Solid form of TRPV4 antagonist

Abstract

This disclosure provides a solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. The compound is useful as a TRPV4 antagonist. [Case 1] TIFF2026525268000269.tif53165

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 512,404, filed on 7 July 2023, the entire contents of which are incorporated by reference.

[0002] field This disclosure relates to a pharmaceutical composition that acts as an antagonist to both wild-type TRPV4 channels and TRPV4 channels possessing disease-causing activating mutations. [Background technology]

[0003] background Transient receptor potential vanilloid type 4, TRPV4, is a member of the transient receptor potential (TRP) superfamily (VenKatachalam and Craig Montell 2007 Annual Reviews Biochemistry (Non-Patent Literature 1)). The TRPV4 gene encodes a non-selective cation channel that is highly permeable to calcium. TRPV4 is activated by a variety of different stimuli, including heat, mechanical stress, and chemicals containing arachidonic acid metabolites. TRPV4 is expressed in numerous different tissues, including, among others, the brain, bladder, skin, heart, lungs, and musculoskeletal tissue.

[0004] The TRPV4 channel is widely expressed in various human cell types. In particular, TRPV4 is expressed in epithelial and endothelial cells, fibroblasts, chondrocytes, nerve cells, and various inflammatory cells (Koivisto et al 2021 NRDD (Non-Patent Literature 2)). TRPV4 has been directly involved in epithelial and endothelial barrier function in relation to lung injury and has been further associated with respiratory diseases through TRPV4-induced ATP release (Koivisto). Genetic and pharmacological studies have linked TRPV4 as a therapeutic target for chronic cough, pulmonary edema, chronic obstructive pulmonary disease, and pulmonary fibrosis (Grace et al 2017, Pharmacology and Therapeutic (Non-Patent Literature 3)). Genetic knockout of TRPV4 results in decreased osteoclast function and calcium regulation, which is important for bone homeostasis and suggests a role of TRPV4 in osteoporosis and other joint diseases. In TRPV4 knockout mice, inflammatory hyperalgesia and mechanical pain were reduced (J. Neurosci. 2004, 18, 4444-4452 (Non-Patent Literature 4), Qu, et al., 2016 BioMed Research International (Non-Patent Literature 5)), and various functional studies have demonstrated TRPV4 signaling in neuropathic pain. TRPV4 is also expressed in the urothelium and detrusor muscle of the bladder, and its activation causes muscle contraction (Birder et al 2007 J. Pharmacol. Exp. Ther. (Non-Patent Literature 6)). Consistent with the role of TRPV4 in bladder-related conditions, inhibition of TRPV4 has been shown to improve bladder function in mouse and rat models of cyclophosphamide-induced cystitis (Prog. Biophys. Mol. Biol. 2010, 1, 2-17 (Non-Patent Literature 7)). This provides evidence that TRPV4 is a therapeutic target in multiple diseases, including respiratory diseases, joint diseases, pain, and bladder dysfunction.

[0005] Furthermore, activation of pathogenic mutations in TRPV4 has been shown to cause several severe Mendelian genetic diseases, including a series of skeletal dysplasias (Nishiura et al. 2012 AJMG (Non-Patent Literature 8)) and peripheral neuropathy (Landoure et al. Nature Genetics 2009 (Non-Patent Literature 9)). The mutations causing all of these diseases appear to contribute to the risk of the diseases by increasing calcium influx into cells (Toft-Beterlsen and MacAulay 2021 Cells (Non-Patent Literature 10)), suggesting the therapeutic effect of TRPV4 inhibitors. These observations suggest the benefits of inhibiting TRPV4 in genetic disorders caused by activating mutations, in addition to several different common diseases caused by wild-type receptor activation.

[0006] GSK2798745 advanced to Phase II clinical trials. Further exploration revealed a circulatingly active metabolite (ACS Med. Chem. Lett. 2021,12,9,1498-1502 (Non-Patent Literature 11)), and the maximum clinically administered dose decreased 4.8-fold due to a lower safety margin established by a 3-month canine toxicity study (Am.J.Cardiovasc. Drugs 2019,19,335-342 (Non-Patent Literature 12)). GSK2798745 failed to demonstrate efficacy across several human disease indications. There is currently a need for a drug useful in antagonizing TRPV4. In particular, there is a need for a drug with lower toxicity, improved potency, improved metabolic stability (e.g., against CYP3A4), lower levels of active circulating metabolites, and / or higher safety margins. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] VenKatachlam and Craig Montell 2007 Annual Reviews Biochemistry [Non-Patent Document 2] Koivisto et al 2021 NRDD [Non-Patent Document 3] Grace et al 2017,Pharmacology and Therapeutic [Non-Patent Document 4] J. Neurosci. 2004, 18, 4444-4452 [Non-Patent Document 5] Qu,et al.,2016 BioMed Research International [Non-Patent Document 6] Birder et al 2007 J.Pharmacol. Exp. Ther. [Non-Patent Document 7] Prog. Biophys. Mol. Biol.2010, 1, 2-17 [Non-Patent Document 8] Nishiura et al 2012 AJMG [Non-Patent Document 9] Landoure et al. Nature Genetics 2009 [Non-Patent Document 10] Toft-Beterlsen and MacAulay 2021 Cells [Non-Patent Document 11] ACS Med. Chem. Lett. 2021,12,9,1498-1502 [Non-Patent Document 12] Am.J.Cardiovasc. Drugs 2019,19,335-342 [Overview of the project]

[0008] Summary of Disclosure In one embodiment, the present disclosure provides compounds useful for antagonizing TRPV4.

[0009] In some embodiments, this disclosure relates to compounds of formula I: [ka] or a salt thereof, wherein L , , d , c is CR a R b and L 2 is CR c R d and R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cyclopropyloxy, or (C3-C5)cyclopropyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cyclopropyloxy, and (C3-C5)cyclopropyl may be substituted by one or more fluoros; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cyclopropyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cyclopropyl may be substituted by one or more fluoros; or R a and R b together are oxo(=O)methylene(=CH2), or R a and R b together with the atoms to which they are attached form spiro(C3-C5)cyclopropyl,<0​​​​​​is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 However, together with the atoms bonded to them, they form a condensed cyclopropyl ring, or R c and R d Together they form oxo (=O)methylene (=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R a , R b , R c , and R d At least one of them is not H, R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro; Or R 1 and R c However, together with the atoms to which they are bonded, they form a condensed cyclopropyl ring; Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R4 However, one or more R x It may also be replaced by; Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy; and A is 0, 1, or 2.

[0010] In some embodiments, this disclosure relates to compounds of formula I: [ka] or provide a salt thereof, in the formula, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, the element is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro; or R a and R b Together they form oxo (=O)methylene (=CH2), or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, the element is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 However, together with the atoms bonded to them, they form a condensed cyclopropyl ring, or R c and R d Together they form oxo (=O)methylene (=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4However, one or more R x It may also be replaced by; Each R x However, any (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyloxy, and (C3-C7) cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5) alkyl, (C3-C5) cycloalkyloxy, and (C3-C5) cycloalkyl groups, and any (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyl group, and (C3-C5) cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy; and A is 0, 1, or 2.

[0011] The disclosure also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0012] The disclosure also provides a method for treating a condition related to TRPV4 modulation in animals, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal.

[0013] This disclosure also provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in pharmacotherapy.

[0014] This disclosure also provides compounds of formula (I) or pharmaceutically acceptable salts thereof for the prophylactic or therapeutic treatment of conditions associated with the modulation of TRPV4.

[0015] The disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmacopoeia for treating conditions associated with the regulation of TRPV4 in animals.

[0016] This disclosure also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.

[0017] Certain compounds of formula (I) exhibit lower toxicity, improved potency, improved metabolic stability (e.g., with respect to CYP3A4), lower levels of active circulating metabolites, and / or higher safety margins. [Brief explanation of the drawing]

[0018] [Figure 1] The X-ray powder diffraction (XRPD) data from Example 21 is shown. [Modes for carrying out the invention]

[0019] Detailed explanation of disclosure Unless otherwise specified, the following definitions are used: Halo or halogen is fluoro, chloro, bromo, or iodine. Alkyl, alkoxy, etc., refer to both linear and branched groups, but references to individual radicals such as propyl include only linear radicals, while branched isomers such as isopropyl are specifically mentioned.

[0020] The term "alkyl" means, either by itself or as part of another substituent, unless otherwise indicated, the number of carbon atoms indicated (i.e., C) 1-5 A C1-C5 alkyl group refers to a linear or branched hydrocarbon radical having 1 to 5 carbon atoms. Examples include (C1-C5)alkyl, (C2-C5)alkyl, (C1-C3)alkyl, (C2-C3)alkyl, and (C3-C5)alkyl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and n-pentyl.

[0021] The term "alkoxy" refers to an alkyl group that is added to the rest of a molecule via an oxygen atom ("oxy").

[0022] The term "carbocyclic ring" refers to a saturated or partially unsaturated (non-aromatic) whole-carbocyclic ring containing a specified number of carbon atoms.

[0023] The term 6-membered heteroaryl refers to the following ring: [ka] Includes.

[0024] When used herein, the wavy line intersecting the bond in the chemical structure refers to a wavy line. [ka] The wavy line indicates the point of attachment of the intersecting bond in the chemical structure to the rest of the molecule.

[0025] To the extent relating to a disease or condition, the terms “to treat,” “to cure,” or “to treat” include inhibiting, eliminating, and / or reducing one or more symptoms of the disease or condition. The terms “to treat,” “to cure,” or “to treat” also refer to both therapeutic and / or preventive measures, the purpose of which is to prevent or slow (mitigate) unwanted physiological changes or impairments, such as the development or transmission of cancer. Beneficial or desired clinical outcomes, whether detectable or undetectable, include, but are not limited to, symptom reduction, attenuation of the degree of the disease or impairment, stabilization of the disease or impairment (i.e., no worsening), delay or slowing of disease progression, mitigation or temporary relief of the disease state or impairment, and remission (partial or complete). “To treat,” “to cure,” or “to treat” may also mean extending survival compared to the predicted survival without treatment. Those who need treatment include those who already have the disease or impairment, as well as those who are prone to developing the disease or impairment, or who need to prevent the disease or impairment. In some embodiments, “to treat,” “to cure,” or “to treat” does not include prevention or prevention.

[0026] The terms “therapeutic dose” or “effective dose” include, but are not limited to, amounts of the Compounds Disclosed that (i) treat or prevent a particular disease, condition or disorder; (ii) reduce, improve or eliminate one or more symptoms of a particular disease, condition or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder as described herein.

[0027] In one embodiment, the compounds of the Disclosure modulate TRPV4. In some embodiments, the modulation is antagonistic. In one embodiment, the TRPV4 antagonists of the Disclosure are useful for treating conditions associated with the hyperactivation of TRPV4. Such conditions include, but are not limited to, congenital distal spinal motor neuropathy, scapular muscular atrophy, Charcot-Marie-Tooth disease type 2C (CMT2C), degenerative osteodysplasia (MD), Kozlowski type spondylometrial dysplasia (SMDK), spondyloetrial dysplasia, Marotoau type, pseudo-Morquio syndrome type 2, parastremmatic dysplasia, autosomal dominant brachydactyly, and familial dysphagia with brachydactyly, all of which are diseases caused by activating mutations of TRPV4.

[0028] In one embodiment, the TRPV4 antagonists of this disclosure may be useful in treating related conditions associated with symptoms overlapping with diseases associated with elevated wild-type TRPV4 and / or caused by TRPV4-activating mutations. Such conditions include, but are not limited to, bladder disorders including, osteodysplasia, osteodysplasia, osteoarthritis, decreased bone density, osteoporosis, peripheral neuropathy, hereditary neuropathy, spinal muscular atrophy, Charcot-Marie-Tooth disease, overactive bladder, urinary incontinence, interstitial cystitis, painful bladder syndrome, bladder urgency, and neurogenic bladder.

