IL-17A modulators

Abstract

Disclosed herein are modulators of IL-17A. The present disclosure provides a compound of the following Formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

Description

Technical Field

[0001] The present disclosure relates to compounds having a [5.6]-fused imidazopyridazine core, pharmaceutical compositions containing the same, and methods of using the same in the treatment of psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis. Background Art

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

[0003] The IL-17 family consists of six cytokines (IL-17A to IL-17F). IL-17A is produced by Th17 cells and CD8 + T cells, γδ cells, NK cells, NKT cells, macrophages and dendritic cells express, and Th17 is involved in inflammation and autoimmunity. IL-17 receptor (IL-17R) refers to a heterodimer formed by IL-17RA and IL-17RC subunits. IL-17A, C receptors are mainly present in epithelial and mesenchymal cells. IL-17A acts as a homodimer (IL-17A / A) or a heterodimer (IL-17A / F) so that signal transduction passes through IL-17R (Isono, F. et al., Inhibiting RORgt / Th17 axis for autoimmune disorders, Drug Discovery Today (2014) Vol.19 (8) 1205-1211). The combination of IL-17A and 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-a, IL-1β, PGE2, and IFN-γ, as well as a variety of chemokines and other effectors (Gaffen, Arthritis Research & Therapy 6:240-247 (2004)).

[0004] Overexpression of IL-17A has been implicated in a variety of diseases, including but not limited to rheumatoid arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, angiogenesis, atherosclerosis, asthma, and multiple sclerosis. In recent years, IL-17A-producing Th17 cells have also been implicated in certain cancers (Ji and Zhang, Cancer Immunol Immunother 59:979-987 (2010)). For example, IL-17-expressing Th17 cells have been shown to be involved in multiple myeloma (Prabhala et al., Blood, online DOI 10.1182 / blood-2009-10-246660, April 15 (2010)) and to be associated with poor prognosis in patients with hepatocellular carcinoma (HCC) (Zhang et al., J Hepatology 50:980-89 (2009)).

[0005] Currently, there are no highly effective, orally administered agents for moderate or severe psoriasis. In some cases, inhibition of IL-17A can increase susceptibility to opportunistic infections. Orally available small molecule inhibitors have relatively short half-lives to improve management of this risk by allowing patients to stop taking the drug and rapidly clear the inhibitor from the body. Summary of the Invention

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

[0007] In one aspect, the present disclosure provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof:

[0008]

[0009] In formula (I),

[0010] W represents hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR9;

[0011] R1 represents 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; any of which may be optionally substituted by one or more of the following groups: deuterium, halogen, CN, -OC 1-3 Alkyl, -NH-C 1-4 Alkyl, or -N(C 1-4 Alkyl)2;

[0012] R2 represents C 4-8 Cycloalkyl, which may be optionally substituted by deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl;

[0013] R3-R5 each independently represent: 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 Alkynyl;

[0014] R6 and R7 each independently represent: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR9;

[0015] Alternatively, R6, R7 and the carbon to which they are attached may form a 3-7 membered ring, which may be substituted by deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or CN;

[0016] R8 represents hydrogen or C 1-6 alkyl;

[0017] R9 means: C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 2-6 Alkenyl, or C 2-6 Alkynyl.

[0018] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0019] 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.

[0020] 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 treating and / or preventing a disorder requiring administration of an IL-17 function modulator.

[0021] 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 manufacture of a medicament for treating and / or preventing a condition requiring administration of an IL-17 function modulator.

[0022] The present invention also provides a method for treating and / or preventing a condition requiring administration of an IL-17 function modulator, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof. DETAILED DESCRIPTION

[0023] For use in medicine, the salt of the compound of formula (I) will be a pharmaceutically acceptable salt. However, other salts can be used to prepare the compound of formula (I) or its pharmaceutically acceptable salt. Standard principles for selecting and preparing pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts, which can be formed, for example, by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0024] The present invention also includes within its scope co-crystals of the compound of formula (I). The technical term "co-crystal" is used to describe the presence of neutral molecular components in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutical co-crystals allows the crystalline form of the active pharmaceutical ingredient to be modified, thereby changing its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters & L. Quere, RSC Publishing, 2012).

[0025] Suitable alkyl groups that may be present on the compounds used in the present invention include straight chain and branched C 1-6 Alkyl groups, such as C 1-4 Alkyl groups. Typical examples include: methyl and ethyl groups, and linear or branched propyl, butyl, and pentyl groups. Specific alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. Derived expressions such as "C 1-6 Alkoxy", "C 1-6 Alkylthio", "C 1-6 Alkylsulfonyl", and "C 1-6 "Alkylamino" should be understood accordingly.

[0026] Suitable alkenyl groups that may be present on the compounds used in the present invention include straight chain and branched C 2-6 Alkenyl groups, such as C 2-4 Alkenyl groups. Typical examples include vinyl groups, and linear or branched propenyl, butenyl, and pentenyl groups. Specific alkenyl groups include vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0027] Suitable alkynyl groups that may be present on the compounds used in the present invention include straight chain and branched C 2-6 Alkynyl groups, such as C 2-4 Alkynyl groups. Typical examples include ethynyl groups, as well as straight-chain or branched propynyl, butynyl, and pentynyl groups. Specific alkynyl groups include: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0028] The term "C 3-6 "Cycloalkyl" refers to a monovalent group of 3 to 6 carbon atoms derived from a saturated monocyclic or bicyclic hydrocarbon. Suitable C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In general, the bicyclic hydrocarbon refers to a spirocyclic hydrocarbon or a bridged bicyclic hydrocarbon, such as

[0029] As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine, and iodine atoms, typically fluorine, chlorine, or bromine.

[0030] As used herein, unless otherwise indicated, the term "a compound of formula (I)" generally includes the compound of formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

[0031] As used herein, the term "solvate" for the purposes of the present invention refers to a form of a compound or its salt in which the solvent molecules form a stoichiometric complex in the solid state, and includes, but is not limited to, water, ethanol, and methanol. A hydrate is a specific form of solvate in which the solvent molecules are water. A hydrate of a compound of the present invention or its salt is a stoichiometric composition of the compound or salt with water, such as a hemihydrate, a monohydrate, or a dihydrate.

[0032] If the compound of formula (I) has one or more asymmetric centers, it may exist as enantiomers accordingly. If the compound according to the invention has two or more asymmetric centers, it may also exist as diastereomers. The present invention should be understood to extend to the use of all such enantiomers and diastereomers, as well as to mixtures thereof in any proportion, including racemates. Unless otherwise indicated, formula (I) and the formulas described below are intended to represent all individual stereoisomers and all possible mixtures thereof. In addition, the compound of formula (I) may exist as tautomers, for example, a ketone (CH2C=O) is equivalent to an enol (CH=CHOH) tautomer, or an amide (NHC=O) is equivalent to a hydroxyimine (N=COH) tautomer. Unless otherwise indicated, formula (I) and the formulas described below are intended to represent all individual tautomers and all possible mixtures thereof.

[0033] It will be understood that each atom present in formula (I) or in the formulae described hereinafter may exist in the form of virtually any of its naturally occurring isotopes, with the most abundant isotopes being preferred. Thus, for example, each hydrogen atom present in formula (I) or in the formulae described hereinafter may be 1 H. 2 H (deuterium), or 3 H (tritium) atoms are present, preferably 1 H. Similarly, for example, each carbon atom present in formula (I) or in the formulae described hereinafter may be 12 C. 13 C. or 14 C atoms are present, preferably 12 C.

[0034] The present disclosure provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof:

[0035]

[0036] In formula (I),

[0037] W represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl may be optionally substituted by: deuterium, halogen, CN, or OR9. Typically, W represents: H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, -(CH2) 1-3 CHF2, -(CH2) 1-3 CF2CH3, -(CH2) 1-3 CF3, or -(CH2) 1-3 OCF3; more typically W represents: H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, -(CH2) 1-3 CHF2, or -(CH2) 1-3 OCF3; in particular, W represents: H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, or -(CH2) 1-3 CHF2, more particularly W represents: H, D, -(CH2) 1-3 OCH3, or -(CH2) 1-3 CN.

[0038] R1 means: 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; any of which may be optionally substituted by one or more of the following groups: hydrogen, deuterium, halogen, CN, -OC 1-3 Alkyl, -NH-C1-4 Alkyl, or -N(C 1-4 Typically, R1 represents: 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, especially R1 represents: 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 particularly R1 represents: C 1-6 Alkyl, -C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl, or -C 2-6 Alkenyl.

[0039] R2 represents C 4-8 Cycloalkyl, which may be optionally substituted by deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; in particular the ring structure is selected from A1, A2, A3, A4, A5, A6, A7, A8, A9, or A10 groups;

[0040]

[0041] in represents a bond to the rest of the molecule, any of which may be optionally substituted by: deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; typically R2 represents a structure selected from A1, A2, A3, A4, A7, A8, A9, or A10; in particular R2 represents a structure selected from A2, A4, A7, A8, A9, or A10; more in particular R2 represents a structure selected from A2, A4, A7, A9, or A10.

[0042] R3-R5 each independently represent: 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 Alkynyl.

[0043] In one embodiment, R3 represents: 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 Alkynyl; typically R3 represents: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, or C 2-6 Alkynyl; in particular R3 represents: hydrogen, deuterium, halogen, C 3-6 Cycloalkyl, or C 2-6 Alkynyl, more particularly R3, represents: hydrogen, deuterium or halogen.

[0044] In one embodiment, R4 represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, or -OC 3-6 Cycloalkyl; typically R4 represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, or C 3-6 Cycloalkyl, in particular R4 represents: hydrogen, deuterium, halogen, -OH, or C 1-6 Alkyl, more particularly R4 represents: hydrogen, deuterium, halogen, or -OH.

[0045] In one embodiment, R5 represents: 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 Alkynyl; typically R5 represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, or -OC 1-6 Alkyl, in particular R5 represents: hydrogen, deuterium, halogen, -OH, or C 1-6 Alkyl, more particularly R5 represents: hydrogen, deuterium, halogen, or -OH.

[0046] R6 and R7 each independently represent: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl group may be optionally substituted by one or more of the following groups: deuterium, halogen, CN, or OR9; typically R6 and R7 each independently represent: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, in particular R6 and R7 each independently represent: C 2-6 Alkenyl, or C 2-6 Alkynyl;

[0047] Alternatively, R6, R7 and the carbon to which they are attached may form a 3-7 membered ring, which may be optionally substituted with deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or CN;

[0048] R8 represents hydrogen or C 1-6 alkyl;

[0049] R9 means: C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 2-6 Alkenyl, or C 2-6 Alkynyl.

[0050] In one embodiment, W represents -CH2OMe. In one embodiment, W represents -CH2CN. In one embodiment, W represents CH2CF2H. In one embodiment, W represents CH2CF3.

[0051] Suitably, the present invention provides a compound of formula (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt thereof:

[0052]

[0053] wherein R1 to R7 are as defined above.

[0054] In one embodiment, the compound of formula (I) is represented by any one of the following formulas (Xa) to (Xj):

[0055]

[0056] wherein W, R1, R3, R4, R5, R6, and R7 are as defined above.

[0057] Typically, the compound of formula (I) is represented by any one of formulas (Xa), (Xb), (Xc), (Xd), (Xg), (Xh), (Xi), and (Xj).

[0058] Suitably, the compound of formula (I) is represented by any one of formulae (Xb), (Xc), (Xd), (Xg), (Xh), (Xi), and (Xj).

[0059] Particularly, the compound of formula (I) is represented by any one of formulas (Xb), (Xi), and (Xj).

[0060] Generally, the present invention provides compounds of formula (IIIa), (IIIb), or (IIIc):

[0061]

[0062] wherein W, R2, R3, R4, R5, R6, and R7 are as defined above; 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.

[0063] Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying examples, their pharmaceutically acceptable salts, their isomers, or their solvates.

[0064] The compounds according to the invention are useful in the treatment and / or prevention of various human ailments, including inflammatory and autoimmune disorders.

[0065] The compounds according to the invention are useful for the treatment and / or prevention of pathological conditions which are mediated by the proinflammatory IL-17 cytokine or which are associated with increased levels of the proinflammatory IL-17 cytokine.

[0066] In general, the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, 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, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonic disease, peritonitis, psoriasis, atopic dermatitis, dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, type I diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory disorders of the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic disorders including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, scleroderma, or systemic sclerosis, cancer (both solid tumors and hematologic malignancies, solid tumors such as melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, hematologic malignancies particularly acute myelogenous leukemia leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, adenocarcinoma, and colon cancer), heart disease, including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydia, and pain (particularly pain associated with inflammation).

[0067] WO 2009 / 089036 discloses that modulators of IL-17 activity can be administered to inhibit or reduce the severity of ocular inflammatory conditions, particularly ocular surface inflammatory conditions, including dry eye syndrome (DES). Therefore, the compounds according to the present invention can be used to treat and / or prevent IL-17-mediated ocular inflammatory conditions, particularly IL-17-mediated ocular surface inflammatory conditions, including dry eye syndrome. Ocular surface inflammatory conditions include: dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal 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 dry eye categories include: keratoconjunctivitis sicca (KCS), Sjögren syndrome, keratoconjunctivitis sicca associated with Sjögren syndrome, keratoconjunctivitis sicca not associated with Sjögren syndrome, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorders, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporative loss.

[0068] Illustratively, the compounds of the present invention are useful in treating and / or preventing a pathological condition 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 airway 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, ankylosing spondylitis and other spondyloarthropathies, cancer, and pain (particularly pain associated with inflammation).

[0069] Suitably, the compounds of the present invention may be used to treat and / or prevent psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis, or ankylosing spondylitis.

[0070] The present invention also provides a pharmaceutical composition comprising the compound according to the present invention as described above, its pharmaceutically acceptable salt, its isomer, or its solvate, and one or more pharmaceutically acceptable carriers.

[0071] The pharmaceutical compositions according to the present invention may be formulated for oral, buccal, parenteral, nasal, topical, ophthalmic, or rectal administration, or for administration by inhalation or insufflation.

[0072] The amount of a compound according to the invention required for the prevention or treatment of a particular disease will vary depending on the compound chosen and the condition of the patient to be treated. However, in general, the daily dosage range may be approximately 10 ng / kg to 1000 mg / kg, typically 100 ng / kg to 100 mg / kg, for example approximately 0.01 mg / kg to 40 mg / kg body weight for oral or buccal administration, approximately 10 ng / kg to 50 mg / kg body weight for parenteral administration, and approximately 0.05 mg to approximately 1000 mg, for example approximately 0.5 mg to approximately 1000 mg, for nasal administration or administration by inhalation or insufflation.

[0073] If desired, the compounds according to the invention may be co-administered with additional pharmaceutically active agents, such as anti-inflammatory molecules.

[0074] Examples of compounds of formula (I) in the present disclosure include the following:

[0075]

[0076]

[0077]

[0078] In another aspect, the present disclosure provides use of the compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof in the preparation of a medicament for treating a disease regulated by IL-17A.

[0079] In a further aspect, the present disclosure provides use of the 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.

[0080] In a further aspect, the present disclosure provides a method for treating a disease mediated by IL-17A, comprising the step of administering a therapeutically effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof to a subject to be treated.

[0081] In one embodiment of the present disclosure, the step of administering a therapeutically effective amount of a compound of the present application, 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 application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof to a subject by conventional means such as oral administration, injection, or topical application.

[0082] In a further aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof.

[0083] In one embodiment of the present disclosure, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, and a pharmaceutical carrier such as ionized water.

[0084] abbreviation

[0085] Ac acetyl

[0086] ACN acetonitrile

[0087] Boc tert-butyloxycarbonyl

[0088] br broad peak

[0089] Butyl

[0090] Cbz carbobenzoxy

[0091] CDI 1,1'-Carbonyldiimidazole

[0092] δ NMR chemical shift, in parts per million downfield from the standard d Doublet

[0093] d day

[0094] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0095] DCE 1,2-dichloroethane

[0096] DCM dichloromethane

[0097] DIAD Diisopropyl azodicarboxylate

[0098] DIEA Diisopropylethylamine

[0099] DMF N,N-dimethylformamide

[0100] DMSO dimethyl sulfoxide

[0101] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0102] EA Ethyl acetate

[0103] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0104] ESI electrospray ionization

[0105] Et ethyl

[0106] g grams

[0107] h hour

[0108] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0109] HBTU O-Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0110] HPLC High-pressure liquid chromatography

[0111] Hz Hertz

[0112] i different

[0113] J coupling constant (NMR spectrum)

[0114] L liter

[0115] LC liquid chromatography

[0116] LiHMDS lithium bis(trimethylsilyl)amide

[0117] m milli, or multiple

[0118] m / z mass-to-charge ratio

[0119] M+ parent molecular ion

[0120] M mole (mole / liter), or trillion

[0121] Me methyl

[0122] min

[0123] μ micro

[0124] MS

[0125] NBS N-bromosuccinimide

[0126] NCS N-chlorosuccinimide

[0127] n positive

[0128] n nanometer

[0129] N nominal (normal) (equivalent concentration)

[0130] NMR Nuclear Magnetic Resonance

[0131] NMP N-Methyl-2-pyrrolidone

[0132] Pd / C Palladium on Carbon

[0133] PE petroleum ether

[0134] Ph Phenyl

[0135] Pr Propyl

[0136] Psi pounds per square inch

[0137] Pv Pivaloyl

[0138] quin quintet

[0139] rt room temperature

[0140] R t Retention time

[0141] s single peak

[0142] SFC Supercritical Fluid Chromatography

[0143] Uncle T

[0144] t Triplet

[0145] TEA triethylamine

[0146] TFA trifluoroacetic acid

[0147] THF Tetrahydrofuran

[0148] TLC thin layer chromatography

[0149] T3P Propanephosphonic acid cyclic trimer

[0150] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0151] Intermediate synthesis

[0152] 1. Synthesis of 4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int 1)

[0153]

[0154] Synthesis of (2E)-2-cyano-2-hydroxyimino-N-phenyl-acetamide 2

[0155] At 25 ° C, 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 NaNO2 (4.74 g, 68.70 mmol, 2.20 eq) in H2O (10 mL). The resulting mixture was stirred at 25 ° C for 18 hours. 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 80g The product was purified by silica flash column (gradient of 0-50% ethyl acetate / petroleum ether at 60 mL / min) to afford compound 2 (5.4 g, 89.62%) as a yellow solid.

[0156] LCMS (ESI): m / z = 190.2 [M+H] + .

[0157] 1 H NMR (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).

[0158] Synthesis of 4-amino-N-phenyl-1,2,5-oxadiazole-3-carboxamide 3

[0159] To a solution of compound 2 (1 g, 5.29 mmol, 1 eq) in THF (20 mL) was added hydroxylamine (453.97 mg, 6.87 mmol, 1.3 eq) (50% solution in water) and stirred at 50 ° C for 16 hours. Subsequently, the resulting mixture was added CDI (1.29 g, 7.93 mmol, 1.5 eq) at 25 ° C and continued to stir for 2 hours. 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by flash silica gel chromatography ( 120g Purification by silica flash column (gradient of 0-30% ethyl acetate in petroleum ether at 100 mL / min) afforded the title compound 3 (7 g, 64%) as a yellow solid.

