WO2022152852A1 - Antagonistes de mrgx2 - Google Patents

Antagonistes de mrgx2 Download PDF

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WO2022152852A1
WO2022152852A1 PCT/EP2022/050754 EP2022050754W WO2022152852A1 WO 2022152852 A1 WO2022152852 A1 WO 2022152852A1 EP 2022050754 W EP2022050754 W EP 2022050754W WO 2022152852 A1 WO2022152852 A1 WO 2022152852A1
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propanamide
piperidin
mmol
alkyl
chloropyridin
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PCT/EP2022/050754
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English (en)
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Edward Brnardic
Jon Collins
Yu Guo
Anthony HANDLON
Louis Lafrance
Daniel Paone
Barry Shearer
Matthew Tallant
Guosen Ye
Maben YING
Huichang Zhang
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2022152852A1 publication Critical patent/WO2022152852A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D237/22—Nitrogen and oxygen atoms
    • 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
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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.
  • the compounds of the present invention may be formulated into pharmaceutical compositions prior to administration to a subject.
  • a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof as defined herein, and a pharmaceutically acceptable excipient.
  • compositions of the invention 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.
  • 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.
  • compound of Formula (I) or pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2 -mediated disease or disorder.
  • 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-Cejalkyl) refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl.
  • alkoxy refers to a group containing an alkyl radical attached through an oxygen linking atom.
  • (C 1 -C 4 )alkoxy refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary “(C 1 -C 4 )alkoxy” groups useful in the present invention include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as "halo(C 1 -C 4 )alkyl", “aryl(C 1 -C 4 )alkyl-”, “(C 1 -C 6 )alkyl-OH” or " (C 1 -C 4 )alkoxy(C 1 -C 4 )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.
  • halo(C 1 -C 4 )alkyl is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical.
  • halo(C 1 -C 4 )alkyl groups useful in the present invention include, but are not limited to, -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1- difluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.
  • aryl(C 1 -C 4 )alkyl” or “phenyl(C 1 -C 4 )alkyl” groups useful in the present invention include, but are not limited to, benzyl and phenethyl.
  • Examples of "(C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-" groups useful in the present invention include, but are not limited to, methoxymethyl, methoxyethyl, methoxyisopropyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, isopropoxyisopropyl, t- butoxymethyl, t-butoxyethyl, and t-butoxyisopropyl.
  • the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms.
  • (C 3 -C 8 )cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms.
  • Exemplary "(C 3 -C 8 )cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • 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,
  • 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.
  • X 1 is CR 5a . In another embodiment X 1 is CR 5a and R 5a is hydrogen. In an embodiment of the invention X 2 is N. In an embodiment of the invention X 3 is CR 5b . In some instances, X 3 is CR 5b and R 5b is hydrogen. In another embodiment of the invention X 4 is CR 6b . In some instances, R 6b is hydrogen In certain embodiments of the invention X 1 is CR 5a , R 5a is hydrogen, X 2 is N, X 3 is CR 5b , R 5b is hydrogen and X 4 is CR 6b wherein R 6b is hydrogen.
  • X 1 is CR 5a
  • R 5a is hydrogen
  • X 2 is N
  • X 3 is N
  • X 4 is CR 6b wherein R 6b is hydrogen
  • Y may be N or CH.
  • Y is N
  • Y is CH
  • Z is O.
  • Z is C(R 2 ).
  • Z is C(R 2 ) 2 .
  • Each R 2 may be hydrogen, F or CH 3 .
  • each R2 is H or each R 2 is F.
  • n may be 0 or 1 as stated above. In an embodiment of the invention n is 1.
  • R 1 is halogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, - O-(C 2 -C 6 )alkenyl, -O-(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl, -O-(C 3 -C 8 )cycloalkyl, -O-aryl, -O- heteroaryl, -CO 2 (C 1 -C 6 )alkyl or -NH(C 1 -C 6 )alkyl wherein any said (C 1 -C 6 )alkyl, -O- heteroaryl, -O-aryl or aryl is optionally substituted one, two, or three times by R 8 .
  • R 1 is O-aryl optionally substituted one, two, or three times by R 8 .
  • R 1 is O-phenyl substituted one, two, or three times by R 8 .
  • R 8 may be F.
  • R 1 is halogen (e.g., fluorine or chlorine) or -O-(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl.
  • R 3 is a 5-membered heteroaryl ring, hydrogen, halogen or OH.
  • R 3 is H, F or OH.
  • R 4 is hydrogen, halogen, 5-membered heteroaryl or 5-6 membered lactam.
  • lactam refers to a cyclic amide.
  • a 5- membered lactam may also be referred to as ⁇ -lactam.
  • a 6-membered lactam may also be referred to as ⁇ -lactam.
  • R 7a and R 7b may be the same or different.
  • R 7a is hydrogen, OH, halogen or methyl.
  • R 7b is hydrogen, OH, halogen or methyl.
  • R 7a and R 7b are each hydrogen.
  • R 7a is hydrogen and R 7b is methyl.
  • R 8 is halogen.
  • R 8 is F.
  • R 10 is -(C 1 -C 6 )alkyl and R 11 is H.
  • R 10 is CH 3 and R11 is H.
  • R 1 is -O-aryl substituted twice with R 8 ;
  • X 1 is CR 5a ;
  • X 2 is N;
  • X 3 is CR 5b ;
  • X 4 is CR 6b ;
  • Y is N;
  • Z is C(R 2 ) 2 ;
  • n is 1;
  • R 2 is hydrogen or F;
  • R 3 , R 4 , R 5a , R 5b and R 6b are each hydrogen;
  • R 7a and R 7b are each hydrogen;
  • R 8 is F;
  • R 10 is CH 3 ; and
  • R 11 is H.
  • R 1 is Cl or O-(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl;
  • X 1 is N or CR 5a;
  • X 2 is N;
  • X 3 is CR 5b ;
  • X 4 is CR 6b ;
  • Y is N;
  • Z is C(R 2 ) 2 ;
  • R 2 is F or hydrogen;
  • R 3 is hydrogen;
  • R 4 is 5-membered heteroaryl;
  • R 5a , R 5b , R 6b is hydrogen;
  • R 7a is hydrogen;
  • R 7b is hydrogen or CH 3
  • R 10 is CH3; and
  • R 11 is hydrogen.
  • 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.
  • 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.
  • Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm.
  • 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, galactarate
  • 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), bi s-(2 -hydroxy ethyl)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,
  • 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 center 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.
  • 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.
  • the compound of Formula (I) is selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof.
  • the invention provides a pharmaceutical composition
  • 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.
  • 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, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo- analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, crohns disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, inter
  • 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 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.
  • 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 was conducted on a Shimadzu LCMS-2020 Xselect CSH C 1 8 column (50mm x 3.0 mm i.d. 2.5pm 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 0.01-3.60 min.: 30% to 70% B, 3.60-4.40 min to 95% B, 5.10-5.20 min. to 5% B, at a flow rate of 1.2 mL/ min. at 45°C.
  • LC/MS Method 2 UPLC was conducted on an Acquity UPLC CSH C 1 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 3 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 4 was conducted on a Shimadzu LCMS-2020 Ascentis CSH C 1 8 column (50mm x 3.0 mm i.d. 2.7pm packing diameter) eluting with 0.05% TFA in water (solvent A) and 0.05% TFA in acetonitrile (solvent B), using the following elution gradient 0.01-1.10 min.: 5% to 95% B, 1.80-1.90 to 5% B, at a flow rate of 1.5 mL/ min. at 40°C.
  • LC/MS Method 5 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.
  • LC/MS Method 7 was conducted on a Poroshell HPH-18 column (50mm x 3.0 mm i.d. 2.7 pm packing diameter) eluting with 6.5 mM NH4HCO3 + NH3 H2O (solvent A) and acetonitrile (solvent B), using the following elution gradient: 0.01-2.00 min.: 10% to 95% B, 2.60-2.75 min. to 10% B at a flow rate of 1.2 mL/ min. at 40°C.
  • LC/MS Method 8 was conducted on a Ascentis Express C 1 8 column (50mm x 3.0 mm i.d. 2.7 pm packing diameter) eluting with water/0.05%TFA (solvent A) and acetonitrile/0.05%TFA (solvent B), using the following elution gradient: 0.01-2.00 min.: 5% to 95% B, 2.60-2.75 min. to 5% B, at a flow rate of 1.5 mL/ min. at 40°C.
  • LC/MS Method 9 was conducted on a Kinetex 2.6 um EVO C 1 8 100A column (50mm x 3.0 mm i.d. 2.6 pm packing diameter) eluting with water/5 mM NH4HCO3 (solvent A) and acetonitrile (solvent B), using the following elution gradient: 0.01-2.10 min.: 10% to 95% B, 2.70-2.75 min. to 10% B at a flow rate of 1.2 mL/ min. at 40°C.
  • LC/MS Method 11 The column used was a Kinetex 2.6 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 90% A (A: Water-5 mM NH4HCO3) and ending at 95% B (B: Acetonitrile) over 2.70 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 12 The column used was a Kinetex 2.6um EVO C 1 8 100A, 2.6 pm, 3.0 x 50 mm. A linear gradient was applied, starting at 90% A (A: Water-5 mM NH4HCO3) and ending at 95% B (B: Acetonitrile) over 2.70 min with a total run time of 2.90 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 13 The column used was a Kinetex 2.6um EVO Cl 8 100A, 2.6 pm, 3.0 x 50 mm.
  • a linear gradient was applied, starting at 90% A (A: Water-5 mM NH4HCO3) and ending at 95% B (B: Acetonitrile) over 5.00 min with a total run time of 5.60 min.
  • the column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 14 The column used was a Xselect CSH C 1 8, 2.5 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95% A (A: Water/0.1%FA) and ending at 95% B (B: Acetonitrile/0.1%FA) over 2.70 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 15 The column used was a Poroshell HPH-C 1 8, 2.7 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 90% A (A: water-6.5 mM NH4HCO3+NH3H2O) and ending at 95% B (B: Acetonitrile) over 2.70 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.50 mL/min.)
  • LC/MS Method 16 The column used was a Xselect CSH C 1 8, 2.5 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95% A (A: water/0.1% FA) and ending at 100% B (B: Acetonitrile/0.1% FA) over 2.70 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.)
  • LC/MS Method 17 The column used was a Kinetex XB-C 1 8, 2.6 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95% A (A: Water/0.1%FA) and ending at 100% B (B: Acetonitrile/0.1%FA) over 2.60 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 18 The column used was a Ascentis Express C 1 8, 2.7 pm, 2.1 x 50 mm. A linear gradient was applied, starting at 90% A (A: water-0.1% FA) and ending at 95% B (B: Acetonitrile-0.1% FA) over 2.70 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.00 mL/min.
  • LC/MS Method 19 The column used was a CORTECS C 1 8, 2.7 pm, 2.1 * 50 mm. A linear gradient was applied, starting at 95% A (A: water-0.09%F A) and ending at 95% B (B: Acetonitrile-0.1% FA) over 2.60 min with a total run time of 3.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 20 The column used was a Xselect CSH C 1 8, 2.5 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95% A (A: water/0.1% FA) and ending at 95% B (B: Acetonitrile/0.1% FA) over 4.70 min with a total run time of 5.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.) LC/MS Method 21 : The column used was a Kinetex XB- C 1 8, 2.6 pm, 3.0 * 50 mm.
