IL-17A modulators

Abstract

Disclosed herein are IL-17A modulators. The present disclosure provides a compound of formula (I) below, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: [Formula 1] JPEG2026501331000092.jpg53170

Description

[Technical Field]

[0001] The present disclosure relates to compounds having an imidazopyridazine [5.6] fused core, pharmaceutical compositions containing same, and their use in the treatment of psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis. [Background technology]

[0002] Immunological function is essential for maintaining homeostasis and effectively responding to disease and abnormal immune responses. Interleukin-17A (IL-17A) is a proinflammatory cytokine that plays a key role in chronic inflammation. IL-17A not only mediates normal immune and inflammatory responses to pathogens, but also plays a role in chronic autoimmune diseases such as psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis.

[0003] The IL-17 family consists of six cytokines (IL-17A to IL-17F). IL-17A mediates the expression of Thl7 cells and CD8 cells, which are involved in the pathogenesis of inflammation and autoimmunity. +IL-17 receptor (IL-17R) is expressed by T cells, gamma-delta cells, NK cells, NKT cells, macrophages, and dendritic cells. IL-17 receptor (IL-17R) refers to a heterodimer formed by the IL-17RA and IL-17RC subunits. IL-17A and C receptors are primarily present on epithelial and mesenchymal cells. IL-17A acts as a homodimer (IL-17A / A) or heterodimer (IL-17A / F) and transduces signals through IL-17R (Isono, F. et al., Inhibiting RORgt / Thl7 axis for autoimmune disorders, Drug Discovery Today (2014) Vol. 19(8) 1205-1211). Binding of IL-17A to IL-17AR stimulates the secretion of various other cytokines in various cell types. For example, IL-17A induces IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, IFN-γ, as well as numerous chemokines and other effectors (Gaffen, Arthritis Research & Therapy 6: 240-247 (2004)).

[0004] Overexpression of IL-17A has been implicated in many diseases, including but not limited to rheumatoid arthritis (RA), bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, angiogenesis, atherosclerosis, asthma, and multiple sclerosis. IL-17A and IL-17A-producing Thl7 cells have recently been implicated in certain cancers (Ji and Zhang, Cancer Immunol Immunother 59: 979-987 (2010)). For example, IL-17-expressing Thl7 cells have been shown to be involved in multiple myeloma (Prabhala et al., Blood, online DOI10.1182 / blood-2009-10-246660, Apr. 15 (2010)) and correlate with poor prognosis in patients with hepatocellular carcinoma (HCC) (Zhang et al., J Hepatology 50: 980-89 (2009)).

[0005] Currently, there are no effective oral medications for moderate to severe psoriasis. Inhibition of IL-17A may increase susceptibility to opportunistic infections in some cases. Orally available small molecule inhibitors with relatively short half-lives could better manage this risk, allowing patients to discontinue administration and rapidly clear the inhibitor from the body. Summary of the Invention

[0006] The objective of the present disclosure is to provide small molecule compounds as IL-17A modulators that can overcome the above problems.

[0007] In one aspect, the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: [ka] In formula (I), W is hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR9; R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl or -C 1-6 alkylene -CH=NO-R8; all of these are deuterium, halogen, CN, -OC 1-3 Alkyl, -NH-C 1-4 Alkyl or -N(C1-4 and optionally substituted with one or more groups selected from the group consisting of alkyl); R2 is C 4-8 Represents cycloalkyl, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 optionally substituted by alkynyl; R3-R5 are each independently hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or -C 2-6 Represents alkynyl; R6 and R7 are each independently hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR9; Or, R6, R7 and the carbon to which they are attached may be selected from deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 may form a 3-7 membered ring optionally substituted with alkynyl or CN; R8 is hydrogen or C 1-6 Represents alkyl; R9 is C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 It represents alkynyl.

[0008] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0009] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, isomer or solvate thereof, for use in therapy.

[0010] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, isomer or solvate thereof, for use in the treatment and / or prophylaxis of a disease in which the administration of a modulator of IL-17 function is indicated.

[0011] The present invention also provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, isomer or solvate thereof, in the preparation of a medicament for the treatment and / or prevention of a disease for which the administration of an IL-17 function modulator is indicated.

[0012] The present invention also provides a method for the treatment and / or prevention of diseases in which the administration of a modulator of IL-17 function is indicated, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

[0013] When used in medicine, the salt of the compound of formula (I) will be a pharmaceutically acceptable salt. However, other salts may also be useful in preparing the compound of formula (I) or its pharmaceutically acceptable salt. The standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. PH Stahl & CG Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) include, for example, acid addition salts that can be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0014] The present invention also encompasses co-crystals of compounds of formula (I) above. The technical term "co-crystal" is used to describe a situation in which neutral molecular components exist in a crystalline compound in a well-defined stoichiometric ratio. By preparing pharmaceutical co-crystals, the crystalline form of the active pharmaceutical ingredient can be modified, thereby altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0015] Suitable alkyl groups which may be present on compounds for use in the present invention include straight and branched C 1-6 Alkyl groups, such as C 1-4 The alkyl groups include alkyl groups. Representative examples include methyl and ethyl groups, as well as straight-chain or branched propyl, butyl, and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. "C 1-6 Alkoxy," "C 1-6 alkylthio", "C 1-6 Alkylsulfonyl" and "C 1-6 Derived expressions such as "alkylamino" should be construed accordingly.

[0016] Suitable alkenyl groups which may be present on compounds for use in the present invention include straight and branched C 2-6 Alkenyl groups, such as C 2-4 Alkenyl groups are included. Representative examples include vinyl groups, and linear or branched propenyl, butenyl, and pentenyl groups. Particular alkenyl groups include vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, and 3-butenyl groups.

[0017] Suitable alkynyl groups which may be present on the compounds used in the present invention include straight and branched C2-6 Alkynyl groups, such as C 2-4 Alkynyl groups are included. Representative examples include ethynyl, and straight-chain or branched propynyl, butynyl, and pentynyl groups. Particular alkynyl groups include ethynyl, 1-propenyl, 2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, etc.

[0018] As used herein, the term "C 3-6 "Cycloalkyl" refers to a monovalent group of 3-6 carbon atoms derived from a saturated monocyclic or bicyclic hydrocarbon. 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Generally, bicyclic hydrocarbons are spiro or bridged bicyclic hydrocarbons, e.g., [ka] Refers to...

[0019] As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine and iodine atoms, and is typically fluorine, chlorine or bromine.

[0020] As used herein, the term "compound of formula (I)" generally includes a compound of formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, unless otherwise specified.

[0021] As used herein, the term "solvate" refers to a form of a compound or its salt in which the solvent molecule forms a stoichiometric complex in the solid state, such as, but not limited to, water, ethanol, and methanol. A hydrate is a specific form of solvate in which the solvent molecule is water. The hydrate of the compound of the present invention or its salt is a stoichiometric composition of the compound or salt with water, such as a hemihydrate, monohydrate, dihydrate, etc.

[0022] When compounds of formula (I) have one or more asymmetric centers, they may accordingly exist as enantiomers. When compounds according to the present invention have two or more asymmetric centers, they may further exist as diastereomers. It is understood that the present invention extends to the use of all such enantiomers and diastereomers, as well as mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted below are intended to represent all individual stereoisomers and their possible mixtures, unless otherwise stated or indicated. Furthermore, compounds of formula (I) may exist as tautomers; for example, keto (CHC=O) is equivalent to the enol (CH=CHOH) tautomer, or amide (NHC=O) is equivalent to the hydroxyimine (N=COH) tautomer. Formula (I) and the formulae depicted below are intended to represent all individual tautomers and their possible mixtures, unless otherwise stated or indicated.

[0023] It is understood that each atom present in formula (I), or in the formulae depicted below, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope being preferred. Thus, by way of example, each hydrogen atom present in formula (I), or in the formulae depicted below, may be: 1 H, 2 H (deuterium) or 3 It may be present as a H (tritium) atom, preferably 1 H. Similarly, by way of example, each carbon atom present in formula (I) or in the formulae depicted below may be: 12 C. 13 C or 14 It may be present as a C atom, preferably 12 It is C.

[0024] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: [ka] In formula (I), W is hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl may be optionally substituted with deuterium, halogen, CN, or OR. Typically, W is H, D, -(CH) 1-3 OCH3, -(CH2) 1-3 CN, -(CH2) 1-3 CHF2, -(CH2) 1-3 CF2CH3, -(CH2) 1-3 CF3 or -(CH2) 1-3 represents OCF3; more typically, W is H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, -(CH2) 1-3 CHF2 or -(CH2) 1-3 specifically, W is H, D, -(CH) 1-3 OCH3, -(CH2) 1-3 CN or -(CH2) 1-3 More specifically, W represents H, D, -(CH) 1-3 OCH3 or -(CH2) 1-3 Represents CN.

[0025] R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl or -C 1-6 alkylene -CH=NO-R8; all of these are hydrogen, deuterium, halogen, CN, -OC 1-3 Alkyl, -NH-C 1-4 Alkyl or -N(C 1-4Typically, R1 is optionally substituted with one or more selected from the group consisting of C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl or -C 1-6 alkylene -CH=NO-R8, specifically, R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 alkynyl, more specifically, R represents C 1-6 Alkyl, -C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl or -C 2-6 represents alkenyl.

[0026] R2 is deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 C optionally substituted by alkynyl 4-8 represents cycloalkyl; in particular represents a ring structure selected from the group consisting of the A1, A2, A3, A4, A5, A6, A7, A8, A9 or A10 groups; [ka]

[0027] Here, " [ka] " is a list of deuterium, halogens, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6represents a bond to the remainder of the molecule, optionally substituted by alkynyl; typically, R2 represents a structure selected from the group consisting of A1, A2, A3, A4, A7, A8, A9, or A10; specifically, R2 represents a structure selected from the group consisting of A2, A4, A7, A8, A9, or A10; more specifically, R2 represents a structure selected from the group consisting of A2, A4, A7, A9, or A10.

[0028] R3-R5 are each independently hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 It represents alkynyl.

[0029] In one embodiment, R3 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 represents alkynyl; typically, R3 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or C 2-6 specifically, R3 is hydrogen, deuterium, halogen, C 3-6 Cycloalkyl or C 2-6 More particularly, R3 represents hydrogen, deuterium or halogen.

[0030] In one embodiment, R4 is hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl or -OC 3-6represents cycloalkyl; typically, R4 is hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl or C 3-6 cycloalkyl, specifically R4 is hydrogen, deuterium, halogen, -OH or C 1-6 More particularly, R4 represents hydrogen, deuterium, halogen or -OH.

[0031] In one embodiment, R5 is hydrogen, deuterium, halogen, —OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 typically R5 represents hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl or -OC 1-6 Specifically, R5 represents hydrogen, deuterium, halogen, —OH, or C 1-6 More particularly, R5 represents hydrogen, deuterium, halogen or -OH.

[0032] R6 and R7 are each independently hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR; typically, R and R are each independently C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Specifically, R and R are each independently selected from the group consisting of C2-6 Alkenyl or C 2-6 It represents alkynyl.

[0033] Or, R6, R7 and the carbon to which they are attached may be selected from deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkynyl or CN may form an optionally substituted 3-7 membered ring.

[0034] R8 is hydrogen or C 1-6 Represents alkyl.

[0035] R9 is C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 It represents alkynyl.

[0036] In one embodiment, W represents -CH2OMe. In one embodiment, W represents -CH2CN. In one embodiment, W represents CH2CF2H. In one embodiment, W represents CH2CF3.

[0037] Suitably, the present invention provides a compound of formula (IIa), (IIb), (IIc) or (IId), or a pharmaceutically acceptable salt thereof: [ka] where R1 to R7 are as defined above.

[0038] In one embodiment, the compound of formula (I) has any one of the following formulae (Xa)-(Xj): [ka] where W, R1, R3, R4, R5, R6 and R7 are as defined above.

[0039] Typically, the compound of formula (I) is represented by any one of formulas (Xa), (Xb), (Xc), (Xd), (Xg), (Xh), (Xi) and (Xj).

[0040] Suitably, the compound of formula (I) is represented by any one of formulae (Xb), (Xc), (Xd), (Xg), (Xh), (Xi) and (Xj).

[0041] Specifically, the compound of formula (I) is represented by any one of formulas (Xb), (Xi) and (Xj).

[0042] In general, the present invention provides compounds of formula (IIIa), (IIIb) or (IIIc): [ka] where W, R2, R3, R4, R5, R6, and R7 are as defined above, m=0, 1, or 2, n=0, 1, 2, or 3, and R 11 = H or F, and R 12 = H or F, and R 13 =H or F.

[0043] Specific novel compounds according to the present invention include each compound, the preparation of which is described in the accompanying Examples, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

[0044] The compounds according to the invention are useful in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune diseases.

[0045] The compounds according to the invention are useful for the treatment and / or prevention of pathological disorders mediated by the pro-inflammatory IL-17 cytokine or associated with elevated levels of the pro-inflammatory IL-17 cytokine.

[0046] In general, pathological conditions include infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infections, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic-onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman's disease, axial spondyloarthritis, spondyloarthropathy such as ankylosing spondylitis, dermatomyositis, myocarditis, uveitis, ectropion, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, and surgical procedures. The therapeutic agent is selected from the group consisting of adhesions, stroke, autoimmune diabetes, type 1 diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory diseases of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome, other autoimmune diseases, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic diseases such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma and systemic sclerosis, cancer (solid cancers such as melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematological malignancies, particularly acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer, and colon cancer), heart disease including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochloremia, and pain (particularly pain associated with inflammation).

[0047] WO 2009 / 089036 discloses that modulators of IL-17 activity can be administered to suppress or reduce the severity of ocular inflammatory diseases, particularly ocular surface inflammatory diseases, including dry eye syndrome (DES). Therefore, the compounds of the present invention are useful for treating and / or preventing IL-17-mediated ocular inflammatory diseases, particularly IL-17-mediated ocular surface inflammatory diseases, including dry eye syndrome. Ocular surface inflammatory diseases include dry eye syndrome, penetrating keratoplasty, corneal transplantation, superficial or partial-thickness keratoplasty, selective endothelial transplantation, corneal neovascularization, keratoprosthetic surgery, corneal and ocular surface inflammatory diseases, conjunctival scarring disorders, ocular autoimmune diseases, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye diseases, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis rounda (KCS), Sjögren's syndrome, Sjögren's syndrome-associated keratoconjunctivitis rounda, non-Sjögren's syndrome-associated keratoconjunctivitis rounda, keratoconjunctivitis sicca, sicca syndrome, xerophthalmia, tear film disorders, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporative loss.

[0048] In general, the compounds of the present invention are useful for the treatment and / or prevention of pathological diseases selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), axial spondyloarthritis, spondyloarthropathy such as ankylosing spondylitis, cancer, pain (particularly pain associated with inflammation).

[0049] Suitably, the compounds of the present invention are useful for the treatment and / or prevention of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis or ankylosing spondylitis.

[0050] The present invention also provides a pharmaceutical composition comprising a compound according to the invention, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, as described above, in combination with one or more pharmaceutically acceptable carriers.

[0051] Pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic, rectal administration, or in a form suitable for administration by inhalation or insufflation.

[0052] The amount of the compound according to the present invention required for the prevention or treatment of a particular condition will vary depending on the compound selected and the condition of the patient being treated. However, in general, the daily dosage can be about 10 ng / kg-1000 mg / kg, typically 100 ng / kg-100 mg / kg, for example, about 0.01 mg / kg-40 mg / kg body weight for oral or buccal administration, about 10 ng / kg-50 mg / kg body weight for parenteral administration, and about 0.05 mg-about 1000 mg, for example, about 0.5 mg-about 1000 mg for nasal administration or administration by inhalation or insufflation.

[0053] If desired, the compounds according to the invention can be co-administered with another pharmaceutically active agent, for example an anti-inflammatory molecule.

[0054] Examples of compounds of formula (I) in the present disclosure include: [ka] JPEG2026501331000011.jpg223170JPEG2026501331000012.jpg250170JPEG2026501331000013.jpg180170

[0055] In another aspect, the disclosure provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof in the preparation of a medicament for treating a disease modulated by IL-17A.

[0056] In a further aspect, the present disclosure provides the use of a compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, for treating a disease mediated by IL-17A.

[0057] In a further aspect, the present disclosure provides a method of treating a disease mediated by IL-17A, comprising administering to a subject to be treated a therapeutically effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

[0058] In one embodiment of the present disclosure, the step of administering a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof to a subject to be treated comprises administering a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof to the subject by conventional means, such as orally, by injection, or topically.

[0059] In a further aspect, the present disclosure provides a pharmaceutical composition comprising the claimed compound, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

[0060] In one embodiment of the present disclosure, the pharmaceutical composition comprises a therapeutically effective amount of the compound, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, and a pharmaceutical carrier such as ionized water.

[0061] [Table 1] JPEG2026501331000015.jpg242170JPEG2026501331000016.jpg13170

[0062] Intermediate synthesis 1. Synthesis of 4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int1) [ka]

[0063] Synthesis of (2E)-2-cyano-2-hydroxyimino-N-phenyl-acetamide 2 To a mixture of compound 1 (5.0 g, 31.22 mmol, 1 eq) and HCl (12 M, 26.01 mL, 10 eq) in MeCN (150 mL) was added dropwise a solution of NaNO (4.74 g, 68.70 mmol, 2.20 eq) in HO (10 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0–50% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give compound 2 (5.4 g, 89.62%) as a yellow solid. LCMS(ESI): m / z=190.2[M+H] + . 1 HNMR (400MHz, DMSO-d6): δ14.65(s, 1H), 10.43(s, 1H), 7.72-7.66(m, 2H), 7.40-7.31(m, 2H), 7.18-7.12(m, 1H).

[0064] Synthesis of 4-amino-N-phenyl-1,2,5-oxadiazole-3-carboxamide 3 To a solution of compound 2 (1 g, 5.29 mmol, 1 eq) in THF (20 mL), hydroxylamine (453.97 mg, 6.87 mmol, 1.3 eq) (50% solution in water) was added and stirred at 50 °C for 16 h. CDI (1.29 g, 7.93 mmol, 1.5 eq) was then added to the resulting mixture at 25 °C and stirred for an additional 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give the title compound 3 (7 g, 64%) as a yellow solid. LC-MS(ESI): m / z=205.1[M+H] + . 1 HNMR (400MHz, DMSO-d6): δ10.97(s, 1H), 7.82-7.74(m, 2H), 7.42-7.35(m, 2H), 7.21-7.14(m, 1H), 6.44(s, 2H).

[0065] Synthesis of 4-chloro-N-phenyl-1,2,5-oxadiazole-3-carboxamide 4 To a solution of compound 3 (2.5 g, 12.24 mmol, 1 eq), LiCl (1.56 g, 36.68 mmol, 751.21 uL, 3.00 eq), MeCN (50 mL), AcOH (52.50 g, 874.24 mmol, 50.00 mL, 71.40 eq), and HCl (12 M, 30.00 mL, 29.40 eq) was added a solution of NaNO (1.26 g, 18.33 mmol, 1.50 eq) in HO (2.5 mL) at 0 °C and stirred at 0 °C for 0.5 h. The resulting mixture was stirred at 25 °C for 17.5 h. The reaction mixture was quenched with NH Cl (aq., 30 mL) at 25 °C and poured into water (100 mL). The aqueous layer was extracted with EtOAc (150 mL), washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give the title compound 4 (2.0 g, 43.83%) as a white solid. LC-MS(ESI): m / z=224.0[M+H] + . 1 HNMR (400MHz, DMSO-d6): δ11.19(s, 1H), 7.80-7.72(m, 2H), 7.45-7.37(m, 2H), 7.25-7.16(m, 1H).

[0066] Synthesis of N-phenyl-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide 5 To a solution of NaH (536.58 mg, 13.42 mmol, 60% purity, 3 eq) in THF (20 mL) was added 2,2,2-trifluoroethanol (671.27 mg, 6.71 mmol, 482.93 uL, 1.50 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. Compound 4 (1 g, 4.47 mmol, 1 eq) in THF (10 mL) was added. The reaction mixture was stirred at 25 °C for 17.5 h. The reaction was quenched with water (40 mL) at 25 °C and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound 5 (1 g, crude) as a yellow solid, which was used in the next step without purification. LC-MS(ESI): m / z=288.1[M+H] + . 1 HNMR (400MHz, DMSO-d6): δ11.07(s, 1H), 7.78-7.67(m, 2H), 7.41-7.37(m, 2H), 7.22-7.14(m, 1H), 5.23-5.17(m, 2H).

[0067] Synthesis of tert-butyl N-phenyl-N-phenyl-N-[4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carbonyl]carbamate 6 A solution of compound 5 (1 g, 3.48 mmol, 1 eq), di-tert-butyl dicarbonate (1.14 g, 5.22 mmol, 1.20 mL, 1.5 eq), DMAP (42.54 mg, 348.20 μmol, 0.1 eq), and DCM (10 mL) was stirred at 25 °C for 18 h. The reaction mixture was then concentrated under reduced pressure to remove the DCM, yielding a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–10% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford the title compound 6 (900 mg, 60.73%) as a white solid. LC-MS(ESI): m / z=797.2[2M+23] + . 1 HNMR (400MHz, DMSO-d6): δ7.54-7.42(m, 3H), 7.34-7.29(m, 2H), 5.33-5.19(m, 2H), 1.27(s, 9H).

[0068] Synthesis of 4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int1) A solution of compound 6 (900 mg, 2.32 mmol, 1 eq) and LiOH HO (146.27 mg, 3.49 mmol, 1.5 eq) in THF (3 mL) and HO (3 mL) (1:1, 6 mL) was stirred at 25 °C for 18 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent. The residue was diluted with water (10 mL) and extracted with EtOAc (15 mL). The aqueous phase was acidified with dilute hydrochloric acid (1 M) to pH = 4 and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title product Int1 (150 mg, crude) as a yellow oil, which was used in the next step without purification. 1 HNMR(400MHz, DMSO-d6): δ12.30(brs, 1H), 4.91-4.80(m, 2H).

[0069] 2. Synthesis of 4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int2) [ka]

[0070] Synthesis of ethyl 6,6,6-trifluoro-3-oxohexanoate 8 To a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (20.29 g, 140.77 mmol) in DCM (700 mL) was added 4,4,4-trifluorobutanoic acid 7 (20 g, 140.77 mmol), followed by DMAP (34.39 g, 281.53 mmol) and DCC (29.04 g, 140.77 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was washed with 1 M HCl (100 mL), HO (500 mL), and brine (500 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give a yellow oil. This oil was dissolved in 700 mL of EtOH and refluxed overnight. The reaction mixture was concentrated to give a residue, which was purified by column chromatography (ethyl acetate / hexane (1:4)) to give the title compound 8 (18 g, 60.27%) as a clear oil. 1 HNMR(400MHz, CDCl3): δ4.21(q, J=7.2Hz, 2H), 3.49(s, 2H), 2.84(d, J=8.0Hz, 2H), 2.53-2.33(m, 2H), 1.29(t, J=7.2Hz, 3H).

[0071] Synthesis of ethyl (2E)-6,6,6-trifluoro-2-(hydroxyimino)-3-oxohexanoate 9 To compound 8 (17.77 g, 83.75 mmol) and concentrated hydrochloric acid (69.80 mL, 837.54 mmol) in MeCN (300 mL) was added a solution of sodium nitrite (12.71 g, 184.26 mmol) in HO (40 mL, 2213.10 mmol) dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into 400 mL of HO, extracted with EtOAc (100 mL × 2), washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 9 (15.42 g, 76.34%) as a yellow oil. 1HNMR(400MHz, CDCl3): δ4.37(q, J=7.2Hz, 2H), 3.09-3.05(m, 2H), 2.49-2.44(m, 2H), 1.34(m, 3H).

[0072] Synthesis of ethyl (2E,3E)-6,6,6-trifluoro-2,3-bis(hydroxyimino)hexanoate 10 Compound 9 (15.42 g, 63.94 mmol), a stir bar, and EtOH (75 mL) were added to a 250 mL three-necked round-bottom flask equipped with a thermometer. The flask was then cooled to 0 °C in an ice / water bath. Hydroxylamine hydrochloride (13.33 g, 191.82 mmol) and sodium acetate (10.49 g, 127.88 mmol) were added, and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was then cooled to rt, filtered, and the filtrate was concentrated to dryness under vacuum to give a brown oil. The oil was then treated with HO (100 mL), followed by the dropwise addition of 1 M NaOH until pH = 9–10. The oil was extracted with DCM (100 mL × 3). The combined extracts were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness under vacuum to give a brown oil. This oil was subjected to silica gel chromatography (0-15% EtOAc / pet ether) to afford the title compound 10 (4.7 g, 28.69%) as a yellow oil. 1 HNMR(400MHz, CDCl3): δ9.43(s, 1H), 9.20(s, 1H), 4.35(q, J=7.2Hz, 2H), 2.97-2.78(m, 2H), 2.39-2.32(m, 2H), 1.34(t, J=7.2Hz, 3H).

[0073] Synthesis of ethyl 4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxylate 11 Compound 10 (2.7 g, 10.54 mmol), a stir bar, CDI (2.56 g, 15.809 mmol), and THF (5 mL) were added to a 20 mL microwave tube. The resulting mixture was stirred and heated at 60 °C for 30 minutes using microwave irradiation, then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo to give the crude product as a yellow oil. This oil was subjected to silica gel chromatography (0-1% MeOH / DCM) to give compound 11 (639 mg, 25.46%) as a colorless oil. 1 HNMR(400MHz, CDCl3): δ4.52(q, J=7.2Hz, 2H), 3.36-3.13(m, 2H), 2.76-2.58(m, 2H), 1.46(t, J=7.2Hz, 3H).