[0160] LC-MS (ESI): m / z = 205.1 [M+H] + .

[0161] 1 H NMR (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).

[0162] Synthesis of 4-chloro-N-phenyl-1,2,5-oxadiazole-3-carboxamide

[0163] 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 H O (2.5 mL) at 0 ° C. and stirred at 0 ° C. for 0.5 h. Subsequently, the resulting mixture was stirred at 25 ° C. for 17.5 hours. The reaction mixture was quenched with NH Cl (aqueous solution, 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 40g The product was purified by silica flash column (gradient of 0-20% ethyl acetate / petroleum ether at 40 mL / min) to afford the title compound 4 (2.0 g, 43.83%) as a white solid.

[0164] LC-MS (ESI): m / z = 224.0 [M+H] + .

[0165] 1 H NMR (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).

[0166] Synthesis of N-phenyl-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide 5

[0167] 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 hours. Subsequently, 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 hours. The reaction was quenched with water (40 mL) at 25 ° C and then extracted with EtOAc (100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound 5 (1 g, crude product) as a yellow solid. Compound 5 was used in the next step without purification.

[0168] LC-MS (ESI): m / z = 288.1 [M+H] + .

[0169] 1 H NMR (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).

[0170] Synthesis of tert-butyl N-phenyl-N-[4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carbonyl]carbamate

[0171] 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 hours. Subsequently, the reaction mixture was concentrated under reduced pressure to remove DCM to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g The mixture was purified by silica flash column using a 20 mL / min gradient of 0-10% ethyl acetate / petroleum ether to afford the title compound 6 (900 mg, 60.73%) as a white solid.

[0172] LC-MS (ESI): m / z = 797.2 [2M + 23] + .

[0173] 1H NMR (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).

[0174] Synthesis of 4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxylic acid (Int 1)

[0175] 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 hours. Subsequently, the reaction mixture was 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 HCl (1 M) until pH = 4 and then extracted with EtOAc (20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the title product Int1 (150 mg, crude product) as a yellow oil, which was used in the next step without purification.

[0176] 1 H NMR (400MHz, DMSO-d6) δ12.30 (br s, 1H), 4.91-4.80 (m, 2H).

[0177] 2. Synthesis of 4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 2)

[0178]

[0179] Synthesis of ethyl 6,6,6-trifluoro-3-oxohexanoate 8

[0180] 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-trifluorobutyric 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 then filtered, and the filtrate was washed with 1M HCl (100 mL), H₂O (500 mL), and brine (500 mL). The organic layer was then dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a yellow oil. The oil was then dissolved in 700 mL of EtOH and refluxed overnight. The reaction mixture was then 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.

[0181] 1 H NMR (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).

[0182] Synthesis of ethyl (2E)-6,6,6-trifluoro-2-(hydroxyimino)-3-oxohexanoate

[0183] At room temperature, to a solution of compound 8 (17.77g, 83.75mmol) and concentrated HCl (69.80mL, 837.54mmol) in MeCN (300mL) was added dropwise a solution of sodium nitrite (12.71g, 184.26mmol) in H o (40mL, 2213.10mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 400mL of H o and extracted with EtOAc (100mL x 2), washed with brine (100mL), dried over anhydrous Na sO , and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO , petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to obtain compound 9 (15.42g, 76.34%) as a yellow oil.

[0184] 1 H NMR (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).

[0185] Synthesis of ethyl (2E,3E)-6,6,6-trifluoro-2,3-bis(hydroxyimino)hexanoate

[0186] To a 250mL three-necked round-bottom flask with a thermometer was added compound 9 (15.42g, 63.94mmol), a stirring rod, and EtOH (75mL), which was then cooled to 0°C in an ice / water bath and filled with hydroxylamine hydrochloride (13.33g, 191.82mmol) and sodium acetate (10.49g, 127.88mmol), followed by stirring at 90°C for 16 hours. The reaction mixture was then cooled to room temperature and filtered, and the filtrate was concentrated to dryness under vacuum to give a brown oil. Subsequently, the oil was treated with H2O (100mL), followed by dropwise addition of NaOH (1M) until pH = 9-10, extracted with DCM (100mL x 3), and the combined extracts were washed with brine (200mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum to give a brown oil. The oil was then chromatographed on silica gel (0-15% EtOAc / pet ether) to give the title compound 10 (4.7 g, 28.69%) as a yellow oil.

[0187] 1 H NMR (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).

[0188] Synthesis of ethyl 4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxylate 11

[0189] Compound 10 (2.7 g, 10.54 mmol), a stirring 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 for 30 minutes while heating at 60 ° C via microwave irradiation and then cooled to room temperature. The reaction mixture was concentrated to dryness under vacuum to give the crude product as a yellow oil. The oil was subjected to silica gel chromatography (0-1% MeOH / DCM) to give compound 11 (639 mg, 25.46%) as a colorless oil.

[0190] 1 H NMR (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).

[0191] Synthesis of 4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 2)

[0192] To a 20 mL microwave tube was added compound 11 (20 mg, 0.084 mmol), a stirring bar, LiOH·H 2 O (0.17 mL, 0.17 mmol), and THF (0.5 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness under vacuum to give the desired product Int 2 (178 mg, crude product) as a colorless oil.

[0193] 1 H NMR (400MHz, DMSO-d6) δ3.28-3.09(m,2H),2.86-2.66(m,2H).

[0194] 3. Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int 3) and (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int 4)

[0195]

[0196] Synthesis of cyclopent-3-en-1-yl benzoate 13

[0197] 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. Subsequently, PhCOCl (66.8 g, 472 mmol) was slowly added and stirred at 25 ° C 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 phases were washed with NH4OH (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluted with (30% EtOAc in PE) to obtain the title compound 13 (20.0 g, 22.3%) as a yellow oil.

[0198] 1 H NMR (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).

[0199] Synthesis of 6,6-difluorobicyclo[3.1.0]hexane-3-ylbenzoate 14

[0200] 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 TMSCF3 (30.2 g, 212 mmol). The reaction mixture was stirred at 75 ° C for 24 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel flash column eluting with 30% EtOAc in PE to obtain the title compound 14 (21 g, 82.96%) as a yellow oil.

[0201] LC-MS (ESI): m / z = 239.0 [M+H] + .

[0202] Synthesis of 6,6-difluorobicyclo[3.1.0]hexane-3-ol 15

[0203] 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 H2O (100 mL). The reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated and the residue was extracted with DCM (200 mL x 3). The combined organic phase was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification using (20% EtOAc in PE) to give the title compound 15 (15.0 g, 50.8%) as a yellow oil.

[0204] LCMS: m / z (ESI) = 135.0 [M+H] + .

[0205] Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int 3) and (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl 4-methylbenzenesulfonate (Int 4)

[0206] Pyridine (31.4mL, 388mmol) and TsCl (37.0g, 193mmol) are added to a solution of compound 15 (13.0g, 96.9mmol) in DCM (200mL). Subsequently, the reaction mixture is stirred at 25°C for 12 hours. The reaction mixture is poured into water (200mL) and extracted with EtOAc (30mL x 3). The combined organic phase is washed with water (30mL), brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue is purified by silica gel flash column purification, eluted with 10% EA in PE, to obtain the desired product Int 3 (13.0g, 32.57%) as a yellow oil and Int 4 (3.5g, 12.53%) as a yellow solid.

[0207] LCMS: m / z (ESI) = 311.0 [M+Na] + .

[0208] 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 (Int 5)

[0209]

[0210] Synthesis of ethyl 2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)-2-((diphenylmethylene)amino)acetate 17

[0211] To a solution of compound Int 4 (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). Subsequently, the reaction mixture was stirred at 100 ° C under N2 for 16 hours. Subsequently, the reaction mixture was quenched with H2O (30 mL). The resulting solution was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluted with (10% EtOAc in PE) to obtain the title compound 17 (8.90 g, 33.6%) as a yellow oil.

[0212] LCMS: m / z (ESI) = 383.9 [M+H] + .

[0213] Synthesis of ethyl 2-amino-2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)acetate 18

[0214] To a solution of compound 17 (8.80 g, 22.9 mmol) in THF (60 mL) was added HCl (2N) (15 mL, 30.0 mmol). Subsequently, the reaction mixture was stirred at 25 ° C 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 neutralized with saturated sodium bicarbonate solution to pH = 8 and then 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.

[0215] LCMS: m / z (ESI) = 220.0 [M+H] + .

[0216] Synthesis of ethyl 2-(((benzyloxy)carbonyl)amino)-2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetate 19

[0217] 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 H2O (20 mL) was added CbzCl (3.69 mL, 26.20 mmol) at 0 ° C. Subsequently, the reaction mixture was stirred at 0 ° 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 x 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluted with (40% EtOAc in PE) to obtain compound 19 (3.70 g, 95.6%) as a white solid.

[0218] LCMS: m / z (ESI) = 354.2 [M+H] + .

[0219] Synthesis of 2-(((Benzyloxy)carbonyl)amino)-2-(6,6-difluorobicyclo[3.1.0]hexane-3-yl)acetic acid 20

[0220] To a solution of compound 19 (3.70 g, 10.50 mmol) in THF (10 mL) and H 2 O (10 mL) was added LiOH (0.50 g, 20.90 mmol) at 25° C. Subsequently, the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was acidified to pH = 4 by 1N HCl. The mixture was extracted with DCM (40 mL x 2). The combined organic phases were 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.

[0221] LCMS: m / z (ESI) = 326.2 [M+H] + .

[0222] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-oxobutanoate 21

[0223] 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 at 25°C under a nitrogen atmosphere for 2 hours before being cooled to -78°C. To a solution of diisopropylamine (6.63 mL, 47.00 mmol) in THF (30 mL) at 0°C under a nitrogen atmosphere was added n-BuLi (18.8 mL, 47.00 mmol). After 10 minutes, tert-butyl acetate (6.309 mL, 47.0 mmol) was added to the mixture at -78°C. After an additional hour, the enolate mixture was added to the mixture via cannula, and the resulting reaction mixture was stirred at -78°C for 1 hour before being quenched with saturated aqueous ammonium chloride (30 mL) at -78°C. 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. Subsequently, the mixture was extracted with EA (100 mL x 3), and the combined organic phases were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel flash column eluting with 18% EtOAc in PE to give the title compound 21 (3.34 g, 75.47%) as a yellow oil.

[0224] LCMS: m / z (ESI) = 446.2 [M+Na] + .

[0225] 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

[0226] To a mixture of compound 21 (3.33 g, 7.08 mmol) and 2,6-lutidine (0.058 mL, 0.495 mmol) in MeOH (10 mL) was added NBS (1.26 g, 7.08 mmol), and the reaction mixture was subsequently stirred at 25 ° C for 1 hour. The reaction mixture was diluted with EA (60 mL) and finally washed with a 50% solution of saturated sodium chloride aqueous solution (40 mL x 2) and a saturated aqueous solution of sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound 22 (3.50 g, 98.44%) as a yellow oil.

[0227] LCMS:m / z(ESI)=523.8,525.8[M+H] + .

[0228] Synthesis of benzyl (3-bromo-1-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-2-oxopropyl)carbamate 23

[0229] To a solution of compound 22 (3.49 g, 6.95 mmol) in toluene (10 mL) was added TFA (1 mL, 13.0 mmol). Subsequently, the reaction mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by silica gel flash column eluting with (12% EtOAc in PE) to obtain compound 23 (2.00 g, 71.57%) as a brown oil.

[0230] LCMS: m / z(ESI)=424.0,426.0[M+Na] + .

[0231] Synthesis of compound (S)-1-((S)-1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 24

[0232] To a solution of compound Int 6 (1.6 g, 3.78 mmol) in MeOH (5 mL) was added HCl (15 mL, 6 mol / L), and the reaction mixture was subsequently 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 solution was extracted with EtOAc (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 24 (1.3 g, 99.34%) as a light yellow solid.

[0233] LCMS: m / z (ESI) = 339.8 [M+H]+ .

[0234] 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

[0235] 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 NaHCO (209 mg, 2.49 mmol) at 25 ° C. Subsequently, the reaction mixture was stirred at 75 ° C for 12 hours. Subsequently, the reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by silica gel flash column eluting with (90% EtOAc in PE) to obtain the title compound 25 (290 mg, 54.42%) as a yellow oil.

[0236] LCMS: m / z (ESI) = 643.2 [M+H] + .

[0237] 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 (Int 5)

[0238] 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 NH 3 .H 2 O (0.8 mL) at 25° C. The reaction mixture was then degassed and purged with H 2 three times and stirred at 25° C. under H 2 (15 psi) for 1 hour. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated to give the title product Int 5 (210 mg, 98.14%) as a yellow solid.

[0239] LCMS: m / z (ESI) = 475.2 [M+H] + .

[0240] 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 (Int 8)

[0241]

[0242] Synthesis of N-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridazin-3-yl-6-d)pivalamide 26

[0243] To a solution of compound Int 6 (500 mg, 1.18 mmol) in THF (30 mL) and D2O (5 mL) was added Pd (dppf) Cl2 (96.3 mg, 0.12 mmol) and N, N, N', N'-tetramethylethyl-enediamine (27.4 mg, 0.24 mmol). After stirring for 10 minutes, NaBD4 (1.15 g, 5.90 mmol) was slowly added. The reaction mixture was stirred at 25 ° C for 2 hours. Water (12 mL) was added to the reaction mixture, and the resulting mixture was extracted with EA (20 mL x3). 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 silica gel flash column to give the title compound 26 (250 mg, 54.3%) as a yellow solid.

[0244] LCMS: m / z (ESI) = 391.2 [M+H] + .

[0245] Synthesis of (S)-1-((S)-1-(6-aminopyridazin-4-yl-3-d)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 27

[0246] 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 hour. The reaction mixture was then concentrated to give compound 27 (130 mg, yield: 63.7%) as a yellow solid.

[0247] LCMS: m / z (ESI) = 307.2 [M+H] + .

[0248] 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

[0249] To a mixture of compound 27 (120 mg, 0.39 mmol) in THF (5 mL) was added NaHCO (165 mg, 1.96 mmol) and Int 7 (reference WO2020146194A1) (190 mg, 0.47 mmol), 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 silica gel flash column purification, eluted with (20% EtOAc in PE) to give compound 28 (80.0 mg, 33.4%) as a yellow solid.

[0250] LCMS: m / z (ESI) = 612.2 [M+H] + .

[0251] 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 (Int 8)

[0252] To a solution of compound 28 (70.0 mg, 0.12 mmol) in NH 3 H 2 O (0.2 mL) and EtOH (2 mL) was added 10% Pd / C (12.2 mg, 0.12 mmol). After degassing and purging with H 2 three times, the reaction mixture was stirred at 25 ° C under H 2 (14.696 psi) for 2 hours. Subsequently, the reaction mixture was filtered and the filtrate was concentrated to give the title product Int 8 (50.0 mg, 91.5%) as a yellow solid.

[0253] LCMS: m / z (ESI) = 478.2 [M+H] + .

[0254] 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 (Int 9)

[0255]

[0256] Synthesis of ethyl 2-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)-2-((diphenylmethylene)amino)acetate 29

[0257] To a solution of compound Int 3 (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 N2 for 16 hours. Subsequently, the reaction mixture was quenched with H2O (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 silica gel flash column purification, eluted with (10% EtOAc in PE) to give the title compound 29 (8.9 g, 33.6%) as a yellow oil.

[0258] LCMS: m / z (ESI) = 383.9 [M+H] + .

[0259] Synthesis of ethyl 2-amino-2-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)acetate

[0260] To a solution of compound 29 (8.8 g, 22.9 mmol) in THF (60 mL) was added HCl (2N) (15 mL, 30.0 mmol), and the reaction mixture was then stirred at 25 ° C for 1 hour. Water (60 mL) was added to the reaction mixture. The resulting mixture was washed with PE (60 mL x 2). The aqueous phase was neutralized with saturated sodium bicarbonate solution to pH = 8 and then 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 30 (2.4 g, 47.7%) as a yellow oil.

[0261] LCMS: m / z (ESI) = 220.0 [M+H] + .

[0262] Synthesis of ethyl 2-(((benzyloxy)carbonyl)amino)-2-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetate 31

[0263] 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 H2O (20 mL) was added CbzCl (3.69 mL, 26.20 mmol) at 0 ° C. Subsequently, the reaction mixture was stirred at 0 ° C for 1 hour. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting reaction mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification using (40% EtOAc in PE) to give compound 31 (3.70 g, 95.6%) as a white solid.

[0264] LCMS: m / z (ESI) = 354.2 [M+H] + .

[0265] Synthesis of 2-(((Benzyloxy)carbonyl)amino)-2-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)acetic acid 32

[0266] To a solution of compound 31 (3.7 g, 10.5 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH (0.5 g, 20.9 mmol) at 25°C. The reaction mixture was then stirred at 25°C for 2 hours. The reaction mixture was acidified to pH = 4 by 1N HCl. The mixture was extracted with DCM (40 mL x 2). The combined organic phases were 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.

[0267] LCMS: m / z (ESI) = 326.2 [M+H] + .

[0268] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-oxobutanoate

[0269] 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 resulting 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) at 0 ° C under a nitrogen atmosphere was added n-BuLi (18.8 mL, 47.0 mmol). After 10 minutes, tert-butyl acetate (6.309 mL, 47.0 mmol) was added to the reaction mixture at -78 ° C. After another hour, the enolate mixture was added to the above mixture via cannula. Subsequently, the reaction mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched with 30 mL of saturated aqueous ammonium chloride 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 phases were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel flash column purification using 18% EtOAc in PE to give compound 33 (3.34 g, 75.47%) as a yellow oil.

[0270] LCMS: m / z (ESI) = 446.2 [M+Na] + .

[0271] 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

[0272] To a mixture of compound 33 (3.33 g, 7.08 mmol) and 2,6-lutidine (0.058 mL, 0.50 mmol) in MeOH (10 mL) was added NBS (1.26 g, 7.08 mmol). Subsequently, the reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with EA (60 mL) and finally washed with a 50% solution of saturated sodium chloride aqueous solution (40 mL x 2) and a saturated aqueous solution of sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound 34 (3.50 g, 98.44%) as a yellow oil.

[0273] LCMS:m / z(ESI)=523.8,525.8[M+H] + .

[0274] Synthesis of benzyl (3-bromo-1-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-2-oxopropyl)carbamate 35

[0275] To a solution of compound 34 (3.49 g, 6.95 mmol) in toluene (10 mL) was added TFA (1 mL, 13.0 mmol). Subsequently, the reaction mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by silica gel flash column eluting with (12% EtOAc in PE) to obtain compound 35 (2.00 g, 71.57%) as a brown oil.

[0276] LCMS: m / z(ESI)=424.0,426.0[M+Na] + .

