutical composition for inhalation.
  • the pharmaceutical composition provided herein comprises one or more disclosed compounds, tautomers thereof, and/or pharmaceutically acceptable salts thereof, and is for oral administration. In other embodiments, the pharmaceutical composition is for intravenous administration.
  • Solid dosage forms for oral administration may include capsules (e.g., soft and hard-filled gelatin capsules), tablets, pills, powders, and granules.
  • Solid dosage forms may be prepared, in some embodiments, with one or more coatings and/or shells such as release controlling coatings, for example enteric coatings.
  • Solid dosage forms may be formulated to release the one or more disclosed compounds (or solvate, tautomer, or pharmaceutically acceptable salt thereof) only, or mostly, or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner.
  • Solid dosage forms may also include, for example, micro-encapsulated forms.
  • Liquid dosage forms for oral administration may include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • Such liquid compositions may include, for example, a pharmaceutically acceptable excipient such as water or other solvents, solubilizing agents, emulsifiers, oils, polyethylene glycols and fatty acid esters, adjuvants, sweetening agents, flavoring agents, or perfuming agents, or any combinations thereof.
  • injectible pharmaceutical compositions include, for example, sterile injectable aqueous compositions (e.g., solutions, suspensions, or emulsions), or oleaginous suspensions.
  • Injectable pharmaceutical compositions may comprise, in some embodiments, one or more solvents and/or diluents, such as water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution, sterile fixed oils, fatty acid, or any combinations thereof.
  • an injectible pharmaceutical composition may be prepared as a lyophilized powder, for example a lyophilized powder that is to be mixed with a liquid diluent prior to injection.
  • Such delay may be accomplished, for example, through the use of a liquid suspension of crystalline or amorphous material with poor water solubility; or dissolving or suspending the compound, or solvate, tautomer, or pharmaceutically acceptable salt thereof, in an oil vehicle; or through an injectable depot form copmrising microencapsule matrixes comprising one or more biodegradable polymers.
  • Pharmaceutical compositions for rectal or vaginal administration may include suppositories that can be prepared, for example using a suitable non-irritating excipient such as cocoa butter, polyethylene glycol, or a suppository wax; or using a fatty emulsion or suspension.
  • Dosage forms for topical or transdermal administration may include, for example, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Ophthalmic pharmaceutical compositions and ear drops may also be prepared.
  • the pharmaceutical compositions provided herein may be packaged in unit-dose or multidose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient (e.g., diluent, carrier, for example water) for injection immediately prior to use.
  • sterile liquid excipient e.g., diluent, carrier, for example water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, or tablets of the kind described herein.
  • Unit dosage formulations include those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient.
  • the subject matter further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary excipient or carrier therefore.
  • Veterinary excipients or carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • the pharmaceutical composition comprising the presently disclosed compounds further comprise a chemotherapeutic agent.
  • the chemotherapeutic agent is an immunotherapeutic agent.
  • Methods of Use The disclosed compounds, or a solvate or pharmaceutically acceptable salt thereof, and compositions comprising same may be useful as pharmaceuticals, as discussed herein.
  • Provided herein are methods of treating a disorder in a subject in need thereof, comprising administering an effective amount of a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof, to the subject.
  • a pharmaceutical composition comprising a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound is a compound of formula (A), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (B), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (C), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 1, or is a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 2, or is a solvate or pharmaceutically acceptable salt thereof.
  • the disorder is a hyperproliferative disorder, such as cancer.
  • a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof for use in treating a disorder in a subject in need thereof.
  • a pharmaceutical composition comprising a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically aceptable excipient, for use in treating a disorder in a subject in need thereof.
  • the compound is a compound of formula (A), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (B), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (C), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 1, or is a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 2, or is a solvate or pharmaceutically acceptable salt thereof.
  • the disorder is a hyperproliferative disorder, such as cancer.
  • the present disclosure also provides for use of a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof, in treating a disorder in a subject in need thereof.
  • a pharmaceutical composition comprising a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in treating a disorder in a subject in need thereof.
  • the compound is a compound of formula (A), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (B), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (C), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 1, or is a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 2, or is a solvate or pharmaceutically acceptable salt thereof.
  • the disorder is a hyperproliferative disorder, such as cancer.
  • a compound as described herein, or a solvate or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disorder in a subject in need thereof.
  • the compound is a compound of formula (A), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (B), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (C), or a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 1, or is a solvate or pharmaceutically acceptable salt thereof.
  • the compound is selected from Table 2, or is a solvate or pharmaceutically acceptable salt thereof.
  • the disorder is a hyperproliferative disorder, such as cancer.
  • the disorder is a hyperproliferative disorder.
  • the hyperproliferative disorder is cancer.
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, Ewing’s sarcoma, gastric cancer, glioma, glioblastoma, head and neck cancer, hepatocellular cancer, laryngeal cancer, lung cancer, acute lymphocytic leukemia, medulloblastoma, melanoma, acute myeloid leukemia, nephroblastoma (Wilm’s tumor), neuroblastoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, rhabdoid cancer, rhabdomyosarcoma, thyroid cancer, renal carcinoma, pancreatic cancer, prostate cancer, and squamous cell carcinoma.
  • bladder cancer breast cancer, cervical cancer, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, E
  • the hyperproliferative disorder is a cancer selected from the group consisting of carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia.