[0074] Synthesis of 4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int2) Compound 11 (20 mg, 0.084 mmol), a stir bar, LiOH HO (0.17 mL, 0.17 mmol), and THF (0.5 mL) were added to a 20 mL microwave tube. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness in vacuo to give the desired product Int2 (178 mg, crude) as a colorless oil. 1 HNMR(400MHz, DMSO-d6): δ3.28-3.09(m, 2H), 2.86-2.66(m, 2H).

[0075] 3. Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int3) and (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int4) [ka]

[0076] Synthesis of cyclopent-3-en-1-ylbenzoic acid 13 To a solution of compound 12 (40.0 g, 476 mmol) in DCM (100 mL) was added TEA (79.2 mL, 572 mmol), and the reaction mixture was stirred at 25° C. for 15 min. Then, PhCOCl (66.8 g, 472 mmol) was added slowly, and the resulting mixture was stirred for 25 min. o The mixture was stirred at RT for 12 hours. Water (500 mL) was added to the reaction mixture. The resulting solution was extracted with DCM (200 mL x 3). The combined organic phase was washed with NHOH (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (30% EtOAc in PE) to give the title compound 13 (20.0 g, 22.3%) as a yellow oil. 1 HNMR(400MHz, CDCl3): δ8.04-8.02(m, 2H), 7.56-7.52(m, 1H), 7.43-7.40(m, 2H), 5.78-5.75(m, 2H), 5.64-5.60(m, 2H), 2.89-2.82(m, 2H), 2.58(d, J=2.4Hz, 1H), 2.53(d, J=2.4Hz, 1H).

[0077] Synthesis of 6,6-difluorobicyclo[3.1.0]hexan-3-ylbenzoic acid 14 To a solution of compound 13 (20.0 g, 106 mmol) in THF (300 mL) was added NaI (7.96 g, 53.1 mmol) and TMSCF (30.2 g, 212 mmol). The reaction mixture was stirred at 75 °C for 24 h. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash column on silica gel eluting with 30% EtOAc in PE to give the title compound 14 (21 g, 82.96%) as a yellow oil. LC-MS(ESI): m / z=239.0[M+H] + .

[0078] Synthesis of 6,6-difluorobicyclo[3.1.0]hexan-3-ol 15 To a solution of compound 14 (21.0 g, 88.2 mmol) in MeOH (100 mL) was added a solution of KOH (6.43 g, 114.0 mmol) in HO (100 mL). The reaction mixture was stirred for 25 o The mixture was stirred at RT for 12 h at RT. The reaction mixture was concentrated, and the residue was extracted with DCM (200 mL x 3). The combined organic phases were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (20% EtOAc in PE) to give the title compound 15 (15.0 g, 50.8%) as a yellow oil. LCMS: m / z(ESI)=135.0[M+H] + .

[0079] Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int3) and (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int4) To a solution of compound 15 (13.0 g, 96.9 mmol) in DCM (200 mL) was added pyridine (31.4 mL, 388 mmol) and TsCl (37.0 g, 193 mmol). The reaction mixture was then stirred for 25 o The mixture was stirred at RT for 12 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 10% EA in PE to give the desired product Int3 (13.0 g, 32.57%) as a yellow oil and Int4 (3.5 g, 12.53%) as a yellow solid. LCMS: m / z(ESI)=311.0[M+Na] + .

[0080] 4. Synthesis of (4S)-1-((1S)-1-(2-(amino((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int5) [ka]

[0081] Synthesis of ethyl 2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-2-((diphenylmethylene)amino)acetate 17 To a solution of compound Int4 (19.9 g, 69.0 mmol) and compound 16 (22.1 g, 82.8 mmol) in toluene (110 mL) was added LiHMDS (82.8 mL, 82.8 mmol, 1 mol / L). The reaction mixture was then diluted to 100°C. o The mixture was stirred at RT for 16 h under N2. The reaction mixture was then quenched with HO (30 mL). The resulting solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (10% EtOAc in PE) to give the title compound 17 (8.90 g, 33.6%) as a yellow oil. LCMS: m / z(ESI)=383.9[M+H] + .

[0082] Synthesis of ethyl 2-amino-2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetate 18 To a solution of compound 17 (8.80 g, 22.9 mmol) in THF (60 mL) was added hydrochloric acid (2 N) (15 mL, 30.0 mmol). oThe mixture was stirred at RT for 1 hour. Water (60 mL) was added to the reaction mixture. The resulting solution was washed with PE (60 mL x 2). The aqueous phase was adjusted to pH = 8 with saturated aqueous sodium bicarbonate and extracted with EA (60 mL x 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 18 (2.40 g, 47.7%) as a yellow oil. LCMS: m / z(ESI)=220.0[M+H] + .

[0083] Synthesis of ethyl 2-(((benzyloxy)carbonyl)amino)-2-((1R,3s,5S)-6,6-difluorobicycle[3.1.0]hexan-3-yl)acetate 19 To a mixture of compound 18 (2.30 g, 10.50 mmol) and NaHCO (2.64 g, 31.50 mmol) in DCM (20 mL) and HO (20 mL) was added CbzCl (3.69 mL, 26.20 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting mixture was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluted with (40% EtOAc in PE) to give compound 19 (3.70 g, 95.6%) as a white solid. LCMS: m / z(ESI)=354.2[M+H] + .

[0084] Synthesis of 2-(((benzyloxy)carbonyl)amino)-2-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetic acid 20 To a solution of compound 19 (3.70 g, 10.50 mmol) in THF (10 mL) and HO (10 mL) was added LiOH (0.50 g, 20.90 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was acidified to pH = 4 with 1 N hydrochloric acid. The mixture was extracted with DCM (40 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 20 (3.40 g, 99.8%) as a white solid. LCMS: m / z(ESI)=326.2[M+H] + .

[0085] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-oxobutanoate 21 To a solution of compound 20 (3.40 g, 10.40 mmol) in THF (30 mL) was added CDI (1.69 g, 10.40 mmol), and the resulting reaction mixture was stirred for 25 minutes under a nitrogen atmosphere. o Stir for 2 hours at -78°C, then o The mixture was cooled to -78°C. To a solution of diisopropylamine (6.63 mL, 47.00 mmol) in THF (30 mL) was added n-BuLi (18.8 mL, 47.00 mmol) under a nitrogen atmosphere at 0°C. After 10 min, tert-butyl acetate (6.309 mL, 47.0 mmol) was added to the mixture at -78°C. o After an additional hour, the enolate mixture was added to the above mixture via cannula, and the resulting reaction mixture was cooled to -78°C. o The mixture was stirred at -78°C for 1 h and quenched with saturated aqueous ammonium chloride (30 mL). The resulting solution was removed from the cold bath, diluted with 60 mL of water, and the solvent volume was reduced to 60 mL under reduced pressure. The mixture was extracted with EA (100 mL x 3), and the combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 18% EtOAc in PE to give the title compound 21 (3.34 g, 75.47%) as a yellow oil. LCMS: m / z(ESI)=446.2[M+Na] + .

[0086] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-bromo-4-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-oxobutanoate 22 To a mixture of compound 21 (3.33 g, 7.08 mmol) and 2,6-dimethylpyridine (0.058 mL, 0.495 mmol) in MeOH (10 mL), NBS (1.26 g, 7.08 mmol) was added, and the reaction mixture was stirred for 25 min. o The mixture was stirred at C for 1 h. The reaction mixture was diluted with EA (60 mL) and washed with a 50% solution of saturated sodium chloride in water (40 mL × 2) and saturated aqueous sodium chloride solution (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound 22 (3.50 g, 98.44%) as a yellow oil. LCMS: m / z(ESI)=523.8, 525.8[M+H] + .

[0087] Synthesis of benzyl (3-bromo-1-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-2-oxopropyl)carbamate 23 To a solution of compound 22 (3.49 g, 6.95 mmol) in toluene (10 mL) was added TFA (1 mL, 13.0 mmol). The reaction mixture was then heated at 80 o The mixture was stirred at C for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (12% EtOAc in PE) to give compound 23 (2.00 g, 71.57%) as a brown oil. LCMS: m / z(ESI)=424.0, 426.0[M+Na] + .

[0088] Synthesis of compound (S)-1-((S)-1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 24 To a solution of compound Int6 (1.6 g, 3.78 mmol) in MeOH (5 mL), hydrochloric acid (15 mL, 6 mol / L) was added and the reaction mixture was heated to 110 o The mixture was stirred at RT for 1 h. The reaction mixture was concentrated to give a yellow residue. The residue was dissolved in DCM (10 mL) and 1N NaOH (10 mL), and the resulting solution was extracted with EtOAc (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 24 (1.3 g, 99.34%) as a pale yellow solid. LCMS: m / z(ESI)=339.8[M+H] + .

[0089] Synthesis of benzyl ((6-chloro-7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,3s,5S)-6,6-difluorobicyclo-[3.1.0]hexan-3-yl)methyl)carbamate 25 To a mixture of compound 23 (400 mg, 0.99 mmol) and compound 24 (282 mg, 0.83 mmol) in THF (30 mL) was added NaHCO3 (209 mg, 2.49 mmol) at 25 °C. The reaction mixture was stirred for 75 o The mixture was stirred at C for 12 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (90% EtOAc in PE) to give the title compound 25 (290 mg, 54.42%) as a yellow oil. LCMS: m / z(ESI)=643.2[M+H] + .

[0090] Synthesis of (4S)-1-((1S)-1-(2-(amino((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int5) To a solution of compound 25 (290 mg, 0.45 mmol) in EtOH (8 mL) was added 10% Pd / C (48.0 mg, 0.45 mmol) and NH3.HO (0.8 mL) at 25 °C. The reaction mixture was then degassed, purged with H2 three times, and stirred under H2 (15 psi) at 25 °C for 1 h. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated to give the title product Int5 (210 mg, 98.14%) as a yellow solid. LCMS: m / z(ESI)=475.2[M+H] + .

[0091] 5. Synthesis of (S)-1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl-6-d)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int8) [ka]

[0092] Synthesis of N-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridazin-3-yl-6-d)pivalamide 26 To a solution of compound Int6 (500 mg, 1.18 mmol) in THF (30 mL) and DO (5 mL) was added Pd(dppf)Cl2 (96.3 mg, 0.12 mmol) and N,N,N',N'-tetramethylethylenediamine (27.4 mg, 0.24 mmol). After stirring for 10 min, NaBD4 (1.15 g, 5.90 mmol) was slowly added. The reaction mixture was stirred at 25 °C for 2 h. Water (12 mL) was added to the reaction mixture, and the resulting mixture was extracted with EA (20 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel to give the title compound 26 (250 mg, 54.3%) as a yellow solid. LCMS: m / z(ESI)=391.2[M+H] + .

[0093] Synthesis of (S)-1-((S)-1-(6-aminopyridazin-4-yl-3-d)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 27 A solution of compound 26 (260 mg, 0.67 mmol) in HCl (6 mol / L) (6 mL) and MeOH (2 mL) was stirred at 110° C. for 1 h. The reaction mixture was then concentrated to give compound 27 (130 mg, 63.7% yield) as a yellow solid. LCMS: m / z(ESI)=307.2[M+H] + .

[0094] Synthesis of benzyl((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl) carbamate 28 To a mixture of compound 27 (120 mg, 0.39 mmol) in THF (5 mL), NaHCO3 (165 mg, 1.96 mmol) and Int7 (see WO2020146194A1) (190 mg, 0.47 mmol) were added, and the resulting reaction mixture was stirred at 75 °C for 12 hours. Water (20 mL) was added to the reaction mixture. The resulting solution was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluted with (20% EtOAc in PE) to give compound 28 (80.0 mg, 33.4%) as a yellow solid. LCMS: m / z(ESI)=612.2[M+H] + .

[0095] Synthesis of (S)-1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl-6-d)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int8) To a solution of compound 28 (70.0 mg, 0.12 mmol) in NHHO (0.2 mL) and EtOH (2 mL) was added 10% Pd / C (12.2 mg, 0.12 mmol). The reaction mixture was degassed and purged with H three times, then stirred under H (14.696 PSI) at 25 °C for 2 h. The reaction mixture was then filtered, and the filtrate was concentrated to give the title product Int8 (50.0 mg, 91.5%) as a yellow solid. LCMS: m / z(ESI)=478.2[M+H] + .

[0096] 6. Synthesis of (4S)-1-(1-(2-(amino((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxy-113-ethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int9) [ka]

[0097] Synthesis of ethyl 2-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-2-((diphenylmethylene)amino)acetate 29 To a solution of compound Int3 (19.9 g, 69.0 mmol) and compound 16 (22.1 g, 82.8 mmol) in toluene (110 mL) was added LiHMDS (82.8 mL, 82.8 mmol, 1 mol / L), and the resulting reaction mixture was stirred at 100 °C under a N atmosphere for 16 h. The reaction mixture was then quenched with HO (30 mL). The resulting solution was extracted with EtOAc (30 mL × 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (10% EtOAc in PE) to give the title compound 29 (8.9 g, 33.6%) as a yellow oil. LCMS: m / z(ESI)=383.9[M+H] + .

[0098] Synthesis of ethyl 2-amino-2-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetate 30 To a solution of compound 29 (8.8 g, 22.9 mmol) in THF (60 mL), HCl (2N) (15 mL, 30.0 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 h. Water (60 mL) was added to the reaction mixture. The resulting mixture was washed with PE (60 mL × 2). The aqueous phase was adjusted to pH = 8 with saturated aqueous sodium bicarbonate and extracted with EA (60 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 30 (2.4 g, 47.7%) as a yellow oil. LCMS: m / z(ESI)=220.0[M+H] + .

[0099] Synthesis of ethyl 2-(((benzyloxy)carbonyl)amino)-2-((1R,3r,5S)-6,6-difluorobicycle[3.1.0]hexan-3-yl)acetate 31 To a mixture of compound 30 (2.30 g, 10.50 mmol) and NaHCO (2.64 g, 31.50 mmol) in DCM (20 mL) and HO (20 mL) was added CbzCl (3.69 mL, 26.20 mmol) at 0 °C. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting reaction mixture was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (40% EtOAc in PE) to give compound 31 (3.70 g, 95.6%) as a white solid. LCMS: m / z(ESI)=354.2[M+H] + .

[0100] Synthesis of 2-(((benzyloxy)carbonyl)amino)-2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetic acid 32 To a solution of compound 31 (3.7 g, 10.5 mmol) in THF (10 mL) and HO (10 mL) was added LiOH (0.5 g, 20.9 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was acidified to pH = 4 with 1 N hydrochloric acid. The mixture was extracted with DCM (40 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 32 (3.4 g, 99.8%) as a white solid. LCMS: m / z(ESI)=326.2[M+H] + .

[0101] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-oxobutanoate 33 To a solution of compound 32 (3.4 g, 10.4 mmol) in THF (30 mL) was added CDI (1.69 g, 10.40 mmol), and the reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 2 hours and then cooled to -78 °C. To a solution of diisopropylamine (6.63 mL, 47.0 mmol) in THF (30 mL) was added n-BuLi (18.8 mL, 47.0 mmol) at 0 °C under a nitrogen atmosphere. After 10 minutes, tert-butyl acetate (6.309 mL, 47.0 mmol) was added to the reaction mixture at -78 °C. After an additional hour, the enolate mixture was added to the above mixture via cannula. The reaction mixture was then stirred at -78 °C for 1 hour. The reaction mixture was quenched with 30 mL of saturated aqueous ammonium chloride solution at -78 °C. The resulting mixture was removed from the cold bath, diluted with 60 mL of water, and the solvent volume was reduced to 60 mL under reduced pressure. The mixture was extracted with EA (100 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 18% EtOAc in PE to give compound 33 (3.34 g, 75.47%) as a yellow oil. LCMS: m / z(ESI)=446.2[M+Na] + .

[0102] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-bromo-4-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-oxobutanoate 34 To a mixture of compound 33 (3.33 g, 7.08 mmol) and 2,6-dimethylpyridine (0.058 mL, 0.50 mmol) in MeOH (10 mL) was added NBS (1.26 g, 7.08 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with EA (60 mL) and washed with a 50% solution of saturated sodium chloride in water (40 mL × 2) and saturated aqueous sodium chloride solution (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound 34 (3.50 g, 98.44%) as a yellow oil. LCMS: m / z(ESI)=523.8, 525.8[M+H] + .

[0103] Synthesis of benzyl (3-bromo-1-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-2-oxopropyl)carbamate 35 To a solution of compound 34 (3.49 g, 6.95 mmol) in toluene (10 mL) was added TFA (1 mL, 13.0 mmol). The reaction mixture was then stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (12% EtOAc in PE) to give compound 35 (2.00 g, 71.57%) as a brown oil. LCMS: m / z(ESI)=424.0, 426.0[M+Na] + .

[0104] Synthesis of benzyl ((6-chloro-7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-113-ethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)carbamate 36 To a solution of compound 35 (400 mg, 0.99 mmol) and compound 24 (282 mg, 0.83 mmol) in THF (30 mL) was added NaHCO (209 mg, 2.49 mmol) at 25 °C. The reaction mixture was stirred at 75 °C for 12 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluted with (90% EtOAc in PE) to give the title compound 36 (290 mg, 54.42%) as a yellow oil. LCMS: m / z(ESI)=643.2[M+H] + .

[0105] Synthesis of (4S)-1-(1-(2-(amino((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxy-113-ethyl)-4-(trifluoromethyl)imidazolidin-2-one Int9 To a solution of compound 36 (290 mg, 0.45 mmol) in EtOH (8 mL) was added 10% Pd / C (48.0 mg, 0.45 mmol) and NH3HO (0.8 mL) at 25 °C. The reaction mixture was then degassed, purged with H2 three times, and stirred under H2 (15 psi) at 25 °C for 1 h. The reaction mixture was then filtered to remove insoluble solids, and the filtrate was concentrated to give the title product Int9 (210 mg, 98.14%) as a yellow solid. LCMS: m / z(ESI)=475.2[M+H] + .

[0106] 7. Synthesis of 4-(cyclobut-1-en-1-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int10) [ka]

[0107] Synthesis of ethyl 3-cyclobutyl-3-oxopropanoate 38 To a solution of compound 37 (25.00 g, 249.70 mmol) in THF (300 mL) was added CDI (40.49 g, 249.70 mmol) in portions at 25 °C. After the addition, the clear solution was stirred at 25 °C for 2 h to obtain solution A. To a solution of n-BuLi (149.82 mL, 374.55 mmol) in THF (700 mL) was added di(prop-2-yl)amine (52.86 mL, 374.55 mmol) slowly at -70 °C under N2. After the addition, the solution was slowly warmed to 0 °C for 30 min and then cooled to -70 °C. Ethyl acetate (36.63 mL, 374.55 mmol) was slowly added. After the addition, the solution was stirred at -70 °C for 1 h, and then solution A was slowly added at -70 °C. After the addition, the solution was stirred at -70 °C for 1 h. The reaction was then quenched with saturated aqueous NH4Cl (250 mL) and extracted with EtOAc (250 mL * 3). The combined organic layers were washed with water (250 mL * 2) and brine (250 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient @ 85 mL / min) to give the title compound 38 (16.00 g, 37.65%) as a colorless oil. 1 HNMR(400MHz, CDCl3): δ4.12(q, J=7.2Hz, 2H), 3.38-3.28(m, 3H), 2.15-2.27(m, 2H), 2.06-2.14(m, 2H), 1.87-1.95(m, 1H), 1.73-1.81(m, 1H), 1.19-1.23(t, J=7.2Hz, 3H).

[0108] Synthesis of ethyl (E)-3-cyclobutyl-2-(hydroxyimino)-3-oxopropanoate 39 Compound 38 (16 g, 94 mmol), a stir bar, and acetic acid (80 mL) were added to a 500 mL round bottle flask under N, and NaNO (9.73 g, 141 mmol) in HO (80 mL) was added dropwise over 1 min at 0 °C. The resulting reaction mixture was warmed to 25 °C and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL), washed with HO (100 mL × 3), brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo to give a residue that was subjected to silica gel chromatography (0-10% petroleum ether / EtOAc) to give compound 39 (15.1 g, 80.64%) as a yellow liquid. 1 HNMR(400MHz, DMSO-d6): δ13.20(s, 1H), 4.24(q, J=7.2Hz, 2H), 3.92-3.83(m, 1H), 2.25-2.08(m, 4H), 1.97-1.92(m, 1H), 1.82-1.71(m, 1H), 1.22(t, J=7.2Hz, 3H).

[0109] Synthesis of ethyl (2Z,3E)-3-cyclobutyl-2,3-bis(hydroxyimino)propanoate 40 Compound 39 (15 g, 75 mmol), a stir bar, and EtOH (150 mL) were added to a 1000 mL three-necked round-bottom flask equipped with a thermometer. The flask was then cooled to 0 °C in an ice / water bath, and azanolchlorane (15.7 g, 226 mmol) and sodium acetate (12.4 g, 151 mmol) were added. The mixture was then heated at 90 °C for 18 h. The reaction mixture was cooled and filtered, and the filtrate was concentrated to dryness in vacuo to give a yellow oil. EtOAc (30 mL) was added to the oil, filtered, and the filtrate was concentrated to dryness in vacuo to give an oil. Silica gel chromatography (0-30% EtOAc / pet ether) afforded the title compound 40 (790 mg, 4.90%) as a yellow oil. LCMS: m / z(ESI)=214.9[M+H] + . 1HNMR(400MHz, DMSO-d6): δ12.57(s, 1H), 11.11(s, 1H), 4.07-3.98(m, 2H), 2.15-2.04(m, 3H), 1.92-1.83(m, 4H), 1.20-1.12(m, 3H)

[0110] Synthesis of ethyl 4-cyclobutyl-1,2,5-oxadiazole-3-carboxylate41 To compound 40 (790 mg, 3.69 mmol) and a stir bar in THF (8 mL) was added CDI (897 mg, 5.53 mmol) in one portion. The resulting reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was concentrated to dryness in vacuo to give an oil. This oil was subjected to silica gel chromatography (0-10% EtOAc / petroleum ether) to give the title compound 41 (366 mg, 50.58%) as a colorless liquid. LCMS: m / z(ESI)=197.0[M+H] + . 1 HNMR(400MHz, CDCl3): δ4.47(q, J=7.2Hz, 2H), 3.91(q, J=8.4Hz, 1H), 2.54-2.33(m, 4H), 2.22-2.07(m, 1H), 2.04-1.94(m, 1H), 1.44(t, J=7.2Hz, 3H).

[0111] Synthesis of ethyl 4-(bromocyclobutyl)-1,2,5-oxadiazole-3-carboxylate 42 Compound 41 (366 mg, 1.87 mmol), a stir bar, NBS (498 mg, 2.80 mmol) in CCl4 (4 mL) was added at 25 °C, and AIBN (30.6 mg, 0.187 mmol) was added in one portion, and the resulting reaction mixture was stirred at 85 °C for 18 h. The reaction mixture was concentrated in vacuo to remove CCl4, and the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0–10% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give title compound 42 (470 mg, 91.59%) as a colorless liquid. 1 HNMR(400MHz, CDCl3): δ4.51(q, J=7.2Hz, 2H), 3.27-3.13(m, 2H), 3.09-2.94(m, 2H), 2.45-2.42(m, 1H), 2.03-1.91(m, 1H), 1.46(t, J=7.2Hz, 3H).

[0112] Synthesis of ethyl 4-(cyclobut-1-enyl)-1,2,5-oxadiazole-3-carboxylate 43 To a solution of compound 42 (250 mg, 0.91 mmol) in toluene (5 mL) was added DBU (415.05 mg, 2.73 mmol) in one portion. The resulting solution was stirred at 100 °C for 2 h. The reaction solution was cooled to rt, diluted with EtOAc (15 mL), washed with water (10 mL * 2) and brine (10 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give compound 43 (60 mg, 34.00%) as a colorless oil. 1 HNMR(400MHz, CDCl3): δ6.92(t, J=1.2Hz, 1H), 4.42(q, J=7.2Hz, 2H), 2.89-2.94(m, 2H), 2.59-2.66(m, 2H), 1.38(t, J=7.2Hz, 3H).

[0113] Synthesis of 4-(cyclobut-1-enyl)-1,2,5-oxadiazole-3-carboxylic acid (Int10) To a solution of compound 43 (60 mg, 0.309 mmol) in EtOH (2 mL), LiOH·HO (0.463 mL, 0.463 mmol) (1 M in HO) was added in one portion. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL), acidified to pH=5 with 1N aqueous hydrochloric acid, and extracted with EtOAc (15 mL*3). The combined organic layers were washed with water (10 mL*2) and brine (10 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound Int10 (35 mg, 68.18%) as a white solid. 1 HNMR(400MHz, CDCl3): δ7.03(s, 1H), 5.52-5.69(m, 1H), 2.98-3.03(m, 2H), 2.69-2.77(m, 2H).

[0114] 8. Synthesis of (S)-1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)-6-methylimidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int11) [ka]

[0115] Synthesis of N-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-6-methylpyridazin-3-yl)pivalamide 44 To a solution of compound In6 (300 mg, 0.71 mmol), compound 1A (355 mg, 1.41 mmol), and Pd(dppf)Cl2 (51.7 mg, 0.071 mmol) in dioxane (5 mL) and HO (1 mL) was added potassium carbonate (293 mg, 2.12 mmol). The reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was cooled to rt and quenched with HO at 25 °C, and the resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by flash column chromatography on silica gel eluted with (60% EA in PE) to give compound 44 (230 mg, 80.5%) as a brown solid. LCMS: m / z(ESI)=404.2[M+H] + .