[0277] Synthesis of benzyl ((6-chloro-7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-1l3-ethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)carbamate 36

[0278] 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. Subsequently, the reaction mixture was stirred at 75 ° C for 12 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by silica gel flash column eluting with (90% EtOAc in PE) to obtain the title compound 36 (290 mg, 54.42%) as a yellow oil.

[0279] LCMS: m / z (ESI) = 643.2 [M+H] + .

[0280] 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-1l3-ethyl)-4-(trifluoromethyl)imidazolidin-2-one Int 9

[0281] 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 NH 3 H 2 O (0.8 mL) at 25° C. The reaction mixture was then degassed and purged with H 2 three times and stirred at 25° C. under H 2 (15 psi) for 1 hour. The reaction mixture was then filtered to remove insoluble solids, and the filtrate was concentrated to give the title product Int 9 (210 mg, 98.14%) as a yellow solid.

[0282] LCMS: m / z (ESI) = 475.2 [M+H] + .

[0283] 7. Synthesis of 4-(cyclobut-1-en-1-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int 10)

[0284]

[0285] Synthesis of ethyl 3-cyclobutyl-3-oxopropionate 38

[0286] To a solution of compound 37 (25.00 g, 249.70 mmol) in THF (300 mL) was added portionwise CDI (40.49 g, 249.70 mmol) at 25°C. After the addition, the clear solution was stirred at 25°C for 2 hours to give Solution A. To a solution of n-BuLi (149.82 mL, 374.55 mmol) in THF (700 mL) at -70°C under N2 was slowly added di(propyl-2-yl)amine (52.86 mL, 374.55 mmol). After the addition, the solution was slowly warmed to 0°C for 30 minutes and then cooled back 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 hour, and then Solution A was slowly added at -70°C. After the addition, the solution was stirred at -70°C for 1 hour. Subsequently, the reaction was quenched with saturated NH4Cl solution (250 mL) and extracted with EtOAc (250 mL*3). The combined organic layer was washed with water (250 mL*2) and brine (250 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography ( 220g Purification by silica flash column, eluting with a gradient of 0-10% ethyl acetate in petroleum ether at 85 mL / min) afforded the title compound 38 as a colorless oil (16.00 g, 37.65%).

[0287] 1H NMR (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).

[0288] Synthesis of ethyl (E)-3-cyclobutyl-2-(hydroxyimino)-3-oxopropionate

[0289] Under N2, compound 38 (16 g, 94 mmol), a stirring bar, acetic acid (80 mL) were added to a 500 mL round-bottom flask. NaNO2 (9.73 g, 141 mmol) in H2O (80 mL) was added dropwise to the mixture at 0 ° C. within 1 minute. The resulting reaction mixture was warmed to 25 ° C. and stirred for 18 hours. Subsequently, the reaction mixture was diluted with DCM (100 mL), washed with H2O (100 mL x3), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under vacuum to obtain a residue, which was then subjected to silica gel chromatography (0-10% petroleum ether / EtOAc) to obtain compound 39 (15.1 g, 80.64%) as a yellow liquid.

[0290] 1 H NMR (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).

[0291] Synthesis of ethyl (2Z,3E)-3-cyclobutyl-2,3-bis(hydroxyimino)propionate

[0292] Compound 39 (15g, 75mmol), stirring rod and EtOH (150mL) are added to a 1000mL three-necked round-bottom flask with a thermometer, which is then cooled to 0°C in an ice / water bath, and filled with hydroxylamine hydrochloride (azanol chlorane) (15.7g, 226mmol) and sodium acetate (12.4g, 151mmol), followed by stirring of the reaction mixture at 90°C for 18 hours. The reaction mixture is cooled and filtered, and the filtrate is concentrated to dryness under vacuum to obtain a yellow oil. The oil is added EtOAc (30mL), filtered, and the filtrate is concentrated to dryness under vacuum to obtain oil. Subsequently, the oil undergoes silica gel chromatography (0-30% EtOAc / petroleum ether) to obtain title compound 40 (790mg, 4.90%) as a yellow oil.

[0293] LCMS: m / z (ESI) = 214.9 [M+H] + .

[0294] 1 H NMR (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).

[0295] Synthesis of ethyl 4-cyclobutyl-1,2,5-oxadiazole-3-carboxylate 41

[0296] To compound 40 (790 mg, 3.69 mmol) in THF (8 mL) and a stirring bar was added CDI (897 mg, 5.53 mmol) in one go. The resulting reaction mixture was stirred at 60 ° C for 18 hours. The reaction mixture was then concentrated to dryness under vacuum to give an oil. The 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.

[0297] LCMS: m / z (ESI) = 197.0 [M+H] + .

[0298] 1 H NMR (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).

[0299] Synthesis of ethyl 4-(bromocyclobutyl)-1,2,5-oxadiazole-3-carboxylate 42

[0300] To compound 41 (366 mg, 1.87 mmol), a stirring bar, and NBS (498 mg, 2.80 mmol) in CCl4 (4 mL) was added AIBN (30.6 mg, 0.187 mmol) in one portion at 25°C, and the resulting reaction mixture was stirred at 85°C for 18 hours. The reaction solution was concentrated under vacuum to remove CCl4 to give a residue which was purified by flash silica gel chromatography ( 4g The product was purified by silica flash column (gradient of 0-10% ethyl acetate / petroleum ether at 20 mL / min) to afford the title compound 42 (470 mg, 91.59%) as a colorless liquid.

[0301] 1 H NMR (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).

[0302] Synthesis of ethyl 4-(cyclobut-1-enyl)-1,2,5-oxadiazole-3-carboxylate 43

[0303] 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 hours. The reaction solution was cooled to room temperature and diluted with EtOAc (15 mL), washed with water (10 mL*2) and brine (10 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g Purification by silica flash column (gradient of 0-10% ethyl acetate / petroleum ether at 30 mL / min as eluent) afforded the title compound 43 (60 mg, 34.00%) as a colorless oil.

[0304] 1 H NMR (400MHz, CDCl3) δ6.92 (t, J = 1.2 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.89-2.94 (m, 2H), 2.59-2.66 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0305] Synthesis of 4-(cyclobut-1-enyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 10)

[0306] To a solution of compound 43 (60 mg, 0.309 mmol) in EtOH (2 mL) was added LiOH HO (0.463 mL, 0.463 mmol) (1 M in HO) in one portion. The resulting solution was stirred at room temperature for 2 hours. The reaction solution was then diluted with water (10 mL), acidified to pH = 5 with 1N HCl solution, and extracted with EtOAc (15 mL * 3). The combined organic layer was washed with water (10 mL * 2) and brine (10 mL * 2), dried over anhydrous NaSO, filtered and concentrated under vacuum to give the title compound Int10 (35 mg, 68.18%) as a white solid.

[0307] 1 H NMR (400MHz, CDCl3) δ7.03(s,1H),5.52-5.69(m,1H),2.98-3.03(m,2H),2.69-2.77(m,2H).

[0308] 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 (Int 11)

[0309]

[0310] Synthesis of N-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-6-methylpyridazin-3-yl)pivalamide 44

[0311] To compound In6 (300mg, 0.71mmol), compound 1A (355mg, 1.41mmol) and Pd (dppf) Cl2 (51.7mg, 0.071mmol) in dioxane (5mL) and H2O (1mL) solution was added potassium carbonate (293mg, 2.12mmol). The reaction mixture was stirred at 110 ° C for 1 hour. The reaction mixture was cooled to room temperature and quenched with H2O at 25 ° C, and the resulting mixture was extracted with EtOAc (100mL x 3). The combined organic phase was washed with water (200mL), brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by silica gel flash column purification using (60% EA in PE) to give compound 44 (230mg, 80.5%) as a brown solid.

[0312] LCMS: m / z (ESI) = 404.2 [M+H] + .

[0313] Synthesis of (S)-1-((S)-1-(6-amino-3-methylpyridazin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 45

[0314] 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 then concentrated to afford the target compound 45 (150 mg, 94.7%) as a yellow solid.

[0315] LCMS: m / z (ESI) = 320.0 [M+H] + .

[0316] 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

[0317] To a solution of compound 45 (200 mg, 0.626 mmol) and compound Int 7 (303 mg, 0.752 mmol) in THF (3 mL) was added NaHCO (315 mg, 3.75 mmol). The reaction mixture was stirred at 75 ° C for 12 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel flash column eluting with 7% MeOH in DCM to give the desired compound 46 (160 mg, 40.8%) as a yellow solid.

[0318] LCMS: m / z (ESI) = 625.2 [M+H] + .

[0319] 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 (Int 11)

[0320] To a solution of compound 46 (160 mg, 0.256 mmol) and NH 3 H 2 O (0.1 mL) in EtOH (1 mL) was added 10% Pd / C (25 mg, 0.023 mmol). The reaction mixture was then degassed and purged with H 2 three times and stirred at 25 ° C under H 2 (15 psi) for 1 hour. The reaction mixture was then filtered and the filtrate was concentrated to give the title product Int 11 (139 mg, 99.5%) as a yellow solid.

[0321] LCMS: m / z (ESI) = 491.2 [M+H] + .

[0322] 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)propionitrile (Int 12)

[0323]

[0324] Synthesis of N-(6-chloro-5-{2-hydroxy-1-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazol-1-yl]ethyl}-1,2-diazin-3-yl)-2,2-dimethylpropionamide

[0325] To a solution of compound Int 6 (450 mg, 1.06 mmol), a stirring bar, and DCM (5 mL) was added BBr3 (3.19 mL, 3.19 mmol) dropwise over 5 minutes. The resulting reaction mixture was stirred at 0°C for 1 hour. Subsequently, another portion of BBr3 (1.06 mL, 1.06 mmol) was added dropwise to the reaction solution at 0°C over 5 minutes. The resulting reaction mixture was stirred for another hour at 0°C. Subsequently, BBr3 (1.06 mL, 1.06 mmol) was added dropwise to the mixture at 0°C over 5 minutes. The resulting reaction mixture was stirred for another hour at 0°C, after which the reaction solution was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution until pH = 7-8. The aqueous phase was extracted with EtOAc (10 mL*3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography ( 12g The mixture was purified by silica flash column (gradient of 0-60% ethyl acetate / petroleum ether at 30 mL / min as eluent) to afford the title compound 47 (100 mg, 22.22%) as a green solid.

[0326] LCMS: m / z (ESI) = 410.1 [M+H]+ .

[0327] Synthesis of 3-{3-chloro-6-[(2,2-dimethylpropionyl)amino]-1,2-diazin-4-yl}-3-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazol-1-yl]propane-1-sulfonic acid 48

[0328] 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 hours. Subsequently, the reaction mixture was quenched by adding ice H2O (40 mL) at 0 ° C, then diluted with EtOAc (30 mL), and extracted with EtOAc (30 mL * 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, 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 purification.

[0329] 1 H NMR(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).

[0330] Synthesis of N-(6-chloro-5-{2-cyano-1-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazol-1-yl]ethyl}-1,2-diazin-3-yl)-2,2-dimethylpropionamide

[0331] To a solution of compound 48 (570 mg, 1.17 mmol), a stirring bar, and K2CO3 (484 mg, 3.51 mmol) in DMF (8 mL) was added TMSCN (0.44 mL, 3.51 mmol) portionwise. The resulting reaction mixture was stirred at 30 ° C for 18 hours. Subsequently, the reaction solution was cooled to 25 ° C, quenched by adding H2O (50 mL) at 25 ° C, then diluted with EtOAc (50 mL), and extracted with EtOAc (50 mL * 2). The combined organic layer was washed with H2O (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 ( 12g Purification by silica flash column (0-30% ethyl acetate / petroleum ether gradient at 30 mL / min as eluent) afforded the title compound 49 (319 mg, 65.2%) as a yellow oil.

[0332] LCMS: m / z (ESI) = 419.1 [M+H] + .

[0333] Synthesis of 3-(6-amino-3-chloro-1,2-diazin-4-yl)-3-[(4S)-2-oxo-4-(trifluoromethyl)tetrahydro-1H-imidazol-1-yl]propionitrile 50

[0334] To a solution of compound 49 (273 mg, 0.12 mmol) and a stirring bar in MeOH (0.5 mL) was added hydrochloric acid (35.3 mg, 0.358 mmol) dropwise over 1 minute. The reaction solution was stirred at 70° C. for 18 hours. The reaction solution was concentrated under vacuum to remove MeOH. The residue was then adjusted to pH 8 using 7M NH 3 / MeOH. The mixture was purified by flash chromatography ( 12g Purification by silica flash column (0-2% MeOH / DCM gradient at 30 mL / min) afforded the title compound 50 as an off-white solid (169 mg, 77% average yield).

[0335] LCMS: m / z (ESI) = 335.1 [M+H] + .

[0336] 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) and 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)

[0337] Compound 50 (169 mg, 0.505 mmol), Int 25 (223 mg, 0.606 mmol), dichlorobis(cycloocta-1,5-diene)bis[iridium (0) ] (17 mg, 0.025 mmol), sodium trifluoromethanesulfonate (8.7 mg, 0.050 mmol), and pyrido [3, 2-h] quinoline (9.1 mg, 0.050 mmol), molecular sieves A solution of (500 mg) in DCE (9 mL) was degassed and purged with Ar 3 times, and then the mixture was stirred at 80 ° C under an Ar atmosphere for 16 hours. The reaction mixture was filtered, the solid was washed with DCM (15 mL) and EtOAc (15 mL), and the combined filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography ( 12g Purification by silica flash column (eluent: 0-55% ethyl acetate / petroleum ether gradient at 30 mL / min) gave the desired two products:

[0338] 51-P1: (70 mg, 22.87%), yellow oil.

[0339] LCMS: m / z (ESI) = 606.2 [M+H] + .

[0340] 51-P2: (80 mg, 26.14%), yellow oil.

[0341] LCMS: m / z (ESI) = 606.2 [M+H] + .

[0342] 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)

[0343] To a 100 mL round-bottom flask was added a solution of compound 51-P1 (70 mg, 0.12 mmol), a stirring bar, Pd / C 10% (100 mg, 0.940 mmol), and MeOH (6 mL) under an H atmosphere (15 psi). The resulting reaction mixture was stirred at 25 ° C for 1 hour. The reaction solution was filtered and washed with MeOH (10 mL). The combined filtrate was concentrated under vacuum 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 purification.

[0344] LCMS: m / z (ESI) = 572.2 [M+H] + .

[0345] To a 100 mL round-bottom flask was added compound 51-P2 (80 mg, 0.13 mmol), a stirring bar, Pd / C 10% (100 mg, 0.94 mmol), and MeOH (7 mL) under an H atmosphere (15 psi). The resulting mixture was stirred at 25 ° C for 30 minutes. The reaction was filtered and washed with MeOH (10 mL), and the combined filtrate was concentrated under vacuum 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.

[0346] LCMS: m / z (ESI) = 572.2 [M+H] + .

[0347] 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-imidazol-1-yl]propionitrile (Int 12)

[0348] 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 minute. The resulting mixture was stirred at 25° C. for 30 minutes, after which the reaction solution was concentrated under vacuum to afford the title product Int12-S1 (51.55 mg, crude product, 100%) as a yellow oil, which was used in the next step without purification.

[0349] LCMS: m / z (ESI) = 472.1 [M+H] + .

[0350] To a solution of compound 52-P2 (67.9 mg, 0.12 mmol) and a stirring 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 solution was concentrated under vacuum to give the desired compound Int 12-S2 (56.01 mg, crude product, 100%) as a yellow oil, which was used in the next step without purification.

[0351] LCMS: m / z (ESI) = 472.2 [M+H] + .

[0352] 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 (Int 11)

[0353]

[0354] Synthesis of N-(5-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide 55

[0355] 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 isopropanol (20 mL) was added TEA (1.69 mL, 12.10 mmol), and the resulting reaction mixture was stirred at 75 ° C for 2 hours, then cooled to room temperature and stirred at room temperature for another 12 hours. Subsequently, the reaction mixture was concentrated to give a yellow residue. The residue was dissolved in MeOH (20 mL), followed by the addition of sodium cyanoborohydride (1.79 g, 28.40 mmol) and stirred at 8 ° C for 30 minutes. HOAc (7.58 g, 40.60 mmol) was added and stirred at 40 ° C for 1 hour. Subsequently, the reaction mixture was concentrated to give a yellow residue. The residue was dissolved in DCM (100 mL) and neutralized with saturated NaHCO 3. The layers were separated and the aqueous layer was extracted with DCM (50 mL x 2). The combined organic phases were combined and washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification using 50% EtOAc in PE to give the title compound 55 (870 mg, 51.17%) as a white solid.

[0356] LCMS: m / z (ESI) = 397.8 [M+H] + .

[0357] Synthesis of N-(6-chloro-5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridazin-3-yl)pivalamide (Int 6)

[0358] 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 hour. The reaction mixture was then concentrated to obtain a yellow residue. The residue was dissolved in EtOAc (50 mL) and washed with 1N HCl (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by silica gel flash column eluting with 50% EtOAc in PE to obtain compound Int 6' (first spot, 350 mg) and the desired compound Int 6 (second spot, 350 mg, see WO2020146194A1).

[0359] LCMS:m / z(ESI)=423.8 / 425.8[M+H] + .

[0360] Synthesis of (S)-1-((S)-1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 24

[0361] To a solution of compound Int 6 (1.6 g, 3.78 mmol) in MeOH (5 mL) was added HCl (15 mL, 6 mol / L), and the reaction mixture was subsequently 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 x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 24 (1.3 g, 99.34%) as a light yellow solid.

[0362] LCMS:m / z(ESI)=339.8 / 341.8[M+H] + .

[0363] 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

[0364] To a solution of compound 24 (600 mg, 1.77 mmol) and compound Int 7 (1.07 g, 2.65 mmol) in THF (30 mL) was added NaHCO (445 mg, 5.30 mmol), and the reaction mixture was stirred at 70 ° C under N for 12 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel flash column eluting with EtOAc to give the title compound 56 (750 mg, 64.51%) as a yellow solid.

[0365] LCMS:m / z(ESI)=645.2 / 647.2[M+H] + .

[0366] 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 (Int 13)

[0367] To a solution of compound 56 (750 mg, 1.16 mmol) in EtOH (30 mL) and NH 3 H 2 O (3 mL) was added 10% Pd / C (61.87 mg, 0.58 mmol, 55% water), and the reaction mixture was stirred at 30 ° C. under H 2 (15 psi) for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to give the title product Int 13 (580 mg, 99.46%) as a yellow solid.

[0368] LCMS: m / z (ESI) = 476.8 [M+H] + .

[0369] 11. Synthesis of 4-carboxy-3-(methyl-d3)-1,2,5-oxadiazole-2-oxide (Int 14)

[0370]

[0371] Synthesis of ethyl 3-oxobutyrate-4,4,4-d3 58

[0372] 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 hour, a solution of acetyl chloride-d3 (2.18 mL, 30.6 mmol) in THF (5 mL) was added dropwise. The resulting reaction mixture was stirred at -78 ° C for 2 hours. Subsequently, 6N HCl (8 mL) and H2O (40 mL) were added to the reaction mixture. The resulting solution was extracted with Et2O (50 mL x 3). The combined organic phase was washed with 3N HCl (40 mL), saturated NaHCO3 (60 mL), and 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.

