Tricyclic 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

Tricyclic 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 and WO2021 / 092240 disclose 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-

[0008] 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

[0009] 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 pharmaceutically salt thereof:wherein the “*” at the carbon bonded to Rdand Rd*is a first stereocenter when Rdand Rd*are different and the “*” at Z2represents a second stereocenter when Z2is not CH2; Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1, 2 or 3 R groups; Z2is CH2 orwherein the wavy lines represent the points of attachment of the Z2group to the 6-membered ring; each R is independently selected from CN, SF5, halogen, (C1-C6)alkyl, -(C0-C6)alkyl-NH2, -OH, (C1-C4)alkoxy, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-NH2, (C1- C4)alkoxy is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, - OH, (C1-C6)alkyl, or (C1-C4)alkoxy;n is 0 or an integer from 1 to 5; L2is -C(O)- orwherein 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 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, CH2 or 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((CI- 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.

[0010] 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.

[0011] 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 need thereof 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.

[0012] 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.

[0013] 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.

[0014] 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. Detailed Description

[0015] 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.

[0016] “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.

[0017] “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.

[0018] “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.

[0019] 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 straightor branched-chain carbon radical. Examples of “halo(C1-C4)alkyl” groups useful in the presentinvention 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.

[0020] 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.

[0021] 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.

[0022] “Halo” means fluoro, chloro, bromo, or iodo; in one embodiment fluoro or chloro.

[0023] 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.

[0024] “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.

[0025] 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.

[0026] “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.

[0027] “Mammal” as used herein means domesticated animals (such as dogs, cats, and horses), and humans. In one embodiment, mammal is a human.

[0028] 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

[0029] 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.

[0030] 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 acceptable acid 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 canbe 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.

[0031] “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.

[0032] 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.

[0033] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0034] 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.

[0035] “Treating” or “treatment” of a disease includes:

[0036] (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;

[0037] (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or

[0038] (3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0039] 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.

[0040] 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 or isomeric form is specifically indicated. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, opticallyenriched, 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] The term hydrate is employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallizationmay 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.

[0045] 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.

[0046] 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. The resulting 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).

[0047] 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.

[0048] The present disclosure also includes polymorphic forms (amorphous as well as crystalline).

[0049] 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’).

[0050] 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 cexolling. 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.

[0051] 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 deuteratedforms 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.

[0052] 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.

[0053] 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.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms 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.

[0055] 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.

[0056] 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.

[0057] 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).

[0058] In one aspect, provided here is a compound of Formula (A) or pharmaceutically salt thereof: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 CH2 orwherein 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, SO2 or 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 twosubstituents 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)- orwherein 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, CH2 or 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((CI- 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] Another aspect of the invention is a compound of Formula (I) or pharmaceutically salt thereof:wherein the “*” at the carbon bonded to Rdand Rd*is a first stereocenter when Rdand Rd*are different and the “*” at Z2represents a second stereocenter when Z2is not CH2; Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1, 2 or 3 R groups; Z2is CH2 orwherein the wavy lines represent the points of attachment of the Z2group to the 6-membered ring; each R is independently selected from CN, SF5, halogen, (C1-C6)alkyl, -(C0-C6)alkyl-NH2, -OH, (C1-C4)alkoxy, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-NH2, (C1- C4)alkoxy is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, - OH, (C1-C6)alkyl, or (C1-C4)alkoxy; n is 0 or an integer from 1 to 5; L2is -C(O)- orwherein 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 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, CH2 or 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((CI- 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.

[0060] In some embodiments, Xgis CH. In some embodiments, Xgis N.

[0061] In some embodiments, each Rdand Rd*are independently chosen from H and CH3. In some embodiments, Rdand Rd*are different, Z2is, and the first and second stereocenters are both S. In some embodiments, 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.

[0062] In some embodiments, two Regroups on adjacent atoms cyclize to form a 3 to 6 membered ring. In some embodiments, two Regroups bound to a single carbon atom cyclize toform 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, CH3 and OCH3.

[0063] 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.

[0064] In some embodiments, n** is Xhis NH or O. In some embodiments, Xhis CH2. In some embodiments, Xh*is NH, NCH3, or O. In some embodiments, Xh*is NH or O. In some embodiments, Xh*is CH2, C(Re)2, or CH(Re). In some embodiments, Xh*is C(Re)2 and each Reis F.

[0065] In some embodiments, L2is C=O. In some embodiments, L2iswherein the wavy line represents the points of attachment to the NH and the C(Rd)(Rd*) groups.

[0066] In some embodiments, each R is independently CN, SF5, F, Cl, CH3, OCH3, O- phenyl, CF3 or OCF3. In some embodiments, each R is independently F, Cl, CH3, O-phenyl, CF3 or OCF3.

[0067] In some embodiments, n^ is 1 or 2. In some embodiments, n^ is 0.

[0068] In some embodiments, Xeis NH and Xfis C=O and the bond between Xeand Xfis a single bond. In some embodiments, Xeis CH2 and 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 CF3 and the bond between Xeand Xfis a double bond.

[0069] In some embodiments, two Rfgroups on adjacent atoms cyclize to form a 3 to 6 membered ring. In some embodiments, two Rfgroups bound 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.

[0070] In some embodiments, Z1is a 12- or 13- membered tricyclic aryl or heteroaryl group. In some embodiments, Z1is chosen from [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene, [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene, 2,2-difluoro-[1,3]dioxolo[4,5-b]thiazolo[4,5- e]pyridinylene, thiazolo[4',5':4,5]benzo[1,2-d]oxazolylene, 6,7-dihydro-5H-indeno[5,6- d]thiazolylene, and 6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazolylene. In someembodiments, Z1is chosen from [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene, [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene, 2,2-difluoro-[1,3]dioxolo[4,5-b]thiazolo[4,5- e]pyridinylene, thiazolo[4',5':4,5]benzo[1,2-d]oxazolylene, 6,7-dihydro-5H-indeno[5,6- d]thiazolylene, and 6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazolylene, each substituted with 0, 1 or 2 R groups. In some embodiments, R is chosen from OH, Cl, F, and CN.

[0071] In some embodiments, Z2is CH2. In some embodiments, Z2is.

[0072] In some embodiments, Z1is 10-16 membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; Z2is CH2; L2is -C(O)-; Xgis N; Xhand Xh*are CH2.

[0073] In some embodiments, Rdand Rd*cyclize to form a 3 to 6 membered ring. In some embodiments, Rdand Rd*cyclize to form a cyclopropyl ring. In some embodiments, each 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.

[0074] In some embodiments, Rd*is methyl. In some embodiments, Rd*is H. In some embodiments, Rdis methyl. In some embodiments, Rdis H. In some embodiments, Rdand Rd*are H. In some embodiments, Rd*is methyl and Rd*is H. 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.

[0075] In some embodiments, compound is a compound of Formula (I), wherein Z1is a 10- to 16- membered tricyclic aryl or 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 methyl. 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.

[0076] In some embodiments, compound is a compound of Formula (I), wherein Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; 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 methyl. In some embodiments, Rdis H; and eachR is independently selected from halo and (C1-C3)alkyl. In some embodiments, Rfis CH3, OCH3, CF3, and OCF3; and R is fluoro.

[0077] In some embodiments, compound is a compound of Formula (I), wherein Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; Z2is ; Xh* h g e fis O; X is CH2; X is CH; X is NH; X is C=O and the bond between Xeand Xfis a single bond; and Rd*is methyl. 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, CF3, and OCF3; and R is fluoro.

[0078] In some embodiments, Z2has stereochemistry of the structure:.

[0079] In some embodiments, Rd*substituent has stereochemistry of the structure:, wherein the wavy lines represent the points of attachment in Formula (I).

[0080] In some embodiments, C4carbon and C5carbon are both in the (S) conformation / configuration , wherein the wavy line represents the point of attachment inFormula (I).

[0081] In some embodiments,wherein the wavy line represents the point of attachment in Formula (I), and wherein Q is a 5- to 6- membered heteroaryl ring and T is a 5- to 6- membered cycloalkyl or heterocycloalkyl; and n is 0, 1, 2 or 3.

[0082] In some embodiments,, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

[0083] In some embodiments,, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

[0084] In some embodiments,, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

[0085] In some embodiments,, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

[0086] In some embodiments, Z1iswherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

[0087] In some embodiments,, wherein the wavy line represents the point of attachment in Formula (I), and wherein Q is a 5- to 6- membered heteroaryl ring and V is a 5- to 6- membered aryl or heteroaryl ring; and n is 0, 1, 2 or 3.

[0088] In some embodiments,wherein the wavy line represents the point of attachment in Formula (I), and wherein Q is a 5- to 6- membered heteroaryl ring; V is a 5- to 6- membered aryl or heteroaryl ring; and each W is independently O, N or S; and n is 0, 1, 2 or 3.

[0089] In some embodiments,wherein the wavy line represents the point of attachment in Formula (I), and Q is a 5- to 6- membered heteroaryl ring; V is a 5- to 6- membered aryl or heteroaryl ring; and T is a 5 to 6 membered cycloalkyl or heterocycloalkyl; and n is 0, 1, 2 or 3.

[0090] In some embodiments,wherein the wavy line represents the point of attachment in Formula (I), and T is a 5- to 6- membered heteroaryl, heterocyclyl, or cycloalkyl ring optionally having 1 or 2 heteroatoms selected from N and S; and n is 0, 1, 2 or 3. General Synthetic Methods

[0091] 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.

[0092] 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).

[0093] 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.

[0094] 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.

[0095] More specifically intermediates and compounds of the present disclosure may be made by the methods shown in the following schemes. Scheme 1:

[0096] 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:

[0097] 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 3:

[0098] 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:

[0099] Step 1: Coupling of a substituted acyl halide, where X2 is Cl or Br, with a substituted amino heterocycle can be accomplished using a base such as triethylamine or pyridine in a polar aprotic solvent such as DCM, at 0°C to room temperature. Step 2: Nucleophilic displacement of X1, where X1 can be a tosylate, nosylate (2-nitrobenzenesulfonyl) or halogen (Cl or Br), can be achieved with amines in polar aprotic solvents with bases. Scheme 5:

[0100] Step 1: Coupling of a substituted acyl halide, where X2 is Cl or Br, with a substituted amino heterocycle can be accomplished using a base such as triethylamine or pyridine in a polar aprotic solvent such as DCM, at 0°C to room temperature. Step 2: Saponification of the acetyl protecting group 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: Activation of the alcohol can be achieved with NsCl (2-benzenesulfonyl chloride), DMAP and triethylamine in polaraprotic solvents such as dichloromethane at 0°C after several hours. Step 4: Nucleophilic displacement of the nosylate (2-nitrobenzenesulfonyl) group can be achieved with amines in polar aprotic solvents with bases. Scheme 6:

[0101] 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 7:Step 1: Coupling of a substituted acyl halide, where X2 is Cl or Br, with a substituted amino heterocycle can be accomplished using a base such as triethylamine or pyridine in a polar aprotic solvent such as DCM, at 0°C to room temperature. Step 2: Nucleophilic displacement of X1,where X1 can be a tosylate, nosylate (2-nitrobenzenesulfonyl) or halogen (Cl or Br), can be achieved with amines in polar aprotic solvents with bases.

[0102] 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

[0103] 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.

[0104] 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.

[0105] 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 activationsyndrome (MCAS), interstitial cystitis, food allergy, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

[0106] 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.

[0107] In some embodiments, the condition is atopic dermatitis.

[0108] 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.

[0109] 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

[0110] 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 oral administration, the compositions may be provided in the form of tablets containing about 1.0 toabout 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0117] 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.

[0118] 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).

[0119] 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)is administered 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.

[0120] In some embodiments, the active ingredients are formulated into a controlled release

[0121] 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.

[0122] Some preferred examples of extended-release compositions suitable for use in the

[0123] 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.

[0124] 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.

[0125] 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 in the 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.

[0126] 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.

[0127] 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 isparticularly advantageous when the separate components are preferably administered in different dosage 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.

[0128] 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.

[0129] 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) asingle tablet or capsule, a bilayer or multilayer tablet or capsule, or through the use of segregated components or 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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 medicalpractice 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 administration and other factors known to practitioners. The compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein.

[0135] 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.

[0136] 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.

[0137] 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 clinicalscore 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 was the 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)).

[0138] 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.

[0139] 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)).

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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; Contact dermatitis, 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.

[0144] 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 lymphoid cell 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-mediatedcytotoxicity, neurofibromatosis, swannamatoisis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, reflux nephropathy, 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.

[0145] 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, TransverseMyelitis, Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis, Vascular Pain and Vulvodynia.

[0146] 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

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] The following abbreviations are used in the text, AcOH = acetic acid, ACN = acetonitrile, BSA = Bovine Serum Albumin, Boc = tert-butoxycarbonyl, CSH = Charged Surface Hybrid, Cbz = benzyloxycarbonyl, DBA = Dibenzylideneacetone, DIBAL = Diisobutylaluminium, DIEA / DIPEA = N,N-diisopropylethylamine, DMA = Dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMSO = dimethyl sulfoxide, DMF =N, N-dimethylacetamide, DAST = Diethylaminosulfur trifluoride, DCM = dichloromethane, DMEM = Dulbecco's Modified Eagle Medium, Et3N or TEA = triethyl amine, EtOH = ethanol, EA or EtOAc = ethyl acetate, ESI = Electrospray Ionization, FA = formic acid, GOI = genes of interest, Hex = hexane, HCl = hydrochloric acid, HBSS = Hanks' Balanced Salt Solution, HEPES = 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid, HATU = hexafluorophosphate azabenzotriazole tetramethyl Uronium, HPLC = High pressure liquid chromatography, HTRF - Homogeneous Time-Resolved Fluorescence, IPA = isopropanol, LCMS = liquid chromatography-mass spectrometry, m-CPBA = meta-chloroperoxybenzoic acid, MeOH = methanol, MeCN = methylcyanide, M+H = a unit higher than the monoisotopic mass of the uncharged molecule, NIS = N-Iodosuccinimide, NMI = N-methylimidazole, OAc = acetate, OBD = optimum bed density, PE = petroleum ether,PMB = p-methoxybenzyl, PPh3= Triphenylphosphine, Prep-HPLC = preparatory scale HPLC, RT = retention time, STAB = Sodium triacetoxyborohydride, TEA = triethylamine, THF = tetrahydrofuran, TLC = thin layer chromatography, TFA = trifluoroacetic acid, Tf2O = Trifluoromethanesulfonic anhydride TMSCN = trimethylsilyl cyanide, TMSCl = trimethylsilyl chloride, TCFH = tetramethylformamidinium hexafluorophosphate, t-BuONa = sodium ter-butyloxide, h = hour, hrs = hours, aq. = aqueous, min. = minute, sat. = saturated, e.e. = enantiomeric excess, UV = ultraviolet, Xphos = 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, Ns = 2- nitrobenzene-1-sulfonyl.

[0153] 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. Synthesis and Characterization Examples

[0154] For certain compounds disclosed herein the absolute stereochemistry has not been independently confirmed but is nonetheless believed to be accurately represented in the name and structure of the disclosed compounds. Thus, for compounds that have indicated stereochemistry, unless otherwise noted in the experimental procedures, the compounds are assigned stereochemistry 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 for Intermediate B. The stereochemistry is conserved during the subsequent reaction sequences. 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 assignment from commercially available vendors. (R)-2-hydroxypropanamide, also referred 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).

[0155] 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.

[0156] Preparation of Intermediate B & Intermediate C: (S)-4-(4,4-difluoropiperidin-3- yl)pyridine 1-oxide and (R)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxideStep 1: tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine-1-carboxylate

[0157] 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 crude 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

[0158] 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. The reaction was quenched with sat. aq. NaHCO3 (50 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 150 mL). The combined organiclayers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude 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

[0159] 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. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude 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

[0160] 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 crude residue was purified by reversed-phase flash chromatography (conditions: column, C18; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 5% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give 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

[0161] 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.