[0029] In one embodiment, the TRPV4 antagonists of this disclosure are useful for treating bone disorders, including bone infections, osteogenesis imperfecta, osteonecrosis, Paget's disease of bone, rickets, achondroplasia, dwarfism, short stature, hypochondrodysplasia, and other genetic disorders of the skeletal system. In one embodiment, TRPV4 antagonists may be useful for treating other neurological disorders, including spinal muscular atrophy, neuropathic pain, pain, motor neuron disorders, chronic pain, bowel pain, and convulsions. In one embodiment, the TRPV4 antagonists of this disclosure are useful for treating diseases in which barrier integrity is impaired and vascular permeability is dysregulated, including but not limited to retinal edema, retinal leakage, diabetes or other causes of macular edema, diabetic neuropathy, disorders associated with intestinal edema, postoperative abdominal edema, local and systemic edema, fluid retention, congestive heart failure, irritable bowel syndrome (IBS), Crohn's disease, diarrhea, bowel abnormalities (hypersensitivity / desensitivity), fecal incontinence, constipation, celiac disease, lactose intolerance, and flatulence, obesity and type 2 diabetes (T2D), colitis / ulcerative colitis, hypertension, atherosclerosis, diseases with edema as a symptom, congestive heart failure, kidney disease or cirrhosis, kidney infections, urinary tract infections, and prostatic hyperplasia. In one embodiment, the TRPV4 antagonists of this disclosure are useful for treating lung diseases including, but not limited to, lung injury, chronic obstructive pulmonary injury, ventilator-induced lung injury, ventilator-associated lung parenchymal hyperinflation, altitude-induced pulmonary edema, and acute respiratory diseases. They are also useful for treating lung diseases including, but not limited to, distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis / rhinitis, asthma, cough, chronic cough, bronchiectasis, sarcoidosis, and pulmonary hypertension. In one embodiment, the TRPV4 antagonists of this disclosure are useful for treating inflammatory diseases, including but not limited to sepsis, diseases involving macrophage activation, microglial activation, neuroinflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, as well as heart disease, glaucoma, viral and bacterial infections, infections, chronic inflammatory diseases (rheumatoid arthritis), tissue repair, multiple organ dysfunction / multiple organ failure, microbial infections, acute brain / lung / liver / kidney injury, neurodegenerative diseases, tumorigenesis, cardiovascular and metabolic diseases, and autoimmune diseases.

[0030] As used herein, the term “mammal” refers to humans, higher non-human primates, rodents, domestic animals, cattle, horses, pigs, sheep, dogs, and cats. In some embodiments, the mammal is a human. As used herein, the term “patient” refers to any animal, including mammals. In one embodiment, the patient is a mammalian patient. In some embodiments, the patient is a human patient.

[0031] The compounds disclosed herein may exist as tautomers in certain cases. Although only one delocalized resonance structure is shown, all such forms are intended within the scope of this disclosure.

[0032] This disclosure also relates to, but is not limited to, deuterium ( 2 It will be understood by those skilled in the art that the claimed compounds include any compound that can be enriched in any or all atoms beyond the naturally occurring isotopic ratios of one or more isotopes, such as H or D. As a non-limiting example, the -CH3 group may be substituted with -CD3. In some embodiments, the compound is enriched with deuterium at a position one position above the naturally occurring isotopic ratio of deuterium. In some embodiments, the compound is enriched with deuterium at a position two positions above the naturally occurring isotopic ratio of deuterium. In some embodiments, the compound is enriched by at least about 75% with deuterium at one position. In some embodiments, the compound is enriched by at least about 75% with deuterium at two positions. In some embodiments, the compound is enriched by at least about 95% with deuterium at one position. In some embodiments, the compound is enriched by at least about 95% with deuterium at two positions. The pharmaceutical compositions of the present disclosure include one or more excipients. When used in combination with the pharmaceutical compositions of the present disclosure, the term “excipient” generally refers to an additional component that, when combined with the compound of formula (I) or a pharmaceutically acceptable salt thereof, provides a corresponding composition. For example, when used in combination with the pharmaceutical compositions of this disclosure, the term “excipients” includes, but is not limited to, carriers, binders, disintegrants, lubricants, sweeteners, flavorings, coatings, preservatives, and colorants.

[0033] As used herein, the term “approximately” refers to an amount, value, or duration that is not more than ±10% of the amount, value, or duration. In some embodiments, “approximately” refers to ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the enumerated amount, value, or duration. In some embodiments, “approximately” refers to ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the enumerated amount, value, or duration. In other embodiments, “approximately” refers to ±5% of the enumerated amount, value, or duration. In some embodiments, “approximately” refers to ±2% or ±1% of the stated amount, value, or duration. For example, in some embodiments, when the term “approximately” is used when enumerating temperatures or temperature ranges, these terms refer to ±5°C, ±2°C, or ±1°C of the enumerated temperature or temperature range. In other embodiments, the term “approximately” refers to ±2°C of the stated temperature or temperature range.

[0034] The stereochemical definitions and conventions used herein generally follow SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., “Tereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of this disclosure may contain asymmetric or chiral centers and therefore exist in different stereoisomers. All stereoisomers of the compounds of this disclosure, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof such as racemic mixtures, are intended to form part of the present invention.

[0035] It will be apparent to those skilled in the art that the compounds of this disclosure having a chiral center can exist as optically active and racemic forms, and can be isolated as optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that this disclosure encompasses any racemic, optically active, polymorphic, or stereoisomer, or mixture thereof, of the compounds of this disclosure having the useful properties described herein, and methods for preparing the optically active form (e.g., by recrystallization techniques to resolve the racemic form, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) are well known in the art.

[0036] Where the bonds in the compound formulas herein are depicted in a non-stereochemical form (e.g., in a plane), the atoms to which those bonds are attached include all stereochemical possibilities. (Bold and dashed rectangle) [ka] The relative stereochemistry is shown. The bonds in the formulas of the compounds herein are represented by bold wedge shapes or dashed wedge shapes. [ka] When depicted as such, it should be understood that the atoms to which the stereochemical bonds are attached are rich in the depicted absolute stereoisomers unless otherwise noted. In some embodiments, this compound may be at least 51% of the shown absolute stereoisomers. In some embodiments, this compound may be at least 60% of the shown absolute stereoisomers. In some embodiments, this compound may be at least 80% of the shown absolute stereoisomers. In some embodiments, this compound may be at least 90% of the shown absolute stereoisomers. In some embodiments, this compound may be at least 95% of the shown absolute stereoisomers. In some embodiments, this compound may be at least 99% of the shown absolute stereoisomers.

[0037] The specific values listed below for radicals, substituents, and ranges are for illustrative purposes only and do not exclude other defined values or other values within the defined ranges for the radicals and substituents. It should be understood that two or more values can be combined. It should also be understood that the values (or subsets thereof) listed below can be excluded.

[0038] For the compounds of the present disclosure, the variable L 1 、L 2 、R a 、R b 、R c 、R d 、R 1 、R 2 、R 4 、and R x each can be selected, where applicable, from the groups described herein, and the variable L 1 、L 2 、R a 、R b 、R c 、R d 、R 1 、R 2 、R 4 、and R x any group described herein with respect to any one of the variable L 1 、L 2 、R a 、R b 、R c 、R d 、R 1 、R 2 、R 4 、and R x is understood to be combinable, where applicable, with any group described herein with respect to one or more of the remainder of the variable L

[0039] Specifically, (C1-C5)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, or 3-pentyl, (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and (C1-C5)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentoxy, or 3-pentoxy.

[0040] In some embodiments of the compounds of formula I, L 1 is CR a R b and L 2 is CR c R d and R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoros, and R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoros, or R a and R b together are oxo(=O)methylene(=CH2), or R a and R b together with the atoms to which they are attached form spiro(C3-C5)cycloalkyl, R cHowever, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d When combined, they form either oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R a , R b , R c , and R d At least one of them is not H, R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy groups, and A is 0, 1, or 2.

[0041] In some embodiments of the compound of formula I, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R bis H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, or R c and R d When combined, they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy groups, and A is 0, 1, or 2.

[0042] In some embodiments of the compound of formula I, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or Ra and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R a , R b , R c , and R d At least one of them is not H, R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more (e.g., 1, 2, 3, or 4) R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy groups, and A is 0, 1, or 2, or L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R aand R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more (e.g., 1, 2, 3, or 4) R xIt may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy groups, and A is 0, 1, or 2.

[0043] In some embodiments of the compound of formula I, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R cHowever, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, Rc(C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R a , R b , R c , and R d At least one of them is not H, R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more (e.g., 1, 2, 3, or 4) R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy groups, and A is 0, 1, or 2.

[0044] In some embodiments of the compound of formula I, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R bis H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, Rc(C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more (e.g., 1, 2, 3, or 4) R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy groups, and A is 0, 1, or 2.

[0045] In some embodiments, the compound of formula (I) or a salt thereof is the compound of formula (II): [ka] or a salt thereof, wherein B is 0, 1, or 2.

[0046] In some embodiments of the compound of formula (II), R 4 However, it is a (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl compound.

[0047] In some embodiments, the compound of formula (I) or a salt thereof is the compound of formula (III): [ka] or a salt thereof, wherein B is 0, 1, or 2.

[0048] In some embodiments of the compound of formula (III), R 4 However, it is a (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl compound.

[0049] In some embodiments, R a However, it is H.

[0050] In some embodiments, R a This is selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoros.

[0051] In some embodiments, R a However, these are H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0052] In some embodiments, R a However, these are halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0053] In some embodiments, R b However, it is H.

[0054] In some embodiments, R b The compounds are halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cyclopropyl may be substituted with one or more fluoropolymers.

[0055] In some embodiments, R bHowever, these are H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0056] In some embodiments, R b However, these are halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0057] In some embodiments, R c However, it is H.

[0058] In some embodiments, R c However, the group is selected from halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro.

[0059] In some embodiments, R c However, these are H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0060] In some embodiments, R c However, these are halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0061] In some embodiments, R 1 and R C However, together with the atoms to which they are bonded, they form a condensed cyclopropyl ring.

[0062] In some embodiments, R d However, it is H.

[0063] In some embodiments, R d However, the group is selected from halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro.

[0064] In some embodiments, R d However, these are H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0065] In some embodiments, R d However, these are halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0066] In some embodiments, R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group.

[0067] In some embodiments, R 1 However, the group is selected from the group consisting of cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, and fluoro.

[0068] In some embodiments, R 1 However, it is H, methyl, cyclopropyl, CF3, CF2H, CFH2, OCF3, or OCF2H.

[0069] In some embodiments, R 1 These are hydroxymethyl, hydroxymethyl, and cyanomethyl.

[0070] In some embodiments, R 1 It is methyl.

[0071] In some embodiments, R 1 H is H.

[0072] In some embodiments, [ka] but, [ka] It is selected from a group consisting of the following elements.

[0073] In some embodiments, A is 0.

[0074] In some embodiments, A is 1.

[0075] In some embodiments, R 2 However, it is cyano.

[0076] In some embodiments, R 2 However, it is 6-cyano.

[0077] In some embodiments, R 4 However, one or more R x It is a phenyl compound that may be substituted with [another compound].

[0078] In some embodiments, R 4 but, [ka] It is selected from the group consisting of the following.

[0079] In some embodiments, R 4However, one or more R x It is pyrimidine-2-yl which may be substituted with [another compound].

[0080] In some embodiments, R 4 but, [ka] It is selected from the group consisting of the following.

[0081] In some embodiments, R 4 However, one R x It is a (C1-C7) alkyl group which may be substituted with [a specific group].

[0082] In some embodiments, R 4 However, one R x It is a (C3-C7) cycloalkyl that may be substituted with a cycloalkyl group.

[0083] In some embodiments, R 4 However, one R x It is a 6-membered heteroaryl that may be substituted with [another compound].

[0084] In some embodiments, R x However, it is a C1-C5 alkyl group that may be substituted with one or more groups independently selected from halo, cyano, and hydroxyl.

[0085] In some embodiments, R x However, it is a C1-C5 alkyl group substituted with hydroxyl.

[0086] In some embodiments, R x However, it is 2-hydroxy-2-methylethyl.

[0087] In some embodiments, the compound of formula (I) or a salt thereof is a compound of formula IV or V. [ka] or a salt thereof, wherein B is 0, 1, or 2.

[0088] In some embodiments, the compound of formula (I) or a salt thereof is the compound of formula IV or Va: [ka] or a salt thereof, wherein B is 0, 1, or 2.

[0089] In some embodiments, the compound of formula (I) or a salt thereof is the compound of formula VI or VII: [ka] or its salt.

[0090] In some embodiments, R c However, it is fluoro, and R d However, it is either H or fluoro.

[0091] In some embodiments, the compound or a salt thereof is [ka] Selected from the group consisting of and their salts.

[0092] In some embodiments, the compound or a salt thereof is [ka] Selected from the group consisting of and their salts.

[0093] In some embodiments, the compound or a salt thereof is [ka] Selected from the group consisting of and their salts.

[0094] In some embodiments, the compound or a salt thereof is [ka] Selected from the group consisting of and their salts.

[0095] In some embodiments, the compound or a salt thereof is [ka] Selected from the group consisting of and their salts.

[0096] In some embodiments, the compound or a salt thereof is [ka] or its salt.

[0097] In some embodiments, the compound or a salt thereof is: [ka] or its salt.