[0373] 1 HNMR (400MHz, CDCl3) δ4.20 (q, J=7.2Hz, 2H), 3.44 (s, 2H), 1.28 (t, J=7.2Hz, 3H).

[0374] Synthesis of (Z)-2-(hydroxyimino)-3-oxobutanoic acid ethyl ester-4,4,4-d3 59

[0375] To a solution of compound 58 (5.00 g, 37.5 mmol) in HOAc (45 mL) and H2O (15 mL) was added sodium nitrite (3.89 g, 56.3 mmol). The reaction mixture was stirred at 25 ° C for 18 hours. Subsequently, the reaction was quenched with saturated NaHCO3 (100 mL) at 25 ° C. The resulting solution was extracted with EtOAc (100 mL x 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 compound 59 (3.00 g, 49.2%) as a yellow oil.

[0376] LCMS: m / z (ESI) = 163.2 [M+H] + .

[0377] Synthesis of ethyl (2E,3E)-2,3-bis(hydroxyimino)butyrate-4,4,4-d3 60

[0378] 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 hours. The reaction solution was concentrated to give a residue, which was purified by silica gel flash column eluting with (35% EA in PE) to give the title compound 60 (4.7 g, 71.7%) as a white solid.

[0379] LCMS: m / z (ESI) = 178.2 [M+H] + .

[0380] Synthesis of 4-(ethoxycarbonyl)-3-(methyl-d3)-1,2,5-oxadiazole 2-oxide 61

[0381] To a solution of compound 60 (2.70 g, 15.20 mmol) in DCM (30 mL) was added (diacetoxy iodine) benzene (5.93 g, 18.20 mmol). The reaction mixture was stirred at 25 ° C for 1 hour. Subsequently, the reaction was quenched with saturated NaHCO (100 mL) at 25 ° C. The resulting solution was extracted with DCM (100 mL x 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 silica gel flash column purification using (15% EA in PE) to give the desired compound 61 (1.5 g, 56.1%) as a yellow oil.

[0382] LCMS: m / z (ESI) = 176.2 [M+H] + .

[0383] Synthesis of 4-carboxy-3-(methyl-d3)-1,2,5-oxadiazole 2-oxide (Int 14)

[0384] To a solution of compound 61 (100 mg, 0.57 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH (95.8 mg, 2.28 mmol). The reaction mixture was stirred at 25 ° C for 1 hour. Subsequently, the reaction mixture was acidified to pH = 4 with 1N HCl. The resulting solution was extracted with EA (100 mL x 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 Int 14 (1.3 g, 59.1%) as a yellow oil.

[0385] LCMS: m / z (ESI) = 148.2 [M+H] + .

[0386] 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 (Int 15)

[0387]

[0388] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-(benzyloxy)cyclobutylidene) acetate 64

[0389] To a mixture of compound 62 (9.0 g, 51.1 mmol) and 63 (33.8 g, 102 mmol) in DCM (100 mL) was added TMG (12.9 g, 112 mmol), and the resulting reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was poured into water (60 mL), and the resulting solution was extracted with EtOAc (60 mL x 3). The combined organic phase was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column elution using (10% EtOAc in PE) to obtain compound 64 (19.0 g, 92.7%) as a white solid.

[0390] LCMS: m / z (ESI) = 382.2 [M+H] + .

[0391] Synthesis of methyl 2-((tert-butyloxycarbonyl)amino)-2-(3-hydroxycyclobutyl)acetate 65

[0392] 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 BoC2O (34.4 g, 157 mmol). After degassing and purging with H2 three times, the resulting reaction mixture was stirred at 25 ° C under H2 (14.696 psi) for 48 hours. 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.

[0393] LCMS: m / z (ESI) = 282.2 [M+Na] + .

[0394] Synthesis of methyl 2-amino-2-(3-hydroxycyclobutyl)acetate 66

[0395] A solution of compound 65 (10 g, 38.6 mmol) in HCl-dioxane (50 mL) was stirred for 2 hours at 25° C. Then, the reaction mixture was concentrated to give the desired compound 66 (7.00 g, 96.9%) as a yellow solid.

[0396] LCMS: m / z (ESI) = 160.2 [M+H] + .

[0397] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-hydroxycyclobutyl)acetate 67

[0398] To a solution of compound 66 (7.00 g, 44.0 mmol) in H2O (50 mL) and DCM (50 mL) was added NaHCO3 (25.9 g, 308 mmol) and CbzCl (11.3 g, 66.0 mmol). The resulting reaction mixture was stirred at 25 ° C for 2 hours. Subsequently, the reaction solution was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluted with (20% EtOAc in PE) to obtain the title compound 67 (9.00 g, 69.8%) as a yellow oil.

[0399] LCMS: m / z (ESI) = 314.0 [M+Na] + .

[0400] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-oxocyclobutyl)acetate 68

[0401] 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 hours. Subsequently, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification using (20% EtOAc in PE) to give the title compound 68 (7.0 g, 78.3%) as a yellow oil.

[0402] LCMS: m / z (ESI) = 314.2 [M+Na] + .

[0403] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(3,3-difluorocyclobutyl)acetate 69

[0404] 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 hours. Water (60 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) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column elution using (20% EtOAc in PE) to obtain the desired compound 69 (1.4 g, 43.4%) as a yellow oil.

[0405] LCMS: m / z (ESI) = 336.2 [M+Na] + .

[0406] Synthesis of 2-(((Benzyloxy)carbonyl)amino)-2-(3,3-difluorocyclobutyl)acetic acid 70

[0407] To a solution of compound 69 (1.40 g, 4.47 mmol) in H2O (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 hours. The reaction solution was acidified to pH = 4 by 1N HCl. The resulting solution was separated, and the aqueous layer was extracted with DCM (10 mL x 3). The combined organic phases were 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.

[0408] LCMS: m / z (ESI) = 322.2 [M+Na] + .

[0409] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(3,3-difluorocyclobutyl)-3-oxobutanoate 71

[0410] 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 hours and then cooled to -78 ° C. At 0 ° C, under a nitrogen atmosphere, a solution of diisopropylamine (2.12 mL, 15.0 mmol) in THF (30 mL) was added n-BuLi (6.0 mL, 15.0 mmol). After 10 minutes, tert-butyl acetate (2.02 mL, 15.0 mmol) was added to the mixture at -78 ° C. After another hour, the enolate mixture was added to the above solution via a cannula. Subsequently, the reaction mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched with 30 mL of saturated aqueous ammonium chloride 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 phases were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel flash column eluting with 10% EA in PE to give the title compound 71 (1.10 g, 82.8%) as a yellow oil.

[0411] LCMS: m / z (ESI) = 420.2 [M+Na] + .

[0412] Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-bromo-4-(3,3-difluorocyclobutyl)-3-oxobutanoate 72

[0413] To a solution 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 hours, then diluted with EA (60 mL) and washed with a 50% solution of saturated sodium chloride aqueous solution (40 mL x 2) and a saturated sodium chloride aqueous solution (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give compound 72 (1.10 g, 83.4%) as a yellow oil.

[0414] LCMS: m / z(ESI)=498.0,500.0[M+Na] + .

[0415] Synthesis of benzyl (3-bromo-1-(3,3-difluorocyclobutyl)-2-oxopropyl)carbamate 73

[0416] 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 hours. The reaction mixture was then concentrated and purified by silica gel flash column eluting with (20% EtOAc in PE) to give compound 73 (800 mg, 90.8%) as a yellow oil.

[0417] LCMS: m / z(ESI)=398.0,400.0[M+Na] + .

[0418] Synthesis of benzyl ((6-chloro-7-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-1,3-ethyl)imidazo[1,2-b]pyridazin-2-yl)(3,3-difluorocyclobutyl)-methyl)carbamate 74

[0419] To a solution of compound 73 (500 mg, 1.33 mmol) in THF (20 mL) was added NaHCO 3 (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 obtain a residue. The residue was purified by silica gel flash column eluting with (20% EtOAc in PE) to obtain compound 74 (320 mg, 58.7%) as a yellow solid.

[0420] LCMS: m / z (ESI) = 617.0 [M+H] + .

[0421] 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 (Int 15)

[0422] To a solution of compound 74 (150 mg, 0.243 mmol) in EtOH (5 mL) and NH 3 H 2 O (0.5 mL) was added 10% Pd / C (25.9 mg, 0.243 mmol). After degassing and purging with H 2 three times, the reaction mixture was stirred at 25 ° C under H 2 (14.696 psi) for 2 hours. Subsequently, the reaction mixture was filtered and the filtrate was concentrated to give the desired compound Int 15 (100 mg, 91.7%) as a yellow solid.

[0423] LCMS: m / z (ESI) = 449.2 [M+H] + .

[0424] 13. Synthesis of 4-vinyl-1,2,5-oxadiazole-3-carboxylic acid (Int 16)

[0425]

[0426] Synthesis of (3E,4E)-3,4-bis(hydroxyimino)dihydrofuran-2(3H)-one 76

[0427] To a solution of compound 75 (10 g, 99.93 mmol) in 3M HCl (60 mL) at 0°C, sodium nitrite (8.96 g, 129.91 mmol) was added portionwise. The resulting reaction solution was stirred at room temperature for 10 minutes. Subsequently, the mixture was added dropwise to a vigorously stirred solution of hydroxylamine hydrochloride (13.89 g, 199.86 mmol) in water (100 mL). The resulting reaction mixture was stirred at room temperature for an additional 2 hours, at which point the purple color of the solution gradually faded. The solid was collected to yield target compound 76 (10.67 g, 74.1%) as a white solid.

[0428] LCMS: m / z (ESI) = 145.0 [M+H] + .

[0429] Synthesis of 4H,6H-furo[3,4-c][1,2,5]oxadiazol-4-one 77

[0430] To a solution of compound 76 (10.67 g, 74.05 mmol) in dioxane (150 mL) was added thionyl chloride (7.89 mL, 111.08 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. Subsequently, the reaction mixture was concentrated under vacuum to give the crude product, which was recrystallized from ethanol to give the pure product 77 (6.07 g, 65.02%) as a light yellow solid.

[0431] LCMS: m / z (ESI) = 127.0 [M+H] + .

[0432] Synthesis of 4-(hydroxymethyl)-N-phenyl-1,2,5-oxadiazole-3-carboxamide 78

[0433] To a solution of compound 77 (2g, 15.86mmol) in DMF (10mL) and EtOH (80mL) was added aniline (1.59mL, 17.45mmol). The reaction mixture was stirred at 25°C for 30 minutes, and then the reaction solution was heated to 50°C and stirred overnight. The reaction solution was concentrated and redissolved in EA (50mL). Water (90mL) was subsequently added, and the two-phase solution was extracted with EA (3x 40mL). The combined organic phase was washed with brine (40mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by silica gel flash column purification using (20% EA in PE) to give the title compound 78 (592mg, 17.02%) as a yellow solid.

[0434] LCMS: m / z (ESI) = 220.0 [M+H] + .

[0435] Synthesis of 4-formyl-N-phenyl-1,2,5-oxadiazole-3-carboxamide 79

[0436] 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 hour and then filtered. The filtrate was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by silica gel flash column purification using (15% EA in PE) to give the title compound 79 (2.1 g, 79.48%) as a yellow oil.

[0437] LCMS: m / z (ESI) = 218.0 [M+H] + .

[0438] Synthesis of N-phenyl-4-vinyl-1,2,5-oxadiazole-3-carboxamide 80

[0439] To a solution of triphenylmethylphosphonium bromide (8.39 g, 23.50 mmol) in toluene (15 mL) was added t-BuOK (2.71 g, 24.17 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. Compound 79 (2.1 g, 7.25 mmol) was then added and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by silica gel flash column eluting with (15% EA in PE) to give compound 80 (703.57 mg, 33.81%) as a light yellow oil.

[0440] LCMS: m / z (ESI) = 216.0 [M+H] + .

[0441] Synthesis of tert-butyl phenyl(4-vinyl-1,2,5-oxadiazole-3-carbonyl)carbamate 81

[0442] To a solution of compound 80 (201 mg, 0.934 mmol) in DCM (10 mL) were 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 hour at 22° C. The reaction solution was concentrated under reduced pressure to give the desired compound 81 (290 mg, crude product) as a yellow oil, which was used in the next step without further purification.

[0443] LCMS: m / z (ESI) = 263.0 [M+H] + .

[0444] Synthesis of 4-vinyl-1,2,5-oxadiazole-3-carboxylic acid (Int 16)

[0445] To a solution of compound 81 (290 mg, crude product) in THF (4 mL) / MeOH (1 mL) was added 2M LiOH (1.29 mL, 2.58 mmol). Subsequently, the reaction mixture was stirred at 40 ° C for 1 hour. The reaction mixture was diluted with 2M HCl (1.3 mL) and then concentrated under vacuum to give a crude product. The crude product was purified by C18 column chromatography using (55% MeCN in water) to give the desired compound Int16 (85 mg, 65.97%) as a light yellow solid.

[0446] LCMS: m / z (ESI) = 139.0 [M-1] - .

[0447] 14. Synthesis of 4-vinyl-1,2,5-oxadiazole-3-carboxylic acid (Int 17)

[0448]

[0449] Synthesis of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide 78

[0450] 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 x 2). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by silica gel flash column purification, eluted with 20% EtOAc in PE to give compound 78 (3.7 g, 74.60%) as a light yellow solid.

[0451] LC-MS (ESI): m / z = 272.0 [M+H] + .

[0452] Synthesis of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide 79

[0453] 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 hours. Subsequently, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted three times with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum 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 viscous oil.

[0454] LC-MS (ESI): m / z = 270.0 [M+H] + .

[0455] Synthesis of (Z)-N-(3-chloro-4-fluorophenyl)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxamide 80 and (E)-N-(3-chloro-4-fluorophenyl)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxamide 81

[0456] At room temperature, under a nitrogen atmosphere, potassium tert-butoxide (1.25 g, 11.13 mmol) was added to a solution of (fluoromethyl)triphenylphosphonium tetrafluoroborate (3.91 g, 10.24 mmol) in toluene (40 mL). After stirring for 30 minutes, 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 hours and then cooled to room temperature. 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 under vacuum. 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%).

[0457] 80:LC-MS(ESI):m / z=286.0[M+H] + .

[0458] 1 H NMR (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).

[0459] 81:LC-MS(ESI):m / z=286.0[M+H] + .

[0460] 1 H NMR (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).

[0461] Synthesis of tert-butyl (Z)-(3-chloro-4-fluorophenyl)(4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carbonyl)carbamate 82

[0462] To a solution of compound 80 (80 mg, 0.80 mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (122.26 mg, 0.560 mmol) and DMAP (5.13 mg, 0.042 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Subsequently, the reaction solution was diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound 82 (100 mg, 92.56%) as a light yellow oil.

[0463] LC-MS (ESI): m / z = 386.0 [M+H] + .

[0464] Synthesis of (Z)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 17)

[0465] 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 H O (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by C18 column chromatography (eluted with 0.5% TFA in water / acetonitrile = 0-100%) to give the title compound Int 17 (30 mg, 73.21%) as a white solid.

[0466] LC-MS (ESI): m / z = 157.0 [MH] - .

[0467] 15. Synthesis of (E)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 18)

[0468]

[0469] Synthesis of tert-butyl (E)-(3-chloro-4-fluorophenyl)(4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carbonyl)carbamate 83

[0470] To a solution of compound 81 (80 mg, 0.28 mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (152.82 mg, 0.70 mmol) and DMAP (6.42 mg, 0.053 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, and dried over anhydrous Na2SO4 to give the title compound 83 as a light yellow oil.

[0471] LC-MS (ESI): m / z = 386.0 [M+H] + .

[0472] Synthesis of (E)-4-(2-fluorovinyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 18)

[0473] To a solution of compound 83 (100 mg, 0.26 mmol) in THF (1 mL) was added LiOH (21.76 mg, 0.52 mmol) and H O (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by C18 column chromatography (eluted with 0.5% TFA in water / acetonitrile = 0-100%) to give the title compound Int 18 (30.0 mg, 73.20%) as a white solid.

[0474] LC-MS (ESI): m / z = 157.0 [MH] - .

[0475] 16. Synthesis of 4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int 19)

[0476]

[0477] Synthesis of 5,5-dimethylfuran-2,4(3H,5H)-dione 86

[0478] 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) was added t-BuOK (33.26 g, 296.98 mmol), and the reaction mixture was stirred at 66°C overnight. The solvent was removed under reduced pressure, and the residue was put into 1M NaOH aqueous solution (20 mL) and Et2O (20 mL). The phases were separated, and the aqueous phase was extracted with Et2O (20 mL). Subsequently, concentrated HCl was added to the aqueous solution at 0°C until pH = 1. The acidified aqueous solution was diluted with CHCl3 / i- The residue was extracted with a mixture of PrOH (5:1) (20 mL x 4), dried over Na2SO4, and the solvent was removed under reduced pressure. It was recrystallized from Et2O to give the title compound 86 (9.6 g, 55.49%) as a light white solid.

[0479] LCMS: m / z (ESI) = 129.0 [M+H] + .

[0480] Synthesis of (3Z,4E)-3,4-bis(hydroxyimino)-5,5-dimethyldihydrofuran-2(3H)-one 87

[0481] To a stirred solution of compound 86 (9.6 g, 74.92 mmol) in 3M HCl (160 mL) was added portionwise NaNO2 (5.09 g, 74.92 mmol). The 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 H2O (60 mL). The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was then filtered to collect the solid, the desired compound 87, as a yellow solid.

[0482] LCMS: m / z (ESI) = 173 [M+H] + .

[0483] Synthesis of 6,6-dimethyl-4H,6H-furo[3,4-c][1,2,5]oxadiazol-4-one 88

[0484] To a solution of compound 87 (5.0 g, 29.05 mmol) in dioxane (50 mL) was added SOCl2 (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 from EtOH (1 mL) to give the desired compound 88 (3.0 g, 67.01%) as a yellow solid.

[0485] 1 H NMR (400MHz, DMSO-d6) δ: 1.87 (s, 6H).

[0486] Synthesis of 4-(2-hydroxypropan-2-yl)-N-phenyl-1,2,5-oxadiazole-3-carboxamide 89

[0487] To a solution of compound 88 (3.0 g, 19.46 mmol) in EtOH (60 mL) and DMF (7.5 mL) was added dropwise aniline (1.95 mL, 21.41 mmol) in EtOH (1 mL). Subsequently, the reaction mixture was stirred at 25 ° C for 30 minutes and then heated to 50 ° C overnight. The solvent was removed under reduced pressure, and the residue was extracted with EtOAc (20 mL) and washed with H2O (50 mL × 1) and brine (50 mL × 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (0% to 20% EA in PE) to obtain the desired compound 89 (1.02 g, 21.19%) as a colorless oil.

[0488] LCMS: m / z (ESI) = 248.0 [M+H] + .