[0116] Synthesis of (S)-1-((S)-1-(6-amino-3-methylpyridazin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 45 To a solution of compound 44 (200 mg, 0.50 mmol) in HCl (1.5 mL, 9.0 mmol) was added MeOH (0.5 mL). The reaction mixture was stirred at 110° C. for 30 minutes. The reaction mixture was concentrated to give the target compound 45 (150 mg, 94.7%) as a yellow solid. LCMS: m / z(ESI)=320.0[M+H] + .

[0117] Synthesis of benzyl ((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-6-methylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate 46 To a solution of compound 45 (200 mg, 0.626 mmol) and compound Int7 (303 mg, 0.752 mmol) in THF (3 mL) was added NaHCO3 (315 mg, 3.75 mmol). The reaction mixture was stirred at 75 °C for 12 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel eluting with (7% MeOH in DCM) to give the desired compound 46 (160 mg, 40.8%) as a yellow solid. LCMS: m / z(ESI)=625.2[M+H] + .

[0118] Synthesis of (S)-1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)-6-methylimidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int11) To a solution of compound 46 (160 mg, 0.256 mmol) and NH3HO (0.1 mL) in EtOH (1 mL) was added 10% Pd / C (25 mg, 0.023 mmol). The reaction mixture was then degassed, purged with H2 three times, and stirred under H2 (15 psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated to give the title product Int11 (139 mg, 99.5%) as a yellow solid. LCMS: m / z(ESI)=491.2[M+H] + .

[0119] 9. Synthesis of 3-(2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-3-((S)-2-oxo-4(trifluoromethyl)imidazolidin-1-yl)propanenitrile (Int12) [ka]

[0120] Synthesis of N-(6-chloro-5-{2-hydroxy-1-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazo1-yl]ethyl}-1,2-diazin-3-yl)-2,2-dimethylpropanamide 47 To a solution of compound Int6 (450 mg, 1.06 mmol), a stir bar, and DCM (5 mL) was added BBr3 (3.19 mL, 3.19 mmol) dropwise over 5 min. The resulting reaction mixture was stirred at 0 °C for 1 h. Next, additional BBr3 (1.06 mL, 1.06 mmol) was added dropwise over 5 min at 0 °C. The resulting reaction mixture was stirred at 0 °C for an additional 1 h. Next, BBr3 (1.06 mL, 1.06 mmol) was added dropwise again over 5 min at 0 °C. After stirring the resulting reaction mixture at 0 °C for an additional 1 h, the reaction solution was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution to pH = 7-8. The aqueous phase was extracted with EtOAc (10 mL * 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-60% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give the target compound 47 (100 mg, 22.22%) as a green solid. LCMS: m / z(ESI)=410.1[M+H] + .

[0121] Synthesis of 3-{3-chloro-6-[(2,2-dimethylpropanoyl)amino]-1,2-diazin-4-yl}-3-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazo1-yl]propane-1-sulfonic acid 48 To a solution of compound 47 (480 mg, 1.17 mmol) in THF (5 mL) was added DIEA (0.61 mL, 3.51 mmol) and MsCl (0.26 mL, 3.32 mmol), and the resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched at 0 °C by the addition of iced HO (40 mL), diluted with EtOAc (30 mL), and extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired compound 48 (570 mg, 99.74%) as a yellow oil, which was used in the next step without further purification. 1 HNMR(400MHz, DMSO-d6): δ10.81(s, 1H), 8.41(s, 1H), 7.86(s, 1H), 5.31-5.25(m, 1H), 4.85-4.75(m, 1H), 4.74-4.63(m, 1H), 4.59-4.40(m, 1H), 3.92-3.80(m, 1H), 3.32-3.28(m, 1H), 3.28(s, 3H), 1.26(s, 9H)

[0122] Synthesis of N-(6-chloro-5-{2-cyano-1-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazo1-yl]ethyl}-1,2-diazin-3-yl)-2,2-dimethylpropanamide 49 To a solution of compound 48 (570 mg, 1.17 mmol), a stir bar, and K2CO3 (484 mg, 3.51 mmol) in DMF (8 mL) was added TMSCN (0.44 mL, 3.51 mmol) in portions. The resulting reaction mixture was stirred at 30 °C for 18 h. The reaction was cooled to 25 °C, quenched by the addition of HO (50 mL) at 25 °C, diluted with EtOAc (50 mL), and extracted with EtOAc (50 mL * 2). The combined organic layers were washed with HO (20 mL * 3) and brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give the title compound 49 (319 mg, 65.2%) as a yellow oil. LCMS: m / z(ESI)=419.1[M+H] + .

[0123] Synthesis of 3-(6-amino-3-chloro-1,2-diazin-4-yl)-3-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazo1-1-yl]propanenitrile 50 To a solution of compound 49 (273 mg, 0.12 mmol) and a stir bar in MeOH (0.5 mL) was added hydrogen chloride (35.3 mg, 0.358 mmol) dropwise over 1 min. The reaction was stirred at 70 °C for 18 h. The reaction was concentrated in vacuo to remove MeOH. The residue was adjusted to pH = 8 with 7 M NH3 / MeOH. The mixture was purified by flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–2% MeOH / DCM gradient @ 30 mL / min) to afford the title compound 50 (169 mg, average yield 77%) as an off-white solid. LCMS: m / z(ESI)=335.1[M+H] + .

[0124] Synthesis of tert-butyl ((6-chloro-7-((S)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (51-P1) & tert-butyl ((6-chloro-7-((R)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (51-P2) Compound 50 (169 mg, 0.505 mmol), Int25 (223 mg, 0.606 mmol), dichloridobis(cycloocta-1,5-diene)bis[iridium] in DCE (9 mL) (0) A solution of 4-( ... 51-P1: (70mg, 22.87%), yellow oil. LCMS: m / z(ESI)=606.2[M+H] + . 51-P2: (80mg, 26.14%), yellow solid LCMS: m / z(ESI)=606.2[M+H] + .

[0125] Synthesis of tert-butyl ((7-((S)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (52-P1) and tert-butyl ((7-((R)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (52-P2) A solution of compound 51-P1 (70 mg, 0.12 mmol), a stir bar, Pd / C 10% (100 mg, 0.940 mmol), and MeOH (6 mL) was added to a 100 mL round bottle flask under an atmosphere of H2 (15 Psi). The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and washed with MeOH (10 mL). The combined filtrate was concentrated in vacuo to give the title compound 52-P1 (62.5 mg, 94.67% yield) as a yellow oil, which was used in the next step without further purification. LCMS: m / z(ESI)=572.2[M+H] + .

[0126] Compound 51-P2 (80 mg, 0.13 mmol), a stir bar, Pd / C 10% (100 mg, 0.94 mmol), and MeOH (7 mL) were added to a 100 mL round bottle flask under an atmosphere of H (15 Psi). The resulting mixture was stirred at 25 °C for 30 min. The reaction was filtered, washed with MeOH (10 mL), and the combined filtrate was concentrated in vacuo to give the title compound 52-P2 (67.9 mg, 89.99%) as a yellow oil, which was used in the next step without purification. LCMS: m / z(ESI)=572.2[M+H] + .

[0127] Synthesis of 3-{2-[amino(4,4-difluorocyclohexyl)methyl]imidazo[2,3-f][1,2]diazin-7-yl}-3-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazo1-1-yl]propanenitrile (Int12) To a solution of compound 52-P1 (62.5 mg, 0.109 mmol) in DCM (2 mL) was added TFA (0.4 mL, 5.22 mmol) dropwise over 1 min. The resulting mixture was stirred at 25 °C for 30 min, after which the reaction was concentrated in vacuo to give the title product Int12-S1 (51.55 mg, crude, 100%) as a yellow oil, which was used in the next step without purification. LCMS: m / z(ESI)=472.1[M+H] + .

[0128] To a solution of compound 52-P2 (67.9 mg, 0.12 mmol) and a stir bar in DCM (2 mL) was added TFA (0.4 mL, 5.22 mmol) dropwise over 1 minute. The resulting reaction mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated in vacuo to give the desired compound Int12-S2 (56.01 mg, crude, 100%) as a yellow oil, which was used in the next step without purification. LCMS: m / z(ESI)=472.2[M+H] + .

[0129] 10. Synthesis of (S)-1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl) imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int13) [ka]

[0130] Synthesis of N-(5-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide 55 To a solution of compound 53 (Cas: 2452465-37-9, 1.16 g, 4.06 mmol) and 54 (Cas: 2322869-99-6) (1.22 g, 6.09 mmol) in isopropyl alcohol (20 mL), TEA (1.69 mL, 12.10 mmol) was added, and the resulting reaction mixture was stirred at 75 °C for 2 h, then cooled to rt and stirred at room temperature for an additional 12 h. The reaction mixture was concentrated to give a yellow residue. The residue was dissolved in MeOH (20 mL), sodium cyanoborohydride (1.79 g, 28.40 mmol) was added, and the mixture was stirred at 8 °C for 30 min. HOAc (7.58 g, 40.60 mmol) was added, and the mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated to give a yellow residue. The residue was dissolved in DCM (100 mL) and neutralized with saturated NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM (50 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel eluting with 50% EtOAc in PE to give the title compound 55 (870 mg, 51.17%) as a white solid. LCMS: m / z(ESI)=397.8[M+H] + .

[0131] Synthesis of N-(6-chloro-5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl) imidazolidin-1-yl)ethyl)pyridazin-3-yl)pivalamide (Int6) To a solution of 55 (880 mg, 2.21 mmol) in THF (20 mL) was added CDI (1.79 g, 11.00 mmol) at 60 °C, and the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was then concentrated to give a yellow residue. The residue was dissolved in EtOAc (50 mL), washed with 1 N hydrochloric acid (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by flash column chromatography on silica gel eluted with 50% EtOAc in PE to give compound Int6' (first spot, 350 mg) and the desired compound Int6 (second spot, 350 mg, see WO2020146194A1). LCMS: m / z(ESI)=423.8 / 425.8[M+H] + .

[0132] Synthesis of (S)-1-((S)-1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 24 To a solution of compound Int6 (1.6 g, 3.78 mmol) in MeOH (5 mL) was added hydrochloric acid (15 mL, 6 mol / L), and the reaction mixture was stirred at 110 °C for 1 hour. The reaction mixture was concentrated to give a yellow residue. The residue was dissolved in DCM (10 mL) and 1N NaOH (10 mL), and the resulting reaction mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 24 (1.3 g, 99.34%) as a pale yellow solid. LCMS: m / z(ESI)=339.8 / 341.8[M+H] + .

[0133] Synthesis of benzyl ((S)-(6-chloro-7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate 56 To a solution of compound 24 (600 mg, 1.77 mmol) and compound Int7 (1.07 g, 2.65 mmol) in THF (30 mL) was added NaHCO (445 mg, 5.30 mmol), and the reaction mixture was then stirred at 70 °C for 12 h under N. The reaction mixture was cooled, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash column on silica gel eluting with EtOAc to give title compound 56 (750 mg, 64.51%) as a yellow solid. LCMS: m / z(ESI)=645.2 / 647.2[M+H] + .

[0134] Synthesis of compound (S)-1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int13) To a solution of compound 56 (750 mg, 1.16 mmol) in EtOH (30 mL) and NH3HO (3 mL) was added 10% Pd / C (61.87 mg, 0.58 mmol, 55% water), and the reaction mixture was stirred under H2 (15 PSI) at 30 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated to give the title product Int13 (580 mg, 99.46%) as a yellow solid. LCMS: m / z(ESI)=476.8[M+H] + .

[0135] 11. Synthesis of 4-carboxy-3-(methyl-d3)-1,2,5-oxadiazole-2-oxide (Int14) [ka]

[0136] Synthesis of ethyl 3-oxobutanoate-4,4,4-d358 To a solution of LiHMDS (67.4 mL, 67.4 mmol, 1 mol / L) in THF (15 mL) was added dropwise a solution of compound 57 (6 mL, 61.3 mmol) in THF (15 mL). After stirring at 78 °C for 1 h, a solution of acetyl-d3 chloride (2.18 mL, 30.6 mmol) in THF (5 mL) was added dropwise. The resulting reaction mixture was stirred at −78 °C for 2 h. Next, 6 N hydrochloric acid (8 mL) and HO (40 mL) were added to the reaction mixture. The resulting solution was extracted with EtO (50 mL × 3). The combined organic phase was washed with 3 N HCl (40 mL), saturated NaHCO (60 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound 58 (10 g, 97.9%) as a yellow oil. 1HNMR(400MHz, CDCl3): δ4.20(q, J=7.2Hz, 2H), 3.44(s, 2H), 1.28(t, J=7.2Hz, 3H).

[0137] Synthesis of ethyl (Z)-2-(hydroxyimino)-3-oxobutanoate-4,4,4-d359 To a solution of compound 58 (5.00 g, 37.5 mmol) in HOAc (45 mL) and HO (15 mL) was added sodium nitrite (3.89 g, 56.3 mmol). The reaction mixture was stirred at 25 °C for 18 h. The reaction was quenched with saturated NaHCO (100 mL) at 25 °C. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 59 (3.00 g, 49.2%) as a yellow oil. LCMS: m / z(ESI)=163.2[M+H] + .

[0138] Synthesis of ethyl (2E,3E)-2,3-bis(hydroxyimino)butanoate-4,4,4-d360 To a solution of compound 59 (6.0 g, 37.00 mmol) and hydroxylamine hydrochloride (7.71 g, 111.0 mmol) in EtOH (100 mL) was added sodium acetate (6.07 g, 74.10 mmol). The reaction mixture was stirred at 25 °C for 3 h. The reaction was concentrated to give a residue which was purified by flash column chromatography on silica gel eluting with (35% EA in PE) to give the title compound 60 (4.7 g, 71.7%) as a white solid. LCMS: m / z(ESI)=178.2[M+H] + .

[0139] Synthesis of 4-(ethoxycarbonyl)-3-(methyl-d3)-1,2,5-oxadiazole 2-oxide 61 To a solution of compound 60 (2.70 g, 15.20 mmol) in DCM (30 mL) was added (diacetoxyiodo)benzene (5.93 g, 18.20 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with saturated NaHCO (100 mL) at 25 °C. The resulting solution was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by flash column chromatography on silica gel eluting with (15% EA in PE) to give the desired compound 61 (1.5 g, 56.1%) as a yellow oil. LCMS: m / z(ESI)=176.2[M+H] + .

[0140] Synthesis of 4-carboxy-3-(methyl-d3)-1,2,5-oxadiazole 2-oxide (Int14) To a solution of compound 61 (100 mg, 0.57 mmol) in THF (0.5 mL) and HO (0.5 mL) was added LiOH (95.8 mg, 2.28 mmol). The reaction mixture was stirred at 25 °C for 1 h. Then, the reaction mixture was acidified with 1N HCl to pH = 4. The resulting solution was extracted with EA (100 mL × 3). The combined organic phases were washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product Int14 (1.3 g, 59.1%) as a yellow oil. LCMS: m / z(ESI)=148.2[M+H] + .

[0141] 12. Synthesis of (4S)-1-((1S)-1-(2-(amino(3,3-difluorocyclobutyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int15) [ka]

[0142] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-(benzyloxy)cyclobutylidene)acetate 64 To a mixture of compound 62 (9.0 g, 51.1 mmol) and 63 (33.8 g, 102 mmol) in DCM (100 mL), TMG (12.9 g, 112 mmol) was added, and the resulting reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (60 mL), and the resulting solution was extracted with EtOAc (60 mL × 3). The combined organic phase was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (10% EtOAc in PE) to give compound 64 (19.0 g, 92.7%) as a white solid. LCMS: m / z(ESI)=382.2[M+H] + .

[0143] Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-2-(3-hydroxycyclobutyl)acetate 65 To a mixture of compound 64 (19.0 g, 49.8 mmol) in MeOH (100 mL) was added 10% Pd / C (5.58 g, 52.4 mmol) and BocO (34.4 g, 157 mmol). The resulting reaction mixture was degassed and purged with H three times, then stirred under H (14.696 PSI) at 25 °C for 48 h. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound 65 (10.0 g, 77.4%) as a yellow solid. LCMS: m / z(ESI)=282.2[M+Na] + .

[0144] Synthesis of methyl 2-amino-2-(3-hydroxycyclobutyl)acetate 66 A solution of compound 65 (10 g, 38.6 mmol) in hydrochloric acid-dioxane (50 mL) was stirred for 2 hours at 25° C. The reaction mixture was then concentrated to give the desired compound 66 (7.00 g, 96.9%) as a yellow solid. LCMS: m / z(ESI)=160.2[M+H] +.

[0145] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-hydroxycyclobutyl) acetate 67 To a solution of compound 66 (7.00 g, 44.0 mmol) in HO (50 mL) and DCM (50 mL) was added NaHCO (25.9 g, 308 mmol) and CbzCl (11.3 g, 66.0 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then extracted with EtOAc (30 mL × 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (20% EtOAc in PE) to give the title compound 67 (9.00 g, 69.8%) as a yellow oil. LCMS: m / z(ESI)=314.0[M+Na] + .

[0146] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-oxocyclobutyl)acetate 68 To a solution of compound 67 (9.0 g, 30.7 mmol) in DCM (10 mL) was added NMO (5.39 g, 46.0 mmol) and TPAP (0.32 g, 0.92 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (20% EtOAc in PE) to give the title compound 68 (7.0 g, 78.3%) as a yellow oil. LCMS: m / z(ESI)=314.2[M+Na] + .

[0147] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3,3-difluorocyclobutyl) acetate 69 To a solution of compound 68 (3.0 g, 10.3 mmol) in DCM (20 mL) was added DAST (8.3 g, 51.5 mmol). The resulting reaction mixture was stirred at 25 °C for 12 h. Water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (20% EtOAc in PE) to give the desired compound 69 (1.4 g, 43.4%) as a yellow oil. LCMS: m / z(ESI)=336.2[M+Na] + .

[0148] Synthesis of 2-(((benzyloxy)carbonyl)amino)-2-(3,3-difluorocyclobutyl)acetic acid 70 To a solution of compound 69 (1.40 g, 4.47 mmol) in HO (10 mL) and THF (10 mL) was added LiOH (0.56 g, 13.4 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was acidified to pH = 4 with 1 N hydrochloric acid. The resulting solution was separated, and the aqueous layer was extracted with DCM (10 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 70 (1.30 g, 97.2%) as a yellow solid. LCMS: m / z(ESI)=322.2[M+Na] + .

[0149] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(3,3-difluorocyclobutyl)-3-oxobutanoate 71 To a solution of compound 70 (1.00 g, 2.46 mmol) in THF (30 mL) was added CDI (0.54 g, 3.34 mmol), and the resulting reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h and then cooled to -78 °C. To a solution of diisopropylamine (2.12 mL, 15.0 mmol) in THF (30 mL) was added n-BuLi (6.00 mL, 15.0 mmol) under a nitrogen atmosphere at 0 °C. After 10 min, tert-butyl acetate (2.02 mL, 15.0 mmol) was added to the mixture at -78 °C. After an additional 1 h, the enolate mixture was added to the above solution via cannula. The reaction mixture was then stirred at -78 °C for 1 h. The reaction mixture was quenched with 30 mL of saturated aqueous ammonium chloride solution at -78 °C. The resulting mixture was removed from the cold bath, diluted with 60 mL of water, and the solvent volume was reduced by 60 mL under reduced pressure. The mixture was extracted with EA (100 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluted with 10% EA in PE to give the title compound 71 (1.10 g, 82.8%) as a yellow oil. LCMS: m / z(ESI)=420.2[M+Na] + .

[0150] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-bromo-4-(3,3-difluorocyclobutyl)-3-oxobutanoate 72 To a mixture of compound 71 (1.10 g, 2.78 mmol) in MeOH (50 mL) was added NBS (500 mg, 2.78 mmol) and 2,6-lutidine (0.0320 mL, 0.278 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. After that, the reaction mixture was diluted with EA (60 mL) and washed with a 50% solution of saturated sodium chloride in water (40 mL × 2) and saturated aqueous sodium chloride solution (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give compound 72 (1.10 g, 83.4%) as a yellow oil. LCMS: m / z(ESI)=498.0, 500.0[M+Na]+ .

[0151] Synthesis of benzyl (3-bromo-1-(3,3-difluorocyclobutyl)-2-oxopropyl)carbamate 73 A solution of compound 72 (1.00 g, 2.11 mmol) in TFA (5 mL) and toluene (50 mL) was stirred at 80° C. for 2 h. The reaction mixture was concentrated and purified by flash column chromatography on silica gel eluted with (20% EtOAc in PE) to give compound 73 (800 mg, 90.8%) as a yellow oil. LCMS: m / z(ESI)=398.0, 400.0[M+Na] + .

[0152] Synthesis of benzyl ((6-chloro-7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-113-ethyl)imidazo[1,2-b]pyridazin-2-yl)(3,3-difluorocyclobutyl)-methyl)carbamate 74 To a solution of compound 73 (500 mg, 1.33 mmol) in THF (20 mL) was added NaHCO (519 mg, 6.18 mmol) and compound 24 (300 mg, 0.883 mmol). The resulting reaction mixture was stirred at 75 °C for 12 hours. Water (20 mL) was added to the reaction mixture, and the resulting mixture was concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluted with (20% EtOAc in PE) to give compound 74 (320 mg, 58.7%) as a yellow solid. LCMS: m / z(ESI)=617.0[M+H] + .

[0153] Synthesis of (4S)-1-(1-(2-(amino(3,3-difluorocyclobutyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int15) To a solution of compound 74 (150 mg, 0.243 mmol) in EtOH (5 mL) and NH3HO (0.5 mL) was added 10% Pd / C (25.9 mg, 0.243 mmol). The reaction mixture was degassed and purged with H2 three times, then stirred under H2 (14.696 PSI) at 25 °C for 2 h. The reaction mixture was then filtered, and the filtrate was concentrated to give the desired compound Int15 (100 mg, 91.7%) as a yellow solid. LCMS: m / z(ESI)=449.2[M+H] + .

[0154] 13. Synthesis of 4-vinyl-1,2,5-oxadiazole-3-carboxylic acid (Int16) [ka]

[0155] Synthesis of (3E,4E)-3,4-bis(hydroxyimino)dihydrofuran-2(3H)-one 76 To a solution of compound 75 (10 g, 99.93 mmol) in 3 M hydrochloric acid (60 mL), sodium nitrite (8.96 g, 129.91 mmol) was added portionwise at 0 °C, and the resulting reaction solution was stirred at rt for 10 min. Next, the solution was added dropwise to a vigorously stirred solution of hydroxylamine hydrochloride (13.89 g, 199.86 mmol) in water (100 mL), and the resulting reaction mixture was stirred at rt for an additional 2 h. The purple color of the solution gradually faded at room temperature. The solid was collected to give the desired compound 76 (10.67 g, 74.1%) as a white solid. LCMS: m / z(ESI)=145.0[M+H] + .

[0156] Synthesis of 4H,6H-furo[3,4-c][1,2,5]oxadiazol-4-one 77 To a solution of compound 76 (10.67 g, 74.05 mmol) in dioxane (150 mL) was added thionyl dichloride (7.89 mL, 111.08 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo to give the crude product, which was recrystallized from ethanol to give pure product 77 (6.07 g, 65.02%) as a pale yellow solid. LCMS: m / z(ESI)=127.0[M+H] + .

[0157] Synthesis of 4-(hydroxymethyl)-N-phenyl-1,2,5-oxadiazole-3-carboxamide 78 To a solution of compound 77 (2 g, 15.86 mmol) in DMF (10 mL) and EtOH (80 mL) was added aniline (1.59 mL, 17.45 mmol). After stirring the reaction mixture at 25 °C for 30 min, the reaction solution was heated to 50 °C and stirred overnight. The reaction was concentrated and redissolved in EA (50 mL). Water (90 mL) was then added, and the biphasic solution was extracted with EA (3 × 40 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by flash column chromatography on silica gel eluting with (20% EA in PE) to give the title compound 78 (592 mg, 17.02%) as a yellow solid. LCMS: m / z(ESI)=220.0[M+H] + .

[0158] Synthesis of 4-formyl-N-phenyl-1,2,5-oxadiazole-3-carboxamide 79 To a solution of compound 78 (2.0 g, 9.12 mmol) in DCM (150 mL) was added Dess-Martin periodinane (7.74 g, 18.25 mmol). The reaction mixture was stirred at 25° C. for 1 h, then filtered, and the filtrate was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue which was purified by flash column chromatography on silica gel eluting with (15% EA in PE) to give the title compound 79 (2.1 g, 79.48%) as a yellow oil. LCMS: m / z(ESI)=218.0[M+H] + .

[0159] Synthesis of N-phenyl-4-vinyl-1,2,5-oxadiazole-3-carboxamide 80 To a solution of triphenylmethylphosphonium bromide (8.39 g, 23.50 mmol) in toluene (15 mL), t- BuOK (2.71 g, 24.17 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Compound 79 (2.1 g, 7.25 mmol) was added and the reaction mixture was cooled to 80° C. o C for 3 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by flash column on silica gel eluting with (15% EA in PE) to give compound 80 (703.57 mg, 33.81%) as a pale yellow oil. LCMS: m / z(ESI)=216.0[M+H] + .

