WO2022152853A1 - Antagonistes de mrgx2 - Google Patents

Antagonistes de mrgx2 Download PDF

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WO2022152853A1
WO2022152853A1 PCT/EP2022/050755 EP2022050755W WO2022152853A1 WO 2022152853 A1 WO2022152853 A1 WO 2022152853A1 EP 2022050755 W EP2022050755 W EP 2022050755W WO 2022152853 A1 WO2022152853 A1 WO 2022152853A1
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octane
pyridin
compound
carboxamide
difluorophenoxy
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PCT/EP2022/050755
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English (en)
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Anthony HANDLON
Daniel Paone
Craig Potteiger
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Glaxosmithkline Intellectual Property Development Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to compounds which are antagonists of MrgX2 (Mas-related Gene X2) and thus are useful as therapeutic agents.
  • mast cells ordinarily reside near blood vessels or nerves, beneath or within epithelia, within airways, gastrointestinal, and genitourinary tracts and near smooth muscle and mucus-producing glands.
  • IgE antibodies activated by IgE antibodies, secreting a wide range of substances with local and systemic effects, including histamine, serotonin, proteases, chemokines, and cytokines. Indeed, mast cells are implicated in the progression and/or maintenance of many diseases.
  • Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2 (also known and referred to herein as MrgX2).
  • MrgX2 and MrgX2 have been reported to be expressed only on certain populations of mast cells. This knowledge provides an opportunity to target mast cell degranulation in a very precise manner.
  • Natural endogenous ligands of Mrgprb2/MRGPRX2 have been reported and are mostly neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP), Cortistatin-14, and pituitary adenylate cyclase activating polypeptide (PACAP). Others include P-defensin, cathelici din (LL-37), and proadrenomedullin N-terminal 20 peptide (PAMP9-20). Given the close proximity between mast cells and sensory nerves in various pathological conditions, it follows that neuropeptide-activated MRGPRX2 could contribute to symptoms of neurogenic inflammation including pain, swelling and pruritus.
  • SP substance P
  • VIP vasoactive intestinal polypeptide
  • Cortistatin-14 Cortistatin-14
  • PAMP9-20 proadrenomedullin N-terminal 20 peptide
  • Mrgprb2/MRGPRX2 agonists induce various symptoms such as flushing, swelling and itch in wild type mice, but not in Mrgprb2-deficient mice.
  • Mrgprb2-deficent mice have also demonstrated significant reductions in inflammation (leukocyte infiltration, including mast cells), swelling, pain and overall clinical score in various disease models.
  • An important and relevant observation was the demonstration that Substance P injection could stimulate the infiltration of leukocytes in wild type and NKR1 (canonical Substance P receptor) KO mice whereas the response was substantially blunted in Mrgprb2 null mice.
  • Mrgprb2/MRGPRX2 as a key receptor in mediating Substance P-induced inflammatory responses, including pain.
  • a Substance P / Mrgprb2 sensory cluster was demonstrated to be critical in driving the clinical score of a severe preclinical model of atopic dermatitis.
  • PACAP and the antimicrobial peptide, LL-37 which is implicated in cutaneous inflammation, were both demonstrated to be upregulated in rosacea. Indeed, mast cell-deficient mice do not develop inflammation/flushing following LL-37 injection thus inferring a role for Mrgprb2.
  • mast cell involvement has been highlighted for inflammatory bowel disease (IBD) and arthritis as well as asthma and migraine.
  • IBD inflammatory bowel disease
  • RA rheumatoid arthritis
  • the number of degranulated mast cells is increased in synovial tissue and is correlated with disease activity, as it is for patients with IBD.
  • a positive correlation between serum Substance P levels and chronic pain intensity has been noted in both osteoarthritic and RA patients and a recent article suggested that the SP- MRGPRX2 axis may play a role in the pathogenesis of RA, especially in the regulation of inflammation and pain.
  • PACAP a role of PACAP in migraine pathogenesis and that it is mediated via activation of mast cells.
  • a potent, selective antagonist of MRGPRX2 that blocks IgE-independent mast cell de-granulation is expected to provide therapeutic benefit in mast-cell driven pathologies including skin disorders such as urticaria, atopic dermatitis and rosacea as well as additional indications like inflammatory bowel disease, arthritis and migraine.