  • Step 2 Synthesis of methyl 5-bromo-2-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl- propyl]pyrazole-3-carboxylate: [0062] To a solution of tert-butyl N-(2-hydroxy-3-methyl-butyl)carbamate (39.0 g, 192 mmol), PPh 3 (201 g, 767 mmol) and methyl 3-bromo-1H-pyrazole-5-carboxylate (39.3 g, 192 mmol) in tetrahydrofuran (200 mL) is added DIAD (77.6 g, 384 mmol, 74.6 mL), and the mixture was stirred at 25 o C
  • Step 3 Synthesis of methyl 1-(1-amino-3-methylbutan-2-yl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride [0063] To methyl 5-bromo-2-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]pyrazole-3- carboxylate (70 g, 180 mmol) in ethyl acetate (700 mL) at 0 o C is added 4N HCl in ethyl acetate (700 mL). The mixture was stirred at 25 °C for 2 hours.
  • Step 4 Synthesis of 2-bromo-7-isopropyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one: [0064] A solution of methyl 1-(1-amino-3-methylbutan-2-yl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride (40 g, 122 mmol) and TEA (32.2 g, 318 mmol, 44.3 mL) in methanol (600 mL) was stirred at 25 °C for 2 hours. The solvent was removed under vacuum and the crude residue was treated with DCM (200 mL).
  • Step 6 Synthesis of (R)-7-cyclopropyl-2-((R)-3-methylmorpholino)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one and (S)-7-cyclopropyl-2-((R)-3-methylmorpholino)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one: [0066] A solution of (3R)-3-methylmorpholine (590 mg, 5.8 mmol), Ruphos Pd G3 (98 mg, 0.12 mmol), Ruphos (55.0 mg, 0.12 mmol), t-BuONa (112 mg, 1.2 mmol)] and (R)-2-bromo-7-isopropyl- 6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (150.0 mg, 0.58 mmol) in N,N-dimethylacetamide (7 mL)
  • Example 2 (S)-7-cyclopropyl-2-((R)-3-methylmorpholino)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one was prepared similarly from (S)-2-bromo-7-isopropyl-6,7-dihydro-5H- pyrazolo[1,5-a]pyrazin-4-one.
  • White solid (36 mg, 22% yield), LCMS [M+H + ] 279.
  • Step 2 Synthesis of tert-butyl (2-cyclobutyl-2-hydroxyethyl)carbamate: [0069] To a solution of tert-butyl N-(2-cyclobutyl-2-oxo-ethyl)carbamate (650 mg, 3.1 mmol) in ethanol (10 mL) was added NaBH4 (350 mg, 9.2 mmol) at room temperature. The resulting solution was stirred for 2 h at 25 °C. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 3 Synthesis of methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)-1-cyclobutylethyl)-1H- pyrazole-5-carboxylate: [0070] To a solution of tert-butyl N-(2-cyclobutyl-2-hydroxy-ethyl)carbamate (440 mg, 2.0 mmol), PPh 3 (850 mg, 3.2 mmol) and methyl 3-bromo-1H-pyrazole-5-carboxylate (450 mg, 2.2 mmol) in tetrahydrofuran (20mL) was added DIAD (700 mg, 3.47 mmol) at 0 °C.
  • DIAD 700 mg, 3.47 mmol
  • Step 4 Synthesis of 2-bromo-7-cyclobutyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one: [0071] To a solution of methyl 5-bromo-2-[2-(tert-butoxycarbonylamino)-1-cyclobutyl- ethyl]pyrazole-3-carboxylate (600 mg, 1.5 mmol) in dichloromethane (10 mL) was added a 4M solution of HCl in dioxane (5 mL) at 25 °C. The resulting solution was stirred for 1 h at 25 °C and the mixture was concentrated under vacuum.
  • Step 5 Synthesis of (R)-7-cyclobutyl-2-((R)-3-methylmorpholin-4-yl)-6,7-dihydro-5H-pyrazolo[1,5- a]pyrazin-4-one and (S)-7-cyclobutyl-2-((R)-3-methylmorpholin-4-yl)-6,7-dihydro-5H-pyrazolo[1,5- a]pyrazin-4-one: [0072] To a mixture of 2-bromo-7-cyclobutyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.37 mmol), (3R)-3-methylmorpholine (180 mg, 1.78 mmol), Ruphos Pd G3 (35 mg, 0.04 mmol), and Ruphos (20 mg, 0.04 mmol) in tetrahydrofuran (2 mL) was added LiHMDS (4 mL, 4 mmol, 1M)
  • Example 4 White solid (23 mg, 21% yield).
  • Step 2 Synthesis of methyl 3-bromo-1-(1-((tert-butoxycarbonyl)amino)-3,3-dimethylbutan-2-yl)- 1H-pyrazole-5-carboxylate: [0076] To a solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (394 mg, 1.9 mmol), tert-butyl N-(2-hydroxy-3,3-dimethylbutyl)carbamate (751 mg, 3.46 mmol), and PPh3 (1.0 g, 3.84 mmol) in tetrahydrofuran (8 mL) was added DIAD (775 mg, 3.83 mmol) dropwise, and the mixture was stirred for 5 hours at room temperature.