[0160] Synthesis of tert-butylphenyl(4-vinyl-1,2,5-oxadiazole-3-carbonyl)carbamate 81 To a solution of compound 80 (201 mg, 0.934 mmol) in DCM (10 mL) was added DMAP (114.1 mg, 0.934 mmol) and di-tert-butyl dicarbonate (0.196 mL, 0.852 mmol), and the reaction mixture was stirred for 1 h at 22° C. The reaction mixture was concentrated under reduced pressure to give the desired compound 81 (290 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS: m / z(ESI)=263.0[M+H] + .

[0161] Synthesis of 4-vinyl-1,2,5-oxadiazole-3-carboxylic acid (Int16) To a solution of compound 81 (290 mg, crude) in THF (4 mL) / MeOH (1 mL) was added 2 M LiOH (1.29 mL, 2.58 mmol). The reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was diluted with 2 M hydrochloric acid (1.3 mL) and concentrated in vacuo to give the crude product. The crude product was purified using C18 column chromatography eluting with (55% MeCN in water) to give the desired compound Int16 (85 mg, 65.97%) as a pale yellow solid. LCMS: m / z(ESI)=139.0[M-1] - .

[0162] 14. Synthesis of 4-vinyl-1,2,5-oxadiazole-3-carboxylic acid (Int17) [ka]

[0163] Synthesis of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide 78 To a solution of compound 77 (2.3 g, 18.24 mmol) in DMF (5 mL) and EtOH (40 mL) was added 3-chloro-4-fluoroaniline (2.92 g, 20.07 mmol). The reaction mixture was stirred at 50 °C for 18 hours. Water (50 mL) was added to the reaction mixture, and the resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by flash column chromatography on silica gel eluted with 20% EtOAc in PE to give compound 78 (3.7 g, 74.60%) as a pale yellow solid. LC-MS(ESI): m / z=272.0[M+H] + .

[0164] Synthesis of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide 79 To a solution of compound 78 (1.5 g, 6.84 mmol) in DCM (60 mL) was added Dess-Martin periodinane (6.09 g, 14.36 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate, extracted three times with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by flash column chromatography to give the desired compound 79 (1.8 g, 60.45%) as a brown, sticky oil. LC-MS(ESI): m / z=270.0[M+H] + .

[0165] Synthesis of (Z)-N-(3-chloro-4-fluorophenyl)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxamide 80 & (E)-N-(3-chloro-4-fluorophenyl)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxamide 81 To a solution of (fluoromethyl)triphenylphosphonium tetrafluoroborate (3.91 g, 10.24 mmol) in toluene (40 mL) was added potassium tert-butoxide (1.25 g, 11.13 mmol) at rt under a nitrogen atmosphere. After stirring for 30 min, a solution of compound 79 (1.2 g, 4.451 mmol) in THF (8 mL) was cannulated into the reaction flask. The resulting solution was heated to 80 °C for 3 h and then cooled to rt. The reaction solution was diluted with EA and saturated NaCl solution. The organic layer was separated, further washed with saturated NaCl solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether to give the title compounds 80 ((Z), 80 mg, 6.29%) and 81 ((E), 100 mg, 7.87%). 80: LC-MS(ESI): m / z=286.0[M+H] + . 1HNMR(400MHz, DMSO-d6): δ11.34(s, 1H), 8.04(dd, J=6.8, 2.8Hz, 1H), 7.74-7.68(m, 1H), 7.62-7.25(m, 2H), 6.44(dd, J=43.6, 5.2Hz, 1H). 81: LC-MS(ESI): m / z=286.0[M+H] + . 1 HNMR(400MHz, DMSO): δ11.35(s, 1H), 8.18-7.82(m, 2H), 7.75-7.68(m, 1H), 7.47(t, J=9.2Hz, 1H), 6.77(dd, J=17.6, 11.6Hz, 1H).

[0166] Synthesis of tert-butyl (Z)-(3-chloro-4-fluorophenyl)(4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carbonyl)carbamate 82 To a solution of compound 80 (80 mg, 0.80 mmol) in DCM (5 mL), di-tert-butyl dicarbonate (122.26 mg, 0.560 mmol) and DMAP (5.13 mg, 0.042 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated in vacuo to give title compound 82 (100 mg, 92.56%) as a pale yellow oil. LC-MS(ESI): m / z=386.0[M+H] + .

[0167] Synthesis of (Z)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxylic acid (Int17) To a solution of compound 82 (100 mg, 0.26 mmol) in THF (1 mL) was added LiOH (21.76 mg, 0.52 mmol in HO (1 mL)), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified using C18 column chromatography (eluted with 0.5% TFA in water / acetonitrile = 0-100%) to give the title compound Int17 (30 mg, 73.21%) as a white solid. LC-MS(ESI): m / z=157.0[MH] - .

[0168] 15. Synthesis of (E)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxylic acid (Int18) [ka]

[0169] Synthesis of tert-butyl (E)-(3-chloro-4-fluorophenyl)(4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carbonyl)carbamate 83 To a solution of compound 81 (80 mg, 0.28 mmol) in DCM (5 mL), di-tert-butyl dicarbonate (152.82 mg, 0.70 mmol) and DMAP (6.42 mg, 0.053 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated aqueous NaCl, and dried over anhydrous NaSO to give the title compound 83 as a pale yellow oil. LC-MS(ESI): m / z=386.0[M+H] + .

[0170] Synthesis of (E)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxylic acid (Int18) To a solution of compound 83 (100 mg, 0.26 mmol) in THF (1 mL), LiOH (21.76 mg, 0.52 mmol) and HO (1 mL) were added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified using C18 column chromatography (eluted with 0.5% TFA in water:acetonitrile = 0-100%) to give the title compound Int18 (30.0 mg, 73.20%) as a white solid. LC-MS(ESI): m / z=157.0[MH] - .

[0171] 16. Synthesis of 4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int19) [ka]

[0172] Synthesis of 5,5-dimethylfuran-2,4(3H,5H)-dione 86 To a solution of methyl acetate 84 (10.71 mL, 134.99 mmol) and compound 85 (18.71 mL, 161.99 mmol) in THF (150 mL), t- BuOK (33.26 g, 296.98 mmol) was added, and the reaction mixture was then stirred at 66 °C overnight. The solvent was removed under reduced pressure, the residue was taken up in 1 M aqueous NaOH (20 mL) and EtO (20 mL), the phases were separated, and the aqueous phase was extracted with EtO (20 mL). Concentrated hydrochloric acid was added to the aqueous solution at 0 °C until pH = 1. The acidified aqueous solution was diluted with CHCl / i- The residue was extracted with PrOH (5:1) mixed solvent (20 mL × 4), dried over NaSO, and the solvent was evaporated under reduced pressure. The residue was recrystallized from EtO to give the title compound 86 (9.6 g, 55.49%) as a pale white solid. LCMS: m / z(ESI)=129.0[M+H] + .

[0173] Synthesis of (3Z,4E)-3,4-bis(hydroxyimino)-5,5-dimethyldihydrofuran-2(3H)-one 87 NaNO (5.09 g, 74.92 mmol) was added portionwise to a stirred solution of compound 86 (9.6 g, 74.92 mmol) in 3 M HCl (160 mL). This yellow solution was stirred at room temperature for 15 minutes and then added dropwise to a vigorously stirred solution of hydroxylamine hydrochloride (10.41 g, 149.85 mmol) in HO (60 mL). The reaction mixture was stirred overnight at 25 °C. The reaction mixture was then filtered, and the solid was collected as a yellow solid, the desired compound 87. LCMS: m / z(ESI)=173[M+H] + .

[0174] Synthesis of 6,6-dimethyl-4H,6H-furo[3,4-c][1,2,5]oxadiazol-4-one 88 To a solution of compound 87 (5.0 g, 29.05 mmol) in dioxane (50 mL) was added SOCl (5.90 mL, 81.33 mmol). The reaction mixture was then stirred at 25 °C overnight. The solvent was removed under reduced pressure, and the residue was recrystallized with EtOH (1 mL) to give the desired compound 88 (3.0 g, 67.01%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6): δ:1.87(s, 6H).

[0175] Synthesis of 4-(2-hydroxypropan-2-yl)-N-phenyl-1,2,5-oxadiazole-3-carboxamide 89 To a solution of compound 88 (3.0 g, 19.46 mmol) in EtOH (60 mL) and DMF (7.5 mL) was added aniline (1.95 mL, 21.41 mmol) in EtOH (1 mL) dropwise. The reaction mixture was then stirred at 25 °C for 30 min and heated to 50 °C overnight. The solvent was removed under reduced pressure, and the residue was extracted with EtOAc (20 mL) and washed with HO (50 mL × 1) and brine (50 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (0% to 20% EA in PE) to give the desired compound 89 (1.02 g, 21.19%) as a colorless oil. LCMS: m / z(ESI)=248.0[M+H] + .

[0176] Synthesis of 2-(4-(phenylcarbamoyl)-1,2,5-oxadiazol-3-yl)propan-2-yl methanesulfonic acid 90 To a solution of compound 89 (300 mg, 1.21 mmol) in DCM (5 mL) was added methanesulfonic anhydride (232.49 mg, 1.34 mmol) and TEA (0.25 mL, 1.82 mmol), and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether to give the title compound 90 (300 mg, 76.00%) as a white solid. LC-MS(ESI): m / z=326.0[M+H] + .

[0177] Synthesis of N-phenyl-4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxamide 91 To a solution of compound 90 (300 mg, 0.92 mmol) in toluene (8 mL) was added TEA (2.56 mL, 18.44 mmol), and the reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to rt and diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether to give the title compound 91 (150 mg, 70.96%) as a white solid. LC-MS(ESI): m / z=230.0[M+H] + .

[0178] Synthesis of tert-butylphenyl (4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carbonyl)carbamate 92 To a solution of compound 91 in DCM (5 mL) was added di-tert-butyl dicarbonate (190.41 mg, 0.87 mmol) and DMAP (7.99 mg, 0.065 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated in vacuo to give title compound 92 (130 mg, 90.49%) as a pale yellow oil. LC-MS(ESI): m / z=330.0[M+H] + .

[0179] Synthesis of 4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int19) To a solution of compound 92 (100 mg, 0.26 mmol) in THF (1 mL) was added LiOH (33.12 mg, 0.79 mmol) and HO (1 mL), and the reaction mixture was stirred at room temperature for 1 h. 18 Direct purification by column chromatography (eluting with 0.5% TFA in water:acetonitrile=0-100%) afforded the title product Int19 (30 mg, 73.21%) as a white solid. LC-MS(ESI): m / z=153.0[MH] - .

[0180] 17. Synthesis of intermediate 4-(1-methylcyclopropoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int20) [ka]

[0181] Synthesis of N-methyl-4-(1-methylcyclopropoxy)-1,2,5-oxadiazole-3-carboxamide 94 To a solution of compound 1-methylcyclopropan-1-ol (446 mg, 6.19 mmol) in THF (5 mL) was added NaH (495 mg, 12.38 mmol) at 0 °C under N. The reaction mixture was stirred at 0 °C for 0.5 h before compound 93 (500 mg, 3.10 mmol) was added. The reaction mixture was stirred at 55 °C for an additional 16 h. The reaction mixture was poured into saturated aqueous NH Cl and extracted with EtOAc (50 mL*3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over Na SO , filtered, and concentrated under reduced pressure to give the desired compound 94 (80 mg, 13.11%) as a white solid. LC / MS: m / z(ESI)=198.0[M+H] + .

[0182] Synthesis of tert-butyl methyl (4-(1-methylcyclopropoxy)-1,2,5-oxadiazole-3-carbonyl)carbamate 95 To a solution of compound 94 (80 mg, 0.41 mmol) in DCM (3 mL) was added (2-methylprop-2-yl)oxidanecarboxylic anhydride (177 mg, 0.81 mmol) and DMAP (14 mg, 0.12 mmol) at 25 °C under N2. After stirring the reaction mixture at 25 °C for 0.5 h, the reaction mixture was poured into saturated aqueous NH4Cl and extracted with DCM (30 mL*3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (0-10% EtOAc in PE) to give the title compound 95 (80 mg, 53.06%) as a white solid. LC / MS: m / z(ESI)=298.0[M+H] + .

[0183] Synthesis of 4-(1-methylcyclopropoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int20) To a solution of compound 95 (80 mg, 0.27 mmol) in THF (2 mL) and water (2 mL) was added LiOH (33 mg, 0.81 mmol). The reaction mixture was stirred at 25 °C for 3 h. Then, the reaction mixture was poured into aqueous hydrochloric acid (2 N) and extracted with EtOAc (20 mL * 3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (0-90% EtOAc in PE) to give the title product Int20 (20 mg, 40.36%) as a white solid. LC / MS: m / z(ESI)=365.0[2M-H] - .

[0184] 18. Synthesis of 4-(1-methylcyclobutoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int21) [ka]

[0185] Synthesis of compound N-methyl-4-(1-methylcyclobutoxy)-1,2,5-oxadiazole-3-carboxamide 96 To a mixture of 1-methylcyclobutan-1-ol (53 mg, 0.619 mmol) in THF (5 mL) was added NaH (148 mg, 3.714 mmol) at 0 °C under N. The reaction mixture was stirred at 0 °C for 0.5 h before compound 93 (100 mg, 0.619 mmol) was added. The reaction mixture was stirred at 55 °C for an additional 16 h. The reaction mixture was poured into saturated aqueous NH Cl and extracted with EtOAc. The combined organic phase was washed with saturated aqueous sodium chloride, dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound 96 (100 mg, 76.48%) as a white solid. LCMS: m / z(ESI)=212.0[M+H] + .

[0186] Synthesis of compound tert-butylmethyl(4-(1-methylcyclobutoxy)-1,2,5-oxadiazole-3-carbonyl)carbamate 97 To a solution of compound 96 (100 mg, 0.473 mmol) in DCM (3 mL) was added (2-methylprop-2-yl)oxidanecarboxylic anhydride (206 mg, 0.947 mmol) and DMAP (17 mg, 0.142 mmol) at 25 °C under N2. After stirring the reaction mixture at 25 °C for 0.5 h, the reaction mixture was poured into saturated aqueous NH4Cl and extracted with DCM (20 mL * 3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (0-10% EtOAc in PE) to give the title compound 97 (100 mg, 69.13%) as a white solid. LCMS: m / z(ESI)=312.0[M+H] + .

[0187] Synthesis of 4-(1-methylcyclobutoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int21) To a solution of compound 97 (100 mg, 0.054 mmol) in THF (2 mL) and water (2 mL) was added LiOH (40 mg). The reaction mixture was stirred at 25 °C for 3 h. Then, the reaction mixture was poured into aqueous HCl (2N) and extracted with EtOAc (20 mL * 3). The combined organic phase was washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by pre-HPLC to give the title product Int21 (30 mg, 20.18%) as a white solid. LCMS: m / z(ESI)=395.0[2M-H] - .

[0188] 19. Synthesis of 4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int22) [ka]

[0189] Synthesis of compound ethyl 3-oxo-3-(spiro[2.2]pentan-1-yl)propanoate 99 To a solution of potassium 3-ethoxy-3-oxopropanoate (3.40 g, 20.00 mmol) in EA (30 mL) was added EtN (6.95 mL, 50.00 mmol) and magnesium chloride (2.86 g, 30.00 mmol) at 0 °C for 30 minutes, and the reaction mixture was stirred at room temperature for 18 hours. To a separate solution of compound 98 (1.12 g, 10 mmol) in THF (10 mL), SoCl (0.7 mL, 10.00 mmol) and a catalytic amount of DMF (0.12 mL) were added with ice cooling. The resulting mixture was stirred for 30 minutes and then at room temperature for 1 hour. The above malonic acid solution was added to this acid chloride solution with cooling, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EA and hydrochloric acid solution. The organic layer was separated, washed with saturated aqueous NaCl, and concentrated in vacuo. Elute the residue with 55% CHCN (0.5% TFA) in HO. 18 Purification by flash column chromatography gave the title compound 99 (1.03 g, 54.38%) as a yellow oil. LCMS = m / z (ESI) = 183.0 [M+H] + .

[0190] Synthesis of ethyl (E)-2-(hydroxyimino)-3-oxo-3-(spiro[2.2]pentan-1-yl)propanoate 100 Compound 99 (1.03 g, 5.65 mmol) was dissolved in HOAc (5 mL), and the resulting solution was cooled to 8 °C. A solution of NaNO (0.43 g, 6.22 mmol) in HO (5 mL) was added dropwise, maintaining the temperature below 15 °C. The reaction mixture was cooled to 5 °C, then warmed to ambient temperature and stirred for 18 h. The reaction mixture was poured into a vigorously stirred mixture of EtOAc and saturated aqueous sodium bicarbonate. After gas evolution ceased, the reaction mixture was separated, and the organic layer was washed with saturated sodium bicarbonate, followed by saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give title compound 100 (1.14 g, 89.13%) as a pale yellow liquid. LCMS: m / z(ESI)=212.0[M+H] + .

[0191] Synthesis of ethyl (2E,3Z)-2,3-bis(hydroxyimino)-3-(spiro[2.2]pentan-1-yl)propanoate 101 To a solution of compound 100 (211.22 mg, 1.00 mmol) in EtOH (5 mL), hydroxylamine hydrochloride (99.09 mg, 3.00 mmol) and NaOAc (164.06 mg, 2.00 mmol) were added, and the reaction mixture was stirred at 80 °C for 18 h. Water (15 mL) was added to the reaction mixture, and the resulting solution was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. This crude product was purified by flash column chromatography on silica gel eluting with (5% MeOH in DCM) to give title compound 101 (128 mg, 32.25%) as a white solid. LCMS: m / z(ESI)=227.0[M+H] + .

[0192] Synthesis of ethyl 4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxylate 102 To a solution of compound 101 (98 mg, 0.433 mmol) in THF (4 mL) was added chloranesulfinyl chloride (51 mg, 0.433 mmol), and the reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was concentrated and purified by elution with (60% MeCN in HO (0.05% TFA)). 18 Direct purification by flash column as above gave the title compound 102 (11 mg, 8.78%) as a white solid. LCMS: m / z(ESI)=209.0[M+H] + .

[0193] Synthesis of 4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int22) To a solution of compound 102 (11 mg, 0.053 mmol) in THF (0.5 mL) and HO (0.5 mL), LiOH (6 mg, 0.158 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then eluted with (40% MeCN in HO (0.05% TFA)). 18 Direct purification by flash column as above gave the desired product Int22 (4.6 mg, 47.85%) as a white solid. LCMS: m / z(ESI)=181.0[M+H] + .

[0194] 20. Synthesis of 4-carboxy-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole 2-oxide (Int23) [ka]

[0195] Synthesis of compound 4-(ethoxycarbonyl)-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole 2-oxide 103 To a solution of compound 10 (870 mg, 3.40 mmol) in DCM (30 mL) was added (diacetoxyiodo)benzene (1.32 g, 4.08 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 12 h. DCM (30 mL) and water (30 mL) were added to the reaction mixture, and the resulting solution was extracted with DCM (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 8% EtOAc in PE to give title compound 103 (290 mg, 33.6%) as a yellow solid. LCMS: m / z(ESI)=255.2[M+H] + .

[0196] Synthesis of 4-carboxy-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole 2-oxide (Int23) To a solution of compound 103 (290 mg, 1.14 mmol) in THF (5 mL) and HO (5 mL) was added LiOH (144 mg, 3.42 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 2 h. Then, the reaction mixture was acidified with 1N HCl to pH = 4 and extracted with DCM (40 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product Int23 (250 mg, 96.91%) as a white solid. LCMS: m / z(ESI)=227.0[M+H] + .

[0197] 21. Synthesis of (4S)-1-((1S)-1-(2-(amino(1,4-dioxaspiro[4.5]decan-8-yl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int24) [ka]

[0198] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate 105 To a solution of methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (33.13 g, 100.00 mmol) in NMP (50 mL) was added DBU (13.45 mL, 90.00 mmol) at 0° C. After the reaction mixture was stirred at 25° C. for 0.5 h, compound 104 (15.62 g, 100.00 mmol) was added at 0° C., and the resulting reaction solution was stirred at 25° C. for 12 h. The reaction was quenched with water (50 mL), and the resulting solution was extracted with EA (30 mL). The organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel eluting with 35% EA in PE to give title compound 105 (17.1 g, 47.32%) as a white solid. LCMS: m / z(ESI)=362.0[M+H] + .

[0199] Methyl 2-amino-2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate 106 To a solution of compound 105 (16.0 g, 44.2 mmol) in THF (200 mL) was added 10% Pd / C (2.00 g, 18.7 mmol) at 25 °C. The reaction mixture was degassed and purged with H three times, then stirred under H (14.696 PSI) at 25 °C for 18 h. The reaction mixture was filtered, and the filtrate was concentrated to give title compound 106 (10.0 g, 98.52%) as a yellow solid. LCMS: m / z(ESI)=230.2[M+H] + .

[0200] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate 107 To a solution of compound 106 (10.0 g, 43.6 mmol) in DCM (60 mL) and HO (60 mL) was added NaHCO (14.6 g, 174 mmol) and benzyl chloromethanoate (9.20 mL, 65.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Water (50 mL) was added to the reaction mixture. The resulting solution was extracted with DCM (100 mL × 3). The combined organic phase was washed with water (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by flash column chromatography on silica gel eluted with 20% EtOAc in PE to give the target compound 107 (9.00 g, 56.78%) as a colorless oil. LCMS: m / z(ESI)=386.2[M+Na] + .

[0201] Synthesis of benzyl (3-(dimethyl(oxo)-16-sulfanylidene)-2-oxo-1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)carbamate 108 A mixture of SOMe3Cl (4.95 g, 38.5 mmol) and tBuOK (3.46 g, 30.8 mmol) in THF (70 mL) was stirred at 25 °C under N2 for 2 h. Then, a solution of compound 107 (7.00 g, 19.2 mmol) in THF (70 mL) was added dropwise. The resulting reaction solution was stirred at 25 °C for 22 h. The reaction mixture was then poured into water (50 mL). The resulting solution was extracted with DCM (50 mL × 3). The combined organic phase was washed with water (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 30% EtOAc in PE to give title compound 108 (3.00 g, 36.76%) as a colorless oil. LCMS: m / z(ESI)=424.2[M+H] + .

[0202] Synthesis of benzyl ((6-chloro-7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(1,4-dioxaspiro[4.5]decan-8-yl)methyl)carbamate 109 To a solution of compound 24 (1.20 g, 3.53 mmol), compound 108 (1.80 g, 4.23 mmol), and [Ir(COD)Cl] (118 mg, 0.18 mmol) in DCE (30 mL), sodium trifluoromethanesulfonate (60.7 mg, 0.35 mmol) and o-phenanthroline (63.6 mg, 0.35 mmol) were added at 25 °C. The resulting reaction solution was stirred at 80 °C for 16 h under N. The reaction solution was then poured into water (20 mL). The resulting solution was extracted with DCM (30 mL × 3). The combined organic phase was washed with water (30 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash column on silica gel eluting with 25% EtOAc in PE to give compound 109 (1.20 g, 50.92%) as a yellow solid. LCMS: m / z(ESI)=667.2[M+H] + .

[0203] Synthesis of the compound (4S)-1-((1S)-1-(2-(amino(1,4-dioxaspiro[4.5]decan-8-yl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int24) To a solution of compound 109 (880 mg, 1.31 mmol) in EtOH (10 mL) was added 10% Pd / C (280 mg, 2.63 mmol) and NH.HO (1 mL) at 25° C. The resulting reaction mixture was degassed and purged with H three times, then stirred under H (14.696 PSI) at 25° C. for 24 h. The reaction mixture was filtered, and the filtrate was concentrated to give the title product Int24 (550 mg, 83.63%) as a yellow oil. LCMS: m / z(ESI)=499.2[M+H] + .

[0204] 22. Synthesis of Intermediate 25: tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int25) [ka]

[0205] A solution of compound 110 (cas:394735-65-0) (5 g, 17.05 mmol, 1 eq) and CDI (3.32 g, 20.46 mmol, 1.2 eq) in THF (50 mL) was degassed and purged with N2 three times, and the resulting mixture was stirred under N2 atmosphere at 0 °C for 2 h to give a solution.

[0206] Another solution of trimethylsulfoxonium iodide (6.00 g, 27.28 mmol, 1.6 eq) and t-BuOK (1 M in THF, 25.57 mL, 1.5 eq) was degassed and purged with N2 three times, and the reaction solution was stirred under N2 atmosphere at 25 °C for 2 h, followed by dropwise addition of the above solution at 25 °C. After the addition, the reaction mixture was stirred at 25 °C for another 2 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL*2). The combined organic layers were washed with brine (50 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (ISCO®; 80 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether @ 80 mL / min) to give the title product Int25 (3.5 g, 56%) as a pale yellow solid. LCMS: m / z(ESI)=368.1[M+H] + .

[0207] 23. Synthesis of Intermediate 26: tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int26) [ka]

[0208] Synthesis of (S)-N-(5-(((2-amino-3,3,3-trifluoropropyl)amino)methyl)-6-chloropyridazin-3-yl)pivalamide 116 To a solution of compound 115 (300 mg, 1.24 mmol) in DCM (16 mL) was added compound 54 (249 mg, 1.24 mmol) and TEA (0.40 mL, 2.73 mmol). The resulting mixture was stirred at 25 °C for 10 min and then heated at 40 °C for 40 min. After this time, the reaction mixture was cooled to room temperature, and sodium cyanoboronate (273 mg, 4.34 mmol), MeOH (2 mL), and HOAc (1.1 mL, 6.45 mmol) were added. The mixture was stirred for 20 min and concentrated to give a residue. The residue was diluted with HO (100 mL) at 25 °C. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column on silica gel eluting with (50% EA in PE) to give compound 116 (244 mg, 55.5%) as a white solid. LCMS: m / z(ESI)=354.2[M+H] + .