  • X is C(R 2 ) 2 , O or NR 3 ;
  • Xi is CH or N; n is 0 or 1;
  • R 1 is -O-R 4 or a halogen
  • each R 2 is independently H or a halogen
  • R 3 is H, halogen, -CO2(Ci-C6)alkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, -CO-(3 -6-membered cycloalkyl), (Ci-Ce)alkyl, CO-NH(Ci-Ce)alkyl, COO(Ci-Ce)alkyl or CN, wherein any (Ci-Ce)alkyl of R 3 is optionally substituted 1, 2 or 3 times with a halogen or CN; and wherein the or 5- or 6-membered heteroaryl of R 3 is optionally substituted with halogen, (Ci-Ce)alkyl or CN;
  • R 4 is phenyl or pyridinyl wherein each phenyl or pyridinyl is optionally substituted with 1, 2 or 3 halogen atoms;
  • R 7 is H, pyridinyl or pyridone wherein the pyridinyl of R 7 is optionally substituted with O or the pyridinyl nitrogen is optionally an N-oxide.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein, and a pharmaceutically acceptable excipient.
  • a method of treating an MrgX2 -mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein.
  • a compound of Formula I or pharmaceutically acceptable salt thereof for use in therapy comprising administering to the human a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein.
  • the compounds of the present invention i.e. compounds of Formula I or pharmaceutically acceptable salts thereof as defined herein, may be advantageous in a number of respects.
  • compounds defined herein are antagonists of MrgX2 and thus may be advantageous in treating MrgX2 mediated diseases.
  • alkyl refers to a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms.
  • (Ci-C6)alkyl refers to an alkyl moiety containing from 1 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to, methyl, ethyl, w-propyl, isopropyl, //-butyl, isobutyl, .s-butyl, /-butyl, pentyl, and hexyl.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as "halo(Ci-C4)alkyl", “aryl(Ci-C4)alkyl-”, or “ (Ci-C4)alkoxy(Ci-C4)alkyl-”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.
  • substituent groups such as "halo(Ci-C4)alkyl", “aryl(Ci-C4)alkyl-”, or “ (Ci-C4)alkoxy(Ci-C4)alkyl-”
  • alkyl is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.
  • aryl(Ci-C4)alkyl” or “phenyl(Ci-C4)alkyl” groups useful in the present invention include, but are not limited to, benz
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms.
  • (C3-C6)cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to six ring carbon atoms.
  • Exemplary "(C3-C6)cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 4- to 6-membered heterocycloalkyl refers to a group or moiety comprising a non-aromatic, monovalent monocyclic radical, which is saturated or partially unsaturated, containing 4, 5, or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen.
  • 4- to 6- membered heterocycloalkyl groups useful in the present invention include, but are not limited to azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4- oxathiolanyl, 1,4-oxathianyl, and 1,4-
  • aryl refers to monocyclic, fused bicyclic, or fused tricyclic groups having 6 to 14 carbon atoms and having at least one aromatic ring.
  • aryl groups are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like.
  • heteroaryl refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heteroaryls useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, di
  • Examples of 5-membered "heteroaryl” groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl.
  • Examples of 6-membered "heteroaryl” groups include oxo-pyridyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl.
  • 6,6-fused “heteroaryl” groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.
  • 6,5-fused “heteroaryl” groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.
  • 5- or 6-membered heteroaryl refers to a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms.
  • 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • halogen and halo refer to fluoro, chloro, bromo, or iodo substituents.
  • hydroxy or “hydroxyl” refer to the radical -OH.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • “Pharmaceutically acceptable” refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • treatment refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • therapeutically effective amounts of a compound of Formula I as well as salts thereof may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • X is C(R 2 ) 2 , O or NR 3 ;
  • Xi is CH or N; n is 0 or 1;
  • R 1 is -O-R 4 or a halogen
  • each R 2 is independently H or a halogen
  • R 3 is H, halogen, -CO2(Ci-C6)alkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, -CO-(3 -6-membered cycloalkyl), (Ci-Ce)alkyl, CO-NH(Ci-C6)alkyl, COO(Ci-Ce)alkyl or CN, wherein any (Ci-Ce)alkyl of R 3 is optionally substituted 1, 2 or 3 times with a halogen or CN; and wherein the or 5- or 6-membered heteroaryl of R 3 is optionally substituted with halogen, (Ci-Ce)alkyl or CN; R 4 is phenyl or pyridinyl wherein each phenyl or pyridinyl is optionally substituted with 1, 2 or 3 halogen atoms (e.g., fluorine); and
  • R 7 is H, pyridinyl or pyridone wherein the pyridinyl of R 7 is optionally substituted with O or the pyridinyl nitrogen is optionally an N-oxide.