  • a linear gradient was applied, starting at 95% A (A: water/0.1% FA) and ending at 90% B (B: Acetonitrile/0.1% FA) over 2.60 min with a total run time of 3.00 min.
  • the column temperature was at 40 °C with the flow rate of 1.20 mL/min.
  • LC/MS Method 22 The column used was a Xselect CSH C 1 8, 2.5 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 95% A (A: water/0.1% FA) at 0.01 min and moving to 100% B (B: Acetonitrile/0.1% FA) over 1.10 min, then to 0% B from 1.70 to 1.75 min, with a total run time of 2.00 min.
  • the column temperature was at 40 °C with the flow rate of 1.20 mL/min.)
  • LC/MS Method 23 The column used was a Cortecs C 1 8, 2.7 pm, 2.1 * 50 mm. A linear gradient was applied, starting at 95% A (A: water/0.1% FA) at 0.01 min and moving to 100% B (B: Acetonitrile/0.1% FA) over 2.00 min, then to 5% B from 2.80 to 2.90 min, with a total run time of 3.00 min.
  • the column temperature was at 40 °C with the flow rate of 1.00 mL/min.)
  • LC/MS Method 24 The column used was a Cortecs C 1 8, 2.7 pm, 2.1 * 50 mm. A linear gradient was applied, starting at 95% A (A: water/0.05% TFA) at 0.01 min and moving to 100% B (B: Acetonitrile/0.05% TFA) over 2.00 min, then to 5% B from 2.80 to 2.90 min, with a total run time of 3.00 min.
  • the column temperature was at 40 °C with the flow rate of 1.00 mL/min.).
  • LC/MS Method 25 The column used was a Xselect CSH C 1 8, 2.5 pm, 3.0 * 50 mm. A linear gradient was applied, starting at 97% A (A: water/0.1% FA) and ending at 97% B (B: Acetonitrile/0.1% FA) over 2.70 min with a total run time of 2.5 min. The column temperature was at 40 °C with the flow rate of 1.0 mL/min.)
  • LC/MS Method 26 was conducted on a Kinetex 2.6 um EVO C 1 8 100A column (50mm x 3.0 mm i.d. 2.6 pm packing diameter) eluting with water/5 mM NH4HCO3 (solvent A) and acetonitrile (solvent B), using the following elution gradient: 0.01-1.10 min.: 10% to 95% B, 1.80-1.85 min. to 10% B at a flow rate of 1.2 mL/ min. at 40°C.
  • LC/MS Method 27 was conducted on a Kinetex XB-C 1 8 column (30mm x 2.1 mm i.d. 1.7 pm packing diameter) eluting with Water/0.05%TFA (solvent A) and Acetonitrile/0.05%TF A (solvent B), using the following elution gradient: 0.01-0.60 min.: 5% to 95% B, 1.00-1.05 min. to 5% B at a flow rate of 1.0 mL/ min. at 40°C.
  • LC/MS Method 28 was conducted on a Poroshell HPH-C 1 8 column (50mm x 3.0 mm i.d. 2.7 pm packing diameter) eluting with 6.5 mM NH4HCO3+NH3H2O (solvent A) and acetonitrile (solvent B), using the following elution gradient: 0.01-1.10 min.: 10% to 95% B, 1.80-1.90 min. to 10% B at a flow rate of 1.2 mL/ min. at 40°C.
  • Step 2 To 6-(cyclopropylmethoxy)pyridazin-3-amine (5.00 g, 30.30 mmol, 1.0 eq) and 2- bromopropanoic acid (6.91 g, 45.46 mmol, 1.5 eq) in DCM (150 mL) were added DMAP (1.11 g, 9.09 mmol, 0.3 eq) and DCC (12.48 g, 60.60 mmol, 2.0 eq).
  • Step 2 A mixture of 5-(cyclopropylmethoxy)-2-nitropyridine (6.6 g, 34.0 mmol, 1.0 eq), MeOH (60.0 mL) and Pd/C (0.6 g, 10%) was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The reaction was stirred 2 h at 25 °C under an atmosphere of hydrogen (balloon), filtered, and concentrated to give crude 5- (cyclopropylmethoxy)pyridin-2-amine (5.8 g) as a yellow solid, which was used without further purification.
  • Step 3 To 5-(cyclopropylmethoxy)pyridin-2-amine (0.50 g, 3.05 mmol, 1.0 eq) and 2- bromopropanoic acid (0.7 g, 4.57 mmol, 1.5 eq) in DCM (10 mL) at 25 °C was added DCC (0.94 g, 4.57 mmol, 1.5 eq), in portions. After 2 h, the reaction was filtered, concentrated and purified by prep-TLC with ethyl acetate: petroleum ether (1: 10) to give 2-bromo-N-(5- (cyclopropylmethoxy)pyridin-2-yl)propanamide (0.9 g, yield: 53%, purity: 95%) as a white solid.
  • Step 2 To 6-nitro-N-propylpyridin-3-amine (780 mg, 4.30 mmol) and DMAP (52.6 mg, 0.430 mmol) in DCM (20 mL) at 0 °C was added Boc2O (1.099 mL, 4.74 mmol). The mixture was stirred at RT for 3 h, concentrated and purified via normal phase chromatography (Combiflash Rf, 80 g silica column), eluting with 0-40% EtOAc in hexanes to afford tert- butyl (6-nitropyridin-3-yl)(propyl)carbamate (1.20 g, 4.27 mmol, 99 % yield) as a light yellow oil.
  • Step 3 To tert-butyl (6-nitropyridin-3-yl)(propyl)carbamate (1.20 g, 4.27 mmol) in ethanol (30 mL) under N 2 was added Pd/C, 10% (0.045 g, 0.427 mmol), and the mixture was hydrogenated under an H 2 balloon overnight. The mixture was filtered through Celite and concentrated to afford tert-butyl (6-aminopyridin-3-yl)(propyl)carbamate (1.02 g, 4.06 mmol, 95 % yield) as an off white solid, which was used without purification.
  • Step 2 A mixture of (E)-5-(prop-1-en-1-yl)pyridin-2-amine (659 mg, 4.91 mmol) and 10% Pd on carbon (150mg, 0.141 mmol) in ethanol (24 mL) was evacuated and purged with hydrogen several times, stirred under a balloon of hydrogen overnight, filtered and concentrated. The residue was stirred with EtOAc (10 mL), and insoluble material was filtered and discarded. The filtrate was purified over silica column, eluting with 0-15% EtOH in EtOAc to afford 5-propylpyridin-2-amine (170 mg, 1.248 mmol, 25.4 % yield).
  • Step 3 A mixture of 2-bromopropanoic acid (271.4 mg, 1.77 mmol, 1.1 eq), DCC (498 mg, 2.41 mmol, 1.5 eq), DMAP (19.6 mg, 0.16 mmol, 0.1 eq) and 5-phenoxypyridin-2-amine (300 mg, 1.61 mmol, 1.0 eq) in DCM (5 mL) was stirred 2 h, quenched with water (100 mL) and extracted with EA (100 mL x3).
  • Step 2 To a mixture of 5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine (80 mg, 0.390 mmol) and 2- bromopropanoic acid (0.042 mL, 0.468 mmol) in dichloromethane (2 mL) were added DCC (121 mg, 0.585 mmol) and DMAP (4.76 mg, 0.039 mmol). After 2.5 h, the mixture was filtered. The filter cake was washed with DCM and the filtrate was concentrated.
  • Step 2 A mixture of 5-(2,4-difluorophenoxy)pyrazin-2-amine (40 g, 179 mmol), (R)-2- bromopropanoic acid (32.9 g, 215 mmol) and silver nitrate (4.57 g, 26.9 mmol) in DCM (700 mL) was treated portionwise with DCC (44.4 g, 215 mmol), maintaining a temperature between 15 and 20 °C using a cold water bath.
  • DCM 700 mL
  • Step 1 To 5-chloropyridin-2-amine (2.56 g, 19.93 mmol) and pyridine (2.417 mL, 29.9 mmol) in THF (80 mL) at 0 °C was added (S)-1-chloro-1-oxopropan-2-yl acetate (3.0 g, 19.93 mmol), dropwise. The mixture was stirred for 1 h, warmed to RT overnight, diluted with H 2 O and extracted with EtOAc (3 X).
  • the material was repurified by reverse phase HPLC (Column: XSELECT CSH C 1 8; 150 mm x 30 mm i.d.; 5 ⁇ m packing diameter; mobile phase 30%-99% acetonitrile:water with 0.1% TFA, flow rate 40 mL/min, retention time 11.6 min) to provide 2-cyclohexyl-N-(6- (cyclopropylmethoxy)pyridazin-3-yl)propanamide (7.5 mg, 0.025 mmol, 9.07 % yield).
  • LCMS (m/z) 304 (M+H) + , RT 1.05 min.
  • LCMS Method 5 1 H NMR (CDCl3) ⁇ ppm: 9.35 (br.
  • Example 2 was synthesized in an analogous manner using the indicated Intermediate.
  • Step 2 To 2-(tetrahydro-2H-pyran-4-yl)propanoic acid (58.7 mg, 0.371 mmol) and HATU (141 mg, 0.371 mmol) in DMF (1 mL) was added a solution of 5-(2,4-difluorophenoxy)pyridin- 2-amine (Intermediate 17, Step 2) (55 mg, 0.248 mmol) and DIEA (0.065 mL, 0.371 mmol) in DMF (1 mL). The reaction was stirred at 50 °C overnight, then at 90 °C for 90 min. Additional DIEA (0.065 mL, 0.371 mmol) was added, and heating was continued for 45 min.
  • Step 2 To ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate (0.48 g, 1.98 mmol) in EtOH (6 mL) was added NaOH(aq) (5N, 1.98 mL, 9.90 mmol). The reaction was heated to 90 °C for 90 min, and then at 40 °C overnight. The mixture was concentrated to remove volatile organics, diluted with water and washed with Et 2 O (2X). The aqueous layer was acidified with 6N HCl and extracted with EtOAc (3X).
  • Step 4 To 2-(4-oxocyclohexyl)propanoic acid (92 mg, 0.540 mmol) and HATU (205 mg, 0.540 mmol) in DMF (0.9 mL) was added a solution of 5-(2,4-difluorophenoxy)pyridin-2-amine (Intermediate 17, Step 2) (80 mg, 0.360 mmol) and DIEA (0.094 mL, 0.540 mmol) in DMF (0.9 mL).
  • This material was chirally separated (column: ChiralPak IG, 20x250mm, 5 micron; flow rate: 20mL/min, solvents: 85:15 AcCN: MeOH [0.1% isopropylamine] for the first 9 minutes, then 50:50 AcCN: MeOH [0.1% isopropylamine], and returning to starting conditions at 19 minutes) to provide four stereoisomers of N-(5-(2,4- difluorophenoxy)pyridin-2-yl)-2-(4-hydroxycyclohexyl)propenamide with retention times of 7.16, 8.04, 10.62 and 11.36 min.