[0209] Synthesis of (S)-N-(6-chloro-5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridazin-3-yl)pivalamide 117 To a solution of compound 116 (240 mg, 0.678 mmol) in THF (6 mL) was added CDI (440 mg, 2.71 mmol), and the reaction mixture was stirred at 65 °C under N atmosphere for 1 h. The reaction mixture was quenched with aqueous NaOH (100 mL) at 25 °C. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column on silica gel eluting with (50% EA in PE) to give compound 117 (220 mg, 85.3%) as a white solid. LCMS: m / z(ESI)=380.0[M+H] + .

[0210] Synthesis of (S)-1-((6-amino-3-chloropyridazin-4-yl)methyl)-4-(trifluoromethyl) imidazolidin-2-one 118 A solution of compound 117 (200 mg, 0.527 mmol) in aqueous hydrochloric acid (3 mL, 4 mol / mL) and MeOH (1 mL) was stirred for 1 h at 110° C. The reaction mixture was concentrated to give the crude desired compound 118 (160 mg, 92.4%) as a white solid. LCMS: m / z(ESI)=296.2[M+H] + .

[0211] Synthesis of benzyl ((6-chloro-7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)carbamate 119 To a solution of compound 118 (170 mg, 0.575 mmol) and compound 23 (277 mg, 0.690 mmol) in THF (1 mL) was added NaHCO (386 mg, 4.60 mmol). The reaction mixture was stirred at 75 °C for 18 h. The reaction was cooled to rt and quenched with HO (100 mL) at 25 °C. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel eluting with (5% MeOH in DCM) to give the title compound 119 (200 mg, 58.07%) as a white solid. LCMS: m / z(ESI)=599.2[M+H] + .

[0212] Synthesis of (4S)-1-((2-(amino((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl) methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (Int26) To a solution of compound 119 (100 mg, 0.167 mmol) in EtOH (10 mL) and NHOH (1 mL) was added Pd / C (17.7 mg, 0.017 mmol). The reaction mixture was degassed, purged with H three times, and stirred under H (1 atm) at 40 °C for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give the desired compound Int26 (70 mg, 97.4%) as a white solid. LCMS: m / z(ESI)=431.2[M+H] + .

[0213] 24. Synthesis of Intermediate 27: (S)-1-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl-6-d)methyl)-4-(trifluoromethyl)imidazolidin-2-one (Int27) [ka]

[0214] Synthesis of (S)-N-(5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridazin-3-yl-6-d)pivalamide 120 To a solution of compound 117 (300 mg, 0.790 mmol) and Pd(dppf)Cl (57.80 mg, 0.079 mmol) in DO (1 mL) and THF (5 mL) was added 2,5-dimethyl-2,5-diazahexane (18.3 mg, 0.158 mmol). The reaction mixture was then degassed, purged with N three times, and stirred at 0 °C for 0.5 h under N (15 psi). NaBD (165 mg, 3.95 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min, then warmed to 25 °C and stirred for 1 h. The reaction was quenched with HO (10 mL) at 25 °C. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash column on silica gel eluting with (5% MeOH in DCM) to give title compound 120 (200 mg, 73.1%) as a white solid. LCMS: m / z(ESI)=347.2[M+H] + .

[0215] Synthesis of (S)-1-((6-aminopyridazin-4-yl-3-d)methyl)-4-(trifluoromethyl)imidazolidin-2-one 121 To a solution of compound 120 (190 mg, 0.549 mmol) in HCl (6 mol / L, 3 mL) was added MeOH (1 mL). After stirring the reaction mixture at 110° C. for 1 hour, the reaction mixture was concentrated to give title compound 121 (140 mg, 97.32%) as a brown solid. LCMS: m / z(ESI)=263.2[M+H] + .

[0216] Synthesis of benzyl ((S)-(4,4-difluorocyclohexyl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)carbamate 122 To a solution of compound 121 (288 mg, 0.713 mmol) and Int7 (170 mg, 0.648 mmol) in THF (1 mL) was added NaHCO (435 mg, 5.18 mmol). The reaction mixture was stirred at 75 °C for 18 h. The reaction was quenched with HO (100 mL) at 25 °C. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel eluting with (5% MeOH in DCM) to give the desired compound 122 (120 mg, 32.6%) as a white solid. LCMS: m / z(ESI)=569.2[M+H] + .

[0217] Synthesis of (S)-1-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl-6-d)methyl)-4-(trifluoromethyl)imidazolidin-2-one (Int27) [ka]

[0218] To a solution of compound 122 (120 mg, 0.211 mmol) in EtOH (10 mL) and NHOH (1 mL) was added Pd / C (22.5 mg, 0.021 mmol). The reaction mixture was degassed, purged with H three times, and stirred under H (1 atm) at 40 °C for 1 h. The reaction mixture was directly filtered, and the filtrate was concentrated to give the title compound Int27 (90 mg, 98.21%) as a brown solid. LCMS: m / z(ESI)=434.2[M+H] + .

[0219] 25. Synthesis of Intermediate 28: tert-butyl (S)-(1-(4-(difluoromethylene)cyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int28) [ka]

[0220] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate 124 To a solution of compound 123 (10.0 g, 45.9 mmol) and BocO (10.5 g, 48.2 mmol) in 1,4-dioxane (30 mL) was added a solution of KCO (12.7 g, 91.9 mmol) in HO (60 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was then diluted with HO (100 mL) and extracted with EA (30 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (0-20% EA in PE) to give compound 124 (11.0 g, 85.11%) as a white solid. LCMS: m / z(ESI)=304.4[M+Na] + .

[0221] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate 125 To a solution of compound 124 (11.0 g, 39.1 mmol) in AcOH (50 mL) was added PtO (0.440 g, 1.96 mmol) at 25 °C, and the resulting reaction mixture was degassed, purged with H three times, and stirred under H (3 MPa) at 30 °C for 36 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash column (0-20% EA in PE) to give compound 125 (7.00 g, 62.30%) as a white solid. LCMS: m / z(ESI)=310.4[M+H] + .

[0222] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate 126 To a solution of compound 125 (7.00 g, 24.4 mmol) in DCM (50 mL) was added NMO (4.28 g, 36.5 mmol) and TPAP (0.260 g, 0.731 mmol) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash column (0-2% EA in PE) to give the desired compound 126 (6.50 g, 93.51%) as a colorless oil. LCMS: m / z(ESI)=308.4[M+Na] + .

[0223] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate 128 To a solution of compound 127 (5.28 g, 27.3 mmol) and compound 126 (6.50 g, 22.8 mmol) in DMF (20 mL) was added a solution of t-BuOK (4.59 g, 41.0 mmol) in THF (20 mL) at -60 °C, and the resulting solution was stirred at -60 °C for 1 h. The reaction mixture was quenched with aqueous NH4Cl (50 mL) and extracted with EA (50 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (0-20% EA in PE) to give compound 128 (5.00 g, 68.73%) as a colorless oil. LCMS: m / z(ESI)=342.4[M+Na] + .

[0224] Synthesis of tert-butyl (S)-(1-(4-(difluoromethylene)cyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl) carbamate (Int28) A solution of trimethylsulfoxonium chloride (3.25 g, 25.1 mmol) and t-BuOK (2.25 g, 20.0 mmol) in THF (30 mL) was stirred at 25 °C for 2 h. Compound 128 (4.00 g, 12.5 mmol) was added to the reaction mixture while maintaining the temperature below 20 °C. The mixture was stirred at 25 °C for 16 h, then quenched with aqueous NH4Cl (10 mL) and extracted with EA (20 mL × 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (0-20% EA in PE) to give compound Int28 (1.50 g, 31.56%) as a colorless oil. LCMS: m / z(ESI)=380.2[M+H] + .

[0225] 26. Synthesis of Intermediate 29: (S)-1-((S)-1-(2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int29) [ka]

[0226] Synthesis of tert-butyl ((S)-(6-chloro-7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)carbamate 129 To a solution of compound Int28 (268 mg, 0.707 mmol), compound 24 (200 mg, 0.589 mmol), [Ir(COD)Cl] (19.8 mg, 0.029 mmol), sodium trifluoromethanesulfonate (10.1 mg, 0.059 mmol), and pyrido[3,2-h]quinoline (10.6 mg, 0.059 mmol) in DCE (10 mL) was added 4A molecular sieves (300 mg). The reaction mixture was degassed and purged with N three times, then stirred under N at 80 °C for 16 h. The reaction mixture was concentrated to give a residue, which was purified by flash column chromatography on silica gel eluting with 5% MeOH in DCM to give the desired compound 129 (240 mg, 65.43%) as a white solid. LCMS: m / z(ESI)=623.0[M+H] + .

[0227] Synthesis of tert-butyl ((S)-(4-(difluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate 130 To a solution of compound 129 (200 mg, 0.321 mmol) in THF (30 mL) and HO (5 mL) was added Pd(dppf)Cl (23.5 mg, 0.032 mmol) and 2,5-dimethyl-2,5-diazahexane (7.46 mg, 0.064 mmol). NaBH (85.0 mg, 2.25 mmol) was then added to the reaction mixture, which was stirred at 25 °C for 2 h. The reaction mixture was quenched with EA (30 mL) and water (30 mL), and the resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel eluting with (90% EtOAc in PE) to give title compound 130 (55.0 mg, 29.11%) as a white solid. LCMS: m / z(ESI)=589.2[M+H] + .

[0228] Synthesis of (S)-1-((S)-1-(2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int29) A solution of compound 130 (52.0 mg, 0.088 mmol) in hydrochloric acid / dioxane (4N) (5 mL) was stirred for 1 hour at 25° C. The reaction mixture was then concentrated in vacuo to give the target compound Int29 (43.0 mg, 99.65%) as a yellow solid. LCMS: m / z(ESI)=489.2[M+H] + .

[0229] 27. Synthesis of Intermediate 30: Benzyl (S)-(3-bromo-1-(4-(difluoromethylene)cyclohexyl)-2-oxopropyl)carbamate (Int30) [ka]

[0230] Synthesis of methyl (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetate 129 To a solution of compound 128 (15 g, 47 mmol) in DCM (150 mL) was added TFA (30 mL, 391 mmol). The reaction mixture was stirred at 25° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give crude compound 129 (11 g, 96.12%) as a colorless oil. LCMS: m / z(ESI)=220[M+H] + .

[0231] Synthesis of methyl (S)-2-(((benzyloxy)carbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate 130 To a solution of compound 129 (11 g, 47 mmol) in DCM (100 mL) and water (100 mL) was added CbzCl (10 mL, 71 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Water (50 mL) was added to the reaction mixture. The resulting solution was extracted with DCM (100 mL × 3). The combined organic phase was washed with water (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by flash column on silica gel (0–20% EtOAc in PE) to give the desired compound 130 (15.6 g, 93.98%) as a colorless oil. LCMS: m / z(ESI)=354[M+H] + .

[0232] Synthesis of (S)-2-(((benzyloxy)carbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid 131 To a solution of compound 130 (15.6 g, 44 mmol) in THF (100 mL) was added a solution of LiOH (3.70 g, 88 mmol) in water (20 mL), and the reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was acidified with 1 N hydrochloric acid to pH = 4 and extracted with DCM (40 mL × 3). The combined organic phase was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 131 (13 g, 78.10%) as a white solid. LCMS: m / z(ESI)=340[M+H] + .

[0233] Synthesis of tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4-(difluoromethylene)cyclohexyl)-3-oxobutanoate 132 To a solution of compound 131 (8.5 g, 25 mmol) in anhydrous THF (100 mL) was added CDI (4.06 g, 25.05 mmol), and the reaction mixture was stirred at 20 °C under N for 2 h. To a solution of diisopropylamine (16 mL, 113 mmol) in anhydrous THF (100 mL), nBuLi (45 mL, 113 mmol) was added at 0 °C under N. The reaction mixture was stirred at 0 °C for 10 min, then cooled to -78 °C, and tert-butyl acetate (15.1 mL, 113 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h. The enolate solution was added to the above solution at -78 °C and stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated NH Cl solution at -78 °C and warmed to rt. The solution was extracted with EtOAc (50 mL × 3). The combined organic phase was concentrated to give a yellow residue, which was purified by flash column (0-30% EtOAc in PE) to give title compound 132 (7 g, 63.88%) as a yellow oil. LCMS: m / z(ESI)=438[M+H] + .

[0234] Synthesis of benzyl (S)-(3-bromo-1-(4-(difluoromethylene)cyclohexyl)-2-oxopropyl)carbamate (Int30) To a solution of compound 132 (7 g, 14.4 mmol) and 2,6-dimethylpyridine (0.2 mL, 1.44 mmol) in MeOH (80 mL), NBS (2.72 g, 15.3 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then stored at -20 °C for 24 h. The reaction mixture was diluted with EtOAc (800 mL). The resulting solution was washed with 50% saturated aqueous NaCl (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was dissolved in toluene (80 mL), and TFA (5.5 mL, 72 mmol) was added. The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated to give a residue, which was purified by flash column chromatography on silica gel (0-30% EA in PE) to give the desired compound Int30 (4 g, 66.73%) as a pale yellow solid. LCMS: m / z(ESI)=416[M+H]+ .

[0235] 28. Synthesis of Intermediate 31: 3-(2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propanenitrile (Int31) [ka]

[0236] Synthesis of benzyl ((1S)-(6-chloro-7-(2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)carbamate 133 To a solution of compound 50 (680 mg, 2.03 mmol) and compound Int30 (930.30 mg, 2.235 mmol) in THF (15 mL) was added NaHCO (1.36 g, 16.2 mmol). The reaction mixture was stirred at 75 °C for 18 hours. The reaction mixture was quenched with HO (100 mL) at 25 °C, and the resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue which was purified by flash column chromatography on silica gel eluted with (5% MeOH in DCM) to give title compound 133 (1.44 g, 97.8%) as a brown solid. LCMS: m / z(ESI)=652.2[M+H] + .

[0237] Synthesis of benzyl ((1S)-(7-(2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)carbamate 134 To a solution of compound 133 (1.44 g, 2.21 mmol) and Pd(dppf)Cl (0.16 g, 0.221 mmol) in HO (2 mL) and THF (10 mL) was added 2,5-dimethyl-2,5-diazahexane (0.07 mL, 0.442 mmol). The reaction mixture was then degassed, purged with N three times, and stirred at 0 °C for 0.5 h under N (15 psi). NaBH (0.42 g, 11.1 mmol) was added, and the mixture was stirred at 0 °C for 30 min, then warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with MeOH (1 mL) at 25 °C, followed by HO (10 mL) at 25 °C. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash column on silica gel eluting with (5% MeOH in DCM) to give compound 134 (680 mg, 49.8%) as a brown solid. LCMS: m / z(ESI)=618.2[M+H] + .

[0238] Synthesis of 3-(2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propanenitrile (Int31) A solution of compound 134 (400 mg, 0.648 mmol) in TFA (3 mL) was stirred at 75° C. for 1 hour. The reaction mixture was quenched with aqueous NaHCO (10 mL) at 25° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue which was purified by flash column chromatography on silica gel eluted with (12% MeOH in DCM) to give Int31 (120 mg, 38.3%) as a brown solid. LCMS: m / z(ESI)=484.2[M+H] + .

[0239] 29. Synthesis of Intermediate 32: (S)-1-((2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (Int32) [ka]

[0240] Synthesis of tert-butyl ((S)-(4-(difluoromethylene)cyclohexyl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate 135 To a solution of compound Int25 (120 mg, 0.316 mmol), compound 118 (82.6 mg, 0.316 mmol), [Ir(COD)Cl] (10.62 mg, 0.016 mmol), sodium trifluoromethanesulfonate (5.44 mg, 0.032 mmol), and pyrido[3,2-h]quinoline (5.70 mg, 0.032 mmol) in DCE (1 mL) was added 4A molecular sieves (150 mg). The reaction mixture was degassed and purged with N three times, then stirred under N at 80 °C for 16 h. The reaction mixture was concentrated to give a residue, which was purified by flash column chromatography on silica gel eluting with 5% MeOH in DCM to give compound 135 (150 mg, 87.1%) as a white solid. LCMS: m / z(ESI)=545.2[M+H] + .

[0241] Synthesis of (S)-1-((2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (Int32) A solution of compound 135 (125 mg, 0.230 mmol) in HCl in dioxane (1 mL, 4 mol / L) was stirred for 1 hour at 25° C. The reaction mixture was concentrated to give the desired compound Int32 (100 mg, 98.1%) as a brown solid. LCMS: m / z(ESI)=445.2[M+H] + .

[0242] 30. Synthesis of Intermediate 33: (4S)-1-((1S)-1-(2-(amino((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-b]pyridazin-7-yl-6-d)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int33) [ka]

[0243] Synthesis of benzyl (((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)carbamate 136 A solution of compound 25 (200 mg, 0.311 mmol) in THF (30 mL) and DO (5 mL) was concentrated in vacuo to give a residue. The residue was redissolved in THF (30 mL) and DO (5 mL), and Pd(dppf)Cl (22.8 mg, 0.031 mmol) and 2,5-dimethyl-2,5-diazahexane (7.23 mg, 0.062 mmol) were added. The mixture was stirred at 0 °C for 10 min, followed by NaBD (130 mg, 3.11 mmol) and stirring at 25 °C for 2 h. The reaction was quenched with EA (30 mL) and water (30 mL). The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel eluting with (90% EtOAc in PE) to give title compound 136 (120 mg, 63.29%) as a white solid. LCMS: m / z(ESI)=610.2[M+H] + .

[0244] Synthesis of (4S)-1-((1S)-1-(2-(amino((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-b]pyridazin-7-yl-6-d)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int33) To a solution of compound 136 (120 mg, 0.197 mmol) in EtOH (8 mL) was added 10% Pd / C (21.0 mg, 0.197 mmol) and NH3.HO (0.8 mL) at 25 °C. The reaction mixture was then degassed, purged with H2 three times, and stirred under H2 (15 psi) at 35 °C for 4 h. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound Int33 (93.0 mg, 99.37%) as a white solid. LCMS: m / z(ESI)=476.0[M+H] + .

[0245] 31. Synthesis of Intermediate 34: 4-(3-fluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int34) [ka]

[0246] Synthesis of compound 4-(benzyloxy)butanoic acid 138 Compound 137 (48.78 mL, 277.39 mmol) and (2,2,6,6-tetramethylhexahydropyridin-1-yl)oxonium (3.07 g, 19.42 mmol) were dissolved in a solution of NaHPO (99.86 g, 832.18 mmol) in MeCN (1000 mL) and HO (860 mL). To this reaction mixture was added 140 mL of aqueous NaClO (62.72 g, 693.48 mmol) and 5% aqueous NaClO (8 mL). The reaction mixture was stirred at 35 °C for 3 h. LCMS indicated the reaction was complete. The pH of the reaction mixture was adjusted to 8.0 by the addition of 2 M aqueous NaOH and stirred for 20 min. The reaction mixture was then extracted with tert-butyl methyl ether (500 mL × 2). The aqueous solution was adjusted to pH=3-4 by adding 3M HCl and extracted with EtOAc (1000 ml×2), the organic layer was washed with brine (300 ml×1), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude desired compound 138 (54.2 g, 100%) as a clear oil. LCMS: m / z(ESI)=195.0[M+H] + .

[0247] Synthesis of compound ethyl 6-(benzyloxy)-3-oxohexanoate 139 CDI (50.04 g, 308.91 mmol) was added to a solution of compound 138 (50 g, 257.43 mmol) in dry THF (500 mL) at room temperature. The reaction mixture was stirred for 2 h. [(3-ethoxy-1,3-dioxopropyl)oxy]potassium (65.72 g, 386.14 mmol) and MgCl2 (29.35 g, 308.91 mmol) were added, and the resulting white suspension was stirred at room temperature overnight. The pH was adjusted to ~3 with hydrogen chloride (2 M aqueous solution), and the mixture was extracted with EA (3 x 500 mL). The combined extracts were dried over Na2SO4, filtered, and the crude compound was purified by silica column chromatography (0%-15% EA in PE) to give title compound 139 (44 g, 64.67%) as a colorless oil. LCMS: m / z(ESI)=265.0[M+H] + .

[0248] Synthesis of compound (Z)-6-(benzyloxy)-2-(hydroxyimino)-3-oxohexanoate ethyl ester 140 A solution of NaNO (17.62 g, 255.37 mmol) in HO (200 mL) was slowly added to a solution of compound 139 (44 g, 170.24 mmol) in AcOH (200 mL) and HO (200 mL) at 5 °C. The reaction mixture was stirred between 5-10 °C for 1 h. The reaction mixture was diluted with HO (200 mL) and extracted with EA (2 × 200 mL). The combined organic layers were washed with saturated aqueous NaHCO, dried over NaSO, and concentrated in vacuo to give crude compound 140 (52 g, 100%) as a yellow oil. LCMS: m / z(ESI)=294.0[M+H] + .

[0249] Synthesis of compound (2Z,3Z)-6-(benzyloxy)-2,3-bis(hydroxyimino)hexanoate ethyl ester 141 Hydroxylamine hydrochloride (13.55 g, 195.01 mmol) was added to a solution of compound 140 (52 g, 177.28 mmol) and NaOAc (29.08 g, 354.56 mmol) in MeOH (600 mL). The reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was diluted with brine (200 mL) and extracted with EtOAc (2 x 300 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated to give a residue that was purified by silica column chromatography (0-30% EA in PE) to give title compound 141 (40.8 g, 74.64%) as a colorless oil. LCMS: m / z(ESI)=309.0[M+H] + .

[0250] Synthesis of compound 3-(3-(benzyloxy)propyl)-4-(ethoxycarbonyl)-1,2,5-oxadiazole 2-oxide 142 To a solution of compound 141 (40.8 g, 132.33 mmol) in DCM (600 mL) was added acetoxyphenyliodanyl acetate (51.47 g, 158.79 mmol) at RT. The resulting mixture was stirred at RT for 2 h. The residue was concentrated under reduced pressure and purified by flash silica gel chromatography (0-10% ethyl acetate / petroleum ether) to give compound 142 (21.7 g, 53.54%) as a clear oil. LCMS: m / z(ESI)=307.0[M+H] + .

[0251] Synthesis of compound ethyl 4-(3-(benzyloxy)propyl)-1,2,5-oxadiazole-3-carboxylate 143 To a solution of compound 142 (21.7 g, 70.841 mmol) in toluene (200 mL), P(OEt) (121.48 mL, 708.41 mmol) was added at rt and stirred at 115 °C overnight. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (EtOAC in PE 0% to 10%) to give title compound 143 (17 g, 82.66%) as a clear oil. LCMS: m / z(ESI)=291.0[M+H] + .

[0252] Synthesis of compound ethyl 4-(3-hydroxypropyl)-1,2,5-oxadiazole-3-carboxylate 144 To a mixture of compound 143 (5.0 g, 17.22 mmol) in EtOH (50 mL) was added Pd / C 10% (500 mg, 4.70 mmol) and concentrated hydrochloric acid (0.3 mL). The reaction mixture was stirred under H at rt overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 144 (2.7 g, 78.31%) as a yellow oil. LCMS: m / z(ESI)=201.0[M+H] + .

[0253] Synthesis of compound ethyl 4-(3-fluoropropyl)-1,2,5-oxadiazole-3-carboxylate 145 To a solution of compound 144 (550 mg, 2.75 mmol) in DCM (6 mL) was added DAST (0.40 mL, 3.02 mmol) dropwise at 0 °C. The reaction mixture was stirred for 30 min at rt. The reaction mixture was quenched with ice water and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over NaSO, filtered, and the resulting crude compound was purified by silica column chromatography (0-10% EA in PE) to give the desired compound 145 (0.17 g, 30.36%) as a colorless oil. LCMS: m / z(ESI)=203.0[M+H] + .

[0254] Synthesis of compound 4-(3-fluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int34) To a solution of compound 145 (170 mg, 0.84 mmol) in THF (3 mL) and HO (0.5 mL), lithium hydroxide (60.41 mg, 2.52 mmol) was added, and the reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction was quenched and acidified to pH = 4 with dilute hydrochloric acid. The solution was concentrated under reduced pressure and purified by pre-HPLC (0-50% MeCN in HO) to give the title compound Int34 (30 mg, 20.49%) as a colorless oil. LCMS: m / z(ESI)=347.0[2M-H] - . [Example]

[0255] Example 1: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide (E1) [ka]

[0256] Compound Int1 (33.39 mg, 157.42 μmol, 1.5 eq), EDCI (50.30 mg, 262.36 μmol, 2.5 eq), and HOSu (18.12 mg, 157.42 μmol, 1.5 eq) were added to DCM (0.5 mL). The resulting reaction solution was stirred at 25 °C for 0.5 h. DIPEA (54.25 mg, 419.78 μmol, 73.12 μL, 4 eq) and Int13 (50 mg, 104.94 μmol, 1 eq) were then added, and the reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (10 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1880*40 mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 7 min) to give the title product E1 (5.1 mg, 7.25%). LCMS: m / z(ESI)=671.0[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.40(d, J=1.2Hz, 1H), 8.42(s, 1H), 8.21(s, 1H), 7.86(s, 1H), 7.72(s, 1H), 5.26-5.04(m, 4H), 4.55-4.41(m, 1H), 3.96-3.74(m, 3H), 3.52-3.43(m, 3H), 2.25-1.52(m, 8H), 1.47-1.15(m, 2H).