[0162] Example 1: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)- 2-(3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide Step 1: 2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine

[0163] Potassium thiocyanate (6.96 g, 71.63 mmol) was added to a solution of 2,2-difluoro- 1,3-benzodioxol-5-amine (3.1 g, 17.91 mmol) in glacial acetic acid (60 mL) at room temperature. Bromine (2.86 g, 17.91 mmol) in 15 mL of glacial acetic acid was added dropwise. The resulting mixture was stirred at room temperature for 12 h. A precipitate formed over time. Upon completion, the solid was collected by filtration. The filter cake was washed with 300 mL glacial acetic acid and air dried to give 2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- amine (6.7g, 91% yield) as a yellow-brown solid. LCMS (ESI) [M+H]+: 231; LCMS (ESI) [M+ACN+H]+: 272

[0164] Step 2: (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl acetate

[0165] A mixture of 2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine (4.0 g, 17.38 mmol) and triethylamine (5.28 g, 52.13 mmol) in DCM (20 mL) was cooled to 0°C. (R)- 1-chloro-1-oxopropan-2-yl acetate (2.88 g, 19.11 mmol) was added slowly so that the temperature of the mixture did not exceed 5°C. The resulting solution was stirred at 5°C until LCMS suggested complete conversion of the starting amine. Upon completion, the solution was concentrated under reduced pressure and the crude residue was directly purified by silica gel column chromatography, eluted with PE / EA (7:3), to afford (R)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl acetate (3.2 g, 53% yield) as a white solid. LCMS (ESI) [M+H]+: 345

[0166] Step 3: (R)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- hydroxypropanamide

[0167] A mixture of lithium hydroxide monohydrate (445 mg, 18.59 mmol) in THF (20 mL) and H2O (4 mL) was cooled to 0°C. (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl acetate was added and the resulting mixture was stirred at 0°C for 3 hours. LCMS suggested complete conversion of the starting acetate. Upon completion, the mixture was poured into water (20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were separated, combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (R)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-hydroxypropanamide (1.9 g, 67% yield) as a white solid. LCMS (ESI) [M+H]+: 303

[0168] Step 4: (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate

[0169] A mixture of (R)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- hydroxypropanamide (1.9 g, 6.29 mmol) and triethylamine (1.27 g, 12.57 mmol) in DCM (10 mL) was cooled to 0°C.2-Nitrobenzenesulfonyl chloride (1.67 g, 7.54 mmol) slowly added so that the temperature of the mixture did not exceed 5°C. The resulting solution was stirred at 5°C until LCMS suggested complete conversion of the starting material. Upon completion, the solution was concentrated under reduced pressure and crude residue was directly loaded onto asilica gel column, eluted with DCM / MeOH (85:15), to afford (R)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (1.3 g, 42% yield) as a white solid. LCMS (ESI) [M+H]+: 488

[0170] Step 5: tert-butyl 3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0171] An oven-dried 20 mL vial was charged with tert-butyl 3-hydroxypiperidine-1- carboxylate (937 mg, 4.7 mmol), 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC-1) (1.68 g, 4.3 mmol) and a magnetic stir bar. After, the vial was vacuumed and refilled with nitrogen gas twice, 2-methoxy-2-methylpropane (12 mL) was added and the reaction stirred at 0 °C for 10 min. Then, a pyridine solution (337 mg, 4.3 mmol. in 0.5 mL 2-methoxy-2-methylpropane) was added dropwise at 0 °C over 2 min. The resulting solution stirred at room temperature for 10 min. A white solid precipitated out during this time. Another oven-dried 40 mL vial was charged with [Ir(dtbbpy)(ppy)2]pf6 (36 mg, 40.0 µmol), [4,4'- Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (97 mg, 0.2 mmol), 1-azabicyclo[2.2.2]octane (517 mg, 4.7 mmol), 5-bromo-2-methoxypyridine (500 mg, 2.7 mmol) and a magnetic stir bar. N,N-Dimethylacetamide (12.5 mL) was added to this vial under an atmosphere of nitrogen. The methyl tert-butyl ether suspension was transferred to a 20 mL syringe under air. Then a syringe filter and new needle were installed on the syringe, before the methyl tert-butyl ether solution was injected through the syringe filter into the dimethylacetamide solution. The reaction mixture was sparged with nitrogen for 15 minutes before sealing with parafilm. The vial was stirred at 1500 rpm stir rate and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-(6- methoxypyridin-3-yl)piperidine-1-carboxylate (500 mg, 64% yield) as a white solid. LCMS (ESI) [M+H]+: 293. Step 6: 5-(piperidin-3-yl)pyridin-2(1H)-one

[0172] A solution of tert-butyl 3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (500 mg, 1.7 mmol) in 5 M HCl in water (8 mL) was stirred at 80°C for 24 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to afford 5-(piperidin-3-yl)pyridin-2(1H)-one (500 mg, crude) as a yellow oil, which was used directly in the subsequent step without further purification. LCMS (ESI) [M+H]+: 179. Step 7: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)propanamide

[0173] To a mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (103 mg, 0.2 mmol) and 5-(piperidin-3- yl)pyridin-2(1H)-one (250 mg, 0.7 mmol) in ACN (6 mL) were added lithium trifluoromethanesulfonate (547 mg, 3.5 mmol) and triethylamine (355 mg, 3.5 mmol) dropwise at 0°C. The resulting mixture was stirred at 0 °C for 20 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)propanamide (80 mg, 25% yield) as a yellow oil. LCMS (ESI) [M+H]+: 463. Step 8: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(6-oxo- 1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide and (S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)propanamide

[0174] (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)propanamide (80 mg) was purified by Prep-Chiral HPLC (Column: Lux 5µ Cellulose-2, 30*250 mm, 5.0 µm; Mobile Phase A: Hex (10 mM NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 234 / 300 nm) to afford first peak (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)-2-((S)-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide (Compound 1) (RT: 10.3 min; Method A, Peak 2, 2.74 min; 13.0 mg, 100% d.e.) as a white solid and second peak (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)propanamide (Compound 2) (RT2: 13.4 min; Method A, Peak 1, 1.38 min; 12.5 mg, 100% d.e.) as a white solid.Example 2: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(2-(6-oxo- 1,6-dihydropyridin-3-yl)morpholino)propanamide Step 1: tert-butyl 2-(6-methoxypyridin-3-yl)morpholine-4-carboxylate

[0175] To a mixture of 5-bromo-2-methoxypyridine (3.20 g, 17.0 mmol) in DMSO (50 mL) were added 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (5.90 g, 25.5 mmol), [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (0.17 g, 170.0 µmol), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (0.41 g, 851.0 µmol), 2,3-dihydro-1H-isoindole-1,3-dione (2.50 g, 17.0 mmol) and N,N,N',N'-tetramethylguanidine (2.94 g, 25.5 mmol) in portions at room temperature. The vial was stirred and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor at 35°C for 2 h. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of H2O. The resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel columnchromatography, eluted with PE / EA (4:1) to afford tert-butyl 2-(6-methoxypyridin-3- yl)morpholine-4-carboxylate (1.10 g, 22% yield) as a white solid. LCMS (ESI) [M+H]+: 295. Step 2: 2-(6-methoxypyridin-3-yl)morpholine

[0176] To a mixture of tert-butyl 2-(6-methoxypyridin-3-yl)morpholine-4-carboxylate (500 mg, 1.7 mmol) in DCM (6 mL) was added trifluoroacetic acid (2 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure to afford 2-(6-methoxypyridin-3-yl)morpholine (500 mg, crude) as a brown oil, which was used in the next reaction without further purification. LCMS (ESI) [M+H]+: 195. Step 3: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(2-(6- methoxypyridin-3-yl)morpholino)propanamide

[0177] To a mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (226 mg, 0.463 mmol) and 2-(6- methoxypyridin-3-yl)morpholine (500 mg, 1.5 mmol) in ACN (8 mL) was added lithium trifluoromethanesulfonate (1.21 g, 7.7 mmol) and Et3N (782 mg, 7.7 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for overnight. The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford (2S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(2-(6-methoxypyridin-3- yl)morpholino)propanamide (180 mg, 24% yield) as a yellow oil. LCMS (ESI) [M+H]+: 479. Step 4: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(2-(6-oxo-1,6- dihydropyridin-3-yl)morpholino)propanamide

[0178] To a mixture of (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)- 2-(2-(6-methoxypyridin-3-yl)morpholino)propanamide (150 mg, 0.3 mmol) and NaI (235 mg, 1.6 mmol) in ACN (5 mL) was added chlorotrimethylsilane (170 mg, 1.6 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(2-(6-oxo-1,6- dihydropyridin-3-yl)morpholino)propanamide (120 mg, 82% yield) as a white solid. LCMS (ESI) [M+H]+: 465. Step 5: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-2-(6-oxo- 1,6-dihydropyridin-3-yl)morpholino)propanamide and (S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-2-(6-oxo-1,6-dihydropyridin-3- yl)morpholino)propanamide

[0179] (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(2-(6-oxo-1,6- dihydropyridin-3-yl)morpholino)propanamide (70 mg) was purified by Prep-Chiral HPLC (Column: CHIRALPAK-IK, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 226 / 306 nm) to afford first peak (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)-2-((S)-2-(6-oxo-1,6-dihydropyridin-3-yl)morpholino)propanamide (Compound 3) (RT1: 14.01 min; Method B, Peak 1, 1.66 min; 20.3 mg, 100% d.e.) as a white solid and second peak (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-2-(6-oxo-1,6- dihydropyridin-3-yl)morpholino)propanamide (Compound 4) (RT2: 17.95 min; Method B, Peak 2 212 min 202 m 100% de) as a white solid

[0180] Example 3: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((3R,5S)-3-fluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide Step 1: tert-butyl (3R,5S)-3-fluoro-5-(6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0181] To a solution of tert-butyl (3S,5S)-3-hydroxy-5-(6-methoxypyridin-3-yl)piperidine-1- carboxylate (500 mg, 1.6 mmol) in DCM (8 mL) was added DAST (1.31 g, 8.1 mmol) dropwise over 10 min at 0°C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with saturated aqueous NaHCO3 solution (10 mL) at 0°C. The aqueous layer was extracted with CH2Cl2 (3 x 12 mL). The combined organic layers were dried over anhydrous Na2SO4, filtration, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (3R,5S)-3-fluoro-5-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (90 mg, 18% yield) as a yellow oil. LCMS (ESI) [M+H]+: 311. dine

[0182] A solution of tert-butyl (3R,5S)-3-fluoro-5-(6-methoxypyridin-3-yl)piperidine-1- carboxylate (90 mg, 0.3 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford 5-((3S,5R)-5- fluoropiperidin-3-yl)-2-methoxypyridine (70 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 211. Step 3: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((3R)-3- fluoro-5-(6-methoxypyridin-3-yl)piperidin-1-yl)propanamide

[0183] A solution of 5-((3S,5R)-5-fluoropiperidin-3-yl)-2-methoxypyridine (60 mg, 0.280 mmol), (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl 2-nitrobenzenesulfonate (153 mg, 0.310 mmol), TEA (72 mg, 0.710 mmol) and lithium trifluoromethanesulfonate (111 mg, 0.710 mmol) in ACN (3 mL) was stirred overnight at 0°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((3R)- 3-fluoro-5-(6-methoxypyridin-3-yl)piperidin-1-yl)propanamide (50 mg, 35% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 495. Step 4: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((3R,5S)-3- fluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide

[0184] A solution of (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((3R)-3-fluoro-5-(6-methoxypyridin-3-yl)piperidin-1-yl)propanamide (50 mg, 0.1 mmol), TMSCl (55 mg, 0.5 mmol) and NaI (76 mg, 0.5 mmol) in ACN (2 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 38% B in 10 min; Wave Length: 254 nm / 220 nm) to afford (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((3R,5S)-3-fluoro- 5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide (Compound 5) (RT1: 7.2 min; 163 mg 34% yield) as an off-white solid7.48 – 7.41 (m, 1H), 7.22 (d, J = 2.7 Hz, 1H), 6.29 (d, J = 9.4 Hz, 1H), 4.79 – 4.55 (m, 1H),

[0185] Example 4: (S)-2-((S)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide Step 1: tert-butyl (S)-3-(picolinamido)piperidine-1-carboxylate

[0186] A solution of tert-butyl (S)-3-aminopiperidine-1-carboxylate (8.00 g, 39.9 mmol), picolinic acid (5.90 g, 47.9 mmol), N-(chloro(dimethylamino)methylene)-N- methylmethanaminium hexafluorophosphate(V) (1.68 g, 59.9 mmol) and 1-methyl-1H- imidazole (9.84 g, 119.8 mmol) in ACN (80 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (6:4) to afford tert-butyl (S)-3-(picolinamido)piperidine-1-carboxylate (9.00 g, 74% yield) as a white solid. LCMS (ESI) [M+H]+: 306. Step 2: tert-butyl (3S,5S)-3-(6-methoxypyridin-3-yl)-5-(picolinamido)piperidine-1- carboxylate

[0187] A solution of tert-butyl (S)-3-(picolinamido)piperidine-1-carboxylate (5.00 g, 16.4 mmol), 5-bromo-2-methoxypyridine (1.85 g, 98.2 mmol), Ag2CO3 (9.03 g, 32.8 mmol), Pd(OAc)2 (368 mg, 1.6 mmol) and 2,6-dimethylbenzoic acid (615 mg, 4.1 mmol) in dioxane (50 mL) was stirred overnight at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction mixture was quenched with water solution (60 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 65 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford tert-butyl (3S,5S)-3-(6-methoxypyridin-3-yl)-5-(picolinamido)piperidine-1-carboxylate (4.20 g, 62% yield) as a yellow oil. LCMS (ESI) [M+H]+: 413.Step 3: tert-butyl (3S,5S)-3-amino-5-(6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0188] A solution of tert-butyl (3S,5S)-3-(6-methoxypyridin-3-yl)-5- (picolinamido)piperidine-1-carboxylate (4.20 g, 10.2 mmol) and NaOH (2.44 g, 61.1 mmol) in isopropanol (45 mL) was stirred at 82°C for 18 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give tert-butyl (3S,5S)-3-amino-5-(6-methoxypyridin- 3-yl)piperidine-1-carboxylate (2.50 g, 80% yield) as a yellow oil. LCMS (ESI) [M+H]+: 308. Step 4: tert-butyl (3S,5S)-3-hydroxy-5-(6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0189] A solution of tert-butyl (3S,5S)-3-amino-5-(6-methoxypyridin-3-yl)piperidine-1- carboxylate (2.50 g, 8.1 mmol) in AcOH (20 mL) was stirred at room temperature for 5 min under nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. Then, a mixture of sodium nitrite (1.40 g, 20.3 mmol) in H2O (10 mL) was added dropwise over 10 min at room temperature. The resulting mixture was stirred at room temperature for an additional 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 solution (50 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in EtOH (20 mL) and NaOH (3.20 g, 81.3 mmol) in H2O (10 mL) and then was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm andUV 220 nm) to afford tert-butyl (3S,5S)-3-hydroxy-5-(6-methoxypyridin-3-yl)piperidine-1- carboxylate (1.30 g, 52% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 309. Step 5: tert-butyl (S)-3-(6-methoxypyridin-3-yl)-5-oxopiperidine-1-carboxylate

[0190] A solution of tert-butyl (3S,5S)-3-hydroxy-5-(6-methoxypyridin-3-yl)piperidine-1- carboxylate (300 mg, 0.970 mmol) in DCM (6 mL) was added Dess-Martin (1.24 g, 292.0 µmol) in portions over 5 min at 0°C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with saturated aqueous Na2O3S2 solution (10 mL) at 0°C. The aqueous layer was extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (S)-3-(6-methoxypyridin-3-yl)-5-oxopiperidine-1-carboxylate (130 mg, 44% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 307. Step 6: tert-butyl (S)-3,3-difluoro-5-(6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0191] To a solution of tert-butyl (S)-3-(6-methoxypyridin-3-yl)-5-oxopiperidine-1- carboxylate (120 mg, 0.390 mmol) in DCM (6 mL) was added DAST (126 mg, 0.8 mmol) dropwise over 5 min at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched with saturated aqueous NaHCO3 solution (10 mL) at 0°C. The aqueous layer was extracted with CH2Cl2 (3 x 12 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (S)-3,3-difluoro-5-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (90 mg, 70% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 329. Step 7: (S)-5-(5,5-difluoropiperidin-3-yl)-2-methoxypyridine

[0192] A solution of tert-butyl (S)-3,3-difluoro-5-(6-methoxypyridin-3-yl)piperidine-1- carboxylate (80 mg, 240.0 µmol) in 4M HCl in 1,4-dioxane (3 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (S)-5- (5,5-difluoropiperidin-3-yl)-2-methoxypyridine (70 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 229. Step 8: (S)-2-((S)-3,3-difluoro-5-(6-methoxypyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0193] A solution of (S)-5-(5,5-difluoropiperidin-3-yl)-2-methoxypyridine (60 mg, 0.260 mmol), (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl 2-nitrobenzenesulfonate (141 mg, 0.280 mmol), TEA (67 mg, 0.660 mmol) and lithium trifluoromethanesulfonate (103 mg, 0.660 mmol) in ACN (3 mL) was stirred overnight at 0°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to afford (S)-2-((S)-3,3-difluoro-5-(6-methoxypyridin-3-yl)piperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (70 mg, 52% yield) as a yellow solid. LCMS (ESI) [M+H]+: 513. Step 9: (S)-2-((S)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0194] A solution of (S)-2-((S)-3,3-difluoro-5-(6-methoxypyridin-3-yl)piperidin-1-yl)-N- (2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (50 mg, 0.1 mmol),TMSCl (55 mg, 0.5 mmol) and NaI (76 mg, 0.5 mmol) in ACN (3 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 38% B in 10 min; Wave Length: 254 nm / 220 nm) to afford (S)-2-((S)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 6) (RT1: 6.2 min; 27.5 mg, 56% yield) as an off-white solid.

[0195] Example 5: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((R)-3-(hydroxymethyl)piperidin-1-yl)propanamide Step 1: (R)-piperidin-3-ylmethanol

[0196] A solution of tert-butyl (R)-3-(hydroxymethyl)piperidine-1-carboxylate (100 mg, 0.460 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure to afford (R)-piperidin-3-ylmethanol (40 mg, crude) as a white solid, which was used in the next step without further purification. Step 2: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3- (hydroxymethyl)piperidin-1-yl)propanamide

[0197] To a solution of (R)-piperidin-3-ylmethanol (40 mg, 0.340 mmol) and (R)-1-((2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (169 mg, 0.340 mmol) in ACN (5 mL) were added lithium trifluoromethanesulfonate (173 mg, 1.1 mmol) and TEA (105 mg, 1.0 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The crude residue was purified by Prep- HPLC (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 18 % B in 10 min; Wave Length: 254 nm / 220 nm) to afford (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)-2-((R)-3-(hydroxymethyl)piperidin-1-yl)propanamide (Compound 7) (RT1: 9.4 min; 15.0 mg, 100% e.e.) as a white solid.

[0198] Example 6: (2S)-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide Step 1: (4,4-difluoropiperidin-3-yl)methanol

[0199] A solution of tert-butyl 4,4-difluoro-3-(hydroxymethyl)piperidine-1-carboxylate (190 mg, 0.750 mmol) in 4 M HCl in 1,4-dioxane (6 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to afford (4,4-difluoropiperidin- 3-yl)methanol (90 mg, crude) as an off-white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 152. Step 2: (2S)-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0200] To a mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (150 mg, 0.3 mmol) and (4,4- difluoropiperidin-3-yl)methanol (55 mg, 0.370 mmol) in ACN (5 mL) were added TEA (93 mg, 0.920 mmol) and lithium trifluoromethanesulfonate (153 mg, 0.980 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 0°C. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse- phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-2-(4,4-difluoro-3- (hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (70 mg, 75% yield) as a white solid. LCMS (ESI) [M+H]+: 436.Step 3: (S)-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide and (S)-2-((S)-4,4-difluoro-3- (hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide

[0201] (2S)-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (70 mg) was purified by Prep- Chiral HPLC (Column: Enantiocel- A4-5, 3.0*25 cm, 5 µm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 224 / 280 nm) to afford first peak (S)-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 8) (RT1: 5.46 min; Method C, Peak 1, 1.15 min; 40.4 mg, 100% d.e.) as a white solid and second peak (S)-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 9) (RT2: 7.18 min; Method C, Peak 2, 1.47 min; 12.4 mg, 98% d.e.) as an off-white solid.