  • Step 2 Ethyl 2-(4,4-difluorocyclohexylidene)acetate (1.87 g, 9.16 mmol), methanol (60 mL) and palladium on carbon (370 mg, 0.348 mmol) (10% w/w, 50% wet) were stirred under an atmosphere of H2 for 16 h, filtered through Celite (rinsing with EtOAc) and concentrated to give crude 5-(pyridin-3-yloxy)pyridin-2-amine (1.81 g, 8.78 mmol, recovery: 96%) as a colorless oil, which was used without purification.
  • Step 3 To ethyl 2-(4,4-difluorocyclohexyl)acetate (250 mg, 1.212 mmol) in THF (3 mL) at -78 °C was added LDA (2M, 1.212 mL, 2.424 mmol), dropwise. After 30 min, iodomethane (0.303 mL, 4.85 mmol)) in THF (0.5 mL) was added dropwise, and the reaction was stirred for 20 min, allowed to warm to rt and stirred overnight. The reaction was quenched with NH4Cl(aq) solution and diluted with EtOAc.
  • Step 4 To ethyl 2-(4,4-difluorocyclohexyl)propanoate (0.267 g, 1.212 mmol) in dioxane (5 mL) was added a solution of LiOH (0.145 g, 6.06 mmol) in water (1.2 mL). The reaction was stirred overnight, acidified with 2N HCl and extracted with EtOAc (3X). The combined organics were dried over sodium sulfate and concentrated to give partially hydrolyzed product. This material was taken up in EtOH (4 mL), treated with NaOH(aq) (5M, 1.212 mL, 6.06 mmol) and heated to 70 °C for 2.5 h.
  • Step 5 To 2-(4,4-difluorocyclohexyl)propanoic acid (63.5 mg, 0.331 mmol) and HATU (126 mg, 0.331 mmol) in DMF (0.7 mL) was added 6-(cyclopropylmethoxy)pyridazin-3-amine (39 mg, 0.236 mmol) (Intermediate 1, Step 1) (80 mg, 0.360 mmol) and DIEA (0.058 mL, 0.331 mmol), washing down walls of the vessel with DMF (0.5 mL).
  • reaction was stirred at 60 °C for 18 h, diluted with EtOAc, washed with pH 4 phosphate buffer (2X) and brine, dried over Na 2 SO 4 , concentrated and purified by silica gel chromatography (12 g cartridge), eluting with 40% EtOAc in heptanes to provide 41 mg of a white solid.
  • This material was chirally separated (column: AD-H, 20x250mm, 5 micron; flow rate: 20 mL/min, solvents: 50:50 AcCN: MeOH) to provide two stereoisomers of N-(5-(2,4- difluorophenoxy)pyridin-2-yl)-2-(4-oxocyclohexyl)propanamide with retention times of 10.107 and 16.565 min.
  • the second peak (16.565 min) was collected to give (R)-N-(6- (cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluorocyclohexyl)propanamide, 13.89 mg.
  • Step 2 To methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (22.72 g, 157 mmol) in DCM (626 ml) was added triethylamine (43.6 ml, 313 mmol) followed by benzyl bromide (37.2 ml, 313 mmol), and the reaction was refluxed at 65 °C overnight. After cooling to 4 °C, NaOH(aq) (5M, 200 mL) was added until the pH reached 12-14. The layers were separated, and the aqueous phase was extracted with DCM (2 X 100 mL). The organic layers were combined, and about 200 mL of DCM was removed in vacuo to reduce the volume.
  • the organic phase was neutralized with HCl(aq) (1.0 M, 200 mL), the layers were separated, and the organic phase was extracted with HCl (1.0 M, 50 mL).
  • the combined aqueous layers were neutralized with sat’d aq NaHCO3 (100 mL), with ice cooling, and the pH was adjusted to 12-14 by adding solid K2CO3.
  • Step 3 To methyl (2S,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (23 g, 98 mmol) in DCM (489 ml) was added tert-butyldiphenylchlorosilane (25.1 ml, 98 mmol). The reaction was cooled to 0 °C, and triethylamine (13.63 ml, 98 mmol) was added, dropwise, followed by DMAP (2.389 g, 19.55 mmol). The mixture was allowed to warm to rt, then stirred overnight and treated with water (200 mL). The aqueous layer was isolated and extracted with EtOAc (200 mL).
  • Step 4 To a suspension of LiAlH 4 (52.8 ml, 106 mmol) in THF (100 ml) at 0 °C was added a solution of methyl (2S,4R)-1-benzyl-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2- carboxylate (25 g, 52.8 mmol) in THF (100 ml), dropwise. After 10 min, the reaction was heated to reflux (80 °C) for 2 h, then cooled to 0 °C. Water (4 mL), 3.75M NaOH solution (4 mL), and additional water (12 mL) were successively added. The mixture was filtered through Celite, rinsing with THF.
  • Step 6 To oxalyl chloride (0.50 mL, 5.71 mmol) in DCM (15 mL) at -78°C was added dimethyl sulfoxide (0.80 mL, 11.27 mmol), dropwise. After 10 minutes a solution of (3R,5R)-1- benzyl-5-((tert-butyldiphenylsilyl)oxy)piperidin-3-ol (1.21 g, 2.71 mmol) in DCM (5 mL) was added dropwise. After 20 minutes, triethylamine (3.0 mL, 21.52 mmol) was added, and after 5 min, the cooling bath was removed. After 30 minutes. the mixture was poured into water and extracted with DCM (2 X).
  • Step 8 To (5R)-1-benzyl-5-((tert-butyldiphenylsilyl)oxy)-3-(trifluoromethyl)-3- ((trimethylsilyl)oxy)piperidine (100 mg, 0.171 mmol) in EtOH (3 mL), under a nitrogen atmosphere, was added 10% palladium on carbon (20 mg, 0.019 mmol). The reaction vessel was fitted with a hydrogen-filled balloon, evacuated and purged with hydrogen (3X), then stirred under a hydrogen atmosphere overnight. The reaction vessel was evacuated and purged with nitrogen, additional 10% palladium on carbon (20 mg, 0.019 mmol) was added, and the reaction vessel was evacuated and purged with hydrogen (3X), then stirred under a hydrogen atmosphere overnight.
  • Example 12 2-(3-(1,1-dioxidothiomorpholino)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2- yl)propanamide
  • Step 1 tert-Butyl 3-oxopiperidine-1-carboxylate (1 g, 5.02 mmol) and thiomorpholine 1,1-dioxide (1.018 g, 7.53 mmol) were stirred in DCE (20 mL) for 5 minutes, followed by addition of acetic acid (0.287 mL, 5.02 mmol) and sodium triacetoxyborohydride (3.19 g, 15.06 mmol).
  • Step 2 tert-Butyl 3-(1,1-dioxidothiomorpholino)piperidine-1-carboxylate (100 mg, 0.314 mmol) was stirred in TFA (1 mL) for 30 min, diluted with DCM and toluene, concentrated and azeotroped with toluene (2X) to yield crude 4-(piperidin-3-yl)thiomorpholine 1,1-dioxide, trifluoroacetic acid salt (137 mg, 0.330 mmol, recovery: 96%) as a bright yellow oil, which was used without purification.
  • Step 3 A mixture of 2-bromo-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide (Intermediate 21) (100 mg, 0.294 mmol), 4-(piperidin-3-yl)thiomorpholine 1,1-dioxide, TFA salt (102 mg, 0.307 mmol), and TEA (0.246 mL, 1.764 mmol) in DMA (2 mL) was stirred at 40 °C overnight.
  • Example 15 Isopropyl 4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidine- 1 carboxylate Step 1 To ethyl 2-(piperidin-4-yl)acetate hydrochloride (1.246 g, 6 mmol) suspended in EtOAc (15 mL) was added sodium carbonate solution (25 mL). After stirring until clear, the organic layer was isolated, dried over Na 2 SO 4 and filtered. To the filtrate was added triethylamine (1.004 mL, 7.20 mmol), and the reaction was cooled in an ice bath.
  • Step 2 To isopropyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (1.00 g, 3.89 mmol) in THF (10 mL) at -78 °C was added LDA (2M, 2.332 mL, 4.66 mmol), dropwise. After 20 min, iodomethane (0.292 mL, 4.66 mmol) in THF (1 mL) was added dropwise, and the reaction was stirred for 20 min, allowed to warm to rt and stirred overnight. The reaction was quenched with NH4Cl(aq) solution and diluted with EtOAc.
  • Step 3 To isopropyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (0.20 g, 0.737 mmol) in EtOH (4 mL) was added NaOH(aq) (5N, 0.737 mL, 3.69 mmol). The reaction was heated to 60 °C 1 h, aged in a refrigerator overnight, concentrated, acidified to pH 1 and extracted with EtOAc (3X). The combined organics were dried over sodium sulfate and concentrated to give crude 2-(1-(isopropoxycarbonyl)piperidin-4-yl)propanoic acid (216 mg, 0.888 mmol, recovery: quantitative) as a colorless oil, which was used without further purification.
  • Step 4 To 2-(1-(isopropoxycarbonyl)piperidin-4-yl)propanoic acid (104 mg, 0.428 mmol) and HATU (163 mg, 0.428 mmol) in DMF (1.2 mL) was added 5-(2,4- difluorophenoxy)pyridin-2-amine (Intermediate 17, Step 2) (68 mg, 0.306 mmol) and DIEA (0.075 mL, 0.428 mmol).
  • Step 2 A mixture of LiOH (1M, 25.9 ml, 25.9 mmol) and tert-butyl 4-(1-ethoxy-1-oxopropan-2- yl)piperidine-1-carboxylate (740 mg, 2.59 mmol) in dioxane (10 ml) was stirred overnight, quenched with NH4Cl and a small amount of 10% citric acid, and extracted with EtOAc. The organic layer was dried over NaHCO 3 and concentrated to give crude 2-(1-(tert- butoxycarbonyl)piperidin-4-yl)propanoic acid (717.6 mg, 2.79 mmol, 108 % yield), which was used without purification.
  • Step 3 A solution of DIEA (0.295 ml, 1.688 mmol) and 5-(2,4-difluorophenoxy)pyridin-2-amine (Intermediate 17, Step 2) (250 mg, 1.125 mmol) in DMF (0.5 ml) was added to 2-(1-(tert- butoxycarbonyl)piperidin-4-yl)propanoic acid (434 mg, 1.688 mmol) and HATU (701 mg, 1.844 mmol) in DMF (0.5 ml), and the reaction was heated to 60°C.
  • Step 4 TFA (2 ml, 26.0 mmol) was added to tert-butyl 4-(1-((5-(2,4-difluorophenoxy)pyridin-2- yl)amino)-1-oxopropan-2-yl)piperidine-1-carboxylate (345 mg, 0.748 mmol) in CHCl3 (1.5 mL). After 20 minutes, the reaction was concentrated and partitioned between DCM and NaHCO3(aq). The DCM layer was concentrated to give crude N-(5-(2,4- difluorophenoxy)pyridin-2-yl)-2-(piperidin-4-yl)propanamide which was used without purification.
  • Step 5 Trifluoroacetic anhydride (14.36 ⁇ l, 0.102 mmol) was added to DIEA (48.4 ⁇ l, 0.277 mmol) and N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(piperidin-4-yl)propanamide (33.4mg, 0.092 mmol) in CHCl3 (308 ⁇ l) at 0 °C. The reaction was allowed to come to 24 °C for 1 h, then cooled back to 0°C. More trifluoroacetic anhydride (20 ⁇ l, 0.142 mmol) was added, and the mixture was brought back 24 °C and stirred overnight.