  • Step 2 Synthesis of methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)-1-cyclopentylethyl)-1H- pyrazole-5-carboxylate: [0083] To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (200 mg, 0.97 mmol), tert-butyl N-(2-cyclopentyl-2-hydroxyethyl)carbamate (291 mg, 1.26 mmol) and PPh 3 (512 mg, 1.95 mmol) in tetrahydrofuran (5 mL) was added DIAD (395 mg, 1.95 mmol) dropwise at room temperature.
  • DIAD 395 mg, 1.95 mmol
  • Step 3 Synthesis of methyl 1-(2-amino-1-cyclopentylethyl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride: [0084] A solution of methyl 5-bromo-2-[2-[(tert-butoxycarbonyl)amino]-1- cyclopentylethyl]pyrazole-3-carboxylate (330 mg, 0.79 mmol) in 4M HCl in dioxane (5 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure to afford the crude product which was used directly in the following step. LCMS [M+H + ] 316.
  • Step 4 Synthesis of 2-bromo-7-cyclopentyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Example 8 White solid (26 mg, 12% yield).
  • Example I-1 Synthesis of Intermediate A - ethyl (R)-3-(3-methylmorpholino)-1H-pyrazole-5- carboxylate: Step 1 – Synthesis of (R)-1-(3-methylmorpholino)ethanone: [0089] To a mixture of (3R)-3-methylmorpholine (60 g, 0.59 mol), dichloromethane (500 mL), and K2CO3 (164 g, 1.19 mol) under nitrogen was added acetyl chloride (51 g, 0.65 mol) at 0 o C. The resulting mixture was stirred for 1 hour at 0 o C.
  • Step 2 Synthesis of (R)-ethyl 4-(3-methylmorpholino)-2,4-dioxobutanoate: [0090] To a 1M solution of t-BuOK (59 g ,0.53 mol) in THF (530 mL) was added 1-[(3R)-3- methylmorpholin-4-yl]ethanone (68 g, 0.47 mol) under nitrogen at 0 o C.
  • Step 3 Synthesis of (R)-ethyl 3-(3-methylmorpholino)-1H-pyrazole-5-carboxylate: [0091] A mixture of ethyl 4-[(3R)-3-methylmorpholin-4-yl]-2,4-dioxo-butanoate (66 g, 0.26 mol), Lawesson’s reagent (210 g, 0.52 mol), and pyridine (2 mL) in tetrahydrofuran (600 mL) was stirred at room temperature for 0.5 hours. Hydrazine monohydrochloride (35.3 g, 0.52 mol) was then added and the mixture was stirred at 60 o C overnight.
  • reaction mixture was diluted with water and extracted with DCM three times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to afford the title compound (25 g, 40% yield) as yellow solid.
  • Step 2 Synthesis of (5aS,8aR)-2-((R)-3-methylmorpholino)-5,5a,6,7,8,8a-hexahydro-4H- cyclopenta[e]pyrazolo[1,5-a]pyrazin-4-one & (5aR,8aS)-2-((R)-3-methylmorpholino)-5,5a,6,7,8,8a- hexahydro-4H-cyclopenta[e]pyrazolo[1,5-a]pyrazin-4-one.
  • N-methoxy-N,1-dimethyl-cyclopropanecarboxamide (10.0 g, 69.8 mmol) was added and the mixture was stirred at 0 o C for 2 hours.
  • the reaction was quenched with ice water, extracted with diethyl ether, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (3.2 g, 38.1 mmol, 55% yield) as a light yellow oil, which was used directly in the next step.
  • Step 3 Synthesis of 2-hydroxy-2-(1-methylcyclopropyl)acetonitrile: [0098] To 1-methylcyclopropanecarbaldehyde (3.2 g, 38.0 mmol) and K2CO3 (1.1 g, 7.8 mmol) in tetrahydrofuran (30 mL) at 0 °C was added TMSCN (4.2 g, 42.4 mmol) dropwise and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate and concentrated under vacuum. The crude residue was added to 1N aq. HCl and the solution was stirred at 25 °C for 2 hours.
  • TMSCN 4.2 g, 42.4 mmol
  • reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (2.0 g, 18.1 mmol, 48%) as a yellow oil, which was used directly in the next step.
  • Step 4 Synthesis of [cyano-(1-methylcyclopropyl)methyl] methanesulfonate: [0099] To a solution of 2-hydroxy-2-(1-methylcyclopropyl)acetonitrile (500 mg, 4.5 mmol) and Et3N (911 mg, 9 mmol) in dichloromethane (10 mL) at 25 °C was added methanesulfonyl chloride (619 mg, 5.4 mmol) dropwise, and the mixture was stirred for 16 hours.
  • Step 5 Synthesis of ethyl 2-[cyano-(1-methylcyclopropyl)methyl]-5-[(3R)-3-methylmorpholin-4- yl]pyrazole-3-carboxylate: [0100] A mixture of [cyano-(1-methylcyclopropyl)methyl] methanesulfonate (743 mg, 3.93 mmol), ethyl 3-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazole-5-carboxylate (470 mg, 1.96 mmol), and Cs2CO3 (1.3 mg, 3.93 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60 o C for 3 hours.