[0202] Example 7: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- morpholinopropanamide Step 1: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- morpholinopropanamide

[0203] To a mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (100 mg, 0.2 mmol) and morpholine (53 mg, 0.6 mmol) in ACN (3 mL) were added lithium trifluoromethanesulfonate (102 mg, 0.650 mmol) and TEA (62 mg, 0.610 mmol) dropwise at 0°C under nitrogen atmosphere. Theresulting mixture was stirred overnight at 0°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 18 % B in 10 min; Wave Length: 254 nm / 220 nm) to afford (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- morpholinopropanamide (Compound 10) (RT1: 15.48 min; 65.6 mg, 100% e.e.) as a white solid.

[0204] Example 8: (S)-2-(4,4-difluoropiperidin-1-yl)-N-(thiazolo[4',5':4,5]benzo[1,2- d]oxazol-6-yl)propanamide Step 1: thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-amine

[0205] To a mixture of benzo[d]oxazol-6-amine (3.00 g, 22.3 mmol) and potassium thiocyanate (6.50 g, 67.0 mmol) in AcOH (50 mL) was added Br2 (3.60 g, 22.3 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water at 0°C. The mixture was neutralized to pH 7 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-amine (1.20 g, 28% yield) as a red solid. LCMS (ESI) [M+H]+: 192. Step 2: (R)-1-oxo-1-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-ylamino)propan-2-yl acetate

[0206] To a mixture of (R)-1-chloro-1-oxopropan-2-yl acetate (500 mg, 3.7 mmol) and TEA (793 mg, 49.2 mmol) in DCM (5 mL) was added thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-amine (796 mg, 4.1 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 3 h. The mixture was concentrated under reduced pressure. The crude residuewas purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (R)-1-oxo- 1-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-ylamino)propan-2-yl acetate (350 mg, 31% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 306. Step 3: (R)-2-hydroxy-N-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-yl)propanamide

[0207] To a mixture of (R)-1-oxo-1-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6- ylamino)propan-2-yl acetate (330 mg, 0.9 mmol) in THF (4 mL) were added H2O (4 mL) and LiOH•H2O (218 mg, 4.9 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 3 h. The mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (R)-2-hydroxy-N-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-yl)propanamide (75 mg, 24% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 264. Step 4: (R)-1-oxo-1-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-ylamino)propan-2-yl 2- nitrobenzenesulfonate

[0208] To a mixture of (R)-2-hydroxy-N-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6- yl)propanamide (75 mg, 0.4 mmol) in DCM (3 mL) were added TEA (86 mg, 1.1 mmol), DMAP (2 mg, 40.0 µmol) and 2-nitrobenzenesulfonyl chloride (62 mg, 0.4 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 3 h. After completion, The reaction mixture was directly purified by silica gel column chromatography, eluted with CH2Cl2 / EA (1:1) to afford (R)-1-oxo-1-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6- ylamino)propan-2-yl 2-nitrobenzenesulfonate (50 mg, 26% yield) as a white solid. LCMS (ESI) [M+H]+: 449. Step 5: (S)-2-(4,4-difluoropiperidin-1-yl)-N-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6- yl)propanamide

[0209] To a mixture of (R)-1-oxo-1-(thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6- ylamino)propan-2-yl 2-nitrobenzenesulfonate (50 mg, 0.1 mmol) and TEA (33 mg, 0.3 mmol) in ACN (2 mL) was added lithium trifluoromethanesulfonate (52 mg, 0.3 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by Prep- HPLC (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 38% B in 10 min; Wave Length: 254 nm / 220 nm) to afford (S)-2-(4,4-difluoropiperidin-1-yl)-N- (thiazolo[4',5':4,5]benzo[1,2-d]oxazol-6-yl)propanamide (Compound 11) (RT1: 6.2 min; 17.8 mg, 100% e.e.) as a white solid.

[0210] Example 9: 4-(4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl)morpholin-2-yl)pyridine 1-oxide Step 1: tert-butyl 2-(pyridin-4-yl)morpholine-4-carboxylate

[0211] To a mixture of 4-bromopyridine (1.00 g, 6.3 mmol) in DMSO (15 mL) were added 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (2.20 g, 9.5 mmol), [4,4'-bis(tert-butyl)- 2,2'-bipyridine]nickel dibromide (154 mg, 0.3 mmol), [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (64 mg, 0.1 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (931 mg, 6.3 mmol) and N,N,N',N'- tetramethylguanidine (1.09 g, 9.5 mmol). The vial was stirred at 1500 rpm stir rate and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor at 35 °C for 2 h. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of H2O. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 2-(pyridin-4-yl)morpholine-4-carboxylate (250 mg, 15% yield) as a yellow oil. LCMS (ESI) [M+H]+: 265. Step 2: 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)pyridine 1-oxide

[0212] To a mixture of tert-butyl 2-(pyridin-4-yl)morpholine-4-carboxylate (230 mg, 0.9 mmol) in DCM (10 mL) was added 3-chlorobenzene-1-carboperoxoic acid (353 mg, 1.7 mmol, 85% purity) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous Na2S2O3 solution (15 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure to afford 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)pyridine 1-oxide (220 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 281. Step 3: 4-(morpholin-2-yl)pyridine 1-oxide

[0213] A solution of 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)pyridine 1-oxide (200 mg, 0.7 mmol) in 4 M HCl in 1,4-dioxane (6 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure to give 4-(morpholin-2-yl)pyridine 1-oxide (199 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 181. Step 4: 4-(4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)morpholin-2-yl)pyridine 1-oxide

[0214] To a mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)ami no)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (500 mg, 1.0 mmol) in acetonitrile (8 mL) were added 4-(morpholin-2-yl)pyridine 1-oxide (185 mg, 1.0 mmol), TEA (581 mg, 5.8 mmol) and lithium trifluoromethanesulfonate (936 mg, 6.0 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred for 20 h at 0°C. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 0% to 60%gradient in 20 min; detector, UV 254 nm) to give 4-(4-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)morpholin-2- yl)pyridine 1-oxide (400 mg, 84% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 465. Step 5: 4-((S)-4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)- 1-oxopropan-2-yl)morpholin-2-yl)pyridine 1-oxide and 4-((R)-4-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)morpholin-2- yl)pyridine 1-oxide

[0215] 4-(4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)morpholin-2-yl)pyridine 1-oxide (180 mg) was purified by Prep-Chiral SFC (Column: CHIRALPAK IA, 3*25 cm, 5 μm; Mobile Phase A: MTBE (10 mM NH3-MeOH), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 273 / 216 nm) to afford first peak 4-((S)-4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)morpholin-2-yl)pyridine 1-oxide (Compound 12) (RT1: 9.96 min; Method D, Peak 1, 1.25 min; 48.8 mg, 100% d.e.) as a white solid and second peak 4- ((R)-4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan- 2-yl)morpholin-2-yl)pyridine 1-oxide (Compound 13) (RT2: 19.07 min; Method D, Peak 2, 2.56 min; 50.2 mg, 100% d.e.) as a white solid.

[0216] Example 10: (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6- dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide Step 1: tert-butyl (E)-3-(5-(((tert-butylsulfinyl)imino)methyl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate

[0217] A solution of tert-butyl 4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidine- 1-carboxylate (400 mg, 1.2 mmol), 2-methylpropane-2-sulfinamide (149 mg, 1.2 mmol) and Cs2CO3 (731 mg, 2.2 mmol) in THF (5 mL) was stirred at room temperature for 24 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford tert-butyl (E)-3-(5-(((tert-butylsulfinyl)imino)methyl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate (360 mg, 69% yield) as a white solid. LCMS (ESI) [M+H]+: 460. Step 2: tert-butyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-6-methoxypyridin- 3-yl)-4,4-difluoropiperidine-1-carboxylate

[0218] A solution of tert-butyl (E)-3-(5-(((tert-butylsulfinyl)imino)methyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (360 mg, 0.780 mmol), trimethyl(trifluoromethyl)silane (334 mg, 2.3 mmol) and tetrabutylammonium difluorotriphenylsilicate (84 mg, 0.150 mmol) in THF (10 mL) was stirred at room temperature for 4 hours under nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl solution (15 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2,2- trifluoroethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (280 mg, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 530. Step 3: 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)-2,2,2-trifluoroethan-1- amine

[0219] A solution of tert-butyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (280 mg, 0.440 mmol) in TFA (5 mL) was stirred at 55°C for 6 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)-2,2,2-trifluoroethan-1-amine (124 mg, 85% yield) as a yellow solid. LCMS (ESI) [M+H]+: 326. Step 4: (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0220] A solution of 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)-2,2,2- trifluoroethan-1-amine (120 mg, 0.360 mmol), (R)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (179 mg, 0.360 mmol), lithium trifluoromethanesulfonate (143 mg, 0.920 mmol) and Et3N (89 mg, 0.880 mmol) in ACN (6 mL) was stirred overnight at 0°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (105 mg, 46% yield) as a yellow solid. LCMS (ESI) [M+H]+: 610. Step 5: (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-

[0221] To a mixture of (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-methoxypyridin-3-yl)- 4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (100 mg, 0.160 mmol) in DCM (3 mL) was added TMSI (0.115 mL, 0.820 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (70 mg, 71% yield) as a white solid. LCMS (ESI) [M+H]+: 596. Step 6: (S)-2-((S)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)- 4,4-difluoropiperidin-1-yl)-N-(2,2-difluorothieno[2',3':4,5]benzo[1,2-d][1,3]dioxol-6- yl)propanamide, (S)-2-((R)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6- dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide, (S)-2-((S)-3-(5-((R)-1-amino- 2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide and (S)-2-((R)-3-(5- ((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0222] (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (70 mg) was purified 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 50% B; Wave Length: 220 / 308 nm) to afford a mixture of Compound 14 and Compound 15 (RT1: 5.55 min; 28 mg) and a mixture Compound 16 and Compound 17 (RT2: 9.0 min; 29 mg). The mixture of Compound 14 and Compound 15 was separated by Prep-Chiral HPLC (Column: Lux 5µ Cellulose-2, 30*250 mm, 5.0 µm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient:isocratic 50% B; Wave Length: 228 / 310 nm) to afford first peak (S)-2-((S)-3-(5-((S)-1-amino- 2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2- difluorothieno[2',3':4,5]benzo[1,2-d][1,3]dioxol-6-yl)propanamide (Compound 14) (RT1: 7.1 min; Method E, Peak 1, 2.69 min; 10.1 mg, 100% d.e.) as a white solid and second peak (S)-2- ((R)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (Compound 15) (RT2: 16.2 min; Method E, Peak 2, 3.81 min; 11.4 mg, 100% d.e.) as a white solid. The mixture of Compound 16 and Compound 17 was separated by Prep- Chiral HPLC (Column: (S, S)-Whelk-O 15 μm Kromasil, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH: ACN=5: 1; Flow rate: 20 mL / min; Gradient: isocratic 20% B; Wave Length: 228 / 210 nm) to afford first peak (S)-2-((S)-3-(5-((R)-1-amino- 2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 16) (RT1: 15.5 min; Method F, Peak 1, 1.15 min; 10.5 mg, 100% d.e.) as a white solid and second peak (S)-2-((R)-3- (5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 17) (RT2: 20.5 min; Method F, Peak 2, 1.45 min; 9.3 mg, 100% d.e.) as a white solid.

[0223] Example 11: (S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6- d]thiazol-2-yl)propanamide Step 1: (S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2- yl)propanamide

[0224] A solution of (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan- 2-yl 2-nitrobenzenesulfonate (50 mg, 0.110 mmol) in ACN (6 mL) were added 4,4- difluoropiperidine (27 mg, 0.220 mmol), lithium trifluoromethanesulfonate (35 mg, 0.220 mmol) and Et3N (23 mg, 0.220 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 24 h. The reaction mixture was directly purified by Prep- HPLC (Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to 63% B in 9 min; Wave Length: 254 nm / 220 nm) to afford (S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro-5H- indeno[5,6-d]thiazol-2-yl)propanamide (Compound 18) (RT1: 7.55 min; 24.3 mg, 59% yield) as a white solid.

[0225] Example 12: (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5- dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2- yl)propanamide Step 1: (6-(4,4-difluoropiperidin-3-yl)-3-methoxypyrazin-2-yl)methanol

[0226] A solution of benzyl 4,4-difluoro-3-(5-methoxy-6- ((methoxymethoxy)methyl)pyrazin-2-yl)piperidine-1-carboxylate (5.00 g, 11.4 mmol) in TFA (30 mL) was stirred at 70°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give (6-(4,4-difluoropiperidin-3-yl)-3-methoxypyrazin-2- yl)methanol (800 mg, 27% yield) as a brown oil. LCMS (ESI) [M+H]+: 260. Step 2: (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-methoxypyrazin-2-yl)piperidin-1-yl)- N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide

[0227] A solution of (6-(4,4-difluoropiperidin-3-yl)-3-methoxypyrazin-2-yl)methanol (250 mg, 1.0 mmol), (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (647 mg, 1.5 mmol), lithium trifluoromethanesulfonate (376 mg, 2.4 mmol) and Et3N (244 mg, 2.4 mmol) in ACN (6 mL) was stirred overnight at 0°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-methoxypyrazin-2-yl)piperidin- 1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (150 mg, 31% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 504.

[0228] Step 3: (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2- yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide

[0229] A solution of (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-methoxypyrazin-2- yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (150 mg, 0.3 mmol), TMSCl (162 mg, 1.5 mmol) and NaI (223 mg, 1.5 mmol) in ACN (5 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5- oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2- yl)propanamide (70 mg, 48% yield) as a yellow solid. LCMS (ESI) [M+H]+: 490. Step 4: (S)-2-((R)-4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2- yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide and (S)-2- ((S)-4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N- (6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide

[0230] (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin- 1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (70 mg) was purified by Prep- HPLC (Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 38% B in 9 min; Wave Length: 254 nm / 220 nm) to afford first peak (S)-2-((R)-4,4-difluoro-3-(6- (hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6- d]thiazol-2-yl)propanamide (Compound 19) (RT1: 10.98 min; Method G, Peak 1, 1.02 min; 11.6 mg, 99% d.e.) as a white solid and second peak (S)-2-((S)-4,4-difluoro-3-(6-(hydroxymethyl)-5- oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2- yl)propanamide (Compound 20) (RT2: 12.20 min; Method G, Peak 2, 1.73 min; 15.8 mg, 96% d.e.) as an off-white solid.

[0231] Example 13: (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin- 3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide Step 1: benzyl 4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidine-1-carboxylate

[0232] A solution of benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate (3.50 g, 8.1 mmol) in 3 M HCl in H2O (17 mL) and THF (17 mL) was stirred for 1 h at 40°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to afford benzyl 4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidine-1-carboxylate (2.80 g, 88% yield) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 391. Step 2: benzyl (E)-3-(5-(((tert-butylsulfinyl)imino)methyl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate

[0233] A solution of benzyl 4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidine-1- carboxylate (2.50 g, 6.4 mmol), 2-methylpropane-2-sulfinamide (1.16 g, 9.6 mmol) and Cs2CO3 (6.26 g, 19.2 mmol) in THF (35 mL) was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of H2O (40 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 45 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford benzyl (E)-3-(5-(((tert-butylsulfinyl)imino)methyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (2.80 g, 88% yield) as a yellow oil. LCMS (ESI) [M+H]+: 494. Step 3: benzyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2-difluoro-2-(phenylsulfonyl)ethyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate

[0234] To a mixture of benzyl (E)-3-(5-(((tert-butylsulfinyl)imino)methyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (500 mg, 1.0 mmol) and ((difluoromethyl)sulfonyl) benzene (214 mg, 1.1 mmol) in THF (10 mL) was added LiHMDS (1 M in THF, 2 mL, 2.0 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 4 h. The reaction was quenched by the addition of sat. aq. NH4Cl (15 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford benzyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2-difluoro-2- (phenylsulfonyl)ethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (450 mg, 64% yield) as a yellow solid. LCMS (ESI) [M+H]+: 686. Step 4: benzyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2-difluoroethyl)-6-methoxypyridin-3- yl)-4,4-difluoropiperidine-1-carboxylate

[0235] To a mixture of benzyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2-difluoro-2- (phenylsulfonyl)ethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (430 mg, 0.6 mmol) in DMF (10 mL) was added AcOH (376 mg, 6.3 mmol), AcONa (514 mg, 6.3 mmol) and H2O (1.36 g, 75.2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 20 min. Then, magnesium (247 mg, 9.4 mmol) was added in portions over 5 min at room temperature. The resulting mixture was stirred at 45°C for additional 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (20 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford benzyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2-difluoroethyl)- 6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (313 mg, 90% yield) as a white solid. LCMS (ESI) [M+H]+: 546. Step 5: 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)-2,2-difluoroethan-1-amine

[0236] A solution of benzyl 3-(5-(1-((tert-butylsulfinyl)amino)-2,2-difluoroethyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (280 mg, 0.440 mmol) in TFA (5 mL) was stirred at 55°C for 6 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to give 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)-2,2-difluoroethan-1-amine (130 mg, 82% yield) as a yellow solid. LCMS (ESI) [M+H]+: 308. Step 6: (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0237] To a mixture of 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)-2,2- difluoroethan-1-amine (130 mg, 0.4 mmol) and (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo [1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (103 mg, 0.2 mmol) in ACN (3 mL) was added TEA (107 mg, 1.1 mmol) and lithium trifluoromethanesulfonate (165 mg, 1.1 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 days. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N- (2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (200 mg, 80% yield) as a yellow oil. LCMS (ESI) [M+H]+: 592. Step 7: (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0238] To a mixture of (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-methoxypyridin-3-yl)- 4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (190 mg, 0.3 mmol) in ACN (5 mL) was added TMSI (0.225 mL, 1.6 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 25 min; detector, UV 254 nm) to give (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (95 mg, 51% yield) as a white solid. LCMS (ESI) [M+H]+: 578. Step 8: (S)-2-((S)-3-(5-((S)-1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide, (S)-2-((R)-3-(5-((S)-1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide, (S)-2-((S)-3-(5-((R)-1-amino-2,2-difluoroethyl)-6-oxo-1,6- dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide and (S)-2-((R)-3-(5-((R)-1- amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0239] (2S)-2-(3-(5-(1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (62 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK IE, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 206 / 228 nm) to afford a mixture of Compound 21 and Compound 22 (RT1: 11.8 min; 27 mg) and a mixture of Compound 23 and Compound 24 (RT2: 15.7 min; 28 mg). The mixture of Compound 21 and Compound 22 was separated by Prep-Chiral HPLC (Column: CHIRALPAKIE, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flowrate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 206 / 228 nm) to afford first peak (S)- 2-((S)-3-(5-((S)-1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (Compound 21) (RT1: 11.8 min; Method H, Peak 1, 1.92 min; 10.4 mg, 100% d.e.) as a white solid and second peak (S)-2-((S)-3-(5-((R)-1-amino-2,2-difluoroethyl)-6-oxo- 1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 22) (RT2: 15.7 min; Method H, Peak 2, 2.50 min; 9.2 mg, 100% d.e.) as a white solid. The mixture of Compound 23 and Compound 24 was separated by Prep-Chiral HPLC (Column: CHIRALPAK IC, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 206 / 228 nm) to afford first peak (S)-2-((R)-3-(5-((S)- 1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 23) (RT1: 9.23 min; Method I, Peak 1, 1.45 min; 14.3 mg, 100% d.e.) as a white solid and second peak (S)-2-((R)-3-(5-((R)-1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (Compound 24) (RT2: 18.7 min; Method I, Peak 2, 3.09 min; 10.0 mg, 100% d.e.) as a white solid.