[0489] Synthesis of 2-(4-(phenylcarbamoyl)-1,2,5-oxadiazol-3-yl)propan-2-yl methanesulfonate 90

[0490] Methanesulfonic anhydride (232.49 mg, 1.34 mmol) and TEA (0.25 mL, 1.82 mmol) were added to a solution of compound 89 (300 mg, 1.21 mmol) in DCM (5 mL), and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether to give the title compound 90 (300 mg, 76.00%) as a white solid.

[0491] LC-MS (ESI): m / z = 326.0 [M+H] + .

[0492] Synthesis of N-phenyl-4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxamide 91

[0493] 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 hours. The reaction mixture was cooled to room temperature and diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using ethyl acetate in petroleum ether to give the title compound 91 (150 mg, 70.96%) as a white solid.

[0494] LC-MS (ESI): m / z = 230.0 [M+H] + .

[0495] Synthesis of tert-butyl phenyl(4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carbonyl)carbamate 92

[0496] 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. Subsequently, the reaction solution was diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to give the title compound 92 (130 mg, 90.49%) as a light yellow oil.

[0497] LC-MS (ESI): m / z = 330.0 [M+H] + .

[0498] Synthesis of 4-(prop-1-en-2-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int 19)

[0499] To a solution of compound 92 (100 mg, 0.26 mmol) in THF (1 mL) were added LiOH (33.12 mg, 0.79 mmol) and H2O (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was stirred by using C 18 Direct purification by column chromatography (eluting with 0.5% TFA in water:acetonitrile = 0-100%) gave the title compound Int19 (30 mg, 73.21%) as a white solid.

[0500] LC-MS (ESI): m / z = 153.0 [MH] - .

[0501] 17. Synthesis of intermediate 4-(1-methylcyclopropyloxy)-1,2,5-oxadiazole-3-carboxylic acid (Int 20)

[0502]

[0503] Synthesis of N-methyl-4-(1-methylcyclopropyloxy)-1,2,5-oxadiazole-3-carboxamide 94

[0504] To a solution of compound 1-methylcyclopropane-1-ol (446 mg, 6.19 mmol) in THF (5 mL) was added NaH (495 mg, 12.38 mmol) at 0 ° C under N2. The reaction mixture was stirred at 0 ° C for 0.5 hours, followed by the addition of compound 93 (500 mg, 3.10 mmol). The reaction mixture was stirred at 55 ° C for another 16 hours. Subsequently, the reaction mixture was poured into a saturated NH4Cl aqueous solution and extracted with EtOAc (50 mL * 3). The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired compound 94 (80 mg, 13.11%) as a white solid.

[0505] LC / MS: m / z (ESI) = 198.0 [M+H] + .

[0506] Synthesis of tert-butyl methyl (4-(1-methylcyclopropyloxy)-1,2,5-oxadiazole-3-carbonyl)carbamate 95

[0507] To a solution of compound 94 (80 mg, 0.41 mmol) in DCM (3 mL) at 25°C under N2 was added (2-methylpropan-2-yl)oxidanecarboxylic anhydride (177 mg, 0.81 mmol) and DMAP (14 mg, 0.12 mmol). The reaction mixture was stirred at 25°C for 0.5 h, after which the reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with DCM (30 mL*3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (EtOAc in PE, 0-10%) to give the title compound 95 (80 mg, 53.06%) as a white solid.

[0508] LC / MS: m / z (ESI) = 298.0 [M+H] + .

[0509] Synthesis of 4-(1-methylcyclopropyloxy)-1,2,5-oxadiazole-3-carboxylic acid (Int 20)

[0510] 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 hours. Subsequently, the reaction mixture was poured into an aqueous HCl solution (2N) and extracted with EtOAc (20 mL * 3). The combined organic phase was washed with a saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (EtOAc in PE, 0-90%) to give the title product 20 (20 mg, 40.36%) as a white solid.

[0511] LC / MS: m / z (ESI) = 365.0 [2M-H] - .

[0512] 18. Synthesis of 4-(1-methylcyclobutyloxy)-1,2,5-oxadiazole-3-carboxylic acid (Int 21)

[0513]

[0514] Synthesis of compound N-methyl-4-(1-methylcyclobutyloxy)-1,2,5-oxadiazole-3-carboxamide 96

[0515] To a mixture of 1-methylcyclobutane-1-ol (53 mg, 0.619 mmol) in THF (5 mL) was added NaH (148 mg, 3.714 mmol) at 0 ° C under N2. The reaction mixture was stirred at 0 ° C for 0.5 hours, after which compound 93 (100 mg, 0.619 mmol) was added. The reaction mixture was stirred at 55 ° C for another 16 hours. Subsequently, the reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc (* 3). The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 96 (100 mg, 76.48%) as a white solid.

[0516] LCMS: m / z (ESI) = 212.0 [M+H] + .

[0517] Synthesis of compound tert-butyl methyl (4-(1-methylcyclobutyloxy)-1,2,5-oxadiazole-3-carbonyl)carbamate 97

[0518] To a solution of compound 96 (100 mg, 0.473 mmol) in DCM (3 mL) at 25°C under N2 was added (2-methylprop-2-yl)oxanecarboxylic anhydride (206 mg, 0.947 mmol) and DMAP (17 mg, 0.142 mmol). The reaction mixture was stirred at 25°C for 0.5 h, after which the reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with DCM (20 mL*3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (EtOAc in PE, 0-10%) to give the title compound 97 (100 mg, 69.13%) as a white solid.

[0519] LCMS: m / z (ESI) = 312.0 [M+H] + .

[0520] Synthesis of 4-(1-methylcyclobutyloxy)-1,2,5-oxadiazole-3-carboxylic acid (Int 21)

[0521] 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 hours. Subsequently, the reaction mixture was poured into an aqueous HCl solution (2N) and extracted with EtOAc (20 mL * 3). The combined organic phase was washed with a saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give the title product Int 21 (30 mg, 20.18%) as a white solid.

[0522] LCMS: m / z (ESI) = 395.0 [2M-H] - .

[0523] 19. Synthesis of 4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int 22)

[0524]

[0525] Synthesis of compound ethyl 3-oxo-3-(spiro[2.2]pentan-1-yl)propionate 99

[0526] To a solution of potassium 3-ethoxy-3-oxopropanoate (3.40 g, 20.00 mmol) in EA (30 mL) was added Et3N (6.95 mL, 50.00 mmol) and magnesium chloride (2.86 g, 30.00 mmol) at 0 ° C. for 30 minutes, and then the reaction mixture was stirred at room temperature for 18 hours. With ice cooling, SOCl2 (0.7 mL, 10.00 mmol) and a catalytic amount of DMF (0.12 mL) were added to another solution of compound 98 (1.12 g, 10 mmol) in THF (10 mL), and the resulting mixture was stirred for 30 minutes, then stirred at room temperature for 1 hour. With cooling, the above-mentioned malonic acid solution was added to the acid chloride solution, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EA and HCl solution. The organic layer was separated, washed with saturated NaCl solution, and concentrated under vacuum. The residue was purified by C 18 Purification by flash column chromatography eluting with 55% CH 3 CN in H 2 O (0.5% TFA) gave the title compound 99 as a yellow oil (1.03 g, 54.38%).

[0527] LCMS: m / z (ESI) = 183.0 [M+H] + .

[0528] Synthesis of ethyl (E)-2-(hydroxyimino)-3-oxo-3-(spiro[2.2]pentan-1-yl)propanoate 100

[0529] 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 NaNO2 (0.43 g, 6.22 mmol) in H2O (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 hours. The reaction mixture was poured into a vigorously stirred mixture of EtOAc and a saturated aqueous solution of sodium bicarbonate. After gas evolution ceased, the reaction mixture was separated, and the organic layer was washed with saturated sodium bicarbonate and then with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound 100 (1.14 g, 89.13%) as a light yellow liquid.

[0530] LCMS: m / z (ESI) = 212.0 [M+H] + .

[0531] Synthesis of ethyl (2E,3Z)-2,3-bis(hydroxyimino)-3-(spiro[2.2]pentan-1-yl)propionate 101

[0532] To a solution of compound 100 (211.22 mg, 1.00 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (99.09 mg, 3.00 mmol) and NaOAc (164.06 mg, 2.00 mmol), and the reaction mixture was stirred at 80 ° C for 18 hours. Water (15 mL) was added to the reaction mixture, and the resulting solution was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel flash column purification, eluted with (5% MeOH in DCM) to give the title compound 101 (128 mg, 32.25%) as a white solid.

[0533] LCMS: m / z (ESI) = 227.0 [M+H] + .

[0534] Synthesis of ethyl 4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxylate 102

[0535] 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 hours. The reaction mixture was then concentrated and purified by C 18 Direct purification by flash column eluting with (60% MeCN in H2O (0.05% TFA)) afforded the title compound 102 (11 mg, 8.78%) as a white solid.

[0536] LCMS: m / z (ESI) = 209.0 [M+H] + .

[0537] Synthesis of 4-(spiro[2.2]pentan-1-yl)-1,2,5-oxadiazole-3-carboxylic acid (Int 22)

[0538] To a solution of compound 102 (11 mg, 0.053 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH (6 mg, 0.158 mmol), and the reaction mixture was stirred at 25°C for 1 hour. 18 Direct purification by flash column eluting with (40% MeCN in H2O (0.05% TFA)) afforded the desired product Int 22 (4.6 mg, 47.85%) as a white solid.

[0539] LCMS: m / z (ESI) = 181.0 [M+H] + .

[0540] 20. Synthesis of 4-carboxy-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole 2-oxide (Int 23)

[0541]

[0542] Synthesis of compound 4-(ethoxycarbonyl)-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole 2-oxide 103

[0543] To a solution of compound 10 (870 mg, 3.40 mmol) in DCM (30 mL) was added (diacetoxy iodine) benzene (1.32 g, 4.08 mmol) at 25 ° C., and the reaction mixture was then stirred at 25 ° C. for 12 hours. DCM (30 mL) and water (30 mL) were added to the reaction mixture, and the resulting solution was extracted with DCM (30 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 a residue. The residue was purified by silica gel flash column purification using 8% EtOAc in PE to give the title compound 103 (290 mg, 33.6%) as a yellow solid.

[0544] LCMS: m / z (ESI) = 255.2 [M+H] + .

[0545] Synthesis of 4-carboxy-3-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole 2-oxide (Int 23)

[0546] To a solution of compound 103 (290 mg, 1.14 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH (144 mg, 3.42 mmol) at 25 ° C. The reaction mixture was stirred for 2 hours at 25 ° C. Subsequently, the reaction mixture was acidified to pH = 4 by 1N HCl and extracted with DCM (40 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title product Int 23 (250 mg, 96.91%) as a white solid.

[0547] LCMS: m / z (ESI) = 227.0 [M+H] + .

[0548] 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 (Int 24)

[0549]

[0550] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate 105

[0551] 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. The reaction mixture was stirred at 25 ° C for 0.5 hours, followed by the addition of compound 104 (15.62 g, 100.00 mmol) at 0 ° C. The resulting reaction solution was stirred at 25 ° C for 12 hours. 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) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column eluting with 35% EA in PE to give the title compound 105 (17.1 g, 47.32%) as a white solid.

[0552] LCMS: m / z (ESI) = 362.0 [M+H] + .

[0553] Synthesis of methyl 2-amino-2-(1,4-dioxaspiro[4.5]decane-8-yl)acetate 106

[0554] 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. After degassing and purging with H 2 three times, the reaction mixture was stirred at 25° C. under H 2 (14.696 psi) for 18 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound 106 (10.0 g, 98.52%) as a yellow solid.

[0555] LCMS: m / z (ESI) = 230.2 [M+H] + .

[0556] Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate 107

[0557] To a solution of compound 106 (10.0 g, 43.6 mmol) in DCM (60 mL) and H2O (60 mL) was added NaHCO3 (14.6 g, 174 mmol) and benzyl chloroformate (9.20 mL, 65.4 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Water (50 mL) was added to the reaction mixture. The resulting solution was extracted with DCM (100 mL x 3). The combined organic phases were washed with water (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by silica gel flash column purification using 20% ​​EtOAc in PE as eluent to give target compound 107 (9.00 g, 56.78%) as a colorless oil.

[0558] LCMS: m / z (ESI) = 386.2 [M+Na] + .

[0559] Synthesis of benzyl (3-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)carbamate 108

[0560] Under N2, a mixture of SOMe3Cl (4.95g, 38.5mmol) and tBuOK (3.46g, 30.8mmol) in THF (70mL) was stirred at 25°C for 2 hours. Subsequently, a solution of compound 107 (7.00g, 19.2mmol) in THF (70mL) was added dropwise. The resulting reaction solution was stirred at 25°C for 22 hours. Subsequently, the reaction mixture was poured into water (50mL). The resulting solution was extracted with DCM (50mL x 3). The combined organic phases were washed with water (50mL), brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluting with 30% EtOAc in PE to obtain the title compound 108 (3.00g, 36.76%) as a colorless oil.

[0561] LCMS: m / z (ESI) = 424.2 [M+H] + .

[0562] 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

[0563] To a solution of compound 24 (1.20 g, 3.53 mmol), compound 108 (1.80 g, 4.23 mmol), and [Ir (COD) Cl] 2 (118 mg, 0.18 mmol) in DCE (30 mL) was added sodium trifluoromethanesulfonate (60.7 mg, 0.35 mmol) and o-phenanthroline (63.6 mg, 0.35 mmol) at 25 ° C. The resulting reaction solution was stirred at 80 ° C under N 2 for 16 hours. Subsequently, the reaction solution was poured into water (20 mL). The resulting solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with water (30 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by silica gel flash column purification using 25% EtOAc in PE to give compound 109 (1.20 g, 50.92%) as a yellow solid.

[0564] LCMS: m / z (ESI) = 667.2 [M+H] + .

[0565] 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 (Int 24)

[0566] 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 3 .H 2 O (1 mL) at 25° C. After degassing and purging with H 2 three times, the resulting reaction mixture was stirred under H 2 (14.696 psi) at 25° C. for 24 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title product Int 24 (550 mg, 83.63%) as a yellow oil.

[0567] LCMS: m / z (ESI) = 499.2 [M+H] + .

[0568] 22. Synthesis of Intermediate 25: (S)-tert-Butyl (1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int 25)

[0569]

[0570] 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 at 0°C under N2 atmosphere for 2 hours to obtain a solution.

[0571] Another solution of trimethylsulfonium 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 at 25 ° C under N2 atmosphere for 2 hours, and then the above solution was added dropwise at 25 ° C. After the addition, the reaction mixture was stirred for another 2 hours at 25 ° C. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL * 2). The combined organic layer was 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 ( 80g Silica flash column, eluting with a gradient of 0-100% ethyl acetate in petroleum ether at 80 mL / min) afforded the title product Int 25 (3.5 g, 56%) as a pale yellow solid.

[0572] LCMS: m / z (ESI) = 368.1 [M+H] + .

[0573] 23. Synthesis of Intermediate 26: (S)-tert-Butyl (1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int 26)

[0574]

[0575] Synthesis of (S)-N-(5-(((2-amino-3,3,3-trifluoropropyl)amino)methyl)-6-chloropyridazin-3-yl)pivalamide 116

[0576] 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 minutes and then heated at 40 ° C for 40 minutes. Afterwards, the reaction mixture was cooled to room temperature and sodium cyanoboranuide (273 mg, 4.34 mmol), MeOH (2 mL), and HOAc (1.1 mL, 6.45 mmol) were added. The mixture was stirred for 20 minutes and then concentrated to obtain a residue. The residue was diluted with H2O (100 mL) at 25 ° C. The resulting solution was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel flash column eluting with (50% EA in PE) to afford compound 116 (244 mg, 55.5%) as a white solid.

[0577] LCMS: m / z (ESI) = 354.2 [M+H] + .

[0578] Synthesis of (S)-N-(6-chloro-5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridazin-3-yl)pivalamide 117

[0579] 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 N2 atmosphere for 1 hour. The reaction mixture was quenched with an aqueous NaOH solution (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) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel flash column eluting with (50% EA in PE) to give compound 117 (220 mg, 85.3%) as a white solid.

[0580] LCMS: m / z (ESI) = 380.0 [M+H] + .

[0581] Synthesis of (S)-1-((6-amino-3-chloropyridazin-4-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one 118

[0582] A solution of compound 117 (200 mg, 0.527 mmol) in aqueous HCl (3 mL, 4 mol / mL) and MeOH (1 mL) was stirred at 110° C. for 1 hour. The reaction mixture was concentrated to give the desired crude compound 118 (160 mg, 92.4%) as a white solid.

[0583] LCMS: m / z (ESI) = 296.2 [M+H] + .

[0584] 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

[0585] 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 hours. Subsequently, the reaction solution was cooled to room temperature and quenched with H at 25 ° C O (100 mL). The resulting solution was extracted with EtOAc (100 mL x 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 crude product. The crude product was purified by silica gel flash column purification, eluted with (5% MeOH in DCM) to give the title compound 119 (200 mg, 58.07%) as a white solid.

[0586] LCMS: m / z (ESI) = 599.2 [M+H] + .

[0587] 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 (Int 26)

[0588] To a solution of compound 119 (100 mg, 0.167 mmol) in EtOH (10 mL) and NH OH (1 mL) was added Pd / C (17.7 mg, 0.017 mmol). The reaction mixture was degassed and purged with H 3 times and stirred at 40 ° C under H (1 atm) for 1 hour. Subsequently, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give the desired compound Int 26 (70 mg, 97.4%) as a white solid.

[0589] LCMS: m / z (ESI) = 431.2 [M+H] + .

[0590] 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 (Int 27)

[0591]

[0592] Synthesis of (S)-N-(5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridazin-3-yl-6-d)pivalamide 120

[0593] To a solution of compound 117 (300 mg, 0.790 mmol) and Pd (dppf) Cl 2 (57.80 mg, 0.079 mmol) in D 2 O (1 mL) and THF (5 mL) was added 2,5-dimethyl-2,5-diazahexane (18.3 mg, 0.158 mmol). Subsequently, the reaction mixture was degassed and purged three times with N 2 and stirred at 0 ° C for 0.5 hours under N 2 (15 psi). NaBD 4 (165 mg, 3.95 mmol) was added, and the reaction mixture was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 1 hour. The resulting solution was extracted with EtOAc (100 mL x 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 silica gel flash column eluting with (5% MeOH in DCM) to give the title compound 120 (200 mg, 73.1%) as a white solid.

[0594] LCMS: m / z (ESI) = 347.2 [M+H] + .

[0595] Synthesis of (S)-1-((6-aminopyridazin-4-yl-3-d)methyl)-4-(trifluoromethyl)imidazolidin-2-one 121

[0596] To a solution of compound 120 (190 mg, 0.549 mmol) in HCl (6 mol / L, 3 mL) was added MeOH (1 mL) and the reaction mixture was stirred at 110° C. for 1 hour, after which the reaction mixture was concentrated to afford the title compound 121 (140 mg, 97.32%) as a brown solid.

[0597] LCMS: m / z (ESI) = 263.2 [M+H] + .