  • Xi is CH or N. In an embodiment Xi is CH.
  • R 1 is -O-R 4 or a halogen.
  • R 1 is a halogen, in specific embodiments, R 1 is a fluorine atom.
  • R 1 is O-R 4 .
  • R 1 is O-R 4 and R 4 is phenyl optionally substituted with 1 or 2 halogen atoms or pyridinyl optionally substituted with 1 or 2 halogen atoms (e.g., fluorine).
  • R 4 is phenyl substituted with 1 or 2 halogen atoms (e.g., fluorine atoms).
  • the phenyl may be substituted at the 4 position with a halogen atom.
  • the phenyl may be substituted at the 2 and 4 positions on the ring with a halogen atom.
  • R 1 is -O-R 4 or a fluorine.
  • the compound is a compound of Formula la or a pharmaceutically acceptable salt thereof, Formula la wherein:
  • Y is N or CH
  • R 5 is a halogen atom; and m is 1 or 2.
  • R 5 is a fluorine atom.
  • Y is N. In an embodiment Y is N and R 5 is fluorine. In some embodiments m is 1, in another embodiment m is 2.
  • Y is CH. In an embodiment Y is CH and R 5 is fluorine. In a further embodiment Y is CH, R 5 is fluorine and m is 2.
  • n may be 0 or 1. In an embodiment of the invention n is 0. In another embodiment n is 1. In compounds of Formula I and Formula la, X is C(R 2 )2, O or NR 3 .
  • X is C(R 2 )2.
  • R 2 may be the same or different.
  • each R 2 is the same and is selected from H or a halogen.
  • each R 2 is H.
  • each R 2 is fluorine.
  • X is C(R 2 )2 and R 7 is pyridinyl or pyridone wherein any pyridinyl is optionally substituted with O.
  • X is O. In a particular embodiment of the invention X is O and n is i.
  • X is NR 3 .
  • R 3 is H, halogen, -CO2(Ci-C6)alkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, -CO-(-3 to 6-membered cycloalkyl), (Ci-Ce)alkyl, CO-NH(Ci-Ce)alkyl, COO(Ci-Ce)alkyl or CN wherein any (Ci-Ce)alkyl is optionally substituted 1, 2 or 3 times with a halogen or CN; and wherein the or 5- or 6-membered heteroaryl is optionally substituted with halogen, (Ci-Ce)alkyl or CN.
  • X is NR 3 and R 3 is halogen, -CO2(Ci-C6)alkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, -CO-(-3 to 6-membered cycloalkyl), (Ci-Ce)alkyl, CO-NH(Ci-Ce)alkyl, COO(Ci-Ce)alkyl or CN wherein any (Ci-Ce)alkyl is optionally substituted 1, 2 or 3 times with a halogen or CN; and wherein the or 5- or 6-membered heteroaryl is optionally substituted with halogen, (Ci-Ce)alkyl or CN.
  • R 3 is a 5- or 6-membered heteroaryl optionally substituted with halogen, (Ci-Ce)alkyl or CN.
  • the 5- or 6-membered heteroaryl may contain 1, 2 or 3 heteroatoms.
  • R 3 is (Ci-Ce)alkyl optionally substituted 1, 2 or 3 times with a halogen.
  • the halogen is a fluorine atom.
  • R 3 is -CH2-CF3.
  • R 3 is -CO2(Ci-C6)alkyl, CO-3-6 membered cycloalkyl, CO- NH(Ci-Ce)alkyl or COO(Ci-Ce)alkyl, wherein any (Ci-Ce)alkyl is optionally substituted 1, 2 or 3 times with a halogen atom. In an embodiment, any (Ci-Ce)alkyl is optionally substituted 1, 2 or 3 times with a fluorine atom
  • the compound of the invention is a compound of Formula lb or a pharmaceutically acceptable salt thereof
  • R 6 is 0-(Ci-C6)alkyl, 3-6-membered cycloalkyl, NH(Ci-Ce)alkyl or (Ci-Ce)alkyl wherein each O-(Ci-Ce)alkyl, 3-6-membered cycloalkyl, NH(Ci-Ce)alkyl, (Ci-Ce)alkyl is optionally substituted 1, 2 or 3 times with a fluorine atom.
  • R 6 is a 3- or 4-membered cycloalkyl, O-(C2-C4)alkyl, NH(C2- C 3 )alkyl, CF 3 or (Ci-C 3 )alkyl-CF 3 .