  • Step 6 Synthesis of (7R)-7-(1-methylcyclopropyl)-2-[(3R)-3-methylmorpholin-4-yl]-6,7-dihydro- 5H-pyrazolo[1,5-a]pyrazin-4-one and (7S)-7-(1-methylcyclopropyl)-2-[(3R)-3-methylmorpholin-4- yl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [0101] A solution of ethyl 2-[cyano-(1-methylcyclopropyl)methyl]-5-[(3R)-3-methylmorpholin-4- yl]pyrazole-3-carboxylate (400 mg, 1.2 mmol) and CoCl 2 (311 mg, 2.4 mmol) in methanol (20 mL) was stirred at 0 o C for 30 min.
  • Step 2 Synthesis of methyl 3-bromo-1-(1-cyano-2-methoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate: [0105] To a solution of methyl 3-bromo-1-(cyanomethyl)-1H-pyrazole-5-carboxylate (1 g, 4 mmol) in tetrahydrofuran (30 ml) was added LiHMDS (6 ml, 1 M solution in THF) at -78 °C under nitrogen. The resulting solution was stirred for 20 min at -78 °C. Dimethyl carbonate (900 mg, 10 mmol) was then added dropwise and the mixture was stirred at -78 °C for 2 hours.
  • LiHMDS 6 ml, 1 M solution in THF
  • Step 3 Synthesis of methyl 1-(3-amino-1-methoxy-1-oxopropan-2-yl)-3-bromo-1H-pyrazole-5- carboxylate: [0106] A mixture of methyl 5-bromo-2-(1-cyano-2-methoxy-2-oxo-ethyl)pyrazole-3-carboxylate (100 mg, 0.33 mmol) and Raney Ni (20 mg) in 2,2,2-trifluoroacetic acid (5 ml) was stirred at room temperature under H 2 atmosphere for 2 hours. The mixture was concentrated under vacuum and the residue was purified by reversed phase chromatography (C18 column, 5% to 95% MeCN in 0.01M aq.
  • Step 5 Synthesis of 2-bromo-7-(2-hydroxypropan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one: [0108] To a solution of methyl 2-bromo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7- carboxylate (53 mg, 0.2 mmol) in tetrahydrofuran (2 ml) was added a 3 M solution of MeMgBr in THF (0.5 ml) dropwise at -78 °C under nitrogen. The mixture was warmed to room temperature and stirred for 2 hours.
  • Step 6 Synthesis of (R)-7-(2-hydroxypropan-2-yl)-2-((R)-3-methylmorpholino)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and (S)-7-(2-hydroxypropan-2-yl)-2-((R)-3- methylmorpholino)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [0109] A mixture of 2-bromo-7-(2-hydroxypropan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (120 mg, 0.44 mmol), (3R)-3-methylmorpholine (90 mg, 0.89 mmol), RuPhos Pd G3 (35 mg, 0.04 mmol), RuPhos (22 mg, 0.05 mmol) and 1M LiHMDS in THF solution (0.4 ml) in tetrahydrofuran
  • Step 2 Synthesis of ethyl 5-[(3R)-3-methylmorpholin-4-yl]-2-(3,3,4,4,4-pentafluoro-1-nitrobutan-2- yl)pyrazole-3-carboxylate: [0113] A solution of ethyl 5-[(3R)-3-methylmorpholin-4-yl]-2H-pyrazole-3-carboxylate (400 mg, 1.67 mmol), (1E)-3,3,4,4,4-pentafluoro-1-nitrobut-1-ene (638.7 mg, 3.34 mmol) and DBU (126 mg, 0.83 mmol) in acetonitrile was stirred overnight at 70 o C.
  • Step 3 Synthesis of ethyl 2-(1-amino-3,3,4,4,4-pentafluorobutan-2-yl)-5-[(3R)-3-methylmorpholin- 4-yl]pyrazole-3-carboxylate: [0114] A solution of ethyl 5-[(3R)-3-methylmorpholin-4-yl]-2-(3,3,4,4,4-pentafluoro-1-nitrobutan- 2-yl)pyrazole-3-carboxylate (400 mg, 0.93 mmol) and Raney Ni (50 mg, 0.58 mmol) in methanol was stirred for 4 hours at room temperature under hydrogen atmosphere.
  • the reaction vessel was capped and heated at 80 °C for 3 hours.
  • the reaction mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (1:2) to afford the title compound (15 g, 60.2 mmol, 67% yield) as a white solid.
  • Step 2 Preparation of N-(4-methoxybenzyl)-3-((R)-3-methylmorpholino)-N-(3,3,3-trifluoro-2- hydroxypropyl)-1H-pyrazole-5-carboxamide: [0119] A solution of 1M t-BuOK in THF (3 mL, 3.0 mmol), 1,1,1-trifluoro-3-(4- methoxybenzylamino)propan-2-ol (500 mg, 2.0 mmol) and (R)-ethyl 3-(3-methylmorpholino)-1H- pyrazole-5-carboxylate (480 mg, 2.0 mmol, Intermediate A, see Example I-1 above) in methanol (10 mL) was stirred at 90 o C overnight.
  • Step 4 Synthesis of (7S)-2-[(3R)-3-methylmorpholin-4-yl]-7-(trifluoromethyl)-6,7-dihydro-5H- pyrazolo[1,5-a]pyrazin-4-one and (7R)-2-[(3R)-3-methylmorpholin-4-yl]-7-(trifluoromethyl)-6,7- dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [0121] A solution of 5-[(4-methoxyphenyl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-7- (trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.71 mmol), TFA (3 mL), and trifluoromethanesulfonic acid (0.6 mL, 6.78 mmol) was stirred at 60 o C for 1 hour.
