Substituted amine compounds, compositions and methods of use

Abstract

The present disclosure provides compounds that are useful for the treatment of conditions mediated by MRGPRX2. Also provided are pharmaceutical compositions containing such compounds, and methods of treatment using such compounds.

Description

Substituted Amine Compounds, Compositions and Methods of Use Field of Invention

[0001] The present disclosure provides compounds that modulate MRGPRX2 and are therefore useful for the treatment of conditions, diseases and / or disorders mediated by MRGPRX2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such. Background

[0002] Mas-related G-protein coupled receptor member X2 is a protein that, in humans, is encoded by the MRGPRX2 gene and is most abundant on cutaneous mast cells.

[0003] Agonists are gyrase inhibitors like ciprofloxacin and non-depolarizing neuromuscular blocking agents like atracurium as well as vancomycin. Activation of MRGPRX2 leads to mast cell degranulation with subsequent pseudo-allergic reactions.

[0004] Mature mammalian 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. Classically, mast cells are 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 (Nature Immunology, 6, 135-142 (2005)).

[0005] Recent work has emphasized the role of the Mas-related G protein-coupled receptor (MRGPR) family, specifically, Mrgprb2, in mast cell activation (Nature, 519, 237-241 (2015)). Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2 (Adv. Immunol., 136, 123-62 (2017)). To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain populations of mast cells (Nature Immunology, 2517, 878-887 (2016); Annu. Rev. Immunol., 38, 49-77 (2020)). This knowledge provides the opportunity to target mast cell degranulation in a very precise manner.

[0006] WO 2022 / 073904 discloses MrgX2 amide antagonists useful for treating MrgX2 mediated diseases such as urticaria and atopic dermatitis. WO2022 / 152852, WO2022 / 152853 and WO2022 / 073905 also disclose MrgX2 amide antagonists useful for treating MrgX2 mediated diseases. WO2021 / 092262 discloses MRGPRX2 antagonists, typically amides, useful for the treatment of inflammatory conditions such as atopic dermatitis.

[0007] In summary, 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 disease conditions and autoimmune disease conditions. Thus, there is a need and a continuing search in this field of art for new therapies. Summary

[0008] The present invention relates to compounds of Formula (I), as described herein including stereochemical isomeric forms thereof and pharmaceutically acceptable salts thereof, which may be useful for mediating MRGPRX2 and / or treating or preventing MRGPRX2 mediated conditions and diseases. More specifically, in some embodiments, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein the “ * ” at the carbon to which Rdand Rd*are bonded is a first stereo center when Rdand Rd*are different; Z2is CH2or wherein the wavy lines represent the points of attachment of the Z2group to the Xh*and the -CH2of the 6-membered ring; wherein the “ * ” at the carbon atom in Z2designates a second stereocenter; with the proviso that when Z2is - CH2, then Ring A is not a thiazolyl; Ring B is a 6-membered aryl or 5- or 6-membered heteroaryl group; each R is independently selected from hydrogen, CN, SF5, halo, (C1-C6)alkyl, -(C0-C6)alkyl- NH2, -(C0-C6)alkyl-NH((C1-C6)alkyl), -(C0-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -(C0- C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, 5- or 6-membered heteroaryl(C1-C4)alkyl-, (C2- C6)alkenyl, -(C2-C6)alkenyl-(C3-C8)cycloalkyl, -OH, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3- C8)cycloalkyl, -O-(C1-C6)alkyl-aryl, -O-(C1-C6)alkyl-5-6 membered heteroaryl, -O-(C2- C6)alkenyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1- C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, or 5-6 memberedheteroaryl, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, 5-6 membered heteroaryl, -C(O)-aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, -OH, (C1-C6)alkyl, (C1- C4)alkoxy, (C3-C8)cycloalkyl, -(C1-C6)- OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halo, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, or (C1- C4)alkoxy; n is 0 or an integer from 1 to 5; L1is C(Rc)(Rc*), O, SO2or C(O); each of Rcand Rc*is independently H, D, halo, (C1-C6)alkyl, or (C2-C6)alkenyl; or Rcand Rc*taken together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; Ring A is a 5-membered arylene or a 5-membered heteroarylene group; each R* is independently selected from hydrogen, OH, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1- C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH; or two R*groups taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halo, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; n* is 0 or an integer from 1 to 3; or one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6-membered ring fused to Ring A; L2is -C(O)- or wherein the wavy line represents the points of attachment to the NH and the C(Rd)(Rd*) groups;Rdand Rd*are each independently H or (C1-C3)alkyl, or (C1-C3)alkoxy, or Rdand Rd*cyclize to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; Xhand Xh*are each independently C(Re) 2, N(Re), or O; Xgis CH or N; each Reis independently H, halo, (C1-C3)alkyl, halo(C1-C3)alkyl, or (C1-C3)alkoxy, or any two Regroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n** is 0 or an integer from 1 to 8; Xjis N, NRf, C(Rf)2, C(Rf) or CH; Xeis N, NRf, C(Rf)2or C(Rf); Xfis SO2, N, C-(halo(C1-C3)alkyl), C-(C1-C3)alkyl, C=O or N+-O-; ------- represents a double or single bond as needed to satisfy atom valences; each Rfis independently H or halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, -(C1- C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl), -(C1-C6)alkyl-NH((C1-C6)alkyl)- OH, - (C1-C6)alkyl-NH((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1- C6)alkyl)- OH, -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3- C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-4- to 6- membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl- SO2-(C1- C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1- C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), - C(O)N(C1-C6)alkyl) (C1-C6)alkyl), -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), - SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any said (C1-C6)alkyl, (C3- C8)cycloalkyl, -(C1-C6)alkyl-OH, - (C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1- C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1- C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halo, OH, or any two Rfgroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n^ is 0 or an integer from 1 to 4.

[0009] Also provided herein, in some embodiments, are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0010] Further provided herein, in some embodiments, are methods of modulating MRGPRX2 activity; and / or methods of modulating mast cell degranulation, and / or methods of treating, preventing or ameliorating an MRGPRX2-mediated disease or disorder in a subject in needthereof, wherein each of these methods independently comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or administering an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0011] Further provided herein, in some embodiments, are methods for treating, preventing or ameliorating a disease or conditions chosen from chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, Asian atopic dermatitis, European atopic dermatitis, rosacea, autoimmune diseases, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, endometriosis, nasal polyps, neuropathic pain, inflammatory pain, pseudo-allergic drug reactions, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, esophagus reflux, asthma, cough, migraine, sinusitis, urticaria, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, contact urticaria, lupus erythematosus (SLE), psoriasis, psoriatic arthritis, bronchial asthma, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain, preferably wherein the condition is atopic dermatitis.

[0012] Also provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. In some embodiment the compound is for use in treating disease or disorder mediated by MRGPRX2.

[0013] Also provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a MRGPRX2-mediated disease or disorder. Brief Description of the Drawings

[0014] Figure 1A shows the experimental X-ray powder diffraction (XRPD) pattern of a crystalline sample of Compound 489.

[0015] Figure 1B is a table of the characteristic peaks in the XRPD pattern of Compound 489 in Figure 1A. Angle [2Th] refers to the two-theta degree position on the x-axis for certain peaks and Rel Intensity [%] refers to the relative intensity shown on the y-axis of the peak, and d Value [Å] refers to the interplanar spacing in angstroms.

[0016] Figure 2A shows the asymmetric unit of Compound 489 as determined by micro electronic diffraction (MicroED) with hydrogen bonds shown as dashed lines.

[0017] Figure 2B shows the results of MicroED structure determination.Detailed Description

[0018] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.

[0019] “Alkyl” means a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms. The term “(C1-C6)alkyl” 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. and the like.

[0020] “Alkenyl” means a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms and at least one carbon-carbon double bond. The term “(C1- C6)alkenyl” refers to an alkenyl moiety containing from 1 to 6 carbon atoms. Exemplary alkenyls include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n -butenyl, isobutenyl, s-butenyl, t-butenyl, pentenyl, and hexenyl. and the like.

[0021] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. The term “(C1-C4)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.

[0022] When the term “alkyl” is used in combination with other substituent groups, such as “halo(C1-C4)alkyl”, “aryl(C1-C4)alkyl-”, or “ (C1-C4)alkoxy(C1-C4)alkyl-”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety. The term “halo(C1-C4)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. Examples of “halo(C1-C4)alkyl” groups useful in the present invention include, but are not limited to, -CF3(trifluoromethyl), -CCI3 (trichloromethyl), 1,1 - difluoroethyl, 2-fluoro-2- methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Examples of “aryl(C1-C4)alkyl” or “phenyl(C1-C4)alkyl” groups useful in the present invention include, but are not limited to, benzyl and phenethyl. Examples of “(C1- C4)alkoxy(C1-C4)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-butoxy ethyl, and t-butoxyisopropyl.

[0023] As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. The term (C3-C8)cycloalkyl”refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary “(C3-C8)cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0024] As used herein, “heterocycloalkyl” represents a group or moiety comprising a nonaromatic, monovalent monocyclic radical, which is saturated or partially unsaturated and includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. The term “4- to 6-membered heterocycloalkyl” refers to a heterocycloalkyl group containing 4, 5, or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 4- to 6- membered heterocycloalkyl groups useful in the present invention include, but are not limited to azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3 -oxathiol any 1, 1,3-oxathianyl, 1,3-dithianyl, 1,4- oxathiolanyl, 1,4-oxathianyl, and 1,4-dithianyl. As used herein, “amino” refers to primary, secondary and tertiary nitrogen containing groups.

[0025] “Halo” means fluoro, chloro, bromo, or iodo; in one embodiment fluoro or chloro.

[0026] As used herein, “aryl” refers to monovalent optionally substituted monocyclic, fused bicyclic, or fused tricyclic groups having 6 to 16 carbon atoms and having at least one aromatic ring that complies with Huckel’s Rule. Examples of “aryl” groups are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like. This term also encompasses bicyclic and tricyclic aryl compounds containing an aryl ring moiety fused to a cycloalkyl ring moiety, containing 5 to 16 ring atoms. As used herein, “arylene” refers to a bivalent aryl group.

[0027] “Heteroaryl” represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, or tricyclic radical containing 5 to 16 ring atoms, including 1 to 6 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic and tricyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 16 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups 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, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl,indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8- naphthyridinyl, and pteridinyl. 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. Examples of 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. Examples of 6,5- fused “heteroaryl” groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl. Examples of 10- to 16- membered tricyclic heteroaryl group include [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazole groups, and the like.

[0028] As used herein, “5- or 6-membered heteroaryl” represents 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. Illustrative examples of 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. As used herein, “heteroarylene” refers to a bivalent heteroaryl group.

[0029] “Oxo” means an =(O) group where the oxygen is bound to any atom and “carbonyl” means a >C(O) or >C=O or C=O group.

[0030] “Mammal” as used herein means domesticated animals (such as dogs, cats, and horses), and humans. In one embodiment, mammal is a human.

[0031] It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridyl” means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl, and so forth.

[0032] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. It is understood that the pharmaceutically acceptable salts are non-toxic. For a review on suitable salts, see Handbook of Pharmaceutical Salts. Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Additional information on suitable pharmaceutically acceptable salts can be found in Remington The Science and Practice of Pharmacy, 23rd ed., Elsevier Science, 2020, which is incorporated herein by reference.

[0033] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocycloalkyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is substituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with alkyl.

[0034] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0035] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0036] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0037] “Treating” or “treatment” of a disease includes: (1) preventing the disease, e.g., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0038] A “therapeutically effective amount” means the amount of a compound of Formula (I) (or any of the embodiments thereof described herein), that, when administered to a mammal for treating a disease, is sufficient to treat the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0039] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry orisomeric form is specifically indicated. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, optically enriched, optically pure, or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Those skilled in the art are familiar with methods for determining absolute stereochemistry e.g., X-Ray powder diffraction. Stereoisomers may also be obtained by stereoselective synthesis into their compounding pure enantiomers by forming a diastereomeric salt with an optically pure chiral base or acid (e.g., 1-phenyl-ethylamine or tartaric acid) and separating the diastereomers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers.

[0040] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof may exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this disclosure. For example, pyrazole tautomers as shown below are equivalent structures. The depiction of one such structure is intended to encompass both structures.

[0041] Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as heteroaryl, heterocyclyl are substituted, they include all the positional isomers.

[0042] The compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof. The term solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and the like.

[0043] The term hydrate is employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g., D2O. d-acetone, d-DMSO. The solvates and / or hydrates preferably exist in crystalline form. A classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0044] The present disclosure also includes the prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof. The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) (or any of the embodiments thereof described herein) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups, however, regenerate original functional groups in vivo or by routine manipulation. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof are also within the scope of this disclosure.

[0045] Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The compounds of the invention may also exist as complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and / or inorganic components which may be in stoichiometric or non-stoichiometric amounts. Theresulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0046] The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins.

[0047] The present disclosure also includes polymorphic forms (amorphous as well as crystalline).

[0048] The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0049] Certain compounds of the present invention or combination agents may exist in more than one crystal form (generally referred to as “polymorphs”). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast colling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

[0050] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0051] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure. For example, compounds of the present invention wherein L1is methylene and a hydrogen is replaced by deuterium is envisioned.

[0052] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0053] In certain embodiments, the compounds disclosed herein have some or all of the 1Hatoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0054] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0055] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0056] Also included within the scope of the invention are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include (i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH3-> -CH2OH): (ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NRR -> -NHR or -NHR); (iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2); (v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and (vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2-> COOH).

[0057] In one aspect, provided here is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: (A) wherein Z1is a 10- to 16-membered tricyclic aryl or heteroaryl group substituted with 0, 1, 2 or 3 R groups, or , wherein the wavy line represents the point of attachment of the Z1group to the NH group; Z2is CH2or wherein the wavy lines represents the points of attachment of the Z2group to the 6-membered ring;Ring B is a 5- or 6-membered aryl or heteroaryl group; each R is independently selected from hydrogen, CN, SF5, halogen, (C1-C6)alkyl, -(C0-C6)alkyl- NH2, -(C0-C6)alkyl-NH((C1- C6)alkyl), -(C0-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -(C0- C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, 5- or 6-membered heteroaryl(C1-C4)alkyl-, (C2- C6)alkenyl, -(C2-C6)alkenyl-(C3-C8)cycloalkyl, -OH, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3- C8)cycloalkyl, -O-(C1-C6)alkyl-aryl, -O-(C1-C6)alkyl-5-6 membered heteroaryl, -O-(C2- C6)alkenyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1- C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, or 5-6 membered heteroaryl, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, (C1- C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, 5-6 membered heteroaryl, -C(O)-aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, -OH, (C1-C6)alkyl, (C1- C4)alkoxy, (C3-C8)cycloalkyl, -(C1-C6)- OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1-C6)alkyl), -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, or (C1- C4)alkoxy; n is 0 or an integer from 1 to 5; L1is CRcRc*, O, SO2or C(O); each of Rcand Rc*is independently H, deuterium, halo, (C1-C6)alkyl, or (C2-C6)alkenyl; or Rcand Rc*taken together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7- membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3- C8)cycloalkyl; Ring A is a 5-membered arylene or heteroarylene group; each R* is independently selected from hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C2- C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1- C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1- C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH; or two R*groups taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; n* is 0 or an integer from 1 to 3; or one of Rcor Rc*and R* taken together with the atom to which they are bound, fuse together to form a 3- to 6- membered ring; L2is -C(O)- or wherein the wavy line represents the points of attachment to the NH and the C RdRd*groups; Rdand Rd*are each independently H or (C1-C3)alkyl, or (C1-C3)alkoxy, or Rdand Rd*cyclize to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; Xhand Xh*are each independently CH2, NH, or O; Xgis CH or N; each Reis independently halo, (C1-C3)alkyl, halo(C1-C3)alkyl, or (C1-C3)alkoxy, or any two Regroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n** is 0 or an integer from 1 to 8; Xeis N, NH, CH2or CH; Xfis SO2, N, C-(halo(C1-C3)alkyl), C-(C1-C3)alkyl, C=O or N+-O-; ------- represents a double or single bond as needed to satisfy atom valences; each Rfis independently H or halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, -(C1- C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl), -(C1-C6)alkyl-NH((C1-C6)alkyl)- OH, - (C1-C6)alkyl-NH((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1- C6)alkyl)- OH, -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3- C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-4- to 6- membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1- C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1- C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), - C(O)N(C1-C6)alkyl) (C1-C6)alkyl), - NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), - SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any said (C1-C6)alkyl, (C3- C8)cycloalkyl, -(C1-C6)alkyl-OH, - (C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1- C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1- C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen, or any two Rfgroups, on the same ring atom or on adjacent ring atoms, cyclize to forma 3 to 6 membered fused or spiro ring; n^ is 0 or an integer from 1 to 4.

[0058] In one aspect, provided here is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: (B) wherein the “ * ” at the carbon to which Rdand Rd*are bonded represents a first stereo center; wherein Z1is a monocyclic or bicyclic heteroaryl group substituted with 0, 1, 2 or 3 R groups, or , wherein the wavy line represents the point of attachment of the Z1group to the NH group; Z2is CH2or wherein the wavy lines represents the points of attachment of the Z2group to the 6-membered ring and wherein the “ * ” at the carbon atom in Z2designates a second stereocenter; Ring B is a 6-membered aryl or 5- or 6-membered heteroaryl group; each R is independently selected from hydrogen, CN, SF5, halogen, (C1-C6)alkyl, -(C0-C6)alkyl- NH2, -(C0-C6)alkyl-NH((C1- C6)alkyl), -(C0-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -(C0- C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, 5- or 6-membered heteroaryl(C1-C4)alkyl-, (C2- C6)alkenyl, -(C2-C6)alkenyl-(C3-C8)cycloalkyl, -OH, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3- C8)cycloalkyl, -O-(C1-C6)alkyl-aryl, -O-(C1-C6)alkyl-5-6 membered heteroaryl, -O-(C2- C6)alkenyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1- C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, or 5-6 membered heteroaryl, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, (C1- C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, 5-6 membered heteroaryl, -C(O)-aryl, or 5-6 membered heteroaryl is optionally substituted one, two,or three times by R1wherein each R1is independently halo, -CN, -SF5, -OH, (C1-C6)alkyl, (C1- C4)alkoxy, (C3-C8)cycloalkyl, -(C1-C6)- OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1-C6)alkyl), -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, or (C1-C4) alkoxy; n is 0 or an integer from 1 to 5; L1is CRcRc*, O, SO2or C(O); each of Rcand Rc*is independently H, D, halo, (C1-C6)alkyl, or (C2-C6)alkenyl; or Rcand Rc*taken together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; Ring A is a 5-membered arylene or heteroarylene group; each R* is independently selected from hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C2- C6)alkenyl, -(C1- C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1- C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1- C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH; or two R*groups taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C1- C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; n* is 0 or an integer from 1 to 3; or one of Rcor Rc*and R* taken together with the atom to which they are bonded, fuse together to form a 3- to 6- membered ring; L2is -C(O)- or wherein the wavy line represents the points of attachment to the NH and the C RdRd*groups; Rdand Rd*are each independently H or (C1-C3)alkyl, or (C1-C3)alkoxy, or Rdand Rd*cyclize to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; Xhand Xh*are each independently C(Re)2, N(Re), CH2, NH, or O; Xgis CH or N; each Reis independently H, halo, (C1-C3)alkyl, halo(C1-C3)alkyl, or (C1-C3)alkoxy, or any twoRegroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n** is 0 or an integer from 1 to 8; Xjis N, NRf, C(Rf)2, C(Rf) or CH; Xeis N, NRf, C(Rf)2or C(Rf); Xfis SO2, N, C-(halo(C1-C3)alkyl), C-(C1-C3)alkyl, C=O or N+-O-; ------- represents a double or single bond as needed to satisfy atom valences; each Rfis independently H or halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, -(C1- C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl), -(C1-C6)alkyl-NH((C1-C6)alkyl)- OH, - (C1-C6)alkyl-NH((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1- C6)alkyl)- OH, -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3- C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-4- to 6- membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1- C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1- C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), - C(O)N(C1-C6)alkyl) (C1-C6)alkyl), - NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), - SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any said (C1-C6)alkyl, (C3- C8)cycloalkyl, -(C1-C6)alkyl-OH, - (C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1- C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1- C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen, or any two Rfgroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n^ is 0 or an integer from 1 to 4.

[0059] In one aspect, provided here is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein the “ * ” at the carbon to which Rdand Rd*are bonded is a first stereo center when Rdand Rd*are different;Z2is CH2or wherein the wavy lines represent the points of attachment of the Z2group to the Xh*and the -CH2of the 6-membered ring; wherein the “ * ” at the carbon atom in Z2designates a second stereocenter; with the proviso that when Z2is -CH2, then Ring A is not a thiazolyl; Ring B is a 6-membered aryl or 5- or 6-membered heteroaryl group; each R is independently selected from hydrogen, CN, SF5, halo, (C1-C6)alkyl, -(C0-C6)alkyl- NH2, -(C0-C6)alkyl-NH((C1- C6)alkyl), -(C0-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -(C0- C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, 5- or 6-membered heteroaryl(C1-C4)alkyl-, (C2- C6)alkenyl, -(C2-C6)alkenyl-(C3-C8)cycloalkyl, -OH, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3- C8)cycloalkyl, -O-(C1-C6)alkyl-aryl, -O-(C1-C6)alkyl-5-6 membered heteroaryl, -O-(C2- C6)alkenyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1- C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, or 5-6 membered heteroaryl, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, (C1- C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, 5-6 membered heteroaryl, -C(O)-aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, -OH, (C1-C6)alkyl, (C1- C4)alkoxy, (C3-C8)cycloalkyl, -(C1-C6)- OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1-C6)alkyl), -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halo, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, or (C1- C4)alkoxy; n is 0 or an integer from 1 to 5; L1is C(Rc)(Rc*), O, SO2or C(O); each of Rcand Rc*is independently H, D, halo, (C1-C6)alkyl, or (C2-C6)alkenyl; or Rcand Rc*taken together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; Ring A is a 5-membered arylene or a 5-membered heteroarylene group; each R* is independently selected from hydrogen, OH, halo, (C1-C6)alkyl, halo(C1-C6)alkyl,(C2-C6)alkenyl, -(C1- C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1- C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1- C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH; or two R*groups taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halo, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; n* is 0 or an integer from 1 to 3; or one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6-membered ring fused to Ring A; L2is -C(O)- or wherein the wavy line represents the points of attachment to the NH and the C(Rd)(Rd*) groups; Rdand Rd*are each independently H or (C1-C3)alkyl, or (C1-C3)alkoxy, or Rdand Rd*cyclize to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; Xhand Xh*are each independently C(Re) 2, N(Re), or O; Xgis CH or N; each Reis independently H, halo, (C1-C3)alkyl, halo(C1-C3)alkyl, or (C1-C3)alkoxy, or any two Regroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n** is 0 or an integer from 1 to 8; Xjis N, NRf, C(Rf)2, C(Rf) or CH; Xeis N, NRf, C(Rf)2or C(Rf); Xfis SO2, N, C-(halo(C1-C3)alkyl), C-(C1-C3)alkyl, C=O or N+-O-; ------- represents a double or single bond as needed to satisfy atom valences; each Rfis independently H or halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, -(C1- C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl), -(C1-C6)alkyl-NH((C1-C6)alkyl)- OH, - (C1-C6)alkyl-NH((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1- C6)alkyl)- OH, -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3- C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-4- to 6- membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1- C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), - C(O)N(C1-C6)alkyl) (C1-C6)alkyl), - NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), - SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any said (C1-C6)alkyl, (C3- C8)cycloalkyl, -(C1-C6)alkyl-OH, - (C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1- C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1- C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halo, OH, or any two Rfgroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n^ is 0 or an integer from 1 to 4.

[0060] In some embodiments, Ring A is imidazolylene, oxazolylene, oxadiazolylene, pyrazolylene, pyrrolylene, thiazolylene, or triazolylene. In some embodiments, Ring A is pyrrolylene, thiazolylene, imidazolylene, pyrazolylene, or triazolylene. In some embodiments, Ring A is imidazolylene. In some embodiments, Ring A is .

[0061] In some embodiments, Ring A is imidazolylene, triazolylene, pyrazolylene, or thiazolylene; n* is 0, 1 or 2; L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form an optionally substituted 3- to 6- membered ring fused to Ring A. In some embodiments, the optionally substituted 3- to 6- membered ring fused to Ring A forms an optionally substituted 8- or 9-membered bicyclic heterocyclylene having 1, 2 or 3 heteroatoms selected from N and S, or an optionally substituted 8- or 9-membered bicyclic heteroarylene having 1, 2 or 3 heteroatoms selected from N and S. In some embodiments, Ring A forms 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylene.

[0062] In some embodiments, the optionally substituted 3- to 6- membered ring fused to Ring A has the structure , wherein Rzis absent or is OH, n' is 0, 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter. In some embodiments, n' is 0, or is 1, or is 2. In some embodiments, n' is 1. In some embodiments, n' is 2.

[0063] In some embodiments, the 3- to 6- membered ring fused to Ring A has a structure selected from:wherein Rzis absent or is OH, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter. In some embodiments, Rzis absent. In some embodiments, Rzis OH.

[0064] In some embodiments, Xgis CH. In some embodiments, Xgis N.

[0065] In some embodiments, Rdand Rd*cyclize to form a 3 to 6 membered ring. In some embodiments, Rdand Rd*are the same and are H or (C1-C3)alkyl. In some embodiments, at least one of Rdand Rd*is (C1-C3)alkoxy. In some embodiments, each Rdand Rd*are independently chosen from H and CH3.