  • reaction was purified via MDAP (XSELECT CSH C 1 8 column), eluting with 50-99% AcCN in 10 mM ammonium bicarbonate in H 2 O (adjusted to pH 10 with ammonia) to give N-(5-(2,4- difluorophenoxy)pyridin-2-yl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)propanamide (10 mg, 0.022 mmol, 23.66 % yield).
  • Example 22 and 23 were synthesized in an analogous manner using the designated Intermediate.
  • Example 24 (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-3-hydroxy-3- (trifluoromethyl)piperidin-1-yl)propanamide A mixture of 3-(trifluoromethyl)piperidin-3-ol hydrochloride (200 mg, 1.18 mmol, 1.0 eq), TEA (590 mg, 5.90 mmol, 5.0 eq) and (R)-2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2- yl)propanamide (Intermediate 3) (351 mg, 1.18 mmol, 1.0 eq) in THF (10 mL) was stirred for 12 h at 40 °C, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2).
  • Vibration circular dichroism Inspection of VCD data in the analysis range indicated that the VCD difference spectrum obtained by subtracting the VCD spectrum of the two stereoisomers differing at the trifluoromethyl position when compared with the VCD difference spectrum of the calculated VCD of fs1ss minus that of fs2sr is a good match with experimentally determined values. Therefore the absolute configuration of the chiral center alpha to the trifluoromethyl group was confirmed to be (R). The confidence limit for this assignment was estimated to be 100% based on the current database that includes 88 previous correct assignments for different chiral structures. The IR spectrum of the sample was compared with the IR spectrum calculated for the various Models. Again, the model spectrum is in good qualitative agreement with experimental results, confirming the overall structure of this sample (i.e., its molecular connectivity) and providing additional support for satisfactory coverage of its solution phase conformational space by the computational analysis.
  • Example 30 was synthesized in an analogous manner using the designated Intermediate Example 31 (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(4,4-difluoropiperidin-1-yl)propanamide
  • S 4,4-difluoropiperidine hydrochloride (173 mg, 1.1 mmol, 1.1 eq) in THF (10 mL) were added 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide (Intermediate 3) (298 mg, 1.0 mmol, 1.0 eq) and TEA (606 mg, 6.0 mmol, 6.0 eq).
  • the reaction was stirred for 15 h at 60 o C, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over Na 2 SO 4 and concentrated.
  • the product was purified by reverse phase column (XBridge Prep C 1 8 OBD), eluting with 42-60% AcCN in water (10 mm/L NH 4 HCO 3 ) to give 220 mg of product.
  • Examples 32-33 was synthesized in an analogous manner using the designated Intermediate.
  • Example 34 (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-hydroxypiperidin-1- yl)propanamide Step 1 To tert-butyl 4,4-difluoro-3-hydroxypiperidine-1-carboxylate (source: Shanghai AQBioPharma Co. Ltd ) (200 mg, 0.84 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL).
  • the first peak (16.220 min) was collected and further chirally separated (column: CHIRALPAK IA, 2x25 cm, 5 um, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH 3 in MeOH], Mobile Phase B: EtOH, A:B 7:3) to provide two peaks with retention times of 6.060 and 7.216 min.
  • Example 44 was synthesized in an analogous manner using the designated Intermediate Example 45a and 45b Ex.45a: (S)-N-(5-chloropyridin-2-yl)-2-((S)-4,4-difluoro-3-(trifluoromethyl)piperidin-1- yl)propanamide or Ex.45b: (S)-N-(5-chloropyridin-2-yl)-2-((R)-4,4-difluoro-3- (trifluoromethyl)piperidin-1-yl)propanamide Step 1 A mixture of 1-benzylpiperidin-4-one (10.0 g, 52.8 mmol, 1.0 eq), TEA (8.84 mL, 63.4 mmol, 1.2 eq), chlorotriethylsilane (9.56 g, 63.4 mmol, 1.2 eq) and sodium iodide (9.50 g, 63.4 mmol, 1.2 eq) in acet
  • Step 2 To a sealed tube containing trifluoromethyl iodide (6.45 g, 32.9 mmol, 10.0 eq) at -90 o C was added 1-benzyl-4-((triethylsilyl)oxy)-1,2,3,6-tetrahydropyridine (1.0 g, 3.29 mmol, 1.0 eq), acetonitrile (15.0 mL), Ru(bpy)3Cl2.6H2O (0.12 g, 0.16 mmol, 0.05 eq), sodium bicarbonate (0.55 g, 6.58 mmol, 2.0 eq) and H 2 O (0.09 mL, 4.94 mmol, 1.5 eq).
  • Step 4 A mixture of 1-benzyl-4,4-difluoro-3-(trifluoromethyl)piperidine (400 mg, 1.43 mmol, 1.0 eq), and Pd/C (152 mg, 10%) in MeOH (15.0 mL) was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The reaction was stirred 1 h at room temperature under an atmosphere of hydrogen (balloon) and filtered.
  • Step 5 A mixture of (R)-2-bromo-N-(5-chloropyridin-2-yl)propanamide (Intermediate 5) (374 mg, 1.42 mmol, 1.2 eq), 4,4-difluoro-3-(trifluoromethyl)piperidine HCl salt (268 mg, 1.20 mmol, 1.0 eq), TEA (1.98 mL, 14.19 mmol, 10.0 eq) and silver(I) nitrate (241 mg, 1.42 mmol, 1.0 eq) in DMA (4.0 mL) was stirred for 12 h at 40 o C, poured into H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3).
  • the first peak (4.301 min) was collected and further separated (column: CHIRALPAK IG, 20x250 mm, 5 um, flow rate: 20 mL/min, Mobile Phase A: [8 mM NH 3 in MeOH], Mobile Phase B: EtOH, A:B 95:5) to provide two peaks with retention times of 11.125 and 13.034 min.
  • Example 50a and 50b Ex.50a: (S)-2-((S)-3-amino-3-(trifluoromethyl)piperidin-1-yl)-N-(5-chloropyridin-2- yl)propanamide or Ex.50b: (S)-2-((R)-3-amino-3-(trifluoromethyl)piperidin-1-yl)-N-(5- chloropyridin-2-yl)propanamide Step 1 To methyl 3,3,3-trifluoro-2-oxopropanoate (10 g, 64 mmol, 1eq) in DCM (100 mL) was added NH 2 Boc (7.5 g, 64 mmol, 1eq).
  • Step 2 To methyl 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoro-2-hydroxypropanoate (11.4 g, 42 mmol, 1 eq) in diethyl ether (50 mL) was added trifluoroacetic anhydride (8.7 g, 42 mmol, 1 eq). After cooling to 0 o C for 1.5 h, pyridine (6.6 g, 84 mmol, 2 eq) was added slowly.
  • Step 3 To prop-2-yn-1-amine (10 g, 0.18 mol, 1 eq) and triethylamine (54 g, 0.54 mol, 3 eq) in DCM (200 mL) at 0 o C was added chlorotrimethylsilane (39 g, 0.36 mol, 2 eq), dropwise. The mixture was stirred 16 h at room temperature, quenched with water (300 mL) and extracted with ethyl acetate (200 mL x 3).
  • Step 4 To 1,1,1-trimethyl-N-(prop-2-yn-1-yl)-N-(trimethylsilyl)silanamine (8.3 g, 42 mmol, 1.2 eq) in THF (100 mL) at -78 o C was added n-BuLi (17 mL, 42 mmol, 2.5 M in hexane, 1.2 eq), dropwise. After 10 min, a solution of methyl (Z)-2-((tert-butoxycarbonyl)imino)- 3,3,3-trifluoropropanoate (9 g, 35 mmol, 1 eq) in THF (10 mL) was added dropwise.
  • Step 7 A mixture of 3-(trifluoromethyl)piperidin-3-amine (1.7 g, 10.1 mmol, 13 eq), (R)-2-bromo- N-(5-chloropyridin-2-yl)propanamide (Intermediate 5) (200 mg, 0.76 mmol, 1 eq) and triethylamine (230 mg, 2.3 mmol, 3 eq) in THF (5 mL) was stirred at 40 o C for 48 h, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3).
  • This material was chirally separated (column: CHIRALPAK IG, 20x250 mm, 5 um, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH 3 in MeOH], Mobile Phase B: EtOH, A:B 7:3) to provide two peaks with retention times of 6.745 and 8.605 min.
  • Example 52a and 52b Ex.52a: (S)-N-(5-chloropyridin-2-yl)-2-((S)-3,3-difluoro-4-hydroxypyrrolidin-1- yl)propanamide or Ex.52b: (S)-N-(5-chloropyridin-2-yl)-2-((R)-3,3-difluoro-4- hydroxypyrrolidin-1-yl)propanamide
  • Step 3 To benzyl 3-((2-oxoethyl)carbamoyl)piperidine-1-carboxylate (700 mg, 2.30 mmol, 1.0 eq) in dichloromethane (50 mL) was added Cl 3 CCCl 3 (1032 mg, 4.59 mmol, 2.0 eq), PPh 3 (1207 mg, 4.59 mmol, 2.0 eq) and TEA (4651 mg, 4.59 mmol, 2.0 eq).
  • Step 4 A mixture of benzyl 3-(oxazol-2-yl)piperidine-1-carboxylate (140 mg, 0.49 mmol, 1.00 eq) and Pd/C (10%, 70 mg) in methanol (10 mL) was stirred under hydrogen for 2 h, filtered and concentrated to give 2-(piperidin-3-yl)oxazole (70 mg, yield: 75%, purity: 80%) as a yellow oil, which was used without purification.
  • Step 5 To 2-(piperidin-3-yl)oxazole (70 mg, 0.5 mmol, 1.0 eq) and (R)-2-bromo-N-(5- chloropyridin-2-yl)propanamide (Intermediate 5) (121 mg, 0.5 mmol, 1.0 eq) in THF (10 mL) was added TEA (233 mg, 2.5 mmol, 5.0 eq). The reaction was stirred at 40 °C for 48 h, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3).
  • Example 54a and 54b Ex.54a: (S)-N-(5-chloropyridin-2-yl)-2-((R)-3-(oxazol-4-yl)piperidin-1-yl)propanamide or Ex.54b: (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(oxazol-4-yl)piperidin-1-yl)propanamide
  • Step 1 To 1-(piperidin-3-yl)ethan-1-one hydrochloride salt (1.00 g, 6.25 mmol, 1.0 eq) and TEA (3.10 g, 30.69 mmol, 5.0 eq) in DCM (50 mL) at 0 o C was added benzyl carbonochloridate (1.25 g, 7.50 mmol, 1.2 eq), dropwise. The resulting solution was stirred at room temperature for 16 h, poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3).
  • Step 3 A mixture of benzyl 3-(2-bromoacetyl)piperidine-1-carboxylate (500 mg, 1.47 mmol, 1.00 eq) and formamide (5 mL) was stirred at 90 o C for 1 h.
  • Step 4 A mixture of benzyl 3-(oxazol-4-yl)piperidine-1-carboxylate (180 mg, 0.67 mmol, 1.00 eq) and Pd/C (10%, 100 mg) in MeOH (15 mL) was stirred for 3 h under an atmosphere of hydrogen, filtered and concentrated to give 4-(piperidin-3-yl)oxazole (90 mg, yield: 90 %, purity: 95%) as yellow oil, which was used without purification.