  • references herein to a compound of Formula I or a salt thereof includes a compound of Formula I as a free base or acid, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of Formula I.
  • the invention is directed to a salt of a compound of Formula I.
  • the invention is directed to a pharmaceutically acceptable salt of a compound of Formula I.
  • the invention is directed to a compound of Formula I or a salt thereof.
  • the invention is directed to a compound of Formula I or a pharmaceutically acceptable salt thereof. Because of its potential use in medicine, it will be appreciated that a salt of a compound of Formula I is preferably pharmaceutically acceptable.
  • “Pharmaceutically acceptable” refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Non-pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCH/VHCA, 2011 (see http://www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html).
  • Non-pharmaceutically acceptable salts are within the scope of the present invention, for example for use as intermediates in the preparation of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Non-pharmaceutically acceptable salts may be used, for example as intermediates in the preparation of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • Base addition salts can be formed by reaction of a compound of Formula I with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
  • Acid addition salts can be formed by reaction of a compound of Formula I with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
  • Salts may be prepared in situ during the final isolation and purification of a compound of Formula I. If a basic compound of Formula I is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base. Similarly, if a compound of Formula I containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid.
  • salt formation may include 1, 2 or more equivalents of acid.
  • Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.
  • Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formula I are included within the scope of the invention, including sub- stoichiometric salts, for example where a counterion contains more than one acidic proton.
  • Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2, 5 -dihydroxybenzoate, di succinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galacta
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-l,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’- dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-l’-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium
  • the compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric centre may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step is required to liberate the desired form.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compounds according to Formula I may also contain double bonds or other centres of geometric asymmetry. Where the stereochemistry of a centre of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form. In an embodiment of the invention, the compound of Formula I is selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may be formulated into pharmaceutical compositions prior to administration to a subject.
  • the invention provides a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as defined herein, and a pharmaceutically acceptable excipient.
  • the excipient may be any suitable pharmaceutically acceptable excipient.
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to an individual and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • Pharmaceutical compositions may be adapted for administration by any appropriate route, for example oral, inhaled, injectable etc.
  • the pharmaceutically acceptable excipient may be any suitable pharmaceutically acceptable excipient such as an edible carbohydrate, for example, starch or mannitol.
  • the compounds of Formula I are antagonists of MrgX2 and, as such can be useful in the treatment of MrgX2-mediated diseases or disorders.
  • a method of treating an MrgX2- mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound of Formula I as described herein or pharmaceutically acceptable salt thereof or the pharmaceutical composition as described herein.
  • the MrgX2 -mediated disease or disorder may be selected from the group consisting of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine.
  • the MrgX2-mediated disease or disorder may be selected from the group consisting ofchronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug- induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, and migraine.
  • the MrgX2-mediated disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine.
  • the MrgX2-mediated disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.
  • the MrgX2 -mediated disease or disorder is chronic spontaneous urticaria.
  • the method of the present invention comprises administering a therapeutically acceptable amount of the compound or composition in any suitable way.
  • the present invention provides a compound or pharmaceutically acceptable salt thereof as described herein for use in therapy. In a further aspect the present invention provides a compound or pharmaceutically acceptable salt thereof as defined herein for use in the treatment of an MrgX2 -mediated disease or disorder.
  • the MrgX2 -mediated disease or disorder may be selected from the group consisting of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, and migraine.
  • the MrgX2-mediated disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine.
  • the MrgX2-mediated disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.
  • the MrgX2 -mediated disease or disorder is chronic spontaneous urticaria.
  • the present invention also provides use of a compound or pharmaceutically acceptable salt as defined herein in the manufacture of a medicament for use in the treatment of an MrgX2-mediated disease or disorder.
  • the MrgX2-mediated disease or disorder may be selected from the group consisting of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, and migraine.
  • the MrgX2 -mediated disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine.
  • the MrgX2 -mediated disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.
  • the MrgX2-mediated disease or disorder is chronic spontaneous urticaria.
  • LC/MS Method 1 UPLC was conducted on an Acquity UPLC CSH Cl 8 column (30mm x 2.1mm i.d. 1.7pm packing diameter) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient 0-1.85 min.: l% to lOO% B, 1.9 to 2.0 min. 100% B, at a flow rate of 1.3 mL/ min. at 45°C.