[0066] In some embodiments, Rdand Rd*are different and Z2is and the first and second stereocenters are both S.

[0067] In some embodiments, Rdand Rd*are different and Z2is and the first and second stereocenters are both R, or the first stereocenter is S and second stereocenter is R, or the first stereocenter is R and second stereocenter is S.

[0068] In some embodiments, two Regroups on adjacent atoms cyclize to form a 3 to 6 membered ring. In some embodiments, two Regroups bonded to a single carbon atom cyclize to form a 3 to 6 membered ring. In some embodiments, at least one Reis halo, (C1-C3)alkyl, or (C1- C3)alkoxy. In some embodiments, each Reis independently chosen from F, CH3and OCH3.

[0069] In some embodiments, Xh*is CH2. In some embodiments, Xh*is C(Re)2and each Reis F.

[0070] In some embodiments, n** is 1, 2, 3, or 4. In some embodiments, n** is 1 or 2. In some embodiments, n** is 0. In some embodiments, n** is 1. In some embodiments, n** is 2. In some embodiments, n** is 3. In some embodiments, n** is 4.

[0071] In some embodiments, Xhis NH or O. In some embodiments, Xhis CH2. In some embodiments, Xh*is NH, NCH3, or O. In some embodiments, Xh*is CH2, C(Re)2, or CH(Re).

[0072] In some embodiments, L2is wherein the wavy line represents the points of attachment to the NH and the C(Rd)(Rd*) groups. In some embodiments, L2is C=O.

[0073] In some embodiments, R* isCH3, or CF3.

[0074] In some embodiments, n* is 1 or 2. In some embodiments, n* is 1. In some embodiments, n* is 0.

[0075] In some embodiments, Ring B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl. In some embodiments, Ring B is phenyl or pyridinyl. In some embodiments, Ring B is phenyl.

[0076] In some embodiments, each R is independently CN, SF5, Cl, F,CH3, OCH3, O-phenyl, CF3or O CF3. In some embodiments, each R is independently F, Cl, CN, CF3or OCF3.

[0077] In some embodiments, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0078] In some embodiments, n^ is 1 or 2. In some embodiments, n^ is 0. In some embodiments, n^ is 1. In some embodiments, n^ is 2.

[0079] In some embodiments, L1is O, CH2, CHCH3, or CD2. In some embodiments, L1is O. In some embodiments, L1is CH2or CD2. In some embodiments, L1is CH2. In some embodiments, L1is absent. In some embodiments, L1is C(Rc)(Rc*).

[0080] In some embodiments, L1is C(Rc)(Rc*) and each Rcand Rc*is independently chosen from H, D and CH3. In some embodiments, at least one of Rcand Rc*is (C1-C3)alkoxy. In some embodiments, at least one of Rcand Rc*is methoxy or ethoxy. In some embodiments, Rcand Rc*are the same and are H, D, or (C1-C3)alkyl. In some embodiments, Rcand Rc*cyclize to form a 3 to 6 membered ring.

[0081] In some embodiments, L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A. In some embodiments, the 3- to 6- membered ring fused to Ring A has the structure , wherein Rzis absent or is OH, n' is 0, 1 or 2, and the “*” at the ring carbon bonded to Rc*represents a third stereocenter. In some embodiments, n' is 1 or 2. In some embodiments, n' is 1. In some embodiments, n' is 2.

[0082] In some embodiments, the 3- to 6- membered ring fused to Ring A has a structure selected from, wherein the ring carbon attached to Ring B is a stereocenter. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from wherein Rzis absent or is OH, and the “*” at the ring carbon bonded to Rc*represents a third stereocenter.

[0083] In some embodiments, Rzis absent. In some embodiments, Rzis OH.

[0084] In some embodiments, Xeis NH and Xfis C=O and the bond between Xeand Xfis a single bond. In some embodiments, Xeis CH2and Xfis C=O and the bond between Xeand Xfis a single bond. In some embodiments, Xeis CH and Xfis N+-O- and the bond between Xeand Xfis a double bond. In some embodiments, Xeis CH and Xfis N and the bond between Xeand Xfis a double bond. In some embodiments, Xeis N and Xfis C-CH3, C-CH2F, C-CHF2. or CF3and the bond between Xeand Xfis a double bond.

[0085] In some embodiments, two Rfgroups on adjacent atoms cyclize to form a 3 to 6 membered ring. In some embodiments, two Rfgroups bonded to a single carbon atom cyclize to form a 3 to 6 membered ring. In some embodiments, each Rfis independently chosen from halo, (C1-C3)alkyl, (C1-C3)alkyl-OH, halo(C1-C3)alkyl, (C1-C3)alkoxy, or aryloxy. In some embodiments, each Rfis independently chosen from CH2-OH, F, Cl, CH3, OCH3, O-phenyl, CF3, and OCF3.

[0086] In some embodiments, Z1is a monocyclic or bicyclic heteroaryl group. In some embodiments, Z1is [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene. In some embodiments, Z1is .

[0087] In some embodiments, Z1is .

[0088] In some embodiments, Z2is CH2. In some embodiments, Z2is . wherein the wavy lines represent the points of attachment of the Z2group to the 6-membered ring In some embodiments, Z2is wherein the wavy lines represent the points of attachment of the Z2group to the 6-membered ring.

[0089] In some embodiments, Z1is a monocyclic or bicyclic heteroaryl group. In some embodiments, Z1is pyridinyl or pyrimidinyl.

[0090] In some embodiments, Z1is and Z2is .

[0091] In some embodiments, Z1is ; ring A is imidazolylene; L2is - C(O)-; Xhis NH; Xh*and Xgare CH2; and Rd*is CH3. In some embodiments, L1is methylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, n is 2 and R is halo.

[0092] In some embodiments, Z1is ; ring A is imidazolylene; L2is -C(O)-; Xgis N; Xhand Xh*, are CH2; and Rd*is CH3. In some embodiments, L1is methylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, n is 2 and R is halo.

[0093] In some embodiments, Z1is ; ring A is imidazolylene; L2is -C(O)-; Z2is ; Xh*is O; Xhis CH2; Xgis CH; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3. In some embodiments, L1is methylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CF3, and OCF3. In some embodiments, n is 2 and R is halo.

[0094] In some embodiments, Z1is ; ring A is imidazolylene; L2is - C(O)-; Z2is ; Xh*is O; Xhis CH2; XgCH; Xeis NH; Xfis C=O and the bond between Xeand Xfis a single bond; and Rd*is CH3. In some embodiments, L1is methylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CF3, and OCF3. In some embodiments, n is 2 and R is halo.

[0095] In some embodiments, Z1is ; ring A is imidazolylene; L2is -C(O)-; Z2is ; Xgis N; Xhand Xh*are CH2; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3. In some embodiments, L1ismethylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CF3, and OCF3. In some embodiments, n is 2 and R is halo.

[0096] In some embodiments, Z1is ; ring A is imidazolylene; L2is - C(O)-; Z2is ; Xgis N; Xhand Xh*are CH2; Xeis NH; Xfis C=O and the bond between Xeand Xfis a single bond; and Rd*is CH3. In some embodiments, L1is methylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CF3, and OCF3. In some embodiments, n is 2 and R is halo.

[0097] In some embodiments, Z1is ; Z2is CH2; L2is -C(O)-; L1is methylene; Xgis N; Xhand Xh*are C. In some embodiments, Ring A is imidazolylene; and Rd*is CH3. In some embodiments, Reis halo or (C1-C3)alkyl; B is phenyl; and R is independently selected from halo and (C1-C3)alkyl. In some embodiments, R is halo and n is 2.

[0098] In some embodiments, Z1is ; Z2is CH2; L2is -C(O)-; L1is methylene; Xgis N; Xhis CH2; and Xh*is O. In some embodiments, Ring A is imidazolylene; and Rd*is CH3. In some embodiments, Reis halo or (C1-C3)alkyl; B is phenyl; and R is independently selected from halo and (C1-C3)alkyl. In some embodiments, R is halo and n is 2.

[0099] In some embodiments, Z1is a monocyclic or bicyclic heteroaryl group substituted with 0, 1 or 2 R groups; Z2is CH2; L2is -C(O)-; Xgis N; Xhand Xh*are C. In some embodiments, Rd*is CH3. In some embodiments, each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, R is fluoro.

[0100] In some embodiments, Z1is a monocyclic or bicyclic heteroaryl group substituted with 0, 1 or 2 R groups; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2; and Xh*is O. In some embodiments, Rd*is CH3. In some embodiments, each Reis independently H, halo or (C1- C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, R is fluoro.

[0101] In some embodiments, Z1is a monocyclic or bicyclic heteroaryl group substituted with 0, 1 or 2 R groups; Z2is ; Xh*is O; Xhis CH2; and XgCH; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3. In some embodiments, Rdis H; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, CH2-OH, OCH3, CF3, and OCF3; and R is fluoro.

[0102] In some embodiments, Z1is a monocyclic or bicyclic heteroaryl group substituted with 0, 1 or 2 R groups; Z2is ; Xh*is O; Xhis CH2; and Xgis CH; Xeis NH; Xfis C=O and the bond between Xeand Xfis a single bond; and Rd*is CH3. In some embodiments, Rdis H; n is 0, 1, or 2; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CH2-OH, CF3, and OCF3; and R is fluoro.

[0103] In some embodiments, Z1is ; ring A is imidazolylene; L2is - C(O)-; Z2is ; Xgis N; Xhand Xh*are CH2; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3. In some embodiments, L1is methylene; Rdis H; and B is phenyl; n is 0, 1, 2, or 3; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CH2-OH, CF3, and OCF3; and R is fluoro.

[0104] In some embodiments, Z1is ; ring A is imidazolylene; L2is -C(O)-; Z2is ; Xgis N; Xhand Xh*are CH2; Xeis NH; Xfis C=O and the bond between Xeand Xfis a single bond; and Rd*is CH3. In some embodiments, Rdis H; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CH2-OH, CF3, and OCF3; and R is fluoro.

[0105] In some embodiments, one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2; and Xh*is O. In some embodiments, Rd*is CH3. In some embodiments, each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1- C3)alkyl. In some embodiments, R is fluoro.

[0106] In some embodiments, one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is ; Xh*and Xhare CH2; Xgis N; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3. In some embodiments, Rcor Rc*and R* taken together with the atoms to which they are bonded fuse together with Ring A to form an 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms. In some embodiments, the 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms comprises a 5 membered heteroaryl group fused to a 5 membered heterocyclic group. In some embodiments, 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms is 6,7-dihydro-5H-pyrrolo[1,2- a]imidazolylene In some embodiments, Rdis H; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, wherein Reis fluoro and n** is 2. In some embodiments, Rfis H.

[0107] In some embodiments, one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is ; Xh*and Xhare CH2; Xgis N; Xeis N; Xfis C(O) and the bond between Xeand Xfis a single bond; and Rd*is CH3. In some embodiments, Rcor Rc*and R* taken together with the atoms to which they are bonded fuse together with Ring A to form an 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms. In some embodiments, the 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms comprises a 5 membered heteroaryl group fused to a 5 membered heterocyclic group. In some embodiments, the bicyclic ring is 6,7- dihydro-5H-pyrrolo[1,2-a]imidazolylene. In some embodiments, Rdis H; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, Reis fluoro and n** is 2. In some embodiments, Rfis H.

[0108] In some embodiments, Rcor Rc*and R* taken together with the atoms to which they are bonded fuse together with Ring A to form an 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms. In some embodiments, B is phenyl, pyridinyl, pyridazinyl or pyrimidinyl and each R is independently F, Cl, CN, CF3or OCF3and n is 2 In some embodiments, B is phenyl and each R is F and n is 2. In some embodiments, Rdand Rd*are different and wherein Z2is and wherein the first and second stereocenters are both S.

[0109] In some embodiments, Rcor Rc*and R* taken together with the atoms to which they are bonded fuse together with Ring A to form an 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms, wherein the 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms is 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolylene. In some embodiments, B is phenyl, pyridinyl, pyridazinyl or pyrimidinyl and each R is independently F, Cl, CN, CF3or OCF3and n is 2. In some embodiments, B is phenyl and each R is F and n is 2. Insome embodiments, Rdand Rd*are different, wherein Z2is , and wherein the first and second stereocenters are both S.

[0110] In some embodiments, the compound is a compound of Formula (I), wherein L1is C(Rc)(Rc*) and one of Rcand Rc*, and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2and Xh*is O. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from . In some embodiments, Rzis absent and Ring B is phenyl or pyridinyl. In some embodiments, Rd*is CH3. In some embodiments, n** is 1 or 2 and each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, n is 0, 1, 2, or 3 and R is fluoro.

[0111] In some embodiments, the compound is a compound of Formula (I), wherein L1is C(Rc)(Rc*) and one of Rcor Rc*, and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2; Xh*is CH2or C(Re)2and each Reis independently halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring Brepresents a third stereocenter. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from . In some embodiments, Rzis absent and Ring B is phenyl or pyridinyl. In some embodiments, Rd*is CH3. In some embodiments, n** is 1 or 2 and each Reis independently H, F or Cl. In some embodiments, n is 0, 1, 2, or 3 and R is fluoro.

[0112] In some embodiments, the compound is a compound of Formula (I), wherein L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is ; Xhis CH2; Xh*is CH2or C(Re)2; Xgis N; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from . In some embodiments, Reis F and n** is 2. In some embodiments, Rfis H. In some embodiments, Rzis absent and Ring B is phenyl or pyridinyl. In some embodiments, Rdis H; and each R is independently selected from halo and (C1-C3)alkyl.

[0113] In some embodiments, the compound is a compound of Formula (I), wherein L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bondedform a 3- to 6- membered ring fused to Ring A; Z2is ; Xhis CH2; Xh*is CH2or C(Re)2; Xgis N; Xeis N; Xfis C(O) and the bond between Xeand Xfis a single bond; and Rd*is CH3. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter. In some embodiments, the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from . In some embodiments, Reis F and n** is 2. In some embodiments, Rfis H. In some embodiments, Rzis absent and Ring B is phenyl or pyridinyl. In some embodiments, Rdis H; and each R is independently selected from halo and (C1-C3)alkyl.

[0114] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is selected from compounds of Formula (Ia), (Ib), (Ic), (Id), and (Ie): (Ia); (Ib);(Ic); (Id); and (Ie) wherein n' is 0, 1 or 2 and the “*” at the carbon bonded to both Ring B and Rc*represents and third stereocenter.

[0115] In some embodiments, the compound is a compound of Formula (Ie).

[0116] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) and the first and second stereocenters are both in an S configuration.

[0117] In some embodiments, the compound is a compound of Formula (Id) and the first stereocenter is in an S configuration.

[0118] In some embodiments, the compound is a compound of Formula (Ie) and the first, and second stereocenters are in an S configuration. In some embodiments, the compound is a compound of Formula (Ie) and the first, and second stereocenters are in an S configuration and the third stereocenter is in an (R) configuration. In some embodiments, the compound is a compound of Formula (Ie) and the first, second, and third stereocenters are in an S configuration. In some embodiments, the compound is a compound of Formula (Id) and the first and second stereocenters are in an S configuration and the third stereocenter is in an R configuration.

[0119] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Id) and R* is (C1-C3)alkyl, halo, halo(C1-C3)alkyl or oxo. In some embodiments, R* is CH3or CF3. In some embodiments, n* is 0 or 1.

[0120] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Id) or (Ie) and Ring B is phenyl or pyridinyl and each R is independently CN, SF5, F, methyl, OCH3, O-phenyl, or CF3; and n is 1, 2 or 3.

[0121] In some embodiments, the compound is a compound of Formula (Ia) or (Id) and n** is 1 or 2.

[0122] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Id) or (Ie) and each Reis independently halo, (C1-C3)alkyl, or (C1-C3)alkoxy. In some embodiments, each Reis F. In some embodiments, each Retogether with the carbon to which they are bonded form a cyclopropyl group.

[0123] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Id) and L1is C(Rc)(Rc*), O, or C(O). In some embodiments, each of Rcand Rc*is independently H, D, halo, (C1-C6)alkyl, or (C2-C6)alkenyl; or Rcand Rc*taken together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C1- C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl. In some embodiments, each of Rcand Rc*is independently H or CH3, or Rcand Rc*together with the carbon to which they are bonded form a cyclopropyl group.

[0124] In some embodiments, the compound is a compound of Formula (Ia), (Ib), or (Id) and L is C(Rc)(Rc*).

[0125] In some embodiments, the compound is a compound of Formula (Ia), (Ib), (Ic) or (Id) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A. In some embodiments, Rcor Rc*and R* taken together with the atoms to which they are bonded fuse together with Ring A to form an 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms. In some embodiments, 8 membered bicyclic heteroaryl or heterocyclic group having two nitrogen atoms comprises a 5 membered heteroaryl group fused to a 5 membered heterocyclic group.

[0126] In some embodiments, the compound is a compound of Formula (Ie) and n' is 1 or 2. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, Rc*is H or methyl. In some embodiments, Ring B is phenyl or pyridinyl and each R is independently CN, SF5, F, Cl, methyl, OCH3, O-phenyl, or CF3; and n is 1, 2 or 3

[0127] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Ie) and Xeis NH and Xfis C=O and the bond between Xeand Xfis a single bond.

[0128] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Ie) and Xeis CH2and Xfis C=O and the bond between Xeand Xfis a single bond.

[0129] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Ie) and Xeis CH and Xfis N+-O- and the bond between Xeand Xfis a double bond.

[0130] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Ie) and Xeis CH and Xfis N and the bond between Xeand Xfis a double bond.

[0131] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Ie) and Xeis N and Xfis C-CH3, C-CH2F, C-CHF2. or CF3and the bond between Xeand Xfis a double bond.

[0132] In some embodiments, the compound is a compound of Formula (Ia) or (Id) and Xh*is CH2, N and O. In some embodiments, the compound is a compound of Formula (Ia) or (Id) and Xh*is C(Re)2and Reis F.

[0133] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Id) or (Ie) and Xhis CH2, N and O.

[0134] In some embodiments, the compound is a compound of Formula (Ia) and ring A is imidazolylene, oxazolylene, oxadiazolylene, pyrazolylene, pyrrolylene, thiazolylene, or triazolylene. In some embodiments, Ring A is pyrrolylene, thiazolylene, imidazolylene, pyrazolylene, or triazolylene.

[0135] In some embodiments, the compound is a compound of Formula (Ia) and Xgis CH or N.

[0136] In some embodiments, the compound is a compound of Formula (Ia) or (Ib) or (Ic) or (Id) or (Ie) and each Rdand Rd*are independently H, (C1-C3)alkyl, or (C1-C3)alkoxy. In some embodiments, Rdand Rd*are the same and are H or (C1-C3)alkyl. In some embodiments, at least one of Rdand Rd*is (C1-C3)alkoxy. In some embodiments, each Rdand Rd*are independently chosen from H, CH3, and OCH3. In some embodiments, Rdand Rd*cyclize to form a cyclopropyl group.

[0137] In some embodiments, the compound is a compound of Formula (Ie), and Ring B is phenyl, n is 2, each R is independently CN, SF5, F, methyl, OCH3, O-phenyl, or CF3, and each Reis independently F, Me, or MeO.

[0138] In some embodiments, the compound of Formula (I) has the structure: or . or a pharmaceutically salt thereof.

[0139] In some embodiments, the compound of Formula (I) has the structure: or or a pharmaceutically salt thereof.

[0140] In some embodiments, the compound of Formula (I) has the structure: or or a pharmaceutically salt thereof.

[0141] In some embodiments, the compound of Formula (I) has the structure: or , or a pharmaceutically salt thereof.

[0142] In some embodiments, the compound of Formula (I) is chosen from 4-(1-(1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((1-(2,4-Difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide; 4-(1-(1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((S)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; and (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((S)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide.

[0143] In some embodiments the compound of Formula I is chosen from: , ; or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments the compound of Formula I is a compound having the structure: , or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments the compound of Formula I is a compound having the structure: , or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments the compound of Formula I is a compound having the structure , or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments the compound of Formula I is a compound having the structureor a pharmaceutically acceptable salt thereof.

[0148] In some embodiments the compound of Formula I is a compound chosen from 2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(3,5-difluorophenyl)-6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((R)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((S)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((R)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((S)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; 4-(1-(1-((5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((R)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((S)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((R)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; and 4-((S)-1-((R)-1-(((S)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-(1-(1-((4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((R)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((S)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((S)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((R)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the compound of Formula (I) is a compound as recited in the Examples and Tables herein, or racemic mixtures thereof, or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of Formula (I) has at least one H replaced by deuterium, D. In some embodiments, Rcand / or Rc*are D. General Synthetic Methods

[0151] Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following exemplary reaction schemes. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. In particular, it is noted that the compounds prepared according to these Schemes may be modified further to provide new Examples within the scope of this invention. In addition, it will be evident from the detailed descriptions given in the Experimental section that the modes of preparation employed extend further than the general procedures described herein. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2005, and “March’s Advanced Organic Chemistry: Reactions Mechanisms and Structure”, 8thEd., Ed.: Smith, M.B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference.

[0152] The starting materials are generally available from commercial sources such as Merck Sigma-Aldrich Inc. and Enamine Ltd. Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including Supplements (also available via the Beilstein online database).

[0153] As an initial note, in the preparation of compounds of the present invention, it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in intermediates). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparative methods and can be readily determined by one of ordinary skill in the art. The use of such protection / deprotection methods is also within the ordinary skill in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Greene’s Protective Groups inorganic Synthesis, John Wiley &Sons, New York 2006.

[0154] For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the Formula I compound.

[0155] More specifically intermediates and compounds of the present disclosure may be made by the methods shown in the following schemes. Scheme 1

[0156] Step 1: Aryl bromides or any aromatic halogen compounds are coupled at the alpha position of a substituted ketone. Reaction conditions typically utilize polar aprotic solvents such as THF and strong bases such as sodium tert-butoxide in the presence of a ligated palladium catalyst, typically generated from palladium acetate with dicyclohexyl[2′,4′,6′-tris(propan-2- yl)[1,1′-biphenyl]-2-yl]phosphane or XPhos, under inert atmospheric conditions at elevated temperatures, typically 50 °C, overnight. Step 2: Difluorination of the ketone is achieved with the N,N-diethyl-S,S-difluorosulfiliminium tetrafluoroborate or XtalFluor-E and triethylamine trihydrofluoride in polar aprotic solvents such as DCM. These transformations are typically run at 0 °C under inert atmospheric conditions overnight. Step 3: Oxidation of the pyridine can be achieved with oxidant such as potassium peroxymonosulfate or Oxone in a mixture of polar aprotic solvents with polar protic solvents in a 1:1 ratio. Typical solvents that are employed in this reaction are acetone and water. Step 4: If required, Boc-deprotection of Xgcan be achieved using an acid such as 4M HCl in dioxane at room temperature overnight. Scheme 2

[0157] Step 1: Protection of a halo substituted nitrogen containing heteroaromatic can be achieved with triphenylmethyl chloride and triethylamine at 0 °C for two hours in polar aprotic solvents. Of particular interest are imidazoles with iodo substitution. Step 2: A substituted amide, can be coupled to a substituted heteroaromatic halide using a copper source such as copper iodide, a base such as potassium carbonate, and a ligand such as (1S,2S)-N,N'- dimethylcyclohexane-1,2-diamine, L-proline, or 1,2-bis(dimethylamino)ethane, in a polar aprotic solvent such as 1,4-dioxane and heated at elevated temperatures around 80°C to 110°Cfor 2-24 h. Step 3: Activation of the alcohol can be achieved using tosyl-Cl and pyridine or triethylamine in polar aprotic solvents or in neat pyridine overnight. Step 4: Nucleophilic displacement of the toyslate group can be achieved with amines in polar aprotic solvents with bases. Step 5: Deprotection of the heterocycles can typically be achieved with an acid source such as HCL in 2M dioxane. Step 6: Alkylation of heterocycles can be achieved with benzyl halides or any other electrophiles under basic conditions in polar aprotic solvents. Scheme 3:

[0158] Step 1: Coupling of a substituted acid with a substituted amino heterocycle can be accomplished using standard peptide coupling conditions. These conditions may include but are not limited to the use of a coupling reagent such as DCC and additive such as silver nitrate or DMAP in a polar aprotic solvent such as THF or DCM with stirring overnight at RT. Step 2: Nucleophilic displacement of the halide group (X1) can be achieved with amines in polar aprotic solvents with bases. Scheme 4:

[0159] Step 1: Aryl bromides or any aromatic halogen compounds, in this case a substituted methoxypyridine, are coupled at the alpha position of a substituted ketone. Reaction conditions utilize the polar aprotic solvents such as THF and strong bases such as sodium tert-butoxide in the presence of a ligated palladium catalyst, typically generated from palladium acetate with dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane or XPhos, under inert atmospheric conditions at elevated temperatures, typically 50 °C, overnight. Step 2: Difluorination of the ketone can be achieved with N,N-diethyl-S,S-difluorosulfiliminium tetrafluoroborate or XtalFluor-E and triethylamine trihydrofluoride in polar aprotic solvents such as DCM. These transformations are typically run at 0 °C under inert atmospheric conditions overnight. Step 3: De-methylation of the methoxy group can be accomplished by using HBr / AcOH with heating at elevated temperatures, typically around 100°C for several hours. Step 4 (If required): Boc-deprotection of Xgcan be achieved with an acid such as 4M HCl in dioxane at room temperature overnight. Scheme 5:

[0160] Step 1: Substituted heteroaromatics (where Z1 is NH) can be alkylated with an electrophile, typically a benzylic halide, using a base such as potassium carbonate, in a polar aprotic solvent such as acetonitrile, with heating at elevated temperatures. Step 2: Substituted heteroaromatic nitro groups can be reduced to their corresponding amino groups with tetrahydroxydiboron and 4, 4’-bypyridine in DMF at 0°C → RT. Step 3: Coupling of a substituted acid with a substituted amino heterocycle can be accomplished using standard peptide coupling conditions. These conditions may include but are not limited to the use of a coupling reagent such as DCC and additive such as silver nitrate or DMAP in a polar aprotic solvent such as THF or DCM with stirring overnight at RT. Step 4: Nucleophilic displacement of the alkyl bromide can be achieved with amines in polar aprotic solvents with bases. Scheme 6

[0161] Step 1: Substituted heteroaromatics, typically substituted with an ester and in the case where Z1 is CH, can be coupled with a halogen containing compound, typically a benzylic halide, using a transition metal catalyst such as palladium acetate, a ligand such as CyJohnPhos, and a base such as cesium carbonate, in a polar aprotic solvent such as 1,4-dioxane, and heated at elevated temperatures, typically 100 °C, for several hours. Step 2: Saponification of a substituted heteroaromatic ester can be accomplished using a strong base such as lithium hydroxide, in a mixture of THF and water at room temperature or with heating. Step 3: Substituted heteroaromatic carboxylic acids can undergo a Curtis rearrangement to generate protected amines, in this case a Boc protected amine, by using DPPA and triethylamine in tert- butanol with heating from 0°C → 100°C. Step 4: Coupling of a substituted acid with a substituted amino heterocycle can be accomplished using standard peptide coupling conditions. These conditions may include but are not limited to the use of a coupling reagent such as DCC and additive such as silver nitrate or DMAP in a polar aprotic solvent such as THF or DCM with stirring overnight at RT. Step 5: Nucleophilic displacement of the alkyl bromide can be achieved with amines in polar aprotic solvents with bases. Step 6: Boc-deprotection can be achieved with an acid such as 4M HCl in dioxane at room temperature overnight. Scheme 7:

[0162] Step 1: A nucleophile, typically one that can be generated from the addition of isopropyl magnesium bromide with a substituted aromatic halide in a polar aprotic solvent such as THF at -30°C → RT, can be added to succinimide at -78°C → RT. The resulting adduct can then be reduced with sodium cyanoborohydride at temperatures that range from 0°C → RT to provide substituted pyrrolidinones. Step 2: Alkylation of a pyrrolidinone can be accomplished using a base such as sodium hydride, in a polar aprotic solvent such as THF. Step 3: Cyclization can be achieved using phosphoryl bromide in a polar aprotic solvent such as acetonitrile with heating at elevated temperatures, typically 80°C after several hours to afford the corresponding substituted 5,5-fused heteroaromatic halide. Step 4: A substituted amide, can be coupled to a substituted heteroaromatic halide using a copper source such as copper iodide, a base such as potassium carbonate or potassium phosphate tribasic, and a ligand such as (1S,2S)-N,N'- dimethylcyclohexane-1,2-diamine, L-proline, or 1,2-bis(dimethylamino)ethane in a polar aprotic solvent such as dioxane and heated at elevated temperatures around 80°C to 110°C for 2-24 h. Step 5: Activation of the alcohol can be achieved with NsCl (2-nitrobenzenesulfonyl chloride), DMAP and triethylamine in polar aprotic solvents such as dichloromethane at 0°C after several hours. Step 6: Nucleophilic displacement of the nosylate group can be achieved with amines in polar aprotic solvents with bases.Scheme 8:

[0163] Step 1: Enol triflates can be formed by reacting an enolizable carbonyl containing compound with base, such as LiHMDS, and a triflating reagent, such as phenyl triflimide, in a polar aprotic solvent, such as THF, typically at temperatures that range from -78°C to RT for 1 – 24 h. Step 2: Coupling of an enol triflates with a boronic acid can be accomplished by using a palladium source, such as Pd(dppf)Cl2, a base, such as cesium carbonate, in a mixture of a polar aprotic solvent, such as 1,4-dioxane or THF, and water, at elevated temperatures, typically 40°C to 100 °C, under inert atmospheric conditions overnight. Step 3: Reduction of alkenes can typically be accomplished with a palladium catalyst, such as palladium on charcoal, in a polar protic solvent, such as methanol, under an atmosphere of hydrogen at room temperature over the course of 1 – 24 h. Step 4-1 (optional in certain cases where Xf= N): Oxidation can be achieved with oxidant such as potassium peroxymonosulfate or Oxone in a mixture of polar aprotic solvents with polar protic solvents in a 1:1 ratio. Typical solvents that are employed in this reaction are acetone and water. Step 4-2 (optional in certain cases where Xe= N and Xf= C– OMe): De-methylation of the methoxy group can be accomplished by using HBr / AcOH with heating at elevated temperatures, typically around 100°C for several hours.Scheme 9:

[0164] Step 1: THP protection of pyrazoles can be accomplished with 3,4-dihydro-2H-pyran and an acid catalyst, such as TsOH, in a polar aprotic solvent, such as THF, at temperatures that range from RT to 70°C, over 1 – 24 h. Step 2: Coupling of a halogenated pyrazole with an alcohol can be achieved using NHC, such as 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate, an iridium catalyst, such as [Ir(ppy)2(dtbbpy)]PF6, a nickel catalyst, such as [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide, and base, such as 1- azabicyclo[2.2.2]octane, in mixtures of pyridine, DMAC and MTBE with photo irradiation with LEDs, typically at 450 nm, under an atmosphere of nitrogen overnight. Step 3: Alkylation of pyrazoles with electrophiles can be accomplished by using a strong base, such as LDA, in a polar aprotic solvent, such as THF, at temperatures that range from -78°C to 0°C, for 1 – 24 h under an inert atmosphere. Step 4: Deprotection of acid labile protecting groups can be accomplished with an acid, such as HCl in 1,4-dioxane, at RT for 1-24 h. Step 5: Fused bicyclic pyrazoles can be formed via cyclization under Mitsunobu conditions that typically utilize triphenylphospine and DEAD or DIAD in polar aprotic solvents such as THF, at temperatures that range from 0°C to 60°C under an inert atmosphere over 1-24 h. Step 6: A substituted amide, can be coupled to a substituted heteroaromatic halide using a copper source such as copper iodide, a base such as potassium carbonate or potassium phosphate tribasic, and a ligand such as (1S,2S)-N,N'-dimethylcyclohexane-1,2-diamine, L-proline, or 1,2-bis(dimethylamino)ethane ina polar aprotic solvent such as dioxane and heated at elevated temperatures around 80°C to 110°C for 2-24 h. Step 7: Activation of the alcohol can be achieved with NsCl (2- nitrobenzenesulfonyl chloride), DMAP and triethylamine in polar aprotic solvents such as dichloromethane at 0°C after several hours. Step 8: Nucleophilic displacement of the nosylate group can be achieved with amines in polar aprotic solvents with bases.

[0165] As can be appreciated by the skilled artisan, the above synthetic Schemes and representative examples (below) are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. The disclosure further encompasses “intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or generated in- situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure. Exemplary embodiments of such intermediate compounds are set forth in the Examples below. Methods of Treating, Administration, and Pharmaceutical Compositions

[0166] In one aspect, provided herein are methods of modulating MRGPRX2 activity comprising administering an effective amount of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0167] Also provided, in some embodiments, is a method of modulating mast cell degranulation comprising administering an effective amount of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0168] Also provided, in some embodiments, is a method of treating, preventing or ameliorating an MRGPRX2-mediated disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the disease is chosen from chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, Asian atopic dermatitis, European atopic dermatitis, rosacea, autoimmune diseases, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, endometriosis, nasal polyps, neuropathic pain, inflammatory pain, pseudo-allergic drug reactions, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, esophagus reflux, asthma, cough, migraine, sinusitis, urticaria, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, contact urticaria, lupus erythematosus (SLE), psoriasis, psoriatic arthritis, bronchial asthma,systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

[0169] Also provided, in some embodiments, is a method of treating a condition chosen from chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, Asian atopic dermatitis, European atopic dermatitis, rosacea, autoimmune diseases, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, endometriosis, nasal polyps, neuropathic pain, inflammatory pain, pseudo-allergic drug reactions, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, esophagus reflux, asthma, cough, migraine, sinusitis, urticaria, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, contact urticaria, lupus erythematosus (SLE), psoriasis, psoriatic arthritis, bronchial asthma, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain comprising administering to the subject an effective amount of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0170] In some embodiments, the condition is atopic dermatitis.

[0171] Also provided, in some embodiments, is the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof for use as a medicament. In some embodiments, the compound is for use in treating disease or disorder mediated by MRGPRX2.

[0172] Also provided, in some embodiments, is the use of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a MRGPRX2-mediated disease or disorder. Pharmaceutical Compositions and Formulations

[0173] In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In one embodiment, the dosage level will be about 0.1 to about 250 mg / kg per day. In another embodiment the dosage level will be about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oraladministration, the compositions may be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.

[0174] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0175] As the compounds of this invention may have utility for the treatment of atopic dermatitis the compounds may be administered topically. Thus, compounds of the invention may be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0176] Also provided, in some embodiments, is a pharmaceutical composition comprising the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0177] Pharmaceutical compositions can be formulated using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries. The formulation can be modified depending upon the route of administration chosen. The pharmaceutical compositions can alsoinclude the compounds described herein in a free base form or a pharmaceutically acceptable salt form.

[0178] Methods for formulation of the pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compositions described herein can be lyophilized or in powder form for re- constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug- delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0179] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0180] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution, or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion.

[0181] For parenteral administration, the compounds can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and non-therapeutic. A vehicle can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0182] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. Thus, in some preferred embodiments, the active ingredient(s) isadministered in a pharmaceutical composition which is an immediate release oral dosage form, preferably but not necessarily including an enteric coating. In some preferred embodiments, the active ingredients(s) are administered in a pharmaceutical composition which is an extended- release oral dosage form, preferably but not necessarily including an enteric coating. In further preferred embodiments, the active ingredients are administered in a pharmaceutical composition which contains both an immediate release dose and an extended-release dose or pulsed release dose of the first agent preferably but not necessarily also including an enteric coating. Such dual release dosage forms achieve release of an initial dose of active ingredient, followed late in time by another pulsed release, or by a sustained release dose. Methodologies for preparing such dual release dosage forms are well known in the art.

[0183] In some embodiments, the active ingredients are formulated into a controlled release matrix tablet, which contains one or more polymeric matrix materials that promote the sustained, delayed or pulsed release profile. Non-limiting examples of such polymeric matrix materials include cellulosic materials as described above, and carbomers, for example those sold by Lubrizol Corporation under the name Carbopol®, for example Carbopol® 71G NF, Carbopol® 971P NF and Carbopol® 974P NF polymers.

[0184] Some preferred examples of extended-release compositions suitable for use in the methods and compositions of the invention include, for example and not limitation, extended- release compositions found in nifedipine formulations such as Adalat CC®, Procardia® XL, Afeditab® CR and Nifedical® XL; and in diltiazem formulations such as Cardizem® CD, Cardizem® LA, Cardizem® SR, Cartia® XT and Dilacor® XR.

[0185] Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing a compound with a pharmaceutically acceptable carrier, excipient, and / or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and / or non- ionic surfactants or polyethylene glycol.

[0186] Compounds of the present disclosure may be used in methods of treating in combination with one or more other combination agents (e.g., one, two, or three other drugs) that are used inthe prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful. In some embodiments, the combination of the drugs together are safer or more effective than either drug alone. In some embodiments the compound disclosed herein and the one or more combination agents have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the purpose intended. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, in some embodiments, the agents are administered together in a single pharmaceutical composition in unit dosage form.

[0187] Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active agent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. In some embodiments, combination therapy includes therapies in which the compound of the present disclosure and one or more other drugs are administered separately, and in some cases, the two or more agents are administered on different, overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. In some embodiments, the combination agent is a drug for reduction of symptoms of ALS. In some embodiments, the combination agent is selected from an NAD supplement (such as nicotinamide riboside, offered under the trade names Basis® or Tru Niagen®), vitamin B12 (oral or injection), glycopyrrolate, atropine, scopolamine, baclofen, tizanidine, mexiletine, an SSRI, a benzodiazepine, Neudexta, riluzole, and edaravone, and combinations thereof.

[0188] Since the present invention has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I a prodrug thereof or a salt of Such compound or prodrug and a second compound as described above. The kit comprises a means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in differentdosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0189] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0190] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, … etc. Second Week, Monday, Tuesday, ... etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken. Also, as the present invention has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients which may be administered jointly, the invention also relates to combining separate pharmaceutical compositions in a single dosage form, Such as (but not limited to) a single tablet or capsule, a bilayer or multilayer tablet or capsule, or through the use of segregated componentsor compartments within a tablet or capsule. The compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subject such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non-domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit. In preferred embodiments, compounds, pharmaceutical compositions, and methods of the present disclosure are used for treating a human.

[0191] The present invention further comprises use of a compound of Formula I for use as a medicament (Such as a unit dosage tablet or unit dosage capsule). In another embodiment, the present invention comprises the use of a compound of Formula I for the manufacture of a medicament (such as a unit dosage tablet or unit dosage capsule) to treat one or more of the conditions discussed herein.

[0192] In practicing the methods described herein, therapeutically effective amounts of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and / or preventing a condition or progression thereof. A pharmaceutical composition can affect the physiology of the subject, such as the immune system, inflammatory response, or other physiologic affect. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.

[0193] Prevent, preventing, and the like can refer to the prevention of the disease or condition in the patient. For example, if an individual at risk of contracting a disease is treated with the methods of the present disclosure and does not later contract the disease, then the disease has been prevented, at least over a period of time, in that individual.

[0194] A therapeutically effective amount can be the amount of a compound or pharmaceutical composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment and can be ascertainable by one skilled in the art using known techniques.

[0195] The compounds or pharmaceutical compositions described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the compound or pharmaceutical composition, the method of administrationand other factors known to practitioners. The compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein.

[0196] One of ordinary skill in the art would understand that the amount, duration, and frequency of administration of a pharmaceutical composition or compound described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been administered, and the like.

[0197] Pharmaceutical compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations. The one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks, or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days or less than 1 day after the first administration. The one or more administrations can occur more than once per day, more than once per week, or more than once per month. The compounds or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days, or daily over a period of one to seven days.

[0198] 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 B-defensin, cathelicidin (LL-37), and proadrenomedullin N-terminal 20 peptide (PAMP9-20) (Journal of Allergy and Clinical Immunology, 138, 700-710 (2016); J. Immunol., 191, 345-352 (2013); BBRC, 349, 1322-28 (2006)). 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. Various observations using knock-out (KO) mice are consistent with the Mrgprb2 / MRGPRX2 receptors playing a role in mast cell-mediated neurogenic inflammation. For instance, Mrgprb2 / MRGPRX2 agonists induce various symptoms such as flushing, swelling and itch in wild type mice, but not in Mrgprb2-deficient mice (Nature, 519, 237-241 (2015); Immunity, 50, 1163-1171 (2019)). Mrgprb2-deficient mice have also demonstrated significant reductions in inflammation (leukocyte infiltration, including mast cells), swelling, pain and overall clinical score in various disease models (Neuron, 101, 412-420 (2019); Immunity, 50, 1163-1171 (2019); Nature Immunology, 20, 1435-1443 (2019)). An important and relevant observation wasthe demonstration that Substance P injection could stimulate the infiltration of leukocytes in wild type and NKRl (canonical Substance Preceptor) KO mice whereas the response was substantially blunted in Mrgprb2 null mice (Neuron, 101, 412-420 (2019)). This observation extends the role of Mrgprb2 / MRGPRX2 as a key receptor in mediating Substance P-induced inflammatory responses, including pain (Neuron, 101, 353-355, (2019) ). Indeed, a Substance P / Mrgprb2 sensory cluster was demonstrated to be critical in driving the clinical score of a severe preclinical model of atopic dermatitis (Nature Immunology, 20, 1435-1443 (2019)).

[0199] In addition to the various reports using Mrgprb2-deficient mice, further evidence suggests a role for various ligands of MRGPRX2 in human disease. For example, in addition to the number of MRGPRX2-expressing mast cells being significantly increased in severe chronic urticaria (Clinical and Molecular Allergy 16, 24 (2018)), PACAP nerve fibers were demonstrated to be in close proximity to tryptase-positive mast cells, providing the morphological basis for increased mast cell - sensory interactions (J. Allergy Clin. Immunol., 134, 622-633 (2014)). In support of this, patients with urticaria exhibit enhanced wheal reactions vs healthy individuals to MRGPRX2 agonists ( e.g., Substance P) when injected intradermally (Allergy, 54, 46-56 (1999)). In addition, PACAP and the antimicrobial peptide, LL-37, which is implicated in cutaneous inflammation, were both demonstrated to be upregulated in rosacea (J. Invest. Dermatol., 15, 53-62, (2011)). Indeed, mast cell-deficient mice do not develop inflammation / flushing following L.L-37 injection (J. Inv. Derm., 134, 2728 (2014)) thus inferring a role for Mrgprb2.

[0200] In addition to skin disorders, mast cell involvement has been highlighted for inflammatory bowel disease (IBD) and arthritis (Immunol. Rev., 217, 38-52 (2007); Pharmacology and Therapeutics, 116, 207-235 (2007)) as well as asthma (Respiratory Research, 19, 1 (2018)) and migraine. In patients with rheumatoid arthritis (RA), 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 (PLOS ONE, 10, e0139206 ((2015)) 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 (Allerg. Intern., 26, S9-S20 (2017)). Finally, there is a growing body of evidence for a role of PACAP in migraine pathogenesis and that it is mediated via activation of mast cells (Frontiers in Cellular Neuroscience, 13, 1-11 (2019)).

[0201] The Formula I compounds of this invention, their prodrugs and the salts of such compounds and prodrugs are all adapted to therapeutic use as agents that mediate the Mas-related G protein-coupled receptor (MRGPRX2) in mammals, particularly humans. For example, these compounds act as MRGPRX2 receptor antagonists and thus are useful for the treatment of the various conditions (e.g., those described herein) in which such action is implicated.

[0202] Given the positive correlation between activation of the MRGPRX2 receptor with the development of itch associated conditions, a pain associated condition, a pseudo-allergic reaction, an autoimmune or inflammatory disorder, or cancer-associated condition, Formula I compounds of this invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacologic action, are useful for the prevention, arrestment and / or regression of an itch associated condition, a pain associated condition, a pseudo-allergic reaction, an autoimmune or inflammatory disorder, or cancer-associated condition.

[0203] As used herein the phrase “pseudo-allergic reaction” refers to an IgE-independent allergic reaction, characterized by histamine release, inflammation, airway contraction, or any combination thereof. A pseudo-allergic reaction may be an anaphylactic reaction. A pseudo-allergic reaction may be caused by a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. Thus, in one embodiment, the method of present invention is provided to treat a pseudo-allergic reaction, such as pseudo-allergic reactions caused by secretagogues, cationic peptidergic drugs, anionic peptidergic drugs, neutral peptidergic drugs, non-steroidal antagonist drugs, neuropeptides, and antimicrobial peptides. In one embodiment, the pseudo-allergic reaction is caused by MCD peptide, Substance P, VIP, PACAP, dynorphin, somatostatin, Compound 48 / 80, cortistatin-14, mastoparan, melettin, cathelicidin peptides, ciprofloxacin, vancomycin, leuprolide, goserelin, histrelin, triptorelin, cetrorelix, ganirelix, degarelix, octreotide, lanreotide, pasireotide, sermorelin, tesamorelin, icatibant, glatiramer acetate, teriparatide, pramlintide, bleomycin, exenatide, glucagon, liraglutide, enfuvirtide, colistimethate, succinylcholine, tubocurarine, atracurium, mivacurium, and rocuronium.

[0204] As used herein, the phrase “itch associated condition” means pruritus (including acute and chronic pruritus) associated with any condition. The itch sensation can originate, e.g., from the peripheral nervous system (e.g., dermal or neuropathic itch) or from the central nervous system (e.g., neuropathic, neurogenic or psychogenic itch). Thus, in one embodiment, the method of present invention is provided to treat an itch associated condition, such as chronic itch; contact dermatitis; allergic blepharitis; anaphylaxis; anaphylactoid drug reactions; Anaphylactic shock; Anemia; Atopic dermatitis; Bullous pemphigoid; Candidiasis; Chicken pox; end-stage renal failure; hemodialysis; Cholestatic pruritis; Chronic urticaria; Contactdermatitis, Dermatitis herpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis; Ectopic eczema; Eosinophilic fasciitis; Epidermolysis bullosa; Erythrasma; Food allergy; Folliculitis; Fungal skin infection; Hemorrhoids; Herpes; HIV infection; Hodgkin’s disease; Hyperthyroidism; Iodinated contrast dye allergy; Iron deficiency anemia; Kidney disease; Leukemia, porphyria; Lymphoma; Mast cell activation syndrome, Malignancy; Mastocystosis; Multiple myeloma; Neurodermatitis; Onchocerciasis; Paget’s disease; Pediculosis; Polycythemia rubra vera; Prurigo nodularis; Lichen Planus; Lichen Sclerosis; Pruritus ani; Pseudo-allergic reactions; Pseudorabies; Psoriasis; Rectal prolapse; Sarcoidosis granulomas; Scabies; Schistosomiasis; Scleroderma, Severe stress, Stasia dermatitis; Swimmer’s itch; Thyroid disease; Tinea cruris; Uremic Pruritus; Rosacea; Cutaneous amyloidosis; Scleroderma; Acne; wound healing; burn healing; ocular itch; and Urticaria.

[0205] As used herein, the term “autoimmune disorder”, or “inflammatory disorder” means a disease or disorder arising from and / or directed against an individual’s own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom. Typically, various clinical and laboratory markers of autoimmune diseases may exist including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposits in tissues, clinical benefit from corticosteroid or immunosuppressive treatments, and lymphoidcell aggregates in affected tissues. Thus, in one embodiment, the method of present invention is provided to treat an autoimmune disorder, such as chronic inflammation, mast cell activation syndrome, Multiple Sclerosis, Steven Johnson’s Syndrome, Toxic Epidermal Necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, allergic rhinitis, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, Crohn’s Disease, ulcerative colitis, lupus erythematous, interstitial cystitis, otitis pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, permanent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatoisis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, refluxnephropathy, polycystic kidney disease, liver fibrosis / cirrhosis, autoimmune liver disease, Biliary atresia, acute and chronic Hepatitis Band C virus, Liver tumors and cancer, Alcoholic liver disease, Polycystic liver disease, Liver cholangiocarcinoma, neuromyelitis optica spectum disorder, cardiovascular disease, and vasculitis.

[0206] As used herein, the phrase “pain associated condition” means any pain due to a medical condition. Thus, in one embodiment, the method of present invention is provided to treat a pain associated condition, such as Acute Pain, Advanced Prostate Cancer, AIDS-Related Pain, Ankylosing Spondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic Cerebral Palsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain, Behcet’s Disease (Syndrome), Burning Mouth Syndrome, Bursitis, Cancer Pain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome, Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease, Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain (CFAP), Chronic Pain, Chronic Pancreatitis, Chronic Pelvic Pain Syndrome, Collapsed Lung (Pneumothorax), Complex Regional Pain Syndrome (RSD), Corneal Neuropathic Pain, Crohn’s Disease, Degenerative Disc Disease, Dental Pain, Dercum’s Disease, Dermatomyositis, Diabetic Peripheral Neuropathy (DPN), Dystonia, Ehlers-Danlos Syndrome (EDS), Endometriosis, Eosinophilia-Myalgia Syndrome (EMS), Erythromelalgia, Fibromyalgia, Gout, Headaches, Herniated disc, Hydrocephalus, lntercostal Neuraligia, Interstitial Cystitis, Irritable Bowel syndrome (IBS), Juvenile Dermatositis (Dermatomyositis), Knee Injury, Leg Pain, Loin Pain- Haematuria Syndrome, Lupus, Lyme Disease, Medullary Sponge Kidney (MSK), Meralgia Paresthetica, Mesothelioma, Migraine, Musculoskeletal pain, Myofascial Pain, Myositis, Neck Pain, Neuropathic Pain, Occipital Neuralgia, Osteoarthritis, Paget’s Disease, Parsonage Turner Syndrome, Pelvic Pain, Periodontitis Pain, Peripheral Neuropathy, Phantom Limb Pain, Pinched Nerve, Polycystic Kidney Disease, Polymyalgia Rhuematica, Polymyositis, Porphyria, Post Herniorrhaphy Pain Syndrome, Post Mastectomy, Postoperative Pain, Pain Syndrome, Post Stroke Pain, Post Thoracotomy Pain Syndrome, Postherpetic Neuralgia (Shingles), Post-Polio Syndrome, Primary Lateral Sclerosis, Psoriatic Arthritis, Pudenda! Neuralgia, Radiculopathy, Raynaud’s Disease, Rheumatoid Arthritis (RA), Sacroiliac Joint Dysfunction, Sarcoidosis, Scheuermann’s Kyphosis Disease, Sciatica, Scoliosis, Shingles (Herpes Zoster), Sjogren’s Syndrome, Spasmodic Torticollis, Sphincter of Oddi Dysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal Cord Injury, Spinal Stenosis, Syringomyelia, Tarlov Cysts, Transverse Myelitis, Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis, Vascular Pain and Vulvodynia.