[0598] 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

[0599] To a solution of compound 121 (288 mg, 0.713 mmol) and Int 7 (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 hours. The reaction was quenched with H2O (100 mL) at 25 ° C. The resulting solution was extracted with EtOAc (100 mL x 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 crude product. The crude product was purified by silica gel flash column purification, eluted with (5% MeOH in DCM) to give the desired compound 122 (120 mg, 32.6%) as a white solid.

[0600] LCMS: m / z (ESI) = 569.2 [M+H] + .

[0601] 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 (Int 27)

[0602]

[0603] To a solution of compound 122 (120 mg, 0.211 mmol) in EtOH (10 mL) and NH OH (1 mL) was added Pd / C (22.5 mg, 0.021 mmol). The reaction mixture was degassed and purged with H 3 times and stirred at 40 ° C under H (1 atm) for 1 hour. The reaction mixture was directly filtered and the filtrate was concentrated to give the title compound Int 27 (90 mg, 98.21%) as a brown solid.

[0604] LCMS: m / z (ESI) = 434.2 [M+H] + .

[0605] 25. Synthesis of Intermediate 28: tert-Butyl (S)-(1-(4-(difluoromethylene)cyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int 28)

[0606]

[0607] Synthesis of methyl (S)-2-((tert-butyloxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate 124

[0608] To a solution of compound 123 (10.0 g, 45.9 mmol) and Boc2O (10.5 g, 48.2 mmol) in 1,4-dioxane (30 mL) was added a solution of K2CO3 (12.7 g, 91.9 mmol) in H2O (60 mL). The mixture was stirred at 25 ° C for 16 hours. Subsequently, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a residue. The residue was purified by flash column (0-20% EA in PE) to obtain compound 124 (11.0 g, 85.11%) as a white solid.

[0609] LCMS: m / z (ESI) = 304.4 [M+Na] + .

[0610] Synthesis of methyl (S)-2-((tert-butyloxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate 125

[0611] To a solution of compound 124 (11.0 g, 39.1 mmol) in AcOH (50 mL) was added PtO2 (0.440 g, 1.96 mmol) at 25 ° C. The resulting reaction mixture was degassed and purged with H2 three times and stirred at 30 ° C for 36 hours under H2 (3 MPa). The mixture was filtered and the filtrate was concentrated under vacuum to obtain a residue. The residue was purified by flash column (0-20% EA in PE) to obtain compound 125 (7.00 g, 62.30%) as a white solid.

[0612] LCMS: m / z (ESI) = 310.4 [M+H] + .

[0613] Synthesis of methyl (S)-2-((tert-butyloxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate 126

[0614] 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 hour. The mixture was concentrated under vacuum to give a residue. The residue was purified by flash column (0-20% EA in PE) to give the desired compound 126 (6.50 g, 93.51%) as a colorless oil.

[0615] LCMS: m / z (ESI) = 308.4 [M+Na] + .

[0616] Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate 128

[0617] 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 hour. The reaction mixture was quenched with NH4Cl aqueous solution (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column (0-20% EA in PE) to give compound 128 (5.00 g, 68.73%) as a colorless oil.

[0618] LCMS: m / z (ESI) = 342.4 [M+Na] + .

[0619] Synthesis of tert-butyl (S)-(1-(4-(difluoromethylene)cyclohexyl)-3-(dimethyl(oxo)-16-sulfanylidene)-2-oxopropyl)carbamate (Int 28)

[0620] A solution of trimethylsulfonium chloride (3.25g, 25.1mmol) and t-BuOK (2.25g, 20.0mmol) in THF (30mL) was stirred at 25°C for 2 hours. Compound 128 (4.00g, 12.5mmol) was added to the reaction mixture, and the internal temperature was kept below 20°C. The mixture was stirred at 25°C for 16 hours, then quenched with NH4Cl aqueous solution (10mL), and extracted with EA (20mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a residue. The residue was purified by flash column (0-20% EA in PE) to obtain compound Int 28 (1.50g, 31.56%) as a colorless oil.

[0621] LCMS: m / z (ESI) = 380.2 [M+H] + .

[0622] 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 (Int 29)

[0623]

[0624] 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

[0625] To a solution of compound Int 28 (268 mg, 0.707 mmol), compound 24 (200 mg, 0.589 mmol), [Ir (COD) Cl] 2 (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). After degassing and purging three times with N 2 , the reaction mixture was stirred at 80 ° C under N 2 for 16 hours. The reaction mixture was concentrated to give a residue, which was purified by silica gel flash column purification using 5% MeOH in DCM to give the desired compound 129 (240 mg, 65.43%) as a white solid.

[0626] LCMS: m / z (ESI) = 623.0 [M+H] + .

[0627] 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

[0628] To a solution of compound 129 (200 mg, 0.321 mmol) in THF (30 mL) and H2O (5 mL) were added Pd(dppf)Cl2 (23.5 mg, 0.032 mmol) and 2,5-dimethyl-2,5-diazahexane (7.46 mg, 0.064 mmol), and the resulting solution was stirred at 0°C for 10 minutes. Subsequently, NaBH4 (85.0 mg, 2.25 mmol) was added to the reaction solution and stirred at 25°C for 2 hours. The reaction was quenched with EA (30 mL) and water (30 mL), and the resulting solution was extracted with EA (30 mL x 2). 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 silica gel flash column eluting with (90% EtOAc in PE) to afford the title compound 130 (55.0 mg, 29.11%) as a white solid.

[0629] LCMS: m / z (ESI) = 589.2 [M+H] + .

[0630] 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 (Int 29)

[0631] A solution of compound 130 (52.0 mg, 0.088 mmol) in HCl / dioxane (4N) (5 mL) was stirred at 25° C. for 1 hour. The reaction mixture was then concentrated in vacuo to give the target compound Int29 (43.0 mg, 99.65%) as a yellow solid.

[0632] LCMS: m / z (ESI) = 489.2 [M+H] + .

[0633] 27. Synthesis of Intermediate 30: (S)-benzyl (3-bromo-1-(4-(difluoromethylene)cyclohexyl)-2-oxopropyl)carbamate (Int 30)

[0634]

[0635] Synthesis of (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetic acid methyl ester 129

[0636] 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.

[0637] LCMS: m / z (ESI) = 220 [M+H] + .

[0638] Synthesis of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate 130

[0639] 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 hour. Water (50 mL) was added to the reaction mixture. The resulting solution was extracted with DCM (100 mL x 3). The combined organic phases were washed with water (50 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by silica gel flash column (0-20% EtOAc in PE) to give the desired compound 130 (15.6 g, 93.98%) as a colorless oil.

[0640] LCMS: m / z (ESI) = 354 [M+H] + .

[0641] Synthesis of (S)-2-(((Benzyloxy)carbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid 131

[0642] 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 then stirred at 0 ° C for 3 hours. The reaction mixture was acidified to pH = 4 by 1N HCl and then extracted with DCM (40 mL x 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.

[0643] LCMS: m / z (ESI) = 340 [M+H] + .

[0644] Synthesis of tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4-(difluoromethylene)cyclohexyl)-3-oxobutanoate 132

[0645] 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. for 2 hours under N2. To a solution of diisopropylamine (16 mL, 113 mmol) in anhydrous THF (100 mL) at 0° C. under N2 was added nBuLi (45 mL, 113 mmol), and the reaction mixture was stirred at 0° C. for 10 minutes. The mixture was 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 hour. The enolate solution was added to the above solution at -78° C. and stirred at -78° C. for 1 hour. The reaction mixture was quenched with a saturated NH4Cl solution at -78° C. and warmed to room temperature. The solution was extracted with EtOAc (50 mL x 3). The combined organic phases were concentrated to give a yellow residue, which was purified by flash column (0-30% EtOAc in PE) to give the title compound 132 (7 g, 63.88%) as a yellow oil.

[0646] LCMS: m / z (ESI) = 438 [M+H] + .

[0647] Synthesis of benzyl (S)-(3-bromo-1-(4-(difluoromethylene)cyclohexyl)-2-oxopropyl)carbamate (Int30)

[0648] To a solution of compound 132 (7 g, 14.4 mmol) and 2,6-lutidine (0.2 mL, 1.44 mmol) in MeOH (80 mL) was added NBS (2.72 g, 15.3 mmol), and the reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was then stored at -20 ° C for 24 hours. The reaction mixture was diluted with EtOAc (800 mL). The resulting solution was washed with 50% saturated aqueous NaCl solution (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was dissolved in toluene (80 mL), and TFA (5.5 mL, 72 mmol) was subsequently added. The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated to obtain a residue, which was purified by silica gel flash column purification (0-30% EA in PE) to obtain the desired compound Int 30 (4 g, 66.73%) as a light yellow solid.

[0649] LCMS: m / z (ESI) = 416 [M+H] +.

[0650] 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)propionitrile (Int 31)

[0651]

[0652] 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

[0653] To a solution of compound 50 (680 mg, 2.03 mmol) and compound Int 30 (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 H2O (100 mL) at 25 ° C, and the resulting solution was extracted with EtOAc (100 mL x3). 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 silica gel flash column purification using (5% MeOH in DCM) to give the title compound 133 (1.44 g, 97.8%) as a brown solid.

[0654] LCMS: m / z (ESI) = 652.2 [M+H] + .

[0655] 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

[0656] To a solution of compound 133 (1.44 g, 2.21 mmol) and Pd(dppf)Cl2 (0.16 g, 0.221 mmol) in H2O (2 mL) and THF (10 mL) was added 2,5-dimethyl-2,5-diazahexane (0.07 mL, 0.442 mmol). Subsequently, the reaction mixture was degassed and purged with N2 three times and stirred at 0°C under N2 (15 psi) for 0.5 hours. NaBH4 (0.42 g, 11.1 mmol) was added and the mixture was stirred at 0°C for 30 minutes, then warmed to 25°C and stirred for 1 hour. The reaction mixture was quenched with MeOH (1 mL) at 25°C and then quenched with H2O (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 silica gel flash column eluting with (5% MeOH in DCM) to give compound 134 (680 mg, 49.8%) as a brown solid.

[0657] LCMS: m / z (ESI) = 618.2 [M+H] + .

[0658] 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)propionitrile (Int 31)

[0659] 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 NaHCO3 aqueous solution (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 silica gel flash column purification using (12% MeOH in DCM) to give Int 31 (120 mg, 38.3%) as a brown solid.

[0660] LCMS: m / z (ESI) = 484.2 [M+H] + .

[0661] 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 (Int 32)

[0662]

[0663] 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

[0664] To a solution of compound Int 25 (120 mg, 0.316 mmol), compound 118 (82.6 mg, 0.316 mmol), [Ir (COD) Cl] 2 (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). After degassing and purging three times with N 2 , the reaction mixture was stirred at 80 ° C under N 2 for 16 hours. The reaction mixture was concentrated to give a residue, which was purified by silica gel flash column purification using 5% MeOH in DCM to give compound 135 (150 mg, 87.1%) as a white solid.

[0665] LCMS: m / z (ESI) = 545.2 [M+H] + .

[0666] Synthesis of (S)-1-((2-((S)-amino(4-(difluoromethylene)cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (Int 32)

[0667] 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.

[0668] LCMS: m / z (ESI) = 445.2 [M+H] + .

[0669] 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 (Int 33)

[0670]

[0671] 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

[0672] A solution of compound 25 (200 mg, 0.311 mmol) in THF (30 mL) and D2O (5 mL) was concentrated under vacuum to give a residue. The residue was redissolved in THF (30 mL) and D2O (5 mL), and Pd(dppf)Cl2 (22.8 mg, 0.031 mmol) and 2,5-dimethyl-2,5-diazahexane (7.23 mg, 0.062 mmol) were added and stirred at 0°C for 10 minutes. Subsequently, NaBD4 (130 mg, 3.11 mmol) was added and stirred at 25°C for 2 hours. The reaction was quenched with EA (30 mL) and water (30 mL). The resulting solution was extracted with EA (30 mL x 2). 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 silica gel flash column eluting with (90% EtOAc in PE) to afford the title compound 136 (120 mg, 63.29%) as a white solid.

[0673] LCMS: m / z (ESI) = 610.2 [M+H] + .

[0674] 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)

[0675] To a solution of compound 136 (21.0 mg, 0.197 mmol) in EtOH (8 mL) was added 10% Pd / C (21.0 mg, 0.197 mmol) and NH 3 .HO (0.8 mL) at 25° C. The reaction mixture was then degassed and purged with H 2 three times and stirred at 35° C. under H 2 (15 psi) for 4 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound Int 33 (93.0 mg, 99.37%) as a white solid.

[0676] LCMS: m / z (ESI) = 476.0 [M+H] + .

[0677] 31. Synthesis of Intermediate 34: 4-(3-Fluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 34)

[0678]

[0679] Synthesis of compound 4-(benzyloxy)butyric acid 138

[0680] 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 MeCN (1000 mL) and NaH2PO4 (99.86 g, 832.18 mmol) in H2O (860 ml). 140 mL of NaClO2 aqueous solution (62.72 g, 693.48 mmol) and a 5% aqueous solution of NaClO (8 mL) were added to the reaction mixture. Subsequently, the reaction mixture was stirred at 35 ° C for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was adjusted to pH = 8.0 by adding 2M NaOH aqueous solution and stirred for 20 minutes. Subsequently, the reaction mixture was extracted with tert-butyl methyl ether (500 ml × 2). The aqueous solution was adjusted to pH 3-4 by adding 3M HCl, extracted with EtOAc (1000 mL×2), and the organic layer was washed with brine (300 ml×1) and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the desired crude compound 138 (54.2 g, 100%) as a clear oil.

[0681] LCMS: m / z (ESI) = 195.0 [M+H] + .

[0682] Synthesis of compound 6-(benzyloxy)-3-oxohexanoic acid ethyl ester 139

[0683] To a solution of compound 138 (50 g, 257.43 mmol) in anhydrous THF (500 mL) was added CDI (50.04 g, 308.91 mmol) at room temperature. The reaction mixture was stirred for 2 hours. [(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 using hydrochloric acid (2M aqueous solution), and the mixture was extracted with EA (3x500 mL). The combined extracts were dried over Na2SO4 and filtered, and the resulting crude compound was purified by silica column chromatography (15% EA in 0%-PE) to give the title compound 139 (44 g, 64.67%) as a colorless oil.

[0684] LCMS: m / z (ESI) = 265.0 [M+H] + .

[0685] Synthesis of compound (Z)-6-(benzyloxy)-2-(hydroxyimino)-3-oxohexanoic acid ethyl ester 140

[0686] To a solution of compound 139 (44 g, 170.24 mmol) in AcOH (200 mL) and H2O (200 mL) was slowly added a solution of NaNO2 (17.62 g, 255.37 mmol) in H2O (200 mL) at 5°C. The reaction mixture was stirred between 5-10°C for 1 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (2 x 200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated under vacuum to give crude compound 140 (52 g, 100%) as a yellow oil.

[0687] LCMS: m / z (ESI) = 294.0 [M+H] + .

[0688] Synthesis of compound (2Z,3Z)-6-(benzyloxy)-2,3-bis(hydroxyimino)hexanoic acid ethyl ester 141

[0689] To a solution of compound 140 (52 g, 177.28 mmol) and NaOAc (29.08 g, 354.56 mmol) in MeOH (600 mL) was added hydroxylamine hydrochloride (13.55 g, 195.01 mmol). The reaction mixture was stirred at 50 ° C for 18 hours. The reaction mixture was diluted with saline solution (200 mL) and extracted with EtOAc (2 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica column chromatography (0-30% EA in PE) to give the title compound 141 (40.8 g, 74.64%) as a colorless oil.

[0690] LCMS: m / z (ESI) = 309.0 [M+H] + .

[0691] Synthesis of compound 3-(3-(benzyloxy)propyl)-4-(ethoxycarbonyl)-1,2,5-oxadiazole 2-oxide 142

[0692] 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 room temperature. The resulting mixture was stirred at room temperature for 2 hours. The residue was concentrated under reduced pressure and purified by flash silica gel chromatography (0-10% ethyl acetate / petroleum ether) to afford compound 142 (21.7 g, 53.54%) as a clear oil.

[0693] LCMS: m / z (ESI) = 307.0 [M+H] + .

[0694] Synthesis of compound 4-(3-(benzyloxy)propyl)-1,2,5-oxadiazole-3-carboxylic acid ethyl ester 143

[0695] To a solution of compound 142 (21.7 g, 70.841 mmol) in toluene (200 mL) was added P(OEt) 3 (121.48 mL, 708.41 mmol) at room temperature and stirred at 115 ° C overnight. LCMS showed that the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (EtOAC in PE, 0% to 10%) to give the title compound 143 (17 g, 82.66%) as a clear oil.

[0696] LCMS: m / z (ESI) = 291.0 [M+H] + .

[0697] Synthesis of compound 4-(3-hydroxypropyl)-1,2,5-oxadiazole-3-carboxylic acid ethyl ester 144

[0698] 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 HCl (0.3 ml). The reaction mixture was stirred at room temperature under H2 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.

[0699] LCMS: m / z (ESI) = 201.0 [M+H] + .

[0700] Synthesis of compound 4-(3-fluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid ethyl ester 145

[0701] 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 at room temperature for 30 minutes. The reaction mixture was quenched with ice water and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over Na2SO4 and filtered, and the resulting crude compound was purified by silica column chromatography (0-10% EA in PE) to obtain the desired compound 145 (0.17 g, 30.36%) as a colorless oil.

[0702] LCMS: m / z (ESI) = 203.0 [M+H] + .

[0703] Synthesis of compound 4-(3-fluoropropyl)-1,2,5-oxadiazole-3-carboxylic acid (Int 34)

[0704] To a solution of compound 145 (170 mg, 0.84 mmol) in THF (3 mL) and H2O (0.5 mL) was added lithium hydroxide (60.41 mg, 2.52 mmol). Subsequently, the reaction mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction was quenched and acidified to pH = 4 with dilute HCl. The solution was concentrated under reduced pressure and purified by preparative HPLC (0-50% MeCN in H2O) to give the title compound Int34 (30 mg, 20.49%) as a colorless oil.

[0705] LCMS: m / z (ESI) = 347.0 [2M-H] - .

[0706] Example

[0707] 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)

[0708]

[0709] Compound Int 1 (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, followed by the addition of DIPEA (54.25 mg, 419.78 μmol, 73.12 μL, 4 eq) and Int 13 (50 mg, 104.94 μmol, 1 eq). The reaction mixture was stirred at 25 ° C for 1.5 hours. 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 obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 7 minutes) to give the title product E1 (5.1 mg, 7.25%).

[0710] LCMS: m / z (ESI) = 671.0 [M+H] + .

[0711] 1 H NMR (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).

[0712] 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)

[0713]

[0714] A mixture of compound Int 2 (20 mg, 95.19 umol, 1.2 eq), Int 13 (37.79 mg, 79.32 umol, 15.48 uL, 1 eq), HOSu (13.69 mg, 118.99 umol, 1.5 eq), EDCI (38.02 mg, 198.31 umol, 2.5 eq), and DIPEA (41.01 mg, 317.29 umol, 55.27 uL, 4 eq) in DCM (0.5 mL) was degassed and purged with N2 three times, and finally the mixture was stirred at 25 °C under N2 atmosphere for 3 hours. The residue was directly purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 6 minutes) to give the target product E2 (15.3 mg, 28.85%) as a white solid.