  • Step 2 Synthesis of methyl 5-bromo-2-[2-(tert-butoxycarbonylamino)-1-cyclopropyl- propyl]pyrazole-3-carboxylate: [0125] A solution of tert-butyl N-(2-cyclopropyl-2-hydroxy-1-methyl-ethyl)carbamate (430 mg, 2 mmol), PPh 3 (2.1 g, 8.0 mmol) and methyl 3-bromo-1H-pyrazole-5-carboxylate (430 mg, 2.1 mmol) in tetrahydrofuran (20 mL) was stirred at 25 °C for 5 mins.
  • Step 3 Synthesis of 2-bromo-7-cyclopropyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one: [0126] A solution of methyl 5-bromo-2-[2-(tert-butoxycarbonylamino)-1-cyclopropyl- ethyl]pyrazole-3-carboxylate (3.6 g, 9.3 mmol) and 4M HCl in dioxane (40 mL) was stirred at 25 °C for 2 hours. The solvent was removed under vacuum and the crude product was dissolved in methanol (40 mL) and TEA (2.7 g, 26.7 mmol).
  • Step 2 Synthesis of 2-bromo-7-cyclopropyl-7-methyl-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one: [0133] To a mixture of sodium borohydride (342 mg, 9.0 mmol) and cobalt chloride (581 mg, 4.5 mmol) in methyl alcohol (6 mL) was added methyl 5-bromo-2-(1-cyano-1-cyclopropyl- ethyl)pyrazole-3-carboxylate (447 mg, 1.5 mmol) at 0 °C. The resulting solution was stirred for 4 hours at 0 °C before being filtered and concentrated under vacuum.
  • Step 3 Synthesis of (7R)-7-cyclopropyl-7-methyl-2-[(3R)-3-methylmorpholin-4-yl]-5,6- dihydropyrazolo[1,5-a]pyrazin-4-one and (7S)-7-cyclopropyl-7-methyl-2-[(3R)-3-methylmorpholin-4- yl]-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one [0134] A mixture of 2-bromo-7-cyclopropyl-7-methyl-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one (110 mg, 0.41 mmol), (3R)-3-methylmorpholine (329 mg, 3.25 mmol), 2-dicyclohexylphosphino- 2',6'-di-i-propoxy-1,1'-biphenyl (38 mg, 0.08 mmol), RuPhos Pd G3 (68 mg, 0.0800 mmol) and
  • Step 2 Synthesis of 2-bromo-7-isopropyl-7-methyl-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one: [0138] To a mixture of methyl 3-bromo-1-(2-cyano-3-methylbutan-2-yl)-1H-pyrazole-5- carboxylate (800 mg, 2.65 mmol) and cobalt chloride (1.03 g, 7.96 mmol) in methanol (15 mL) at - 10 °C was added sodium borohydride (618.0 mg, 16.3 mmol) batch wise. The mixture was stirred for 4 hours at 25 °C and the resulting solution was concentrated under vacuum.
  • Step 3 Synthesis of (7S)-7-isopropyl-7-methyl-2-[(3R)-3-methylmorpholin-4-yl]-5,6- dihydropyrazolo[1,5-a]pyrazin-4-one and (7R)-7-isopropyl-7-methyl-2-[(3R)-3-methylmorpholin-4- yl]-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one [0139] To a solution of 2-bromo-7-isopropyl-7-methyl-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one (220 mg, 0.81 mmol), (3R)-3-methylmorpholine (816 mg, 8.1 mmol), 2-dicyclohexylphosphino-2',6'- di-i-propoxy-1,1'-biphenyl (75.0 mg, 0.16 mmol) and RuPhos Pd G3 (135.0 mg, 0.16 mmol)
  • Step 2 Synthesis of methyl 3-bromo-1-(1-cyano-1-cyclopropylpropyl)-1H-pyrazole-5-carboxylate: [0143] To a mixture of NaH (0.17 g, 7.1 mmol) and dimethyl sulfoxide (20 ml) was added methyl 5-bromo-2-[cyano(cyclopropyl)methyl]pyrazole-3-carboxylate (1.0 g, 3.5 mmol) and iodoethane (1.6 g, 10.3 mmol) at 0 °C. The resulting solution was stirred for 1 h at 25 °C and the reaction was quenched with saturated aq.
  • Step 3 Synthesis of 2-bromo-7-cyclopropyl-7-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one: [00114] To methyl 5-bromo-2-(1-cyano-1-cyclopropyl-propyl)pyrazole-3-carboxylate (700 mg, 2.24 mmol) in MeOH (20 mL) was added CoCl2 (850 mg, 6.5 mmol) and NaBH4 (850.0 mg, 22.37 mmol) and the mixture was stirred at 25 °C for 16 hours.
  • Step 4 Synthesis of (R)-7-cyclopropyl-7-ethyl-2-((R)-3-methylmorpholino)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and (S)-7-cyclopropyl-7-ethyl-2-((R)-3- methylmorpholino)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one: [0145] A mixture of 2-bromo-7-cyclopropyl-7-ethyl-5,6-dihydropyrazolo[1,5-a]pyrazin-4-one (160 mg, 0.56 mmol), (3R)-3-methylmorpholine (570 mg, 5.6 mmol), RuPhos Pd G3 (96 mg, 0.11 mmol, RuPhos (55 mg, 0.12 mmol) and 1M LiHMDS in THF (5.6 mL, 5.6 mmol) in te
  • the reaction was quenched with saturated aq. NaHCO 3 solution (100 mL), extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was dissolved in 1M aq. HCl (100 ml) and stirred for 2 hours at room temperature. The reaction mixture was extracted with ethyl acetate and organic layer was concentrated under reduced pressure to afford the crude product (1.8 g) which was used directly.