[0207] As used herein the phrase “cancer associated condition” means any disease arising from the proliferation of malignant cancerous cells. Thus, in one embodiment, the method of present invention is provided to treat a cancer / tumor associated condition, such as adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia- telangiectasia, Beckwith-Wiedemann syndrome, cholangiocarcinoma, birt-hogg-dube syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), prostrate, basal cell, melanoma, colon, colorectal, bladder, kidney cancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lung cancer (non-small cell, small cell), leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T cell lymphocytic, eosinophilic), Liver Cancer, Li-Fraumeni syndrome, lymphoma (Hodgkin and non-Hodgkin), lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma, multiple endocrine neoplasia, multiple myeloma, MUTYH-associated polyposis, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, neuroblastoma, neuroendocrine tumors, neurofibromatosis, penile cancer, parathyroid cancer, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary gland tumor, pleuropulmonary blastoma, oral and oropharyngeal, thyroid, uterine, pancreatic, carney complex, brain and spinal cord cancer, cervical cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary, leiomyomastosis and renal cell cancer, hereditary pancreatitis, hereditary papillary renal carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS related cancers, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, culver cancer, Werner syndrome and Xeroderma pigmentosum. EXAMPLES

[0208] The following preparations of compounds of Formula (I) and intermediates are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0209] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0210] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 °C to about 150 °C, or from about 0 °C to about 125 °C or at about room (or ambient) temperature, e.g., about 20 °C.

[0211] Compounds of Formula (I) and sub formulae and species described herein, including those where the substituent groups as defined herein, can be prepared as illustrated and described below.

[0212] Unless otherwise noted, all reagents were used without further purification.1H NMR spectra were obtained in CDCl3, DMSO-d6, or CD3OD, unless stated otherwise, at room temperature on a Bruker AVANCE III HD 300MHz, Bruker AVANCE III HD 400MHz, or AVANCE NEO 400MHz instrument or an NMR spectrometer of similar caliber. When more than one conformer was detected, the chemical shifts for the most abundant one is reported. Chemical shifts of1H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

[0213] The following abbreviations are used in the text: LCMS = liquid chromatography-mass spectrometry, ESI = Electrospray Ionization, M+H = a unit higher than the monoisotopic mass of the uncharged molecule, HPLC = High pressure liquid chromatography, Prep-HPLC = preparatory scale HPLC, AcOH = acetic acid, AIBN = azobisisobutyronitrile, ACN or MeCN = acetonitrile, PE = petroleum ether, EA or EtOAc = ethyl acetate, XtalFluor-E = N,N-Diethyl-S,S-difluorosulfiliminium tetrafluoroborate, BSA = Bovine Serum Albumin, DAST = Diethylaminosulfur trifluoride, DIEA = N,N-diisopropylethylamine, DEA = diethanolamine, DMA = Dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMEDA = N,N'- Dimethylethylenediamine, DMSO = dimethyl sulfoxide, DMF = N, N-dimethylacetamide, DCC = N,N’-Dicyclohexylcarbodiimide, DCM = dichloromethane, DMEM = Dulbecco’s Modified Eagle Medium, DPPA = Diphenylphosphoryl azide, DIBAL = Diisobutylaluminium hydride, EtOH = ethanol, EGTA = (ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid), FA = formic acid, MeOH = methanol, MtBE = methyl tert-butyl ether, MCPBA = meta- Chloroperoxybenzoic acid, NBS = n-bromosuccinimide, NCS = n-chrlorosuccinimide, Otf = Trifluoromethanesulfonate, TEA or Et3N = triethylamine, GOI = genes of interest, TsCl = p- toluenesulfonyl chloride, hERG = human ether-a-go-go-related gene, HBSS = Hanks’ Balanced Salt Solution, HEPES = 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid, HOBT = Hydroxybenzotriazole, LDA = Lithium diisopropylamide, SFC = Supercritical fluid chromatography, THF = tetrahydrofuran, TLC = thin layer chromatography, TBAF = tetra-n- butylammonium fluoride, TMSBr = Bromotrimethylsilane, TMSCl = trimethylsilyl chloride, TMSCN = trimethylsilyl cyanide, TCFH = Chloro-N,N,N',N'-tetramethylformamidinium Hexafluorophosphate, TrtCl = Triphenylmethyl chloride, t-BuOH = tert-butyl alcohol, t-BuONa = sodium tert-butyloxide, Oac = acetate, NMI = 1-Methylimidazole, POCl3 = Phosphoryl chloride, POBr3 = Phosphoryl chloride, py = pyridine, Pd / C = palladium on carbon, HTRF - Homogeneous Time-Resolved Fluorescence, RT = retention time, h = hour, hrs = hours, aq. = aqueous, min. = minute, sat. = saturated, equiv = equivalent, e.e. = enantiomeric excess, UV = ultraviolet, XPhos = 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, Ns = 2- nitrobenzene-1-sulfonyl.

[0214] Unless otherwise indicated, the chemical names used herein are generated using the Chemdraw Professional Version 23.1.164-bit, or Chemdraw Professional Version 16.0, or Marvin JS 21.19.0 software naming programs.

[0215] Synthesis and Characterization Examples

[0216] For certain compounds disclosed herein the absolute stereochemistry has not been independently confirmed. At least one or more of the stereocenters’ absolute stereochemistry are believed to be accurately represented in the name and structure of the disclosed compounds. For some compounds the stereochemistry is assigned based on analogy to known literature stereoisomers. For example, Intermediate B was determined to be the preferred stereoisomer for potency and was assigned (S) based on prep chiral HPLC and analogy to known literature stereoisomers. See WO2022 / 073904 Example 132 for assignment of stereochemistry forIntermediate B. Inspection of VCD data in the analysis range indicated that the VCD spectrum for fs1ss is a good match with experimental determined values. The stereochemistry of the substituted methylene moiety (-C(Rd*)(Rd)-) is believed to be accurate based on the absolute stereochemical assignemt from commercially available vendors. (R)-2-hydroxypropanamide, also refered to as (R)-(+)-Lactamide, was either purchased from Bide Pharmatech Ltd. (CAS # 598-81-2; Catalog # BD47136) or BBChem Co., Ltd (CAS # 598-81-2; Catalog # BB211065; Batch # BB211065A23082301).

[0001] But, in some instances, the absolute stereo configurations of one or more chiral centers are arbitrarily assigned (e.g., stereochemistry of one chiral center is known and remaining chiral centers arbitrarily assigned). Accordingly, the enantiomers or diastereomers are identified by their respective properties, for example, retention times on a prep chiral HPLC, chiral SFC, NMR shift or optical rotation or its biological activities (e.g., as described further in the Examples). Thus, should the stereochemistry assigned to any compound or compounds ultimately be proven incorrect, then the analytical data (e.g., prep chiral HPLC, chiral SFC, NMR shift or optical rotation or biological activity) associated with each compound is determinative of the actual identity of the compound. In addition, in light of such corrected stereochemical designation appropriate adjustments to the stereochemistry identification contained in the description, examples, tables and claims should be adjusted as needed by one skilled in the art. For example, the stereochemistry of Example 53 compound 489 (see Figures 1A, 1B, 2A) has been determined by MicroED utilizing vapor diffusion in ACN / DIPE (as described in Example 53 Step 8) to be 4-((S)-1-((S)-1-(((R)-5-(3,5-difluorophenyl)-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 489). The absolute stereochemistry of the other compounds has not been determined by MicroED.

[0002] Chiral analytical separation methods (e.g., supercritical fluid chromatography (SFC), and high performance liquid chromatography (HPLC)) used in the following synthetic examples are summarized in Table A below. These methods were used to identify a single compound / stereoisomer from a mixture of chiral compounds based on a peak retention time. TABLE A

[0003] Synthesis of Intermediate B & C: (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide and (R)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine-1-carboxylate

[0004] A mixture of t-BuONa (19.8 g, 205.69 mmol), XPhos (4.9 g, 10.28 mmol), Pd(OAc)2(1.2 g, 5.14 mmol), 4-bromopyridine (10.0 g, 63.29 mmol) and tert-butyl 4-oxopiperidine-1- carboxylate (14.3 g, 71.99 mmol) in THF (200 mL) was stirred at 50 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was diluted with water at 0 °C. The aqueous layer was extracted with EtOAc (3 x 300 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / EA (1:1) to afford tert-butyl 4-oxo-3- (pyridin-4-yl)piperidine-1-carboxylate (9.0 g, 63% yield) as an off-white solid. LCMS (ESI) [M+H]+: 277. Step 2: tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate

[0005] To a mixture of triethylamine trihydrofluoride (11.0 g, 68.03 mmol) and XtalFluor-E (23.4 g, 102.05 mmol) in DCM (100 ml) was added tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine- 1-carboxylate (9.4 g, 34.01 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C overnight under a nitrogen atmosphere. The reaction was quenched with sat. aq. NaHCO3 (50 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2(3 x 150 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (3.0 g, 29% yield) as a yellow oil. LCMS (ESI) [M+H]+: 299. Step 3: 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0006] To a mixture of tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (3.0 g, 10.05 mmol) and K2CO3(4.2 g, 30.16 mmol) in 1:1 acetone / water (70 mL) was added Oxone (3.4 g, 20.11 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with sat. aq. sodium hyposulfite (50 mL) at 0 °C. Theresulting mixture was extracted with CH2Cl2(3 x 100 mL). Dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (7:1) to afford 4-(1-(tert- butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (2.6 g, 82% yield) as a yellow oil. LCMS (ESI) [M+H]+: 315 Step 4: 4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0007] A mixture of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (2.6 g, 8.27 mmol) in 4M HCl in 1,4-dioxane (24 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10mmol / L NH4HCO3), 5% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm. This resulted in 4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (1.7 g, 95% yield) as a yellow solid. LCMS (ESI) [M+H]+: 215. Step 5: (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide and (R)-4-(4,4-difluoropiperidin- 3-yl)pyridine 1-oxide

[0008] 4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (500 mg) was separated by prep-Chiral- HPLC (Column: CHIRALPAK IG, 3x25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 50% B; Column Temperature(℃): 35; Back Pressure(bar): 120; Wave Length: 270 / 250 nm; RT1(min): 4; RT2(min): 7.28) to afford (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (180 mg, 100% e.e.) (Intermediate B) and (R)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (310 mg, 100% e.e.) (Intermediate C). The isomers are tentatively assigned by analogy to the known stereochemistry in example 132 in WO2202 / 073904. LCMS (ESI) [M+H]+: 215. Synthesis of Intermediate D & E: 4-((S)-1-((S)-1-((1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxideStep 1: 4-nitro-1-trityl-1H-imidazole

[0009] To a mixture of 4-nitro-1H-imidazole (10 g, 88.44 mmol) and triethylamine (16 g, 154 mmol) in DMF (20 mL) was added triphenylmethyl chloride (24.5 g, 88.44 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water and filtered. The filter cake was collected and air dried to afford 4-nitro-1-trityl-1H-imidazole (28 g, 89% yield) as a white solid. LCMS (ESI) [M+H]+: 356.13 Step 2: 1-trityl-1H-imidazol-4-amine

[0010] A solution of tetrahydroxydiboron (20 g, 224 mmol) in DMF (20 mL) was slowly added into a solution of 4-nitro-1-trityl-1H-imidazole (20 g, 56.28 mmol) and 4, 4’ bipyridine (1g, 5.6 mmol) in DMF (40 mL) at 0 °C. Upon completion of the addition, the solution turned purple and was allowed to warm back to room temperature. The solution was stirred for another 30 minutes and became colorless again. TLC suggested complete consumption of the starting material. The mixture was poured into water (200 mL) and extracted with EA (3 x 200 mL). The organic layers were separated, combined, dried over MgSO4, filtered and concentrated under vacuum to give crude 1-trityl-1H-imidazol-4-amine (18 g, 98% quant), which was used directly in the next step directly without further purification. Step 3: 2-bromo-N-(1-trityl-1H-imidazol-4-yl)propanamide

[0011] A mixture of 1-trityl-1H-imidazol-4-amine (12 g, 30.73 mmol), 2-bromopropanoic acid (18.8 g, 122.92 mmol), DCC (18.54 g, 90 mmol) and AgNO3 (1 g, 3.3 mmol) in DCM (50 mL) was stirred overnight at room temperature. The resulting mixture was filtered and the precipitate was washed with DCM (3 x 10 mL). The resulting mixture was concentrated under vacuum. Theresidue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2- bromo-N-(1-trityl-1H-imidazol-4-yl)propanamide (15.3 g, 87% yield) as a white solid. LCMS (ESI) [M+H]+: 460.09. Step 4: 4-((3S)-4,4-difluoro-1-(1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2- yl)piperidin-3-yl)pyridine 1-oxide

[0012] Into a 8-mL sample vial was placed 2-bromo-N-(1-trityl-1H-imidazol-4-yl)propanamide (14 g, 30.41 mmol), Intermediate B (6.51g, 30.41 mmol), N, N-diisopropylethylamine (16 mL) and DMA (20 mL). The mixture was stirred at room temperature for 24h until LCMS suggested the completion of the reaction. The resulting solution was allowed to cool down to room temperature, poured into water (10 mL) and extracted with EA (3 × 10 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (methanol: dichloromethane = 1:15) to give 4-((3S)-4,4-difluoro-1-(1- oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide (14.5g, 77%) as a white solid. LCMS (ESI) [M+H]+: 594. Step 5: 4-((3S)-1-(1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide

[0013] HCl (10 mL, 20 mmol, 2M in dioxane) was added into a 50 mL round bottom flask containing 4-((3S)-4,4-difluoro-1-(1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2- yl)piperidin-3-yl)pyridine 1-oxide (14.5g, 24.4mmol). The mixture was stirred at 25 °C for 3 hours until LCMS suggested the completion of the reaction. The mixture was concentrated and triturated with dioxane (3 × 10 mL) to give 4-((3S)-1-(1-((1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (9.1g, 95%) as a white solid. LCMS (ESI) [M+H]+: 352.Step 6: 4-((S)-1-((S)-1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin- 3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0014] 4-((3S)-1-(1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (12 g) was purified by Prep-Chiral SFC with the following conditions Column: CHIRALPAK IG, 3×25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH: DCM=1: 1(20mM NH3); Flow rate: 40 mL / min; Gradient: isocratic 40% B; Column Temperature(°C): 35; Back Pressure(bar): 90; Wave Length: 210 / 238 nm; RT1(min): 4.58; RT2(min): 6.37; Sample Solvent: MeOH: DCM=1: 1; Injection Volume: 0.6 mL to afford 4- ((S)-1-((S)-1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate D) (5.3 g, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1H-imidazol- 4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate E) (3.6 g, 100% e.e.) as a white solid. Example 1: 4-(1-(1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 1-(2,4-difluorobenzyl)-4-nitro-1H-imidazole

[0015] A mixture of 1-(bromomethyl)-2,4-difluorobenzene (500 mg, 2.42 mmol) and 4- nitroimidazole (350 mg, 3.10 mmol), K2CO3(1.0 g, 7.24 mmol) in DMF (10 mL) was stirred for 1 hour at room temperature. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4and filtered. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-(2,4-difluorobenzyl)-4-nitro-1H-imidazole (500 mg, 86% yield) as a white solid. LCMS (ESI) [M+H]+: 240. Step 2: 1-(2,4-difluorobenzyl)-1H-imidazol-4-amine

[0016] A mixture of 1-(2,4-difluorobenzyl)-4-nitro-1H-imidazole (500 mg, 2.09 mmol) and 10% Pd / C (50 mg, anhydrous) in DCM (10 mL) was stirred for 1 hour at room temperature under a hydrogen atmosphere (2 ATM). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 15 mL). The filtrate was concentrated under reduced pressure to afford 1-(2,4-difluorobenzyl)-1H-imidazol-4-amine (400 mg, crude) as a yellow oil which was used in the next step without further purification. LCMS (ESI) [M+H]+: 210. Step 3: (2R)-2-Bromo-N-(1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)propanamide

[0017] A mixture of 1-(2,4-difluorobenzyl)-1H-imidazol-4-amine (400 mg, 1.91 mmol), (2R)-2- bromopropanoic acid (351 mg, 2.29 mmol), DCC (473 mg, 2.29 mmol) and AgNO3 (65 mg, 0.38 mmol) in DCM (8 mL) was stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (2R)-2-Bromo-N-(1-(2,4-difluorobenzyl)-1H-imidazol-4- yl)propanamide (270 mg, 41% yield) as a white solid. LCMS (ESI) [M+H]+: 344. Step 4: 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0018] A mixture of (2R)-2-bromo-N-{1-[(2,4-difluorophenyl)methyl]imidazol-4- yl}propanamide (100 mg, 0.29 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (52 mg, 0.24 mmol) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30×150 mm, 5µm;Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 30% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 12.28) to afford 4-((3S)-1- (1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin- 3-yl)pyridine 1-oxide (50 mg, 36% yield) as a white solid. LCMS (ESI) [M+H]+: 478. Step 5: 4-((S)-1-((S)-1-((1-(2,4-Difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1-(2,4-difluorobenzyl)- 1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0019] 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (50 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ, 3×25 cm, 5 μm; Mobile Phase A: Hex(0.1% DEA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 212 / 268 nm; RT1(min): 27.06; RT2(min): 30.17; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number Of Runs: 3) to afford 4-((S)-1-((S)-1-((1-(2,4- Difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 1) (Method A, 2.07 min, peak 1, 17.7 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 2) (Method A, 2.65 min, peak 2, 3 mg, 100% e.e.) as a white solid.

[0020] Table 1Step 6: 4-((3R)-1-(1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0021] A mixture of (2R)-2-bromo-N-{1-[(2,4-difluorophenyl)methyl]imidazol-4- yl}propanamide (100 mg, 0.29 mmol), (R)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (52 mg, 0.24 mmol) (Intermediate C) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 30% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 12.28) to afford 4-((3R)-1-(1-((1-(2,4- difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (50 mg, 36% yield) as a white solid. LCMS (ESI) [M+H]+: 478. Step 7: 4-((R)-1-((S)-1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((R)-1-((R)-1-((1-(2,4-difluorobenzyl)- 1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0022] 4-((3R)-1-(1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (50 mg) was purified by Chiral HPLC with the following conditions (Column: CHIRALPAK IC, 2×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 20 mL / min; Gradient: isocratic 50% B; Wave Length: 268 / 214 nm; RT1(min): 6.82; RT2(min): 13.98; Sample Solvent: MeOH) to afford 4-((R)-1-((S)-1-((1-(2,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 3) (Method B, 1.09 min, peak 1, 16.1 mg, 100% e.e.) as a white solid and 4-((R)-1-((R)-1-((1-(2,4-difluorobenzyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 4) (Method B, 2.21 min, peak 2, 6.2 mg, 100% e.e.) as a white solid.

[0023] Table 2Example 2: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-iodo-1-trityl-1H-imidazole

[0024] To a mixture of 4-iodo-1H-imidazole (5 g, 25.7 mmol) and triethylamine (7.83 g, 77.3 mmol) in DMF (20 mL) was added triphenylmethyl chloride (7.19 g, 25.7 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water and filtered. The filter cake was collected and air dried to afford 4-iodo-1-trityl-1H-imidazole (9 g, 80.03% yield) as a white solid. LCMS (ESI) [M+H]+: 437. Step 2: 2-hydroxy-N-(1-trityl-1H-imidazol-4-yl)propanamide

[0025] A mixture of 4-iodo-1-trityl-1H-imidazole (7 g, 16.044 mmol), lactamide (1.43 g, 16.044 mmol), copper iodide (0.31 g, 1.604 mmol), K2CO3(6.65 g, 48.132 mmol, 3 equiv) and (1S,2S)- N,N'-Dimethyl-1,2-cyclohexanediamine (0.23 g, 1.604 mmol, 0.1 equiv) in dioxane (40 mL) was stirred for 2 hours at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was loaded onto a silica gel column and eluted with DCM / MeOH (98:2). This yielded 2-hydroxy-N-(1-trityl-1H-imidazol-4-yl)propanamide (4.05 g, 63.51% yield) as a yellow oil. LCMS (ESI) [M+H]+: 398. Step 3: 1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2-yl 4-methylbenzenesulfonate

[0026] To a mixture of 2-hydroxy-N-(1-trityl-1H-imidazol-4-yl)propanamide (1.2 g, 3.019 mmol) and DIEA (1.17 g, 9.057 mmol) in DCM (15 mL) was added tosyl chloride (1.15 g, 6.038 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 24 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2- yl 4-methylbenzenesulfonate (600 mg, 36.03% yield) as a yellow oil. LCMS (ESI) [M+H]+:552. Step 4: 4-((3S)-4,4-difluoro-1-(1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2- yl)piperidin-3-yl)pyridine 1-oxide

[0027] Into a 8-mL sample vial was placed 1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan- 2-yl 4-methylbenzenesulfonate (150 mg, 0.272 mmol), Intermediate B (58.25 mg, 0.272 mmol), Hunig’s Base (96 µL) and DMA (2 mL). The mixture was stirred at 50 ℃ for 5 hours until LCMS suggested the completion of the reaction by complete consumption of the starting material. The resulting solution was allowed to cool down to room temperature, poured into water (10 mL) and extracted with EA (3 * 10 mL). Organic layers were combined, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (methanol: dichloromethane = 1:15) to give 4-((3S)-4,4-difluoro-1-(1-oxo-1-((1-trityl-1H- imidazol-4-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide (130 mg, 80.53%) as a yellow oil. LCMS (ESI) [M+H]+: 594. Step 5: 4-((3S)-1-(1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide

[0028] HCl (3 mL, 6 mmol, 2M in dioxane) was added into a 8-mL sample vial containing 4- ((3S)-4,4-difluoro-1-(1-oxo-1-((1-trityl-1H-imidazol-4-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide (130 mg, 0.219 mmol). The mixture was stirred at 25℃ for 3 hours until LCMS suggested the completion of the reaction by complete consumption of the starting material. The mixture was concentrated and the crude residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:2 methanol: dichloromethane = 1:15) to give 4-((3S)-1-(1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (70 mg, 91%) as yellow oil. LCMS (ESI) [M+H]+: 352. Step 6: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0029] In a 8-mL sample vial was placed 4-((3S)-1-(1-((1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (70 mg, 0.199 mmol), 1-(bromomethyl)-3,5- difluorobenzene (41.24 mg, 0.199 mmol), K2CO3(82.60 mg, 0.598 mmol) and 5 mL DMF. The mixture was stirred at 25 ℃ for 5 hours until LCMS suggested the completion of the reaction. The mixture was directly purified by Prep-HPLC [Mobile Phase A: water (0.1% NH4HCO3), Mobile Phase B: acetonitrile; Gradient: 50% B to 80% B in 8 min; Rt: 6.03 min] to give 4-((3S)- 1-(1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (35 mg, 36.79%) as a yellow oil. LCMS (ESI)[M+H]+: 478. Step 7: 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1-(3,5-difluorobenzyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0030] 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (35mg) was separated by prep-Chiral-HPLC (Column: CHIRALPAK IC, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 212 / 268 nm; RT1(min): 6.5; RT2(min): 11.3) to afford 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-1H-imidazol- 4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 6) (Method C, 0.79 min, peak 1, 16.0 mg, 100% e.e.) and 4-((S)-1-((R)-1-((1-(3,5-difluorobenzyl)- 1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 5) (Method C, 1.99 min, peak 2, 15.0 mg, 100% e.e.).

[0031] Table 3Example 3: 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-nitro-2-(trifluoromethyl)-1H-imidazole

[0032] 2-(trifluoromethyl)-1H-imidazole (1.0 g, 7.35 mmol) was slowly added into a 20 mL sample vial containing HNO3 (3 mL, 98% in H2O) and H2SO4 (3 mL, 98% in H2O). The resulting mixture was heated and stirred for 1 hour at 100 °C. Upon completion of the reaction as monitored by TLC. The mixture was cooled to room temperature and slowly poured into ice water (40 mL). The white precipitate was collected by filtration to afford crude 4-nitro-2- (trifluoromethyl)-1H-imidazole (1.5g) after air-dry. This crude was further purified by flash column chromatography (PE / EA = 1:1) to afford 4-nitro-2-(trifluoromethyl)-1H-imidazole (800 mg, 61.5% yield) as a white solid. LCMS (ESI) [M+H]+: 182. Step 2: 1-(2,4-difluorobenzyl)-4-nitro-2-(trifluoromethyl)-1H-imidazole

[0033] A mixture of 4-nitro-2-(trifluoromethyl)-1H-imidazole (500 mg, 2.76 mmol), 1- (bromomethyl)-2,4-difluorobenzene (686 mg, 3.31 mmol) and potassium carbonate (762 mg, 5.52 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 3 hours until completion by LCMS. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 15 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (PE / EA = 3:2) to yield 1-(2,4-difluorobenzyl)-4-nitro-2- (trifluoromethyl)-1H-imidazole (300mg, 35.4% yield). LCMS (ESI) [M+H]+: 308. Step 3: 1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-amine

[0034] A solution of tetrahydroxydiboron (292 mg, 3.25 mmol) in DMF (2 mL) was slowly added into a solution of 1-(2,4-difluorobenzyl)-4-nitro-2-(trifluoromethyl)-1H-imidazole (200mg, 651.2 µmol) and 4, 4’ bipyridine (10mg, 65.1 µmol) in DMF (2 mL) at 0 °C. Upon completion of the addition, the solution turned purple and was allowed to warm back to room temperature. The solution was stirred for another 30 minutes and became colorless again. TLCsuggested a complete consumption of the starting material. The mixture was poured into water (20 mL) and extracted with EA (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated under vacuum to give crude 1-(2,4-difluorobenzyl)-2- (trifluoromethyl)-1H-imidazol-4-amine (180 mg, 99.4% quant), which was used for next step directly without further purification. Step 4: 2-bromo-N-(1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)propanamide

[0035] A mixture of 1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-amine (400 mg, 649.36 µmol), 2-bromopropanoic acid (298 mg, 1.95 mmol), DCC (473 mg, 2.29 mmol) and DMAP (65 mg, 64.9 µmol) in THF (5 mL) was stirred for overnight at room temperature. LCMS suggested completely consumption of the starting material. Upon completion, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (95:5) to afford 2-bromo-N-(1-(2,4-difluorobenzyl)- 2-(trifluoromethyl)-1H-imidazol-4-yl)propanamide (120 mg, 44.8% yield) as a yellow oil. LCMS (ESI) [M+H]+: 412. Step 5: 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0036] A mixture of 2-bromo-N-(1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)propanamide (100 mg, 0.29 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (52 mg, 0.24 mmol) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography,eluted with DCM / MeOH (90:10) to afford 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2- (trifluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (55.0 mg, 41.7% yield) as a white solid. LCMS (ESI) [M+H]+: 546. Step 6: 4-((S)-1-((S)-1-((1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)- 1-((1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0037] 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (55mg) was separated by Prep- Chiral HPLC with the following conditions Column: CHIRALPAK IE, 3×25 cm, 5 μm; Mobile Phase A: HEX: MtBE=1: 1(1: 1(0.5% 2M NH3-MEOH), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 15% B; Wave Length: 217 / 270 nm; RT1(min): 17.2; RT2(min): 23.6; Sample Solvent: MeOH: DCM=8:1; Injection Volume: 1 mL; Number Of Runs: 2 to afford 4-((S)-1-((S)-1-((1-(2,4-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 7) (Method D, 2.02 min, peak 1, 9.0 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1-(2,4-difluorobenzyl)-2- (trifluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 8) (Method D, 2.82 min, peak 2, 6.0 mg, 100% e.e.) as a white solid.