[0240] Example 14: (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1- yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide Step 1: (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide

[0241] A solution of 5-(2,2-difluorocyclohexyl)pyrazin-2(1H)-one (100 mg, 0.4 mmol), (R)- 1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (138 mg, 0.3 mmol), TEA (175 mg, 1.7 mmol) and lithium trifluoromethanesulfonate (280 mg, 1.7 mmol) in ACN (10 mL) was stirred for 48 h at 0°C. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (2S)-2-(4,4-difluoro-3-(5-oxo-4,5- dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (75 mg, 52% yield) as a white solid. LCMS (ESI) [M+H]+: 460.

[0242] Step 2: (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)- N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide and (S)-2-((S)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2- yl)propanamide

[0243] (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (75 mg) was purified by Prep-Chiral HPLC (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 220 / 254 nm) to afford first peak (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2- yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (Compound 25) (RT1: 11.31 min; Method J, Peak 1, 1.71 min; 9.0 mg, 100% d.e.) as a white solid and second peak (S)-2-((S)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro- 5H-indeno[5,6-d]thiazol-2-yl)propanamide (Compound 26) (RT2: 13.58 min; Method J, Peak 2, 2.56 min; 9.6 mg, 98% d.e.) as a white solid.

[0244] Example 15: (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1- yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide Step 1: (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide

[0245] To a solution of (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl 2-nitrobenzenesulfonate (171 mg, 0.350 mmol) and 5-(4,4-difluoropiperidin-3- yl)pyridin-2(1H)-one (300 mg, 0.7 mmol) in ACN (10 mL) were added lithium trifluoromethanesulfonate (546 mg, 3.5 mmol) and Et3N (354 mg, 3.5 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 20 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase flashchromatography (C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 40 ml / min; gradient: 45% B to 55% B in 15 min; Wave Length: 254 nm / 220 nm) to afford (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (85 mg, 49% yield) as a yellow solid. LCMS (ESI) [M+H]+: 459. Step 2: (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide and (S)-2-((R)-4,4-difluoro-3-(6-oxo- 1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2- yl)propanamide

[0246] (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (85 mg) was purified by Prep-Chiral HPLC (Column: Lux 5µ Cellulose-2, 30*250 mm, 5.0 µm; Mobile Phase A: Hex (10 mM NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 234 / 300 nm) to afford first peak (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide (Compound 27) (RT1: 10.3 min; Method K, Peak 2, 4.96 min; 10.7 mg, 83% d.e.) as a white solid and second peak (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro- 5H-indeno[5,6-d]thiazol-2-yl)propanamide (Compound 28) (RT2: 13.4 min; Method K, Peak 1, 2.49 min, 9.9 mg, 95% d.e.) as a white solid.

[0247] Example 16: (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1- yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide Step 1: (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide

[0248] A solution of (R)-1-((6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (65 mg, 0.140 mmol) and 5-(4,4- difluoropiperidin-3-yl)pyridin-2(1H)-one (200 mg, 0.467 mmol) in ACN (6 mL) was added lithium trifluoromethanesulfonate (364 mg, 2.3 mmol) and Et3N (236 mg, 2.3 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 20 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse- phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (2S)-2-(4,4-difluoro-3-(6-oxo- 1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2- d]thiazol-2-yl)propanamide (45 mg, 68% yield) as a yellow solid. LCMS (ESI) [M+H]+: 477. Step 2: (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide and (S)-2-((R)-4,4- difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro- [1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide

[0249] (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7- dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide (45 mg) was purified by Prep-Chiral HPLC (Column: Lux 5µ Cellulose-2, 30*250 mm, 5.0 µm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 230 / 312 nm) to afford first peak (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2- yl)propanamide (Compound 29) (RT1: 14.7 min; Method L, Peak 1, 2.65 min; 6.9 mg, 100% d.e.) as a white solid and second peak (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide (Compound 30) (RT2: 18.8 min; Method L, Peak 2, 3.35 min; 4.7 mg, 98% d.e.) as a white solid.

[0250] Example 17: (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide Step 1: (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0251] A solution of (S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)ami no)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (171 mg, 0.350 mmol), 5-(4,4-difluoropiperidin- 3-yl)pyridin-2(1H)-one (300 mg, 0.7 mmol), lithium trifluoromethanesulfonate (546 mg, 3.5 mmol) and Et3N (354 mg, 3.5 mmol) in ACN (10 mL) was stirred at 0°C for 20 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase column chromatography (C18 silica gel eluted with ACN in water (0.1% formic acid), 5% to 50% gradient in 20 min; detector, UV 254 nm) to afford (2S)-2-(4,4-difluoro-3-(6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (85 mg, 24% yield) as a yellow solid. LCMS (ESI) [M+H]+: 499. Step 2: (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide and (S)-2-((R)-4,4- difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0252] (2S)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (85 mg) was purified by Prep-Chiral HPLC (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20% B; Wave Length: 202 / 220 / 267 nm) to afford first peak (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (Compound 31) (RT1: 12.59 min; Method K, Peak 2, 1.43 min; 14.7 mg, 99% d.e.) as a white solid and second peak (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 32) (RT2: 15.63 min; Method K, Peak 1, 0.87 min; 14.4 mg, 99% d.e.) as a white solid.

[0253] Example 18: (S)-N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(4,4- difluoropiperidin-1-yl)propanamide Step 1: [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine

[0254] To a mixture of benzo[d][1,3]dioxol-5-amine (15.00 g, 109.3 mmol) and potassium thiocyanate (15.94 g, 164.1 mmol) in AcOH (200 mL) was added Br2(17.48 g, 109.4 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched with water at 0°C. The mixture was neutralized to pH 7 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine (15.90 g, 75% yield) as a brown solid. LCMS [M+H]+: 195. Step 2: (R)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl acetate

[0255] To a mixture of [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine (500 mg, 2.5 mmol) and (R)-1-chloro-1-oxopropan-2-yl acetate (387 mg, 2.5 mmol) in DCM (10 mL) was added TEA (781 mg, 7.5 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 0°C. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (R)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl acetate (300 mg, 38% yield) as a light yellow solid. LCMS [M+H]+: 309. Step 3: (R)-N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-hydroxypropanamide

[0256] To a mixture of (R)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1- oxopropan-2-yl acetate (300 mg, 0.9 mmol) in THF (5 mL) and H2O (1 mL) was added LiOH monohydrate (69 mg, 2.9 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for additional 2 h. The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (R)-N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- hydroxypropanamide (210 mg, 81% yield) as an off-white solid. LCMS [M+H]+: 267. Step 4: (R)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate

[0257] To a mixture of (R)-N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- hydroxypropanamide (200 mg, 0.7 mmol) and TEA (228 mg, 2.2 mmol) in DCM (8 mL) was added 2-nitrobenzene-1-sulfonyl chloride (166 mg, 0.7 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for additional 2 h. The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford (R)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (190 mg, 56% yield) as an off- white solid. LCMS [M+H]+: 452 Step 5: (S)-N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(4,4-difluoropiperidin-1- yl)propanamide

[0258] To a mixture of (R)-1-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-ylamino)-1- oxopropan-2-yl 2-nitrobenzenesulfonate (120 mg, 0.3 mmol) and 4,4-difluoropiperidine (96 mg, 0.8 mmol) in ACN (6 mL) were added lithium trifluoromethanesulfonate (132 mg, 0.8 mmol) and TEA (80 mg, 0.8 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for additional 2 h. The mixture was concentrated under reduced pressure and the crude residue was purified by Prep-HPLC (Column: XBridge Prep Phenyl OBD Column 30*250 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 39% B in 2 min, 39% to 57% B in 12 min; Wave Length: 254 nm / 220 nm) to afford (S)-N-([1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)-2-(4,4-difluoropiperidin-1-yl)propanamide (Compound 33) (RT1: 9.83 min; 41.2 mg, 100% e.e.) as a white solid.

[0259] Example 19: (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide Step 1: (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0260] A solution of 5-(4,4-difluoropiperidin-3-yl)pyrazin-2(1H)-one (100 mg, 0.4 mmol), (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (150 mg, 0.3 mmol), TEA (175 mg, 1.7 mmol) and lithium trifluoromethanesulfonate (280 mg, 1.7 mmol) in ACN (3 mL) was stirred for 48 h at 0°C. Themixture was concentrated under reduced pressure and the crude residue was purified by reverse- phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-2-(4,4-difluoro-3-(5-oxo- 4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide (80 mg, 51% yield) as a white solid. LCMS (ESI) [M+H]+: 500. Step 2: (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide and (S)-2-((S)-4,4- difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0261] (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (80 mg) was purified by Prep-Chiral HPLC (Column: Chiral NQ(2) 5 µm, 30*250 mm; Mobile Phase A: Hex (0.1% Formic Acid), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 228 / 304 nm) to afford first peak (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 34) (RT1: 5 min; Method M, Peak 1, 1.50 min; 19.1 mg, 100% d.e.) as a white solid and second peak (S)-2-((S)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N- (2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 35) (RT2: 9 min; Method M, Peak 2, 2.06 min; 18.5 mg, 100% d.e.) as a white solid.

[0262] Example 20: 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)amino)-1-oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide Step 1: tert-butyl 4-fluoro-3-(pyridin-4-yl)piperidine-1-carboxylate

[0263] An oven-dried 40 mL vial was charged with tert-butyl 4-fluoro-3-hydroxypiperidine- 1-carboxylate (1.00 g, 4.6 mmol), 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC-1)(1.65 g, 4.2 mmol) and a magnetic stir bar. After the vial was vacuumed and refilled with nitrogen gas twice, 2-methoxy-2-methylpropane (24 mL) was added and the reaction stirred at 0°C for 10 min. Then, a pyridine solution (330 mg, 4.2 mmol. in 1.0 mL 2-methoxy-2-methylpropane) was added dropwise at 0°C over the course of 2 min. The resulting solution stirred at room temperature for 10 min. A white solid precipitated out during this time. Another oven-dried 60 mL vial was charged with [Ir(dtbbpy)(ppy)2]PF6 (36 mg, 39.0 µmol), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (95 mg, 0.2 mmol), 1- azabicyclo[2.2.2]octane (507 mg, 4.6 mmol), 4-bromopyridine (412 mg, 2.6 mmol) and a magnetic stir bar. N,N-dimethylacetamide (25 mL) was added to this vial under an atmosphere of nitrogen. The methyl tert-butyl ether suspension was transferred to a 50 mL syringe under air. Then a syringe filter and new needle were installed on the syringe, before the methyl tert-butyl ether solution was injected through the syringe filter into the dimethylacetamide solution. The reaction mixture was sparged with nitrogen for 15 minutes before sealing with parafilm. The vial was stirred and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with water (3 x 70 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4- fluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (400 mg, 55% yield) as a white solid. LCMS (ESI) [M+H]+: 281. Step 2: 4-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-3-yl)pyridine 1-oxide

[0264] A mixture of tert-butyl 4-fluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (400 mg, 1.4 mmol) and 3-chlorobenzene-1-carboperoxoic acid (1.20 g, 7.1 mmol, 85% purity) in DCM (8 mL) was stirred at room temperature for 1 h. The reaction was quenched by the addition of sat. aq. Na2S2O3 (10 mL) at 0°C. The aqueous layer was extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 5% to 100% gradient in 20 min;detector, UV 220 nm and UV 200 nm) to give 4-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-3- yl)pyridine 1-oxide (200 mg, 47% yield) as a white solid. LCMS (ESI) [M+H]+: 297. Step 3: 4-(4-fluoropiperidin-3-yl)pyridine 1-oxide

[0265] A mixture of 4-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-3-yl)pyridine 1-oxide (200 mg, 1.0 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-(4-fluoropiperidin-3- yl)pyridine 1-oxide (200 mg, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 197. Step 4: 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide

[0266] A solution of 4-(4-fluoropiperidin-3-yl)pyridine 1-oxide (200 mg, 1.0 mmol), (R)-1- ((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (497 mg, 1.0 mmol), Et3N (206 mg, 2.0 mmol) and lithium trifluoromethanesulfonate (318 mg, 2.0 mmol) in ACN (6 mL) was stirred at 0°C for 20 h. The resulting mixture was concentrated under reduced pressure and the crude residue was directly purified by reverse phase column chromatography (C18 silica gel eluted with ACN in water (0.1% formic acid), 0% to 100% gradient in 25 min; detector, UV 254 nm and UV 220 nm) to afford 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide (160 mg, 33% yield) as a white solid. LCMS (ESI) [M+H]+: 481. Step 5: 4-((3S,4R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide, 4-((3R,4R)-1-((S)-1- ((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4- fluoropiperidin-3-yl)pyridine 1-oxide, 4-((3S,4S)-1-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4-fluoropiperidin- 3-yl)pyridine 1-oxide and 4-((3R,4S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide

[0267] 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide (160 mg) was separated by prep-chiral HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 30% B in 2 min, 30% to 43% B in 11 min; Wave Length: 254 nm / 220 nm) to afford a mixture of Compound 36 and Compound 37 (RT1: 12.03 min; 48 mg) and mixture of Compound 38 and Compound 39 (RT2: 12.87 min; 58 mg). The mixture of Compound 36 and Compound 37 (48 mg) was separated by Prep-Chiral HPLC (Column: CHIRAL ART Cellulose- SZ, 2.0*25 cm, 5 µm; Mobile Phase A: MTBE (10 mM NH3-MeOH), Mobile Phase B: MeOH; Flow rate: 20 mL / min; Gradient: isocratic 30% B; Wave Length: 220 / 272 nm) to afford 4- ((3S,4R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide (Compound 36) (RT1: 9.5 min; Method N, Peak 1, 1.78 min; 8.2 mg, 100% d.e.) as a white solid and second peak 4-((3R,4R)-1- ((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)- 4-fluoropiperidin-3-yl)pyridine 1-oxide (Compound 37) (RT2: 12 min; Method N, Peak 2, 2.30 min; 19.2 mg, 100% d.e.) as a white solid. The mixture of Compound 38 Compound 39 (58 mg) was separated by Prep-Chiral HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ, 2.0*25 cm, 5 µm; Mobile Phase A: MTBE (10 mM NH3-MeOH), Mobile Phase B: MeOH; Flow rate: 20 mL / min; Gradient: isocratic 30% B; Wave Length: 220 / 272 nm) to afford 4-((3S,4S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)- 1-oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide (Compound 38) (RT1: 8.5 min; Method N, Peak 1, 1.60 min; 7.5 mg, 100 % d.e.) as a white solid and second peak 4-((3R,4S)-1- ((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)- 4-fluoropiperidin-3-yl)pyridine 1-oxide (Compound 39) (RT2: 10.2 min; Method N, Peak 2, 1.93 min; 19.6 mg, 100 % d.e.) as a white solid.