[0715] LCMS: m / z (ESI) = 669.2 [M+H] + .

[0716] 1 H NMR(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).

[0717] Example 3: Synthesis of 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 (E3-0 1), and 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)

[0718]

[0719] To a solution of compound Int 5 (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 h. The reaction mixture was purified by preparative HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20APUV detector, column: Ultimate XB-C18, 50×250 mm×10 μm; mobile phase A: H 2 O and NH 4 HCO 3 (10 mmol / L); mobile phase B: CH 3 CN; gradient: B from 40% to 80% in 30 minutes, maintaining 100% B for 3 minutes; flow rate: 70 mL / min; Rt=14.8 minutes, column temperature: 30° C.; wavelength: 214 nm, 254 nm) to give the target product E3 (25.3 mg, 17.9%) as a white solid.

[0720] LCMS: m / z (ESI) = 611.2 [M+H] + .

[0721] 1H NMR: 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).

[0722] Compound E3 (24.1 mg, 0.0390 mmol) was further separated by SFC (column: Daicel ChiralPak AD, 40 mm ID 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) to obtain the title products E3-01 (7.7 mg, 32.0%) and E3-02 (6.8 mg, 28.2%).

[0723] E3-01:

[0724] LCMS: m / z (ESI) = 611.2 [M+H] + .

[0725] 1 H NMR: (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).

[0726] E3-02:

[0727] LCMS: m / z (ESI) = 611.2 [M+H] + .

[0728] 1 H NMR: (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).

[0729] 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), and 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)

[0730]

[0731] To a solution of compound Int 8 (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, after which water (20 mL) was added to the reaction mixture. The resulting mixture was 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 preparative HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu, SPD-20APUV detector, column: Ultimate XB-C18, 50×250 mm×10 μm; mobile phase A: H2O with NH4HCO3 (10 mmol / L); mobile phase B: CH3CN; gradient: B from 40% to 80% in 30 minutes, maintaining 100% B for 3 minutes; flow rate: 70 mL / min; Rt=17.3 minutes and 18.3 minutes, 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%).

[0732] E4-01:

[0733] LCMS: m / z (ESI) = 588.2 [M+H] + .

[0734] 1 H NMR: (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).

[0735] E4-02:

[0736] LCMS: m / z (ESI) = 588.2 [M+H] +.

[0737] 1 H NMR: (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).

[0738] Example 5: Synthesis of 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), and 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)

[0739]

[0740] To a solution of compound Int 9 (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. Subsequently, 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 stirred at 25 ° C for 1 hour. The resulting solution was extracted with EA (30 mL x 2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification using (4% MeOH in DCM) to give the target product E5 (108 mg, 69.92% yield) as a white solid.

[0741] LCMS: m / z (ESI) = 611.2 [M+H] + .

[0742] 1 H NMR: 1 H NMR (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).

[0743] 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 ID x 250 mm, 10 μm, mobile phase A: supercritical NA mobile phase B: ethanol, A:B: 0:100, wavelength: 214 nm, flow: 70 mL / min, column temperature: RT, injection: 30 mL, cycle time: 18 minutes] to obtain the desired products E5-01 (43.6 mg, 36.03% yield) and E5-02 (32.8 mg, 27.11% yield).

[0744] E5-01:

[0745] LCMS: m / z (ESI) = 611.1 [M+H] + .

[0746] 1 H NMR: 1H NMR(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)。

[0747] E5-02:

[0748] LCMS:m / z(ESI)=611.2[M+H] + 。

[0749] 1 H NMR:(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),2.23–1.97(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)。

[0750] Example 6: 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 (E6-01), 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 (E6-02). 2), 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 (E6-03), 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)

[0751]

[0752] 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 minutes. Subsequently, compound Int12-S2 (72 mg, 0.15 mmol) and DIEA (0.106 mL, 0.611 mmol) were added to the reaction solution. The resulting reaction solution was stirred at 30 ° C for 18 hours. The reaction was quenched with MeOH (0.5 mL) and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography ( 4g The product was purified by silica flash column (0-0.5% MeOH / DCM gradient at 18 mL / min eluent) to give a solid. The solid was then further subjected to two SFC separations (DAICEL CHIRALPAK IG column, 10 μm, 250 x 30 mm; 40-40% (v / v) CO₂-EtOH (0.1% NH₃H₂O)) to give the desired products E6-01 (4.7 mg, 5.07% yield) and E6-02 (12.1 mg, 13.04%) as white solids.

[0753] E6-01:

[0754] LCMS:m / z(ESI)=608.3[M+H] + 。

[0755] 1 H NMR(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)。

[0756] E6-02:

[0757] LCMS:m / z(ESI)=608.3[M+H] + 。

[0758] 1 H NMR(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)。

[0759] 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. Compound Int12-S1 (92.0 mg, 0.195 mmol) and DIEA (0.136 mL, 0.781 mmol) were then 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 under vacuum to give a residue. The residue was purified by flash silica gel chromatography ( 4g The mixture was purified twice using a silica flash column (0-0.5% MeOH / DCM gradient at 18 mL / min as eluent) to give a yellow oil (60 mg). The oil was purified by HPLC (Xtimate C18 column, 10 μm, 150 x 40 mm; 45-75% (v / v) water (FA)-ACN) to give a crude product (25 mg). The crude product was further purified by SFC (DAICEL CHIRALPAK AD column, 10 μm, 250 x 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.

[0760] E6-03:

[0761] LCMS: m / z (ESI) = 608.3 [M+H] + .

[0762] 1 H NMR (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),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),1.6 8-1.62(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).

[0763] E6-04:

[0764] LCMS: m / z (ESI) = 608.3 [M+H] + .

[0765] 1 H NMR(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),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),1.6 8-1.61(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).

[0766] 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)

[0767]

[0768] To a solution of compound Int 13 (33 mg, 0.060 mmol), a stirring bar, T3P (50% in EA) (115 mg, 0.180 mmol), TEA (0.058 mL, 0.42 mmol) and DCM (1 mL) was added compound Int 10 (10 mg, 0.060 mmol) in one portion. The resulting reaction mixture was stirred at 25 ° C for 18 hours. The reaction was quenched with H2O (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 under vacuum to give a residue, which was purified by HPLC (Boston Green ODS column, 5 μm, 150 x 30 mm; 55-85% (v / v) H2O (containing FA) / MeCN)) to give the title product E7 (7.8 mg, 20.75%) as a white solid.

[0769] LCMS: m / z (ESI) = 625.2 [M+H] + .

[0770] 1 H NMR(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).

[0771] 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)

[0772]

[0773] To a solution of compound Int 11 (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 hour. The reaction was then quenched with H2O 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 crude product. The crude product was purified by silica gel flash column eluting with (5% MeOH in DCM) to give the title product E8 (36.2 mg, 23.5%) as a white solid.

[0774] LCMS: m / z (ESI) = 599.4 [M+H] + .

[0775] 1H NMR: (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).

[0776] 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)

[0777]

[0778] To a solution of compound Int 13 (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 hour. The reaction was quenched with H2O (100 mL) at 25 ° C. The resulting solution was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel flash column purification, eluted with (5% MeOH in DCM) to give the title compound E9-1 (43 mg, 56.3%) as a yellow oil.

[0779] LCMS: m / z (ESI) = 606.2 [M+H] + .

[0780] To a solution of compound E9-1 (47.0 mg, 0.078 mmol) in toluene (2 mL) was added P(OEt)3 (257 mg, 1.55 mmol). The reaction mixture was stirred at 120 ° C for 18 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by reverse phase column (50% ACN in water) to give the title compound E12 (8.4 mg, 18.3%) as a white solid.

[0781] LCMS: m / z (ESI) = 590.2 [M+H]+ .

[0782] 1 H NMR (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).

[0783] 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), and 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)

[0784]

[0785] To a solution of compound Int 15 (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 phases were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20APUV detector, column: Ultimate XB-C18, 50×250 mm×10 μm; mobile phase A: H 2 O and NH 4 HCO 3 (10 mmol / L); mobile phase B: CH 3 CN; gradient: B from 30% to 60% in 30 min, maintaining 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 target product E10 (39.3 mg, 33.5%) as a white solid.

[0786] LCMS: m / z (ESI) = 585.2 [M+H] + .

[0787] 1 H NMR: (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).

[0788] Compound E10 (38.0 mg, 0.0650 mmol) was further purified by SFC (column: Daicel ChiralPak AD, 40 mm ID 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) to give the title products E10-01 (9.7 mg, 25.5%) and E10-02 (8.2 mg, 21.6%) as white solids.

[0789] E10-01:

[0790] LCMS: m / z (ESI) = 585.4 [M+H] + .

[0791] 1 H NMR: (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).

[0792] E10-02:

[0793] LCMS: m / z (ESI) = 585.4 [M+H] + .

[0794] 1 H NMR: (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).

[0795] 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)

[0796]

[0797] To a solution of compound Int 16 (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 Int 13 (50 mg, 0.105 mmol) was added. The resulting reaction mixture was stirred for another hour. Subsequently, the reaction mixture was concentrated under vacuum to obtain a residue. The residue was first purified by silica gel flash column eluting with (10% MeOH in DCM) and then with (45% MeCN in water) C 18 Column chromatography afforded the desired product E11 (11 mg, 17.50%) as a white solid.

[0798] LCMS: m / z (ESI) = 599.0 [M+H] + .

[0799] 1 H NMR: 1 H NMR (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).

[0800] 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)

[0801]

[0802] To a solution of compound Int 13 (30 mg, 0.063 mmol) in DMF (4 mL) was added compound Int17 (29.86 mg, 0.094 mmol), HATU (35.91 mg, 0.094 mmol) and DIPEA (24.41 mg, 0.19 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture and extracted with EA (20 mL x 2). The combined organic layer was washed with a saturated aqueous NaCl solution (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the desired product E12 (6.0 mg, 15.46%) as a white solid.

[0803] LC-MS (ESI): m / z = 617.0 [M+H] + .

[0804] 1 H NMR (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).

[0805] 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)

[0806]

[0807] To a solution of compound Int 13 (40 mg, 0.084 mmol) in DMF (2 mL) was added compound Int8 (26.56mg, 0.168mmol) , 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. Subsequently, the reaction mixture was diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum. 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.

[0808] LC-MS (ESI): m / z = 617.0 [M+H] + .

[0809] 1 H NMR(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).

[0810] 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)

[0811]

[0812] To a solution of compound Int 13 (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. Subsequently, the reaction mixture was diluted with EA and saturated NaCl solution. The organic layer was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by C 18 Purification by column chromatography (eluting with 0.5% TFA in water:acetonitrile = 0-100%) gave the title compound E14 as a white solid.

[0813] LC-MS (ESI): m / z = 613.0 [M+H] + .

[0814] 1 H NMR(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,1 H),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).

[0815] 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-methylcyclopropyloxy)-1,2,5-oxadiazole-3-carboxamide (E15)

[0816]

[0817] To a mixture of compound Int 13 (30 mg, 0.063 mmol) in DMF (2 mL) was added compound Int 20 (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 quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (20 mL * 3). The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (80% EtOAc in PE) to give the title product E15 (3 mg, 7.41%) as a white solid.

[0818] LCMS: m / z (ESI) = 643.0 [M+H] + .

[0819] 1 H NMR (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).

[0820] 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-methylcyclobutyloxy)-1,2,5-oxadiazole-3-carboxamide (E16)

[0821]

[0822] To a solution of compound Int 13 (30 mg, 0.063 mmol) in DMF (2 mL) was added compound Int 21 (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. Subsequently, the reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc (20 mL * 3). The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (40% EtOAc in PE) to give the title product E16 (10 mg, 20.82%) as a white solid.

[0823] LCMS: m / z (ESI) = 657 [M+H] + .

[0824] 1 H NMR (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,2 H),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).

[0825] 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)

[0826]

[0827] To a solution of compound Int 22 (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 solution was stirred at 25 ° C for 1 hour. The reaction solution was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated under vacuum. The crude product was first purified by silica gel flash column using (10% MeOH in DCM) as eluent and then by C 18 Flash column purification using (45% MeCN in H2O (0.01% TFA)) afforded the title product E17 (4 mg) as a white solid.

[0828] LC / MS: m / z (ESI) = 639.0 [M+H] + .

[0829] 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).

[0830] 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)

[0831]

[0832] 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

[0833] To a solution of compound Int 9 (100mg, 0.211mmol) in EA (5mL) was added TEA (0.234mL, 1.686mmol), and stirred at 25°C for 5 minutes. Subsequently, compound Int 23 (52.4mg, 0.232mmol) and T3P (1.07g, 1.69mmol, 50% in EA) were added, and stirred at 25°C for 1 hour. EA (30mL) and water (30mL) were added to the reaction mixture. The resulting solution was extracted with EA (30mL x 2). The combined organic phases were washed with water (30mL), brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification, eluted with 4% MeOH in DCM to give the title compound 111 (100mg, 69.51%) as a white solid.

[0834] LCMS: m / z (ESI) = 683.2 [M+H] + .

[0835] 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)

[0836] At 25 ° C, P (OEt) 3 (488 mg, 2.94 mmol) was added to a solution of compound 111 (100 mg, 0.147 mmol) in toluene (20 mL). Subsequently, the reaction mixture was stirred at 120 ° C for 12 hours. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL x 2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluted with 4% MeOH in DCM to obtain the title product E18 (55.0 mg, 56.32%) as a white solid.

[0837] LCMS: m / z (ESI) = 667.0 [M+H] + .

[0838] 1 H NMR: (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).

[0839] Compound E18 (30.0 mg, 0.045 mmol) was further purified by SFC [system: Waters SFC 150, column name: Daicel ChiralPaK AD, column size: 40 mm ID x 250 mm, 10 μm, mobile phase A: supercritical CO2, mobile phase B: 7 M NH3 in 0.1% MeOH, A:B: 60:40, wavelength: 214 nm, flow: 120 mL / min, column temperature: RT, injection: 1.5 mL, cycle time: 5.5 minutes] to obtain the target products E18-01 (6.90 mg, 23.0%) and E18-02 (6.9 mg, 23.0%).

[0840] E18-01:

[0841] LCMS: m / z (ESI) = 667.2 [M+H] + .

[0842] 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).

[0843] E18-02:

[0844] LCMS: m / z (ESI) = 667.2 [M+H] + .

[0845] 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=1 0.4,3.6Hz,1H),3.44(s,3H),3.29–3.21(m,3H),2.79–2.61(m,2H),2.4 8–2.29(m,1H),2.23–1.97(m,3H),1.82–1.68(m,1H),1.68–1.52(m,1H).

[0846] 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)

[0847]

[0848] 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

[0849] To a solution of compound Int 24 (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 x 3). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel flash column purification, eluting with 5% MeOH in DCM to give the title compound 112 (600 mg, 85.69%) as a yellow solid.

[0850] LCMS: m / z (ESI) = 635.2 [M+H] + .

[0851] 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

[0852] A mixture of compound 112 (600 mg, 0.95 mmol) in 2N HCl (aq) (27.3 mL, 54.70 mmol) and THF (5 mL) was stirred at 25 ° C for 3 hours. The reaction mixture was extracted with DCM (20 mL x 3). The organic layer was washed with saturated NaHCO (aqueous solution, 50 mL), dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by silica gel flash column eluting with 10% MeOH in DCM to give the title compound 113 (450 mg, 80.60%) as a yellow solid.

[0853] LCMS: m / z (ESI) = 591.2 [M+H] + .

[0854] 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)

[0855] Under N2 protection, at -78 ° C, 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) was added a solution of t-BuOK (85.5 mg, 0.762 mmol) in THF (10 mL). Subsequently, the reaction mixture was stirred at -78 ° C for 1 hour. Saturated NH4Cl (20 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (20 mL×3). The combined organic phases were 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 silica gel flash column eluting with 5% MeOH in DCM to give a crude product (70 mg). The crude product was purified by preparative HPLC [equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20APUV detector, column: Ultimate XB-C18, 50×250 mm×10 μm; mobile phase A: H 2 O and NH 4 HCO 3 (10 mmol / L); mobile phase B: CH 3 CN; gradient: B from 40% to 80% in 30 min, maintaining 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.

[0856] LCMS: m / z (ESI) = 625.4 [M+H] + .

[0857] 1 H NMR: (400MHz, CD3OD) δ8.38 (d, J=2.0Hz, 1H), 8.12 (s, 1H), 7.89–7.83 (m, 1H), 5.26–5.1 7(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,3 H),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).

[0858] 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 mm 3 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH (0.1% DEA), A:B: 85:15, wavelength: 214 nm, flow: 90 mL / min, column temperature: RT, injection: 2 mL, cycle time: 5.5 min] to give the title products E19-01 (8.2 mg, 45.56% yield) and E19-02 (9.5 mg, 52.78%) as white solids.

[0859] E19-01:

[0860] LCMS: m / z (ESI) = 625.2 [M+H] + .

[0861] 1 H NMR(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).

[0862] E19-02:

[0863] LCMS: m / z (ESI) = 625.2 [M+H] + .

[0864] 1H NMR(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).

[0865] 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), and 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)

[0866]

[0867] 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)

[0868] At -60 ° C under N2 atmosphere, to a solution of compound 113 (129 mg, 0.339 mmol) in THF (5 mL) was added LiHMDS (0.339 mL, 0.339 mmol), and the resulting reaction mixture was stirred at -60 ° C for 1 hour. Subsequently, compound (fluoromethyl) triphenyl (tetrafluoro-15-boraneyl [boraneyl]) -15-phosphine (100 mg, 0.169 mmol) was added, and the reaction mixture was stirred at -60 ° C for 2 hours. EA (30 mL) and water (30 mL) were added to the reaction mixture. The resulting solution was extracted with EA (30 mL x2). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash column purification, eluting with 3% MeOH in DCM to obtain a crude product. The crude product was purified by preparative HPLC (equipment: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20APUV detector, column: Kromasil 100-10-C18, 50×250 mm×10 μm; mobile phase A: H2O and NH4HCO3 (10 mmol / L); mobile phase B: CH3CN; gradient: B from 35% to 75% in 0.7 h, maintaining 100% B for 3 minutes; flow rate: 70 mL / min; Rt=20.75 minutes, column temperature: 30°C; wavelength: 214 nm, 254 nm) to give the title product E20 (55.0 mg, 53.55%) as a white solid.

[0869] LCMS: m / z (ESI) = 607.2 [M+H] + .

[0870] 1 H NMR: (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).

[0871] Compound E20 (52.0 mg, 0.086 mmol) was further purified by SFC [system: YMC K-PrepLAB100G, column name: Daicel ChiralPaK IB N, column size: 40 mm ID 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: 80 mL / min, column temperature: RT, injection: 30 mL, cycle time: 20 minutes] to give the target products E20-01 (19.0 mg, 36.54%) and E20-02 (14.0 mg, 26.92%) as white solids.

[0872] E20-01:

[0873] LCMS: m / z (ESI) = 607.4 [M+H] + .