[0038] Table 4Example 4: 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 1-(2,4-difluorobenzyl)-2-methyl-4-nitro-1H-imidazole

[0039] A solution of 1-(bromomethyl)-2,4-difluorobenzene (500 mg, 2.41 mmol), 2-methyl-4- nitro-1H-imidazole (368 mg, 2.89 mmol) and K2CO3(1 g, 7.23 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-(2,4-difluorobenzyl)-2-methyl-4-nitro-1H-imidazole (550 mg, 89% yield) as a white solid. LCMS (ESI) [M+H]+: 254. Step 2: 1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-amine

[0040] A solution of 1-(2,4-difluorobenzyl)-2-methyl-4-nitro-1H-imidazole (550 mg, 2.17 mmol) and 10% Pd / C (55 mg, anhydrous) in DCM (5 mL) was stirred for 2 hours at room temperature under hydrogen atmosphere (2 atm). The resulting mixture was filtered, and the filter cake was washed with DCM (3x10 mL). The filtrate was concentrated under reduced pressure to afford 1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-amine (450 mg, crude) as a white solid which was used with no further purification. LCMS (ESI) [M+H]+: 224. Step 3: 2-bromo-N-(1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)propanamide

[0041] A mixture of 1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-amine (450 mg, 2.01 mmol), 2-bromopropanoic acid (370 mg, 2.41 mmol), DCC (499 mg, 2.41 mmol) and AgNO3 (68 mg, 0.40 mmol) in DCM (10 mL) was stirred for overnight at room temperature under air atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-bromo-N-(1-(2,4- difluorobenzyl)-2-methyl-1H-imidazol-4-yl)propanamide (350 mg, 48.47% yield) as a white solid. LCMS (ESI) [M+H]+: 358. Step 4: 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0042] A mixture of 2-bromo-N-(1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4- yl)propanamide (100 mg, 0.27 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (71 mg, 0.33 mmol) and TEA (85 mg, 0.84 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD Column, 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 30% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 12.28) to afford 4-((3S)- 1-(1-((1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (80 mg, 58% yield) as a white solid. LCMS (ESI) [M+H]+: 492 Step 5: 4-((S)-1-((S)-1-((1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1-(2,4- difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0043] 4-((3S)-1-(1-((1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (80 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK IE, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 40% B; Wave Length: 268 / 214 nm; RT1(min): 6.2; RT2(min): 7.58; Sample Solvent: MEOH; Injection Volume: 1.0 mL; Number Of Runs: 3) to afford 4-((S)-1-((S)-1-((1-(2,4- difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 9) (Method E, 0.75 min, peak 1, 27.9 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1-(2,4-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 10) (Method E, 0.94 min, peak 2, 14 mg, 100% e.e.) as a white solid.

[0044] Table 5Example 5: 4-((3S)-1-(1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-bromopropanamide

[0045] A mixture of [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine (70 mg, 360.44 µmol), 2-bromopropanoic acid (55.14 mg, 360.44 µmol), NMI (45 mg, 540.66 µmol) and TCFH (227 mg, 540.66 µmol) in ACN (2 mL) was stirred for overnight at room temperature. LCMS suggested complete consumption of the starting material. The resulting mixture was directly purified by reverse phase column chromatography, eluted with formic acid (0.1 M in H2O) to afford N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-bromopropanamide (75 mg, 63.5% yield) as a white solid. LCMS (ESI) [M+H]+: 329.15 / 331.15. Step 2: 4-((3S)-1-(1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0046] A mixture of N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-bromopropanamide (75 mg, 227.85 µmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (49 mg, 227.85 µmol) and TEA (70 mg, 684.2 µmol) in DMA (1 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to 4-((3S)-1-(1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (46.0 mg, 43.8% yield) as a white solid. LCMS (ESI) [M+H]+: 463.12. Step 3: 4-((S)-1-((S)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((S)-1- ([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0047] 4-((3S)-1-(1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (46mg) was separated by Prep-HPLC with the following conditions Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 19% B to 35% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 12.15 / 12.77 to afford first peak 4-((S)-1-((S)-1- ([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl)-4,4-difluoropiperidin- 3-yl)pyridine 1-oxide (Compound 12) (Method F, 4.08 min, peak 1, 15.0 mg, 96.64% e.e.) as a white solid and second peak 4-((S)-1-((S)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- ylamino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 11) (Method F, 4.52 min, peak 2, 9.0 mg, 100% e.e.) as a white solid.

[0048] Table 6Example 6: 4-((3S)-1-(1-((1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 1-(3,5-difluorophenyl)ethan-1-ol

[0049] A mixture of 1-(3,5-difluorophenyl)ethan-1-one (2g, 12.81 mmol, 1 equiv) and sodium boron hydride (1.45g, 39 mmol, 3 equiv) in methanol (10 mL) was stirred for 5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford 1-(3,5- difluorophenyl)ethan-1-ol (1.5 g, 74% yield) as a white solid. Step 2: 1-(1-bromoethyl)-3,5-difluorobenzene

[0050] A mixture of 1-(3,5-difluorophenyl)ethan-1-ol (1.5g, 9.48 mmol, 1 equiv) and PBr3 (2.56g, 9.48 mmol, 1 equiv) in DCM (10 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-(1-bromoethyl)-3,5-difluorobenzene (1g, 47% yield) as light yellow oil. Step 3: 1-(1-(3,5-difluorophenyl)ethyl)-4-nitro-1H-imidazole

[0051] A mixture of 4-nitro-1H-imidazole (511 mg, 4.52 mmol, 1 equiv), 1-(1-bromoethyl)-3,5- difluorobenzene (1g, 4.52 mmol, 1 equiv), K2CO3(1.6 g, 13 mmol, 3 equiv) in ACN (10 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (9:1) to afford 1-(1-(3,5-difluorophenyl)ethyl)-4-nitro-1H-imidazole (1g, 87% yield) as a white solid.

[0052] LCMS (ESI) [M+H]+: 254.07. Step 4: 1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-amine

[0053] A solution of 1-(1-(3,5-difluorophenyl)ethyl)-4-nitro-1H-imidazole (350 mg, 0.86 mmol, 1 equiv) and tetrahydroxydiboron(166 mg, 3.3 mmol, 4 equiv) in DMF (3 mL) was added 4- (pyridin-4-yl)pyridine (10 mg, 0.38 mmol, 0.3 equiv) dropwise at 0 °C .The resulting mixture was stirred at 0 °C for 15 minutes. Upon completion, the mixture was diluted with water (10mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. This resulted in 1-(1-(3,5-difluorophenyl)ethyl)-1H- imidazol-4-amine (248 mg, 80% yield) as a white solid, which was used for next step directly without further purification.

[0054] LCMS (ESI) [M+H]+: 224.09. Step 5: 2-bromo-N-(1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)propanamide

[0055] A solution of 1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-amine (248 mg, 1.1 mmol, 1 equiv), DIEA (500 mg, 3.6 mmol, 3 equiv) and 2-bromopropanoyl bromide (280 mg, 1.1 mmol, 1 equiv) in THF (8 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-bromo-N-(1-(1-(3,5- difluorophenyl)ethyl)-1H-imidazol-4-yl)propanamide (159 mg, 39% yield) as a white solid.

[0056] LCMS (ESI) [M+H]+: 358.03 Step 6: 4-((3S)-1-(1-((1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0057] A mixture of 2-bromo-N-(1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4- yl)propanamide (159 mg, 0.44 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (95 mg, 0.44 mmol) and TEA (100 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford 4-((3S)-1-(1-((1-(1-(3,5-difluorophenyl)ethyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (58.0mg, 26% yield) as a white solid.

[0058] LCMS (ESI) [M+H]+: 492.19.Step 7: 4-((S)-1-((S)-1-((1-((S)-1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide, 4-((S)-1-((R)-1-((1-((R)-1-(3,5- difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide, 4-((S)-1-((R)-1-((1-((S)-1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((S)- 1-((1-((R)-1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0059] 4-((3S)-1-(1-((1-(1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (58.0 mg) was separated by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10mmol / L NH4HCO3), 5% to 100% gradient in 20 min to give two portions (24 mg, RT: 11 min, 27 mg, RT: 14 min), each is a mixture of diastereomers. The first portion was separated by Prep-Chiral HPLC with the following conditions Column: CHIRALPAK IA, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 212 / 268 nm; RT1(min): 5.89; RT2(min): 10.08; Sample Solvent: MEOH; Injection Volume: 2.6 mL; Number Of Runs: 2 to afford 4-((S)-1-((R)- 1-((1-((S)-1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 13) (Method G, 1.07 min, peak 1, 6.9 mg,100% e.e.) as a white solid (RT1) and 4-((S)-1-((S)-1-((1-((R)-1-(3,5-difluorophenyl)ethyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 14) (Method G, 2.45 min, peak 2, 8.6 mg, 98.94% e.e.) (RT2). The second portion was separated by Column: CHIRALPAK IE, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 20% B; Wave Length: 214 / 272 nm; RT1(min): 9.87; RT2(min): 16.12; Sample Solvent: MeOH: DCM=1:1; Injection Volume: 2.0 mL; Number Of Runs: 2 to afford 4-((S)-1-((S)-1-((1-((S)-1-(3,5- difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 15) (Method H, 1.26 min, peak 1, 8.7 mg, 100% e.e.) as a white solid (RT1) and 4-((S)-1-((R)-1-((1-((R)-1-(3,5-difluorophenyl)ethyl)-1H-imidazol-4-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 16) (Method H, 1.59 min, peak 2, 7.5 mg, 100% e.e.) (RT2) as a white solid.

[0060] Table 7Example 7: 4-((3S)-1-(1-((1-(3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 3-(bromomethyl)-5-fluorobenzonitrile

[0061] A mixture of 3-fluoro-5-methylbenzonitrile (500 mg, 3.7 mmol, 1 equiv), AIBN (728mg, 4.44 mmol, 1.2 equiv), NBS (790 mg, 4.44 mmol, 1.2 equiv) in CCl4 (5 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE to afford 3-(bromomethyl)-5- fluorobenzonitrile (320 mg, 40% yield) as light yellow oil. Step 2: 3-fluoro-5-((2-methyl-4-nitro-1H-imidazol-1-yl)methyl)benzonitrile

[0062] A mixture of 2-methyl-4-nitro-1H-imidazole (190 mg, 1.5 mmol, 1 equiv), 3- (bromomethyl)-5-fluorobenzonitrile (320mg, 1.5 mmol, 1 equiv), K2CO3(621 mg, 4.5 mmol, 3 equiv) in ACN (5 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (9:1) to afford 3-fluoro-5-((2-methyl-4-nitro-1H-imidazol-1- yl)methyl)benzonitrile (224 mg, 57% yield) as a white solid.

[0063] LCMS (ESI) [M+H]+: 261.07. Step 3: 3-((4-amino-2-methyl-1H-imidazol-1-yl)methyl)-5-fluorobenzonitrile

[0064] A solution of 3-fluoro-5-((2-methyl-4-nitro-1H-imidazol-1-yl)methyl)benzonitrile (224 mg, 0.86 mmol, 1 equiv) and tetrahydroxydiboron(166 mg, 3.3 mmol, 4 equiv) in DMF (3 mL) was added 4-(pyridin-4-yl)pyridine (10 mg, 0.38 mmol, 0.3 equiv) dropwise at 0 °C .The resulting mixture was stirred at 0 °C for 15 minutes. Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. This resulted in 3-((4-amino-2-methyl-1H- imidazol-1-yl)methyl)-5-fluorobenzonitrile (150 mg, 75% yield) as a white solid, which was used for next step directly without further purification.

[0065] LCMS (ESI) [M+H]+: 231.10. Step 4: 2-bromo-N-(1-(3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)propanamide

[0066] A solution of 3-((4-amino-2-methyl-1H-imidazol-1-yl)methyl)-5-fluorobenzonitrile (150 mg, 0.65 mmol, 1 equiv), DIEA (250 mg, 1.8 mmol, 3 equiv) and 2-bromopropanoyl bromide (140 mg, 0.65 mmol, 1 equiv) in DCM (5 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-bromo-N-(1-(3-cyano-5- fluorobenzyl)-2-methyl-1H-imidazol-4-yl)propanamide (144 mg, 60% yield) as a white solid.

[0067] LCMS (ESI) [M+H]+: 365 Step 5: 4-((3S)-1-(1-((1-(3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0068] A mixture of 2-bromo-N-(1-(3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4- yl)propanamide (144 mg, 0.39 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (84 mg, 0.39 mmol) and TEA (100 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford 4-((3S)-1-(1-((1-(3-cyano-5-fluorobenzyl)-2- methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (86.7 mg, 44% yield) as a white solid.

[0069] LCMS (ESI) [M+H]+: 499.20. Step 6: 4-((S)-1-((S)-1-((1-(3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1-(3- cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0070] 4-((3S)-1-(1-((1-(3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (86.7 mg) was separated by Prep-Chiral HPLC with the following conditions Column: CHIRALPAK IE, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 40% B; Wave Length: 212 / 270 nm; RT1(min): 7.39; RT2(min): 8.20; Sample Solvent: MeOH: DCM=1:1; Injection Volume: 0.6 mL; Number Of Runs: 6 to afford 4-((S)-1-((S)-1-((1- (3-cyano-5-fluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 17) (Method E, 0.75 min, peak 1, 24.9 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1-(3-cyano-5-fluorobenzyl)-2-methyl-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 18) (Method E, 0.90 min, peak 2, 30.0 mg, 98.94% e.e.) as a white solid.

[0071] Table 8Example 8: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 1-(3,5-difluorobenzyl)-2-methyl-4-nitro-1H-imidazole

[0072] A mixture of 2-methyl-4-nitro-1H-imidazole (700 mg, 5.51 mmol, 1 equiv), 1- (bromomethyl)-3,5-difluorobenzene (1.14g, 5.51 mmol, 1 equiv), K2CO3(1.60 g, 11.59 mmol, 3 equiv) in ACN (10 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (9:1) to afford 1-(3,5-difluorobenzyl)-2-methyl-4-nitro-1H-imidazole (630 mg, 53% yield) as a white solid.

[0073] LCMS (ESI) [M+H]+: 254.10. Step 2: 1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-amine

[0074] A solution of 1-(3,5-difluorobenzyl)-2-methyl-4-nitro-1H-imidazole (300 mg, 1.18 mmol, 1 equiv) and tetrahydroxydiboron (466 mg, 4.80 mmol, 4 equiv) in DMF (3 mL) was added 4-(pyridin-4-yl)pyridine (60 mg, 0.38 mmol, 0.3 equiv) dropwise at 0 °C .The resulting mixture was stirred at 0 °C for 15 minutes. Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. This resulted in 1-(3,5-difluorobenzyl)-2-methyl-1H- imidazol-4-amine (180 mg, 68% yield) as a white solid, which was used for next step directly without further purification.

[0075] LCMS (ESI) [M+H]+: 224.09. Step 3: 2-bromo-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)propanamide

[0076] A solution of 1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-amine (180 mg, 0.80 mmol, 1 equiv), DCC (180 mg, 0.95 mmol, 1.2 equiv), DMAP (50 mg, 0.5 mmol, 0.5 equiv) and α-bromopropionic acid (298 mg, 1.94 mmol, 3 equiv) in THF (5 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-bromo- N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)propanamide (201 mg, 69% yield) as a white solid.

[0077] LCMS (ESI) [M+H]+: 358 Step 5: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0078] A mixture of 2-bromo-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4- yl)propanamide (100 mg, 0.29 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (52 mg, 0.24 mmol) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-methyl-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (33.0 mg, 24% yield) as a white solid. LCMS (ESI) [M+H]+: 546. Step 6: 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1-(3,5- difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0079] 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (33.0mg) was separated by Prep-Chiral HPLC with the following conditions Column: CHIRALPAK IE, 3×25 cm, 5 μm; Mobile Phase A: HEX: MtBE=1: 1(1: 1(0.5% 2M NH3-MEOH), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 15% B; Wave Length: 217 / 270 nm; RT1(min): 17.2; RT2(min): 23.6; Sample Solvent: MeOH: DCM=8: 1; Injection Volume: 1 mL; Number Of Runs: 2 to afford 4- ((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 19) (Method E, 0.71 min, peak 1, 10.0 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1-(3,5-difluorobenzyl)-2-methyl-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 20) (Method E, 0.87 min, peak 2, 11.0 mg, 100% e.e.) as a white solid.

[0080] Table 9 Compound# Characterization DataExample 9: N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-(4,4-difluoropiperidin- 1-yl)propanamide Step 1: N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-(4,4-difluoropiperidin-1- yl)propanamide

[0081] A mixture of 2-bromo-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4- yl)propanamide (100 mg, 0.29 mmol), 4,4-difluoropiperidine (78 mg, 0.58 mmol) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford N-(1- (3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-(4,4-difluoropiperidin-1-yl)propanamide (29.0 mg, 26% yield) as a white solid.

[0082] LCMS (ESI) [M+H]+: 399.17. Step 2: (S)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-(4,4-difluoropiperidin- 1-yl)propanamide and (R)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-(4,4- difluoropiperidin-1-yl)propanamide

[0083] N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-(4,4-difluoropiperidin-1- yl)propanamide (29.0mg) was separated by prep chiral HPLC (Column: CHIRAL ART Cellulose-SZ, 3×25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B:EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 214 / 244 nm;RT1(min): 6.2; RT2(min): 8.4; Sample Solvent: ETOH: DCM=1: 1; Injection Volume: 1 mL; Number Of Runs: 1) to afford (S)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2- (4,4-difluoropiperidin-1-yl)propanamide (Compound 21) (Method I, 0.74 min, peak 1, 14.1 mg, 100% e.e.) as a white solid and (R)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2- (4,4-difluoropiperidin-1-yl)propanamide (Compound 22) (Method I, 1.18 min, peak 2, 13.5 mg, 99.82% e.e.) as a white solid.

[0084] Table 10Example 10: N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2- morpholinopropanamide Step 1: N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-morpholinopropanamide

[0085] A mixture of 2-bromo-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4- yl)propanamide (100 mg, 0.29 mmol), morpholine (48 mg, 0.58 mmol) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford N-(1-(3,5- difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-morpholinopropanamide (43.0 mg, 42% yield) as a white solid.

[0086] LCMS (ESI) [M+H]+: 365.17. Step 2: (S)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2- morpholinopropanamide and (R)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2- morpholinopropanamide

[0087] N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-morpholinopropanamide (43.0mg) was separated by prep chiral HPLC (Column: CHIRAL ART Cellulose-SZ, 3×25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 214 / 224 nm; RT1(min): 8.6; RT2(min): 11.8; Sample Solvent: EtOH DCM=3: 2; Injection Volume: 1.2 mL; Number Of Runs: 2) to afford (S)-N-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-morpholinopropanamide (Compound 23) (Method I, 1.01 min, peak 1, 13.8 mg, 100% e.e.) as a white solid and (R)-N-(1- (3,5-difluorobenzyl)-2-methyl-1H-imidazol-4-yl)-2-morpholinopropanamide (Compound 24) (Method I, 1.39 min, peak 2, 10.3 mg, 99.9% e.e.) as a white solid.

[0088] Table 11Example 11: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-nitro-2-(trifluoromethyl)-1H-imidazole

[0089] 2-(trifluoromethyl)-1H-imidazole (1.0 g, 7.35 mmol) was slowly added into a 20 mL sample vial containing HNO3 (3 mL, 98% in H2O) and H2SO4 (3 mL, 98% in H2O). The resulting mixture was heated and stirred for 1 hour at 100 °C. Upon completion of the reaction as monitored by TLC. The mixture was cooled to room temperature and slowly poured into ice water (40 mL). The white precipitate was collected by filtration and air dried to give crude 4-nitro-2-(trifluoromethyl)-1H-imidazole (1.5 g), which was further purified by flash column chromatography (PE / EA; 1:1) to afford 4-nitro-2-(trifluoromethyl)-1H-imidazole (800 mg, 61.5% yield) as a white solid. LCMS (ESI) [M+H]+: 182. Step 2: 1-[(3,5-difluorophenyl)methyl]-4-nitro-2-(trifluoromethyl)imidazole

[0090] A mixture of 4-nitro-2-(trifluoromethyl)-1H-imidazole (700 mg, 3.86 mmol, 1 equiv), 1- (bromomethyl)-3,5-difluorobenzene (800 mg, 3.866 mmol, 1 equiv), K2CO3(1.60 g, 11.59 mmol, 3 equiv) in ACN (10 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (9:1) to afford 1-[(3,5-difluorophenyl)methyl]-4-nitro- 2-(trifluoromethyl)imidazole (630 mg, 53% yield) as a white solid.

[0091] LCMS (ESI) [M+H]+: 308. Step 3: 1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-amine

[0092] A solution of 1-[(3,5-difluorophenyl)methyl]-4-nitro-2-(trifluoromethyl)imidazole (200 mg, 0.65 mmol, 1 equiv) and tetrahydroxydiboron(233 mg, 2.60 mmol, 4 equiv) in DMF (3 mL) was added 4,4′−Dipyridyl (30 mg, 0.19 mmol, 0.3 equiv) dropwise at 0 °C .The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. This resulted in 1-(3,5- difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-amine (180 mg, 99% yield) as a white solid. This crude product was carried to the next step without further purification.

[0093] LCMS (ESI) [M+H]+: 278. Step 4: 2-bromo-N-(1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)propanamide

[0094] A solution of 1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-amine (180 mg, 0.64 mmol, 1 equiv), DCC (160 mg, 0.77 mmol, 1.2 equiv), DMAP (39 mg, 0.32 mmol, 0.5 equiv) and α-bromopropionic acid (298 mg, 1.94 mmol, 3 equiv) in THF (5 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-bromo-N-(1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)propanamide (201 mg, 75% yield) as a white solid.

[0095] LCMS (ESI) [M+H]+: 412 Step 5: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0096] A mixture of 2-bromo-N-(1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)propanamide (100 mg, 0.29 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (52 mg, 0.24 mmol) and TEA (74 mg, 0.73 mmol) in DMA (3 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were separated, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2- (trifluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (14 mg, 21% yield) as a white solid. LCMS (ESI) [M+H]+: 546. Step 6: 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)- 1-((1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0097] 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (14mg) was separated by Prep- Chiral HPLC with the following conditions Column: CHIRALPAK IE, 3×25 cm, 5 μm; Mobile Phase A: HEX: MtBE=1: 1(1: 1(0.5% 2M NH3-MEOH), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 15% B; Wave Length: 217 / 270 nm; RT1(min): 17.2; RT2(min): 23.6; Sample Solvent: MeOH: DCM=8: 1; Injection Volume: 1 mL; Number Of Runs: 2 to afford 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 25) (Method A, 0.93 min, peak 1, 2.0 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((1-(3,5-difluorobenzyl)-2- (trifluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 26) (Method A, 1.46 min, peak 2, 4.9 mg, 100% e.e.) as a white solid.

[0098] Table 12Example 12: 4-((3S)-1-(1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide Step 1: ethyl 2-(3,5-difluorobenzyl)oxazole-4-carboxylate

[0099] A solution of ethyl 1,3-oxazole-4-carboxylate (5 g, 35.42 mmol, 1 equiv) in dioxane (20 mL) was treated with 1-(bromomethyl)-3,5-difluorobenzene (8.8 g, 42.51 mmol, 1.2 equiv), Pd(OAc)2(0.8 g, 3.54 mmol, 0.1 equiv), Cs2CO3(23.09 g, 70.85 mmol, 2 equiv), (2- Biphenyl)dicyclohexylphosphine (CyJohnPhos) (2.48 g, 7.08 mmol, 0.2 equiv) for 2 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (5:1) to afford ethyl 2- (3,5-difluorobenzyl)oxazole-4-carboxylate (4.5 g, 47% yield) as a brown solid.

[0100] LCMS (ESI) [M+H]+: 268. Step 2: 2-(3,5-difluorobenzyl)oxazole-4-carboxylic acid

[0101] A solution of ethyl 2-(3,5-difluorobenzyl)oxazole-4-carboxylate (4 g, 14.96 mmol, 1 equiv) and LiOH (1.79 g, 74.84 mmol, 5 equiv) in THF (20 mL) and H2O (20 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 1 with conc. HCl. The resulting mixture was concentrated under reduced pressure to remove organic solvent. The precipitated solids were collected by filtration and washed with acetone. This resulted in 2-(3,5- difluorobenzyl)oxazole-4-carboxylic acid (3 g, 83%yield) as a brown solid.