[0268] Example 21: (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1- yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide Step 1: tert-butyl 3-(5-methoxypyrazin-2-yl)-4-oxopiperidine-1-carboxylate

[0269] A solution of 2-bromo-5-methoxypyrazine (10.00 g, 52.9 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (12.60 g, 63.4 mmol), t-BuONa (10.10 g, 105.8 mmol), Pd(OAc)2 (1.10 g, 5.2 mmol) and XPhos (5.00 g, 10.5 mmol) in THF (120 mL) was stirred for 3 h at 45°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filter cake was washed with EtOAc (3 x 150 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford tert-butyl 3-(5-methoxypyrazin-2-yl)-4- oxopiperidine-1-carboxylate (15.00 g, 92% yield) as a yellow oil. LCMS (ESI) [M+H]+: 308. Step 2: tert-butyl 4,4-difluoro-3-(5-methoxypyrazin-2-yl)piperidine-1-carboxylate

[0270] To a mixture of tert-butyl 3-(5-methoxypyrazin-2-yl)-4-oxopiperidine-1-carboxylate (5.00 g, 16.2 mmol) in DCM (50 mL) was added DAST (5.20 g, 32.5 mmol) dropwise at 0°C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate solution (60 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford tert-butyl 4,4-difluoro-3-(5-methoxypyrazin-2-yl)piperidine-1-carboxylate (1.40 g, 26% yield) as a yellow oil. LCMS (ESI) [M+H]+: 330. Step 3: 5-(4,4-difluoropiperidin-3-yl)pyrazin-2(1H)-one

[0271] A solution of tert-butyl 4,4-difluoro-3-(5-methoxypyrazin-2-yl)piperidine-1- carboxylate (700 mg, 2.1 mmol) in 5 M HCl in water (10 mL) was stirred for 3 h at 80°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to afford 5-(4,4-difluoropiperidin-3-yl)pyrazin-2(1H)-one (560 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 216. Step 4: (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7- dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide

[0272] A solution of 5-(4,4-difluoropiperidin-3-yl)pyrazin-2(1H)-one (150 mg, 0.6 mmol), (R)-1-((6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (270 mg, 0.5 mmol), TEA (329 mg, 3.2 mmol) and lithium trifluoromethanesulfonate (525 mg, 3.3 mmol) in ACN (10 mL) was stirred for 48 h at 0°C. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:9) to afford (2S)-2-(4,4-difluoro-3-(5- oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2- d]thiazol-2-yl)propanamide (96 mg, 34% yield) as a white solid. LCMS (ESI) [M+H]+: 478. Step 5: (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7- dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide and (S)-2-((S)-4,4- difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro- [1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide

[0273] (2S)-2-(4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7- dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide (95 mg) was purified by Prep-Chiral HPLC (Column: CHIRALPAK-IK, 3*25 cm, 5 μm; Mobile Phase A: Hex (0.1% Formic Acid), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 220 / 319 nm) to afford first peak (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2- yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide (Compound 40) (RT1: 20 min; Method O, Peak 1, 2.13 min; 17.1 mg, 100% d.e.) as a white solid and second peak (S)-2-((S)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)- N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide (Compound 41) (RT2: 25 min; Method O, Peak 2, 3.15 min; 28.0 mg, 100% d.e.) as a white solid.

[0274] Example 22: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)- 2-(3-(5-(1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide Step 1: 1-(5-bromo-2-methoxypyridin-3-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-ol

[0275] A solution of 5-bromo-3-iodo-2-methoxypyridine (10.00 g, 31.9 mmol) in THF (100 mL) was addediPrMgCl•LiCl (29 mL, 38.2 mmol, 1.3 M in THF) dropwise at -60°C under nitrogen atmosphere. The mixture was stirred at -20°C for 30 min. Then, 2-((tert- butyldimethylsilyl)oxy)acetaldehyde (6.66 g, 38.2 mmol) was added dropwise over 10 min at - 60°C. The resulting mixture was stirred at -20°C for an additional 2 h. The reaction was quenched with saturated aqueous NH4Cl solution (80 mL) at 0°C. The aqueous layer was extracted with EA (3 x 120 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 40%) to afford 1-(5-bromo-2-methoxypyridin-3-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (7.50 g, 65% yield) as a yellow oil. LCMS (ESI) [M+H]+: 362. Step 2: 1-(5-bromo-2-methoxypyridin-3-yl)ethane-1,2-diol

[0276] To a solution of 1-(5-bromo-2-methoxypyridin-3-yl)-2-((tert- butyldimethylsilyl)oxy)ethan-1-ol (7.50 g, 20.7 mmol) in THF (80 mL) was added TBAF (62.1 mL, 62.1 mmol, 1M in THF) at 0°C. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 90 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 50%) to afford 1-(5-bromo-2-methoxypyridin-3-yl)ethane-1,2- diol (3.20 g, 62% yield) as a yellow solid. LCMS (ESI) [M+H]+: 248. Step 3: 5-bromo-3-(2,4,7,9-tetraoxadecan-5-yl)-2-methoxypyridine

[0277] To a solution of 1-(5-bromo-2-methoxypyridin-3-yl)ethane-1,2-diol (3.20 g, 12.9 mmol) in DMF (30 mL) was added with bromomethyl methyl ether (8.06 g, 64.5 mmol) and sodium hydride (60% in mineral oil, 0.93 g, 38.7 mmol) in portions at 0°C. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 50%) to afford 5- bromo-3-(2,4,7,9-tetraoxadecan-5-yl)-2-methoxypyridine (3.00 g, 69% yield) as a colorless oil. LCMS (ESI) [M+H]+: 336. Step 4: tert-butyl 3-(5-(2,4,7,9-tetraoxadecan-5-yl)-6-methoxypyridin-3-yl)-4- oxopiperidine-1-carboxylate

[0278] A solution of 5-bromo-3-(2,4,7,9-tetraoxadecan-5-yl)-2-methoxypyridine (3.00 g, 8.9 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.13 g, 10.7 mmol), t-BuONa (2.57 g, 26.8 mmol), X-Phos (0.85 g, 1.8 mmol) and Pd(OAc)2 (0.20 g, 0.9 mmol) in THF (50 mL) was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of H2O (55 mL) at 0°C. The resulting mixture was extracted with EA (3 x 60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 60%) to afford tert-butyl 3-(5- (2,4,7,9-tetraoxadecan-5-yl)-6-methoxypyridin-3-yl)-4-oxopiperidine-1-carboxylate (2.00 g, 49% yield) as a colorless oil. LCMS (ESI) [M+H]+: 455. Step 5: tert-butyl 3-(5-(2,4,7,9-tetraoxadecan-5-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate

[0279] To a solution of tert-butyl 3-(5-(2,4,7,9-tetraoxadecan-5-yl)-6-methoxypyridin-3-yl)- 4-oxopiperidine-1-carboxylate (1.60 g, 3.5 mmol) in DCM (12 mL) was added DAST (1.70 g, 10.6 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with saturated aqueous NaHCO3 solution (15 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 100%) to afford tert-butyl 3-(5-(2,4,7,9- tetraoxadecan-5-yl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (800 mg, 48% yield) as a yellow oil. LCMS (ESI) [M+H]+: 477. Step 6: 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)ethane-1,2-diol

[0280] To a mixture of tert-butyl 3-(5-(2,4,7,9-tetraoxadecan-5-yl)-6-methoxypyridin-3-yl)- 4,4-difluoropiperidine-1-carboxylate (800 mg, 1.7 mmol) in DCM (10 mL) was added TFA (5 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford 1-(5-(4,4-difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)ethane-1,2-diol (750 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 289. Step 7: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-(1,2- dihydroxyethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide

[0281] To a solution of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (634 mg, 1.3 mmol) and 1-(5-(4,4- difluoropiperidin-3-yl)-2-methoxypyridin-3-yl)ethane-1,2-diol (750 mg, 2.6 mmol) in acetonitrile (8 mL) was added lithium trifluoromethanesulfonate (2.10 g, 13.0 mmol) and Et3N (1.31 g, 13.0 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 20 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)- N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-(1,2-dihydroxyethyl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (420 mg, 28% yield) as a yellow solid. LCMS [M+H]+: 573. Step 8: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-(1,2- dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide

[0282] To a solution of (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)-2-(3-(5-(1,2-dihydroxyethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide (400 mg, 0.7 mmol) in acetonitrile (8 mL) was added TMSI (0.490 mL, 3.5 mmol) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 20 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 64% B in 10 min; Wave Length: 254 nm / 220 nm) toafford (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-(1,2- dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (RT1: 11.47 min; 250 mg, 64% yield) as a yellow solid. LCMS (ESI) [M+H]+: 559. Step 9: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(5-((R)- 1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide and (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((R)-1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide and (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((S)-3-(5-((S)-1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide and (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((R)-3-(5-((S)-1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- l) r n mid

[0283] (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-(1,2- dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (100 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 35% B in 2 min, 35% to 40% B in 11 min; Wave Length: 254 nm / 220 nm) to afford a mixture of Compound 42 and Compound 44 (RT1: 10.17 min; 40 mg) and a mixture Compound 43 and Compound 45 (RT2: 10.78 min; 40 mg). The mixture of Compound 42 and Compound 44 was separated by Prep-Chiral HPLC (Column: Chiral NQ(2) 5 µm, 250*30 mm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30% B; Wave Length: 228 / 304 nm) to afford first peak (S)- N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(5-((R)-1,2- dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 42) (Method P, Peak 1, 1.37 min; 12.9 mg, 100% d.e.) as a white solid and second peak (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(5-((S)-1,2- dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 44) (Method P, Peak 2, 1.96 min; 11.8 mg, 95% d.e.) as a white solid. The mixture of Compound 43 and Compound 45 was separated by Prep-Chiral HPLC (Column: EnontiocelIDA-3, 0.46*5 cm, 3µm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient: isocratic 50% B; Wave Length: 228 / 304 nm) to afford first peak (S)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((R)-1,2-dihydroxyethyl)-6- oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 43) (Method Q, Peak 1, 1.17 min; 15.6 mg, 100% d.e.) as a white solid and second peak (S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((S)-1,2-dihydroxyethyl)-6-oxo-1,6- dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 45) (Method Q, Peak 2, 1.95 min; 15.2 mg, 95% d.e.) as a white solid.

[0284] Example 23: 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide Step 1: tert-butyl 3-(pyridin-4-yl)piperidine-1-carboxylate

[0285] An oven-dried 20 mL vial was charged with tert-butyl 3-hydroxypiperidine-1- carboxylate (502 mg, 2.5 mmol), 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC-1) (901 mg, 2.3 mmol) and a magnetic stir bar. After the vial was vacuumed and refilled with nitrogen gas twice, 2-methoxy-2-methylpropane (12 mL) was added and the reaction stirred at 0°C for 10 min. Then, a pyridine solution (180 mg, 2.3 mmol, in 1.0 mL 2-methoxy-2-methylpropane) was added dropwise at 0°C over the course of 2 min. Theresulting solution stirred at room temperature for 10 min. A white solid precipitated out during this time. Another oven-dried 40 mL vial was charged with [Ir(dtbbpy)(ppy)2]PF6 (20 mg, 21.0 µmol), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (52 mg, 0.1 mmol), 1- azabicyclo[2.2.2]octane (277 mg, 2.5 mmol), 4-bromopyridine (225 mg, 1.4 mmol) and a magnetic stir bar. N,N-dimethylacetamide (13 mL) was added to this vial under an atmosphere of nitrogen. The methyl tert-butyl ether suspension was transferred to a 50 mL syringe under air. Then a syringe filter and new needle were installed on the syringe, before the methyl tert-butyl ether solution was injected through the syringe filter into the dimethylacetamide solution. The reaction mixture was sparged with nitrogen for 15 minutes before sealing with parafilm. The vial was stirred at 1500 rpm stir rate and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 35 mL). The combined organic layers were washed with water (3 x 45 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-(pyridin-4-yl)piperidine-1-carboxylate (410 mg, 90% yield) as a white solid. LCMS (ESI) [M+H]+: 263. Step 2: 4-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyridine 1-oxide

[0286] A solution of tert-butyl 3-(pyridin-4-yl)piperidine-1-carboxylate (350 mg, 1.3 mmol) and 3-chlorobenzene-1-carboperoxoic acid (460 mg, 2.7 mmol, 85% purity) in DCM (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of sat. aq. Na2S2O3 (8 mL) at 0 °C. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 100% gradient in 20 min; detector, UV 220 nm and UV 200 nm) to give 4-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyridine 1-oxide (260 mg, 70% yield) as a white solid. LCMS (ESI) [M+H]+: 279. Step 3: 4-(piperidin-3-yl)pyridine 1-oxide

[0287] A mixture of 4-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyridine 1-oxide (260 mg, 70.0 µmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure to give 4-(piperidin-3-yl)pyridine 1- oxide (60 mg, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 179. Step 4: 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide

[0288] A solution of 4-(piperidin-3-yl)pyridine 1-oxide (60 mg, 0.330 mmol), ((R)-1-((2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (164 mg, 330.0 µmol), Et3N (68 mg, 0.670 mmol) and lithiumtrifluoromethanesulfonate (105 mg, 0.7 mmol) in acetonitrile (3 mL) was stirred at 0°C for 48 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase column chromatography (C18 silica gel eluted with ACN in water (0.1% formic acid), 0% to 100% gradient in 25 min; detector, UV 254 nm and UV 220 nm) to afford 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide (125 mg, 80% yield) as a yellow solid. LCMS (ESI) [M+H]+: 463. Step 5: 4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)- 1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide and 4-((R)-1-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)piperidin-3-

[0289] 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide (120 mg) was separated by prep-HPLC(Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 26% B in 10 min; Wave Length: 254 nm / 220 nm) to afford 4-((S)-1-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide (Compound 49) (RT1: 9.57 min; Method R, Peak 1, 3.65 min; 25.4 mg, 100 % d.e.) as a white solid and second peak 4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide (Compound 50) (RT2: 10.32 min; Method R, Peak 2, 4.46 min; 18.1 mg, 100 % d.e.) as a white solid.

[0290] Example 24: 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1-oxide Step 1: tert-butyl 3-(2-chloropyridin-4-yl)-4-oxopiperidine-1-carboxylate

[0291] To a solution of 2-chloro-4-fluoropyridine (50.00 g, 380.2 mmol) and tert-butyl 4- oxopiperidine-1-carboxylate (90.90 g, 456.2 mmol) in DMF (1000 mL) were added NaH (60% in mineral oil, 22.80 g, 950.3 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 40°C for 2 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with saturated aqueous NH4Cl solution (800 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 (1500 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 70%) to afford tert-butyl 3-(2-chloropyridin-4-yl)-4-oxopiperidine-1-carboxylate (12.50 g, 14% yield) as a yellow solid. LCMS (ESI) [M+H]+: 311. Step 2: tert-butyl 3-(2-chloropyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate

[0292] To a solution of tert-butyl 3-(2-chloropyridin-4-yl)-4-oxopiperidine-1-carboxylate (12.50 g, 40.2 mmol) in DCM (1000 mL) was added DAST (19.40 g, 120.7 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated aqueous NaHCO3 solution (800 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 (3 × 1200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 10% - 65%) to afford tert- butyl 3-(2-chloropyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate (7.50 g, 56% yield) as a colorless oil. LCMS (ESI) [M+H]+: 333. Step 3: tert-butyl 4,4-difluoro-3-(2-vinylpyridin-4-yl)piperidine-1-carboxylate

[0293] A solution of tert-butyl 3-(2-chloropyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate (7.50 g, 22.5 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.10 g, 27.0 mmol), Cs2CO3 (22.00 g, 67.6 mmol) and Pd(dppf)Cl2•CH2Cl2 (1.84 g, 2.3 mmol) in dioxane (500 mL) and H2O (100 mL) was stirred at 80°C for 6 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and was directly purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give tert-butyl 4,4-difluoro-3-(2-vinylpyridin-4-yl)piperidine-1- carboxylate (6.10 g, 83% yield) as a yellow oil. LCMS (ESI) [M+H]+: 325. Step 4: tert-butyl 3-(2-(1,2-dihydroxyethyl)pyridin-4-yl)-4,4-difluoropiperidine-1- carboxylate

[0294] A solution of tert-butyl 4,4-difluoro-3-(2-vinylpyridin-4-yl)piperidine-1-carboxylate (6.00 g, 18.5 mmol), OsO4 (0.40 g, 1.9 mmol) and NMO (6.50 g, 55.5 mmol) in t-BuOH (100mL) and H2O (20 mL) was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous sodium hyposulfite solution (80 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 10% - 70%) to afford tert-butyl 3-(2-(1,2- dihydroxyethyl)pyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate (850 mg, 12% yield) as a yellow oil. LCMS (ESI) [M+H]+: 359. Step 5: 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2-(1,2- dihydroxyethyl)pyridine 1-oxide

[0295] To a solution of tert-butyl 3-(2-(1,2-dihydroxyethyl)pyridin-4-yl)-4,4- difluoropiperidine-1-carboxylate (850 mg, 2.4 mmol) in acetone (5 mL) were added H2O (5 mL), K2CO3 (655 mg, 4.7 mmol) and Oxone (797 mg, 4.7 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 h. The reaction was quenched with saturated aqueous sodium hyposulfite solution (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 10% - 75%) to afford 4-(1-(tert- butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1-oxide (700 mg, 78% yield) as a yellow solid. LCMS (ESI) [M+H]+: 375. Step 6: 4-(4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1-oxide

[0296] A solution of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2-(1,2- dihydroxyethyl)pyridine 1-oxide (700 mg, 1.9 mmol) in 4M HCl in 1,4-dioxane (20 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 4-(4,4-difluoropiperidin-3-yl)-2-(1,2- dihydroxyethyl)pyridine 1-oxide (410 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 275.Step 7: 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1-oxide

[0297] To a solution of 4-(4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1- oxide (400 mg, 1.5 mmol) and (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (355 mg, 0.7 mmol) in CH3CN (10 mL) was added TEA (368 mg, 3.6 mmol) and lithium trifluoromethanesulfonate (568 mg, 3.6 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 days. The resulting mixture was concentrated under reduced pressure and the crude residue was directly purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to afford 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1- oxide (100 mg, 12% yield) as a white solid. LCMS (ESI) [M+H]+: 559. Step 8: 4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((R)-1,2-dihydroxyethyl)pyridine 1-oxide, 4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((R)-1,2-dihydroxyethyl)pyridine 1-oxide, 4- ((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((S)-1,2-dihydroxyethyl)pyridine 1-oxide and 4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((S)-1,2-dihydroxyethyl)pyridine 1-oxide

[0298] 4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(1,2-dihydroxyethyl)pyridine 1-oxide (80 mg)was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 46% B in 9 min; Wave Length: 254 nm / 220 nm) to afford a mixture of Compound 51 and Compound 52 (RT1: 9.87 min; 35 mg) and a mixture of Compound 53 and Compound 54 (RT2: 10.87 min; 35 mg). The mixture of Compound 51 and Compound 52 was separated by Prep-Chiral HPLC (Column: Lux 5µ Cellulose-2, 30*250 mm, 5.0 µm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH: ACN=5: 1; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 220 / 270 nm) to afford first peak 4-((S)-1-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin- 3-yl)-2-((R)-1,2-dihydroxyethyl)pyridine 1-oxide (Compound 51) (RT1: 6.07 min; Method S, Peak 1, 1.23 min; 12.7 mg, 100% d.e.) as a white solid and second peak 4-((R)-1-((S)-1-((2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)-2-((R)-1,2-dihydroxyethyl)pyridine 1-oxide (Compound 52) (RT2: 7.06 min; Method S, Peak 2, 1.51 min; 14.4 mg, 93% d.e.) as a white solid. The mixture of Compound 53 and Compound 54 was separated by Prep-Chiral HPLC (Column: Lux 5µ Cellulose-2, 30*250 mm, 5.0 µm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH: ACN=5: 1; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 254 / 220 nm) to afford first peak 4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((S)-1,2-dihydroxyethyl)pyridine 1-oxide (Compound 53) (RT1: 10.23 min; Method S, Peak 1, 1.95 min; 11.3 mg, 100% d.e.) as a white solid and second peak 4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((S)-1,2- dihydroxyethyl)pyridine 1-oxide (Compound 54) (RT2: 12.93 min; Method S, Peak 2, 2.43 min; 14.1 mg, 97% d.e.) as a white solid.