  • Step 5 A mixture of 4-(piperidin-3-yl)oxazole (90 mg, 0.59 mmol, 1.0 eq), (R)-2-bromo-N-(5- chloropyridin-2-yl)propanamide (Intermediate 5) (155 mg, 0.59 mmol, 1.0 eq) and TEA (598 mg, 5.88 mmol, 10.0 eq) in THF (8 mL) was stirred for 18 h at 40 o C, quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3).
  • Example 56 (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(1H-1,2,4-triazol-5- yl)piperidin-1-yl)propanamide
  • Step 1 A mixture of 1-benzyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (20.0 g, 68.73 mmol, 1.0 eq) and TsOH (2 g, 11.6 mmol, 0.2 eq) and ethane-1,2-diol (22.0 g, 354.83 mmol, 5.0 eq) in toluene (500 mL) was heated to reflux under a Dean-Stark apparatus.
  • Step 2 To 8-benzyl 6-methyl 1,4-dioxa-8-azaspiro[4.5]decane-6,8-dicarboxylate (16.0 g, 47.80 mmol, 1.0 eq) in MeOH (300 mL) and H 2 O (150 mL) at 25 °C was added NaOH (5.73 g, 143.3 mmol, 3.0 eq). After 16 h, the organic solvent was removed under vacuum, and the reaction was diluted with water (100 mL). The pH was adjusted to 3 with 1 M HCl, and the mixture was extracted with ethyl acetate (300 mL x 2).
  • Step 3 To 8-((benzyloxy)carbonyl)-1,4-dioxa-8-azaspiro[4.5]decane-6-carboxylic acid (13.50 g, 42.10 mmol, 1.0 eq) in DMF (100 mL) at 25 o C was added HATU (19.19 g, 50.50 mmol, 1.2 eq) and DIEA (16.40 g, 127.2 mmol, 3.0 eq). After 30 min, NH 4 Cl (4.46 g, 84.20 mmol, 2.0 eq) was added.
  • Step 4 A mixture of benzyl 6-carbamoyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (13.20 g, 41.30 mmol, 1.0 eq) in DMF-DMA (250 mL) was stirred at 110 o C for 3 h, concentrated under vacuum, then dissolved in AcOH (200 mL). N2H4 ⁇ H2O (80 %, 15 mL) was added, and the reaction was stirred at 90 o C.
  • Step 5 To benzyl 6-(1H-1,2,4-triazol-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (10.0 g, 29.10 mmol, 1.0 eq) in DMF (100 mL) at 0 o C was added NaH (1.75 g, 43.70 mmol, 1.5 eq, 60%), in portions. After 30 min, benzyl chloride (5.44 g, 34.9 mmol, 1.2 eq) was added dropwise, and the resulting mixture was stirred at 25 o C.
  • Step 7 To benzyl 3-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)-4-oxopiperidine-1-carboxylate (5.80 g, 13.81 mmol, 1.0 eq) in DCM (100 mL) at 0 o C was added DAST (8.89 g, 55.24 mmol, 4.0 eq) in DCM (150 mL), dropwise. The reaction was stirred at room temperature overnight, quenched with ice water (150 mL) and exacted with DCM (150 mL x 2).
  • Step 8 A mixture of benzyl 4,4-difluoro-3-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)piperidine- 1-carboxylate (3.3 g, 7.46 mmol) and palladium hydroxide on carbon (5.24 g, 7.46 mmol) in methanol (60 mL) was stirred under hydrogen at 25°C for 2 h, filtered, concentrated and purified over C 1 8 silica (120 g column), eluting with 5-95% AcCN in water (10 mM NH4HCO3) to afford 4,4-difluoro-3-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)piperidine (1.7 g, 2.51 mmol, 33.7 % yield) as a colorless oil.
  • Step 2 To potassium tert-butoxide (2.70 g, 28.09 mmol, 2.5 eq) in THF (20 mL) was added tri- tert-butylphosphane (2.26 g, 1.12 mmol, 0.1 eq, 10 wt% in hexanes) and palladium (II) acetate (252 mg, 1.12 mmol, 0.1 eq). After 10 min, tert-butyl 4-oxopiperidine-1- carboxylate (3.35 g, 16.85 mmol, 1.5 eq) and 3-bromo-1-(4-methoxybenzyl)-1H-pyrazole (3.00 g, 11.23 mmol, 1.0 eq) were added.
  • Step 3 To tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-oxopiperidine-1-carboxylate (50.00 g, 129.87 mmol, 1.0 eq) in dichloromethane (400 mL) at 0 °C was added DAST (41.82 g, 259.74 mmol, 2.0 eq), dropwise, and the mixture was stirred at room temperature for 10 h. The reaction was quenched with water (500 mL) and extracted with dichloromethane (500 mL x 3).
  • Step 4 A solution of tert-butyl 4,4-difluoro-3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)piperidine- 1-carboxylate (450 mg, 1.11 mmol, 1.0 eq) in trifluoroacetic acid (10 mL) was stirred at 100 °C for 10 h. The solvent was removed to give 450 mg crude 4,4-difluoro-3-(1H- pyrazol-5-yl)piperidine TFA salt, as a yellow oil which was used without purification.
  • Examples 62-64 were synthesized in an analogous manner using the designated Intermediate in Step 5
  • Example 65 (S)-2-((S)-3-(1H-pyrazol-5-yl)piperidin-1-yl)-N-(5-(cyclopropylmethoxy)pyridin-2- yl)propanamide Step 1
  • DIPEA 1-(piperidin-3-yl)ethenone hydrochloride (2.0 g, 12.22 mmol) in THF (50 mL) at 0 °C)
  • DIPEA 5.34 mL, 30.6 mmol
  • benzyl carbonochloridate 1.919 mL, 13.44 mmol
  • Example 76 (2S)-2-(3-(1H-pyrazol-5-yl)piperidin-1-yl)-N-(5-(propylamino)pyridin-2-yl)propanamide Step 1 To 3-(1H-pyrazol-5-yl)piperidine (Example 65, Step 3 racemate) (95 mg, 0.626 mmol) and tert-butyl (R)-(6-(2-bromopropanamido)pyridin-3-yl)(propyl)carbamate (Intermediate 14) (220 mg, 0.570 mmol) in DMSO (4.0 mL) was added triethylamine (0.318 mL, 2.278 mmol).
  • Step 2 A mixture of tert-butyl (6-((2S)-2-(3-(1H-pyrazol-5-yl)piperidin-1- yl)propanamido)pyridin-3-yl)(propyl)carbamate (220 mg, 0.482 mmol) and TFA (4.0 mL, 51.9 mmol) was stirred for 1 hour, concentrated and made basic with sat. NaHCO 3 .
  • Step 1 To 1H-pyrazole-3-boronic acid (1.27 g, 11.11 mmol) and 3-bromo-5-methylpyridine (1.50 g, 8.55 mmol) in dioxane (68 mL) were added 1M aqueous cesium fluoride (3.93 g, 25.64 mmol), Pd 2 dba 3 (577 mg, 0.60 mmol), and S-Phos (537 mg, 1.28 mmol) under argon.
  • 1M aqueous cesium fluoride (3.93 g, 25.64 mmol
  • Pd 2 dba 3 577 mg, 0.60 mmol
  • S-Phos 537 mg, 1.28 mmol
  • Step 2 3-Methyl-5-(1H-pyrazol-5-yl)pyridine (240 mg, 1.51 mmol) was dissolved in MeOH (76 mL) and TFA (0.23 mL), and the mixture was hydrogenated using an H-Cube (70 mm CatCart of 5 % Rh/Al 2 O 3 , 100 °C, 50 bar, 0.5 mL/min). The collected material was concentrated, and the crude product was purified by prep HPLC (conditions not reported) to afford trans-3-methyl-5-(1H-pyrazol-5-yl)piperidine (145 mg, 58 %) as a yellow oil.
  • Example 78a and 78b Ex.78a: (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(1-(2- hydroxyethyl)-1H-pyrazol-3-yl)piperidin-1-yl)propanamide or Ex.78b: (S)-N-(5- (cyclopropylmethoxy)pyridin-2-yl)-2-((R)-4,4-difluoro-3-(1-(2-hydroxyethyl)-1H-pyrazol- 3-yl)piperidin-1-yl)propanamide Step 1 To (2S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(4,4-difluoro-3-(1H-pyrazol-3- yl)piperidin-1-yl)propanamide (Example 61) (490 mg, 1.21
  • This material was chirally separated (column: CHIRAL ART Cellulose - SB, 2 x 25 cm, 5 ⁇ m, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH3 in MeOH], Mobile Phase B: EtOH, A:B 9:1) to provide four peaks with retention times of 14.926, 17.919, 20.788 and 33.897 min.
  • Step 1 To 1H-pyrazole-3-boronic acid (1.27 g, 11.11 mmol) and 3-bromo-4-methylpyridine (1.50 g, 8.55 mmol) in dioxane (69 mL) were added 1M aqueous cesium fluoride (3.93 g, 25.64 mmol), Pd2dba3 (577 mg, 0.60 mmol), and S-Phos (537 mg, 1.28 mmol) under argon. The mixture was stirred in a pressure proof vessel for 16-20 hours at 100 °C, concentrated and purified by column chromatography, eluting with 0-5 % MeOH in CHCl3.
  • Example 80 (S)-2-((S)-3-(1H-pyrrol-2-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide Step 1 To tert-butyl 3-oxopiperidine-1-carboxylate (10 g, 50 mmol, 1.0 eq) in THF (200 mL) at - 78 o C was added LiHMDS (60 ml, 60 mmol, 1.2 eq, 1 M in tetrahydrofuran), dropwise.
  • LiHMDS 60 ml, 60 mmol, 1.2 eq, 1 M in tetrahydrofuran
  • HMPA HMPA (17.4 ml, 100 mmol, 2.0 eq) was added dropwise, followed after 15 min by dropwise addition of PhNTf2 (21.4 g, 60 mmol, 1.2 eq) in THF (80 mL). The temperature was increased to room temperature naturally, and the reaction mixture was stirred for 13 h, quenched with water (200 mL) and extracted with ethyl acetate (500 mL ⁇ 3).
  • Step 2 A mixture of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- carboxylate (5.5 g, 16.6 mmol, 1.0 eq), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (5.25 g, 24.9 mmol, 1.5 eq), Pd(dppf)Cl2 (1.22 g, 1.66 mmol, 0.1 eq) and Na2CO3 (3.52 g, 33.2 mmol, 2.0 eq) in dioxane (160 mL) and water (40 mL) was evacuated and flushed with nitrogen three times, stirred at 90 °C for 12 h, filtered, concentrated and diluted with water (100 mL).
  • Step 3 A mixture of tert-butyl 5-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (4 g, 11.5 mmol, 1.0 eq), tetrahydrofuran (20 mL) and CH 3 ONa (20 mL, 30% in methanol) was stirred for 1 h, concentrated, diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 4 A mixture of tert-butyl 5-(1H-pyrrol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 4.4 mmol, 1.0 eq), methanol (20 mL) and Pd(OH) 2 /C (110 mg, 0.2 eq) was evacuated and flushed three times with hydrogen, stirred 2 h under hydrogen, filtered, concentrated and purified over a silica gel column, eluting with methanol : dichloromethane (1:10) to give 673 mg (purity: 95%, yield: 61%) tert-butyl 3-(1H-pyrrol-2-yl)piperidine-1-carboxylate as a yellow solid.