[0098] In some embodiments, the disclosure provides 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof that have lower toxicity than GSK2798745.

[0100] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof having improved efficacy compared to GSK2798745.

[0101] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof that have improved metabolic stability (e.g., with respect to CYP3A4) compared to GSK2798745.

[0102] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof having lower levels of active cyclic metabolites than GSK2798745.

[0103] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof having a higher maximum safety value than GSK2798745.

[0104] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof that have improved metabolic stability (e.g., with respect to CYP3A4) and substantially the same or improved potency compared to GSK2798745.

[0105] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof that have improved metabolic stability (e.g., with respect to CYP3A4) and substantially the same or improved potency compared to GSK2798745.

[0106] In some embodiments, the present disclosure provides a solid form of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile having one or more XRPD diffraction signals at about 7.04, about 7.07, about 7.09, about 10.33, about 10.35, about 18.87, and about 24.02°2θ. In some embodiments, the disclosure provides a solid form of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile having XRPD diffraction signals at approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.33, approximately 10.35, approximately 18.87, and approximately 24.02°2θ. With respect to the XRPD peaks, the term "approximately" means ±0.2°2θ. In some embodiments, the XRPD peaks are signals.

[0107] In some embodiments, the present disclosure provides a solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. [ka]

[0108] In some embodiments, the solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile exhibits X-ray powder diffraction patterns of approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, and 1. It has one or more signals represented by 2θ° selected from the group consisting of 5.58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0109] In some embodiments, the solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile exhibits X-ray powder diffraction patterns of approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, and 15. It has at least three signals represented by 2θ° selected from the group consisting of 58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0110] In some embodiments, the solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile exhibits X-ray powder diffraction patterns of approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, and 15. It has at least six signals represented by 2θ° selected from the group consisting of 58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0111] In some embodiments, the solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile exhibits X-ray powder diffraction patterns of approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, and 15. It has at least nine signals represented by 2θ° selected from the group consisting of 58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0112] In some embodiments, the solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile exhibits X-ray powder diffraction patterns of approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, and 15. It has at least 12 signals represented by 2θ° selected from the group consisting of 58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0113] In some embodiments, the solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile exhibits an X-ray powder diffraction pattern with signals represented by 2θ° at approximately 7.04, 7.07, 7.09, 10.33, 10.35, 18.87, and 24.02.

[0114] In some embodiments, the disclosure provides pharmaceutical compositions comprising a solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.

[0115] In some embodiments, the present disclosure provides a method for treating a TRPV4-related condition, the method comprising administering 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile in solid form or a pharmaceutical composition thereof to a subject.

[0116] In some embodiments, the present disclosure provides a solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile for the prophylactic or therapeutic treatment of conditions associated with TRPV4.

[0117] In some embodiments, the present disclosure provides a solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile for the manufacture of a drug for treating a condition associated with TRPV4.

[0118] In some embodiments, the present disclosure provides for the use of a solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutical composition thereof, for the treatment of conditions associated with TRPV4.

[0119] In some embodiments, the present disclosure provides 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile having substantially the same XRPD diffraction pattern as shown in Figure 1. In some embodiments, the term “substantially the same” refers to XRPD diffraction patterns having at least three similar signals.

[0120] A process for preparing the compound of formula I is provided as a further embodiment of the present disclosure and is described by the following procedure, where the meaning of general radical is as given above unless otherwise modified.

[0121] When the compound is sufficiently basic or acidic, salts of the compound of formula I may be useful as intermediates for isolating or purifying the compound of formula I. Alternatively, administration of the compound of formula I as a pharmaceutically acceptable acid or basic salt may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylates, methanesulfonates, acetates, citrates, malons, tartrates, succinates, benzoates, ascorbic acid, α-ketoglutaric acid, and α-glycerophosphate. Suitable inorganic salts, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates, may also be formed.

[0122] Salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid that provides a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be produced.

[0123] The compound of Formula I can be formulated as a pharmaceutical composition and administered to mammalian hosts such as human patients in various forms suitable for a selected route of administration, i.e., orally or parenterally, intravenously, intramuscularly, topically or subcutaneously.

[0124] Therefore, the compound may be administered systemically, for example, orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilated food carrier. They may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. In the case of oral therapeutic administration, the active compound may be incorporated with one or more excipients and may be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and preparations should contain at least 0.1% of the active compound. The proportion of compositions and preparations can, of course, be varied and may conveniently be about 2-60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dosage level is obtained.

[0125] Tablets, lozenges, pills, capsules, etc., may also contain: binders such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry liver. If the unit dosage form is a capsule, it may contain, in addition to the above types of materials, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may exist to modify the physical form of the solid unit dosage form, either as a coating or otherwise. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. The syrup or elixir may contain the active compound as a sweetener, sucrose or fructose, methyl and propylparabens as preservatives, dyes and flavorings, such as cherry or orange flavor. Naturally, any materials used in preparing any unit dosage form must be pharmaceutically acceptable and substantially nontoxic in the amounts used. Furthermore, the active compound may be incorporated into sustained-release formulations and devices.

[0126] The active compound may also be administered intravenously or intraperitoneally by injection or infusion. Solutions of the active compound or its salts can be prepared in water mixed with an optional non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof and / or oils. These preparations contain preservatives to inhibit microbial growth under normal storage and use conditions.

[0127] Suitable pharmaceutically acceptable dosage forms for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient, suitable for immediate preparation of sterile injections or insoluble solutions, or optionally, dispersions encapsulated in liposomes. In all cases, the final dosage form must be sterile and stable under manufacturing and storage conditions. Liquid carriers may be solvents or liquid dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Inhibition of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Extension of absorption of injectable compositions can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0128] Sterile injectable solutions are prepared by incorporating the required amount of the active compound, along with the various other components mentioned above, into a suitable solvent, and then, if necessary, by subsequent filtration sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying techniques, which yield a powder obtained by combining the active ingredients present in a pre-sterile filtered solution with any desired additional ingredients.

[0129] For topical administration, the compounds of the present invention may be applied in their pure form, i.e., when they are liquids. However, it is generally preferable to administer them topically as a composition or formulation, combined with a dermatologically acceptable carrier that may be solid or liquid.

[0130] Useful solid carriers include fine solids such as talc, clay, crystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol, glycol, or water-alcohol / glycol mixtures, in which the compound can be dissolved or dispersed at an effective level with the optional aid of a non-toxic surfactant. Auxiliaries such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid composition can be applied from an absorbent pad, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump or aerosol sprayer.

[0131] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, aliphatic alcohols, modified cellulose, or modified mineral materials can also be used with liquid carriers to form pastes, gels, ointments, soaps, etc., that can be applied directly to the user's skin.

[0132] Examples of useful skin compositions that can be used to deliver compounds of formula I to the skin are known in the art; see, for example, Jacquet et al. (U.S. Patent No. 4,608,392), Geria (U.S. Patent No. 4,992,478), Smith et al. (U.S. Patent No. 4,559,157), and Wortzman (U.S. Patent No. 4,820,508).

[0133] The effective dosage of the compounds of formula I can be determined by comparing their in vitro and in vivo activities in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known to those skilled in the art; see, for example, U.S. Patent No. 4,938,949.

[0134] The amount of compound, or its activated salt or derivative, required for treatment varies depending not only on the specific salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the subject. It is determined on a case-by-case basis and ultimately at the discretion of the attending physician or clinician.

[0135] The desired dose may be conveniently administered as a single dose or as divided doses administered at appropriate intervals, for example, two, three, four, or more times per day. The divided dose itself may be further divided into several separate doses at loose intervals, for example, multiple inhalations from an inhaler or multiple doses applied to the eye.

[0136] The compounds of this disclosure may be administered alone or in combination with one or more other therapeutic agents selected from the group consisting of endothelin receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta-blockers, aldosterone antagonists, ionotropes, NSAIDs, nitric oxide donors, calcium channel modulators, muscarinic antagonists, anti-inflammatory steroids, bronchodilators, antihistamines, leukotriene antagonists, HMG-CoA reductase inhibitors, non-selective adrenergic receptor and α1-adrenergic receptor biantagonists, type 5 phosphodiesterase inhibitors, and renin inhibitors.

[0137] Accordingly, in some embodiments, the Disclosure also provides compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier. The Disclosure also provides a kit comprising a compound of formula I or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging materials, and instructions for administering the compound of formula I or a pharmaceutically acceptable salt thereof and the other therapeutic agent(s) to an animal for treating a condition associated with the modulation of TRPV4.

[0138] The biological activity of the compound can be determined using any suitable assay for evaluating TRPV4 antagonist activity, as well as using any suitable tissue or in vivo model. For example, the biological activity of the compound can be evaluated using the assay described in Example 23 herein, or using the assays and models described in International Patent Application Publication Nos. WO2012 / 174340, WO2012 / 174342, WO2013 / 012500, and WO2017 / 199199.

[0139] How to use In some embodiments, the present disclosure provides methods for regulating TRPV4 expression using the compounds of the present disclosure or salts thereof.

[0140] In some embodiments, the Disclosure provides methods for modulating TRPV4 expression with pharmaceuticals comprising the compounds of the Disclosure or salts thereof.

[0141] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a therapeutically effective amount of the compound or a salt thereof to the subject.

[0142] In some embodiments, a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a therapeutically effective amount of the compound or salt thereof, or a pharmaceutical composition thereof.

[0143] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, and such method includes administering a compound or salt thereof to a subject.

[0144] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a compound or salt thereof, or a pharmaceutical composition thereof.

[0145] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof, or pharmaceutical compositions, for use in modulating TRPV4 expression.

[0146] In some embodiments, the Disclosure provides compounds or salts thereof of the Disclosure, or pharmaceutical compositions thereof, for use in the treatment or prevention of a disease or disorder.

[0147] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[0148] In some embodiments, the Disclosure provides compounds of the Disclosure or salts thereof for use in the treatment of diseases or disorders disclosed herein.

[0149] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating TRPV4 expression.

[0150] In some aspects, the Disclosure provides the use of a compound or a salt thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder of the Disclosure.

[0151] In some embodiments, the Disclosure provides the use of a compound or a salt thereof in the manufacture of a pharmaceutical product for treating a disease or disorder of the Disclosure.

[0152] In some embodiments, the disease or disorder is related to the TRPV4 involved.

[0153] In some embodiments, the Disclosure provides a method for treating a condition associated with TRPV4 modulation, comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a solid form thereof.

[0154] In some embodiments, the Disclosure provides a compound of the Disclosure or a salt thereof, or a solid form thereof, for use in pharmacotherapy.

[0155] In some embodiments, the Disclosure provides compounds of the Disclosure or salts thereof or solids thereof for the prophylactic or therapeutic treatment of conditions related to TRPV4 regulation.

[0156] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or salts thereof or solids thereof for preparing pharmacopoeias for treating conditions associated with TRPV4 regulation in animals.

[0157] In some embodiments, the salt is the pharmaceutically acceptable salt.

[0158] In some embodiments, the compound is administered to the subject.

[0159] In some embodiments, the compound is administered to animals.

[0160] In some embodiments, the subject is an animal.

[0161] In some embodiments, the subject is a human.

[0162] In some embodiments, the disease or disorder is a respiratory disease or disorder.

[0163] In some embodiments, the disease or disorder is chronic cough, pulmonary edema, chronic obstructive pulmonary disease, or pulmonary fibrosis.

[0164] In some embodiments, the disease or disorder is inflammatory hyperalgesia.

[0165] In some embodiments, this disorder or condition is mechanical pain.

[0166] In some embodiments, the disease is neuropathic pain.

[0167] In some embodiments, the disease or disorder is a bladder-related condition.

[0168] In some embodiments, the disease or disorder is a respiratory disease, a joint disease, pain, or bladder dysfunction.

[0169] In some embodiments, the disease or disorder is a joint disease.

[0170] In some embodiments, this disease or disorder is pain.

[0171] In some embodiments, the disease or disorder is bladder dysfunction.

[0172] In some embodiments, the disease or disorder is a Mendelian genetic disease.

[0173] In some embodiments, the disease or disorder is a skeletal malformation.

[0174] In some embodiments, regulation is inhibition.

[0175] In some embodiments, the regulation is antagonistic.

[0176] Synthesis method Compounds of formula (I) can be prepared using the synthesis methods and intermediates described in the following examples. Compounds of formula (I) can also be prepared using well-known synthesis methods and intermediate compounds, including, for example, the synthesis methods and intermediate compounds described in International Patent Application Publication Nos. WO2012 / 174340, WO2012 / 174342, WO2013 / 012500, and WO2017 / 199199. Schemes 1 to 6 illustrate intermediates and methods that can be used to prepare compounds of formula (I).