[0299] Example 25: (S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro- [1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide Step 1: (S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2- d]thiazol-2-yl)propanamide

[0300] A solution of (R)-1-((6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (40 mg, 80.0 µmol), 4,4-difluoropiperidine (21 mg, 0.170 mmol), TEA (17 mg, 0.170 mmol) and lithium trifluoromethanesulfonate (27 mg, 0.170 mmol) in acetonitrile (3 mL) was stirred at 0°C for 12 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give (S)-2-(4,4-difluoropiperidin- 1-yl)-N-(6,7-dihydro-[1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazol-2-yl)propanamide (Compound 58) (15.2 mg, 100% e.e.) as a white solid.

[0301] Example 26: 4-(1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide Step 1: 6,7-dihydro-5H-indeno[5,6-d]thiazol-2-amine

[0302] To a mixture of 2,3-dihydro-1H-inden-5-amine (20.00 g, 150.0 mmol) and potassium thiocyanate (43.80 g, 450.0 mmol) in AcOH (200 mL) was added Br2 (24.00 g, 150.0 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The mixture was neutralized to pH 7 with saturated aqueous sodium bicarbonate solution (220 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 6,7-dihydro-5H-indeno[5,6-d]thiazol-2-amine (11.00 g, 39% yield) as a light grey solid. LCMS [M+H]+: 191.Step 2: (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl acetateand Et3N (4.79 g, 47.0 mmol) in DCM (35 mL) was added (R)-1-chloro-1-oxopropan-2-yl acetate (3.56 g, 24.0 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 24 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl acetate (2.50 g, 52% yield) as a white solid. LCMS [M+H]+: 305. Step 3: (R)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)-2-hydroxypropanamide

[0304] To a mixture of (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl acetate (2.40 g, 8.0 mmol) in THF (30 mL) and H2O (6 mL) was added LiOH•H2O (1.65 g, 39.0 mmol) in portions at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 24 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 3) to afford (R)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)-2-hydroxypropanamide (2.00 g, 97% yield) as a white solid. LCMS (ESI) [M+H]+: 263. Step 4: (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate

[0305] To a mixture of (R)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)-2- hydroxypropanamide (1.00 g, 4.0 mmol) and 2-nitrobenzene-1-sulfonyl chloride (850 mg, 4.0 mmol) in DCM (12 mL) was added Et3N (1.16 g, 11.0 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 24 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl 2-nitrobenzenesulfonate (300 mg, 18% yield) as a white solid. LCMS (ESI) [M+H]+: 448. Step 5: 4-bromo-2-((methoxymethoxy)methyl)pyridine

[0306] A solution of (4-bromopyridin-2-yl)methanol (2.00 g, 11.0 mmol) in DCM (30 mL) were added DIEA (2.75 g, 21.0 mmol) and bromomethyl methyl ether (2.66 g, 21.0 mmol) dropwise at 0°C. The resulting mixture was stirred at 38°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 50%) to afford 4-bromo-2-((methoxymethoxy)methyl)pyridine (1.50 g, 53% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 232. Step 6: tert-butyl 3-(2-((methoxymethoxy)methyl)pyridin-4-yl)-4-oxopiperidine-1- carboxylate

[0307] A solution of 4-bromo-2-((methoxymethoxy)methyl)pyridine (1.00 g, 4.3 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.03 g, 5.2 mmol), t-BuONa (1.24 g, 12.9 mmol), X- Phos (0.41 g, 0.9 mmol) and Pd(OAc)2 (0.10 g, 0.4 mmol) in THF (10 mL) was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with H2O solution (20 mL) at 0°C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 100%) to afford tert-butyl 3-(2- ((methoxymethoxy)methyl)pyridin-4-yl)-4-oxopiperidine-1-carboxylate (500 mg, 33% yield) as a yellow oil. LCMS (ESI) [M+H]+: 351.Step 7: tert-butyl 4,4-difluoro-3-(2-((methoxymethoxy)methyl)pyridin-4-yl)piperidine-1- carboxylate

[0308] To a mixture of tert-butyl 3-(2-((methoxymethoxy)methyl)pyridin-4-yl)-4- oxopiperidine-1-carboxylate (500 mg, 1.4 mmol) in DCM (8 mL) was added DAST (690 mg, 4.3 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 100%) to afford tert-butyl 4,4-difluoro-3-(2- ((methoxymethoxy)methyl)pyridin-4-yl)piperidine-1-carboxylate (280 mg, 53% yield) as a yellow oil. LCMS (ESI) [M+H]+: 373 Step 8: 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2- ((methoxymethoxy)methyl)pyridine 1-oxide

[0309] To a mixture of tert-butyl 4,4-difluoro-3-(2-((methoxymethoxy)methyl)pyridin-4- yl)piperidine-1-carboxylate (280 mg, 0.9 mmol) in DCM (5 mL) was added 3- chloroperoxybenzoic acid (441 mg, 2.6 mmol, 85% purity) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous sodium thiosulfate solution (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 12 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 100%) to afford 4-(1-(tert- butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2-((methoxymethoxy)methyl)pyridine 1-oxide (240 mg, 82% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 389. Step 9: 4-(4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide

[0310] To a mixture of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2- ((methoxymethoxy)methyl)pyridine 1-oxide (240 mg, 0.7 mmol) in DCM (4 mL) was added trifluoroacetic acid (2 mL) dropwise at 0°C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford 4-(4,4- difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide (300 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 245. Step 10: 4-(1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide

[0311] To a mixture of (R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl 2-nitrobenzenesulfonate (257 mg, 0.6 mmol) and 4-(4,4-difluoropiperidin-3-yl)- 2-(hydroxymethyl)pyridine 1-oxide (280 mg, 1.1 mmol) in acetonitrile (8 mL) was added lithium trifluoromethanesulfonate (894 mg, 5.7 mmol) and Et3N (580 mg, 5.7 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 20 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase flash chromatography (C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate:40 ml / min; gradient: 45%B to 55%B in 15 min; Wave Length: 254 nm / 220 nm) to afford 4-(1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide (80 mg, 14% yield) as a white solid. LCMS (ESI) [M+H]+: 489. Step 11: 4-((S)-1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2- yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide and 4-((R)-1-((S)-1-((6,7- dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3- yl)-2-(hydroxymethyl)pyridine 1-oxide

[0312] 4-(1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide (80 mg) was purified by Prep- HPLC (Column: XBridge Shield RP18 OBD Column 19*250 mm, 10 μm; 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 28% B in 2 min, 28% to 45% B in 11 min; Wave Length: 254 nm / 220 nm) to afford first peak 4-((S)-1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide (Compound 60) (RT1: 10.47 min; Method U, Peak 1, 4.70 min; 28.2 mg, 89% d.e.) as a white solid and second peak 4-((R)-1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide (Compound 61) (RT2: 11.17 min; Method U, Peak 2, 4.97 min; 21.8 mg, 94% d.e.) as a white solid.

[0313] Example 27: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)- 2-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide Step 1: tert-butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-oxopiperidine-1- carboxylate

[0314] To a mixture of pyrimidine-2,4(1H,3H)-dione (6.50 g, 57.9 mmol) in DMF (20 mL) were added K2CO3 (24.00 g, 173.9 mmol) and tert-butyl 3-bromo-4-oxopiperidine-1- carboxylate (16.10 g, 57.9 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 6 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filter cake was washed with CH2Cl2 (3 x 25 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by reverse- phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give tert- butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-oxopiperidine-1-carboxylate (1.30 g, 6% yield) as a yellow solid. LCMS (ESI) [M+H]+: 310.Step 2: tert-butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidine-1- carboxylate

[0315] To a mixture of tert-butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4- oxopiperidine-1-carboxylate (1.30 g, 4.2 mmol) in DCM (15 mL) was added DAST (3.40 g, 21.0 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated aqueous NaHCO3 solution (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidine-1-carboxylate (370 mg, 27% yield) as a white solid. LCMS (ESI) [M+H]+: 332. Step 3: 1-(4,4-difluoropiperidin-3-yl)pyrimidine-2,4(1H,3H)-dione

[0316] A solution of tert-butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4- difluoropiperidine-1-carboxylate (370 mg, 1.1 mmol) in 4 M HCl in 1,4-dioxane (6 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum to give 1-(4,4-difluoropiperidin-3-yl)pyrimidine-2,4(1H,3H)-dione (250 mg, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 232. Step 4: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide

[0317] To a mixture of 1-(4,4-difluoropiperidin-3-yl)pyrimidine-2,4(1H,3H)-dione (240 mg, 1.0 mmol) in ACN (6 mL) were added (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (202 mg, 0.4 mmol), lithium trifluoromethanesulfonate (939 mg, 6.0 mmol) and Et3N (588 mg, 5.8 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 24 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3- (2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide (70 mg, 13% yield) as a white solid. LCMS (ESI) [M+H]+: 516. Step 5: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide and (S)-N- (2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide

[0318] (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide (68 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 39% B to 55% B in 10 min; Wave Length: 254 nm / 220 nm) to afford first peak (S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 62) (RT1: 7.6 min; Method A, Peak 1, 0.84 min; 16.8 mg, 92% d.e.) as a white solid and second peak (S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 63) (RT2: 8.08 min; Method A, Peak 2, 1.35 min; 15 mg, 93% d.e.) as a white solid.

[0319] Example 28: 2-(aminomethyl)-4-(1-((S)-1-((2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 4-bromo-2-(1,3-dioxolan-2-yl)pyridine

[0320] To a mixture of 4-bromopicolinaldehyde (10.00 g, 53.8 mmol), ethylene glycol (5.01 g, 80.6 mmol) and TsOH (0.93 g, 5.4 mmol) in toluene (110 mL) was stirred at 130°C for 12 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (EA / PE 0% - 100%) to afford 4-bromo-2-(1,3-dioxolan-2-yl)pyridine (8.00 g, 65% yield) as a white solid. LCMS (ESI) [M+H]+: 230. Step 2: tert-butyl 3-(2-(1,3-dioxolan-2-yl)pyridin-4-yl)-4-oxopiperidine-1-carboxylate

[0321] To a mixture of 4-bromo-2-(1,3-dioxolan-2-yl)pyridine (8.00 g, 34.8 mmol) in dioxane (100 mL) were added tert-butyl 4-oxopiperidine-1-carboxylate (8.31 g, 41.7 mmol), t- BuONa (10.03 g, 104.3 mmol), XPhos (3.32 g, 7.0 mmol) and Pd(OAc)2 (0.78 g, 3.5 mmol). The resulting mixture was stirred overnight at 40°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and was then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 100%) to afford tert-butyl 3-(2-(1,3-dioxolan-2-yl)pyridin-4-yl)-4-oxopiperidine-1-carboxylate (5.00 g, 41% yield) as a yellow solid. LCMS (ESI) [M+H]+: 349. Step 3: tert-butyl 3-(2-(1,3-dioxolan-2-yl)pyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate

[0322] To a mixture of tert-butyl 3-(2-(1,3-dioxolan-2-yl)pyridin-4-yl)-4-oxopiperidine-1- carboxylate (5.00 g, 14.5 mmol) in DCM (60 mL) was added DAST (6.95 g, 43.0 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution (65 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE 0% - 70%) to afford tert-butyl 3-(2-(1,3-dioxolan-2-yl)pyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate (2.00 g, 38% yield) as a yellow solid. LCMS (ESI) [M+H]+: 371. Step 4: tert-butyl 4,4-difluoro-3-(2-formylpyridin-4-yl)piperidine-1-carboxylate

[0323] To a mixture tert-butyl 3-(2-(1,3-dioxolan-2-yl)pyridin-4-yl)-4,4-difluoropiperidine- 1-carboxylate (2.00 g, 5.4 mmol) in 1M HCl in H2O (20 mL) was stirred at 80°C for 3 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was dissolved in DCM (25 mL). Then, Boc2O (1.77 g, 8.1 mmol) and TEA (1.64 g, 16.2 mmol) were added at 25 °C under nitrogen atmosphere. After 2 h, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (EA / PE 5% - 75%) to afford tert-butyl 4,4- difluoro-3-(2-formylpyridin-4-yl)piperidine-1-carboxylate (1.50 g, 85% yield) as a yellow oil. LCMS (ESI) [M+H]+: 327. Step 5: tert-butyl 3-(2-(aminomethyl)pyridin-4-yl)-4,4-difluoropiperidine-1-carboxylate

[0324] To a mixture of tert-butyl 4,4-difluoro-3-(2-formylpyridin-4-yl)piperidine-1- carboxylate (1.50 g, 4.6 mmol) in MeOH (20 mL) were added NH4OAc (3.54 g, 46.0 mmol) and NaBH3CN (0.87 g, 13.8 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give tert-butyl 3-(2-(aminomethyl)pyridin-4-yl)-4,4- difluoropiperidine-1-carboxylate (300 mg, 20% yield) as a white solid. LCMS (ESI) [M+H]+: 328. Step 6: tert-butyl 4,4-difluoro-3-(2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridin-4-yl)piperidine-1-carboxylate

[0325] A mixture of tert-butyl 3-(2-(aminomethyl)pyridin-4-yl)-4,4-difluoropiperidine-1- carboxylate (150 mg, 0.5 mmol), 2,5-dioxopyrrolidin-1-yl (2-(trimethylsilyl)ethyl) carbonate (178 mg, 0.7 mmol) and TEA (139 mg, 1.4 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give tert-butyl 4,4-difluoro-3-(2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridin-4-yl)piperidine-1-carboxylate (100 mg, 46% yield) as a yellow solid. LCMS (ESI) [M+H]+: 472. Step 7: 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridine 1-oxide

[0326] To a mixture of tert-butyl 4,4-difluoro-3-(2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridin-4-yl)piperidine-1-carboxylate (90 mg, 0.2 mmol) and m-CPBA (99 mg, 0.6 mmol, 85% purity) in DCM (5 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous sodium thiosulfate solution (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 12 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to give 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin- 3-yl)-2-((((2-(trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridine 1-oxide (60 mg, 65% yield) as a white solid. LCMS (ESI) [M+H]+: 488. Step 8: 4-(4,4-difluoropiperidin-3-yl)-2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridine 1-oxide

[0327] A mixture of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridine 1-oxide (60 mg, 0.2 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure to give 4-(4,4-difluoropiperidin-3-yl)-2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridine 1-oxide (80 mg, crude) as a white solid, which was used in the next reaction without further purification. LCMS (ESI) [M+H]+: 388. Step 9: 2-(aminomethyl)-4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0328] A mixture of 4-(4,4-difluoropiperidin-3-yl)-2-((((2- (trimethylsilyl)ethoxy)carbonyl)amino)methyl)pyridine 1-oxide (80 mg, 0.2 mmol), (R)-1-((2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl 2- nitrobenzenesulfonate (101 mg, 0.2 mmol), TEA (42 mg, 0.4 mmol) and lithium trifluoromethanesulfonate (64 mg, 0.4 mmol) in ACN (3 mL) was stirred at 0°C for 48 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reverse- phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm and UV 220 nm) to afford 2- (aminomethyl)-4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (40 mg, 37% yield) as a white solid. LCMS (ESI) [M+H]+: 528. Step 10: 2-(aminomethyl)-4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 2- (aminomethyl)-4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0329] 2-(aminomethyl)-4-(1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (40 mg) was separated by Prep-HPLC (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 26% B in 10 min; Wave Length: 254 nm / 220 nm) to afford first peak 2-(aminomethyl)-4-((S)-1- ((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 64) (RT1: 9.57 min; Method V, Peak 1, 1.96 min; 8.1 mg, 100% d.e.) as a white solid and second peak 2-(aminomethyl)-4-((R)-1-((S)-1- ((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide (Compound 65) (RT2: 10.32 min; Method V, Peak 2, 2.73 min; 8.3 mg, 100% d.e.) as a white solid

[0330] Example 29: (2S)-2-(4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide Step 1: 5-bromo-3-(1,3-dioxolan-2-yl)-2-methoxypyridine

[0331] A solution of 5-bromo-2-methoxynicotinaldehyde (20.00 g, 92.6 mmol), ethane-1,2- diol (28.73 g, 462.9 mmol) and TsOH (797 mg, 4.6 mmol) in toluene (200 mL) was stirred overnight at 130°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 5-bromo-3-(1,3-dioxolan- 2-yl)-2-methoxypyridine (20.00 g, 83% yield) as a yellow oil. LCMS (ESI) [M+H]+: 260. Step 2: benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4-oxopiperidine-1- carboxylate