[0102] LCMS (ESI) [M+H]+: 240. Step 3: tert-butyl (2-(3,5-difluorobenzyl)oxazol-4-yl)carbamate

[0103] A solution of 2-(3,5-difluorobenzyl)oxazole-4-carboxylic acid (3 g, 12.54 mmol, 1 equiv) in t-BuOH (50 mL) was treated with TEA (5.08 g, 50.17 mmol, 4 equiv) for 2 h at room temperature under nitrogen atmosphere followed by the addition of DPPA (10.36 g, 37.62 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred overnight at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (3:1) to afford tert-butyl (2-(3,5- difluorobenzyl)oxazol-4-yl)carbamate (600 mg, 15% yield) as a brown solid.

[0104] LCMS (ESI) [M+H]+: 311.Step 4: tert-butyl (2-bromopropanoyl)(2-(3,5-difluorobenzyl)oxazol-4-yl)carbamate

[0105] A solution of tert-butyl (2-(3,5-difluorobenzyl)oxazol-4-yl)carbamate (200 mg, 0.64 mmol, 1 equiv) in THF (3 mL) was treated with NaH (60% in mineral oil, 77 mg, 3.22 mmol, 5 equiv) for 15 min at 0 °C under nitrogen atmosphere followed by the addition of 2- bromopropanoyl bromide (417 mg, 1.93 mmol, 3 equiv) dropwise at 0 °C. The reaction was quenched by the addition of MeOH. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (2:3) to afford tert-butyl (2-bromopropanoyl)(2-(3,5-difluorobenzyl)oxazol-4-yl)carbamate (170 mg, 59% yield) as a yellow solid.

[0106] LCMS (ESI) [M+H]+: 445. Step 5: 4-((3S)-1-(1-((tert-butoxycarbonyl)(2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0107] tert-butyl (2-bromopropanoyl)(2-(3,5-difluorobenzyl)oxazol-4-yl)carbamate (170 mg, 0.38 mmol, 1 equiv) in DMA (3 mL) was treated with (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (81 mg, 0.38) and TEA (4 mg, 0.03 mmol, 0.1 equiv) and the mixture was stirred for 2 days at room temperature. The resulting solution was poured into water (10 mL) and extracted with CH2Cl2. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (15:1) to afford 4-((3S)-1-(1-((tert-butoxycarbonyl)(2-(3,5-difluorobenzyl)oxazol-4-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (90 mg, 40% yield) as a dark yellow oil.

[0108] LCMS (ESI) [M+H]+: 579. Step 6: 4-((3S)-1-(1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0109] A solution of 4-((3S)-1-(1-((tert-butoxycarbonyl)(2-(3,5-difluorobenzyl)oxazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (90 mg, 0.15 mmol, 1 equiv) and TFA (2 mL) in DCM (2 mL) was stirred for 2 h at room temperature .The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 24% B to 44% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.25 / 8.55) to afford 4-((3S)-1-(1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (35 mg, 47% yield) as a white solid.

[0110] LCMS (ESI) [M+H]+: 479. Step 7: 4-((S)-1-((S)-1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((2-(3,5-difluorobenzyl)oxazol- 4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0111] 4-((3S)-1-(1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (35 mg, 0.07 mmol, 1 equiv) was purified by Chiral- HPLC with the following conditions (Column: CHIRAL ART Cellulose-SB, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 10% B; Wave Length: 276 / 218 nm; RT1(min): 14.16; RT2(min): 17.24; Sample Solvent: MEOH; Injection Volume: 1.5 mL; Number Of Runs: 2) to afford 4-((S)-1- ((S)-1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 27) (Method J, 1.63 min, peak 1, 4.1 mg, 100% e.e.) as a white solid and 4-((S)-1-((R)-1-((2-(3,5-difluorobenzyl)oxazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 28) (Method J, 1.97 min, peak 2, 3.6 mg, 99.715% e.e.) as a white solid.

[0112] LCMS (ESI) [M+H]+: 479.

[0113] Table 13Example 13: N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2-difluorospiro[2.3]hexane-1- carboxamide Step 1: ethyl 2,2-difluorospiro[2.3]hexane-1-carboxylate

[0114] A mixture of ethyl 2-cyclobutylideneacetate (1 g, 7.13 mmol), sodium iodide (2.11g, 14.26 mmol), trimethyl(trifluoromethyl)silane (3.03 g, 21.39 mmol) in freshly distilled THF (10 mL) was stirred for 14 h at 80 °C. The resulting mixture was poured into water (40 mL) and extracted with PE (3 × 30 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to afford crude ethyl 2,2-difluorospiro[2.3]hexane-1- carboxylate (1.2g, 53% yield) as colorless oil, which was used in the next step without further purification.1H NMR (400 MHz, Chloroform-d) δ 4.17 (q, J = 7.1 Hz, 2H), 3.17 – 3.08 (m, 2H), 2.95 – 2.76 (m, 2H), 2.63 – 2.19 (m, 1H), 2.11 (p, J = 8.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). Step 2: 2,2-difluorospiro[2.3]hexane-1-carboxylic acid

[0115] A mixture of ethyl 2,2-difluorospiro[2.3]hexane-1-carboxylate (1.2 g, 6.31 mmol), sodium hydroxide (2.52 g, 63.1 mmol) in methanol (10 mL) and water (10 mL) was stirred for 3 h at room temperature. The pH of the resulting mixture was adjusted to 3 and excess methanol was removed under reduced pressure. The crude residue was extracted with EA (3 × 10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to afford crude 2,2-difluorospiro[2.3]hexane-1-carboxylic acid (900 mg, 88% yield) as colorless oil, which was used in the next step without further purification.

[0116] LCMS (ESI) [M-H]+: 161.1. Step 3: 1-(3,5-difluorobenzyl)-4-nitro-1H-imidazole

[0117] A mixture of 4-nitro-1H-imidazole (700 mg, 5.51 mmol), 1-(bromomethyl)-3,5- difluorobenzene (1.14 g, 5.51 mmol), potassium carbonate (1.60 g, 11.59 mmol) in ACN (10 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (9:1) to afford 1-(3,5-difluorobenzyl)-4-nitro-1H-imidazole (630 mg, 53% yield) as a white solid.

[0118] LCMS (ESI) [M+H]+: 240.1. Step 4: 1-(3,5-difluorobenzyl)-1H-imidazol-4-amine

[0119] A solution of 1-(3,5-difluorobenzyl)-4-nitro-1H-imidazole (300 mg, 1.18 mmol) and tetrahydroxydiboron (466 mg, 4.80 mmol) in DMF (3 mL) was added 4-(pyridin-4-yl)pyridine (60 mg, 0.38 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 15 minutes. Upon completion, the mixture washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford 1-(3,5- difluorobenzyl)-1H-imidazol-4-amine (180 mg, 68% yield) as a white solid, which was used in the next step without further purification.

[0120] LCMS (ESI) [M+H]+: 210.1. Step 5: N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2-difluorospiro[2.3]hexane-1- carboxamide

[0121] A solution of 1-(3,5-difluorobenzyl)-1H-imidazol-4-amine (180 mg, 0.80 mmol), DCC (180 mg, 0.95 mmol), DMAP (50 mg, 0.5 mmol) and 2,2-difluorospiro[2.3]hexane-1-carboxylicacid (298 mg, 1.94 mmol) in THF (5 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)-2,2-difluorospiro[2.3]hexane-1-carboxamide (14.1 mg, 4.64% yield) as a white solid.

[0122] LCMS (ESI) [M+H]+: 354.1 Step 6: (R)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2-difluorospiro[2.3]hexane-1- carboxamide and (S)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2- difluorospiro[2.3]hexane-1-carboxamide

[0123] N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2-difluorospiro[2.3]hexane-1- carboxamide (8.0 mg) was separated by prep chiral HPLC (Column: CHIRAL ART Cellulose- SZ, 3×25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 20% B; Wave Length: 240 / 208 nm; RT1(min): 5.54; RT2(min): 7.54) to afford (R)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2- difluorospiro[2.3]hexane-1-carboxamide (Compound 29) (2.6 mg, 100 e.e.) as a white solid and (S)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)-2,2-difluorospiro[2.3]hexane-1-carboxamide (Compound 30) (2.6 mg, 99.9% e.e.) as a white solid.

[0124] Table 14Example 14: 4-((S)-1-((S)-1-((1-(4-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(4-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0125] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) were added 1- (bromomethyl)-4-chloro-2-fluorobenzene (25 mg, 0.11 mmol, 1.3 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4- ((S)-1-((S)-1-((1-(4-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 31) (14.4 mg, 34% yield) as a white solid.

[0126] LCMS (ESI) [M+H]+: 494.1

[0127] 1H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J = 6.8 Hz, 2H), 7.64 – 7.51 (m, 3H), 7.37 – 7.09 (m, 4H), 5.23 (s, 2H), 3.73 – 3.48 (m, 2H), 3.06 – 3.00 (m, 2H), 2.66 – 2.58 (m, 1H), 2.31 – 2.09 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H). Example 15: 4-[(3S)-4,4-difluoro-1-[(1S)-1-({1-[(2,3,4,5-tetrafluorophenyl)methyl]imidazol- 4-yl}carbamoyl)ethyl]piperidin-3-yl]pyridin-1-ium-1-olate Step 1: 4-[(3S)-4,4-difluoro-1-[(1S)-1-({1-[(2,3,4,5-tetrafluorophenyl)methyl]imidazol-4- yl}carbamoyl)ethyl]piperidin-3-yl]pyridin-1-ium-1-olate

[0128] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) were added 1- (bromomethyl)-2,3,4,5-tetrafluorobenzene (23 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogenatmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4- [(3S)-4,4-difluoro-1-[(1S)-1-({1-[(2,3,4,5-tetrafluorophenyl)methyl]imidazol-4- yl}carbamoyl)ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Compound 32) (19.4 mg, 44% yield) as a white solid.

[0129] LCMS [M+H]+: 514.2

[0130] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.17 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 1.5 Hz, 1H), 7.51 – 7.43 (m, 1H), 7.37 (d, J = 6.6 Hz, 2H), 7.29 (d, J = 1.5 Hz, 1H), 5.25 (s, 2H), 3.55 (d, J = 6.9 Hz, 1H), 3.45 (d, J = 26.0 Hz, 2H), 3.02 – 2.82 (m, 3H), 2.17 – 1.98 (m, 2H), 1.18 (s, 3H). Example 16: 4-((S)-1-((S)-1-((1-(5-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(5-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0131] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) were added 2- (bromomethyl)-4-chloro-1-fluorobenzene (25 mg, 0.11 mmol, 1.3 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 2% B in 1.5 min, 2% B to 15% B in 2 min, 15% B to 36% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.6) to afford 4-((S)-1-((S)-1-((1-(5-chloro-2-fluorobenzyl)- 1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 33) (6.8 mg, 15% yield) as a white solid.

[0132] LCMS [M+H]+: 494.2

[0133] 1H NMR (300 MHz, Methanol-d4) δ 8.29 (d, J = 6.6 Hz, 2H), 7.66 – 7.50 (m, 3H), 7.45 – 7.26 (m, 3H), 7.16 (t, J = 9.1 Hz, 1H), 5.24 (s, 2H), 3.73 – 3.41 (m, 2H), 3.10 – 2.84 (m, 3H), 2.68 – 2.59 (m, 1H), 2.46 – 2.05 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H). Example 17: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(3,4,5-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(3,4,5-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0134] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) were added 5- (bromomethyl)-1,2,3-trifluorobenzene (25 mg, 0.11 mmol, 1.3 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30×150, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 14% B in 2 min, 14% to 33% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9.33) to afford 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(3,4,5- trifluorobenzyl)-1H-imidazol-4-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide (Compound 34) (13.2 mg, 31% yield) as a white solid.

[0135] LCMS [M+H]+: 496.2

[0136] 1H NMR (300 MHz, Methanol-d4) δ 8.29 (d, J = 7.2 Hz, 2H), 7.66 – 7.54 (m, 3H), 7.30 (d, J = 1.6 Hz, 1H), 7.07 (t, J = 6.9 Hz, 2H), 5.17 (s, 2H), 3.73 – 3.46 (m, 2H), 3.11 – 2.86 (m, 3H), 2.66 – 2.53 (m, 1H), 2.40 – 2.04 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H). Example 18: 4-((S)-1-((S)-1-((1-(2-chloro-5-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxideStep 1: 4-((S)-1-((S)-1-((1-(2-chloro-5-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0137] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) was added 2- (bromomethyl)-1-chloro-4-fluorobenzene (22 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 34% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 10.7) to afford 4-((S)-1-((S)-1-((1-(2-chloro-5-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 35) (21.7 mg, 51% yield) as a white solid.

[0138] LCMS [M+H]+: 494.1

[0139] 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 5.1 Hz, 2H), 7.62 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 6.4 Hz, 2H), 7.47 (dd, J = 8.9, 5.0 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.16 – 7.10 (m, 1H), 6.97 (d, J = 8.9 Hz, 1H), 5.31 (s, 2H), 3.64 – 3.49 (m, 2H), 3.08 – 2.91 (m, 1H), 2.74 – 2.62 (m, 1H), 2.40 – 2.12 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H).

[0140] Example 19: 4-((S)-4,4-difluoro-1-((S)-1-((1-(4-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-((1-(4-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0141] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) were added 1-(bromomethyl)-4-fluorobenzene (20 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.35) to afford 4- ((S)-4,4-difluoro-1-((S)-1-((1-(4-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)piperidin-3-yl)pyridine 1-oxide (Compound 36) (11.4 mg, 28% yield) as a white solid.

[0142] LCMS [M+H]+: 460.2

[0143] 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 5.1 Hz, 2H), 7.65 – 7.56 (m, 3H), 7.35 – 7.27 (m, 3H), 7.08 (t, J = 6.6 Hz, 2H), 5.15 (s, 2H), 3.70 – 3.56 (m, 1H), 3.55 – 3.45 (m, 1H), 3.02 (s, 1H), 3.00 (d, J = 3.5 Hz, 1H), 2.97 – 2.84 (m, 1H), 2.69 – 2.58 (m, 1H), 2.36 – 2.15 (m, 2H), 1.31 (d, J = 7.0 Hz, 3H). Example 20: 4-((S)-4,4-difluoro-1-((S)-1-((1-(2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-((1-(2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0144] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-2-fluorobenzene (18 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.65) to afford 4- ((S)-4,4-difluoro-1-((S)-1-((1-(2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)piperidin-3-yl)pyridine 1-oxide (Compound 37) (5.5 mg, 13% yield) as a white solid.

[0145] LCMS [M+H]+: 460.2

[0146] 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 6.8 Hz, 2H), 7.71 – 7.54 (m, 3H), 7.48 – 7.29 (m, 3H), 7.26 – 7.03 (m, 2H), 5.25 (s, 2H), 3.72 – 3.43 (m, 2H), 3.06 – 3.01 (m, 2H), 2.96 – 3.89 (m, 1H), 2.70 – 2.58 (m, 1H), 2.38 – 2.13 (m, 2H), 1.31 (d, J = 7.0 Hz, 3H). Example 21: 4-((S)-4,4-difluoro-1-((S)-1-((1-(3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-((1-(3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0147] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-3-fluorobenzene (21mg, 0.11 mmol, 1.3 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.65) to afford 4- ((S)-4,4-difluoro-1-((S)-1-((1-(3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)piperidin-3-yl)pyridine 1-oxide (Compound 38) (11.9 mg, 29% yield ) as a white solid.

[0148] LCMS [M+H]+: 460.3

[0149] 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 7.2 Hz, 2H), 7.66 – 7.50 (m, 3H), 7.45 – 7.24 (m, 2H), 7.18 – 6.88 (m, 3H), 5.20 (s, 2H), 3.71 – 3.44 (m, 2H), 3.09 – 2.87 (m, 3H), 2.71 – 2.54 (m, 1H), 2.41 – 2.07 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H). Example 22: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,3,5-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,3,5-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0150] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) were added 1- (bromomethyl)-2,3,5-trifluorobenzene (25 mg, 0.11 mmol, 1.3 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.65) to afford 4- ((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,3,5-trifluorobenzyl)-1H-imidazol-4-yl)amino)propan-2- yl)piperidin-3-yl)pyridine 1-oxide (Compound 39) (7.2 mg, 16% yield) as a white solid.

[0151] LCMS [M+H]+: 496.1

[0152] 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 6.5 Hz, 2H), 7.70 – 7.53 (m, 3H), 7.33 (s, 1H), 7.21 – 7.16 (m, 1H), 6.93 – 6.82 (m, 1H), 5.30 (s, 2H), 3.64 – 3.49 (m, 2H), 3.08 – 3.00 (m, 2H), 2.99 – 2.93 (m, 1H), 2.66 – 2.61 (m, 1H), 2.42 – 2.09 (m, 2H), 1.33 (d, J = 6.7 Hz, 3H). Example 23: 4-((S)-1-((S)-1-((1-(2,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(2,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0153] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) were added 2- (bromomethyl)-1,4-difluorobenzene (21 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogenatmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30×150, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 10% B in 2 min, 10% to 15% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.78) to afford 4-((S)-1-((S)-1-((1-(2,5-difluorobenzyl)-1H-imidazol- 4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 40) (4.6 mg, 11% yield) as a white solid.

[0154] LCMS [M+H]+: 478.1

[0155] 1H NMR (300 MHz, Methanol-d4) δ 8.29 (d, J = 7.1 Hz, 2H), 7.63 (s, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.33 (d, J = 1.6 Hz, 1H), 7.24 – 7.03 (m, 2H), 5.26 (s, 2H), 3.66 – 3.52 (m, 1H), 3.50 – 3.42 (m, 1H), 3.08 - 2.92 (m, 1H), 2.74 – 2.54 (m, 1H), 2.34 – 2.12 (m, 2H), 1.34 (d, J = 7.0 Hz, 3H). Example 24: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2-(trifluoromethyl)benzyl)-1H- imidazol-4-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2-(trifluoromethyl)benzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0156] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-2-(trifluoromethyl)benzene (25 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30×150, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 15% B in 2 min, 15% to 35% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.9) to afford 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide (Compound 41) (11 mg, 25% yield) as a white solid.

[0157] LCMS [M+H]+: 510.2

[0158] 1H NMR (300 MHz, Methanol-d4) δ 8.29 (d, J = 6.9 Hz, 2H), 7.83 – 7.76 (m, 1H), 7.69 – 7.49 (m, 5H), 7.31 – 7.17 (m, 2H), 5.43 (s, 2H), 3.65 – 3.49 (m, 2H), 3.09 – 2.96 (m, 2H), 2.78 – 2.60 (m, 1H), 2.35 – 2.06 (m, 2H), 1.34 (d, J = 7.0 Hz, 3H). Example 25: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,3,4-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,3,4-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0159] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-2,3,4-trifluorobenzene (21 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min ; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm ; RT1(min): 8.55) to afford 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,3,4-trifluorobenzyl)-1H-imidazol-4-yl)amino)propan- 2-yl)piperidin-3-yl)pyridine 1-oxide (Compound 42) (7.2 mg, 16% yield) as a white solid.

[0160] LCMS [M+H]+: 496.1

[0161] 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 6.2 Hz, 2H), 7.72 – 7.51 (m, 3H), 7.29 (s, 1H), 7.19 – 7.07 (m, 2H), 5.27 (s, 2H), 3.70 – 3.43 (m, 2H), 3.09 – 2.90 (d, m, 2H), 2.69 – 2.54 (m, 1H), 2.42 – 2.09 (m, 2H), 1.31 (d, J = 6.7 Hz, 3H). Example 26: 4-((S)-1-((S)-1-((1-(3-chlorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxideStep 1: 4-((S)-1-((S)-1-((1-(3-chlorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0162] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) were added 1- (bromomethyl)-3-chlorobenzene (21 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 1% B to 1% B in 1.5 min, 1% B to 15% B in 2 min, 15% B to 35% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.88): 9) to afford 4-((S)-1-((S)-1-((1-(3-chlorobenzyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 43) (16.9 mg, 40% yield) as a white solid.

[0163] LCMS [M+H]+: 476.0

[0164] 1H NMR (300 MHz, Methanol-d4) δ 8.31 (d, J = 6.2 Hz, 2H), 7.66 (s, 1H), 7.62 – 7.57 (m, 2H), 7.40 – 7.35 (m, 2H), 7.31 (s, 2H), 7.28 – 7.21 (m, 1H), 5.21 (s, 2H), 3.73 – 3.47 (m, 2H), 3.09 – 2.90 (m, 1H), 2.75 – 2.60 (m, 1H), 2.42 – 2.11 (m, 2H), 1.34 (d, J = 6.9 Hz, 3H). Example 27: 4-((S)-1-((S)-1-((1-(4-chloro-3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(4-chloro-3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0165] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) was added 5- (bromomethyl)-2-chloro-1,3-difluorobenzene (25 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 36% B in 8 min; RT1(min): 9.52) to afford 4-((S)-1-((S)-1-((1-(4-chloro- 3,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 44) (15.2 mg, 34% yield) as a light yellow solid.

[0166] LCMS [M+H]+: 512.2

[0167] 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.17 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 1.6 Hz, 1H), 7.43 – 7.18 (m, 5H), 5.17 (s, 2H), 3.64 – 3.42 (m, 3H), 3.01 - 2.88 (m, 3H), 2.32 – 2.08 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H). Example 28: 4-((S)-1-((S)-1-((1-(4-chloro-2,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(4-chloro-2,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0168] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-4-chloro-2,5-difluorobenzene (27 mg, 0.11 mmol, 1.3 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified byPrep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min ; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.95) to afford 4- ((S)-1-((S)-1-((1-(4-chloro-2,5-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 45) (8.6 mg, 19% yield) as a white solid.

[0169] LCMS [M+H]+: 512.2

[0170] 1H NMR (300 MHz, Methanol-d4) δ 8.29 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.53 – 7.40 (m, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.30 – 7.19 (m, 1H), 5.26 (d, J = 1.4 Hz, 2H), 3.74 – 3.49 (m, 2H), 3.07 – 2.95 (m, 3H), 2.72 – 2.54 (m, 1H), 2.43 – 2.09 (m, 2H), 1.34 (d, J = 7.0 Hz, 3H). Example 29: 4-((S)-1-((S)-1-((1-(3,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(3,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0171] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) were added 4- (bromomethyl)-1,2-difluorobenzene (19 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.65) to afford 4- ((S)-1-((S)-1-((1-(3,4-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 46) (10 mg, 24 % yield) as a white solid.

[0172] LCMS [M+H]+: 478.2

[0173] 1H NMR (400 MHz, Methanol-d4) δ 8.29 ( J = 7.2 Hz, 2H), 7.66 – 7.53 (m, 3H), 7.28 (s, 1H), 7.26 – 7.18 (m, 2H), 7.15 – 7.09 (m, 1H), 5.17 (s, 2H), 3.78 – 3.46 (m, 2H), 3.12 – 3.03 (m, 2H), 2.96 – 2.90 (m, 1H), 2.72 – 2.54 (m, 1H), 2.41 – 2.09 (m, 2H), 1.32 (d, J = 7.2 Hz, 3H). Example 30: 4-((S)-1-((S)-1-((1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0174] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) were added 4- (bromomethyl)-1-chloro-2-fluorobenzene (23 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 1% B to 1% B in 1.5 min, 1% B to 15% B in 2 min, 15% B to 33% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.9.) to afford 4-((S)-1-((S)-1-((1-(4-chloro-3-fluorobenzyl)- 1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 47) (11.4 mg, 26% yield) as a white solid.

[0175] LCMS [M+H]+: 494.2

[0176] 1H NMR (400 MHz, Methanol-d4) δ 8.29 ( J = 7.2 Hz, 2H), 7.65 – 7.56 (m, 3H), 7.51 – 7.46 (m, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.21 – 7.03 (m, 2H), 5.19 (s, 2H), 3.66 – 3.42 (m, 2H), 3.09 – 2.96 (m, 3H), 2.77 – 2.55 (m, 1H), 2.44 – 2.09 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H). Example 31: 4-((S)-1-((S)-1-((1-(2-chloro-4-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(2-chloro-4-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0177] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-2-chloro-4-fluorobenzene (21 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4- ((S)-1-((S)-1-((1-(2-chloro-4-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 48) (19.9 mg, 46.56% yield) as a white solid.

[0178] LCMS [M+H]+: 494.1

[0179] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.16 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 1.6 Hz, 1H), 7.58 – 7.49 (m, 1H), 7.40 – 7.35 (m, 3H), 7.32 – 7.25 (m, 1H), 7.23 (d, J = 1.6 Hz, 1H), 5.24 (s, 2H), 3.62 – 3.46 (m, 3H), 3.09 – 2.75 (m, 3H), 2.23 – 2.03 (m, 2H), 1.16 (d, J = 6.9 Hz, 3H). Example 32: 4-((S)-1-((S)-1-((1-(2,3-difluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(2,3-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0180] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1-(bromomethyl)-2,3-difluorobenzene (20 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4- ((S)-1-((S)-1-((1-(2,3-difluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 49) (20.5 mg, 49% yield) as a white solid.