[0177] [ka] [ka]

[0178] Scheme 2 [ka]

[0179] Scheme 3 [ka]

[0180] Scheme 4 [ka]

[0181] Scheme 5 [ka]

[0182] Scheme 6 [ka]

[0183] Scheme 7 [ka]

[0184] Scheme 8 [ka]

[0185] Scheme 9 [ka] Further examples of the present disclosure are provided below by non-limiting embodiments.

[0186] Exemplary Embodiments Exemplary Embodiment 1. Compound of Formula I: [ka] or provide a salt thereof, in the formula, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R dis H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d When combined, they form either oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R a , R b , R c , and R d At least one of them is not H, R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R xIt may also be replaced by; Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy; and A is 0, 1, or 2, or Compounds of formula I: [ka] or provide a salt thereof, in the formula, L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. Rc However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, or R c and R d When combined, they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by; Each R xHowever, any (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyloxy, and (C3-C7) cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5) alkyl, (C3-C5) cycloalkyloxy, and (C3-C5) cycloalkyl groups, and any (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyl group, and (C3-C5) cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy; and A is 0, 1, or 2.

[0187] Exemplary Embodiment 2. A compound or salt described in Exemplary Embodiment 1, wherein the formula is: L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R cHowever, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d When combined, they form either oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R a , R b , R c , and R d At least one of them is not H, R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy groups, and A is 0, 1, or 2.

[0188] Exemplary Embodiment 3. A compound or salt described in Exemplary Embodiment 1, wherein the formula is: L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R bis H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, or R c and R d When combined, they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy groups, and A is 0, 1, or 2.

[0189] Exemplary Embodiment 4. A compound or salt of Exemplary Embodiment 1, wherein the formula is: L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R bis H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R a , R b , R c , and R d At least one of them is not H, R 1is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy groups, and A is 0, 1, or 2, or A compound or salt according to claim 1, wherein, L 1 However, CR a R b And, L 2 However, CR c R d And, R aHowever, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkyl group. R 1 However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy groups, and A is 0, 1, or 2.

[0190] Exemplary Embodiment 5. A compound or salt described in Exemplary Embodiment 4, wherein the formula is: L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R bis H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, Rc(C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R a , R b , R c , and R d At least one of them is not H, R 1is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, or (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, cyano, and fluoro, or R 1 and R c Together with the atoms bonded to them, they form a condensed cyclopropyl ring. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more fluoropolymers. R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, C1-C5)alkyl, and hydroxy groups, and A is 0, 1, or 2.

[0191] Exemplary Embodiment 6. A compound or salt described in Exemplary Embodiment 4, wherein the formula is: L 1 However, CR a R b And, L 2 However, CR c R d And, R a However, H, halo, cyano, (C1-C5 alkyl, (C1-C5) alkoxy, or (C3-C5) cycloalkyl may be substituted with one or more fluoro groups, R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R a and R b When combined, they become oxo(=O)methylene(=CH2) or R a and R b However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R c However, H is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, R d is H, halo, cyano, Rc(C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro, or R c and R 1 Together with the atoms bonded to them, they form a condensed cyclopropyl ring, R c and R d However, together they form oxo(=O)methylene(=CH2), or R c and R d However, together with the atoms bonded to them, they form a spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl, R 1However, it is a (C1-C3) alkyl group substituted with one or more fluoropolymers. Each R 2 However, any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C1-C3)alkylsulfonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy compounds may be substituted with one or more fluoro compounds; R 4 However, it is a (C1-C7) alkyl, (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and any R 4 However, one or more R x It may also be replaced by, Each R x However, any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C7)cycloalkyl group may be independently selected from the group consisting of hydroxy, halo, cyano, C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl groups, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl group may be substituted with one or more groups independently selected from halo, cyano, and hydroxy groups, and A is 0, 1, or 2.

[0192] Exemplary Embodiment 7. The compound or salt of Exemplary Embodiment 4, which is a compound of formula (II): [ka] or a salt thereof, in the formula R 4 However, it is a (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and B is 0, 1, or 2.

[0193] Exemplary Embodiment 8. The compound or salt of Exemplary Embodiment 4, which is a compound of formula (III): [ka] or a salt thereof, in the formula R 4However, it is a (C3-C7) cycloalkyl, phenyl, or 6-membered heteroaryl, and B is 0, 1, or 2.

[0194] Exemplary Embodiment 9. A compound or salt according to any one of Exemplary Embodiments 1 to 8, wherein R a H is H.

[0195] Exemplary embodiment 10. R a The compound or salt according to any one of the exemplary embodiments 1 to 8, wherein the compound is selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro.

[0196] Exemplary embodiment 11. R a The compound or salt according to any one of the exemplary embodiments 1 to 8, wherein the compound is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0197] Exemplary embodiment 12. R a The compound or salt described in any one of the exemplary embodiments 1 to 8, wherein the compound is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0198] Exemplary embodiment 13. The R b A compound or salt according to any one of exemplary embodiments 1 to 12, wherein is H.

[0199] Exemplary embodiment 14. R bThe compound or salt according to any one of the exemplary embodiments 1 to 12, wherein the compound is a halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoros.

[0200] Exemplary embodiment 15. R b The compound or salt according to any one of the exemplary embodiments 1 to 12, wherein is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0201] Exemplary embodiment 16. R b The compound or salt according to any one of the exemplary embodiments 1 to 12, wherein the compound is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0202] Exemplary Embodiment 17. A compound or salt according to any of the exemplary embodiments 1-16, wherein R c H is H.

[0203] Exemplary embodiment 18. R c The compound or salt according to any one of the exemplary embodiments 1 to 16, wherein the compound is selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoro.

[0204] Exemplary embodiment 19. R cThe compound or salt according to any one of the exemplary embodiments 1 to 16, wherein the compound is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0205] Exemplary embodiment 20. R c The compound or salt described in any one of the exemplary embodiments 1 to 16, wherein the compound is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0206] Exemplary embodiment 21. R 1 and R c However, the compounds or salts described in any one of the exemplary embodiments 1 to 16, wherein they, together with the atoms to which they are bonded, form a condensed cyclopropyl ring.

[0207] Exemplary Embodiment 22. A compound or salt according to any of the exemplary embodiments 1-21, wherein R d H is H.

[0208] Exemplary embodiment 23. R d The compound or salt according to any one of the exemplary embodiments 1 to 21, wherein the compound is selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl, and any (C1-C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl may be substituted with one or more fluoros.

[0209] Exemplary embodiment 24. R d The compound or salt according to any one of the exemplary embodiments 1 to 21, wherein is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0210] Exemplary embodiment 25. R d The compound or salt described in any one of the exemplary embodiments 1 to 21, wherein the compound is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl, or (C3-C5) cycloalkyl.

[0211] Exemplary embodiment 26. R c and R d A compound or salt according to any one of exemplary embodiments 1 to 16, wherein the atoms bonded to them together form a spiro(C3-C5)cycloalkyl group.

[0212] Exemplary embodiment 27. R 1 The compound or salt according to any one of exemplary embodiments 1 to 20 and 22 to 26, wherein the compound is selected from the group consisting of cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy, and any cyclopropyl, (C1-C3)alkyl, and (C1-C3)alkoxy may be substituted with one or more groups independently selected from hydroxy, (C1-C3)alkoxy, benzyloxy, and fluoro.

[0213] Exemplary embodiment 28. The R 1 The compound or salt according to any one of the exemplary embodiments 1 to 20 and 22 to 26, wherein is H, methyl, cyclopropyl, CF3, CF2H, CFH2, OCF3, or OCF2H.

[0214] Exemplary embodiment 29. R 1 The compound or salt according to any one of exemplary embodiments 1-20 and 22-26, wherein the compound is hydroxy, hydroxymethyl, or cyanomethyl.

[0215] Exemplary embodiment 30. R 1 A compound or salt according to any one of exemplary embodiments 1-20 and 22-26, wherein the compound is methyl.

[0216] Exemplary embodiment 31. R 1 A compound or salt according to any one of exemplary embodiments 1 to 20 and 22 to 26, wherein H is present.

[0217] Exemplary embodiment 32. The base [ka] but, [ka] A compound or salt according to any one of the exemplary embodiments 1 to 31, selected from groups comprising:

[0218] Exemplary Embodiment 33. A compound or salt according to any one of Exemplary Embodiments 1 to 31, wherein A is 0.

[0219] Exemplary Embodiment 34. A compound or salt according to any one of Exemplary Embodiments 1 to 31, wherein A is 1.

[0220] Exemplary embodiment 35. R 2 However, the compound or salt described in exemplary embodiment 34 is cyano.

[0221] Exemplary embodiment 36. R 2 The compound or salt described in exemplary embodiment 34, which is 6-cyano.

[0222] Exemplary embodiment 37. R 4 However, one or more R x A compound or salt according to any one of exemplary embodiments 1 to 36, which is a phenyl that may be substituted with.

[0223] Exemplary embodiment 38. R 4 but, [ka] A compound according to any one of exemplary embodiments 1 to 36, selected from the group consisting of the following.

[0224] Exemplary embodiment 39. R 4 However, one or more R x A compound or salt according to any one of exemplary embodiments 1 to 36, which is pyrimidine-2-yl which may be substituted with.

[0225] Exemplary embodiment 40. R 4 but, [ka] A compound according to any one of embodiments 1 to 36, selected from the group consisting of the following.

[0226] Exemplary embodiment 41. R 4 However, one or more R x A compound according to any one of the exemplary embodiments 1 to 36, which is a (C1-C7) alkyl that may be substituted with a (C1-C7) alkyl group.

[0227] Exemplary embodiment 42. R 4 However, one or more R x A compound according to any one of exemplary embodiments 1 to 36, which is a (C3-C7) cycloalkyl that may be substituted with a cycloalkyl group.

[0228] Exemplary embodiment 43. R 4 However, one R x A compound according to any one of exemplary embodiments 1 to 36, which is a 6-membered heteroaryl that may be substituted with .

[0229] Exemplary embodiment 44. R x The compound according to any one of the exemplary embodiments 41 to 43, wherein the compound is a C1-C5 alkyl group which may be substituted with one or more groups independently selected from halo, cyano, and hydroxyl groups.

[0230] Exemplary embodiment 45. R x The compound is a hydroxylated C1-C5 alkyl group, as described in any one of the exemplary embodiments 41 to 43.

[0231] Exemplary embodiment 46. R x The compound is 2-hydroxy-2-methylethyl, as described in any one of the exemplary embodiments 41 to 43.

[0232] Exemplary embodiment 47. Compound of formula IV or V: [ka] A compound or salt described in Exemplary Embodiment 1, which is a salt thereof, wherein B is 0, 1, or 2.

[0233] Exemplary embodiment 48. Compound of formula IV or Va: [ka] Alternatively, a compound or salt described in Embodiment 1, wherein B is 0, 1, or 2.

[0234] Exemplary embodiment 49. Compound of formula VI or VII: [ka] The compound or salt described in Exemplary Embodiment 1, or a salt thereof.

[0235] Exemplary embodiment 50. R c is fluoro, R d The compound or salt described in Exemplary Embodiment 1, wherein the compound is H or fluoro.

[0236] Exemplary embodiment 51. [ka] A compound or salt according to exemplary embodiment 1, selected from the group consisting of and salts thereof.

[0237] Exemplary embodiment 52. [ka] A compound or salt according to exemplary embodiment 1, selected from the group consisting of and salts thereof.

[0238] Exemplary embodiment 53. [ka] A compound or salt according to exemplary embodiment 1, selected from the group consisting of and salts thereof.

[0239] Exemplary embodiment 54. [ka] A compound or salt according to exemplary embodiment 1, selected from the group consisting of and salts thereof.

[0240] Exemplary embodiment 55. In the formula: [ka] The compound or salt described in Exemplary Embodiment 1, or a salt thereof.

[0241] Exemplary embodiment 56. In the formula: [ka] The compound or salt described in Exemplary Embodiment 1, or a salt thereof.

[0242] Exemplary Embodiment 57. A pharmaceutical composition comprising a compound described in any one of Exemplary Embodiments 1 to 56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0243] Exemplary Embodiment 58. A method for treating a TRPV4-related condition, comprising administering a compound or a pharmaceutically acceptable salt thereof described in any one of Exemplary Embodiments 1 to 56.

[0244] Exemplary Embodiment 59. A compound or a pharmaceutically acceptable salt thereof described in any one of the exemplary embodiments 1 to 56 for use in the treatment of a condition associated with TRPV4.