  • Step 2 Synthesis of tert-butyl 3-bromo-1H-pyrazole-5-carboxylate: [0149] A mixture of 5-bromo-2H-pyrazole-3-carboxylic acid (4.0 g, 20 mmol), tert-butyl bromide (14.4 g, 105 mmol), benzyltriethylammonium chloride (4.8 g, 21.0 mmol) and K2CO3 (14.4 g, 105.0 mmol) in N,N-dimethylformamide (60 ml) was stirred overnight at 60 °C under nitrogen.
  • Step 3 Synthesis of tert-butyl 3-bromo-1-(cyano(cyclopropyl)methyl)-1H-pyrazole-5-carboxylate: [0150] To a solution of 3-bromo-1H-pyrazole-5-carboxylate (960 mg, 4 mmol), 2-cyclopropyl-2- hydroxyacetonitrile (450 mg, 4.6 mmol) and PPh 3 (1.2 g, 4.6 mmol) in tetrahydrofuran (30 ml) at 0 °C was added DIAD (1.0 g, 5.0 mmol) dropwise under nitrogen and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure.
  • DIAD 1.0 g, 5.0 mmol
  • Step 4 Synthesis of tert-butyl 3-bromo-1-(1-cyano-1-cyclopropylethyl)-1H-pyrazole-5-carboxylate: [0151] To a solution of tert-butyl 3-bromo-1-(cyano(cyclopropyl)methyl)-1H-pyrazole-5- carboxylate (500 mg, 1.5 mmol) in DMSO (5.0 ml) at room temperature was added NaH (74 mg, 3.1 mmol) batchwise and the mixture was stirred for 30 minutes. Iodomethane (653 mg, 4.6 mmol) was then added dropwise to the solution and the mixture was stirred for an additional 2 hours. The reaction was quenched with saturated aq.
  • Step 5 Synthesis of 2'-bromo-7'-cyclopropyl-7'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5- a]pyrazin]-4'(5'H)-one: [0152] To a solution of tert-butyl 5-bromo-2-(1-cyano-1-cyclopropyl-ethyl)pyrazole-3-carboxylate (240 mg, 0.7 mmol) and Ti(OiPr)4 (284 mg, 1 mmol) in tetrahydrofuran (15mL) at room temperature was added a 2M solution of EtMgBr in THF (1 ml).
  • Step 2 Synthesis of (R)-7'-cyclopropyl-2'-((R)-3-methylmorpholino)-7'H-spiro[cyclopropane-1,6'- pyrazolo[1,5-a]pyrazin]-4'(5'H)-one and (S)-7'-cyclopropyl-2'-((R)-3-methylmorpholino)-7'H- spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazin]-4'(5'H)-one [0157] A mixture of 2-bromo-7-cyclopropyl-spiro[5,7-dihydropyrazolo[1,5-a]pyrazine-6,1'- cyclopropane]-4-one (135 mg, 0.50 mmol), (3R)-3-methylmorpholine (101 mg, 1 mmol), RuPhos Pd G3 (40 mg, 0.05 mmol), RuPhos (23 mg, 0.05
  • Step 2 Synthesis of tert-butyl 3-bromo-1-(1-cyano-2-methylpropyl)-1H-pyrazole-5-carboxylate: [0161] A solution of tert-butyl 3-bromo-1H-pyrazole-5-carboxylate (570 mg, 2.3 mmol), 2- hydroxy-3-methyl-butanenitrile (350 mg, 3.5 mmol), PPh3 (734 mg, 2.8 mmol) and DIAD (600 mg, 3 mmol) in THF (30 ml) was stirred at 25 o C for 12 hours.
  • Step 3 Synthesis of 2'-bromo-7'-isopropyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazin]- 4'(5'H)-one: [0162] A solution of tert-butyl 5-bromo-2-(1-cyano-2-methyl-propyl)pyrazole-3-carboxylate (200 mg, 0.6 mmol), Ti(OiPr)4 (258 mg, 0.9 mmol) and EtMgBr (0.1 ml, 3 M solution in Et2O) in THF (20 ml) was stirred at room temperature for 12 hours.
  • Step 2 Synthesis of methyl 5-[(3R)-3-methylmorpholin-4-yl]-2-[3,3,3-trifluoro-2- (trifluoromethanesulfonyloxy)propyl]pyrazole-3-carboxylate: [0167] To a solution of methyl 5-[(3R)-3-methylmorpholin-4-yl]-2-(3,3,3-trifluoro-2- hydroxypropyl)pyrazole-3-carboxylate (880 mg, 2.61 mmol) and pyridine (825 mg, 10.44 mmol) in dichloromethane at 0 o C was added trifluoromethanesulfonic anhydride (2.2 g, 7.8 mmol) dropwise and the mixture was stirred for 2 hours.