  • Step 5 To tert-butyl 3-(1H-pyrrol-2-yl)piperidine-1-carboxylate (673 mg, 2.69 mmol, 1.0 eq) in DMF (15 mL) at 0 o C was added NaH (215 mg, 5.38 mmol, 2.0 eq, 60%). After 30 min, 4- methylbenzenesulfonyl chloride (615 mg, 3.23 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 2 h, quenched with water (20 mL) and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 6 A mixture of tert-butyl 3-(1-tosyl-1H-pyrrol-2-yl)piperidine-1-carboxylate (849 mg, 2.1 mmol, 1.0 eq), dichloromethane (8 mL) and TFA (2 mL) was stirred for 0.5 h and concentrated to give 606 mg (purity: 90%, yield: 95%) 5-(1-tosyl-1H-pyrrol-2-yl)-1,2,3,6- tetrahydropyridine as a yellow solid, which was used without purification.
  • Step 7 A mixture of 5-(1-tosyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (as a free base) (606 mg, 2 mmol, 1.0 eq), 2-bromo-N-(5-chloropyridin-2-yl)propanamide (Intermediate 5) (1.05 g, 4 mmol, 2.0 eq) and TEA (2.02 g, 20 mml, 10.0 eq) in tetrahydrofuran (10 mL) was stirred at 40 o C for 12 h, concentrated and purified over a silica gel column, eluting with ethyl acetate : petroleum ether (1: 2) to give 628 mg (purity: 95%, yield: 65%) N-(5- chloropyridin-2-yl)-2-(3-(1-tosyl-1H-pyrrol-2-yl)piperidin-1-yl)propanamide as
  • Step 8 A mixture of N-(5-chloropyridin-2-yl)-2-(3-(1-tosyl-1H-pyrrol-2-yl)piperidin-1- yl)propanamide (520 mg, 1.07 mmol, 1.0 eq) and TBAF (25 mL, 1M in tetrahydrofuran) was stirred at 50 o C for 72 h, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3).
  • the second peak (13.259 min) was collected and further chirally separated (column: CHIRAL PAK IF, 2x25cm, 5 um, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH 3 in MeOH], Mobile Phase B: EtOH, A:B 95:5) to provide two peaks with retention times of 10.904 and 12.886 min.
  • the second peak (12.886 min) was collected to give 20 mg (purity: 99%, yield: 5.6%) of (S)-2-((S)-3-(1H-pyrrol-2-yl)piperidin-1-yl)-N-(5- chloropyridin-2-yl)propanamide as a white solid.
  • Example 81a and 81b Ex.81a: (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(1-methyl-1H- pyrazol-3-yl)piperidin-1-yl)propanamide or Ex.81b: (S)-N-(5- (cyclopropylmethoxy)pyridin-2-yl)-2-((R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-3- yl)piperidin-1-yl)propanamide Step 1 To t-BuONa (3.16 g, 32.8 mmol, 2.5 eq) in THF (16 mL) at 25 o C were added (t-Bu)3P (10 % in hexane, 2.66 g, 1.32 mmol, 0.1 eq) and Pd(OAc) 2 (294 mg, 1.30 mmol,
  • Step 2 To tert-butyl 3-(1-methyl-1H-pyrazol-3-yl)-4-oxopiperidine-1-carboxylate (1 g, 4.36 mmol, 1.0 eq) in DCM (10 mL) at 0 o C was added DAST (1.40 g, 8.72 mmol, 2.0 eq), dropwise. The reaction was stirred for 18 h at room temperature, quenched with ice water (60 mL) and extracted with DCM (60 mL x 3).
  • Step 5 Benzyl 3-carbamoyl-5-methylenepiperidine-1-carboxylate (6.2 g, 22.6 mmol, 1.0 eq) in DMF-DMA (70 mL) was stirred for 3 hours at 110 o C and concentrated to give 6.3 g crude benzyl (E)-3-(((dimethylamino)methylene)carbamoyl)-5-methylenepiperidine-1- carboxylate as a yellow oil, which was used without purification.
  • Step 6 To benzyl (E)-3-(((dimethylamino)methylene)carbamoyl)-5-methylenepiperidine-1- carboxylate (6.3 g, 19.1 mmol, 1.0 eq) in AcOH (60 mL) was added N 2 H 4. H 2 O (80%, 6 mL), and the mixture was stirred at 90 o C. After 18 h, the reaction was concentrated, diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3).
  • Step 7 To benzyl 3-methylene-5-(1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (4.8 g, 16.1 mmol, 1.0 eq) in DMF (50 mL) at 0 o C was added NaH (60%, 966 mg, 24.2 mmol, 1.5 eq), in portions. After 30 min, benzyl chloride (3.8 g, 24.2 mmol, 1.5 eq) was added dropwise, and the reaction was stirred at room temperature. After 2 h, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3).
  • Step 8 A mixture of benzyl 3-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-5- methylenepiperidine-1-carboxylate (3.0 g, 7.17 mmol, 1.0 eq) and Pd/C (300 mg) in MeOH (30 mL) was stirred for 15 h under an H2 atmosphere, filtered and concentrated to give 2.0 g crude 3-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-5-methylpiperidine as yellow oil, which was used without purification. LCMS (m/z) 287 (M+H)+.
  • Step 9 To 3-(1-(4-Methoxybenzyl)-1H-1,2,4-triazol-5-yl)-5-methylpiperidine (2.0 g, 7.0 mmol, 1.0 eq) in THF (50 mL) were added (R)-2-Bromo-N-(5-fluoropyridin-2-yl)propanamide (Intermediate 4) (1.72 g, 7.0 mmol, 1.0 eq) and TEA (7.0 g, 70.0 mmol, 10.0 eq), and the mixture was stirred at 40 o C. After 72 h, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3).
  • the first peak (10.037 min) was collected further chirally separated (column: CHIRALPAK IG, 20x250 mm, 5 um, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH3 in MeOH], Mobile Phase B: EtOH, A:B 9:1) to provide two peaks with retention times of 15.100 and 18.300 min.
  • the first peak (15.100 min) was collected to give 20 mg (purity: 98.8%, yield: 2%) (S)-N-(5-fluoropyridin-2-yl)-2-((3S,5S)-3-methyl-5-(1H-1,2,4-triazol-5-yl)piperidin-1- yl)propanamide as white solid.
  • Step 3 A mixture of tert-butyl 5-(1H-pyrrol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.66 g, 6.69 mmol, 1.0 eq) and Pd(OH) 2 /C (200 mg, 20%) in MeOH (20 mL) was stirred for 15 h under an atmosphere of hydrogen, filtered and concentrated go give 1.24 g (purity: 40%, yield: 74%) of tert-butyl 3-(1H-pyrrol-3-yl)piperidine-1-carboxylate as a yellow solid, which was used without purification.
  • Step 6 A mixture of 3-(1-tosyl-1H-pyrrol-3-yl)piperidine (as free base) (527 mg, 1.73 mmol, 1.0 eq), 2-bromo-N-(5-chloropyridin-2-yl)propanamide (Intermediate 5) (454 mg, 1.73 mmol, 1.0 eq), TEA (1.40 g, 13.86 mmol, 8.0 eq) and KI (287 mg, 1.73 mmol, 1.0 eq) in THF (20 mL) was stirred for 15 h at 60 o C, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3).
  • Step 7 N-(5-Chloropyridin-2-yl)-2-(3-(1-tosyl-1H-pyrrol-3-yl)piperidin-1-yl)propanamide (240 mg, 0.49 mmol, 1.0 eq) in TBAF (20 mL, 1.0 mol/L in THF) was stirred for 35 h at 50 o C, quenched with NH4Cl (50 mL, aq., sat.) and extracted with ethyl acetate (50 mL x 3).
  • the first peak (5.126 min) was further chirally separated (column: CHIRAL PAK IG, 20x250 mm, 5 um, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH 3 in MeOH], Mobile Phase B: EtOH, A:B 85:15) to provide two peaks with retention times of 10.141 and 11.277 min.
  • the second peak (11.277 min) was collected to give 2.8 mg (purity: 99.7%, yield: 2%) of (S)-2-((R)-3-(1H- pyrrol-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide as a white solid.
  • Example 84 (2S)-N-(5-chloropyridin-2-yl)-2-(3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)piperidin-1- yl)propanamide Step 1 To 4-bromo-1H-pyrazole (2.00 g, 13.61 mmol) and 1-(chloromethyl)-4-methoxybenzene (2.77 g, 17.69 mmol) in DMSO (40 mL) was added K2CO3 (5.64 g, 40.8 mmol). After 4 hours, the mixture was diluted with water and extracted with DCM (3X).
  • Step 2 To tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1.5 g, 4.85 mmol), Na2CO3 (1.028 g, 9.70 mmol) and 4-bromo-1-(4- methoxybenzyl)-1H-pyrazole (1.944 g, 7.28 mmol) in water (5.00 mL) and dioxane (15.0 mL) was added PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.396 g, 0.485 mmol).
  • Step 3 To tert-butyl 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1.80 g, 4.87 mmol) in ethanol (10 mL) under N 2 was added Pd/C, 10% (0.052 g, 0.487 mmol).
  • Step 4 A mixture of tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate (1.52 g, 4.09 mmol) and TFA (5.0 mL, 64.9 mmol) was stirred at RT for 30 min, heated at 50 °C overnight, cooled to RT, concentrated and treated carefully with sat. NaHCO 3 until basic. The mixture was extracted with DCM (3X).
  • Step 1 To 3-(1H-1,2,4-triazol-5-yl)pyridine (1.0 g, 6.84 mmol) and potassium carbonate (1.891 g, 13.68 mmol) in DMF (25 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (2.427 mL, 13.68 mmol).
  • Step 2 To 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)pyridine (1.83 g, 6.62 mmol) in methanol (50 mL) was added acetic acid (0.758 mL, 13.24 mmol) followed by palladium hydroxide (20% on carbon) (2.324 g, 3.31 mmol). The reaction was evacuated and purged with hydrogen several times, then stirred overnight under a balloon of hydrogen. The mixture was filtered through Celite, concentrated, treated with 10% aq K 2 CO 3 (30 mL) and extracted with 15% IPA/DCM (2 x 80 mL).
  • Example 86 was synthesized in an analogous manner using the designated Intermediate in Step 3.
  • Example 87 (2S)-2-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide
  • Step 1 A mixture of benzyl 3-carbamoylpiperidine-1-carboxylate (2.0 g, 7.62 mmol) and 1,1- dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75 mmol) was heated at 100 °C for 3 h, concentrated and dissolved in acetic acid (10 mL).
  • Example 88a and 88b Ex.88a: (S)-2-((R)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-N-(5-chloropyridin-2- yl)propanamide or Ex.88b: (S)-2-((S)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-N-(5- chloropyridin-2-yl)propanamide Step 1 To 4-bromo-1H-pyrazole (2.00 g, 13.61 mmol) in THF (50 mL) was added NaH (0.653 g, 16.33 mmol).