[0245] Exemplary Embodiment 60. A compound or a pharmaceutically acceptable salt thereof described in any one of Exemplary Embodiments 1 to 56 for the prophylactic or therapeutic treatment of a condition associated with TRPV4.

[0246] Exemplary Embodiment 61. Use of any one of the exemplary embodiments 1 to 56 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating a condition associated with TRPV4.

[0247] Exemplary Embodiment 1B. Solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. [ka]

[0248] Exemplary Embodiment 2B. A solid form of Exemplary Embodiment 1B, the form is approximately 7.02, approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.31, approximately 10.33, approximately 10.35, approximately 10.37, approximately 15.56, approximately 15.58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19 The X-ray powder diffraction pattern shows one or more signals represented by 2θ° selected from the group consisting of 0.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0249] Exemplary Embodiment 3B. A solid form of Exemplary Embodiment 1B, the form is approximately 7.02, approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.31, approximately 10.33, approximately 10.35, approximately 10.37, approximately 15.56, approximately 15.58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19 The X-ray powder diffraction pattern is shown having at least three signals represented by 2θ°, selected from the group consisting of 0.47, approximately 19.49, approximately 22.39, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0250] Exemplary Embodiment 4B. Approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, 15.58, 15.60, 18.85, 18.87, 18.89, 18.91, 19.20, 19.22, 19.24, 19.42, 19.45, 19.47, 19.49, 22.39, 2 A solid form of an exemplary embodiment 1B, showing an X-ray powder diffraction pattern having at least six signals represented by 2θ°, selected from the group consisting of 2.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0251] Exemplary Embodiment 5B. Approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, 15.58, 15.60, 18.85, 18.87, 18.89, 18.91, 19.20, 19.22, 19.24, 19.42, 19.45, 19.47, 19.49, 22.39, 2 A solid form of an exemplary embodiment 1B, showing an X-ray powder diffraction pattern having at least nine signals represented by 2θ°, selected from the group consisting of 2.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0252] Exemplary Embodiment 6B. Approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, 15.58, 15.60, 18.85, 18.87, 18.89, 18.91, 19.20, 19.22, 19.24, 19.42, 19.45, 19.47, 19.49, 22.39, 2 A solid form of an exemplary embodiment 1B, showing an X-ray powder diffraction pattern exhibiting at least 12 signals represented by 2θ°, selected from the group consisting of 2.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.59.

[0253] Exemplary Embodiment 7B. A solid form of exemplary Embodiment 1B, showing an X-ray powder diffraction pattern with signals represented by 2-θ angles at approximately 7.04, 7.07, 7.09, 10.33, 10.35, 18.87, and 24.02.

[0254] Exemplary Embodiment 8B. A pharmaceutical composition comprising the solid form described in any one of Exemplary Embodiments 1B to 7B and a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.

[0255] Exemplary Embodiment 9B. A method for treating a condition associated with TRPV4, comprising administering to a subject a solid form of any one of the exemplary embodiments 1B to 7B or a pharmaceutical composition of exemplary embodiment 8B.

[0256] Exemplary Embodiment 10B. A solid form according to any one of the exemplary embodiments 1B to 7B for the prophylactic or therapeutic treatment of a condition associated with TRPV4.

[0257] Exemplary Embodiment 11B. Use of a solid form according to any one of Exemplary Embodiments 1B to 7B for the manufacture of a drug for treating a condition associated with TRPV4.

[0258] Exemplary Embodiment 12B. A solid form according to any one of Exemplary Embodiments 1B to 7B, or a pharmaceutical composition according to Exemplary Embodiment 8B, for the treatment of a condition associated with TRPV4. [Examples]

[0259] For illustrative purposes, a neutral compound of formula (I) is synthesized and tested in the examples. The neutral compound of formula (I) can be converted to a salt of the corresponding compound using the techniques prescribed in the art (for example, by saponification of an ester to a carboxylate salt, or by hydrolysis of an amide to form the corresponding carboxylic acid, and then by converting the carboxylic acid to a carboxylate salt).

[0260] Example 1. Preparation: 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0261] Reaction scheme [ka] [ka]

[0262] Detailed instructions rac-4,4-dimethyl-3-(nitromethyl)cyclohexane-1-one [ka] Nitromethane (3.83 g, 62.81 mmol, 1.2 equivalents) was added to a solution of 4,4-dimethylcyclohexa-2-en-1-one (6.50 g, 52.34 mmol, 1 equivalent) and benzyltrimethylammonium hydroxide (13.13 g, 78.51 mmol, 1.5 equivalents) in methanol (60 mL). The resulting mixture was stirred overnight at room temperature and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product, 4,4-dimethyl-3-(nitromethyl)cyclohexane-1-one (6.70 g, yield 46%), as a pale yellow oil.

[0263] rac-8,8-dimethyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane [ka] Ethylene glycol (3.37 g, 54.26 mmol, 1.5 equivalents) was added to a solution of 4,4-dimethyl-3-(nitromethyl)-cyclohexane-1-one (6.70 g, 36.17 mmol, 1 equivalent) and trimethoxymethane (5.76 g, 54.26 mmol, 1.5 equivalents) in dichloromethane (100 mL). The resulting reaction mixture was stirred at room temperature for 5 minutes and then cooled to 0°C in an ice bath. Methanesulfonic acid (0.52 g, 5.42 mmol, 0.15 equivalents) was added dropwise to this mixture. The resulting mixture was removed from the bath, warmed to room temperature, and stirred for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product, rac-8,8-dimethyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (6 g, yield 72.3%), as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 4.73(dd,J=12.6,3.9Hz,1H),4.25(dd,J=12.6,10.1Hz,1H),3.85-3.82(m,4H),2.17(d d, J=12.0, 10.1Hz, 1H), 1.58-1.42(m, 5H), 1.39-1.33(m, 1H), 0.96(s, 3H), 0.80(s, 3H).

[0264] rac-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] Palladium on carbon (10%, 0.28 g, 2.62 mmol, 0.1 equivalent) was added to a solution of rac-8,8-dimethyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (6.0 g, 26.17 mmol, 1 equivalent) in methanol (60 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was washed with methanol (3 × 100 mL). The filtrate was concentrated under reduced pressure to obtain the crude product rac-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (crude 6 g) as a colorless oil. LCMS (ESI-MS) m / z = 200 [M + H] + .

[0265] rac-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] Potassium carbonate (8.32 g, 60.21 mmol, 2 equivalents) was added to a solution of rac-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (6 g, 30.1 mmol, 1 equivalent) and 3-fluoro-4-nitrobenzonitrile (5 g, 30.1 mmol, 1 equivalent) in acetonitrile (60 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography, eluted with ethyl acetate in 0% to 10% petroleum ether, and concentrated under vacuum to obtain the desired product rac-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (7 g, yield 67.3%) as an orange solid. 1H NMR(400MHz,DMSO-d6)δ 8.38-8.31(m,1H),8.18(dd,J=17.2,8.6Hz,1H),8.10-7.96(m,2H),3.94-3.79(m , 4H), 3.55-3.49(m, 1H), 3.14-3.06(m, 1H), 1.85-1.30(m, 7H), 1.07-0.89(m, 6H). LCMS(ESI-MS)m / z=346[M+H] + .

[0266] rac-4-amino-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] Palladium on carbon (10%, 0.22 g, 2.03 mmol, 0.1 equivalent) was added to a solution of rac-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (7 g, 20.27 mmol, 1 equivalent) in methanol (70 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was washed with methanol (3 × 100 mL). The filtrate was concentrated under reduced pressure to obtain the crude product rac-4-amino-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (crude 6 g) as a colorless oil. LCMS (ESI-MS) m / z = 316 [M + H] + .

[0267] rac-1-((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Formic acid (0.88 g, 19.02 mmol, 1 equivalent) was added to a solution of rac-4-amino-3-(((8,8-dimethyl-1,4-dioxaspiro[4,5]decane-7-yl)methyl)amino)benzonitrile (6 g, 19.02 mmol, 1 equivalent) in trimethoxymethane (58.54 g, 551.64 mmol, 29 equivalents). The resulting mixture was heated to 80°C, stirred for 3 hours, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 100% petroleum ether. The fractions containing the desired mass signal were combined and concentrated under vacuum to obtain the desired product, rac-1-((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4 g, 60.6% yield in 2 steps), as a white solid. LC-MS (ESI-MS) m / z = 326 [M + H] + .

[0268] rac-1-((2,2-dimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-1-((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.80 g, 11.68 mmol, 1 equivalent) in formic acid (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1-((2,2-dimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 3.50 g) as a white solid. LCMS (ESI-MS) m / z = 282 [M + H] + .

[0269] rac-1-(((3S,5R)-6,6-dimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Sodium hydride (60% in oil, 1.19 g, 49.76 mmol, 4 equivalents) was added to a solution of trimethylsulfoxonium iodide (10.95 g, 49.76 mmol, 4 equivalents) in dimethyl sulfoxide (100 mL), and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture in dimethyl sulfoxide (35 mL), a solution of rac-1-((2,2-dimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.50 g, 12.44 mmol, 1 equivalent) was added dropwise. After 8 minutes, the reaction mixture was cooled to 0°C, slowly quenched with 200 mL of water, and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1-(((3S,5R)-6,6-dimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 3g) as a yellow oil. LCMS (ESI-MS) m / z = 296 [M + H] + .

[0270] rac-1-(((5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Lithium tert-butoxide (1.63 g, 20.31 mmol, 2 equivalents) was added to a solution of ethyl carbamate (18.10 g, 203.12 mmol, 20 equivalents) in N-methylpyrrolidone (10 mL). After stirring at room temperature for 5 minutes, rac-1-(((3S,5R)-6,6-dimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g, 10.16 mmol, 1 equivalent) was added dropwise to N-methylpyrrolidone (10 mL). Subsequently, the reaction mixture was heated to 100 °C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography, eluted 0% to 2% with methanol in dichloromethane, and concentrated under vacuum to obtain the desired product rac-1-(((5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3g, 75.9% yield in 3 steps) as a white solid. LCMS (ESI-MS) m / z = 339 [M + H] + .

[0271] rac-1-(((5S,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Copper(I) iodide (562.78 mg, 2.95 mmol, 1 equivalent) in 1,4-dioxane (10 mL), rac-1-(((5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 2.95 mmol, 1 equivalent), 2-(5-chloropyrazine-2-yl)propan-2-ol (0.51 g, 2.95 mmol, 1 equivalent), N 1 , N 2 -dimethylethane-1,2-diamine (0.52 g, 5.91 mmol, 2 equivalents) and tripotassium phosphate (1.25 g, 5.91 mmol, 2 equivalents) were added under a nitrogen atmosphere. The resulting mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the resulting mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 4% dichloromethane. The fractions were combined and concentrated under vacuum to obtain the desired product rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (800 mg, yield 57.1%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 9.10(d,J=1.5Hz,1H),8.56-8.54(m,2H),8.22(d,J=1.4Hz,1H),7.81(d,J=8.4Hz,1H),7.59(dd,J=8.4,1.5Hz,1H),5.38(s,1H),4.52(dd,J= 14.2,3.7Hz,1H),4.07(dd,J=14.3),11.1Hz,1H),3.86(d,J=10.2Hz,1H),3.75(d,J=10.2Hz,1H),2.11(dd,J=15.1,12.7Hz,1H),1.87-1.64(m , 4H), 1.42(d, J=1.7Hz, 8H), 1.20(s, 3H), 1.01(s, 3H). LCMS(ESI-MS)m / z=475[M+H] + .

[0272] 1-(((5S,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7S)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (800 mg, 1.68 mmol, 1 equivalent) was subjected to HPLC under the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile phase A: MtBE (0.5% 2M NH3-MeOH) -- HPLC; Mobile phase B: EtOH -- HPLC; Flow rate: 15 mL / min; Gradient: 50% B ~ 50% at 15 min B; Wavelength: 220 / 254 nm; RT1 (min): 7.11, RT2 (min): 11.56; Sample solvent: EtOH--HPLC; Injection volume: 1 mL; Separation was performed by preparative chiral HPLC. The desired fractions were combined and lyophilized to obtain the product.

[0273] The first isomer to elute was 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (228.7 mg, purity 96.6%, 100% ee, yield 28.5%) as a white solid. This was confirmed by X-ray crystal structure analysis. 1H NMR(400MHz,DMSO-d6)δ 9.10(d,J=1.5Hz,1H),8.56-8.54(m,2H),8.22(d,J=1.4Hz,1H),7.81(d,J=8.4Hz,1 H),7.59(dd,J=8.4,1.5Hz,1H),5.38(s,1H),4.52(dd,J=14.2,3.7Hz,1H),4.07(dd, J=14.3), 11.1Hz, 1H), 3.86(d, J=10.2Hz, 1H), 3.75(d, J=10.2Hz, 1H), 2.11(dd, J=15 .1, 12.7Hz, 1H), 1.87-1.64(m, 4H), 1.42(d, J=1.7Hz, 8H), 1.20(s, 3H), 1.01(s, 3H). LCMS(ESI-MS)m / z=475[M+H] + .