[0181] LCMS [M+H]+: 478.1

[0182] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.16 (d, J = 6.8 Hz, 2H), 7.61 (d, J = 1.5 Hz, 1H), 7.48 – 7.39 (m, 1H), 7.37 (d, J = 6.7 Hz, 2H), 7.29 – 7.20 (m, 2H), 7.18 – 7.10 (m, 1H), 5.28 (s, 2H), 3.62 (m, 3H), 3.03 – 2.79 (m, 3H), 2.18 – 1.99 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H). Example 33: 4-((S)-1-((S)-1-((1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0183] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol, 1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-3,5-dichlorobenzene (23 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4- ((S)-1-((S)-1-((1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 50) (14.7 mg, 33% yield) as a white solid.

[0184] LCMS [M+H]+: 510.1

[0185] 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.16 (d, J = 7.2 Hz, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 7.41 (d, J = 2.0 Hz, 2H), 7.36 (d, J = 6.7 Hz, 2H), 7.31 (d, J = 1.5 Hz, 1H), 5.15 (s, 2H), 3.55 (q, J = 6.9 Hz, 1H), 3.48 – 3.41 (m, 2H), 3.03 - 2.88 (m, 3H), 2.26 – 2.03 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H). Example 34: 4-((S)-1-((S)-1-((1-(2-chloro-3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(2-chloro-3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0186] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3 (41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl)-2-chloro-3-fluorobenzene (23 mg, 0.10 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 15% B to 35% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.65) to afford 4- ((S)-1-((S)-1-((1-(2-chloro-3-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 51) (17.8 mg, 41% yield) as a light yellow solid.

[0187] LCMS [M+H]+: 494.2

[0188] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.17 (d, J = 7.0 Hz, 2H), 7.63 (d, J = 1.5 Hz, 1H), 7.47 – 7.34 (m, 4H), 7.24 (d, J = 1.6 Hz, 1H), 7.13 – 7.06 (m, 1H), 5.31 (s, 2H), 3.67 – 3.42 (m, 3H), 2.99 – 2.85 (m, 3H), 2.26 – 2.03 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H). Example 35: 4-((S)-1-((S)-1-((1-((3,5-difluorophenyl)methyl-d2)-1H-imidazol-4-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxideStep 1: (3,5-difluorophenyl)methan-d2-ol-d

[0189] To a mixture of methyl 3,5-difluorobenzoate (500 mg, 2.90 mmol, 1 equiv) in THF (5 mL) was added lithium aluminum deuteride (2.9 mL, 1M in THF) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. To quench the reaction solid sodium sulfate decahydrate was slowly added until no bubbles were present. The resulting mixture was filtered, and the filter cake was washed with THF (5 mL). The filtrate was concentrated under reduced pressure to afford (3,5-difluorophenyl)methan-d2-ol-d (270 mg, 63% yield) as a colorless oil. LCMS (ESI) [M+H]+: 148. Step 2: 1-(bromomethyl-d2)-3,5-difluorobenzene

[0190] A mixture of (3,5-difluorophenyl)methan-d2-ol-d (200 mg, 1.36 mmol, 1 equiv) and bromotrimethylsilane (312 mg, 2.04 mmol, 1.5 equiv) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were washed with brine (3 x 8 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. This resulted in 1-(bromomethyl-d2)-3,5-difluorobenzene (134 mg, 47% yield) as a colorless oil. LCMS (ESI) [M+H]+: 209. Step 3: 4-((S)-1-((S)-1-((1-((3,5-difluorophenyl)methyl-d2)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0191] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol,1 equiv) and Cs2CO3(42 mg, 0.13 mmol, 1.5 equiv) in DMF (0.5 mL) was added 1- (bromomethyl-d2)-3,5-difluorobenzene (19 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm ; RT1(min): 8.65) to afford 4-((S)-1-((S)-1-((1-((3,5-difluorophenyl)methyl-d2)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 52) (8.5 mg, 20% yield assumed ) as a white solid.

[0192] LCMS [M+H]+: 480.2

[0193] 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.17 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 6.8 Hz, 2H), 7.30 (d, J = 1.6 Hz, 1H), 7.24 – 7.16 (m, 1H), 7.10 – 7.03 (m, 2H), 3.66 – 3.48 (m, 3H), 3.03 – 2.81 (m, 3H), 2.26 - 2.08 (m, 2H), 1.17 (d, J = 6.8 Hz, 3H). Example 36: 4-((S)-1-((S)-1-((1-(3-cyano-5-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(3-cyano-5-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0194] To a solution of 4-((S)-1-((S)-1-((1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate D) (30 mg, 0.08 mmol, 1 equiv) and Cs2CO3(41 mg, 0.12 mmol, 1.5 equiv) in DMF (0.5 mL) was added 3-(bromomethyl)-5- fluorobenzonitrile (20 mg, 0.09 mmol, 1.1 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred at -30 °C for 2 h. The resulting mixture was filtered, and the filter cake was washed with DMF (0.5 mL). The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4-((S)-1-((S)-1-((1-(3-cyano-5-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 53) (7.1 mg, 16% yield) as a yellow solid.

[0195] LCMS [M+H]+: 485.1

[0196] 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.17 (d, J = 6.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 7.42 – 7.27 (m, 3H), 5.21 (s, 2H), 3.67 – 3.42 (m, 3H), 3.03 – 2.80 (m, 3H), 2.23 – 1.96 (m, 2H), 1.17 (d, J = 6.8 Hz, 3H). Example 37: 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide Step 1: tert-butyl 3-(6-methoxypyridin-3-yl)-4-oxopiperidine-1-carboxylate

[0197] A mixture of 5-bromo-2-methoxypyridine (1.0 g, 5.31 mmol, 1 equiv), tert-butyl 4- oxopiperidine-1-carboxylate (1.3 g, 6.52 mmol, 1.2 equiv), t-BuONa (1.5 g, 15.60 mmol, 3 equiv), XPHOS (0.5 g, 1.04 mmol, 0.2 equiv) and Pd(OAc)2(0.1 g, 0.44 mmol, 0.1 equiv) in dioxane (20 mL) was stirred for 1 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 25 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / EA (3:1) to afford tert-butyl 3-(6-methoxypyridin-3-yl)-4-oxopiperidine-1-carboxylate (500 mg, 30% yield) as a yellow oil. LCMS (ESI) [M+H]+: 307. Step 2: tert-butyl 4,4-difluoro-3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0198] To a mixture of tert-butyl 3-(6-methoxypyridin-3-yl)-4-oxopiperidine-1-carboxylate (490 mg, 1.60 mmol, 1 equiv) in DCM (5 mL) was added DAST (516 mg, 3.20 mmol, 2 equiv) dropwise at 0 °C under N2 atmosphere. The final reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by the addition of sat. sodium hyposulfite (aq.) (12 mL) at 0° C. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4,4-difluoro-3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (300 mg, 57% yield) as a white solid. LCMS (ESI) [M+H]+: 329. Step 3: 5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one

[0199] A solution of tert-butyl 4,4-difluoro-3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (300 mg, 0.91 mmol, 1 equiv) in HBr / AcOH (1 mL) was stirred for 1 h at 100 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:1) to 5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (150 mg, 76% yield) as a yellow oil. LCMS (ESI) [M+H]+: 215 Step 4: (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one

[0200] 5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (150 mg) was separated by prep-Chiral- HPLC (Column: CHIRALPAK IG, 3×25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 214 / 303 nm; RT1(min): 13.2; RT2(min): 19.3; Sample Solvent: MeOH: DCM=1: 1; Number Of Runs: 4) to afford (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (60 mg, 100% e.e.) and (R)-5-(4,4- difluoropiperidin-3-yl)pyridin-2(1H)-one (70 mg, 100% e.e.). LCMS (ESI) [M+H]+: 215. Step 5: 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide

[0201] A solution of (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (60 mg, 0.28 mmol, 1 equiv), 2-bromo-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (116 mg, 0.33 mmol, 1.2 equiv), KI (56 mg, 0.33 mmol, 1.2 equiv) and TEA (85 mg, 0.84 mmol, 3 equiv) in DMA (1 mL) was stirred for 1 h at 60 °C under N2atmosphere. The mixture was allowed to cool down to room temperature. The residue was dissolved in water (3 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (3 x 6 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30×150 mm, 5µm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 20% B in 2 min, 20% B to 41% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 10.07) to afford 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide (70 mg, 52% yield) as a white solid. LCMS (ESI) [M+H]+: 478. Step 6: (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide and (R)-2-((S)-4,4-difluoro-3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4- yl)propanamide

[0202] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide (70 mg) was separated by prep-Chiral-HPLC (Column: CHIRALPAK IA, 3×25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 210 / 220 nm; RT1(min): 9.5; RT2(min): 20.3; Sample Solvent: ETOH: DCM=1: 1; Injection Volume: 2 mL; Number Of Runs: 2) to afford (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (Compound 54) (Method L, 1.01 min, peak 1, 30.2 mg, 100% e.e.) and (R)-2-((S)-4,4-difluoro-3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (Compound 55) (Method L, 1.75 min, peak 2, 23.3 mg, 100% e.e.).

[0203] Table 15 Compound# Characterization Data 54 LCMS (ESI) [M+H]+: 478.3Example 38: 4-((3S)-1-(1-((5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: N-cyano-2-(3,5-difluorophenyl)acetamide

[0204] A solution of (3,5-difluorophenyl)acetic acid (2.0 g, 11.61 mmol, 1 equiv), hydroxybenzotriazole or HOBT (0.8 g, 5.80 mmol, 0.5 equiv), TEA (3.5 g, 34.85 mmol, 3 equiv) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide or EDCI (3.3 g, 17.42 mmol, 1.5 equiv) in DMF (20 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (25 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 35 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm and UV 220 nm to afford N-cyano-2-(3,5- difluorophenyl)acetamide (1.8 g, 78% yield) as a white solid. LCMS [M+H]+: 197. Step 2: 5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-amine

[0205] A solution of N-cyano-2-(3,5-difluorophenyl)acetamide (1.0 g, 5.09 mmol, 1 equiv), hydroxylamine hydrochloride (0.5 g, 7.65 mmol, 1.5 equiv) and pyridine (1.2 g, 15.29 mmol, 3 equiv) in EtOH (10 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under reducedpressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm and UV 220 nm to afford 5-(3,5-difluorobenzyl)-1,2,4- oxadiazol-3-amine (260 mg, 24% yield) as a white oil. LCMS [M+H]+: 212. Step 3: 2-bromo-N-(5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)propanamide

[0206] A solution of 5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-amine (250 mg, 1.18 mmol, 1 equiv) and pyridine (281 mg, 3.55 mmol, 3 equiv) in DCM (3 mL) was treated with 2- bromopropanoyl bromide (383 mg, 1.77 mmol, 1.5 equiv) at 0°C under nitrogen atmosphere. The final reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (5 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:10) to afford 2-bromo-N-(5-(3,5-difluorobenzyl)-1,2,4- oxadiazol-3-yl)propanamide (190 mg, 46% yield) as a white solid. LCMS [M+H]+: 346. Step 4: 4-((3S)-1-(1-((5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0207] A solution of 2-bromo-N-(5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)propanamide (120 mg, 0.34 mmol, 1 equiv), TEA (175 mg, 1.73 mmol, 5 equiv) and (S)-4-(4,4-difluoropiperidin- 3-yl)pyridine 1-oxide (Intermediate B) (74 mg, 0.34 mmol, 1 equiv) in DMA (2 mL) was stirred overnight at room temperature under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 34 % B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 11.08) to afford 4-((3S)-1-(1-((5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (50 mg, 30% yield) as a light yellow oil. LCMS [M+H]+: 480. Step 5: 4-((S)-1-((S)-1-((5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((5-(3,5-difluorobenzyl)- 1,2,4-oxadiazol-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0208] 4-((3S)-1-(1-((5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (50 mg) was separated by prep-Chiral-HPLC (Column: CHIRALPAK ID, 3×25 cm, 5 μm; Mobile Phase A: MtBE (0.1% FA), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 15% B; Wave Length: 212 / 274 nm; RT1(min): 12.06; RT2(min): 16.18; Sample Solvent: MEOH; Injection Volume: 1.3 mL; Number Of Runs: 1) to afford 4-((S)-1-((S)-1-((5-(3,5-difluorobenzyl)-1,2,4-oxadiazol-3- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 56) (Method M, 1.20 min, peak 1, 8.9 mg, 83.7% e.e.) and 4-((S)-1-((R)-1-((5-(3,5-difluorobenzyl)- 1,2,4-oxadiazol-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 57) (Method M, 1.36 min, peak 2, 3.7 mg, 84.3% e.e.).

[0209] Table 16Example 39: 4-((3S)-1-(1-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 2-(3,5-difluorophenyl)acetonitrile

[0210] A solution of TMSCN (0.6 g, 5.79 mmol, 1.2 equiv) and TBAF (1.4 g, 5.31 mmol, 1.1 equiv) in THF (10 mL) was stirred for 1 h at 0 °C under N2 atmosphere. To the above mixturewas added 1-(bromomethyl)-3,5-difluorobenzene (1.0 g, 4.83 mmol, 1 equiv) dropwise at room temperature. The resulting mixture was stirred at 80 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (1:1) to afford 2-(3,5-difluorophenyl)acetonitrile (530 mg, 71% yield) as a white solid. LCMS (ESI) [M+H]+: 154. Step 2: (Z)-2-(3,5-difluorophenyl)-N'-hydroxyacetimidamide

[0211] A solution of 2-(3,5-difluorophenyl)acetonitrile (520 mg, 3.39 mmol, 1 equiv) and hydroxylamine hydrochloride (283 mg, 4.07 mmol, 1.2 equiv) and TEA (859 mg, 8.48 mmol, 2.5 equiv) in EtOH (5 mL) was stirred at 60 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / EA (1:1) to afford (Z)-2-(3,5-difluorophenyl)- N'-hydroxyacetimidamide (500 mg, 79% yield) as a white solid. LCMS (ESI) [M+H]+: 187. Step 3: 3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-amine

[0212] To a mixture of (Z)-2-(3,5-difluorophenyl)-N'-hydroxyacetimidamide (500 mg, 2.69 mmol, 1 equiv) and K2CO3(1.1 g, 8.05 mmol, 3 equiv) in DMF (5 mL) was added cyanogen bromide (341 mg, 3.21 mmol, 1.2 equiv) dropwise at 0° C under N2 atmosphere. The final reaction mixture was stirred at room temperature for 2 h. The solution was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5- amine (145 mg, 25% yield) as a white solid. LCMS (ESI) [M+H]+: 212. Step 4: 2-bromo-N-(3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)propanamide

[0213] To a mixture of 3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-amine (145 mg, 0.68 mmol, 1 equiv) and pyridine (163 mg, 2.06 mmol, 3 equiv) in DCM (2 mL) were added 2- bromopropanoyl bromide (296 mg, 1.37 mmol, 2 equiv) dropwise at 0 °C under N2 atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (3 x 7 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-bromo- N-(3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)propanamide (150 mg, 63% yield) as a white solid. LCMS (ESI) [M+H]+: 346. Step 5: 4-((3S)-1-(1-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0214] A solution of 2-bromo-N-(3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)propanamide (150 mg, 0.43 mmol, 1 equiv) and (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Intermediate B) (111 mg, 0.51 mmol, 1.2 equiv) and TEA (132 mg, 1.3 mmol, 3 equiv) in DMA (2 mL) was stirred at room temperature overnight under air atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30×150 mm, 5µm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 20% B in 2 min, 20% B to 41% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.07) to afford 4-((3S)-1-(1-((3-(3,5- difluorobenzyl)-1,2,4-oxadiazol-5-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (75 mg, 36% yield) as a white solid. LCMS (ESI) [M+H]+: 480. Step 6: 4-((S)-1-((S)-1-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((3-(3,5-difluorobenzyl)- 1,2,4-oxadiazol-5-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0215] 4-((3S)-1-(1-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (75 mg) was separated by prep-Chiral-HPLC (Column: CHIRAL ART Cellulose-SB, 3×25 cm, 5 μm; Mobile Phase A: MtBE (0.1% FA), Mobile Phase B: MEOH; Flow rate: 20 mL / min; Gradient: isocratic 15% B; Wave Length: 214 / 274 nm; RT1(min): 8.03; RT2(min): 10.22; Sample Solvent: MEOH; Injection Volume: 0.5 mL; Number Of Runs: 4) to afford 4-((S)-1-((S)-1-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 58) (Method N, 1.03 min, peak 1, 25.2 mg, 100% e.e.) and 4-((S)-1-((R)-1-((3-(3,5-difluorobenzyl)- 1,2,4-oxadiazol-5-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 59) (Method N, 1.30 min, peak 2, 21.2 mg, 99% e.e.).

[0216] Table 17Example 40: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: methyl 4-bromo-1-(3,5-difluorobenzyl)-1H-imidazole-2-carboxylate

[0217] A mixture of methyl 4-bromo-1H-imidazole-2-carboxylate (5.0 g, 24.4 mmol), 1-(1- bromoethyl)-3,5-difluorobenzene (5.1g, 24.4 mmol), K2CO3(10.1 g, 72 mmol) in ACN (20 mL) was stirred for 2 hours at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (9:1) to afford methyl 4-bromo-1-(3,5-difluorobenzyl)-1H-imidazole-2-carboxylate (6.2g, 77% yield) as a white solid.

[0218] LCMS (ESI) [M+H]+: 332.12. Step 2: (4-bromo-1-(3,5-difluorobenzyl)-1H-imidazol-2-yl)methanol

[0219] A mixture of methyl 4-bromo-1-(3,5-difluorobenzyl)-1H-imidazole-2-carboxylate (6 g, 18.2 mmol) and sodium borohydride (2.2 g, 54 mmol) in methanol (20 mL) was stirred for 5 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford (4- bromo-1-(3,5-difluorobenzyl)-1H-imidazol-2-yl)methanol (4.7 g, 85% yield) as a white solid

[0220] LCMS (ESI) [M+H]+: 303.11 Step 3: 4-bromo-1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazole

[0221] A mixture of methyl (4-bromo-1-(3,5-difluorobenzyl)-1H-imidazol-2-yl)methanol (2g, 6.6 mmol) and DAST (1.2g, 7.3 mmol) in DCM (20 mL) was stirred for 5 hours at -10oC. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford 4-bromo-1-(3,5-difluorobenzyl)- 2-(fluoromethyl)-1H-imidazole (630 mg, 31% yield) as a white solid LCMS (ESI) [M+H]+: 306.10 Step 4: N-(1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)-2- hydroxypropanamide

[0222] A mixture of 4-bromo-1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazole (400 mg, 1.3 mmol), lactamide (117 mg, 1.3 mmol), copper iodide (24.8 mg, 0.13 mmol), K2CO3(361 mg, 2.62 mmol) and DMEDA (23 mg, 0.262 mmol) in dioxane (5 mL) was stirred for 2 hours at90 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was loaded onto a silica gel column and eluted with DCM / MeOH (98:2). This yielded N-(1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)-2-hydroxypropanamide (170 mg, 41% yield) as a yellow oil. LCMS (ESI) [M+H]+: 314.28. Step 5: 1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl 4-methylbenzenesulfonate

[0223] To a mixture of N-(1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)-2- hydroxypropanamide (170 mg, 0.54 mmol) and DIEA (136 mg, 1.1 mmol) in DCM (2 mL) was added tosyl chloride (103.45 mg, 0.54 mmol) in portions at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for 24 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 1-((1-(3,5- difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl 4- methylbenzenesulfonate (138 mg, 54.4% yield) as a yellow oil. LCMS (ESI) [M+H]+:468.46. Step 6: 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0224] Into a 8-mL sample vial was placed 1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl 4-methylbenzenesulfonate (138 mg, 0.30 mmol), Intermediate B (63.3 mg, 0.30 mmol), TEA (96 uL), KI (cat) and DMA (2 mL). The mixture was stirred at 50°C for 5 hours until LCMS suggested the completion of the reaction by complete consumption of the starting material. The resulting solution was allowed to cool down to room temperature, poured into water (10 mL) and extracted with EA (3 × 10 mL). Organic layers were combined, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (methanol: dichloromethane = 1:15) to give 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (27 mg, 18%) as a light yellow solid. LCMS (ESI) [M+H]+: 510.19. Step 7: 4-((S)-1-((S)-1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((1-(3,5- difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0225] 4-((3S)-1-(1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (27.0 mg) was separated by prep- Chiral-HPLC Column: CHIRALPAK IF, 2×25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 212 / 268 nm; RT1(min): 13.6; RT2(min): 17.7; Sample Solvent: ETOH: DCM=1: 1; Injection Volume: 0.8 mL; Number Of Runs: 5 to afford 4-((S)-1-((S)-1-((1-(3,5- difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 60) (Method O, 2.06 min, peak 1, 4.6 mg, 100% e.e.) and 4-((S)-1-((R)-1-((1-(3,5-difluorobenzyl)-2-(fluoromethyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 61) (Method O, 2.97 min, peak 2, 3.2 mg, 100% e.e.).

[0226] Table 18Example 41: 4-((S)-4,4-difluoro-1-((S)-1-((1-(5-fluoro-2-(trifluoromethyl)benzyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-((1-(5-fluoro-2-(trifluoromethyl)benzyl)-1H-imidazol-4- yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0227] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol) and Cs2CO3(43 mg, 0.13 mmol) in DMF (0.5 mL) was added 2-(bromomethyl)-4-fluoro-1- (trifluoromethyl)benzene (24 mg, 0.09 mmol) at -30 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -30 °C under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 14% B to 34% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 9.43) to afford 4-((S)-4,4-difluoro-1-((S)-1-((1- (5-fluoro-2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)piperidin-3- yl)pyridine 1-oxide (Compound 62) (19.8 mg, 44% yield) as a white solid. LCMS [M+H]+: 528.11H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.18 (d, J = 6.8 Hz, 2H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.47 – 7.34 (m, 3H), 7.25 (d, J = 1.5 Hz, 1H), 7.07 – 6.86 (m, 1H), 5.37 (s, 2H), 3.62 – 3.53 (m, 1H), 3.51 – 3.37 (m, 2H), 3.02 – 2.81 (m, 3H), 2.15 – 2.01 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H). Example 42: 4-((S)-1-((S)-1-((1-((3-chloropyridin-4-yl)methyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-((3-chloropyridin-4-yl)methyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0228] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol) and Cs2CO3(42 mg, 0.13 mmol) in DMF (0.5 mL) was added 4-(bromomethyl)-3- chloropyridine (19 mg, 0.09 mmol) at -30°C under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -30 °C under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min ; Gradient: 23% B to 43% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.64) to afford 4-((S)-1-((S)-1-((1-((3-chloropyridin-4-yl)methyl)- 1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 63) (16.7 mg, 40% yield) as a yellow solid.

[0229] LCMS [M+H]+: 477.1

[0230] 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.66 (s, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.24 – 8.13 (m, 2H), 7.64 (d, J = 1.6 Hz, 1H), 7.41 – 7.29 (m, 3H), 6.98 (d, J = 5.0 Hz, 1H), 5.35 (s, 2H), 3.65 - 3.48 (m, 1H), 3.05 – 2.83 (m, 3H), 2.55 (d, J = 4.7 Hz, 1H), 2.21 – 1.97 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H). Example 43: 4-((S)-1-((S)-1-((1-(3-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(3-chloro-2-fluorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0231] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol) and Cs2CO3(42 mg, 0.13 mmol) in DMF (0.5 mL) was added 1-(bromomethyl)-3-chloro-2- fluorobenzene (25 mg, 0.11 mmol) at -30 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -30 °C under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min ; Gradient: 23% B to 43% B in 9 min; Wave Length:254nm / 220nm; RT1(min): 8.95) to afford 4-((S)-1-((S)-1-((1-(3-chloro-2-fluorobenzyl)-1H- imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 64) (13.7 mg, 32% yield) as a light yellow solid.

[0232] LCMS [M+H]+: 494.1

[0233] 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.15 (d, J = 6.6 Hz, 2H), 7.80 (s, 1H), 7.58 – 7.49 (m, 1H), 7.33 (d, J = 6.6 Hz, 2H), 7.25 (d, J = 4.0 Hz, 2H), 7.22 – 7.14 (m, 1H), 5.26 (s, 2H), 3.77 – 3.48 (m, 3H), 3.22 – 3.05 (m, 2H), 2.79 – 2.72 (m, 1H), 2.30 – 2.13 (m, 2H), 1.27 (d, J = 6.7 Hz, 3H). Example 44: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,4,5-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((1-(2,4,5-trifluorobenzyl)-1H-imidazol-4- yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0234] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.09 mmol) and Cs2CO3(42 mg, 0.13 mmol) in DMF (0.5 mL) was added 1-(bromomethyl)-2,4,5- trifluorobenzene (25 mg, 0.11 mmol) at -30°C under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -30°C under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30×150, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 15% B in 2 min, 15% to 35% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.9) to afford 4-((S)- 4,4-difluoro-1-((S)-1-oxo-1-((1-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)amino)propan-2- yl)piperidin-3-yl)pyridine 1-oxide (Compound 65) (11 mg, 26% yield) as a white solid.

[0235] LCMS (ESI) [M+H]+: 496.1

[0236] 1H NMR (400 MHz, Methanol-d4) δ 8.38 – 8.23 (m, 2H), 7.67 – 7.53 (m, 3H), 7.43 – 7.19 (m, 3H), 5.21 (s, 2H), 3.62 – 3.47 (m, 2H), 3.05 – 2.94 (m, 3H), 2.66 – 2.61 (m, 1H), 2.21 – 2.11 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H).Example 45: 4-((S)-1-((S)-1-((1-(2,3-dichlorobenzyl)-1H-imidazol-4-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-((S)-1-((S)-1-((1-(2,3-dichlorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0237] To a mixture of 4-[(3S)-4,4-difluoro-1-[(1S)-1-[(1H-imidazol-4- yl)carbamoyl]ethyl]piperidin-3-yl]pyridin-1-ium-1-olate (Intermediate D) (30 mg, 0.08 mmol) and Cs2CO3(42 mg, 0.13 mmol) in DMF (0.5 mL) were added 1-(bromomethyl)-2,3- dichlorobenzene (22 mg, 0.09 mmol) at -30 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -30 °C under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (0.5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30×150 mm, 5µm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min ; Gradient: 23% B to 43% B in 9 min; Wave Length: 254 nm / 220 nm ; RT1(min): 8.78) to afford 4-((S)-1-((S)-1-((1-(2,3- dichlorobenzyl)-1H-imidazol-4-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)pyridine 1-oxide (Compound 66) (17.6 mg, 39% yield) as a light yellow solid.