[0257] Example 2: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E2) [ka]

[0258] A mixture of compound Int2 (20 mg, 95.19 μmol, 1.2 eq), Int13 (37.79 mg, 79.32 μmol, 15.48 μL, 1 eq), HOSu (13.69 mg, 118.99 μmol, 1.5 eq), EDCI (38.02 mg, 198.31 μmol, 2.5 eq) and DIPEA (41.01 mg, 317.29 μmol, 55.27 μL, 4 eq) in DCM (0.5 mL) was degassed and purged with N2 three times, after which the mixture was stirred under N2 atmosphere at 25 °C for 3 h. The residue was directly purified by prep-HPLC (column: Boston Green ODS150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 6 min) to obtain the target product E2 (15.3 mg, 28.85%) as a white solid. LCMS: m / z(ESI)=669.2[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.52(d, J=8.8Hz, 1H), 8.39(s, 1H), 8.26(s, 1H), 7.87(s, 1H), 7.72(s, 1H), 5.19-5.11(m, 2H), 4.55-4.35(m, 1H), 3.96-3.89(m, 1H), 3.87-3.74(m, 2H), 3.45-3.35(m, 1H), 3.33(s, 3H), 3.21-3.08(m, 2H), 2.82-2.61(m, 2H), 2.26-2.13(m, 1H), 2.10-1.87(m, 3H), 1.86-1.55(m, 3H), 1.41-1.23(m, 2H).

[0259] Example 3: 4-Cyclopropyl-N-((1R)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E3-01 Synthesis of )&4-cyclopropyl-N-((1S)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E3-02) [ka]

[0260] To a solution of compound Int5 (110 mg, 0.232 mmol) in EtOAc (10 mL) was added 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (53.6 mg, 0.348 mmol), TEA (1.61 mL, 11.6 mmol), and T3P (2.95 g, 9.28 mmol, 50% in EA). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by prep-HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector; column: Ultimate XB-C18, 50 × 250 mm × 10 μm; mobile phase A: NH4HCO3 (10 mmol / L) in HO; mobile phase B: CH3CN; gradient: 40% to 80% B in 30 min, hold at 100% B for 3 min; flow rate: 70 mL / min; Rt = 14.8 min; column temperature: 30 °C; wavelength: 214 nm, 254 nm) to give the desired product E3 (25.3 mg, 17.9%) as a white solid. LCMS: m / z(ESI)=611.2[M+H] + . 1HNMR: δ8.37 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 5.24 - 5.18 (m, 2H), 4.38 - 4.33 (m, 1H), 4.02 - 3.96 (m, 1H), 3.95 - 3.91 (m, 2H), 3.53 - 3.49 (m, 1H), 3.44 (s, 3H), 2.86 - 2.76 (m, 1H), 2.42 - 2.35 (m, 1H), 2.30 - 2.25 (m, 1H), 2.05 - 1.98 (m, 3H), 1.91 - 1.89 (m, 2H), 1.14 - 1.10 (m, 2H), 1.04 - 1.00 (m, 2H).

[0261] Compound E3 (24.1 mg, 0.0390 mmol) was further separated by SFC (column: Daicel ChiralPak AD, 40 mm I.D. x 250 mm, 10 um; mobile phase A: supercritical CO2, mobile phase B: EtOH (0.1% NH3H2O); A:B = 0:100, flow rate: 80 mL / min; nozzle pressure: 100 Bar; column temperature: 38 °C; wavelength: 220 nm), and the title products E3-01 (7.7 mg, 32.0%) and E3-02 (6.8 mg, 28.2%) were obtained. E3-01: LCMS: m / z(ESI)=611.2[M+H] + . 1 HNMR: (400 MHz, CD3OD) δ8.37 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 5.24 - 5.18 (m, 2H), 4.38 - 4.33 (m, 1H), 4.02 - 3.96 (m, 1H), 3.95 - 3.91 (m, 2H), 3.53 - 3.49 (m, 1H), 3.44 (s, 3H), 2.86 - 2.76 (m, 1H), 2.42 - 2.35 (m, 1H), 2.30 - 2.25 (m, 1H), 2.05 - 1.98 (m, 3H), 1.91 - 1.89 (m, 2H), 1.14 - 1.10 (m, 2H), 1.04 - 1.00 (m, 2H). E3-02: LCMS: m / z(ESI)=611.2[M+H]+ . 1 HNMR: (400MHz, CD3OD)δ8.37(d, J=2.4Hz, 1H), 8.11(s, 1H), 7.86(s, 1H), 5.24-5.18(m, 2H), 4.38-4.33(m, 1H), 4.02-3.96(m, 1H), 3.95-3.91(m, 2H), 3.53-3.49(m, 1H), 3.44(s, 3H), 2.86-2.76(m, 1H), 2.42-2.35(m, 1H), 2.30-2.25(m, 1H), 2.05-1.98(m, 3H), 1.91-1.89(m, 2H), 1.14-1.10(m, 2H), 1.04-1.00(m, 2H).

[0262] Example 4. Synthesis of 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-1,2,5-oxadiazole-3-carboxamide (E4-01) & 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-1,2,5-oxadiazole-3-carboxamide (E4-02) [ka]

[0263] To a solution of compound Int8 (40.0 mg, 0.084 mmol) in EtOAc (5 mL) was added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (16.1 mg, 0.126 mmol), TEA (0.582 mL, 4.19 mmol), and T3P (1.07 g, 3.35 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 hour, and then water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector; column: mobile phase A: NH4HCO3 (10 mmol / L) in HO; mobile phase B: CH3CN; gradient: 40% to 80% B in 30 min, hold at 100% B for 3 min; flow rate: 70 mL / min; Rt = 17.3 min and 18.3 min; column temperature: 30 °C; wavelength: 214 nm, 254 nm) to give the desired products E4-01 (15.9 mg, 32.3%) and E4-02 (1.6 mg, 3.24%). E4-01: LCMS: m / z(ESI)=588.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.37(s, 0.1H), 8.13(s, 1H), 7.86(s, 0.8H), 5.27-5.24(m, 1H), 5.22-5.19(m, 1H), 4.38-4.32(m, 1H), 4.02-3.96(m, 1H), 3.95-3.91(m, 2H), 3.53-3.50(m, 1H), 3.44(s, 3H), 2.51(s, 3H), 2.24-2.19(m, 1H), 2.10-1.99(m, 3H), 1.84-1.70(m, 2H), 1.67-1.63(m, 1H), 1.53-1.37(m, 2H). E4-02: LCMS: m / z(ESI)=588.2[M+H] + . 1HNMR: (400MHz, CD3OD)δ8.42(s, 0.1H), 8.13(s, 1H), 7.93(s, 0.8H), 5.26-5.24(m, 1H), 5.22-5.18(m, 1H), 4.34-4.29(m, 1H), 4.02-3.99(m, 1H), 3.94-3.90(m, 1H), 3.73-3.64(m, 2H), 3.44(s, 3H), 2.51(s, 3H), 2.23-2.17(m, 1H), 2.10-1.97(m, 3H), 1.87-1.70(m, 2H), 1.66-1.63(m, 1H), 1.53-1.37(m, 2H).

[0264] Example 5: 4-Cyclopropyl-N-((S)-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E5-01 Synthesis of 4-cyclopropyl-N-((R)-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E5-02) [ka]

[0265] To a solution of compound Int9 (120 mg, 0.253 mmol) in EA (10 mL) was added TEA (0.281 mL, 2.023 mmol), and the reaction mixture was stirred at 25° C. for 5 minutes. 4-Cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (46.8 mg, 0.304 mmol) and T3P (1.28 g, 2.02 mmol, 50% in EA) were added, and the mixture was stirred at 25° C. for 1 hour. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel eluting with (4% MeOH in DCM) to give the desired product E5 (108 mg, 69.92% yield) as a white solid. LCMS: m / z(ESI)=611.2[M+H] + . 1 HNMR: 1 HNMR(400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.11(s, 1H), 7.86(s, 1H), 5.29-5.16(m, 2H), 4.43-4.28(m, 1H), 4.09-3.86(m, 3H), 3.51(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 2.46-2.31(m, 2H), 2.23-1.98(m, 3H), 1.84-1.69(m, 1H), 1.67-1.51(m, 1H), 1.20-1.08(m, 2H), 1.07-0.96(m, 2H).

[0266] Compound E5 (121 mg, 0.198 mmol) was further purified by SFC [system: YMC K-PrepLAB100G, column name: Daicel ChiralPaK AD, column size: 40 mm I.D. × 250 mm, 10 μm, mobile phase A: supercritical NA, mobile phase B: ethanol, A:B:0:100, wavelength: 214 nm, flow rate: 70 mL / min, column temperature: RT, injection: 30 mL; cycle time: 18 min] to obtain the target compounds E5-01 (43.6 mg, yield 36.03%) and E5-02 (32.8 mg, yield 27.11%). E5-01: LCMS: m / z(ESI)=611.1[M+H] + . 1 HNMR: 1 HNMR(400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.11(s, 1H), 7.89-7.83(m, 1H), 5.31-5.16(m, 2H), 4.46-4.25(m, 1H), 4.10-3.85(m, 3H), 3.51(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 3.30-3.21(m, 1H), 2.50-2.28(m, 2H), 2.18-1.96(m, 3H), 1.85-1.70(m, 1H), 1.67-1.52(m, 1H), 1.19-1.08(m, 2H), 1.05-0.92(m, 2H). E5-02: LCMS: m / z(ESI)=611.2[M+H] + . 1HNMR: (400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.86(s, 1H), 5.31-5.14(m, 2H), 4.47-4.23(m, 1H), 4.10-3.79(m, 3H), 3.51(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 3.30-3.22(m, 1H), 2.53-2.31(m, 2H), 2.23-1.6Hz, 1H), 3.44(s, 3H), 3.30-3.22(m, 1H), 2.53-2.31(m, 2H), 2.23-1.97(m, 3H), 1.83-1.71(m, 1H), 1.69-1.51(m, 1H), 1.25-1.07(m, 2H), 1.05-0.94(m, 2H).

[0267] Example 6: N-((7-(2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E6-01) & N-((7-(2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E6-02) Synthesis of N-((7-(2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E6-03) and N-((7-(2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E6-04) [ka]

[0268] To a solution of compound 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (47 mg, 0.31 mmol) and EDCI (58.6 mg, 0.305 mmol) in DCM (2 mL) was added 1-hydroxytetrahydropyrrole-2,5-dione (26.4 mg, 0.229 mmol). The resulting reaction mixture was stirred at 30 °C for 40 min. Next, compound Int12-S2 (72 mg, 0.15 mmol) and DIEA (0.106 mL, 0.611 mmol) were added to the reaction mixture. The resulting reaction mixture was stirred at 30 °C for 18 h. The reaction was quenched with MeOH (0.5 mL) and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0–0.5% MeOH / DCM @ 18 mL / min) to give a solid. The solid was then subjected to SFC separation (DAICEL CHIRALPAK IG column, 10 μm, 250 × 30 mm; 40-40% (v / v) CO₂-EtOH (0.1% NH₃H₂O) twice) to obtain the target compounds E6-01 (4.7 mg, 5.07% yield) and E6-02 (12.1 mg, 13.04%) as white solids. E6-01: LCMS: m / z(ESI)=608.3[M+H] + . 1HNMR(400MHz, CD3OD)δ8.40(d, J=2.4Hz, 1H), 8.19(s, 1H), 7.98-7.92(m, 1H), 5.49-5.41(m, 1H), 5.28(d, J=8.4Hz, 1H), 4.48-4.34(m, 1H), 3.90(t, J=10.0Hz, 1H), 3.52-3.44(m, 1H), 3.43-3.37(m, 2H), 2.44-2.36(m, 1H), 2.29-2.19(m, 1H), 2.11-1.99(m, 3H), 1.87-1.65(m, 3H), 1.54-1.48(m, 1H), 1.45-1.36(m, 1H), 1.19-1.10(m, 2H), 1.05-0.99(m, 2H) E6-02: LCMS: m / z(ESI)=608.3[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.40(d, J=2.4Hz, 1H), 8.19(s, 1H), 8.00-7.90(m, 1H), 5.50-5.42(m, 1H), 5.29(d, J=8.4Hz, 1H), 4.48-4.33(m, 1H), 3.90(t, J=10.0Hz, 1H), 3.52-3.44(m, 1H), 3.42-3.34(m, 2H), 2.45-2.35(m, 1H), 2.31-2.17(m, 1H), 2.13-1.96(m, 3H), 1.86-1.62(m, 3H), 1.57-1.47(m, 1H), 1.44-1.38(m, 1H), 1.19-1.09(m, 2H), 1.05-0.99(m, 2H).

[0269] To a solution of compound 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (60.2 mg, 0.390 mmol) and EDCI (74.8 mg, 0.390 mmol) in DCM (2 mL) was added 1-hydroxytetrahydropyrrole-2,5-dione (33.7 mg, 0.293 mmol). The reaction mixture was stirred at 30 °C for 40 minutes. Next, compound Int12-S1 (92.0 mg, 0.195 mmol) and DIEA (0.136 mL, 0.781 mmol) were added to the reaction mixture. The resulting reaction mixture was stirred at 30 °C for 18 hours. The reaction was quenched with MeOH (0.5 mL) and concentrated in vacuo to give a residue. The residue was purified twice by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0–0.5% MeOH / DCM gradient @ 18 mL / min) to give a yellow oil (60 mg). This oil was purified by HPLC (Xtimate C18 column, 10 μm, 150 × 40 mm; 45–75% (v / v) water (FA)-ACN) to give the crude product (25 mg). The crude product was further purified by SFC (Daicel ChiralPak AD column, 10 μm, 250 × 30 mm; 55–55% (v / v) CO₂-EtOH (0.1% NH₃H₂O)) to give the title products E6-03 (5 mg, 4.22% yield) and E6-04 (9.2 mg, 7.77%) as white solids. E6-03: LCMS: m / z(ESI)=608.3[M+H] + . 1HNMR(400MHz, CD3OD)δ8.43(d, J=2.4Hz, 1H), 8.18(s, 1H), 8.00-7.91(m, 1H), 5.52-5.43(m, 1H), 5.28(d, J=8.4Hz, 1H), 4.35-4.27(m, 1H), 3.73-3.66(m, 1H).43(m, 1H), 5.28(d, J=8.4Hz, 1H), 4.35-4.27(m, 1H), 3.73-3.66(m, 1H), 3.60-3.46(m, 2H), 3.40-3.33(m, 1H), 2.47-2.34(m, 1H), 2.27-2.17(m, 1H), 2.08-1.96(m, 3H), 1.87-1.71(m, 2H), 1.68-1.62(m, 1H), 1.57-1.46(m, 1H), 1.41-1.35(m, 1H), 1.17-1.10(m, 2H), 1.05-0.98(m, 2H). E6-04: LCMS: m / z(ESI)=608.3[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.43(d, J=2.0Hz, 1H), 8.18(s, 1H), 8.00-7.92(m, 1H), 5.53-5.43(m, 1H), 5.28(d, J=8.4Hz, 1H), 4.37-4.24(m, 1H), 3.74-3.64(m, 1H).43(m, 1H), 5.28(d, J=8.4Hz, 1H), 4.37-4.24(m, 1H), 3.74-3.64(m, 1H), 3.61-3.45(m, 2H), 3.40-3.32(m, 1H), 2.47-2.35(m, 1H), 2.27-2.19(m, 1H), 2.12-1.97(m, 3H), 1.87-1.70(m, 2H), 1.68-1.61(m, 1H), 1.52-1.44(m, 1H), 1.42-1.35(m, 1H), 1.17-1.10(m, 2H), 1.05-0.99(m, 2H).

[0270] Example 7 Synthesis of 4-(cyclobut-1-en-1-yl)-N-((S)-(4,4-difluorocyclohexyl) (7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E7) [ka]

[0271] To a solution of compound Int13 (33 mg, 0.060 mmol), a stir bar, T3P (50% in EA) (115 mg, 0.180 mmol), TEA (0.058 mL, 0.42 mmol), and DCM (1 mL) was added compound Int10 (10 mg, 0.060 mmol) in one portion. The resulting reaction mixture was stirred at 25 °C for 18 h. The reaction was quenched with HO (3 mL), and the aqueous phase was extracted with DCM (3 mL * 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by HPLC (Boston Green ODS column, 5 μm, 150 × 30 mm; 55-85% (v / v) HO (with FA) / MeCN)) to give the title product E7 (7.8 mg, 20.75%) as a white solid. LCMS: m / z(ESI)=625.2[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.38(s, 1H), 8.13(s, 1H), 7.87(s, 1H), 6.75(s, 1H), 5.31-5.25(m, 1H), 5.24-5.19(m, 1H), 4.44-4.30(m, 1H), 4.05-3.90(m, 3H), 3.58-3.48(m, 1H), 3.44(s, 3H), 2.96-2.88(m, 2H), 2.69-2.60(m, 2H), 2.33-2.17(m, 1H), 2.15-1.95(m, 3H), 1.89-1.62(m, 3H), 1.58-1.34(m, 2H).

[0272] Example 8 Synthesis of 4-cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-6-methylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E8) [ka]

[0273] To a solution of compound Int11 (120 mg, 0.245 mmol), TEA (1.36 mL, 9.78 mmol), and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (37.7 mg, 0.245 mmol) in EA (2 mL) was added T3P (3.11 g, 4.89 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with HO at 25 °C. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic phases were washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel eluted with (5% MeOH in DCM) to give the title product E8 (36.2 mg, 23.5%) as a white solid. LCMS: m / z(ESI)=599.4[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.06(s, 1H), 7.96(s, 1H), 5.29-5.23(m, 2H), 4.37-4.29(m, 1H), 4.03-3.90(m, 3H), 3.47(s, 3H), 3.31-3.21(m, 1H), 2.56(s, 3H), 2.45-2.38(m, 1H), 2.25-2.01(m, 4H), 1.89-1.67(m, 3H), 1.60-1.37(m, 2H), 1.19-1.12(m, 2H), 1.08-1.00(m, 2H).

[0274] Example 9 Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(methyl-d3)-1,2,5-oxadiazole-3-carboxamide (E9) [ka]

[0275] To a solution of compound Int13 (60 mg, 0.126 mmol), TEA (0.700 mL, 5.03 mmol), and Int14 (22.2 mg, 0.151 mmol) in EA (0.5 mL) was added T3P (1.61 g, 2.51 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with HO (100 ml) at 25 °C. The resulting solution was extracted with DCM (100 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. This crude product was purified by flash column chromatography on silica gel eluted with (5% MeOH in DCM) to give the title compound E9-1 (43 mg, 56.3%) as a yellow oil. LCMS: m / z(ESI)=606.2[M+H] + .

[0276] To a solution of compound E9-1 (47.0 mg, 0.078 mmol) in toluene (2 mL), P(OEt) (257 mg, 1.55 mmol) was added. The reaction mixture was stirred at 120 °C for 18 hours. The reaction mixture was concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography (50% ACN in water) to give the title compound E12 (8.4 mg, 18.3%) as a white solid. LCMS: m / z(ESI)=590.2[M+H] + . 1HNMR(400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.14(s, 1H), 7.87(s, 1H), 5.26(d, J=8.4Hz, 1H), 5.23-5.17(m, 1H), 4.38-4.33(m, 1H), 4.04-3.90(m, 3H), 3.53-3.50(m, 1H), 3.44(s, 3H), 2.24-2.15(m, 1H), 2.15-1.97(m, 3H), 1.88-1.62(m, 3H), 1.54-1.37(m, 2H).

[0277] Example 10: Synthesis of 4-cyclopropyl-N-((S)-(3,3-difluorocyclobutyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E10-01) & 4-cyclopropyl-N-((R)-(3,3-difluorocyclobutyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E10-02) [ka]

[0278] To a solution of compound Int15 (90.0 mg, 0.201 mmol) in EtOAc (5 mL) was added 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (37.1 mg, 0.241 mmol), TEA (1.40 mL, 10.0 mmol), and T3P (2.55 g, 8.03 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 hour. Water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector, column: mobile phase A: NH4HCO3 (10 mmol / L) in HO; mobile phase B: CH3CN; gradient: 30% to 60% B in 30 min, hold at 100% B for 3 min; flow rate: 70 mL / min; Rt = 20.25 min, column temperature: 30 °C; wavelength: 214 nm, 254 nm) to give the desired product E10 (39.3 mg, 33.5%) as a white solid. LCMS: m / z(ESI)=585.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.38(d, J=2.4Hz, 1H), 8.14(s, 1H), 7.87(s, 1H), 5.44(d, J=9.6Hz, 1H), 5.22-5.19(m, 1H), 4.38-4.32(m, 1H), 4.03-3.90(m, 3H), 3.52-3.48(m, 1H), 3.44(s, 3H), 2.98-2.87(m, 1H), 2.85-2.72(m, 1H), 2.71-2.41(m, 4H), 1.21-1.10(m, 2H), 1.09-1.00(m, 2H).

[0279] Compound E10 (38.0 mg, 0.0650 mmol) was further purified by SFC (column: Daicel ChiralPak AD, 40 mm I.D. x 250 mm, 10 μm; mobile phase A: supercritical CO, mobile phase B: EtOH (0.1% NHHO); A:B = 0:100, flow rate: 80 mL / min; nozzle pressure: 100 Bar; column temperature: 38 °C; wavelength: 220 nm) to give the title products E10-01 (9.7 mg, 25.5%) and E10-02 (8.2 mg, 21.6%) as white solids. E10-01: LCMS: m / z(ESI)=585.4[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.14(s, 1H), 7.87(s, 1H), 5.44(d, J=9.6Hz, 1H), 5.20(t, J=5.6Hz, 1H), 4.38-4.31(m, 1H), 4.03-3.90(m, 3H), 3.52-3.48(m, 1H), 3.44(s, 3H), 2.99-2.87(m, 1H), 2.82-2.42(m, 5H), 1.19-1.12(m, 2H), 1.07-1.01(m, 2H). E10-02: LCMS: m / z(ESI)=585.4[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.14(s, 1H), 7.87(s, 1H), 5.44(d, J=9.6Hz, 1H), 5.20(t, J=5.6Hz, 1H), 4.38-4.31(m, 1H), 4.04-3.89(m, 3H), 3.52-3.48(m, 1H), 3.44(s, 3H), 2.99-2.87(m, 1H), 2.83-2.43(m, 5H), 1.21-1.10(m, 2H), 1.08-1.00(m, 2H).

[0280] Example 11: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-vinyl-1,2,5-oxadiazole-3-carboxamide (E11) [ka]

[0281] To a solution of compound Int16 (22 mg, 0.157 mmol) in DMF (1 mL) was added HATU (51.72 mg, 0.136 mmol) and DIPEA (0.056 mL, 0.314 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, and compound Int13 (50 mg, 0.105 mmol) was added. The resulting reaction mixture was stirred for an additional hour. The reaction mixture was then concentrated in vacuo to provide a residue. The residue was first purified by flash column chromatography on silica gel eluting with (10% MeOH in DCM) followed by C elution with (45% MeCN in water). 18 Purification by column chromatography gave the desired product E11 (11 mg, 17.50%) as a white solid. LCMS: m / z(ESI)=599.0[M+H] + . 1 HNMR: 1HNMR(400MHz, DMSO-d6): δ9.63(d, J=8.8Hz, 1H), 8.42(d, J=2.0Hz, 1H), 8.26(s, 1H), 7.88(d, J=2.0Hz, 1H), 7.73(d, J=2.4Hz, 1H), 6.90(dd, J=18.0, 11.2Hz, 1H), 6.19(d, J=18.0Hz, 1H), 5.82(d, J=11.8Hz, 1H), 5.32-5.02(m, 2H), 4.54-4.42(m, 1H), 3.95-3.70(m, 4H), 3.30(s, 3H), 2.25-2.13(m, 1H), 2.12-1.94(m, 2H), 1.93-1.56(m, 4H), 1.45-1.25(m, 2H).

[0282] Example 12: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-((Z)-2-fluorovinyl)-1,2,5-oxadiazole-3-carboxamide (E12) [ka]

[0283] To a solution of compound Int13 (30 mg, 0.063 mmol) in DMF (4 mL), compound Int17 (29.86 mg, 0.094 mmol), HATU (35.91 mg, 0.094 mmol), and DIPEA (24.41 mg, 0.19 mmol) were added, and the resulting reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by pre-TLC (DCM / MeOH = 10 / 1) to give the desired product E12 (6.0 mg, 15.46%) as a white solid. LC-MS(ESI): m / z=617.0[M+H]+ . 1 HNMR(400MHz, DMSO-d6): δ9.57(d, J=8.8Hz, 1H), 8.41(d, J=2.0Hz, 1H), 8.26(s, 1H), 7.88(d, J=2.0Hz, 1H), 7.72(d, J=2.4Hz, 1H), 7.36(dd, J=79.2, 5.2Hz, 1H), 6.32(dd, J=43.2, 5.2Hz, 1H), 5.22-5.08(m, 2H), 4.54-4.42(m, 1H), 3.96-3.75(m, 4H), 3.33(s, 3H), 2.23-2.14(m, 1H), 2.08-1.93(m, 3H), 1.86-1.71(m, 2H), 1.64-1.56(m, 1H), 1.40-1.22(m, 2H).