[0274] Secondly, an isomer eluted: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (213.1 mg, purity 99.9%, 100% ee, yield 26.6%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.10(d,J=1.5Hz,1H),8.56-8.54(m,2H),8.22(d,J=1.4Hz,1H),7.81(d,J=8.4Hz,1H),7.59(dd,J=8.4,1.5Hz,1H),5.38(s,1H),4.52(dd,J= 14.2,3.7Hz,1H),4.07(dd,J=14.3),11.1Hz,1H),3.86(d,J=10.2Hz,1H),3.75(d,J=10.2Hz,1H),2.11(dd,J=15.1,12.7Hz,1H),1.87-1.64(m , 4H), 1.42(d, J=1.7Hz, 8H), 1.20(s, 3H), 1.01(s, 3H). LCMS(ESI-MS)m / z=475[M+H] + .

[0275] Example 2. Preparation of 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0276] Reaction scheme [ka] [ka]

[0277] Detailed instructions N,N-dibenzyl-1-methoxymethaneamine [ka] Potassium carbonate (47.29 g, 342.1 mmol, 1.5 equivalents) and sodium sulfate (48.60 g, 342.1 mmol, 1.5 equivalents) were added to a mixture of dibenzylamine (45 g, 228.1 mmol, 1 equivalent) and paraformaldehyde (6.78 g, 75.27 mmol, 0.3 equivalents) in methanol (250 mL). The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the crude product N,N-dibenzyl-1-methoxymethaneamine (crude, 50 g) as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d): δ 7.44-7.33 (m, 9H), 7.31 (q, J=3.1, 2.3Hz, 1H), 4.08 (s, 2H), 3.88 (s, 4H), 3.29 (s, 3H). LC-MS (ESI-MS): m / z=242 [M+H] + .

[0278] rac-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decane-8-one [ka] (S)-Proline (4.77 g, 41.43 mmol, 0.2 equivalents) was added to a stirred mixture of N,N-dibenzyl-1-methoxymethaneamine (50 g, 207.18 mmol, 1 equivalent) in dimethyl sulfoxide (500 mL), followed by the addition of 1,4-dioxaspiro[4.5]decan-8-one (323.58 g, 2071.82 mmol, 10 equivalents). The resulting mixture was stirred at 40°C for 16 hours, diluted with water (2000 mL), and extracted with ether (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified in 0% to 50% acetonitrile by reverse phase (water containing 0.1% ammonium bicarbonate) to obtain the desired product rac-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decane-8-one (30 g, yield 39.6%) as a pale yellow solid. LC-MS (ESI-MS) m / z = 366 [M + H] + .

[0279] rac-N,N-dibenzyl-1-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] Diethylaminosulfur trifluoride (6.62 g, 41.04 mmol, 1.5 equivalents) was added dropwise to a stirred mixture of rac-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decan-8-one (10 g, 27.36 mmol, 1 equivalent) in dichloromethane (100 mL) under a nitrogen atmosphere at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding saturated sodium bicarbonate aqueous solution (200 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether. The fractions were combined and concentrated under vacuum to obtain rac-N,N-dibenzyl-1-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (2.8 g, yield 26.4%) as a colorless oil. LCMS (ESI-MS) m / z = 388 [M + H] + .

[0280] rac-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] Palladium on carbon (10%, 1.0 g, 2.52 mmol, 0.35 equivalents) was added under a nitrogen atmosphere to a solution of rac-N,N-dibenzyl-1-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (2.8 g, 7.23 mmol, 1 equivalent) in methanol (20 mL). The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude product rac-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (crude 1.2 g) as a colorless oil. LCMS (ESI-MS) m / z = 208 [M + H] + .

[0281] rac-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] Potassium carbonate (2.4 g, 17.37 mmol, 3 equivalents) was added to a mixture of rac-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (1.2 g, 5.79 mmol, 1 equivalent) and 3-fluoro-4-nitrobenzonitrile (0.96 g, 5.79 mmol, 1 equivalent) in acetonitrile (15 mL). The resulting mixture was heated to 60°C, stirred overnight, and quenched by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 17% petroleum ether. The fractions were combined and concentrated under vacuum to obtain rac-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (840 mg, 32.9% yield in 2 steps) as an orange oil. LCMS (ESI-MS) m / z = 354 [M+H] + .

[0282] rac-4-amino-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] Iron powder (1.58 g, 28.3 mmol, 10 equivalents) was added to a mixture of rac-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (1 g, 2.83 mmol, 1 equivalent) and ammonium chloride (0.61 g, 11.3 mmol, 4 equivalents) in a mixed solvent of water (3 mL) and ethanol (6 mL). The resulting mixture was then stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was washed with ethanol (30 mL). The filtrate was concentrated under vacuum, the residue was diluted with dichloromethane (30 mL), and washed with water (3 × 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product rac-4-amino-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (crude, 700 mg) as a yellow solid. LCMS (ESI-MS) m / z = 324 [M + H] + .

[0283] rac-1-((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Formic acid (185 mg, 4.02 mmol, 2 equivalents) was added to a mixture of rac-4-amino-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (650 mg, 2.01 mmol, 1 equivalent) and triethyl orthoformate (297.92 mg, 2.01 mmol, 1 equivalent) in tetrahydrofuran (5 mL). The resulting mixture was heated to 80°C, stirred for 12 hours, and then concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 10% dichloromethane. The fractions were combined and concentrated under vacuum to obtain rac-1-((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg, 63.6% yield in 2 steps) as a yellow solid. LC-MS (ESI-MS) m / z = 334 [M + H] + .

[0284] rac-1-((2,2-difluoro-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-1-((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg, 1.8 mmol, 1 equivalent) in formic acid (4 mL) was stirred overnight at 70°C. The resulting mixture was concentrated under vacuum to obtain the crude product rac-1-((2,2-difluoro-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 400 mg) as a yellow solid. LCMS (ESI-MS) m / z = 290 [M + H] + .

[0285] rac-1-(((3S,5S)-6,6-difluoro-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A stirred mixture of rac-1-((2,2-difluoro-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitride (400 mg, 1.38 mmol, 1 equivalent) in dimethyl sulfoxide (5 mL) was heated to 35°C to dissolve all solids. Trimethylsulfoxonium iodide (456.45 mg, 2.07 mmol, 1.5 equivalents) was added to the solution, followed by potassium tert-butoxide (232.74 mg, 2.07 mmol, 1.5 equivalents). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0%-8% dichloromethane. The fractions were combined and concentrated under vacuum to obtain rac-1-(((3S,5S)-6,6-difluoro-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, yield 71.7%) as a yellow solid. LCMS (ESI-MS) m / z = 304 [M + H] + .

[0286] rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Lithium tert-butoxide (158.36 mg, 1.98 mmol, 2 equivalents) was added to a mixture of rac-1-(((3S,5S)-6,6-difluoro-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrilate (300 mg, 0.99 mmol, 1 equivalent) and ethyl carbamate (132.18 mg, 1.48 mmol, 1.5 equivalents) in N-methyl-2-pyrrolidinone (5 mL). The reaction mixture was then heated to 75°C and stirred overnight. After the reaction mixture cooled to room temperature, it was eluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 10% dichloromethane. The fractions were combined and concentrated under vacuum to obtain rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4,5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, yield 87.4%) as a yellow solid. LCMS (ESI-MS) m / z = 347 [M + H] + .

[0287] rac-1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Cuprous iodide (198 mg, 1.03 mmol, 1.2 equivalents) in 1,4-dioxane (5 mL), rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.87 mmol, 1 equivalent), 2-(5-chloropyrazine-2-yl)propan-2-ol (149.5 mg, 0.87 mmol, 1 equivalent), N1 , N 2 A mixture of dimethylethane-1,2-diamine (152.7 mg, 1.73 mmol, 2 equivalents) and tribasic potassium phosphate (441 mg, 2.08 mmol, 2.4 equivalents) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 10% dichloromethane. The fractions were combined and concentrated under vacuum to obtain rac-1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, yield 24%) as a yellow solid. LCMS (ESI-MS) m / z = 483 [M + H] + .

[0288] 1-(((5R,7R)-8,8-difluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] rac-1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (150 mg, 0.310 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK ID, 2*25 cm, 5 μm, mobile phase A: Hex:DCM=3:1 (0.5% 2M NH3-methanol)-HPLC, mobile phase B: ethanol-HPLC, flow rate: 20 mL / min, gradient: 17 min, 45%B~45%B; wavelength: 220 nm. The desired fractions were combined and lyophilized to obtain two products.

[0289] The first isomer to elute was 1-(((5R,7R)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (26.4 mg, purity 96.2%, 100% ee, yield 17.6%) as a white solid. This was confirmed by X-ray structural analysis. 1 H NMR(300MHz,DMSO-d6)δ 9.17(s,1H),8.57(d,J=8.0Hz,2H),8.30(s,1H),7.83(d,J=8.5Hz,1H),7.62(s,1H),5.39-5.37(m,1H),4. 66-4.64(m, 1H), 4.38-4.36(m, 1H), 3.93-3.91(m, 2H), 2.90-2.88(m, 1H), 2.28-1.78(m, 6H), 1.44(s, 6H). LCMS(ESI-MS)m / z=483[M+H] + .

[0290] The second isomer that eluted was 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (30.5 mg, 98.7% purity, 97.4% ee, yield 20.3%), which was obtained as a white solid. This was confirmed by X-ray structural analysis. 1 H NMR(300MHz,DMSO-d6)δ 9.17(s,1H),8.71-8.55(m,2H),8.30(s,1H),7.83(d,J=8.0Hz,1H),7.65-7.47(m,1H),5.50-5.22(m,1H),4.68(d,J=9.6H) z,1H),4.39-4.37(m,1H),3.93-3.91(m,2H),2.90-2.89(m,1H),2.31-2.06(m,4H),1.90-1.89(m,2H),1.53-1.37(m,6H). LCMS(ESI-MS)m / z=483[M+H] + .

[0291] Example 3. 1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Preparation of dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0292] Reaction scheme [ka] [ka]

[0293] Detailed instructions rac-N,N-dibenzyl-1-(8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] Potassium tert-butoxide (6.1 g, 54.72 mmol, 2 equivalents) was added to a mixture of methyltriphenylphosphonium bromide (11.7 g, 32.83 mmol, 1.2 equivalents) in toluene (100 mL), followed by the addition of rac-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decan-8-one (10 g, 27.36 mmol, 1 equivalent). The resulting mixture was stirred at 100°C for 4 hours, diluted with water (200 mL), and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 20% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product, rac-N,N-dibenzyl-1-(8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (9.2 g, yield 92.5%), as a yellow solid. LC-MS (ESI-MS) m / z = 364 [M + H] + .

[0294] rac-N-((7,10-dioxa dispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-N-benzyl-1-phenylmethaneamine [ka] Methylene iodide (1.77 mL, 22 mmol, 2 equivalents) and diethylzinc (22.01 mL, 22 mmol, 2 equivalents) were added to a mixture of rac-N,N-dibenzyl-1-(8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (4 g, 11 mmol, 1 equivalent) in dichloromethane (50 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with saturated ammonium chloride aqueous solution (100 mL), and extracted with dichloromethane (3 × 60 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by reverse-phase distillation with water (containing 0.1% ammonium bicarbonate) in 0% to 40% acetonitrile to obtain the desired product rac-N-((7,10-dioxaspiro[2.2.4 6 .2 3 Dodecane-4-yl-methyl-N-benzyl-1-phenylmethaneamine (3g, yield 72.2%) was obtained as a yellow solid. LC-MS (ESI-MS) m / z = 378 [M + H] + .

[0295] rac-(7,10-dioxadispiro[2.2.4 6 .2 3 ] Dodecane-4-yl)methaneamine [ka] Palladium on carbon (10%, 532.77 mg, 5 mmol, 0.6 equivalents) is dissolved in methanol (250 mL) in rac-N-((7,10-dioxa dispiro[2.2.4 6 .2 3 It was added to a mixture of rac-(7,10-dioxadispiro[2.2.4])-dodecane-4-yl(methyl)-N-benzyl-1-phenylmethaneamine (3g, 7.94 mmol, 1 equivalent). The resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product rac-(7,10-dioxadispiro[2.2.4]). 6 .2 3 Dodecane-4-yl)methaneamine (crude, 1g) was obtained as a yellow oil. LCMS (ESI-MS) m / z = 198 [M + H] + .