  • Step 2 To tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1.50 g, 4.85 mmol), Na 2 CO 3 (1.028 g, 9.70 mmol) and 4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.017 g, 7.28 mmol) in water (5.00 mL) and dioxane (15.0 mL) was added PdCl2(dppf)-CH2Cl2adduct (0.396 g, 0.485 mmol).
  • Step 3 To tert-butyl 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.68 g, 4.43 mmol) in ethanol (10 mL) under N2 was added Pd/C, 10% (0.047 g, 0.443 mmol), and the mixture was hydrogenated under an H2 balloon overnight.
  • Step 4 A mixture of tert-butyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)piperidine-1-carboxylate (350 mg, 0.917 mmol) and TFA (3.0 mL, 38.9 mmol) was stirred for 3 hours and concentrated to afford 3-(1H-pyrazol-4-yl)piperidine, trifluoroacetic acid salt (243 mg, 0.916 mmol, 100 % yield) as a colorless wax, which was used without purification.
  • Step 1 To 2-(benzyloxy)-5-bromopyridine (1.00 g, 3.80 mmol, 1.0 eq) and tert-butyl 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.41 g, 4.56 mmol, 1.2 eq) in dioxane/water (50 mL, 4/1) were added Pd(dppf)Cl2 (621 mg, 0.85 mmol, 0.2 eq) and sodium carbonate (1.21 g, 11.40 mmol, 3.0 eq). The reaction was flushed with nitrogen and stirred at 60 o C.
  • Step 2 A mixture of tert-butyl 6'-(benzyloxy)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate (1.20 g, 3.28 mmol, 1.0 eq) and Pd/C (10%, 1.20 g) in methanol (15 mL) was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen.
  • Step 4 A mixture of [3,3'-bipiperidin]-6-one (as free base) (300 mg, 1.65 mmol, 1.0 eq), (R)-2- bromo-N-(5-chloropyridin-2-yl)propanamide (Intermediate 5) (522 mg, 1.98 mmol, 1.2 eq) and triethylamine (833 mg, 8.35 mmol, 5.0 eq) in tetrahydrofuran (20 mL) was stirred for 16 h at 40 o C, poured into water (80 mL) and extracted with ethyl acetate (80 mL x 3).
  • Step 2 To XtalFluor-E (199 g, 868 mmol) in DCM (585 mL) at -1.1 °C was slowly added a solution of triethylamine trihydrofluoride (140 g, 868 mmol) and pyridine (34.3 g, 434 mmol) in DCM (414 mL), followed by a solution of tert-butyl 3-(6-methoxypyridin-3-yl)- 4-oxopiperidine-1-carboxylate (133 g, 434 mmol) in DCM (794 mL).
  • Step 3 To a 48% aqueous solution of hydrobromic acid (40.9 mL, 361 mmol) was added a solution of tert-butyl 4,4-difluoro-3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (12.6 g, 38.4 mmol) in toluene (40 mL), dropwise. The reaction was stirred at 95 °C overnight, concentrated, taken up in 2-MeTHF (100 mL) and treated with a 3M solution of hydrochloric acid in cyclopentylmethyl ether (CPME) (130 mL).
  • CPME cyclopentylmethyl ether
  • the first-eluting isomer (3.981 min) was stirred in AcCN (250 mL) at 60 °C with activated charcoal (3 g) for 90 min. The mixture was filtered through Celite, concentrated, and the residue was triturated with AcCN to provide (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (2.568 g, 11.87 mmol, recovery: 31 %) as a light tan solid.
  • Step 4 (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (500 mg, 2.334 mmol) was dissolved in methanol (10 mL) and platinum(IV) oxide (106 mg, 0.467 mmol) was then added to the reaction. The reaction was purged with hydrogen and the hydrogenation was conducted with hydrogen balloon. The reaction was stirred at room temperature for 40 h. The reaction was filtered through Celite and solid was washed by methanol (3 X 10 mL).
  • Step 5 To a solution of (R)-2-bromo-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (Intermediate 17) (196 mg, 0.550 mmol) in DMA (2 ml) was added (S)-4',4'-difluoro-[3,3'- bipiperidin]-6-one (120 mg, 0.550 mmol) followed by TEA (0.230 mL, 1.650 mmol) and silver nitrate (187 mg, 1.100 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (10 mL) and then filtered to remove silver salts.
  • Step 2 XtalFluor-E (6210 mg, 27.1 mmol) was dissolved in Dichloromethane (DCM) (30 mL) and chilled with an ice batch. In an separate vial, triethylamine trihydrofluoride (4.42 mL, 27.1 mmol) and pyridine (1.097 mL, 13.56 mmol) were dissolved in Dichloromethane (DCM) (15 mL) and the mixture was then slowly added into reaction. The mixture was stirred in icebath for 20 min.
  • DCM Dichloromethane
  • tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4-oxopiperidine-1-carboxylate (5186 mg, 13.56 mmol) in Dichloromethane (DCM) (15 mL) was then slowly added to the reaction. The reaction was then stirred for 30 min with icebath and additional 3h at room temperature. The reaction was chilled in an icebath.100 mL sat. NaHCO3 solution was slowly added to reaction mixture, followed by 100 mL DCM. The ending point pH ⁇ 8. Layers were separated and aqueous layer was extracted by DCM (2 X 100 mL). The combined organic layer was washed by brine and dried over Na2SO4.
  • DCM Dichloromethane
  • Step 3 tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (1.16 g, 2.87 mmol) was dissolved in Methanol (15 mL) and Pd-C (0.305 g, 0.287 mmol) was then added to the reaction. The reaction was purged with hydrogen and the hydrogenation was conducted with hydrogen balloon. After one hour of reaction, LCMS showed all starting material was consumed and desired product was formed. The reaction was filtered through Celite and solid was washed by methanol (3 X 10mL).
  • Step 4 tert-butyl 4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate (460 mg, 1.463 mmol) and cesium carbonate (715 mg, 2.195 mmol) was dissolved in N,N- Dimethylformamide (DMF) (6.5 mL).2,2,2-trifluoroethyl trifluoromethanesulfonate (0.316 mL, 2.195 mmol) was then added to the reaction. The reaction was stirred at room temperature for 1h. The reaction was then diluted with EtOAc (100 mL) and the organic layer was washed with water (20 mL) and brine (20 mL).
  • DMF N,N- Dimethylformamide
  • Step 5 tert-butyl 4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3- yl)piperidine-1-carboxylate (330 mg, 0.833 mmol) was dissolved in Methanol (10 mL) and Pd-C (89 mg, 0.083 mmol) was then added to the reaction. The reaction was purged with hydrogen and the hydrogenation was conducted with hydrogen balloon. After one hour of reaction, LCMS showed all starting material was consumed and desired product was formed. The reaction was filtered through Celite and solid was washed by methanol (3 X 10mL).
  • Step 6 To tert-butyl 4,4-difluoro-6'-oxo-1'-(2,2,2-trifluoroethyl)-[3,3'-bipiperidine]-1-carboxylate (300 mg, 0.749 mmol) was added HCl in dioxane (3 mL, 12.00 mmol). After stirring at room temperature for 2h, The organic solvents were removed in vacuo to give 4',4'- difluoro-1-(2,2,2-trifluoroethyl)-[3,3'-bipiperidin]-6-one, Hydrochloride (250 mg, 0.742 mmol, 99 % yield). The product was used in next step without purification.
  • the mixture was stirred at rt overnight.
  • the reaction mixture was filtered to remove some silver salts.
  • the filtrate was diluted with EtOAc and washed with satd. K2CO3 solution.
  • the organic phase was washed 1x with a mix of satd. K2CO3 solution and brine, then dried over Na2SO4, filtered and concentrated.
  • the sample was purified by reverse phase C 1 8 AQ 100g Gold (Gradient 50% to 80% B over 19min, flow rate 60 mL/min, A: Water with 10mM Ammonium Bicarb and 0.075% Ammonium Hydroxide/B: Acetonitrile) and obtained (2S)-2-(4,4-difluoro-6'-oxo-1'-(2,2,2-trifluoroethyl)-[3,3'-bipiperidin]-1-yl)-N-(5-(2,4- difluorophenoxy)pyridin-2-yl)propanamide (107 mg, 0.180 mmol, 45.9 % yield) (mixture of 4 diastereomers).
  • Example 99 was synthesized in an analogous manner, using the designated Intermediate in Step 7.
  • Example 100a and 100b Ex.100a: (S)-2-((R)-3-(1H-pyrazol-1-yl)piperidin-1-yl)-N-(5-chloropyridin-2- yl)propanamide or Ex.100b: (S)-2-((S)-3-(1H-pyrazol-1-yl)piperidin-1-yl)-N-(5- chloropyridin-2-yl)propanamide
  • Step 1 To tert-butyl 3-hydroxypiperidine-1-carboxylate (3.00 g, 15.93 mmol, 1.0 eq) and TEA (2.26 g, 22.39 mmol, 1.5 eq) in DCM (100 mL) at 0 °C was added MsCl (1.87 g, 16.42 mmol, 1.1 eq), dropwise. The reaction was stirred at room temperature for 2 h, poured into water (300 mL) and extracted with dichloromethane (200 mL x 3).
  • Step 2 To 1H-pyrazole (975 mg, 14.29 mmol, 2.0 eq) and DMF (50 mL) at 0 °C was added NaH (60%, 516 mg, 12.9 mmol, 1.8 eq), in portions. The reaction was stirred at room temperature for 1 hour, then tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (200 mg, 7.14 mmol, 1.0 eq) in DMF (10 mL) was added. The mixture was stirred at 100 °C for 16 h, poured into water (400 mL) and extracted with ethyl acetate (300 mL x 3).
  • Step 3 A mixture of tert-butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate (300 mg, 1.36 mmol, 1.0 eq), dichloromethane (9 mL) and TFA (3 mL) was stirred at rt for 2 h and concentrated to give 3-(1H-pyrazol-1-yl)piperidine as a yellow solid, which was used without purification.
  • Step 4 A mixture of 3-(1H-pyrazol-1-yl)piperidine (as free base) (90 mg, 0.6 mmol, 1.0 eq), (R)- 2-bromo-N-(5-chloropyridin-2-yl)propanamide (Intermediate 5) (156 mg, 0.6 mmol, 1.0 eq) and TEA (301 mg, 3.0 mmol, 5.0 eq) in THF (10 mL) was stirred at 40 °C for 24 h, poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3).
  • Example 101a and 101b Ex.101a: (S)-2-((R)-3-(2H-1,2,3-triazol-2-yl)piperidin-1-yl)-N-(5-chloropyridin-2- yl)propanamide or Ex.101b: (S)-2-((S)-3-(2H-1,2,3-triazol-2-yl)piperidin-1-yl)-N-(5- chloropyridin-2-yl)propanamide Step 1 To DMF (10 mL) and NaH (60%, 240 mg, 6.00 mmol, 1.0 eq) was added 2H-1,2,3-triazole (412 mg, 5.97 mmol, 1.0 eq).
  • tert-butyl 3-((methylsulfonyl)oxy)piperidine- 1-carboxylate (Example 100, Step 1) (2.00 g, 7.17 mmol, 1.2 eq) in DMF (3 mL) was added dropwise, and the reaction was stirred at 60 o C. After 20 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3).