  • Mass spectrum was recorded on a Waters Acquity QDa mass detector using alternative-scan positive and negative mode electrospray ionisation, scan range of 100 to 1000 AMU, with targeted sample frequency of 8 Hz.
  • LC/MS Method 2 UPLC was conducted on an Acquity UPLC CSH Cl 8 column (30mm x 2.1mm i.d. 1.7pm packing diameter) eluting with 10 mM ammonium bicarbonate in water adjusted to pH 10 with 25% ammonium hyrdroxide solution (solvent A) and acetonitrile (solvent B), using the following elution gradient 0-1.85 min.: 0% to 100% B, 1.9 to 2.0 min. 100% B, at a flow rate of 1.3 mL/ min. at 45°C. Mass spectrum was recorded on a Waters Acquity QDa mass detector using alternative-scan positive and negative mode
  • LC/MS Method 3 UPLC was conducted on an Acquity UPLC CSH Cl 8 column (30mm x 2.1mm i.d. 1.7pm packing diameter) eluting with 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), using the following elution gradient 0-1.85 min.: 1% to 100% B, 1.9 to 2.0 min. 100% B, at a flow rate of 1.3 mL/ min. at 45°C.
  • Mass spectrum was recorded on a Waters Acquity QDa mass detector using alternative-scan positive and negative mode electrospray ionisation, scan range of 100 to 1000 AMU, with targeted sample frequency of 8 Hz.
  • a solid mixture of iron (13.86 g, 248 mmol) and ammonium chloride (13.28 g, 248 mmol) was added to a solution of 5-(2,4-difluorophenoxy)-2-nitropyridine (6.26 g, 24.82 mmol) in ethanol (40 mL) and water (10 mL), and the mixture was heated to 90 °C. After 5 h, the reaction was allowed to cool to ambient temperature, and the EtOH was removed by concentration. EtOAc (150 mL) was added, and the mixture was filtered over Celite, with EtOAc rinsing (150 mL).
  • Examples 2-4 were synthesized in an analogous manner, using the indicated commercially available carboxylic acids.
  • Example 6 was synthesized in an analogous manner using the indicated commercially available carboxylic acid.
  • Example 1 To tert-butyl l-((5-(2,4-difluorophenoxy)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (Example 1) (690 mg, 1.502 mmol) in dioxane (2 mL) was added HC1 in dioxane (4N, 2.252 mL, 9.01 mmol) and H2O (0.027 mL, 1.502 mmol).
  • Examples 8-10 were synthesized in an analogous manner, using the indicated commercially available halides.
  • Examples 12-19 were synthesized in an analogous manner, using the indicated commercially available acylating/alkylating agent.
  • Example 21 was synthesized in an analogous manner, using the indicated commercially available halide.
  • Enantiomers of 3-(pyridin-4-yl)cyclohexan-l-one (6.7g in 56 ml of MeOH, 30.6 mmol, 80% pure) were separated using the following conditions: (Instrument: SFC 80; Column: Chiralpak AD 30x250mm, 5u; Co-solvent: 15% MeOH; Flow rate: 65 g/min; UV wavelength: 250 nm; Temperature: 30°C; Injection vol: 1 ml; Stacking injection: 7.9 min. Desired fractions, enantiomer 1 (8-9.5 min) and enantiomer 2 (10.2-15 min) were collected.
  • Enantiomers of 3-(6-methoxypyridin-3-yl)cyclohexan-l-one (8.23g) were purified on an IG column using isocratic 100% Acetonitrile. Enantiomer 1 (4.61 min) and enantiomer 2 (7.71 min) were collected to give 3.62 g (100% ee, yield 41%) of enantiomer 1, (R)- 3-(6- methoxypyridin-3-yl)cyclohexan-l-one as a colorless oil; LCMS (ES) m/z 206.3 [M+H] + ; and 3.35 g (99% ee, yield 46%) of enantiomer 2 as a colorless oil; LCMS (ES) m/z 206.3 [M+H] + .
  • TMS-C1 (126 pl, 0.982 mmol) was added to a stirring mixture of (5A)-N-(5-((5- fluoropyridin-2-yl)oxy)pyridin-2-yl)-5-(6-methoxypyridin-3-yl)spiro[2.5]octane-l- carboxamide (146.8 mg, 0.327 mmol) and sodium iodide (147 mg, 0.982 mmol) in acetonitrile (8.2 mL). The mixture was stirred for 16 h at 50 °C, concentrated, taken up in EtOAc and washed with saturated NaHCCL, followed by saturated Na2S2Ch, then brine.