[0296] rac-3-(((7,10-dioxa dispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)amino(-4-nitrobenzonitrile) [ka] Potassium carbonate (1.12 g, 8.11 mmol, 2 equivalents) is dissolved in acetonitrile (20 mL) and rac-(7,10-dioxa dispiro[2.2.4 6 .2 3 rac-3-(((7,10-dioxadispiro[2.2.4]) was added to a mixture of dodecane-4-yl)methanamine (800 mg, 4.05 mmol, 1 equivalent) and 3-fluoro-4-nitrobenzonitrile (0.67 g, 4.05 mmol, 1 equivalent). The resulting mixture was stirred at 50°C for 4 hours, diluted with water (100 mL), and extracted with dichloromethane (3 × 40 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 15% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product rac-3-(((7,10-dioxadispiro[2.2.4] 6 .2 3 Dodecane-4-yl(methyl)amino(4-nitrobenzonitrile) (1.2 g, yield 86.3%) was obtained as a yellow solid. LC-MS (ESI-MS) m / z = 344 [M + H] + .

[0297] rac-1-((7,10-dioxa dispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Iron (975.79 mg, 17.47 mmol, 5 equivalents) was dissolved in a mixed solvent of methanol (60 mL) and ethyl acetate (60 mL) and rac-3-(((7,10-dioxa dispiro[2.2.46 .2 3 rac-1-((7,10-dioxadispiro[2.2.4]) was added to a mixture of dodecane-4-yl(methyl)amino(-4-nitrobenzonitrile) (1.2 g, 3.49 mmol, 1 equivalent), trimethoxymethane (370.85 mg, 3.49 mmol, 1 equivalent), and formic acid (160.84 mg, 3.49 mmol, 1 equivalent). The resulting mixture was stirred at 64°C for 4 hours and concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 50% petroleum ether. The fractions were combined and concentrated under vacuum to obtain rac-1-((7,10-dioxadispiro[2.2.4]) 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg, 62% yield) was obtained as a yellow solid. LC-MS (ESI-MS) m / z = 324 [M + H] + .

[0298] rac-1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] In formic acid (7 mL), rac-1-((7,10-dioxadispiro[2.2.4 6 .2 3 A mixture of rac-1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg, 2.16 mmol, 1 equivalent) was heated to 70°C, stirred overnight, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 70% petroleum ether. The fractions were combined and concentrated under vacuum to obtain rac-1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, yield 82.8%) as a yellow solid. LCMS (ESI-MS) m / z = 280 [M + H]+ .

[0299] rac-1-(((3S,5S)-1-oxadispiro[2.2.2 6 .2 3 Decan-5-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Sodium hydroxide (60%, 143.2 mg, 3.58 mmol, 2 equivalents) was added to a mixture of rac-1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.79 mmol, 1 equivalent) and trimethylsulfoxonium iodide (787 mg, 3.58 mmol, 2 equivalents) in dimethyl sulfoxide (2 mL). The resulting mixture was stirred at room temperature for 1 hour, diluted with water (40 mL), and extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product rac-1-(((3S,5S)-1-oxadispiro[2.2.2 6 .2 3 Decan-5-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 470 mg) was obtained as a white solid. LC-MS (ESI-MS) m / z = 294 [M + H] + .

[0300] rac-1-(((4S,6S)-8-oxo-7-oxa-9-azadhispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of lithium tert-butoxide (64.13 mg, 0.8 mmol, 0.5 equivalents) and ethyl carbamate (713 mg, 8 mmol, 5 equivalents) in N-methyl-2-pyrrolidone (11.75 mL) was stirred at room temperature for 10 minutes, followed by rac-1-(((3S,5S)-1-oxadispiro[2.2.2 6 .2 3 ]Decan-5-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (470 mg, 1.60 mmol, 1 equivalent) was added. The resulting mixture was stirred at 75°C for 4 hours. After cooling to room temperature, the resulting mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1-(((4S,6S)-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 420 mg) was obtained as a white solid. LC-MS (ESI-MS) m / z = 337 [M + H] +

[0301] rac-1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadhispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Cuprous iodide (113.23 mg, 0.59 mmol, 0.5 equivalents) is mixed with rac-1-(((4S,6S)-8-oxo-7-oxa-9-azadispiro[2.2.4] in 1,4-dioxane (15 mL). 6 .2 3]dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 1.19 mmol, 1 equivalent), 2-(5-chloropyrazine-2-yl)propan-2-ol (205.25 mg, 1.19 mmol, 1 equivalent), N 1 ,N 2 -dimethylethane-1,2-diamine (209.64 mg, 2.38 mmol, 2 equivalents) and tribasic potassium phosphate (504.80 mg, 2.38 mmol, 2 equivalents) were added to a mixture. The resulting mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 60% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product rac-1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, yield 71.3%) was obtained as a white solid. LC-MS (ESI-MS) m / z = 473 [M + H] + .

[0302] 1-(((4R,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadhispiro[2.2.4 6 .2 3 ]dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile and (((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] rac-1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadispiro-[2.2.4 6 .2 3 A racemic compound of dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 0.84 mmol, 1 equivalent) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH3-MeOH) --HPLC, mobile phase B: EtOH --HPLC; flow rate: 15 mL / min; gradient: 30% B ~ 30% B in 17 mins; wavelength: 220 / 254 nm; RT1 (min): 10.68; RT2 (min): 13.184; sample solvent: EtOH --HPLC; injection volume: 0.4 mL. The desired fractions were combined and lyophilized to obtain two products.

[0303] The first isomer to elute: as a white solid, 1-(((4R,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (173.6 mg, purity 99.1%, 100.0% ee). 1H NMR(300MHz,DMSO-d6)δ 9.26(d,J=1.5Hz,1H),8.60(d,J=1.5Hz,1H),8.51(s,1H),8.28(d,J=1.5Hz,1H), 7.82(d, J=8.4Hz, 1H), 7.58(dd, J=8.4, 1.5Hz, 1H), 5.44(s, 1H), 4.54(dt, J=16.2, 8.1Hz, 2H), 3.91(q, J=10.3Hz, 2H), 2.49-2.40(m, 1H), 2.30-2.19(m, 1H), 2.14-2 .00(m, 1H), 1.93-1.72(m, 4H), 1.46(s, 6H), 0.95-0.82(m, 1H), 0.41-0.17(m, 3H). LCMS(ESI-MS)m / z=473[M+H] + .

[0304] Secondly, the isomer that elutes is 1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azadispiro[2.2.4], which appears as a white solid. 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (159.8 mg, purity 99.1%, 99.0% ee). Absolute configuration confirmed by X-ray crystal structure. 1 H NMR(300MHz,DMSO-d6)δ 9.26(d,J=1.5Hz,1H),8.60(d,J=1.5Hz,1H),8.50(s,1H),8.28(d,J=1.5Hz,1H) , 7.82(d, J=8.4Hz, 1H), 7.58(dd, J=8.4, 1.5Hz, 1H), 5.43(s, 1H), 4.52(t, J=8.0 Hz, 2H), 3.91(q, J=10.3Hz, 2H), 2.49-2.38(m, 1H), 2.33-2.20(m, 1H), 2.15-2.0 1(m, 1H), 1.93-1.72(m, 4H), 1.45(s, 6H), 0.97-0.80(m, 1H), 0.38-0.20(m, 3H). LCMS(ESI-MS)m / z=473[M+H] + .

[0305] Example 4. Preparation of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0306] Reaction scheme [ka] [ka]

[0307] Detailed instructions 1-Methoxy-5-methylcyclohexa-1,4-diene [ka] Ammonia (1200 mL) was concentrated in an empty, oven-dried three-necked round-bottom flask under an inert nitrogen atmosphere at -78°C, and equipped with a cold finger containing dry ice acetone. To this, 1-methoxy-3-methylbenzene (64 g, 524.59 mmol, 1 equivalent) in diethyl ether (600 mL) was added, followed by tert-butanol (420 mL). Then, lithium wire (36.41 g, 5245.9 mmol, 10 equivalents) was carefully added. After the addition, the reaction mixture was heated to -33°C, after which the reaction mixture turned dark blue. The reaction contents were stirred at -33°C for 3 hours, after which ammonium chloride (14.03 g, 2622.95 mmol, 5 equivalents) was added. The reaction mixture was then removed from the -33°C bath, the cold finger was removed, and the reaction contents (exposed to air) were heated to room temperature and stirred for a further 14 hours. The resulting organic material was dissolved in 1000 mL of pentane and washed with water (3 × 1000 mL). The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 1-methoxy-5-methylcyclohexa-1,4-diene (crude, 60 g) as a yellow oil. LCMS (ESI-MS) m / z = 125 [M + H] + .

[0308] 3-Methylcyclohexa-3-en-1-one [ka] Oxalic acid (6.53 g, 72.58 mmol, 0.15 equivalents) was added to a solution of 1-methoxy-5-methylcyclohexa-1,4-diene (60 g, 483.87 mmol, 1 equivalent) in methanol (400 mL) and water (100 mL). The resulting solution was stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure to obtain the crude product 3-methylcyclohexa-3-en-1-one (crude, 50 g) as a white solid. LCMS (ESI-MS) m / z = 111 [M + H] + .

[0309] 1-Methyl-7-oxabicyclo[4.1.0]heptan-3-one [ka] 3-chloroperbenzoic acid (101.97 g, 590.90 mmol, 1.3 equivalents) was added to a solution of 3-methylcyclohexa-3-en-1-one (50 g, 454.54 mmol, 1 equivalent) in dichloromethane (500 mL) at 0°C. The reaction mixture was stirred at 0°C for 3 hours, and the reaction product was quenched with 500 mL of saturated sodium thiosulfate aqueous solution and stirred for 5 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 500 mL). The combined organic matter was washed with saturated sodium bicarbonate aqueous solution (3 × 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 1-methyl-7-oxabicyclo[4.1.0]heptan-3-one (crude, 54 g) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ 3.23(d,J=2.9Hz,1H),2.80(d,J=19.0Hz,1H),2.59(dd,J=19.0,0.9Hz,1H),2.43-2.33(m,2H),2.23-2.14(m,2H),1.38(s,3H). LCMS(ESI-MS)m / z=127[M+H] + .

[0310] 4-((tert-butyldiphenylsilyl)oxy)-3-methylcyclohex-2-en-1-one [ka] 117.80 g, 428.57 mmol, 1 equivalent of tert-butyldiphenylsilyl chloride was added under a nitrogen atmosphere to a solution of 1-methyl-7-oxabicyclo[4.1.0]heptan-3-one (54 g, 428.57 mmol, 1 equivalent), diisopropylethylamine (110.78 g, 857.14 mmol, 2 equivalents), and 4-dimethylaminopyridine (10.47 g, 85.71 mmol, 0.2 equivalents) in 600 mL of dichloromethane. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into 500 mL of dichloromethane and 500 mL of water, and the layers were separated. The organic layer was washed, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether. The fractions with the desired mass signal were combined and concentrated under vacuum to obtain the desired product 4-((tert-butyldiphenylsilyl)oxy)-3-methylcyclohex-2-en-1-one (60 g, 31.3% yield in 4 steps) as a pale yellow oil. LCMS (ESI-MS) m / z = 365 [M+H] + .

[0311] rac-(3S,4R)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-3-(nitromethyl)cyclohexane-1-one [ka] Nitromethane (4.01 g, 65.75 mmol, 1.2 equivalents) was added to a solution of 4-((tert-butyldiphenylsilyl)oxy)-3-methylcyclohex-2-en-1-one (20 g, 54.94 mmol, 1 equivalent) and benzyltrimethylammonium hydroxide (13.75 g, 82.41 mmol, 1.5 equivalents) in methanol (100 mL). The resulting mixture was stirred overnight at room temperature and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0%-10% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product, rac-(3S,4R)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-3-(nitromethyl)cyclohexane-1-one (18 g, yield 77.1%), as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.62-7.49(m,4H),7.42-7.36(m,6H),4.41-4.33(m,2H),3.65-3.59(m,1H),2.34-1.99(m,6H),1.09-0.98(m,12H). LCMS(ESI-MS)m / z=426[M+H] + .