[0874] 1 H NMR: (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).

[0875] E20-02:

[0876] LCMS: m / z (ESI) = 607.4 [M+H] + .

[0877] 1H NMR: (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).

[0878] 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)

[0879]

[0880] 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

[0881] To a solution of compound Int 5 (55.0 mg, 0.116 mmol) in EtOAc (5 mL) was added compound Int 23 (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 phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification using (4% MeOH in DCM) to give the title compound 114 (30.0 mg, 37.9%) as a white solid.

[0882] LCMS: m / z (ESI) = 683.2 [M+H] + .

[0883] 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)

[0884] 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). After degassing and purging with N2 three times, the reaction mixture was stirred at 120° C. under N2 for 12 hours. The reaction mixture was concentrated to give a residue. The reaction mixture was purified by preparative 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: H 2 O and NH 4 HCO 3 (10 mmol / L); mobile phase B: CH 3 CN; gradient: B from 45% to 75% in 30 minutes, maintaining 100% B for 3 minutes; flow rate: 70 mL / min; Rt=9.0 minutes, column temperature: 30° C.; wavelength: 214 nm, 254 nm) to give the title product E21 (8.00 mg, 27.3%) as a white solid.

[0885] LCMS: m / z (ESI) = 667.2 [M+H] + .

[0886] 1 HNMR: (400MHz, CD3OD) δ8.39 (d, J = 2.4Hz, 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).

[0887] Compound E21 (90.0 mg, 0.135 mmol) was further separated by SFC (system: Waters prepSFC150Mgm, column: Daicel ChiralPak AD, 40 mm ID 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) to obtain E21-01 (19.4 mg, 21.6%) and E21-02, 23.0%) as white solids.

[0888] E21-01:

[0889] LCMS: m / z (ESI) = 667.2 [M+H] + .

[0890] 1 H NMR: (400MHz, CD3OD) δ8.37(d,J=2.0Hz,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),3.44(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).

[0891] E21-02:

[0892] LCMS: m / z (ESI) = 667.2 [M+H] + .

[0893] 1 H NMR: (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).

[0894] Example 22: Synthesis of 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-3-carboxamide (E22-01), and 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)

[0895]

[0896] To a solution of compound Int 29 (43.0 mg, 0.088 mmol) in EA (5 mL) was added TEA (0.098 mL, 0.704 mmol) and stirred at 25 ° C for 5 minutes, compound Int 2 (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. Subsequently, the reaction was quenched with EA (30 mL) and water (30 mL). The resulting solution was extracted with EA (30 mL x 2). 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 silica gel flash column purification using (4% MeOH in DCM) to elute to give the target product E22 (34.0 mg, 56.75%) as a white solid.

[0897] E22 (34.0 mg, 0.050 mmol) was further purified by SFC [system: Waters PrepSFC 150, column name: Regis WhelkO1 (R,R), column size: 40 mm ID x 250 mm, 10 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH, A:B: 65:35, wavelength: 210 nm, flow: 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.

[0898] E22-01:

[0899] LCMS: m / z (ESI) = 681.0 [M+H] + .

[0900] 1 H NMR: (400MHz, CD3OD) δ8.38 (d, J=2.0Hz, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 5.26–5.1 8(m,2H),4.43–4.29(m,1H),4.03–3.88(m,3H),3.51(dd,J=10.4,3.6Hz,1H),3.4 4(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).

[0901] E22-02:

[0902] LCMS: m / z (ESI) = 681.0 [M+H] + .

[0903] 1 H NMR: (400MHz, CD3OD) δ8.28 (d, J=2.0Hz, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 5.14–5.0 8(m,2H),4.31–4.22(m,1H),3.90–3.82(m,3H),3.42(dd,J=10.4,3.6Hz,1H),3.3 3(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).

[0904] 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), and 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)

[0905]

[0906] To a solution of compound Int 32 (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 hour. The reaction mixture was quenched with H2O (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, which was purified by silica gel flash column eluting with (5% MeOH in DCM) to give E23 (41.6 mg, 28.4%) as a white solid.

[0907] LCMS: m / z (ESI) = 637.0 [M+H] + .

[0908] 1 H NMR (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=2 0Hz,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).

[0909] Compound E23 (40 mg, 0.063 mmol) was further purified by SFC (column: ChiralPak AD-H (Dacel), 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.

[0910] E23-01:

[0911] LCMS: m / z (ESI) = 637.0 [M+H] + .

[0912] 1 H NMR (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=2 0Hz,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).

[0913] E23-02:

[0914] LCMS: m / z (ESI) = 637.0 [M+H] + .

[0915] 1 H NMR (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=2 0Hz,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).

[0916] 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)

[0917]

[0918] To a solution of compound Int 27 (117 mg, 0.270 mmol), TEA (1.51 mL, 10.7 mmol), and compound Int 2 (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 hour. Subsequently, the reaction was quenched with H2O (100 mL) at 25 ° C, and the resulting solution was extracted with EtOAc (100 mL x 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 crude product. The crude product was purified by silica gel flash column eluting with (5% MeOH in DCM) to give the target product E25 (47.3 mg, 28.1%) as a white solid.

[0919] LCMS: m / z (ESI) = 626.0 [M+H] + .

[0920] 1 H NMR: (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. 28–2.17(m,1H),2.13–1.96(m,3H),1.86–1.60(m,3H),1.47–1.33(m,2H).

[0921] Example 26: 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-6-d)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E26- 01), and 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)

[0922]

[0923] To a solution of compound Int 8 (110 mg, 0.230 mmol) in EA (10 mL) was added TEA (0.256 mL, 1.843 mmol) and stirred at 25 ° C for 5 minutes. Subsequently, compound Int 2 (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 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 a residue. The residue was purified by silica gel flash column purification, eluted with (3% MeOH in DCM) to give the target product E26 (60.0 mg, 38.90%) as a white solid.

[0924] LCMS: m / z (ESI) = 670.2 [M+H] + .

[0925] E26 (55.0 mg, 0.082 mmol) was further purified by SFC [system: YMC K-PrepLAB100G, column name: Daicel ChiralPak IB N, column size: 40 mm ID x 250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: EtOH (0.1% NH 3 .H 2 O), A:B: 60:40, wavelength: 210 nm, flow: 80 mL / min, column temperature: RT, injection: 25 mL, cycle time: 18 minutes] to give E26-01 (25.0 mg, 45.45%) and E26-02 (13.0 mg, 23.64%) as white solids.

[0926] E26-01:LCMS:m / z(ESI)=670.0[M+H] + .

[0927] 1H NMR(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= 10.4,3.6Hz,1H),3.46(s,3H),3.29–3.25(m,2H),2.76–2.67(m,2H),2.3 0–2.22(m,1H),2.14–2.00(m,3H),1.85–1.65(m,3H),1.56–1.40(m,2H).

[0928] E26-02:LCMS:m / z(ESI)=670.0[M+H] + .

[0929] 1 H NMR(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).

[0930] Example 29: Synthesis of 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)ethyl)imidazo[1,2-b]pyridazin-2-yl-6-d)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E29- 01), and 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)

[0931]

[0932] To a solution of compound Int 33 (85.0 mg, 0.179 mmol) in EA (20 mL) was added TEA (0.199 mL, 1.43 mmol), and stirred at 25 ° C for 5 minutes, compound Int 2 (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 x 2). 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 silica gel flash column purification, eluted with (4% MeOH in DCM) to give E29 (70.0 mg, 58.65%) as a white solid.

[0933] LCMS: m / z (ESI) = 668.0 [M+H] + .

[0934] E29 (54.0 mg, 0.081 mmol) was further purified by SFC [system: Waters PrepSFC 150 Mgm, column name: Regis WhelkO1 (R, R), column size: 40 mm ID x 250 mm, 10 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH (0.1% NH3.H2O), A:B: 50:50, wavelength: 210 nm, flow: 120 mL / min, column temperature: RT, injection: 25 mL, cycle time: 6 minutes] to give E29-01 (13.0 mg, 24.07%) and E29-02 (9.00 mg, 16.67%) as white solids.

[0935] E29-01:

[0936] LCMS: m / z (ESI) = 668.2 [M+H] + .

[0937] 1 H NMR: (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).

[0938] E29-02:

[0939] LCMS: m / z (ESI) = 668.2 [M+H] + .

[0940] 1 H NMR: (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),2.77–2.63(m,2H),2.34–2.25(m,1H),2.08–1.99(m,3H),1.94–1.86(m,2H).

[0941] Example 30: Synthesis of N-((S)-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methylimidazo[1,2-b]pyridazin-2-yl)methyl)-4-(3,3,3-trifluoropropyl)-1,2,5-oxadiazole-3-carboxamide (E30- 01), and 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)

[0942]

[0943] To a solution of compound Int 26 (70 mg, 0.163 mmol), TEA (0.900 mL, 6.50 mmol), and compound Int 2 (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 hour. Subsequently, the reaction mixture was quenched with H2O (50 mL). The resulting solution was extracted with EtOAc (100 mL x 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 crude product. The crude product was purified by preparative 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: H 2 O and NH 3 OH (10 mmol / L); mobile phase B: CH 3 CN; gradient: B from 47% to 77% in 30 min, maintaining 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.

[0944] LCMS: m / z (ESI) = 623.2 [M+H] + .

[0945] 1 H NMR: (400MHz, CD3OD) δ8.37(d,J=2.0Hz,1H),8.12(s,1H),7.82(d,J=1.2H z,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).

[0946] Compound E30 (30 mg, 0.034 mmol) was further separated by SFC (column: ChiralPak AD-H, Daicel Chemical Co., 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 E30-01 (12.5 mg, 41.67% yield) and E30-02 (12.3 mg, 41.00%) as white solids.

[0947] E30-01:

[0948] LCMS: m / z (ESI) = 623.2 [M+H] + .

[0949] 1 H NMR (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).

[0950] E30-02:

[0951] LCMS: m / z (ESI) = 623.2 [M+H] + .

[0952] 1 H NMR (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).

[0953] 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)

[0954]

[0955] To a solution of compound Int 31 (160 mg, 0.3 mmol) in DMF (10 mL) was added compound Int 2 (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 was diluted with EA (30 mL) and saturated NaCl solution (30 mL). The organic layer was separated, washed with saturated NaCl solution (30 mL x2), and concentrated under vacuum. The residue was purified by column chromatography (eluting with 100% EA) to obtain the desired product E33 (95 mg). Compound E33 was further separated by SFC (column: RR-Whelk-O1 4.6*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.

[0956] LCMS: m / z (ESI) = 676.0 [M+H] + .

[0957] 1 H NMR: (400MH z ,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).

[0958] Example 35: Synthesis of 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), and 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). 02), and 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), and 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)

[0959]

[0960] To a solution of compound Int 31 (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 quenched with H2O (100 mL) at 25 ° C. The resulting solution was extracted with EtOAc (100 mL x3). The combined organic phases were washed with water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel flash column purification, 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 separated by SFC (column: ChiralPak AD-H Daicel Chemical Co., 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 E35-01 (4.4 mg, 3.12%) and E35-02 (3.1 mg, 2.20%) as white solids.

[0961] The second product E35-P2 (16 mg) was further separated by SFC (column: ChiralPak AD-H Daicel Chemical Co., 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 E35-03 (4.7 mg, 3.33%) and E35-04 (1.7 mg, 1.21%) as white solids.

[0962] E35-01:

[0963] LCMS: m / z (ESI) = 620.2 [M+H] + .

[0964] 1H NMR(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)。

[0965] E35-02:

[0966] LCMS:m / z(ESI)=620.2[M+H] + 。

[0967] 1 H NMR(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)。

[0968] E35-03:

[0969] LCMS:m / z(ESI)=620.2[M+H] + 。

[0970] 1H NMR(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,1 H),1.96-1.79(m,2H),1.74-1.65(m,1H),1.29–1.11(m,4H),1.08–1.00(m,2H).

[0971] E35-04:

[0972] LCMS: m / z (ESI) = 620.2 [M+H] + .

[0973] 1 H NMR(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,1 H),1.97–1.78(m,2H),1.75-1.65(m,1H),1.30–1.11(m,4H),1.09–1.00(m,2H).

[0974] 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)

[0975]

[0976] To a solution of compound Int 31 (40 mg, 0.083 mmol) and compound Int 34 (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). Subsequently, the reaction mixture was stirred at 25 ° C for 1.5 hours. The reaction mixture was extracted with EtOAc (20 mL) and washed with brine (20 ml × 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (0.1% HCOOH, 0%-80% MeCN in H2O) to give the desired product E36-01 (15 mg, 28.35%) as a white solid.

[0977] LCMS: m / z (ESI) = 640.0 [M+H] + .

[0978] 1 H NMR(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),4.4 1(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).

[0979] HT-29 cell-based human IL-17A neutralization assay

[0980] IL-17A can mimic the secretion of CXCL1 / GROα by epithelial and other cells.To test the ability of compounds to neutralize the bioactivity of IL-17A, a HT-29 cell-based human IL-17A neutralization assay was used.

[0981] HT-29 cells (human colorectal adenocarcinoma epithelial cells, ATCC #HTB-38) were grown in tissue culture flasks using McCoy 5A (modified) medium (Gibco #16600-082) supplemented with 10% FBS (complete medium) until 50-80% confluency. 20,000 HT-29 cells (in 190 μl) were plated per treated well of a 96-well plate (Costar #3599). Compounds were serially diluted from 80,000 nM to 1 nM in complete medium in the 96-well plate, and 10 μl of the compound solution was added to each treated well. Subsequently, 2 μl of human IL-17A (R&D #7955-IL) in DPBS was added to each treated well at a final concentration of 200 ng / ml. Cells were grown in an incubator for 48 hours (37°C, 5% CO2).

[0982] At the end of the incubation period, the culture supernatant was centrifuged at room temperature (500 × g) for 5 minutes, and CXCL1 / GROα was measured using a commercial ELISA kit (R&D # DY275). Treatment with vehicle alone served as NC, while treatment with IL-17A served as BK. IC50 values ​​for the compounds were calculated using GraphPad Prism 8 software.

[0983] The results are listed below in Table 1. The IC50 values ​​provided in the Examples illustrate the activity of the compounds of claim 1 as IL-17A inhibitors.

[0984] Table 1

[0985]

[0986]

[0987] Oral bioactivity in mice

[0988] The oral bioactivity (%F) of the compounds of the present invention can be determined in mice by determining the 24-hour plasma AUC (nM*hour) after intravenous and oral administration, essentially as described below. Male mice (n=6) were administered the compound via intravenous (IV) bolus (1 mg / kg) or oral administration (3 or 10 mg / kg). 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 bleeding using K2EDTA as an anticoagulant. Approximately 20 uL of blood was collected via capillary tubes and transferred to cards as dried blood spots. The cards were allowed to dry for at least 2 hours before being transferred for analysis. Compound blood concentrations in each mouse were measured by liquid chromatography / tandem mass spectrometry at time points of 0.08 (IV only), 0.25, 0.5, 0.75, 2, 4, 8, and 24 hours. Oral bioactivity (%F) was determined by the following equation: [%F = (AUC / dose)po / (AUC / dose)iv]. The oral bioactivity results for the Examples are provided in the table below. These data demonstrate the pharmacologically favorable oral availability of each compound of the invention.

[0989] CD1 mouse PK

[0990]

Claims

1. A compound of the following formula (I), or a pharmaceutically acceptable salt, isomer, or solvate thereof: In formula (I), W represents hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR9; R1 represents 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; any of which may be optionally substituted by one or more of the following groups: deuterium, halogen, CN, -OC 1-3 Alkyl, -NH-C 1-4 Alkyl, or -N(C 1-4 Alkyl)2; R2 represents C 4-8 Cycloalkyl, which may be optionally substituted by deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; R3-R5 each independently represent: 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 Alkynyl; R6 and R7 each independently represent: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, CN, or OR9; Alternatively, R6, R7 and the carbon to which they are attached may form a 3-7 membered ring, which may be substituted by deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or CN; R8 represents hydrogen or C 1-6 alkyl; R9 means C 1-6 Alkyl, C 3-6 Cycloalkyl, 1-C 2-6 Alkenyl, or C 2-6 Alkynyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, an isomer, or a solvate thereof, wherein W represents: H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, -(CH2) 1-3 CHF2, -(CH2) 1-3 CF2CH3, -(CH2) 1-3 CF3, or -(CH2) 1-3 OCF3; more typically W represents: H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, -(CH2) 1-3 CHF2, or -(CH2) 1- 3OCF3; in particular, W represents: H, D, -(CH2) 1-3 OCH3, -(CH2) 1-3 CN, or -(CH2) 1-3 CHF2, more particularly W represents: H, D, -(CH2) 1-3 OCH3, or -(CH2) 1-3 CN; or R1 means: 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, typically R1 represents: 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 typically R1 represents: C 1-6 Alkyl, -C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, -OC 3-6 Cycloalkyl, or -C 2-6 alkenyl; or R2 represents a ring structure selected from the following: A1, A2, A3, A4, A5, A6, A7, A8, A9, or A10 groups: in represents a bond to the rest of the molecule, any of which may be optionally substituted by: deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; or R3 represents: 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 Alkynyl; typically R3 represents: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, or C 2-6 Alkynyl; in particular R3 represents: hydrogen, deuterium, halogen, C 3-6 Cycloalkyl, or C 2-6 Alkynyl, more particularly R3 represents: hydrogen, deuterium, or halogen; or R4 represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, or -OC 3-6 Cycloalkyl; typically R4 represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, or C 3-6 Cycloalkyl, more typically R4 represents: hydrogen, deuterium, halogen, -OH, or C 1-6 Alkyl, even more typically R4 represents: hydrogen, deuterium, halogen, or -OH; or R5 represents: 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 Alkynyl; typically R5 represents: hydrogen, deuterium, halogen, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, or -OC 1-6 Alkyl, more typically R5 represents: hydrogen, deuterium, halogen, -OH, or C 1-6 Alkyl, even more typically R5 represents: hydrogen, deuterium, halogen, or -OH; or R6 and R7 each independently represent: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, typically R6 and R7 each independently represent C 2-6 Alkenyl, or C 2-6 Alkynyl.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, or solvate thereof, wherein the compound of formula (I) is a compound of formula (IIa), (IIb), (IIc), or (IId): wherein R1 to R7 are as defined in claim 1.

4. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a solvate thereof, wherein the compound of formula (I) is represented by any one of the following formulas (Xa) to (Xj): wherein W, R1, R3, R4, R5, R6, and R7 are as defined in claim 1.

5. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, an isomer thereof, or a solvate thereof, wherein the compound of formula (I) is a compound of formula (IIIa), (IIIb), or (IIIc): wherein W, R2, R3, R4, R5, R6, and R7 are 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. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, an isomer, or a solvate thereof, wherein the compound of formula (I) is selected from the following:

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 diseases regulated 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 diseases mediated by IL-17A.

9. A method for treating and / or preventing diseases mediated by IL-17A, comprising the step of administering a therapeutically effective amount 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 to a subject to be treated.

10. A pharmaceutical composition comprising the 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.

Images