[0284] Example 13: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-((E)-2-fluorovinyl)-1,2,5-oxadiazole-3-carboxamide (E13) [ka]

[0285] To a solution of compound Int13 (40 mg, 0.084 mmol) in DMF (2 mL) was added compound Int8 (26.56 mg, 0.168 mmol), HATU (63.85 mg, 0.168 mmol), and N,N-diisopropylethylamine (54.28 mg, 0.420 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated NaCl, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by C18 column chromatography (eluted with 0.5% TFA in water:acetonitrile = 0-100%) to give the title product E13 (15 mg) as a white solid. LC-MS(ESI): m / z=617.0[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.62(d, J=8.8Hz, 1H), 8.42(d, J=2.4Hz, 1H), 8.29(s, 1H), 8.02-7.70(m, 3H), 6.71(dd, J=18.0, 11.6Hz, 1H), 5.30-5.01(m, 2H), 4.54-4.40(m, 1H), 3.96-3.80(m, 4H), 3.33(s, 3H), 2.25-2.12(m, 1H), 2.10-1.90(m, 3H), 1.89-1.59(m, 3H), 1.43-1.24(m, 2H).

[0286] Example 14: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxamide (E14) [ka]

[0287] To a solution of compound Int13 (25 mg, 0.052 mmol) in DMF (2 mL) was added compound Int19 (16.17 mg, 0.105 mmol), HATU (39.90 mg, 0.105 mmol), and N,N-diisopropylethylamine (33.91 mg, 0.262 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with EA and saturated aqueous NaCl. The organic layer was separated, washed with saturated NaCl, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by HPLC. 18 Purification by column chromatography (eluting with 0.5% TFA in water:acetonitrile=0-100%) gave the title compound E14 as a white solid. LC-MS(ESI): m / z=613.0[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.74(d, J=9.2Hz, 1H), 8.43(d, J=2.0Hz, 1H), 8.22(s, 1H), 7.98-7.81(m, 1H), 7.73(d, J=2.4Hz, 1H), 5.65(s, 1H), 5.52(d, J=1.6Hz, 1H), 5.21(t, J=8.4Hz, 1H), 5.12(dd, J=8.0, 5.2Hz, 1H), 4.61-4.40(m, 1H), 4.01-3.71(m, 3H), 3.52-3.48(m, 1H), 3.33(s, 3H), 2.23-2.10(m, 4H), 2.09-1.95(m, 2H), 1.93-1.55(m, 4H), 1.42-1.28(m, 2H).

[0288] Example 15: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1,2,5-oxadiazole-3-carboxamide (E15) [ka]

[0289] To a mixture of compound Int13 (30 mg, 0.063 mmol) in DMF (2 mL) was added compound Int20 (17 mg, 0.076 mmol), DIPEA (24 mg, 0.189 mmol), and HATU (31 mg, 0.082 mmol). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (20 mL * 3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by pre-TLC (80% EtOAc in PE) to give the title product E15 (3 mg, 7.41%) as a white solid. LCMS: m / z(ESI)=643.0[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.18(d, J=9.2Hz, 1H), 8.42(d, J=2.4Hz, 1H), 8.22(d, J=5.2Hz, 1H), 7.86(d, J=2.0Hz, 1H), 7.73(d, J=2.0Hz, 1H), 5.26-5.04(m, 2H), 4.56-4.39(m, 1H), 4.01-3.55(m, 3H), 3.48(dd, J=10.4, 3.6Hz, 1H), 3.33(s, 3H), 2.20-2.08(m, 1H), 2.06-1.93(m, 2H), 1.86-1.72(m, 4H), 1.63(s, 3H), 1.47-1.17(m, 4H), 1.11-1.00(m, 1H), 0.85-0.73(m, 1H).

[0290] Example 16: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(1-methylcyclobutoxy)-1,2,5-oxadiazole-3-carboxamide (E16) [ka]

[0291] To a solution of compound Int13 (30 mg, 0.063 mmol) in DMF (2 mL) was added compound Int21 (17 mg, 0.076 mmol), DIPEA (24 mg, 0.189 mmol), and HATU (31 mg, 0.082 mmol). The reaction mixture was stirred at 25 °C for 1.5 hours. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (20 mL*3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by pre-TLC (40% EtOAc in PE) to give the title product E16 (10 mg, 20.82%) as a white solid. LCMS: m / z(ESI)=657[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.20(d, J=8.8Hz, 1H), 8.44(d, J=2.0Hz, 1H), 8.26(s, 1H), 7.87(d, J=12.0Hz, 1H), 7.75(d, J=2.0Hz, 1H), 5.22(t, J=8.0Hz, 1H), 5.14(dd, J=8.0, 5.2Hz, 1H), 4.60-4.41(m, 1H), 3.99-3.62(m, 3H), 3.50(dd, J=10.4, 4.0Hz, 1H), 3.35(s, 3H), 2.48-2.38(m, 2H), 2.24-2.14(m, 3H), 2.08-1.96(m, 2H), 1.94-1.64(m, 6H), 1.63(s, 3H), 1.46-1.28(m, 2H).

[0292] Example 17: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxamide (E17) [ka]

[0293] To a solution of compound Int22 (9.84 mg, 0.055 mmol) in DCM (2 mL) was added compound Int13 (20 mg, 0.042 mmol), HATU (23.96 mg, 0.063 mmol), and DIPEA (0.021 mL, 0.126 mmol), and the resulting reaction was stirred at 25 °C for 1 h. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated aqueous NaCl, and then concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting first with (10% MeOH in DCM) and then with (45% MeCN (0.01% TFA) in HO). 18 Purification by flash column as above gave the title product E17 (4 mg) as a white solid. LC / MS: m / z(ESI)=639.0[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.09(d, J=8.8Hz, 1H), 8.42(d, J=2.0Hz, 1H), 8.29(s, 1H), 7.90(s, 1H), 7.73(d, J=2.0Hz, 1H), 5.30-4.99(m, 2H), 4.54-4.39(m, 1H), 3.92-3.86(m, 2H), 3.81-3.76(m, 1H), 3.52-3.43(m, 1H), 3.34(s, 3H), 2.80(dd, J=7.6, 4.0Hz, 1H), 2.23-2.14(m, 1H), 2.06-1.89(m, 3H), 1.85-1.71(m, 2H), 1.70-1.64(m, 2H), 1.62-1.53(m, 1H), 1.40-1.16(m, 3H), 1.11-0.97(m, 3H).

[0294] Example 18: Synthesis of N-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E18) [ka]

[0295] Synthesis of compound 4-((((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamoyl)-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-2-oxide 104 To a solution of compound Int9 (100 mg, 0.211 mmol) in EA (5 mL), TEA (0.234 mL, 1.686 mmol) was added and stirred at 25 °C for 5 minutes. After that, compound Int23 (52.4 mg, 0.232 mmol) and T3P (1.07 g, 1.69 mmol, 50% in EA) were added and stirred at 25 °C for 1 hour. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 4% MeOH in DCM to give title compound 111 (100 mg, 69.51%) as a white solid. LCMS: m / z(ESI)=683.2[M+H] + .

[0296] Synthesis of N-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E18) To a solution of compound 111 (100 mg, 0.147 mmol) in toluene (20 mL) was added P(OEt) (488 mg, 2.94 mmol) at 25 °C. The reaction mixture was then stirred at 120 °C for 12 h. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 4% MeOH in DCM to give the title product E18 (55.0 mg, 56.32%) as a white solid. LCMS: m / z(ESI)=667.0[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.85(s, 1H), 5.29-5.14(m, 2H), 4.43-4.26(m, 1H), 4.04-3.85(m, 3H), 3.50(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 3.30-3.21(m, 3H), 2.76-2.62(m, 2H), 2.43-2.30(m, 1H), 2.22-2.00(m, 3H), 1.80-1.70(m, 1H), 1.63-1.53(m, 1H).

[0297] Compound E18 (30.0 mg, 0.045 mmol) was further purified by SFC [System: Waters SFC150, Column: Daicel ChiralPak AD, Column dimensions: 40 mm I.D. x 250 mm, 10 μm, Mobile phase A: Supercritical CO2, Mobile phase B: 0.1% 7M NH3 in MeOH, A:B: 60:40, Wavelength: 214 nm, Flow rate: 120 mL / min, Column temperature: RT, Injection volume: 1.5 mL, Cycle time: 5.5 min] to give the target compounds E18-01 (6.90 mg, 23.0%) and E18-02 (6.9 mg, 23.0%). E18-01: LCMS: m / z(ESI)=667.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.85(s, 1H), 5.28-5.16(m, 2H), 4.44-4.29(m, 1H), 4.03-3.88(m, 3H), 3.54-3.47(m, 1H), 3.44(s, 3H), 3.29-3.20(m, 3H), 2.80-2.62(m, 2H), 2.45-2.31(m, 1H), 2.20-1.99(m, 3H), 1.81-1.70(m, 1H), 1.64-1.51(m, 1H). E18-02: LCMS: m / z(ESI)=667.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.85(s, 1H), 5.33-5.14(m, 2H), 4.46-4.25(m, 1H), 4.10-3.85(m, 3H), 3.50(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 3.29-3.21(m, 3H), 2.79-2.61(m, 2H), 2.48-2.29(m, 1H), 2.23-1.97(m, 3H), 1.82-1.68(m, 1H), 1.68-1.52(m, 1H).

[0298] Example 19: Synthesis of 4-cyclopropyl-N-((4-(difluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E19) [ka]

[0299] Synthesis of compound 4-cyclopropyl-N-((7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(1,4-dioxaspiro[4.5]decan-8-yl)methyl)-1,2,5-oxadiazole-3-carboxamide 112 To a solution of compound Int24 (550 mg, 1.10 mmol), 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (187 mg, 1.21 mmol), and TEA (1.22 mL, 8.82 mmol) in EtOAc (10 mL) was added T3P (2.80 g, 8.82 mmol, 50% in EA) at 25 °C, and the reaction mixture was stirred at 25 °C for 1 hour. Water (10 mL) was added to the reaction mixture. The resulting solution was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel eluting with 5% MeOH in DCM to give title compound 112 (600 mg, 85.69%) as a yellow solid. LCMS: m / z(ESI)=635.2[M+H] + .

[0300] Synthesis of compound 4-cyclopropyl-N-((7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-oxocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide 113 A mixture of compound 112 (600 mg, 0.95 mmol) in 2N hydrochloric acid (aq) (27.3 mL, 54.70 mmol) and THF (5 mL) was stirred at 25 °C for 3 h. The reaction mixture was extracted with DCM (20 mL × 3). The organic layer was washed with saturated NaHCO (aq, 50 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column on silica gel eluting with 10% MeOH in DCM to give title compound 113 (450 mg, 80.60%) as a yellow solid. LCMS: m / z(ESI)=591.2[M+H] + .

[0301] Synthesis of 4-cyclopropyl-N-((4-(difluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E19) Under N2 protection, a solution of t-BuOK (85.5 mg, 0.762 mmol) in THF (10 mL) was added to a mixture of compound 113 (150 mg, 0.254 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (147.19 mg, 0.762 mmol) in THF (10 mL) at -78 °C. The reaction mixture was then stirred at -78 °C for 1 h. Saturated NH4Cl was added to the reaction mixture. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 5% MeOH in DCM to give the crude product (70 mg). The crude product was purified by prep-HPLC [equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector, column: mobile phase A: NH4HCO3 (10 mmol / L) in HO; mobile phase B: CH3CN; gradient: 40% to 80% B in 30 min, hold at 100% B for 3 min; flow rate: 70 mL / min; Rt = 19.5 min, column temperature: 30 °C; wavelength: 214 nm, 254 nm] to give the title product E19 (8.0 mg, 5.04%) as a white solid. LCMS: m / z(ESI)=625.4[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.89-7.83(m, 1H), 5.26-5.17(m, 2H), 4.42-4.29(m, 1H), 4.05-3.91(m, 3H), 3.52(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 2.57-2.49(m, 1H), 2.49-2.40(m, 1H), 2.40-2.35(m, 1H), 2.29-2.16(m, 1H), 2.09-2.00(m, 1H), 1.94-1.77(m, 2H), 1.73-1.64(m, 1H), 1.29-1.07(m, 4H), 1.06-0.98(m, 2H).

[0302] Compound E19 (18.0 mg, 0.029 mmol) was further purified by SFC [system: Waters UPCC, column name REGIS(S, S)WHELK-O1, column size: 100*3 mm3 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH (0.1% DEA), A:B: 85:15, wavelength: 214 nm, flow rate: 90 mL / min, column temperature: RT, injection: 2 mL, cycle time: 5.5 min] to give the title products E19-01 (8.2 mg, yield 45.56%) and E19-02 (9.5 mg, yield 52.78%) as white solids. E19-01: LCMS: m / z(ESI)=625.2[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.87(s, 1H), 5.27-5.17(m, 2H), 4.41-4.32(m, 1H), 4.06-3.90(m, 3H), 3.52(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 2.59-2.34(m, 3H), 2.30-2.15(m, 1H), 2.09-2.00(m, 1H), 1.95-1.78(m, 2H), 1.73-1.63(m, 1H), 1.25-1.09(m, 4H), 1.07-0.98(m, 2H). E19-02: LCMS: m / z(ESI)=625.2[M+H] + . 1HNMR(400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.87(s, 1H), 5.27-5.17(m, 2H), 4.42-4.31(m, 1H), 4.05-3.89(m, 3H), 3.52(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 2.58-2.33(m, 3H), 2.28-2.17(m, 1H), 2.09-2.00(m, 1H), 1.96-1.79(m, 2H), 1.73-1.64(m, 1H), 1.25-1.10(m, 4H), 1.06-0.97(m, 2H).

[0303] Example 20: Synthesis of 4-cyclopropyl-N-((1S)-(4-(fluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E20-01) & 4-cyclopropyl-N-((1R)-(4-(fluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E20-02) [ka]

[0304] Synthesis of 4-cyclopropyl-N-((4-(fluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (E20) To a solution of compound 113 (129 mg, 0.339 mmol) in THF (5 mL) was added LiHMDS (0.339 mL, 0.339 mmol) under a N2 atmosphere at -60 °C, and the resulting reaction mixture was stirred at -60 °C for 1 h. Next, the compound (fluoromethyl)triphenyl(tetrafluoro-15-boranyl)-15-phosphane (100 mg, 0.169 mmol) was added, and the reaction mixture was stirred at -60 °C for 2 h. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 3% MeOH in DCM to give the crude product. The crude product was purified by prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu SPD-20AP UV Detector, Column: Mobile phase A: NH4HCO3 (10 mmol / L) in HO; Mobile phase B: CH3CN; Gradient: 35% to 75% B in 0.7 h, hold at 100% B for 3 min; Flow rate: 70 mL / min; Rt = 20.75 min, Column temperature: 30 °C; Wavelength: 214 nm, 254 nm) to give the title product E20 (55.0 mg, 53.55%) as a white solid. LCMS: m / z(ESI)=607.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.11(s, 1H), 7.87(s, 1H), 6.62-6.30(m, 1H), 5.30-5.15(m, 2H), 4.46-4.29(m, 1H), 4.08-3.87(m, 3H), 3.57-3.49(m, 1H), 3.44(s, 3H), 2.93-2.72(m, 1H), 2.46-2.34(m, 1H), 2.34-1.60(m, 6H), 1.26-1.07(m, 4H), 1.06-0.97(m, 2H).

[0305] Compound E20 (52.0 mg, 0.086 mmol) was further purified by SFC [system: YMC K-PrepLAB 100 g, column name: Daicel ChiralPaK IB N, column size: 40 mm I.D. x 250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: 0.1% DEA ethanol, A:B: 80:20, wavelength: 214 nm, flow rate: 80 mL / min, column temperature: RT, injection: 30 mL, cycle time: 20 min] to obtain the target products E20-01 (19.0 mg, 36.54%) and E20-02 (14.0 mg, 26.92%) as white solids. E20-01: LCMS: m / z(ESI)=607.4[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.11(s, 1H), 7.87(d, J=0.8Hz, 1H), 6.66-6.27(m, 1H), 5.34-5.12(m, 2H), 4.45-4.30(m, 1H), 4.04-3.90(m, 3H), 3.52(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 2.93-2.73(m, 1H), 2.46-2.32(m, 1H), 2.30-2.11(m, 2H), 2.10-1.85(m, 2H), 1.81-1.62(m, 2H), 1.27-1.08(m, 4H), 1.05-0.98(m, 2H). E20-02: LCMS: m / z(ESI)=607.4[M+H] + . 1HNMR: (400MHz, CD3OD)δ8.38(d, J=2.4Hz, 1H), 8.12(s, 1H), 7.87(d, J=0.8Hz, 1H), 6.63-6.30(m, 1H), 5.28-5.16(m, 2H), 4.45-4.28(m, 1H), 4.04-3.91(m, 3H), 3.53(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 2.90-2.73(m, 1H), 2.46-2.34(m, 1H), 2.31-2.10(m, 2H), 2.08-1.85(m, 2H), 1.83-1.64(m, 2H), 1.24-1.08(m, 4H), 1.07-0.97(m, 2H).

[0306] Example 21: Synthesis of N-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E21) [ka]

[0307] Synthesis of compound 4-((((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamoyl)-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-2-oxide 110 To a solution of compound Int5 (55.0 mg, 0.116 mmol) in EtOAc (5 mL) was added compound Int23 (26.2 mg, 0.116 mmol), TEA (0.806 mL, 5.80 mmol), and T3P (1.46 g, 4.64 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 hour. Water (20 mL) was added to the reaction mixture. The resulting solution was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel eluting with (4% MeOH in DCM) to give title compound 114 (30.0 mg, 37.9%) as a white solid. LCMS: m / z(ESI)=683.2[M+H] + .

[0308] Synthesis of N-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E21) To a solution of compound 114 (30.0 mg, 0.044 mmol) in toluene (2 mL) was added triethyl phosphite (146 mg, 0.88 mmol). The reaction mixture was degassed and purged with N three times, then stirred under N atmosphere at 120 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector, column: mobile phase A: NH4HCO3 (10 mmol / L) in HO; mobile phase B: CH3CN; gradient: 45% to 75% B in 30 min, hold at 100% B for 3 min; flow rate: 70 mL / min; Rt = 9.0 min, column temperature: 30 °C; wavelength: 214 nm, 254 nm) to give the title product E21 (8.00 mg, 27.3%) as a white solid. LCMS: m / z(ESI)=667.2[M+H] + . 1 HNMR: (400 MHz, CD3OD) δ 8.39 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 5.26 - 5.20 (m, 2H), 4.39 - 4.33 (m, 1H), 4.06 - 3.92 (m, 3H), 3.54 - 3.51 (m, 1H), 3.46 (s, 3H), 3.30 - 3.23 (m, 2H), 2.90 - 2.79 (m, 1H), 2.79 - 2.64 (m, 2H), 2.36 - 2.26 (m, 1H), 2.09 - 2.02 (m, 3H), 1.95 - 1.90 (m, 2H)

[0309] Compound E21 (90.0 mg, 0.135 mmol) was further purified by SFC (system: Waters prepSFC 150Mgm, column: Daicel ChiralPak AD, 40 mm I.D. x 250 mm, 10 um; mobile phase A: supercritical CO2, mobile phase B: MeOH; A:B = 0:50, flow rate: 120 mL / min; nozzle pressure: 100 Bar; column temperature: 38 °C; wavelength: 210 nm), and E21-01 (19.4 mg, 21.6%) and E21-02 (23.0%) were obtained as white solids. E21-01: LCMS: m / z(ESI)=667.2[M+H] + . 1 HNMR: (400 MHz, CD3OD) δ 8.37 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 5.24 - 5.19 (m, 2H), 4.40 - 4.31 (m, 1H), 4.02 - 3.91 (m, 3H), 3.52 - 3.49 (m, 1H), �.44 (s, 3H), 3.26 - 3.23 (m, 2H), 2.86 - 2.82 (m, 1H), 2.75 - 2.63 (m, 2H), 2.31 - 2.26 (m, 1H), 2.05 - 2.00 (m, 3H), 1.92 - 1.89 (m, 2H). E21-02: LCMS: m / z(ESI)=667.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.86(s, 1H), 5.24-5.19(m, 2H), 4.42-4.31(m, 1H), 4.03-3.90(m, 3H), 3.52-3.49(m, 1H), 3.44(s, 3H), 3.27-3.23(m, 2H), 2.83-2.78(m, 1H), 2.77-2.62(m, 2H), 2.31-2.26(m, 1H), 2.05-2.00(m, 3H), 1.92-1.89(m, 2H).

[0310] Example 22. N-((S)-(4-(difluoromethylene)cyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3carboxamide (E22-01 Synthesis of N-((S)-(4-(difluoromethylene)cyclohexyl)(7-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E22-02) [ka]

[0311] To a solution of compound Int29 (43.0 mg, 0.088 mmol) in EA (5 mL), TEA (0.098 mL, 0.704 mmol) was added and stirred at 25 °C for 5 minutes. Compound Int2 (20.4 mg, 0.097 mmol) and T3P (448 mg, 0.704 mmol, 50% in EA) were added, and the resulting solution was stirred at 25 °C for 1 hour. The reaction was then quenched with EA (30 mL) and water (30 mL). The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (4% MeOH in DCM) to give the desired product E22 (34.0 mg, 56.75%) as a white solid.

[0312] E22 (34.0 mg, 0.050 mmol) was further purified by SFC [System: Waters prepSFC 150 Mgm, Column: RegisWhelkO1 (R, R), Column dimensions: 40 mm I.D x 250 mm, 10 μm, Mobile phase A: supercritical CO2, Mobile phase B: MeOH, A:B: 65:35, Wavelength: 210 nm, Flow rate: 120 mL / min, Column temperature: RT, Injection: 25 mL, Cycle time: 12 min] to give E22-01 (17.0 mg, 50.00%) and E22-02 (1.00 mg, 2.94%) as white solids. E22-01: LCMS: m / z(ESI)=681.0[M+H] + . 1HNMR: (400MHz, CD3OD)δ8.38(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.86(s, 1H), 5.26-5.18(m, 2H), 4.43-4.29(m, 1H), 4.03-3.88(m, 3H), 3.51(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 3.28-3.19(m, 2H), 2.82-2.60(m, 2H), 2.58-2.39(m, 2H), 2.32-2.16(m, 1H), 2.12-1.98(m, 1H), 1.95-1.76(m, 2H), 1.72-1.62(m, 1H), 1.26-1.08(m, 2H). E22-02: LCMS: m / z(ESI)=681.0[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.28(d, J=2.0Hz, 1H), 8.02(s, 1H), 7.76(s, 1H), 5.14-5.08(m, 2H), 4.31-4.22(m, 1H), 3.90-3.82(m, 3H), 3.42(dd, J=10.4, 3.6Hz, 1H), 3.33(s, 3H), 3.17-3.12(m, 2H), 2.65-2.54(m, 2H), 2.46-2.32(m, 2H), 2.16-2.07(m, 1H), 1.97-1.90(m, 1H), 1.82-1.71(m, 2H), 1.61-1.54(m, 1H), 1.14-1.00(m, 2H).

[0313] Example 23: Synthesis of N-((R)-(4-(difluoromethylene)cyclohexyl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E23-01) & N-((S)-(4-(difluoromethylene)cyclohexyl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E23-02) [ka]

[0314] To a solution of compound Int32 (102 mg, 0.230 mmol), TEA (1.27 mL, 9.18 mmol), and compound Int2 (57.8 mg, 0.275 mmol) in EA (1 mL) was added T3P (1.36 mL, 4.59 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with HO (100 ml) at 25 °C. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic phases were washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by flash column chromatography on silica gel eluted with (5% MeOH in DCM) to give E23 (41.6 mg, 28.4%) as a white solid. LCMS: m / z(ESI)=637.0[M+H] + . 1HNMR(400MHz, MeOD)δ8.27(d, J=2.0Hz, 1H), 8.02(s, 1H), 7.73(d, J=0.8Hz, 1H), 5.12(d, J=8.4Hz, 1H), 4.44(d, J=16.0Hz, 1H), 4.33(d, J=16.0Hz, 1H), 4.29-4.21(m, 1H), 3.64(t, J=20Hz, 1H), 3.45-3.41(m, 1H), 3.17-3.07(m, 2H), 2.70-2.53(m, 2H), 2.43-3.32(m, 2H), 2.20-2.06(m, 1H), 1.96-1.93(m, 1H), 1.81-1.71(m, 2H), 1.59-1.56(m, 1H), 1.16-0.98(m, 2H)

[0315] Compound E23 (40 mg, 0.063 mmol) was further purified by SFC (column: ChiralPak AD-H Daicel Chemical Industries, Ltd, 250*30 mm ID, 5 um; mobile phase A: Na, mobile phase B: MeOH; A:B = 100:0, flow rate: 120 mL / min; nozzle pressure: 100 Bar; column temperature: 38 °C; wavelength: 220 nm) to give the final products E23-01 (9.5 mg, 23.7% yield) and E23-02 (33.5 mg, 83.7%) as white solids. E23-01: LCMS: m / z(ESI)=637.0[M+H] + . 1HNMR(400MHz, CD3OD)δ8.27(d, J=2.0Hz, 1H), 8.02(s, 1H), 7.73(d, J=0.8Hz, 1H), 5.12(d, J=8.4Hz, 1H), 4.44(d, J=16.0Hz, 1H), 4.33(d, J=16.0Hz, 1H), 4.29-4.21(m, 1H), 3.64(t, J=20Hz, 1H), 3.45-3.41(m, 1H), 3.17-3.07(m, 2H), 2.70-2.53(m, 2H), 2.43-3.32(m, 2H), 2.20-2.06(m, 1H), 1.96-1.93(m, 1H), 1.81-1.71(m, 2H), 1.59-1.56(m, 1H), 1.16-0.98(m, 2H). E23-02: LCMS: m / z(ESI)=637.0[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.27(d, J=2.0Hz, 1H), 8.02(s, 1H), 7.73(d, J=0.8Hz, 1H), 5.12(d, J=8.4Hz, 1H), 4.44(d, J=16.0Hz, 1H), 4.33(d, J=16.0Hz, 1H), 4.29-4.21(m, 1H), 3.64(t, J=20Hz, 1H), 3.45-3.41(m, 1H), 3.17-3.07(m, 2H), 2.70-2.53(m, 2H), 2.43-3.32(m, 2H), 2.20-2.06(m, 1H), 1.96-1.93(m, 1H), 1.81-1.71(m, 2H), 1.59-1.56(m, 1H), 1.16-0.98(m, 2H).