  • the diastereomers were separated and the product purified using Mass Directed Automated Purification (MDAP).
  • the HPLC conditions were XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature.
  • Example 33 was synthesized in an analogous manner using the designated Intermediate in Example 34
  • Example 34 could be synthesized in analogous manner to Example 27 or 33 with the appropriate intermediate.
  • the estimated LC/MS: (M+H)+ 489.
  • Example 35 could be synthesised in an analogue manner to Example 26 or Example 32 using the appropriate intermediate.
  • the estimated LC/MS: (M+H)+ 488. BIOLOGICAL DATA
  • a Ca 2+ mobilization assay was used to assess the activity of the compounds of this invention.
  • a HEK293 cell line with stably expressing human MRGPRX2 and mouse Galphal5 genes was used in the assay. Briefly, cells were seeded into black clear-bottomed 384-well plates at 1.5 x io 4 cells/well and culture at 37°C for 24 hours prior to assay.
  • Cortistatin- 14 (PCKNFFWKTFSSCK, Disulfide Bridge: 2-13, TFA salt, GeneScript) was measured on FLIPR TETRA (Molecular Devices) instrument as increased fluorescence intensity (488 nm excitation/530 nm emission) upon receptor binding, leading to G-protein activation and Ca 2+ mobilization.
  • FLIPR TETRA Molecular Devices
  • An activation dose response curve was produced for Corti statin- 14 to determine the EC50 value of the agonist on the day of assay.
  • Compounds of this invention were prepared as 1 mM or 10 mM solution in DMSO.
  • the pIC50s for each compound of this invention were averaged to determine a mean value, for a minimum of 2 experiments.
  • the compounds of Examples 1 - 33 inhibited MRGPRX2 activation in the above method with a pIC50 value between approximately 5 and 9.4.
  • Examples 34 and 35 could be tested in the same assay, and would be expected to demonstrate the same activity as Examples 1-33.

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Abstract

Cette invention concerne des composés de formule I qui sont des antagonistes de MrgX2 (gène X2 associé au Mas) et sont ainsi utiles en tant qu'agents thérapeutiques, en particulier des agents thérapeutiques destinés à être utilisés dans le traitement de l'urticaire spontanée chronique, la mastocytose, l'urticaire au froid, la dermatite atopique, la rosacée, la maladie de Crohn, la rectocolite hémorragique, la fibromyalgie, les polypes nasaux, la douleur neuropathique, la douleur inflammatoire, les démangeaisons chroniques, les réactions anaphylactoïdes induites par les médicaments, le syndrome métabolique, le reflux gastro-œsophagien, l'asthme, la toux, ou la migraine.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012047703A2 (fr) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques
WO2014137728A1 (fr) * 2013-03-04 2014-09-12 Merck Sharp & Dohme Corp. Composés inhibant l'activité enzymatique de la kinase à répétition riche en leucine
WO2019014427A1 (fr) * 2017-07-12 2019-01-17 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
WO2019078968A2 (fr) * 2017-10-18 2019-04-25 Angex Pharmaceutical, Inc. Composés cycliques en tant qu'agents immunomodulateurs
WO2020223255A1 (fr) * 2019-04-29 2020-11-05 Solent Therapeutics, Llc Dérivés de 1,1-dioxyde de 3-amino-4h-benzo[e][1,2,4]thiadiazine en tant qu'inhibiteurs de mrgx2

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Publication number Priority date Publication date Assignee Title
WO2012047703A2 (fr) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques
WO2014137728A1 (fr) * 2013-03-04 2014-09-12 Merck Sharp & Dohme Corp. Composés inhibant l'activité enzymatique de la kinase à répétition riche en leucine
WO2019014427A1 (fr) * 2017-07-12 2019-01-17 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
WO2019078968A2 (fr) * 2017-10-18 2019-04-25 Angex Pharmaceutical, Inc. Composés cycliques en tant qu'agents immunomodulateurs
WO2020223255A1 (fr) * 2019-04-29 2020-11-05 Solent Therapeutics, Llc Dérivés de 1,1-dioxyde de 3-amino-4h-benzo[e][1,2,4]thiadiazine en tant qu'inhibiteurs de mrgx2

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BERGE, J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
MALIK L ET AL: "Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 6, 15 March 2009 (2009-03-15), pages 1729 - 1732, XP026005867, ISSN: 0960-894X, [retrieved on 20090130], DOI: 10.1016/J.BMCL.2009.01.085 *

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