[0332] A solution of 5-bromo-3-(1,3-dioxolan-2-yl)-2-methoxypyridine (18.00 g, 69.2 mmol), benzyl 4-oxopiperidine-1-carboxylate (24.22 g, 103.8 mmol), t-BuONa (19.95 g, 207.6 mmol), Pd(OAc)2 (1.55 g, 6.9 mmol) and XPhos (6.60 g, 13.8 mmol) in dioxane (200 mL) was stirred at 40°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford benzyl 3-(5-(1,3-dioxolan- 2-yl)-6-methoxypyridin-3-yl)-4-oxopiperidine-1-carboxylate (20.00 g, 70% yield) as a yellow solid. LCMS (ESI) [M+H]+: 413. Step 3: benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1- carboxylate

[0333] To a mixture of benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4- oxopiperidine-1-carboxylate (5.00 g, 12.1 mmol) in DCM (50 mL) was added DAST (5.86 g, 36.4 mmol) dropwise over 10 min at 0°C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by the addition of sat. sodium bicarbonate (aq.) at 0°C. The aqueous layer was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate (3.50 g, 66% yield) as a brown oil. LCMS (ESI) [M+H]+: 435. Step 4: 5-(4,4-difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2-methoxypyridine

[0334] To a mixture of benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate (3.50 g, 8.1 mmol) in MeOH (45 mL) was added Pd / C (2.20 g,20.7 mmol, 10% Pd). The resulting mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (8:1) to afford 5-(4,4- difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.80 g, 74% yield) as a yellow oil. LCMS (ESI) [M+H]+: 301. Step 5: 5-(4,4-difluoropiperidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde

[0335] A solution of 5-(4,4-difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.20 g, 4.0 mmol) in 4 M HCl in 1,4-dioxane (12 mL) was stirred for 2 h at 80°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum to afford 5-(4,4-difluoropiperidin-3-yl)-2-oxo-1,2- dihydropyridine-3-carbaldehyde (1.20 g, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 243. Step 6: tert-butyl 4,4-difluoro-3-(5-formyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-1- carboxylate

[0336] A solution of 5-(4,4-difluoropiperidin-3-yl)-2-oxo-1,2-dihydropyridine-3- carbaldehyde (1.20 g, 4.9 mmol), Boc2O (11.8 g, 5.4 mmol) and TEA (1.50 g, 14.9 mmol) in DCM (12 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4,4-difluoro-3-(5- formyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate (600 mg, 35% yield) as a yellow solid. LCMS (ESI) [M+H]+: 343. Step 7: tert-butyl 4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidine-1-carboxylate

[0337] A solution of tert-butyl 4,4-difluoro-3-(5-formyl-6-oxo-1,6-dihydropyridin-3- yl)piperidine-1-carboxylate (100 mg, 0.3 mmol), AcOH (1.8 mg, 30.0 µmol) and morpholine (31 mg, 0.4 mmol) in DCM (5 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. Then, sodium bis(acetyloxy)boranuidyl acetate (62 mg, 0.3 mmol) was added over 1 min at 0°C. The mixture was stirred at room temperature for an additional 1 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse- phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give tert-butyl 4,4-difluoro-3-(5- (morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate (80 mg, 66% yield) as a yellow solid. LCMS (ESI) [M+H]+: 414. Step 8: 5-(4,4-difluoropiperidin-3-yl)-3-(morpholinomethyl)pyridin-2(1H)-one

[0338] A solution of tert-butyl 4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.2 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred for 1 h at room temperature. The mixture was allowed to cool down to room temperature. The reaction mixture was concentrated under reduced pressure to afford 5-(4,4- difluoropiperidin-3-yl)-3-(morpholinomethyl)pyridin-2(1H)-one (60 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 314. Step 9: (2S)-2-(4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-

[0339] A solution of 5-(4,4-difluoropiperidin-3-yl)-3-(morpholinomethyl)pyridin-2(1H)-one (50 mg, 0.2 mmol), (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)- 1-oxopropan-2-yl 2-nitrobenzenesulfonate (93 mg, 0.2 mmol), Et3N (40 mg, 0.4 mmol) and lithium trifluoromethanesulfonate (62 mg, 0.4 mmol) in acetonitrile (3 mL) was stirred overnight at 0°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give (2S)-2-(4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (50 mg, 52% yield) as a yellow solid. LCMS (ESI) [M+H]+: 598. Step 10: (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide and (S)-2-((R)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0340] (2S)-2-(4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (50 mg) was separated by Prep-HPLC (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 52% B in 10 min; Wave Length: 254 nm / 220 nm) to afford first peak (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 66) (RT1: 8.9 min; Method W, Peak 1, 1.51 min; 14.3 mg, 100% d.e.) as a white solid and second peak (S)-2-((R)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Compound 67) (RT2: 9.5 min; Method W, Peak 2, 2.66 min; 19.2 mg, 99% d.e.) as a white solid.

[0341] Example 30: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)- 2-(3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)propanamide Step 1: tert-butyl 3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)- 4,4-difluoropiperidine-1-carboxylate

[0342] A solution of tert-butyl 4,4-difluoro-3-(5-formyl-6-oxo-1,6-dihydropyridin-3- yl)piperidine-1-carboxylate (160 mg, 0.5 mmol), 4,4-difluoropiperidine (57 mg, 0.5 mmol) and acetic acid (0.5 mL) in DCM (5 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. To the above mixture was added sodium bis(acetyloxy)boranuidyl acetate (99 mg, 0.5 mmol) in portions over 5 mins at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give tert- butyl 3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate (120 mg, 57% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 448. Step 2: 3-((4,4-difluoropiperidin-1-yl)methyl)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)- one

[0343] A solution of tert-butyl 3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6- dihydropyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (110 mg, 0.3 mmol) in 4M HCl in 1,4-dioxane (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to give 3-((4,4-difluoropiperidin-1-yl)methyl)-5-(4,4- difluoropiperidin-3-yl)pyridin-2(1H)-one (90 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 348.Step 3: (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-((4,4- difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide

[0344] A solution of 3-((4,4-difluoropiperidin-1-yl)methyl)-5-(4,4-difluoropiperidin-3- yl)pyridin-2(1H)-one (80 mg, 0.2 mmol), (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo [1,2- d] thiazol-6-yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (135 mg, 0.3 mmol), TEA (58 mg, 0.6 mmol) and lithium trifluoromethanesulfonate (86 mg, 0.6 mmol) in acetonitrile (5 mL) was stirred at 0°C for 20 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford (2S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6- oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (60 mg, 41% yield) as a yellow solid. LCMS (ESI) [M+H]+: 632. Step 4: (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-3-(5-((4,4- difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide and (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((R)-3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)propanamide

[0345] (2S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-(3-(5-((4,4- difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1- yl)propanamide (60 mg) was separated by Prep-HPLC (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 52% B in 10 min; Wave Length: 254 nm / 220 nm) to afford first peak (S)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- ((S)-3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)propanamide (Compound 68) (RT1: 8.8 min; Method X, Peak 1, 4.40min; 20.5 mg, 100% d.e.) as a white solid and second peak (S)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((4,4-difluoropiperidin-1- yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide (Compound 69) (RT2: 9.3 min; Method X, Peak 2, 5.48 min; 25.8 mg, 99% d.e.) as a white solid.

[0346] Example 31: 4-((3S)-1-(1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide Step 1: 2-bromo-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0347] A mixture of 2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine (150 mg, 0.65 mmol), 2-bromopropanoic acid (99.7 mg, 0.65 µmol), 1-methylimidazole (90 mg, 1.08 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (454 mg, 1.08 mmol) in ACN (3 mL) was stirred overnight at room temperature. The resulting mixture was directly purified by reverse phase column chromatography (C18 silica gel eluted with formic acid (0.1 M in H2O)) to afford 2-bromo-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide (157 mg, 65% yield) as a white solid. LCMS (ESI) [M+H]+: 365.15 / 367.15. Step 2: 4-((3S)-1-(1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0348] A mixture of 2-bromo-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (80 mg, 0.227 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide(Intermediate B, 49 mg, 0.227 mmol) and TEA (70 mg, 0.684 mmol) 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). The organic layers were separated, combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford 4-((3S)-1-(1- ((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-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]+: 499.10. Step 3: 4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)- 1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide and 4-((S)-1-((R)-1-((2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4- difluoropiperidin-3-yl)pyridine 1-oxide

[0349] 4-((3S)-1-(1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)amino)-1- oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (46 mg) was separated by Prep- HPLC (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 34% B in 2 min, 34% to 50% B in 10 min; Wave Length: 254 nm / 220 nm) to afford first peak 4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 77) (RT1: 9.3 min; Method R, Peak 1, 3.64 min; 12.4 mg, 96.9% e.e.) as a white solid and second peak 4-((S)-1-((R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (Compound 78) (RT2: 10.4 min; Method R, Peak 2, 4.05 min; 11.2 mg, 100% e.e.) as a white solid.

[0350] Example 32: 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

[0351] A mixture of [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-amine (70 mg, 0.360 mmol), 2-bromopropanoic acid (55.14 mg, 0.360 mmol), 1-methylimidazole (45 mg, 0.540 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (227 mg, 0.540 mmol) in ACN (2 mL) was stirred overnight at room temperature. The resulting mixture was directly purified by reverse phase column chromatography (C18 silica gel 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

[0352] A mixture of N-([1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)-2- bromopropanamide (75 mg, 0.227 mmol), (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (49 mg, 0.227 mmol) and TEA (70 mg, 0.684 mmol) in DMA (1 mL) was stirred for 2 days at room temperature. The resulting mixture was poured into water (20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford 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-((R)-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

[0353] 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 mg) was separated by Prep-HPLC (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: 19% B to 35% B in 9 min; Wave Length: 254 nm / 220 nm) 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 80) (RT1: 12.15 min; Method Y, Peak 1, 4.08 min; 15.0 mg, 96.64% e.e.) as a white solid and second peak 4-((S)-1-((R)-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 81) (RT2: 12.77 min; Method Y, Peak 2, 4.52 min; 9.0 mg, 100% e.e.) as a white solid.

[0354] Example 33: 2-(3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0355] Step 1: 5-bromo-3-(1,3-dioxolan-2-yl)-2-methoxypyridine

[0356] A mixture of 5-bromo-2-methoxynicotinaldehyde (5.0 g, 23.14 mmol), ethylene glycol (4.2 g, 69.72 mmol), and TsOH (400 mg, 2.314 mmol) in toluene (20 mL) was stirred at 110 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and then poured into water (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with CH2Cl2 / EA (1:1) to afford 5-bromo-3-(1,3-dioxolan-2-yl)-2-methoxypyridine (3.9 g, 64% yield) as an off-white solid. LCMS (ESI) [M+H]+: 261.

[0357] Step 2: benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4-oxopiperidine- 1-carboxylate

[0358] A mixture of t-BuONa (1.98 g, 20.5 mmol), XPhos (490 mg, 1.0 mmol), Pd(OAc)2 (120 mg, 0.514 mmol), 5-bromo-3-(1,3-dioxolan-2-yl)-2-methoxypyridine (3.9 g, 14.99 mmol) and benzyl 4-oxopiperidine-1-carboxylate (3.5 g, 14.99 mmol) in THF (30 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 50 mL). The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with CH2Cl2 / EA (1:1), to afford benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4-oxopiperidine-1- carboxylate (2.8 g, 45% yield) as an off-white solid. LCMS (ESI) [M+H]+: 413.

[0359] Step 3: benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate

[0360] To a solution of benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4- oxopiperidine-1-carboxylate (2.8 g, 6.79 mmol) in DCM (10 mL) was added DAST (3.3 g, 20.4 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C overnight. The reaction was quenched with sat. aq. NaHCO3 at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1), to afford benzyl 3-(5-(1,3- dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (872 mg, 29% yield) as a white solid. LCMS (ESI) [M+H]+: 435.

[0361] Step 4: 5-(4,4-difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2-methoxypyridine

[0362] To a solution of benzyl 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidine-1-carboxylate (872 mg, 2.0 mmol) in methanol (10 mL) was added palladium (500 mg, 10% on charcoal). The resulting mixture was stirred overnight under a hydrogenatmosphere. Upon completion, the mixture was filtered over celite. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1), to afford 5-(4,4-difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2- methoxypyridine (512 mg, 85% yield) as a light-yellow oil. LCMS (ESI) [M+H]+: 301.

[0363] Step 5: 2-(3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0364] A mixture of 2-bromo-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (305 mg, 832.4 µmol), 5-(4,4-difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2- methoxypyridine (250 mg, 832.4 µmol) and K2CO3 (70 mg, 684.2 µmol) in acetonitrile (5 mL) was stirred for 6 hours at 80°C. The resulting mixture was poured into water (20 mL). The aqueous layer was The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford 2-(3-(5-(1,3-dioxolan-2-yl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (266.0 mg, 54% yield) as a white solid. LCMS (ESI) [M+H]+: 585.4.

[0365] Step 6: 2-(4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidin-1-yl)-N- (2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0366] To a 10 mL round bottom flask containing 2-(3-(5-(1,3-dioxolan-2-yl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (266 mg, 455.0 µmol) was added HCl (5 mL, 30% aq). The resulting mixture was stirred for one hour at room temperature. Upon completion, the mixture was concentrated under reduced pressure to afford 2-(4,4-difluoro-3-(5- formyl-6-methoxypyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide (226 mg, 92% yield) as a light yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 541.

[0367] Step 7: 2-(3-(5-(aminomethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0368] To a 10 mL round bottom flask containing 2-(4,4-difluoro-3-(5-formyl-6- methoxypyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide (176 mg, 325.6 µmol) was added NH3 (1 mL, 2 mmol, 2 M in CH3OH). The resulting mixture was stirred for 20 minutes at room temperature. Then, STAB (103 mg, 488.4 mmol) was added and the resulting mixture was allowed to stir for an additional 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford 2-(3-(5-(aminomethyl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (131 mg, 74% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 542.

[0369] Step 8: 2-(3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-

[0370] To a 10 mL round bottom flask containing 2-(3-(5-(aminomethyl)-6-methoxypyridin- 3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (130 mg, 240.0 µmol) and sodium iodide (36 mg, 240.0 µmol) in THF (6 mL) was added TMSCl (0.1 mL, 791 µmol). The resulting mixture was stirred for 2 hours at room temperature. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford 2-(3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (94 mg, 74% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 528.

[0371] Step 9: (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide, (R)-2-((R)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide, (R)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide and (S)-2-((R)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0372] 2-(3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)- N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (94 mg) was separated by Prep-HPLC (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 29% B in 9 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.42 / 12.42). The first peak was further separated by Chiral-HPLC (Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 50% B; Wave Length: 228 / 304 nm; RT1(min): 13.7; RT2(min): 27.5; Sample Solvent: ETOH: DCM=3: 4; Number Of Runs: 5) to afford first peak Compound 84 (R)- 2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method AA, Peak 1, 1.26 min; 10.3 mg, 100% e.e.) as a white solid and Compound 85 (S)-2-((R)-3-(5-(aminomethyl)-6- oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method AA, Peak 2, 2.99 min; 10.1 mg, 100% e.e.) as a white solid.

[0373] The second peak was further separated by Chiral-HPLC (Column: CHIRALPAK IG, 3*25 cm, 10 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: IPA; Flow rate: 38 mL / min; Gradient: % B; Wave Length: 220 / 254 nm; RT1(min): 11.87; RT2(min): 28; Sample Solvent: MEOH: DCM=3: 1; Injection Volume: 1.2 mL; Number Of Runs: 3) to afford first peak Compound 82 (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method Z, Peak 1, 1.60 min; 10.5 mg, 100% e.e.) as a white solid and Compound 83 (R)-2-((R)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (Method Z, Peak 2, 3.01 min; 12.5 mg, 100% e.e.) as a white solid.

[0374] Example 34: (2S)-2-(4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0375] Step 1: (2S)-2-(3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4- difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-

[0376] A mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (649 mg, 1.33 mmol), 5-(4,4- difluoropiperidin-3-yl)-3-(1,3-dioxolan-2-yl)-2-methoxypyridine (400 mg, 1.33 mmol), triethylamine (244 mg, 1.9 mmol) and lithium trifluoromethanesulfonate (312 mg, 1.9 mmol) in acetonitrile (5 mL) was stirred for 6 hours at 0 °C. 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 under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (2S)-2-(3-(5- (1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (547.0 mg, 70% yield) as a white solid. LCMS (ESI) [M+H]+: 585.4.

[0377] Step 2: (2S)-2-(4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidin-1-yl)- N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide

[0378] To a 10 mL round bottom flask containing (2S)-2-(3-(5-(1,3-dioxolan-2-yl)-6- methoxypyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (547 mg, 935.7 µmol) was added HCl (5 mL, 30% aq). The resulting mixture was stirred for 1 hour at room temperature. Upon completion, the mixture was concentrated under reduced pressure to afford (2S)-2-(4,4-difluoro- 3-(5-formyl-6-methoxypyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (428 mg, 85% yield) as a light yellow oil, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 541.

[0379] Step 3: (2S)-2-(4,4-difluoro-3-(6-methoxy-5-((methylamino)methyl)pyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0380] To a 10 mL round bottom flask containing (2S)-2-(4,4-difluoro-3-(5-formyl-6- methoxypyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide (180 mg, 333 µmol) was added methylamine (1 mL, 1 mmol, 1 M in THF). The resulting mixture was stirred for 20 minutes at room temperature, then STAB (103 mg, 488.4 mmol) was added. The resulting mixture was stirred for an additional 2 hours. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (2S)-2-(4,4-difluoro-3-(6-methoxy-5-((methylamino)methyl)pyridin-3-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (92 mg, 49.7% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 556.

[0381] Step 4: (2S)-2-(4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0382] To a 10 mL round bottom flask containing (2S)-2-(4,4-difluoro-3-(6-methoxy-5- ((methylamino)methyl)pyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (92 mg, 166 µmol) and sodium iodide (36 mg, 240.0 µmol) in THF (6 mL) was added TMSCl (0.1 mL, 791 µmol). The resulting mixture was stirred for 2 hours at room temperature. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (2S)-2-(4,4-difluoro-3-(5- ((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (41 mg, 46% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 542.5.