[0316] Example 25: Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E25) [ka]

[0317] To a solution of compound Int27 (117 mg, 0.270 mmol), TEA (1.51 mL, 10.7 mmol), and compound Int2 (68.06 mg, 0.324 mmol) in EA (1 mL) was added T3P (1.60 mL, 5.39 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 h. The reaction was then quenched with HO (100 mL) at 25 °C, and the resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel eluting with (5% MeOH in DCM) to give the desired product E25 (47.3 mg, 28.1%) as a white solid. LCMS: m / z(ESI)=626.0[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.13(s, 1H), 7.82(s, 1H), 5.25(d, J=8.8Hz, 1H), 4.54(d, J=16.0Hz, 1H), 4.41(d, J=16.0Hz, 1H), 4.38-4.29(m, 1H), 3.73(t, J=10.4Hz, 1H), 3.54-3.50(m, 1H), 3.27-3.21(m, 2H), 2.75-2.62(m, 2H), 2.27-3.21(m, 2H).4Hz, 1H), 3.54-3.50(m, 1H), 3.27-3.21(m, 2H), 2.75-2.62(m, 2H), 2.28-2.17(m, 1H), 2.13-1.96(m, 3H), 1.86-1.60(m, 3H), 1.47-1.33(m, 2H).

[0318] Example 26: N-((S)-(4,4-difluorocyclohexyl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E26-01 Synthesis of N-((S)-(4,4-difluorocyclohexyl)(7-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E26-02) [ka]

[0319] To a solution of compound Int8 (110 mg, 0.230 mmol) in EA (10 mL), TEA (0.256 mL, 1.843 mmol) was added and stirred at 25 °C for 5 minutes. After that, compound Int2 (53.2 mg, 0.253 mmol) and T3P (1.17 g, 1.84 mmol, 50% in EA) were added and stirred at 25 °C for 1 hour. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting mixture was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (3% MeOH in DCM) to give the desired product E26 (60.0 mg, 38.90%) as a white solid. LCMS: m / z(ESI)=670.2[M+H] + .

[0320] E26 (55.0 mg, 0.082 mmol) was subjected to SFC [System: YMC K-PrepLAB 100 g, Column: Daicel ChiralPak IB N, Column dimensions: 40 mm I.D x 250 mm, 10 μm, Mobile phase A: n-hexane, Mobile phase B: EtOH (0.1% NH 3. Further purification using a 25 mL / min column (HO), A:B:60:40, wavelength: 210 nm, flow rate: 80 mL / min, column temperature: RT, injection: 25 mL, cycle time: 18 min) afforded E26-01 (25.0 mg, 45.45%) and E26-02 (13.0 mg, 23.64%) as white solids. E26-01: LCMS: m / z(ESI)=670.0[M+H] + . 1 HNMR(400MHz, CD3OD)δ: 8.16(s, 1H), 7.88(s, 1H), 5.28(d, J=8.4Hz, 1H), 5.23(t, J=5.6Hz, 1H), 4.42-4.34(m, 1H), 4.05-3.92(m, 3H), 3.53(dd, J=10.4, 3.4, 3.6Hz, 1H), 3.46(s, 3H), 3.29-3.25(m, 2H), 2.76-2.67(m, 2H), 2.30-2.22(m, 1H), 2.14-2.00(m, 3H), 1.85-1.65(m, 3H), 1.56-1.40(m, 2H). E26-02: LCMS: m / z(ESI)=670.0[M+H] + . 1HNMR(400MHz, CD3OD)δ: 8.16(s, 1H), 7.95(s, 1H), 5.28(d, J=8.4Hz, 1H), 5.21(t, J=5.6Hz, 1H), 4.41-4.27(m, 1H), 4.12-3.90(m, 2H), 3.81-3.64(m, 2H), 3.46(s, 3H), 3.30-3.25(m, 2H), 2.77-2.66(m, 2H), 2.33-2.19(m, 1H), 2.17-1.99(m, 3H), 1.90-1.67(m, 3H), 1.56-1.38(m, 3H).

[0321] Example 29: N-((S)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl) Synthesis of N-((R)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E29-02) [ka]

[0322] To a solution of compound Int33 (85.0 mg, 0.179 mmol) in EA (20 mL), TEA (0.199 mL, 1.43 mmol) was added and stirred at 25 °C for 5 minutes. After that, compound Int2 (37.6 mg, 0.179 mmol) and T3P (910 mg, 1.43 mmol, 50% in EA) were added and stirred at 25 °C for 1 hour. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL × 2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluting with (4% MeOH in DCM) to give E29 (70.0 mg, 58.65%) as a white solid. LCMS: m / z(ESI)=668.0[M+H] + .

[0323] E29 (54.0 mg, 0.081 mmol) was further purified by SFC [System: Waters PrepSFC 150 Mgm, Column: Regis WhelkO1 (R,R), Column dimensions: 40 mm I.D x 250 mm, 10 μm, Mobile phase A: Supercritical CO2, Mobile phase B: MeOH (0.1% NH 3. HO), A:B:50:50, wavelength: 210 nm, flow rate: 120 mL / min, column temperature: RT, injection volume: 25 mL, cycle time: 6 min] to obtain E29-01 (13.0 mg, 24.07%) and E29-02 (9.00 mg, 16.67%) as white solids. E29-01: LCMS: m / z(ESI)=668.2[M+H] + . 1HNMR: (400MHz, CD3OD)δ8.12(s, 1H), 7.86(s, 1H), 5.30-5.14(m, 2H), 4.41-4.31(m, 1H), 4.03-3.90(m, 3H), 3.54-3.48(m, 1H), 3.44(s, 3H), 3.27-3.22(m, 2H), 2.88-2.78(m, 1H), 2.76-2.63(m, 2H), 2.34-2.23(m, 1H), 2.09-1.97(m, 3H), 1.94-1.85(m, 2H). E29-02: LCMS: m / z(ESI)=668.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.12(s, 1H), 7.86(s, 1H), 5.27-5.16(m, 2H), 4.42-4.28(m, 1H), 4.03-3.90(m, 3H), 3.50(dd, J=10.4, 3.6Hz, 1H), 3.44(s, 3H), 3.27-3.22(m, 2H), 2.88-2.78(m, 1H), 2.77-2.22(m, 2H).6Hz, 1H), 3.44(s, 3H), 3.27-3.22(m, 2H), 2.88-2.78(m, 1H), 2.77-2.63(m, 2H), 2.34-2.25(m, 1H), 2.08-1.99(m, 3H), 1.94-1.86(m, 2H).

[0324] Example 30: N-((S)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0] Synthesis of N-((R)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E30-01) & N-((R)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E30-02) [ka]

[0325] To a solution of compound Int26 (70 mg, 0.163 mmol), TEA (0.900 mL, 6.50 mmol), and compound Int2 (34.1 mg, 0.163 mmol) in EA (0.5 mL) was added T3P (2.07 g, 3.25 mmol, 50% in EA). The reaction mixture was stirred at 25 °C for 1 h. Then, the reaction mixture was quenched with HO (50 mL). The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector; column: Ultimate XB-C18, 50 × 250 mm × 10 μm; mobile phase A: NH3OH (10 mmol / L) in HO; mobile phase B: CH3CN; gradient: 47% to 77% B in 30 min, hold at 100% B for 3 min; flow rate: 20 mL / min; Rt = 18.6 min; column temperature: 30 °C; wavelength: 214 nm, 254 nm) to give the title product E30 (30 mg, 24.6%) as a white solid. LCMS: m / z(ESI)=623.2[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.82(d, J=1.2Hz, 1H), 5.22(d, J=9.6Hz, 1H), 4.55-4.40(m, 2H), 4.37-4.32(m, 1H), 3.74(t, J=20.4Hz, 1H), 3.54-3.51(m, 1H), 3.28-3.18(m, 2H), 2.83-2.80(m, 1H), 2.76-2.63(m, 2H), 2.30-2.25(m, 1H), 2.10-1.97(m, 3H), 1.90-1.88(m, 2H).

[0326] Compound E30 (30 mg, 0.034 mmol) was further purified by SFC (column: ChiralPak AD-H Daicel Chemical Industries, Ltd, 250*30 mm ID, 5 um; mobile phase A: Na, mobile phase B: MeOH; A:B = 100:0, flow rate: 120 mL / min; nozzle pressure: 100 Bar; column temperature: 38 ° C; wavelength: 220 nm) to obtain E30-01 (12.5 mg, yield 41.67%) and E30-02 (12.3 mg, yield 41.00%) as white solids. E30-01: LCMS: m / z(ESI)=623.2[M+H] + . 1HNMR(400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.82(d, J=1.2Hz, 1H), 5.22(d, J=9.6Hz, 1H), 4.55-4.40(m, 2H), 4.37-4.32(m, 1H), 3.74(t, J=10Hz, 1H), 3.54-3.51(m, 1H), 3.28-3.18(m, 2H), 2.83-2.80(m, 1H), 2.76-2.63(m, 2H), 2.30-2.25(m, 1H), 2.10-1.97(m, 3H), 1.90-1.88(m, 2H). E30-02: LCMS: m / z(ESI)=623.2[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.37(d, J=2.0Hz, 1H), 8.12(s, 1H), 7.82(d, J=1.2Hz, 1H), 5.22(d, J=9.6Hz, 1H), 4.55-4.40(m, 2H), 4.37-4.32(m, 1H), 3.74(t, J=10Hz, 1H), 3.54-3.51(m, 1H), 3.28-3.18(m, 2H), 2.83-2.80(m, 1H), 2.76-2.63(m, 2H), 2.30-2.25(m, 1H), 2.10-1.97(m, 3H), 1.90-1.88(m, 2H).

[0327] Example 33: Synthesis of N-((S)-(7-((R)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E33-01) [ka]

[0328] To a solution of compound Int31 (160 mg, 0.3 mmol) in DMF (10 mL) was added compound Int2 (93.87 mg, 0.45 mmol), HATU (169.89 mg, 0.45 mmol), and N,N-diisopropylethylamine (115.49 mg, 0.89 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (30 mL) and saturated aqueous NaCl (30 mL). The organic layer was separated, washed with saturated aqueous NaCl (30 mL × 2), and concentrated in vacuo. The residue was purified by column chromatography (eluted with 100% EA) to give the desired product E33 (95 mg). Compound E33 was further separated by SFC (column: RR-Whelk-O14.6*100mm5um; mobile phase A: supercritical CO2, mobile phase B: MeOH [0.2% NH3 (7M in MeOH)]; A:B = 70:30, flow rate: 120 mL / min; column temperature: 40 °C; wavelength: 210 nm) to obtain E33-01 (30 mg, 14.91%) as a white solid. LCMS: m / z(ESI)=676.0[M+H] + . 1 HNMR: (400MHz, CD3OD)δ8.39(s, 1H), 8.17(s, 1H), 7.94(s, 1H), 5.49-5.37(m, 1H), 5.27-5.19(m, 1H), 4.50-4.35(m, 1H), 3.95-3.80(m, 1H), 3.51-3.34(m, 3H), 3.28-3.20(m, 2H), 2.76-2.60(m, 2H), 2.56-2.40(m, 2H), 2.31-2.15(m, 1H), 2.010-2.00(m, 1H), 1.95-1.76(m, 2H), 1.72-1.62(m, 1H), 1.32-1.11(m, 2H).

[0329] Example 35: N-((S)-(7-((S)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E35-01) & N-((R)-(7-((S)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E35-02) )&N-((S)-(7-((R)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E35-03)& Synthesis of N-((R)-(7-((R)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (E35-04) [ka]

[0330] To a solution of compound Int31 (110 mg, 0.228 mmol) in EA (1 mL) was added 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (42.1 mg, 0.273 mmol), TEA (1.26 mL, 9.11 mmol), and T3P (1.44 g, 4.55 mmol, 50% in EA) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with HO (100 mL) at 25 °C. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel eluted with 5% MeOH in DCM to give E35-P1 (16 mg) and E35-P2 (16 mg) as white solids. The first product, E35-P1 (16 mg), was further purified by SFC (column: ChiralPak AD-H Daicel Chemical Industries, Ltd, 250*30 mm ID, 5 μm; mobile phase A: Na, mobile phase B: MeOH; A:B = 100:0, flow rate: 120 mL / min; nozzle pressure: 100 Bar; column temperature: 38 °C; wavelength: 220 nm) to give E35-01 (4.4 mg, 3.12%) and E35-02 (3.1 mg, 2.20%) as white solids.

[0331] The second product, E35-P2 (16 mg), was further purified by SFC (column: ChiralPak AD-H Daicel Chemical Industries, Ltd, 250*30 mm ID, 5 μm; mobile phase A: Na, mobile phase B: MeOH; A:B=100:0, flow rate: 120 mL / min; nozzle pressure: 100 Bar; column temperature: 38°C; wavelength: 220 nm) to give E35-03 (4.7 mg, 3.33%) and E35-04 (1.7 mg, 1.21%) as white solids. E35-01: LCMS: m / z(ESI)=620.2[M+H] + . 1HNMR(400MHz, CD3OD)δ8.42(d, J=2.0Hz, 1H), 8.16(s, 1H), 7.97(d, J=2.0Hz, 1H), 5.51-5.43(m, 1H), 5.24(d, J=8.4Hz, 1H), 4.37-4.27(m, 1H), 3.73-3.66(m, 1H), 3.60-3.44(m, 2H), 3.40-3.33(m, 1H), 2.59-2.34(m, 3H), 2.28-2.15(m, 1H), 2.10-2.00(m, 1H), 1.95-1.75(m, 2H), 1.72-1.63(m, 1H), 1.28-1.10(m, 4H), 1.06-0.99(m, 2H). E35-02: LCMS: m / z(ESI)=620.2[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.44(d, J=2.0Hz, 1H), 8.18(s, 1H), 7.99(d, J=2.0Hz, 1H), 5.52-5.46(m, 1H), 5.26(d, J=8.4Hz, 1H), 4.38-4.28(m, 1H), 3.73-3.66(m, 1H), 3.61-3.45(m, 2H), 3.42-3.35(m, 1H), 2.60-2.37(m, 3H), 2.31-2.17(m, 1H), 2.12-2.02(m, 1H), 1.97-1.78(m, 2H), 1.74-1.64(m, 1H), 1.31-1.13(m, 4H), 1.08-1.00(m, 2H). E35-03: LCMS: m / z(ESI)=620.2[M+H] + . 1HNMR(400MHz, CD3OD)δ8.41(d, J=2.0Hz, 1H), 8.18(s, 1H), 7.97(d, J=2.0Hz, 1H), 5.49-5.42(m, 1H), 5.26(d, J=8.4Hz, 1H), 4.48-4.37(m, 1H), 3.91(t, J=10.0Hz, 1H), 3.54-3.37(m, 3H), 2.60-2.36(m, 3H), 2.31-2.18(m, 1H), 2.11-2.02(m, 1H), 1.96-1.79(m, 2H), 1.74-1.65(m, 1H), 1.29-1.11(m, 4H), 1.08-1.00(m, 2H). E35-04: LCMS: m / z(ESI)=620.2[M+H] + . 1 HNMR(400MHz, CD3OD)δ8.41(d, J=2.0Hz, 1H), 8.18(s, 1H), 7.97(d, J=2.0Hz, 1H), 5.49-5.42(m, 1H), 5.26(d, J=8.4Hz, 1H), 4.48-4.37(m, 1H), 3.92(t, J=10.0Hz, 1H), 3.56-3.37(m, 3H), 2.61-2.35(m, 3H), 2.31-2.16(m, 1H), 2.11-2.02(m, 1H), 1.97-1.78(m, 2H), 1.75-1.65(m, 1H), 1.30-1.11(m, 4H), 1.09-1.00(m, 2H).

[0332] Example 36: Synthesis of N-((S)-(7-((R)-2-cyano-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(difluoromethylene)cyclohexyl)methyl)-4-(3-fluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E36-01) [ka]

[0333] To a solution of compound Int31 (40 mg, 0.083 mmol) and compound Int34 (21.61 mg, 0.124 mmol) in DMF (5 mL) was added HATU (47.19 mg, 0.124 mmol) and DIPEA (32.08 mg, 0.248 mmol). The reaction mixture was then stirred at 25 °C for 1.5 h. The reaction mixture was extracted with EtOAc (20 mL), washed with brine (20 mL × 3), and the combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by pre-HPLC (0.1% HCOOH, 0%-80% MeCN in HO) to give the dithioate product E36-01 (15 mg, 28.35%) as a white solid. LCMS: m / z(ESI)=640.0[M+H] + . 1 HNMR(400MHz, DMSO-d6): δ9.44(d, J=9.2Hz, 1H), 8.36(s, 1H), 8.27(s, 1H), 8.02(s, 1H), 7.91(s, 1H), 5.36(t, J=7.6Hz, 1H), 5.14(t, J=8.4Hz, 1H), 4.56-4.49(m, 2H), 4.41(t, J=6.0Hz, 1H), 3.78(t, J=10.4Hz, 1H), 3.27-3.22(m, 1H), 2.99(t, J=7.6Hz, 2H), 2.43-2.28(m, 3H), 2.15-1.94(m, 4H), 1.80(s, 2H), 1.60(s, 1H), 1.23-1.01(m, 3H).

[0334] HT-29 cell-based human IL-17A neutralization assay IL-17A can stimulate epithelial and other cells to secrete CXCL1 / GROα. To test the ability of compounds to neutralize the biological activity of IL-17A, an HT-29 cell-based human IL-17A neutralization assay was used.

[0335] HT-29 cells (human colon adenocarcinoma epithelial cells, ATCC #HTB-38) were grown in tissue culture flasks in McCoy's 5A (modified) medium (Gibco #16600-082) supplemented with 10% FBS (complete medium) until 50-80% confluent. 20,000 HT-29 cells (in 190 μl) were plated into each treatment well of a 96-well plate (Costar #3599). Compounds were serially diluted in complete medium from 80,000 nM to 1 nM, and 10 μl of compound solution was added to each treatment well. Next, 2 μl of human IL-17A (R&D #7955-IL) in DPBS was added to each treatment well at a final concentration of 200 ng / ml. The cells were cultured for 48 hours in an incubator (37°C, 5% CO2).

[0336] After incubation, the culture supernatant was centrifuged (500 × g) at room temperature for 5 minutes, and CXCL1 / GROα levels were measured using a commercially available ELISA kit (R&D #DY275). Treatment with medium alone was designated NC, and treatment with IL-17A was designated BK. The IC50 values ​​of the compounds were calculated using GraphPad Prism 8 software.

[0337] The results are shown below in Table 1. The IC50 values ​​provided for the examples demonstrate the activity of the compounds of claim 1 as inhibitors of IL-17A. [Table 2] JPEG2026501331000080.jpg192170

[0338] Oral bioavailability in mice The oral bioavailability (%F) of compounds of the present invention can be determined in mice by measuring the 24-hour plasma AUC (nM*hr) after intravenous and oral administration, essentially as follows: Male mice (n=6) were administered the compound via an intravenous (IV) bolus (1 mg / kg) or oral (3 or 10 mg / kg) administration. For intravenous administration, a vehicle of 5% DMSO / 10% solutol / 85% saline was used at a volume of 5 mL / kg. For oral administration, a vehicle of 5% DMSO / 10% solutol / 85% saline was used at a volume of 10 mL / kg. Blood was sampled by saphenous venipuncture using K2EDTA as an anticoagulant. Approximately 20 μL of blood was collected in a capillary tube and transferred to a card as a dried blood spot. The card was allowed to dry for at least 2 hours before shipping for analysis. The blood concentration of each compound in each mouse was measured by liquid chromatography / tandem mass spectrometry at 0.08 (intravenous administration only), 0.25, 0.5, 0.75, 2, 4, 8, and 24 hours. Oral bioavailability (%F) was calculated using the following formula: [F = (AUC / dose)po / (AUC / dose)iv]. The oral bioavailability results of the examples are shown in the table below. These data demonstrate the pharmacologically advantageous oral availability of various compounds of the present invention.

[0339] [Table 3]

Claims

1. A compound of formula (I) below, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: 【Chemistry 1】 In formula (I), W is hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl is deuterium, halogen, CN or OR 9 and optionally substituted with one or more groups selected from the group consisting of: R 1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl or -C 1-6 Alkylene -CH=NOR 8 These all represent deuterium, halogen, CN, -OC 1-3 Alkyl, -NH-C 1-4 Alkyl or -N(C 1-4 alkyl) 2 and optionally substituted with one or more groups selected from the group consisting of: R 2 is C 4-8 Represents cycloalkyl, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 optionally substituted by alkynyl; R 3 -R 5 are each independently hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 represents alkynyl; R 6 and R 7 are each independently hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl is deuterium, halogen, CN or OR 9 and optionally substituted with one or more groups selected from the group consisting of: Or, R 6 , R 7 and the carbons to which they are attached are deuterium, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 It may form a 3-7 membered ring which may be substituted with alkynyl or CN; R 8 is hydrogen or C 1-6 represents alkyl; R 9 is C 1-6 Alkyl, C 3-6 Cycloalkyl, 1-C 2-6 Alkenyl or C 2-6 It represents alkynyl.

2. W is H, D, -(CH 2 ) 1-3 OCH 3 , -(CH 2 ) 1-3 CN, -(CH 2 ) 1-3 CHF 2 , -(CH 2 ) 1-3 CF 2 CH 3 , -(CH 2 ) 1-3 CF 3 or -(CH 2 ) 1-3 OCF 3 more typically, W represents H, D, -(CH 2 ) 1-3 OCH 3 , -(CH 2 ) 1-3 CN, -(CH 2 ) 1-3 CHF 2 or -(CH 2 ) 1-3 OCF 3 Specifically, W represents H, D, -(CH 2 ) 1-3 OCH 3 , -(CH 2 ) 1-3 CN or -(CH 2 ) 1-3 CHF 2 More specifically, W represents H, D, -(CH 2 ) 1-3 OCH 3 or -(CH 2 ) 1-3 represents CN; or R 1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl or -C 1-6 Alkylene -CH=NOR 8 Typically, R 1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 represents alkynyl, more typically R 1 is C 1-6 Alkyl, -C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl or -C 2-6 represents alkenyl; or R 2 represents a ring structure selected from the group consisting of the A1, A2, A3, A4, A5, A6, A7, A8, A9 or A10 groups: 【Chemistry 2】 Here, " 【Transformation 3】 " is a list of deuterium, halogens, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 represents the bond to the rest of the molecule, optionally substituted by alkynyl; or R 3 are hydrogen, deuterium, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 represents alkynyl; typically, R 3 are hydrogen, deuterium, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or C 2-6 represents alkynyl; specifically, R 3 are hydrogen, deuterium, halogens, C 3-6 Cycloalkyl or C 2-6 represents alkynyl, more specifically R 3 represents hydrogen, deuterium or a halogen; or R 4 are hydrogen, deuterium, halogens, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl or -OC 3-6 represents cycloalkyl; typically, R 4 are hydrogen, deuterium, halogens, -OH, C 1-6 Alkyl or C 3-6 represents cycloalkyl, more typically R 4 is hydrogen, deuterium, halogen, -OH or C 1-6 represents alkyl, and even more typically R 4 represents hydrogen, deuterium, halogen or -OH; or R 5 are hydrogen, deuterium, halogens, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 2-6 Alkenyl or C 2-6 represents alkynyl; typically, R 5 are hydrogen, deuterium, halogens, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl or -OC 1-6 represents alkyl, more typically R 5 is hydrogen, deuterium, halogen, -OH or C 1-6 represents alkyl, and even more typically R 5 represents hydrogen, deuterium, halogen or -OH; or R 6 and R 7 are each independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 represents alkynyl, typically R 6 and R 7 are each independently 2-6 Alkenyl or C 2-6 represents alkynyl, 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

3. 3. The compound of formula (I) according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (IIa), (IIb), (IIc) or (IId), or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: 【Chemistry 4】 where R 1 From R 7 is as defined in claim 1.

4. The compound of formula (I) according to claim 1 or 2, wherein the compound of formula (I) is represented by any one of the following formulae (Xa)-(Xj), or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: 【Transformation 5】 where W, R 1 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined in claim 1.

5. 3. The compound of formula (I) according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof: 【Transformation 6】 where W, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined in claim 1; m = 0, 1 or 2; n = 0, 1, 2 or 3; R 11 = H or F; R 12 = H or F; R 13 = H or F.

6. 3. The compound of formula (I) according to claim 1 or 2, wherein the compound of formula (I) is selected from the following: 【Transformation 7】 【change】 【change】 【change】

7. Use of a compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof in the preparation of a medicament for treating and / or preventing a disease modulated by IL-17A.

8. Use of a compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, for treating and / or preventing a disease mediated by IL-17A.

9. A method for treating and / or preventing a disease mediated by IL-17A, comprising administering to a subject to be treated a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

10. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

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