[0238] LCMS [M+H]+: 510.2

[0239] 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.19 – 8.12 (m, 2H), 7.70 – 7.60 (m, 2H), 7.45 – 7.34 (m, 3H), 7.25 (d, J = 1.5 Hz, 1H), 7.18 – 7.13 (m, 1H), 5.32 (s, 2H), 3.62 – 3.53 (m, 1H), 3.51 – 3.41 (m, 1H), 3.01 – 2.82 (m, 3H), 2.53 – 2.48 (m, 1H), 2.23 – 2.03 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H). Example 46: 2-(4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N- (1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide Step 1: tert-butyl 3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxopiperidine-1- carboxylate

[0240] A solution of 5-bromo-1-methylpyridin-2-one (2.0 g, 10.64 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (2.5 g, 12.76 mmol), XPhos (0.5 g, 1.06 mmol), Pd2(dba)3 (2.0 g, 2.13 mmol) and t-BuONa (3.1 g, 31.91 mmol) in dioxane (25 mL) was stirred for overnight at 40°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (30 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxopiperidine-1- carboxylate (850 mg, 26% yield) as a light-yellow oil. LCMS (ESI) [M+H]+: 307. Step 2: tert-butyl 4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-1- carboxylate

[0241] To a mixture of tert-butyl 3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxopiperidine- 1-carboxylate (840 mg, 2.74 mmol) in DCM (10 mL) was added DAST (1.3 g, 8.23 mmol) dropwise at 0°C. The resulting mixture was stirred overnight at 0°C under a nitrogen atmosphere. The reaction was quenched by the addition of sat. aq. NaHCO3 (15mL) at 0°C. The aqueous layer was extracted with CH2Cl2(3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 220 nm. This resulted in tert-butyl 4,4-difluoro-3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)piperidine-1-carboxylate (350 mg, 39% yield) as a brown solid. LCMS (ESI) [M+H]+: 329. Step 3: 5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one

[0242] A solution of tert-butyl 4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)piperidine-1-carboxylate (340 mg, 1.04 mmol) in 4M HCl in 1,4-dioxane (10 mL)was stirred for 1 hour at room temperature under an ambient atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.11% NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 220 nm. This resulted 5-(4,4- difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one (185 mg, 78% yield) as a white solid. LCMS (ESI) [M+H]+: 229. Step 4: (S)-5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one and (R)-5-(4,4- difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one

[0243] 5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2-one (180 mg) was purified by Prep- Chiral-HPLC with the following conditions (Column: CHIRALCEL AY-H, 2×25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 225 / 235 nm; RT1(min): 7.2; RT2(min): 11.4) to afford (S)-5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one (73 mg, peak 1, 100% e.e.) and (R)-5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one (70 mg, peak 2, 100% e.e.). LCMS (ESI) [M+H]+: 229. Step 5: 2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1- (3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide

[0244] A solution of (S)-5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one (73 mg, 0.32 mmol), 2-bromo-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (121 mg, 0.35 mmol), KI (58 mg, 0.35 mmol) and TEA (162 mg, 1.6 mmol) in DMA (5 mL) was stirred for overnight at 60°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254nm. This resulted in 2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1- yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (78 mg, 50% yield) as a white solid. LCMS (ESI) [M+H]+: 492. Step 6: (S)-2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)- N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide and (R)-2-((S)-4,4-difluoro-3-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H- imidazol-4-yl)propanamide

[0245] 2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide (78 mg) was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK ID, 2×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 20 mL / min; Gradient: isocratic 30% B; Wave Length: 234 / 220 nm; RT1(min): 3.99; RT2(min): 7.47) to afford (S)-2-((S)-4,4- difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)- 1H-imidazol-4-yl)propanamide (Compound 67) (Method P, 0.57 min, peak 1, 25.8 mg, 100% e.e.) and (R)-2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N- (1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (Compound 68) (Method P, 1.09 min, peak 2, 29.3 mg, 100% e.e.).

[0246] Table 19 Compound# Characterization Data LCMS (ESI) [M+H]+: 492.2 1 67 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.81 – 7.61 (m, 2H), 7.37 - 7.17 (m, 3H), 7.14 – 6.93 (m, 2H), 6.33 (d, J = 9.3 Hz, 1H), 5.17 (s, 2H), 3.56 – 3.50 (m, 1H), 3.46 – 3.40 (m, 3H), 3.16 – 2.93 (m, 3H), 2.68 – 2.62 (m, 1H), 2.25 - 2.03 (m, 2H), 1.19 (d, J = 6.7 Hz, 3H). LCMS (ESI) [M+H]+: 492.1 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.68 – 7.64 (m, 2H), 7.44 – 7.35 (m, 1H), 7.30 68 (d, J = 1.6 Hz, 1H), 7.27 – 7.15 (m, 1H), 7.09 – 7.01 (m, 2H), 6.34 (d, J = 9.4 Hz, 1H), 5.17 (s, 2H), 3.56 – 3.51 (m, 1H), 3.40 (s, 3H), 3.12 – 3.08 (m, 1H), 2.89 – 2.73 (m, 3H), 2.49 – 2.43 (m, 1H), 2.23 – 2.06 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H).Step 7: 2-((R)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1- (3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide

[0247] A solution of (R)-5-(4,4-difluoropiperidin-3-yl)-1-methylpyridin-2(1H)-one (70 mg, 0.31 mmol), 2-bromo-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (116 mg, 0.34 mmol), KI (56 mg, 0.34 mmol) and TEA (155 mg, 1.5 mmol) in DMA (1.5 mL) was stirred for overnight at 60°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was dissolved in water (3 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (3 x 6 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 2-((R)-4,4-difluoro-3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (70 mg, 46% yield) as a white solid. LCMS (ESI) [M+H]+: 492. Step 8: (S)-2-((R)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)- N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide and (R)-2-((R)-4,4-difluoro-3-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H- imidazol-4-yl)propanamide

[0248] 2-((R)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1- (3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (73mg) was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 3×25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 234 / 220 nm; RT1(min): 5.38; RT2(min): 11.59) to afford : (S)-2-((R)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(1-(3,5- difluorobenzyl)-1H-imidazol-4-yl)propanamide (Compound 69) (Method Q, 0.78 min, peak 1, 27.0 mg, >99% e.e.) and (R)-2-((R)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide (Compound 70) (Method Q, 1.81 min, peak 2, 21.8 mg, >99% e.e.).

[0249] Table 20Example 47: 2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(1-(3,5-difluorobenzyl)-1H-imidazol-4-yl)propanamide Step 1: (5-bromo-2-methoxypyridin-3-yl)methanol

[0250] To a mixture of 5-bromo-2-methoxynicotinic acid (5.0 g, 21.54 mmol) in THF (50 mL) was added 1M BH3-THF in THF (32.3 mL, 32.3mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (5-bromo-2- methoxypyridin-3-yl)methanol (3.9 g, 83% yield) as a white solid. LCMS (ESI) [M+H]+: 218. Step 2: 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine

[0251] A mixture of (5-bromo-2-methoxypyridin-3-yl)methanol (3.9 g, 17.9 mmol), tert- butylchlorodimethylsilane (13.4 g, 89.4 mmol), imidazole (12.1 g, 178.9 mmol) and DMAP (218 mg, 1.78 mmol) in DMF (40 mL) was stirred at 60 °C for 2 hours. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (80 mL). The resulting mixture was extracted with EtOAc (3 x 55 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 5- bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine (5.1 g, 85% yield) as a white solid. LCMS (ESI) [M+H]+: 332. Step 3: tert-butyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxypyridin-3-yl)-4- oxopiperidine-1-carboxylate

[0252] A mixture of 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine (5.1 g, 15.34 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.6 g, 18.41 mmol, 1.2 equiv), t- BuONa (5.9 g, 61.38 mmol), Pd(OAc)2(344 mg, 1.53 mmol) and XPhos (1.4 g, 3.06 mmol) in THF (60 mL) was stirred at 45 °C for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 70 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxypyridin-3-yl)-4-oxopiperidine-1- carboxylat...

Claims

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein the “ * ” at the carbon to which Rdand Rd*are bonded is a first stereo center when Rdand Rd*are different; Z2is CH2or wherein the wavy lines represent the points of attachment of the Z2group to the Xh*and the -CH2of the 6-membered ring; wherein the “ * ” at the carbon atom in Z2designates a second stereocenter; with the proviso that when Z2is -CH2, then Ring A is not a thiazolyl; Ring B is a 6-membered aryl or 5- or 6-membered heteroaryl group; each R is independently selected from hydrogen, CN, SF5, halo, (C1-C6)alkyl, -(C0-C6)alkyl- NH2, -(C0-C6)alkyl-NH((C1- C6)alkyl), -(C0-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -(C0- C6)alkyl-(C3-C8)cycloalkyl, -(C0-C6)alkyl-aryl, 5- or 6-membered heteroaryl(C1-C4)alkyl-, (C2- C6)alkenyl, -(C2-C6)alkenyl-(C3-C8)cycloalkyl, -OH, (C1-C4)alkoxy, -O-(C1-C6)alkyl- (C3- C8)cycloalkyl, -O-(C1-C6)alkyl-aryl, -O-(C1-C6)alkyl-5-6 membered heteroaryl, -O-(C2- C6)alkenyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1- C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, or 5-6 membered heteroaryl, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-(C3-C8)cycloalkyl, -(C0- C6)alkyl-aryl, (C1- C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O- aryl, 5-6 membered heteroaryl, -C(O)-aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, -OH, (C1-C6)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1- C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1-C6)alkyl), -O-(C3- C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or threesubstituents independently selected from halo, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1- C6)alkyl-O-(C1-C6)alkyl, or (C1- C4)alkoxy; n is 0 or an integer from 1 to 5; L1is C(Rc)(Rc*), O, SO2or C(O); each of Rcand Rc*is independently H, D, halo, (C1-C6)alkyl, or (C2-C6)alkenyl; or Rcand Rc*taken together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7- membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3- C8)cycloalkyl; Ring A is a 5-membered arylene or a 5-membered heteroarylene group; each R* is independently selected from hydrogen, OH, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C2-C6)alkenyl, -(C1- C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1- C6)alkyl)((C1- C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1- C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH; or two R*groups taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halo, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; n* is 0 or an integer from 1 to 3; or one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6-membered ring fused to Ring A; L2is -C(O)- or wherein the wavy line represents the points of attachment to the NH and the C(Rd)(Rd*) groups; Rdand Rd*are each independently H or (C1-C3)alkyl, or (C1-C3)alkoxy, or Rdand Rd*cyclize to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; Xhand Xh*are each independently C(Re)2, N(Re), or O; Xgis CH or N; each Reis independently H, halo, (C1-C3)alkyl, halo(C1-C3)alkyl, or (C1-C3)alkoxy, or any two Regroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring;n** is 0 or an integer from 1 to 8; Xjis N, NRf, C(Rf)2, C(Rf) or CH; Xeis N, NRf, C(Rf)2or C(Rf); Xfis SO2, N, C-(halo(C1-C3)alkyl), C-(C1-C3)alkyl, C=O or N+-O-; ------- represents a double or single bond as needed to satisfy atom valences; each Rfis independently H or halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkoxy, -(C1- C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1- C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl), -(C1-C6)alkyl-NH((C1-C6)alkyl)- OH, -(C1-C6)alkyl-NH((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1- C6)alkyl)-OH, -(C1-C6)alkyl-N-((C1-C6)alkyl)((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl- NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl- 4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl- SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1- C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1- C6)alkyl), -C(O)N(C1-C6)alkyl) (C1-C6)alkyl), - NH2, -NH(C1-C6)alkyl, -N((C1- C6)alkyl)((C1-C6)alkyl), -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, - (C1-C6)alkyl-NH2, -(C1-C6)alkyl- NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6- membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halo, OH, or any two Rfgroups, on the same ring atom or on adjacent ring atoms, cyclize to form a 3 to 6 membered fused or spiro ring; n^ is 0 or an integer from 1 to 4.

2. The compound of claim 1, wherein Xgis CH.

3. The compound of claim 1, wherein Xgis N.

4. The compound of any one of claims 1 to 3, wherein Rdand Rd*cyclize to form a 3 to 6 membered ring.

5. The compound of any one of claims 1 to 3, wherein each Rdand Rd*are the same and are H or (C1-C3)alkyl.

6. The compound of any one of claims 1 to 3, wherein one of Rdand Rd*is (C1-C3)alkoxy.

7. The compound of any one of claims 1 to 3, wherein each Rdand Rd*are independently chosen from H and CH3.

8. The compound of claim 1, wherein Rdand Rd*are different, Z2is , and the first and second stereocenters are both S.

9. The compound of claim 1, wherein Rdand Rd*are different, Z2is , and wherein the first and second stereocenters are both R, or wherein the first stereocenter is S and second stereocenter is R, or wherein the first stereocenter is R and second stereocenter is S.

10. The compound of any one of claims 1 to 9, wherein two Regroups bonded to a single carbon atom cyclize to form a 3 to 6 membered ring.

11. The compound of any one of claims 1 to 9, wherein at least one Reis halo, (C1-C3)alkyl, or (C1-C3)alkoxy.

12. The compound of any one of claims 1 to 9, wherein each Reis independently chosen from H, F, CH3and OCH3.

13. The compound of any one of claims 1 to 9, wherein n** is 1 or 2.

14. The compound of any one of claims 1 to 13, wherein Xhis NH or O.

15. The compound of any one of claims 1 to 13, wherein Xhis CH2.

16. The compound of any one of claims 1 to 15, wherein Xh*is O, or C(Re)2.

17. The compound of any one of claims 1 to 16, wherein Xh*is O; or is C(Re)2and each Reis F or two Regroups bonded to a single carbon atom cyclize to form a 3 membered ring.

18. The compound of any one of claims 1 to 17, wherein L2is C=O.

19. The compound of any one of claims 1 to 18, wherein R* is CH3or CF3.

20. The compound of any one of claims 1 to 19, wherein n* is 1.

21. The compound of any one of claims 1 to 19, wherein n* is 0.

22. The compound of any one of claims 1 to 21, wherein Ring B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl.

23. The compound of any one of claims 1 to 21, wherein Ring B is phenyl or pyridinyl.

24. The compound of any one of claims 1 to 23, wherein each R is independently CN, SF5, F, Cl, CH3, OCH3, O-phenyl, CF3or OCF3.

25. The compound of any one of claims 1 to 23, wherein each R is independently F, Cl, CN, CF3or OCF3.

26. The compound of any one of claims 1 to 25, wherein n is 1, 2 or 3.

27. The compound of any one of claims 1 to 25, wherein n is 1 or 2.

28. The compound of any one of claims 1 to 27, wherein n^ is 1 or 2.

29. The compound of any one of claims 1 to 27, wherein n^ is 0.

30. The compound of any one of claims 1 to 29, wherein L1is O, CH2, CHCH3, or CD2.

31. The compound of any one of claims 1 to 29, wherein, L1is C(Rc)(Rc*).

32. The compound of claim 31, wherein each Rcand Rc*are independently H or CH3.

33. The compound of claim 31, wherein one of Rcor Rc*and R* taken together with the atoms to which they are bonded form an optionally substituted 3- to 6- membered ring fused to Ring A.

34. The compound of any one of claims 1 to 33, wherein Ring A is imidazolylene, oxazolylene, oxadiazolylene, pyrazolylene, pyrrolylene, thiazolylene, or triazolylene.

35. The compound of claim 31, wherein Ring A is imidazolylene, triazolylene, pyrazolylene, or thiazolylene; n* is 1 or 2; L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form an optionally substituted 3- to 6- membered ring fused to Ring A.

36. The compound of claim 35, wherein the optionally substituted 3- to 6- membered ring fused to Ring A forms an optionally substituted 8- or 9-membered bicyclic heterocyclylene having 1, 2 or 3 heteroatoms selected from N and S, or an optionally substituted 8- or 9- membered bicyclic heteroarylene having 1, 2 or 3 heteroatoms selected from N and S.

37. The compound of claim 35, wherein the optionally substituted 3- to 6- membered ring fused to Ring A has the structure , wherein Rzis absent or is OH, n' is 0, 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter.

38. The compound of claim 37, wherein n' is 1.

39. The compound of claim 37 or 38, wherein Rcis H.

40. The compound of claim 35, wherein the 3- to 6- membered ring fused to Ring A has a structure selected from:wherein Rzis absent or is OH, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter.

41. The compound of claim 40, wherein Rzis absent.

42. The compound of claim 35, wherein the 3- to 6- membered ring fused to Ring A forms 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylene.

43. The compound of any one of claims 1 to 42, wherein Xeis NH and Xfis C=O and the bond between Xeand Xfis a single bond.

44. The compound of any one of claims 1 to 42, wherein Xeis CH2and Xfis C=O and the bond between Xeand Xfis a single bond.

45. The compound of any one of claims 1 to 42, wherein Xeis CH and Xfis N+-O- and the bond between Xeand Xfis a double bond.

46. The compound of any one of claims 1 to 42, wherein Xeis CH and Xfis N and the bond between Xeand Xfis a double bond.

47. The compound of any one of claims 1 to 42, wherein Xeis N and Xfis C-CH3, C-CH2F, C-CHF2. or CF3and the bond between Xeand Xfis a double bond.

48. The compound of any one of claims 1 to 47, wherein two Rfgroups on adjacent atoms cyclize to form a 3 to 6 membered ring.

49. The compound of any one of claims 1 to 47, wherein two Rfgroups bonded to a single carbon atom cyclize to form a 3 to 6 membered ring.

50. The compound of any one of claims 1 to 47, wherein each Rfis independently chosen from halo, (C1-C3)alkyl, (C1-C3)alkyl-OH, halo(C1-C3)alkyl, (C1-C3)alkoxy, or aryloxy.

51. The compound of any one of claims 1 to 47, wherein each Rfis independently chosen from CH2-OH, F, Cl, CH3, OCH3, O-phenyl, CF3, and OCF3.

52. The compound of any one of claims 1 to 51, wherein Z2is CH2.

53. The compound of claim 1, wherein L1is C(Rc)(Rc*) and one of Rcand Rc*, and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2; and Xh*is O.

54. The compound of claim 53, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from, wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter.

55. The compound of claim 54, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from .

56. The compound of claim 55, wherein Rzis absent and Ring B is phenyl or pyridinyl.

57. The compound of claim 56, wherein Rd*is CH3.

58. The compound of claim 57, wherein n** is 1 or 2 and each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl.

59. The compound of claim 58, wherein n is 0, 1, 2, or 3 and R is fluoro.

60. The compound of claim 1, wherein L1is C(Rc)(Rc*) and one of Rcor Rc*, and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2; Xh*is C(Re)2and each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl.

61. The compound of claim 60, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter.

62. The compound of claim 61, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from .

63. The compound of claim 62, wherein Rzis absent and Ring B is phenyl or pyridinyl.

64. The compound of claim 63, wherein Rd*is CH3.

65. The compound of claim 64, wherein n** is 1 or 2 and each Reis independently H, F or Cl.

66. The compound of claim 65, wherein n is 0, 1, 2, or 3 and R is fluoro.

67. The compound of claim 1, wherein L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to Ring A; Z2is ; Xhis CH2; Xh*is CH2or C(Re)2; Xgis N; Xeis CH; Xfis N+-O- and the bond between Xeand Xfis a double bond; and Rd*is CH3.

68. The compound of claim 67, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter.

69. The compound of claim 68, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from .

70. The compound of claim 69, wherein Reis F and n** is 2.

71. The compound of claim 70, wherein Rfis H.

72. The compound of claim 71, wherein Rzis absent and Ring B is phenyl or pyridinyl.

73. The compound of claim 72, wherein Rdis H; and each R is independently selected from halo and (C1-C3)alkyl.

74. The compound of claim 73, wherein each R is independently selected from F, Cl and CH3.

75. The compound of claim 1, wherein L1is C(Rc)(Rc*) and one of Rcor Rc*and R* taken together with the atoms to which they are bonded form a 3- to 6- membered ring fused to RingA; Z2is ; Xhis CH2; Xh*is CH2or C(Re)2; Xgis N; Xeis N; Xfis C(O) and the bond between Xeand Xfis a single bond; and Rd*is CH3.

76. The compound of claim 75, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from , wherein Rzis absent or OH, n' is 1 or 2, and the “*” at the ring carbon bonded to Ring B represents a third stereocenter.

77. The compound of claim 76, wherein the 3- to 6- membered ring fused to Ring A forms a group having a structure selected from .

78. The compound of claim 77, wherein Reis F and n** is 2.

79. The compound of claim 78, wherein Rfis H.

80. The compound of claim 79, wherein Rzis absent and Ring B is phenyl or pyridinyl.

81. The compound of claim 80, wherein Rdis H; and each R is independently selected from halo and (C1-C3)alkyl.

82. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is Formula (Ie): (Ie) wherein n' is 0, 1 or 2 and the “*” at the carbon bonded to both Ring B and Rc*represents a third stereocenter.

83. The compound of claim 82, wherein Rdis H and Rd*is Me.

84. The compound of claim 82 or 83, wherein the first and second stereocenters are in an S configuration.

85. The compound of claim 82 or 83, wherein the first stereocenter is in an S configuration, the second stereocenter is in an S configuration, and the third stereocenter is in an R configuration.

86. The compound of any one of claims 82 to 85, wherein Ring B is phenyl or pyridinyl.

87. The compound of any one of claims 82 to 86, wherein each R is independently CN, SF5, F, methyl, OCH3, O-phenyl, or CF3.

88. The compound of any one of claims 82 to 87, wherein n is 1, 2 or 3.

89. The compound of any one of claims 82 to 88 wherein Ring B is phenyl, n is 2 and each R is F.

90. The compound of any one of claims 82 to 89 wherein each Reis independently halo, (C1- C3)alkyl, or (C1-C3)alkoxy.

91. The compound of any one of claims 82 to 89 wherein each Reis independently F, Me, or MeO.

92. The compound of any one of claims 82 to 89 wherein each Reis F.

93. The compound of any one of claims 82 to 89 wherein each Retogether with the carbon to which they are bonded form a cyclopropyl group.

94. The compound of any one of claims 82 to 93, wherein n' is 1 or 2.

95. The compound of any one of claims 82 to 94, wherein Xeis NH and Xfis C=O and the bond between Xeand Xfis a single bond.

96. The compound of any one of claims 82 to 94, wherein Xe is CH and Xf is N+-O- and thebond between Xeand Xfis a double bond.

97. The compound of any one of claims 82 to 96, wherein Xh*is CH2, N or O.

98. The compound of claim 1 having a structure chosen from:or a pharmaceutically acceptable salt thereof.

99. A compound having the structure: , or a pharmaceutically acceptable salt thereof.

100. A compound having the structure , or a pharmaceutically acceptable salt thereof.

101. A compound having the structureor a pharmaceutically acceptable salt thereof.

102. A compound chosen from 2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(3,5-difluorophenyl)-6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((R)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((S)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((R)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-((S)-5-(3,5- difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide; 4-(1-(1-((5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((R)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((S)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((R)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; and 4-((S)-1-((R)-1-(((S)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-(1-(1-((4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((R)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-(((S)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((S)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((R)-1-(((R)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; or a pharmaceutically acceptable salt thereof.

103. A compound 4-((S)-1-((S)-1-(((R)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof.

104. A compound (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N- ((S)-5-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propanamide, or a pharmaceutically acceptable salt thereof.

105. A compound 4-((S)-1-((S)-1-(((R)-4-(3,5-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof.

106. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt of any one of claims 1 to 105 and a pharmaceutically acceptable excipient.

107. A method of modulating MRGPRX2 activity, the method comprising administering an effective amount of a compound of any one of claims 1 to 105, or a pharmaceutical composition of claim 106.

108. A method of modulating mast cell degranulation comprising administering an effective amount of a compound of any one of claims 1 to 105, or a pharmaceutical composition of claim 106.

109. A method of treating, preventing or ameliorating an MRGPRX2-mediated disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of claims 1 to 105, or a pharmaceutical composition of claim 106.

110. The method of claim 109, wherein the disease is chosen from chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, Asian atopic dermatitis, European atopic dermatitis, rosacea, autoimmune diseases, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, endometriosis, nasal polyps, neuropathic pain,inflammatory pain, pseudo-allergic drug reactions, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, esophagus reflux, asthma, cough, migraine, sinusitis, urticaria, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, contact urticaria, lupus erythematosus (SLE), psoriasis, psoriatic arthritis, bronchial asthma, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

111. A method of treating a condition chosen from chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, Asian atopic dermatitis, European atopic dermatitis, rosacea, autoimmune diseases, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, endometriosis, nasal polyps, neuropathic pain, inflammatory pain, pseudo-allergic drug reactions, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, esophagus reflux, asthma, cough, migraine, sinusitis, urticaria, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, contact urticaria, lupus erythematosus (SLE), psoriasis, psoriatic arthritis, bronchial asthma, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain comprising administering to the subject an effective amount of a compound of any one of claims 1 to 105, or a pharmaceutical composition of claim 106.

112. The method of claim 111, wherein the condition is atopic dermatitis.

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