  • Step 1 To 1H-pyrazole-3-boronic acid (1.17 g, 10.25 mmol) and 3-bromo-2-methylpyridine (1.50 g, 8.55 mmol) in dioxane (68 mL) were added 1M aqueous cesium fluoride (3.28 g, 21.36 mmol), Pd2dba3 (412 mg, 0.43 mmol), and S-Phos (358 mg, 0.85 mmol), under argon. The mixture was stirred in a pressure-proof vessel for 16-20 hours at 100 °C, diluted with water and extracted with DCM.
  • Example 103 (S)-N-(5-chloropyridin-2-yl)-2-((2S,3R)-2-methyl-3-(1H-pyrazol-5-yl)piperidin-1- yl)propanamide and (S)-N-(5-chloropyridin-2-yl)-2-((2R,3S)-2-methyl-3-(1H-pyrazol-5- yl)piperidin-1-yl)propanamide (1:1 mix.) Step 1 2-Methyl-3-(1H-pyrazol-5-yl)pyridine (Example 102, Step 1) (893 mg, 5.61 mmol) in MeOH (56 mL) and TFA (0.87 mL) was hydrogenated using an H-Cube (70 mm CatCart of 10 % Pd/C, 80 °C, 50 bar, 1 mL/min).
  • Step 1 To 1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (5.0 g, 18.99 mmol) in acetonitrile (60 mL) was added CDI (3.70 g, 22.79 mmol), in portions. After 1 h, potassium 3-ethoxy- 3-oxopropanoate (3.23 g, 18.99 mmol) and magnesium chloride (1.808 g, 18.99 mmol) were added, and the resulting mixture was stirred overnight, concentrated, diluted with water, neutralized with citric acid and extracted with EtOAc (3X).
  • Step 2 To benzyl 3-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (4.86 g, 14.58 mmol) in ethanol (60 mL) was added hydrazine monohydrate (1.095 g, 21.87 mmol), slowly, and the mixture was stirred overnight and concentrated. The residue was purified via normal phase chromatography (Combiflash Rf, 120 g silica column), eluting with 30-90% EtOAc in DCM to afford benzyl 3-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1-carboxylate (3.69 g, 12.25 mmol, 84 % yield) as a colorless oil.
  • Step 3 To benzyl 3-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1-carboxylate (800 mg, 2.65 mmol) in ethanol (30 mL) under N 2 was added Pd/C, 10% (28.3 mg, 0.265 mmol), and the mixture was hydrogenated under an H2 balloon overnight. The reaction was filtered through Celite and concentrated to afford 5-(piperidin-3-yl)-1H-pyrazol-3-ol (416 mg, 2.488 mmol, 94 % yield) as an off white solid, which was used without purification. LCMS (ES, m/s): 168 [M+H] + .
  • Step 4 To 5-(piperidin-3-yl)-1H-pyrazol-3-ol (170 mg, 1.015 mmol) and (R)-1-((5-chloropyridin- 2-yl)amino)-1-oxopropan-2-yl 4-methylbenzenesulfonate (Intermediate 23) (300 mg, 0.846 mmol) in DMSO (4.0 mL) was added DIEA (0.591 mL, 3.38 mmol). After 2 days, the mixture was diluted with water and extracted with EtOAc (3 X).
  • Example 105 (2S)-N-(5-chloropyridin-2-yl)-2-(3-(4-methyl-1H-pyrazol-5-yl)piperidin-1-yl)propanamide 670 7 Step 1 To 1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (5.5 g, 20.89 mmol), N,O- dimethylhydroxylamine hydrochloride (2.445 g, 25.07 mmol), HOBt (4.80 g, 31.3 mmol) and DIEA (10.95 mL, 62.7 mmol) in THF (100 mL) at 0 °C was added EDC (6.01 g, 31.3 mmol), in portions.
  • Step 2 To benzyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (6.05 g, 19.75 mmol) in THF (80 mL) at -78 °C was added ethylmagnesium bromide (3.0 M in ether, 7.90 mL, 23.70 mmol), dropwise, and the mixture was allowed to warm up to RT. After 1 hour, the reaction was quenched with sat. NH4Cl and extracted with EtOAc (3 X).
  • Step 3 To benzyl 3-propionylpiperidine-1-carboxylate (4.91 g, 17.83 mmol) in DMF (40 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (6.37 g, 53.5 mmol), and the mixture was heated at 140 °C for 6 h, then concentrated. The residue was dissolved in ethanol (40.0 mL), and con. HCl (1.0 mL, 11.85 mmol) was added dropwise. After 10 min, hydrazine monohydrate (1.749 mL, 35.7 mmol) was added. The reaction was refluxed overnight, cooled to RT, concentrated, diluted with water and extracted with EtOAc (3 X).
  • Step 5 To 3-(4-methyl-1H-pyrazol-5-yl)piperidine (138 mg, 0.835 mmol) and (R)-2-bromo-N-(5- chloropyridin-2-yl)propanamide (Intermediate 5) (200 mg, 0.759 mmol) in DMSO (4.0 mL) was added triethylamine (0.423 mL, 3.04 mmol). The mixture was stirred overnight, diluted with water and extracted with EtOAc (3 X).
  • Example 106 (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-methyl-3-(1H-pyrazol-5-yl)piperidin-1- yl)propanamide Step 1 To ethyl piperidine-3-carboxylate (6.0 g, 38.2 mmol) and sodium bicarbonate (12.82 g, 153 mmol) in THF (120 mL) and water (60 mL) at 0 °C was added Cbz-Cl (8.17 mL, 57.2 mmol), dropwise. After stirring at RT overnight, the mixture was diluted with water and extracted with EtOAc (3 X).
  • Step 3 To 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (9.2 g, 30.1 mmol) in methanol (90 mL) and water (30.0 mL) was added LiOH (1.443 g, 60.3 mmol). After 1 h, the mixture was diluted with water, the MeOH was removed, and the pH was adjusted to approximately 3-4 with 2N HCl.
  • Step 4 To 1-((benzyloxy)carbonyl)-3-methylpiperidine-3-carboxylic acid (5.5 g, 19.83 mmol), N,O-dimethylhydroxylamine hydrochloride (2.322 g, 23.80 mmol), HOBt (4.56 g, 29.7 mmol) and DIEA (10.39 mL, 59.5 mmol) in THF (80 mL) at 0 °C was added EDC (5.70 g, 29.7 mmol), in portions. The mixture was allowed to warm to RT overnight, diluted with water and extracted with EtOAc (3 X).
  • Step 5 To benzyl 3-(methoxy(methyl)carbamoyl)-3-methylpiperidine-1-carboxylate (5.16 g, 16.11 mmol) in THF (50 mL) at -78 °C was added methylmagnesium bromide in 2-Me-THF (approximately 3.4 M, 5.68 mL, 19.33 mmol), dropwise, and the reaction was allowed to warm to RT. After 1 hour, the mixture was quenched with sat. NH 4 Cl and extracted with EtOAc (3 X).
  • Step 6 To benzyl 3-acetyl-3-methylpiperidine-1-carboxylate (2.78 g, 10.10 mmol) in DMF (20 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (3.61 g, 30.3 mmol). The mixture was heated at 140 °C for 6 hours and concentrated. The residue was dissolved in ethanol (20 mL), and conc. HCl (0.6 mL, 7.11 mmol) was added dropwise. After 10 min, hydrazine monohydrate (4.95 mL, 101 mmol) was added, and the resulting mixture was refluxed overnight, then concentrated. The residue was diluted with water and extracted with EtOAc (3 X).
  • Step 7 To benzyl 3-methyl-3-(1H-pyrazol-5-yl)piperidine-1-carboxylate (1.56 g, 5.21 mmol) in ethanol (20 mL) under N 2 was added Pd/C, 10% (0.055 g, 0.521 mmol), and the mixture was hydrogenated under an H 2 balloon overnight. The reaction was filtered through Celite, washed with EtOH, and concentrated to afford 3-methyl-3-(1H-pyrazol-5-yl)piperidine (0.865 g, 5.23 mmol, 100 % yield) as colorless oil. LCMS (ES, m/s): 166 [M+H]+.
  • Step 8 To 3-methyl-3-(1H-pyrazol-5-yl)piperidine (142 mg, 0.860 mmol) and (R)-1-((5- chloropyridin-2-yl)amino)-1-oxopropan-2-yl 4-methylbenzenesulfonate (Intermediate 23) (305 mg, 0.860 mmol) in DMSO (6 mL) was added DIEA (0.300 mL, 1.719 mmol). After 2 days, the mixture was diluted with water and extracted with EtOAc (3 X).
  • Step 2 To benzyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.0 g, 6.84 mmol) in THF (30 mL) at -78 °C was added methylmagnesium bromide in 2-Me-THF (approximately 3.4 M, 2.57 mL, 8.21 mmol), dropwise, and the reaction was allowed to warm to RT. After 1 hour, the mixture was quenched with sat. NH 4 Cl and extracted with EtOAc (3 X).
  • Step 4 To benzyl 3-(1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (1.05 g, 3.87 mmol) in ethanol (20 mL) under N2 was added Pd/C, 10% (0.041 g, 0.387 mmol), and the mixture was hydrogenated under an H 2 balloon overnight. The reaction was filtered through Celite, washed with EtOH, and concentrated to afford 5-(pyrrolidin-3-yl)-1H-pyrazole (520 mg, 3.79 mmol, 98 % yield) as colorless oil. LCMS (ES, m/s): 138 [M+H]+.
  • Example 108a and 108b Ex.108a: (S)-N-(5-chloropyridin-2-yl)-2-((R)-2- (trifluoromethyl)morpholino)propanamide or Ex.108b: (S)-N-(5-chloropyridin-2-yl)-2- ((S)-2-(trifluoromethyl)morpholino)propanamide
  • the first peak (5.256 min) was collected and further chirally separated (column: CHIRALPAK IG, 2x25 cm, 5 um, flow rate: 20 mL/min, Mobile Phase A: Hex [8 mM NH3 in MeOH], Mobile Phase B: EtOH, A:B 9:1) to provide two peaks with retention times of 6.608 and 7.240 min.
  • Example 109 (S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-morpholinopropanamide (R)-2-bromo-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (Intermediate 17) (110 mg, 0.308 mmol) and silver nitrate (52.3 mg, 0.308 mmol) were dissolved in N,N- Dimethylformamide (DMF) (3 mL) at RT. Then added morpholine (0.040 mL, 0.462 mmol) and TEA (0.064 mL, 0.462 mmol).
  • DMF N,N- Dimethylformamide
  • Examples 110-113 were synthesized in an analogous manner using the designated amine.
  • 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.
  • FLIPR TETRA Molecular Devices
  • An activation dose response curve was produced for Cortistatin-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 – 113 inhibited MRGPRX2 activation in the above method with a pIC50 value between approximately 5 and 9.4.
  • Biological Data The exemplified compounds were tested according to the FLIPR TETRA assay described above and were found to be MrgX2 antagonists with pIC50 > 5.
  • the compounds of examples 1-113 exhibited a pIC50 between 5 and 9.4.
  • Examples 8, 24, 30, 33, 49, 57, 61, 77, 92, 94, 95, 98 and 111 exhibited a pIC50 ⁇ 8.0.

Abstract

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