  • trifluoromethanesulfonic anhydride 2.2 g, 7.8 mmol
  • Step 3 Synthesis of methyl 2-(2-azido-3,3,3-trifluoropropyl)-5-[(3R)-3-methylmorpholin-4- yl]pyrazole-3-carboxylate: A solution of methyl 5-[(3R)-3-methylmorpholin-4-yl]-2-[3,3,3-trifluoro-2- (trifluoromethanesulfonyloxy)propyl]pyrazole-3-carboxylate (840 mg, 1.79 mmol) and sodium azide (232 mg, 3.58 mmol) in dimethyl sulfoxide was stirred for overnight at room temperature.
  • Step 4 Synthesis of 3-[2-(4-chlorophenyl)ethyl]-5-[(7-methyl-6-oxo-purin-1-yl)methyl]-1,3,4- oxadiazol-2-one: [0168] A mixture of methyl 2-(2-azido-3,3,3-trifluoropropyl)-5-[(3R)-3-methylmorpholin-4- yl]pyrazole-3-carboxylate (650 mg, 1.8 mmol) and 10% Pd/C (287 mg) in methanol was stirred for 4 hours at room temperature under hydrogen atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the title compound (500 mg, 82%) as light yellow oil.
  • Step 2 Synthesis tert-butyl 1,2-dicyclopropyl-2-hydroxyethylcarbamate: [0173] To a solution of tert-butyl N-(1-cyclopropyl-2-oxo-ethyl)carbamate (200 mg, 1 mmol) in tetrahydrofuran (5 mL) at 0 °C was added a solution of 1M cyclopropylmagnesiumbromide in THF (1.5 mL, 1.5 mmol) dropwise and the mixture was stirred for 2 hours. The reaction was quenched with saturated aq. NH 4 Cl solution, extracted with ethyl acetate, concentrated under vacuum.
  • Step 3 Synthesis of methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)-1,2-dicyclopropylethyl)-1H- pyrazole-5-carboxylate: [0174] A solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (770 mg, 3.76 mmol), tert-butyl N-(1,2-dicyclopropyl-2-hydroxy-ethyl)carbamate (700 mg, 2.9 mmol), PPh3 (1.1 g, 4.2 mmol), and DIAD (1.1 g, 5.79 mmol) in tetrahydrofuran (10 mL) was stirred at 25 °C for 3 hours.
  • Step 4 Synthesis of 2-bromo-6,7-dicyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one: [0175] A solution of methyl 5-bromo-2-[2-(tert-butoxycarbonylamino)-1,2-dicyclopropyl- ethyl]pyrazole-3-carboxylate (480.0 mg, 1.12 mmol) in 4M HCl in dioxane (5 mL) was stirred at 25 °C for 2 hours. The solvent was removed under vacuum. The residue was dissolved with methanol and TEA (5.0 ml) and the resulting solution was stirred at 25 ° C for 2 hours.
  • Step 5 Synthesis of (6S,7S)-6,7-dicyclopropyl-2-((R)-3-methylmorpholino)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and (6R,7R)-6,7-dicyclopropyl-2-((R)-3- methylmorpholino)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  • Step 2 Synthesis of tert-butyl 5-cyclopropyl-4,4-dimethyl-2-oxo-oxathiazolidine-3-carboxylate: [0180] A solution of tert-butyl N-(2-cyclopropyl-2-hydroxy-1,1-dimethyl-ethyl)carbamate (1.3 g, 5.7 mmol) and TEA (1.72 g, 17.0 mmol)] in dichloromethane (30 mL) was stirred at -40 o C. Then a solution of SOCl 2 (800 mg, 6.78 mmol) in dichloromethane (10 mL) was added dropwise and the mixture was stirred at -40 o C for 1 hour.
  • SOCl 2 800 mg, 6.78 mmol
  • Step 3 Synthesis of tert-butyl 5-cyclopropyl-4,4-dimethyl-2,2-dioxo-oxathiazolidine-3-carboxylate: [0181] To a solution of tert-butyl 5-cyclopropyl-4,4-dimethyl-2-oxo-oxathiazolidine-3-carboxylate (1.2 g, 4.36 mmol) in acetonitrile (10 mL), dichloromethane (10 mL), and water (10 mL) at 0 o C was added RuCl3 ⁇ 3H2O (336 mg, 1.32 mmol) and NaIO4 (1.4 g, 6.54 mmol), and the mixture was stirred for 1 hour.
  • Step 4 Synthesis of ethyl 2-[2-(tert-butoxycarbonylamino)-1-cyclopropyl-2-methyl-propyl]-5-[(3R)- 3-methylmorpholin-4-yl]pyrazole-3-carboxylate: [0182] A mixture of tert-butyl 5-cyclopropyl-4,4-dimethyl-2,2-dioxo-oxathiazolidine-3- carboxylate (665 mg, 2.3 mmol), Cs 2 CO 3 (1 g, 3.1 mmol) and ethyl 3-[(3R)-3-methylmorpholin-4-yl]- 1H-pyrazole-5-carboxylate (365 mg, 1.53 mmol) in N,N-di
  • Step 5 Synthesis of (7S)-7-cyclopropyl-6,6-dimethyl-2-[(3R)-3-methylmorpholin-4-yl]-5,7- dihydropyrazolo[1,5-a]pyrazin-4-one and (7R)-7-cyclopropyl-6,6-dimethyl-2-[(3R)-3- methylmorpholin-4-yl]-5,7-dihydropyrazolo[1,5-a]pyrazin-4-one [0183] A solution of ethyl 2-[2-(tert-butoxycarbonylamino)-1-cyclopropyl-2-methyl-propyl]-5- [(3R)-3-methylmorpholin-4-yl]pyrazole-3-carboxylate (130 mg, 0.29 mmol) in 4 M HCl in dioxane (10 mL) was stirred at 25 o C for 2 hours.