[0383] Step 5: (S)-2-((S)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide and (S)-2-((R)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo- 1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0384] (2S)-2-(4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (41 mg) was separated by Prep-HPLC (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 29% B in 9 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.85 / 13.12) to afford first peak Compound 86 (S)-2-((S)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide (Method V, Peak 1, 0.91 min; 15.1 mg, 100% e.e.) as a white solid and second peak Compound 87 (S)-2-((R)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol- 6-yl)propanamide (Method V, Peak 2, 0.96 min; 16.5 mg, 100% e.e.) as a white solid.

[0385] Example 35: (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0386] Step 1: (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-methoxypyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0387] To a solution of (2S)-2-(4,4-difluoro-3-(5-formyl-6-methoxypyridin-3-yl)piperidin-1- yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (220 mg, 407 µmol) in THF (5 mL) was added sodium borohydride (49 mg, 1 mmol). The resulting mixture was stirred for 2 hours at 50°C. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-methoxypyridin- 3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide (147 mg, 66% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 543.5.

[0388] Step 2: (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-

[0389] To a 10 mL round bottom flask containing (2S)-2-(4,4-difluoro-3-(5- (hydroxymethyl)-6-methoxypyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (147 mg, 271 µmol) and sodium iodide (45 mg, 271.0 µmol) in THF (6 mL) was added TMSCl (0.1 mL, 791 µmol). The resulting mixture was stirred for 2 hours at room temperature. Upon completion, the mixturewas concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (2S)-2-(4,4-difluoro-3-(5- (hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (73 mg, 51% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 529.1.

[0390] Step 3: (S)-2-((S)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin- 3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide and (S)-2-((R)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6- dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0391] (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (73 mg) was separated by Prep-HPLC with the following conditions Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 51% B in 9 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.13 / 9.65 to afford first peak Compound 88 (S)-2-((S)-4,4-difluoro-3-(5- (hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method AB, Peak 1, 1.97 min; 15.4 mg, 100% e.e.) as a white solid and second peak Compound 89 (S)-2-((R)-4,4-difluoro-3- (5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method AB, Peak 2, 2.12 min; 19.5 mg, 100% e.e.) as a white solid.

[0392] Example 36: (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5- dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6-yl)propanamide

[0393] Step 1: methyl 6-bromo-3-methoxypyrazine-2-carboxylate

[0394] To a mixture of methyl 3-amino-6-bromopyrazine-2-carboxylate (20 g, 86.193 mmol) in sulfuric acid (200 mL) was added sodium nitrite (17.8 g, 258.6 mmol) at 0°C. The mixture was stirred at 25 °C for 30 min. The reaction was then quenched with methanol (500 mL) at 0°C. The reaction was concentrated under reduced pressure to remove methanol. The crude residue was diluted with water and EA. The aqueous layer was extracted with EA (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:2), to afford methyl 6-bromo-3-methoxypyrazine-2-carboxylate (7 g, 33% yield) as a colorless oil. LCMS (ESI) [M+H]+: 248.05

[0395] Step 2: (6-bromo-3-methoxypyrazin-2-yl)methanol

[0396] To a mixture of methyl 6-bromo-3-methoxypyrazine-2-carboxylate (7 g, 28.34 mmol) in THF (50 mL) was added DIBAL-H (20 mL, 80 mmol, 2M in THF) at 0°C under nitrogen atmosphere. The mixture was stirred at 25°C for 2 h. Upon completion, the reaction was quenched with water (60 mL). The aqueous layer was extracted with EA (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 2), to afford (6-bromo-3-methoxypyrazin-2-yl)methanol (6.1 g, 98% yield) as a colorless oil. LCMS (ESI) [M+H]+: 220.04

[0397] Step 3: 5-bromo-2-methoxy-3-((methoxymethoxy)methyl)pyrazine

[0398] To a mixture of (6-bromo-3-methoxypyrazin-2-yl)methanol (6.1 g, 29.5 mmol) and N,N-diisopropylethylamine (11.4 g, 90 mmol) in DCM (20 mL) was added chloromethyl methylether (7.35 g, 59 mmol) at 0°C. The mixture was stirred at 40°C for 2 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column, eluted with PE / EA (7:3), to afford 5-bromo-2-methoxy-3- ((methoxymethoxy)methyl)pyrazine (2 g, 77.4% yield) as a white solid. LCMS (ESI) [M+H]+: 263.04

[0399] Step 4: benzyl 3-(5-methoxy-6-((methoxymethoxy)methyl)pyrazin-2-yl)-4- oxopiperidine-1-carboxylate

[0400] To a mixture of 5-bromo-2-methoxy-3-((methoxymethoxy)methyl)pyrazine (2 g, 7.6 mmol), XPhos (362 mg, 0.760 mmol) and palladium acetate (170 mg, 0.760 mmol) in THF (30 mL) was added t-BuONa (2.02 g, 23 mmol) at 0°C. The mixture was stirred at 50°C under nitrogen atmosphere for 2 h. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column, eluted with PE / EA (1:1), to afford benzyl 3-(5-methoxy-6-((methoxymethoxy)methyl)pyrazin-2-yl)-4-oxopiperidine-1- carboxylate (714 mg, 45.22% yield) as a yellow oil. LCMS (ESI) [M+H]+: 416.17

[0401] Step 5: benzyl 4,4-difluoro-3-(5-methoxy-6-((methoxymethoxy)methyl)pyrazin- 2-yl)piperidine-1-carboxylate

[0402] To a mixture of benzyl 3-(5-methoxy-6-((methoxymethoxy)methyl)pyrazin-2-yl)-4- oxopiperidine-1-carboxylate (600 mg, 1.44 mmol) in DCM (10 mL) was added DAST (0.47 g, 2.88 mmol) at 0°C. The mixture was stirred at 25°C for 5 h. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column, eluted with PE / EA (1:1), to afford benzyl 4,4-difluoro-3-(5-methoxy-6- ((methoxymethoxy)methyl)pyrazin-2-yl)piperidine-1-carboxylate (170 mg, 26.91% yield) as a yellow oil. LCMS (ESI) [M+H]+: 438.17

[0403] Step 6: (6-(4,4-difluoropiperidin-3-yl)-3-methoxypyrazin-2-yl)methanol

[0404] A mixture of benzyl 4,4-difluoro-3-(5-methoxy-6- ((methoxymethoxy)methyl)pyrazin-2-yl)piperidine-1-carboxylate (170 mg, 388.6 µmol) in TFA (5 mL) was stirred at 70°C for 5 h. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase column chromatography, eluted with NH4HCO3 (1% in H2O) and acetonitrile, to afford (6-(4,4-difluoropiperidin-3-yl)-3- methoxypyrazin-2-yl)methanol (80 mg, 79.4% yield) as a yellow oil. LCMS (ESI) [M+H]+: 260.3

[0405] Step 7: (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-methoxypyrazin-2- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0406] A mixture of (R)-1-((2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)amino)-1-oxopropan-2-yl 2-nitrobenzenesulfonate (150 mg, 308.6 µmol), (6-(4,4- difluoropiperidin-3-yl)-3-methoxypyrazin-2-yl)methanol (80 mg, 308.6 µmol), triethylamine (109.8 mg, 0.9 mmol) and lithium trifluoromethanesulfonate (127.8 mg, 0.9 mmol) in acetonitrile (2 mL) was stirred for 6 hours at 0°C. The resulting mixture was poured into water (20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10) to afford (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-methoxypyrazin-2-yl)piperidin-1-yl)-N-(2,2- difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (71.0 mg, 42.3% yield) as a white solid. LCMS (ESI) [M+H]+: 544.4.

[0407] Step 8: (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2- yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0408] To a 10 mL round bottom flask containing (2S)-2-(4,4-difluoro-3-(6- (hydroxymethyl)-5-methoxypyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (71 mg, 130.6 µmol) and sodium iodide (36 mg, 240.0 µmol) in THF (6 mL) was added TMSCl (0.1 mL, 791 µmol). The resulting mixture was stirred for 2 hours at room temperature. Upon completion, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (90:10), to afford (2S)-2-(4,4-difluoro-3-(6- (hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (35 mg, 54% yield) as a white solid. LCMS (ESI) [M+H]+: 530.4.

[0409] Step 9: (S)-2-((R)-4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin- 2-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide and (S)-2-((S)-4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5- dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2- d]thiazol-6- l)propanamide

[0410] (2S)-2-(4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin- 1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (35 mg) was separated by Prep-HPLC (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 9 min; Wave Length: 254 nm / 220 nm) Compound 90 (S)-2-((R)-4,4- difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method AC, Peak 1, 2.89 min; 2.9 mg, 100% e.e.) as a white solid and second peak Compound 91 (S)-2-((S)-4,4-difluoro-3-(6- (hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro- [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6-yl)propanamide (Method AC, Peak 2, 3.04 min; 3.3 100% hi lid90 LCMS (ESI) [M+H]+: 530.2.

[0411] Example 37: (2S)-2-(4,4-difluoro-3-(4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]pyridin- 7-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazol-6- yl)propanamide

[0412] Step 1: ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate

[0413] A solution of ethyl 4-oxotetrahydrofuran-3-carboxylate (20 g, 124 mmol) and DIPEA (6.5 g, 200 mmol) in DCM (200 mL) was stirred at -78 °C. To the above mixtur...

Claims

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein the “*” at the carbon bonded to Rdand Rd*is a first stereocenter when Rdand Rd*are different and the “*” at Z2represents a second stereocenter when Z2is not CH2; Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1, 2 or 3 R groups; Z2is CH2 orwherein the wavy lines represent the points of attachment of the Z2group to the 6-membered ring; each R is independently selected from CN, SF5, halogen, (C1-C6)alkyl, -(C0-C6)alkyl-NH2, -OH, (C1-C4)alkoxy, wherein any said (C1-C6)alkyl, -(C0-C6)alkyl-NH2, (C1- C4)alkoxy is optionally substituted one, two, or three times by R1wherein each R1is independently halo, -CN, -SF5, - OH, (C1-C6)alkyl, or (C1-C4)alkoxy; n is 0 or an integer from 1 to 5; L2is -C(O)- orwherein 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 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, CH2 or 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((CI- 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.

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 at least 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.. The compound of claim 1, wherein Rdand Rd*are different, Z2isand 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 7, wherein two Regroups bound to a single carbon atom cyclize to form a 3 to 6 membered ring.

11. The compound of any one of claims 1 to 7, wherein at least one Reis halo, (C1-C3)alkyl, or (C1-C3)alkoxy.

12. The compound of any one of claims 1 to 7, wherein each Reis independently chosen from F, CH3 and OCH3.

13. The compound of any one of claims 1 to 12, 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 NH or O.

17. The compound of any one of claims 1 to 15, wherein Xh*is CH2, C(Re)2, or CH(Re).

18. The compound of any one of claims 1 to 17, wherein Xh*is C(Re)2 and each Reis F.

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

20. The compound of any one of claims 1 to 19, wherein each R is independently CN, SF5, F, Cl, CH3, OCH3, O-phenyl, CF3 or OCF3.

21. The compound of any one of claims 1 to 19, wherein each R is independently F, Cl, CH3, O-phenyl, CF3 or OCF3.

22. The compound of any one of claims 1 to 21, wherein n^ is 1 or 2.

23. The compound of any one of claims 1 to 21, wherein n^ is 0.

24. The compound of any one of claims 1 to 23, wherein Xeis NH and Xfis C=O and the bond between Xeand Xfis a single bond.

25. The compound of any one of claims 1 to 23, wherein Xeis CH2 and Xfis C=O and the bond between Xeand Xfis a single bond.

26. The compound of any one of claims 1 to 23, wherein Xeis CH and Xfis N+-O- and the bond between Xeand Xfis a double bond.

27. The compound of any one of claims 1 to 23, wherein Xeis CH and Xfis N and the bond between Xeand Xfis a double bond.

28. The compound of any one of claims 1 to 23, wherein Xeis N and Xfis C-CH3, C-CH2F, C-CHF2. or CF3 and the bond between Xeand Xfis a double bond.

29. The compound of any one of claims 1 to 28, wherein two Rfgroups on adjacent atoms cyclize to form a 3 to 6 membered ring.

30. The compound of any one of claims 1 to 28, wherein two Rfgroups bound to a single carbon atom cyclize to form a 3 to 6 membered ring.

31. The compound of any one of claims 1 to 28, wherein each Rfis independently chosen from halo, (C1-C3)alkyl, (C1-C3)alkyl-OH, halo(C1-C3)alkyl, (C1-C3)alkoxy, or aryloxy.

32. The compound of any one of claims 1 to 28, wherein each Rfis independently chosen from CH2-OH, F, Cl, CH3, OCH3, O-phenyl, CF3, and OCF3.

33. The compound of any one of claims 1 to 32, wherein Z1is a 12- or 13- membered tricyclic aryl or heteroaryl group.

34. The compound of any one of claims 1 to 33, wherein Z1is chosen from [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene, [1,3]dioxolo[4',5':4,5]benzo[1,2-d]thiazolylene, 2,2-difluoro-[1,3]dioxolo[4,5-b]thiazolo[4,5-e]pyridinylene, thiazolo[4',5':4,5]benzo[1,2- d]oxazolylene, 6,7-dihydro-5H-indeno[5,6-d]thiazolylene, and 6,7-dihydro- [1,4]dioxino[2',3':4,5]benzo[1,2-d]thiazolylene, each substituted with 0, 1 or 2 R groups chosen from OH, Cl, F, and CN.

35. The compound of any one of claims 1 to 34, wherein Z2is CH2.

36. The compound of any one of claims 1 to 34, wherein Z2is.

37. The compound of claim 1, wherein Z1is 10-16 membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; Z2is CH2; L2is -C(O)-; Xgis N; Xhand Xh*are CH2.

38. The compound of claim 37, wherein Rd*is methyl.

39. The compound of claim 38, wherein each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl.

40. The compound of claim 39, wherein R is fluoro.

41. The compound of claim 1, wherein Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; Z2is CH2; L2is -C(O)-; Xgis N; Xhis CH2 and Xh*is O.

42. The compound of claim 41, wherein Rd*is methyl.

43. The compound of claim 42, wherein each Reis independently H, halo or (C1-C3)alkyl; and each R is independently selected from halo and (C1-C3)alkyl.

44. The compound of claim 43, wherein R is fluoro.

45. The compound of claim 1, wherein Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; 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 methyl.

46. The compound of claim 45, wherein Rdis H; and each R is independently selected from halo and (C1-C3)alkyl.

47. The compound of claim 46, wherein Rfis CH3, OCH3, CF3, and OCF3; and R is fluoro.

48. The compound of claim 1, wherein Z1is a 10- to 16- membered tricyclic aryl or heteroaryl group substituted with 0, 1 or 2 R groups; Z2ish* h; X is O; X is CH2; Xgis CH; Xeis NH; Xfis C=O and the bond between Xeand Xfis a single bond; and Rd*is methyl.

49. The compound of claim 48, wherein Rdis H; n is 0, 1, or 2; and each R is independently selected from halo and (C1-C3)alkyl.

50. The compound of claim 49, wherein Rfis CH3, OCH3, CF3, and OCF3; and R is fluoro.

51. The compound of any one of claims 1-50, wherein Z2has stereochemistry of the structure:.

52. The compound of any one of claims 1-51, wherein the Rd*substituent has stereochemistry of the structure:, wherein the wavy lines represent the points of attachment in Formula (I).

53. The compound of any one of claims 1-50, wherein the C4carbon and C5carbon are both in the (S) conformation / configuration, wherein the wavy line represents the point of attachment in Formula (I).

54. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I), and wherein Q is a 5- to 6- membered heteroaryl ring and T is a 5- to 6- membered cycloalkyl or heterocycloalkyl; and n is 0, 1, 2 or 3.

55. The compound of any one of claims 1-53, wherein Z1 is, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

56. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

57. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

58. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

59. The compound of any one of claims 1-53, wherein Z1isor, wherein the wavy line represents the point of attachment in Formula (I); and n is 0, 1, 2 or 3.

60. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I), and wherein Q is a 5- to 6- membered heteroaryl ring and V is a 5- to 6- membered aryl or heteroaryl ring; and n is 0, 1, 2 or 3.

61. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I), and wherein Q is a 5- to 6- membered heteroaryl ring; V is a 5- to 6- membered aryl or heteroaryl ring; and each W is independently O, N or S; and n is 0, 1, 2 or 3.

62. The compound of any one of claims 1-53, wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I), and Q is a 5- to 6- membered heteroaryl ring; V is a 5- to 6- membered aryl or heteroaryl ring; and T is a 5 to 6 membered cycloalkyl or heterocycloalkyl; and n is 0, 1, 2 or 3.

63. The compound of any one of claims 1-53 wherein Z1is, wherein the wavy line represents the point of attachment in Formula (I), and T is a 5- to 6- membered heteroaryl, heterocyclyl, or cycloalkyl ring optionally having 1 or 2 heteroatoms selected from N and S; and n is 0, 1, 2 or 3.

64. A compound selected fromor racemic mixtures thereof, or pharmaceutically salts thereof.

65. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt of any one of claims 1 to 64 and a pharmaceutically acceptable excipient.

66. A method of modulating MRGPRX2 activity comprising administering an effective amount of a compound of any one of claims 1 to 64, or a pharmaceutical composition of claim 65.

67. A method of modulating mast cell degranulation comprising administering an effective amount of a compound of any one of claims 1 to 64, or a pharmaceutical composition of claim 65.

68. 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 64, or a pharmaceutical composition of claim 65.

69. The method of claim 68, 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.

70. 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 64, or a pharmaceutical composition of claim 65.

71. The method of claim 70, wherein the condition is atopic dermatitis.

72. A compound of any one of claims 1 to 64 for use as a medicament.

73. The compound of claim 72 wherein the compound is for use in treating disease or disorder mediated by MRGPRX2.

74. The compound of claim 72 or 73, wherein the compound is for use in 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.

75. The compound for use of claim 74, wherein the condition is atopic dermatitis.

76. Use of a compound of any one of claims 1 to 64 in the manufacture of a medicament for treating a MRGPRX2-mediated disease or disorder.

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