  • Step 2 Synthesis of ethyl 1-(3,3-dimethyl-2-oxocyclopentyl)-3-((R)-3-methylmorpholino)-1H- pyrazole-5-carboxylate: [0187] To a solution of ethyl 5-[(3R)-3-methylmorpholin-4-yl]-2-(2-oxocyclopentyl)pyrazole-3- carboxylate (1.0 g, 3.1 mmol) in tetrahydrofuran (10 mL) was added NaH (125 mg, 3.1 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C.
  • Step 3 Synthesis of (R)-6,6-dimethyl-2-(3-methylmorpholino)-5,6,7,8-tetrahydro-4H-cyclopenta[e] pyrazolo[1,5-a]pyrazin-4-one: [0188] To a solution of ethyl 2-(3,3-dimethyl-2-oxo-cyclopentyl)-5-[(3R)-3-methylmorpholin-4- yl]pyrazole-3-carboxylate (150 mg, 0.43 mmol) in toluene (6mL) was added NH 3 in MeOH (4.3 mL, 0.43 mmol) at room temperature. The resulting solution was stirred for 16 h at 140 o C.
  • Step 4 Synthesis of 6,6-dimethyl-2-((R)-3-methylmorpholino)-5,5a,6,7,8,8a-hexahydro-4H- cyclopenta[e]pyrazolo[1,5-a]pyrazin-4-one: [0189] To a solution of (R)-6,6-dimethyl-2-(3-methylmorpholino)-5,6,7,8-tetrahydro-4H- cyclopenta[e] pyrazolo[1,5-a]pyrazin-4-one (45.0 mg, 0.15 mmol) in methyl alcohol (5 mL) was added 10% Pd/C (100 mg, 0.15 mmol) at room temperature.
  • Step 2 Synthesis of (R)-7-cyclopropyl-2-((R)-3-methylmorpholino)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one and (S)-7-cyclopropyl-2-((R)-3-methylmorpholino)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one [0191] To a solution of 2-bromo-7-cyclopropyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.59 mmol), RuPhos Pd G3 (49 mg, 0.06 mmol),RuPhos (27 mg, 0.06 mmol) and (R)-3- methylmorpholine (296 mg, 2.93 mmol) in tetrahydrofuran (1 mL) was added a solution of 1 M LiHDMS in THF (1.5 mL, 1.5
  • Examples 44-71 Compounds of Examples 44-71 were synthesized generally following the procedures of Examples 1-43. Stereochemistry of the lactam ring and lactam ring substituents was arbitrarily assigned. A summary of the characterization data is provided in Table 3 below. Table 3: Compounds of Examples 44-71.
  • Biological Example 1 VPS34 ADP-Glo kinase assay [0194] Experimental compound in DMSO was dispensed to a 384-well microplate via acoustic dispenser at 50 nl per well.
  • eGFP positive cells were sorted using FACS to obtain a mixed pool.
  • Cells were seeded overnight at a density of 2000 cells/well in 384-well microplates with optically-clear bottom (Perkin Elmer) for imaging. Cells were then treated in duplicate for 4 h with 0.5 ⁇ M or 5 ⁇ M internal PI3K project library compounds or vehicle, DMSO (Sigma) only, for untreated controls. Final DMSO content was 0.05% (v/v).
  • Cells were fixed with 4% paraformaldehyde (Electron Microscopy Sciences) and DNA stained with 2 ⁇ g/ml Hoechst 33342 (Invitrogen).

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Abstract

L'invention concerne des composés de formule (A), ainsi que des solvates et des sels pharmaceutiquement acceptables correspondants. L'invention concerne en outre des méthodes d'utilisation desdits composés, notamment pour le traitement d'un trouble hyperprolifératif chez un sujet le nécessitant.
PCT/US2021/056651 2020-10-28 2021-10-26 Composés de morpholine substitués WO2022093820A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011001112A1 (fr) * 2009-07-02 2011-01-06 Sanofi-Aventis NOUVEAUX DERIVES DE 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
WO2012085244A1 (fr) * 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
FR2992314A1 (fr) * 2012-06-22 2013-12-27 Sanofi Sa Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one comportant une morpholine substituee, leur preparation et leur utilisation pharmaceutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011001112A1 (fr) * 2009-07-02 2011-01-06 Sanofi-Aventis NOUVEAUX DERIVES DE 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
WO2012085244A1 (fr) * 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
FR2992314A1 (fr) * 2012-06-22 2013-12-27 Sanofi Sa Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one comportant une morpholine substituee, leur preparation et leur utilisation pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HONG LIN ET AL: "Synthesis and structureactivity relationships of imidazo[1,2-]pyrimidin-5(1)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 22, no. 6, 24 January 2012 (2012-01-24), pages 2230 - 2234, XP028402846, ISSN: 0960-894X, [retrieved on 20120204], DOI: 10.1016/J.BMCL.2012.01.092 *

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