[0312] rac-tert-butyl(((7S,8R)-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane-8-yl)oxy)diphenylsilane [ka] Ethylene glycol (4.33 g, 69.72 mmol, 1.5 equivalents) was added to a solution of rac-(3S,4R)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-3-(nitromethyl)cyclohexane-1-one (19.8 g, 46.58 mmol, 1 equivalent) and trimethoxymethane (7.40 g, 69.72 mmol, 1.5 equivalents) in dichloromethane (100 mL). The resulting reaction mixture was stirred at room temperature for 5 minutes and then cooled to 0°C in an ice bath. Methanesulfonic acid (0.67 g, 6.97 mmol, 0.15 equivalents) was added dropwise to this mixture. The resulting mixture was removed from the bath, warmed to room temperature, and stirred for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether. The fractions were combined and concentrated under vacuum to obtain the desired product, rac-tert-butyl(((7S,8R)-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane-8-yl)oxy)diphenylsilane (18.5 g, yield 84.7%), as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.62-7.49(m,4H),7.42-7.36(m,6H),4.41-4.33(m,2H),3.50-3.34(m ,4H), 3.25-3.19(m, 1H), 1.65-1.49(m, 6H), 1.09(s, 9H), 0.98(s, 3H). LCMS(ESI-MS)m / z=470[M+H] + .

[0313] rac-((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] Iron powder (21.75 g, 389.4 mmol, 10 equivalents) was added to a solution of rac-tert-butyl(((7S,8R)-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane-8-yl)oxy)diphenylsilane (18.3 g, 39.01 mmol, 1 equivalent) and ammonium chloride (8.33 g, 155.76 mmol, 4 equivalents) in a mixed solvent of ethanol (120 mL) and water (40 mL). The resulting mixture was heated to 80°C and stirred for 2 hours. After cooling to room temperature, the resulting mixture was filtered, and the filtered cake was washed with ethanol (2 × 200 mL). The filtrate was concentrated under reduced pressure to obtain the crude product rac-((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (crude, 17g) as a yellow solid. LCMS (ESI-MS) m / z = 440 [M+H] + .

[0314] rac-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] Potassium carbonate (10.68 g, 77.3 mmol, 2 equivalents) was added to a solution of rac-((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (17 g, 38.7 mmol, 1 equivalent) and 3-fluoro-4-nitrobenzonitrile (6.41 g, 38.7 mmol, 1 equivalent) in acetonitrile (150 mL). The resulting mixture was heated to 40°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 15% petroleum ether. The fractions having the desired mass signal were combined and concentrated under vacuum to obtain the desired product rac-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (14 g, 61.3% yield in 2 steps) as an orange solid. 1 H NMR(400MHz,DMSO-d6)δ 8.30-8.26(m,1H),7.61-7.48(m,4H),7.41-7.34(m,7H),7.15(dd,J=8.2,4.6Hz,1H),6.74(s,1H),3.59-3.57 (m, 4H), 3.44-3.34(m, 1H), 3.02-2.99(m, 1H), 2.88-2.85(m, 1H), 1.85-1.30(m, 6H), 1.07(s, 9H), 0.94(s, 3H). LCMS(ESI-MS)m / z=586[M+H] + .

[0315] rac-4-amino-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] Iron powder (13.34 g, 238.91 mmol, 10 equivalents) was added to a solution of rac-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (14 g, 23.93 mmol, 1 equivalent) and ammonium chloride (5.11 g, 95.56 mmol, 4 equivalents) in a mixed solvent of ethanol (120 mL) and water vapor (40 mL). The resulting mixture was heated to 80°C and stirred for 2 hours. After cooling to room temperature, the resulting mixture was filtered, and the filtered cake was washed with ethanol (2 × 200 mL). The filtrate was concentrated under reduced pressure to obtain the crude product rac-4-amino-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (crude, 13 g) as a yellow solid. LCMS (ESI-MS) m / z = 556 [M + H] + .

[0316] rac-1-(((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Formic acid (1.08 g, 23.38 mmol, 1 equivalent) was added to a solution of rac-4-amino-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (13 g, 23.4 mmol, 1 equivalent) in trimethoxymethane (71.95 g, 678 mmol, 29 equivalents). The resulting mixture was heated to 80°C, stirred for 3 hours, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 100% petroleum ether. The fractions having the desired mass signal were combined and concentrated under vacuum to obtain the desired product rac-1-(((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 73.9% yield in 2 steps) as a pink solid. 1 H NMR(400MHz,DMSO-d6)δ 8.40-8.35(m,1H),7.98-7.93(m,1H),7.82-7.79(m,1H),7.63-7.51(m,5H),7.36-7.29(m , 6H), 3.59-3.46(m, 6H), 3.44-3.34(m, 1H), 1.59-1.43(m, 6H), 1.01(s, 9H), 0.98(s, 3H). LCMS(ESI-MS)m / z=566[M+H] + .

[0317] rac-1-(((1S,2R)-2-((tert-butyldiphenylsilyl)oxy)-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-1-(((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 17.7 mmol, 1 equivalent) was stirred overnight at 70°C in formic acid (100 mL). The reaction mixture was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1-(((1S,2R)-2-((tert-butyldiphenylsilyl)oxy)-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 10 g) as a yellow solid. LCMS(ESI-MS)m / z=522[M+H] + .

[0318] rac-1-(((3S,5S,6R)-6-((tert-butyldiphenylsilyl)oxy)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Sodium hydride (60% in mineral oil, 3.07 g, 76.6 mmol, 4 equivalents) was added to a solution of trimethylsulfoxonium iodide (16.87 g, 76.6 mmol, 4 equivalents) in dimethyl sulfoxide (100 mL), and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture, rac-1-(((1S,2R)-2-((tert-butyldiphenylsilyl)oxy)-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 19.19 mmol, 1 equivalent) was added dropwise to dimethyl sulfoxide (100 mL). After 8 minutes, the reaction mixture was cooled to 0°C, slowly quenched with 200 mL of water, and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1-(((3S,5S,6R)-6-((tert-butyldiphenylsilyl)oxy)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitri (crude, 10 g) as a yellow solid. LCMS (ESI-MS) m / z = 536 [M + H] + .

[0319] rac-1-(((5S,7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Lithium tert-butoxide (2.99 g, 37.32 mmol, 2 equivalents) was added to a solution of ethyl carbamate (33.21 g, 373.20 mmol, 20 equivalents) in N-methylpyrrolidone (100 mL). After stirring at room temperature for 5 minutes, a solution of rac-1-(((3S,5S,6R)-6-((tert-butyldiphenylsilyl)oxy)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 18.69 mmol, 1 equivalent) was added dropwise to N-methylpyrrolidone (100 mL). Subsequently, the reaction mixture was heated to 100 °C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0-2% dichloromethane. The fractions with the desired mass signal were combined and concentrated under vacuum to obtain the desired product, rac-1-(((5S,7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (5.5 g, 53.8% yield in 3 steps), as a pale pink solid. 1 H NMR(400MHz,DMSO-d6)δ 8.40-8.35(m,1H),7.98-7.93(m,1H),7.82-7.79(m,1H),7.63-7.51(m,5H),7.36-7.29(m,6H),6.50(s,1 H),3.59-3.46(m,2H),3.44-3.34(m,1H),3.25-3.20(m,2H),1.79-1.45(m,6H),1.22(s,9H),0.97(s,3H). LCMS(ESI-MS)m / z=579[M+H] + .

[0320] rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0321] rac-1-(((5S,7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride (579 mg, 1 mmol, 1 equivalent) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 1 mL, 1 mmol, 1 equivalent). The mixture was stirred overnight at room temperature. The following day, calcium carbonate (200.18 mg, 2 mmol, 2 equivalents) and DOWEX 50WX8-400 (800 mg, 1 equivalent) were added to the reaction mixture, followed by methanol (2 mL). The resulting mixture was stirred at room temperature for 1 hour, filtered, and the filtrate was washed with methanol (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 10% dichloromethane. The fractions with the desired mass signal were combined and concentrated under vacuum to obtain the desired product rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (270 mg, yield 79.4%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.30(s,1H),7.98-7.93(m,1H),7.82-7.79(m,1H),7.63-7.51(m,1H),6.45(s,1H),4.75(s,1 H), 3.63-3.59(m, 2H), 3.47-3.35(m, 1H), 3.25-3.20(m, 2H), 1.81-1.47(m, 6H), 0.97(s, 3H). LCMS(ESI-MS)m / z=341[M+H] + .

[0322] rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Dess-Martin periodinane (224.45 mg, 0.53 mmol, 1.2 equivalents) was added to a solution of rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (150 mg, 0.44 mmol, 1 equivalent) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 3 hours. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 2% dichloromethane. The fractions containing the desired mass signal were combined and concentrated under vacuum to obtain the desired product rac-1-((((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (130 mg, yield 87.18%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.30(s,1H),7.98-7.93(m,1H),7.82-7.79(m,1H),7.63-7.51(m,1H),6.45(s,1H),3. 63-3.59(m, 2H), 3.25-3.20(m, 2H), 2.35-2.29(m, 2H), 2.11-1.85(m, 4H), 1.12(s, 3H). LCMS(ESI-MS)m / z=339[M+H] + .

[0323] rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Copper(I) iodide (72.37 mg, 0.38 mmol, 1 equivalent) in 1,4-dioxane (2 mL), rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (130 mg, 0.38 mmol, 1 equivalent), 2-(5-chloropyrazine-2-yl)propan-2-ol (65.74 mg, 0.38 mmol, 1 equivalent), N 1 ,N 2 Dimethylethane-1,2-diamine (66.88 mg, 0.76 mmol, 2 equivalents) and tripotassium phosphate (161.32 mg, 0.76 mmol, 2 equivalents) were added under a nitrogen atmosphere. The resulting mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the resulting mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 3% dichloromethane. The fractions having the desired mass signal were combined and concentrated under vacuum to obtain the desired product rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, yield 54.7%) as a pale yellow solid. 1H NMR (300MHz, DMSO-d6)δ 9.27(s, 1H), 8.64(d, J=4.0Hz, 1H), 8.32(d, J=10.1Hz, 2H), 7.86-7.79(m, 1H), 7.60(t, J=5.6Hz, 1H), 5.44(d, J=3.3Hz, 1H), 4.85(d, J=14.7Hz, 1H), 4.60(d, J=14.9Hz, 1H), 4. 16(d, J=10.1Hz, 1H), 4.05(d, J=10.5Hz, 1H), 3.19(s, 1H), 2.58(d, J=12.4Hz, 2H), 2.46 -2.19(m, 3H), 1.47(t, J=3.2Hz, 6H), 0.95(d, J=3.6Hz, 3H).LCMS(ESI-MS)m / z=475[M+H] + .

[0324] 1-(((5S,7S)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.21 mmol, 1 equivalent) Conditions: Column: CHIRALPAK ID, 2*25 cm, 5 μm, Mobile phase A: EtOH--HPLC, Mobile phase B: MtBE (0.5% 2M NH3-MeOH)--HPLC, Flow rate: 13 mL / min, Gradient: 50% B~50% at 13 min B was separated by preparative chiral HPLC using a sample solvent of EtOH:DCM=1:1 with wavelengths of 220 / 254 nm, RT1 (min): 8.31, RT2 (min): 23.51, and an injection volume of 2 mL. The desired fractions were combined and freeze-dried to obtain the product.

[0325] The first isomer to elute was 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (25.6 mg, purity 98.8%, 98.5% ee, yield 25.6%), which was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 9.27(s,1H),8.64(d,J=4.0Hz,1H),8.32(d,J=10.1Hz,2H),7.86-7.79(m,1H),7 .60(t, J=5.6Hz, 1H), 5.44(d, J=3.3Hz, 1H), 4.85(d, J=14.7Hz, 1H), 4.60(d, J=1 4.9Hz, 1H) 4.16(d, J=10.1Hz, 1H), 4.05(d, J=10.5Hz, 1H), 3.19(s, 1H), 2.58(d, J=12.4Hz, 2H), 2.46-2.19(m, 3H), 1.47(t, J=3.2Hz, 6H), 0.95(d, J=3.6Hz, 3H). LCMS(ESI-MS)m / z=475[M+H] + .

[0326] The second isomer that eluted was 1-(((5R,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (22.7 mg, purity 99.6%, 100% ee, yield 22.7%), which was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 9.27(s,1H),8.64(d,J=4.0Hz,1H),8.32(d,J=10.1Hz,2H),7.86-7.79(m,1H),7 .60(t, J=5.6Hz, 1H), 5.44(d, J=3.3Hz, 1H), 4.85(d, J=14.7Hz, 1H), 4.60(d, J=1 4.9Hz, 1H) 4.16(d, J=10.1Hz, 1H), 4.05(d, J=10.5Hz, 1H), 3.19(s, 1H), 2.58(d, J=12.4Hz, 2H), 2.46-2.19(m, 3H), 1.47(t, J=3.2Hz, 6H), 0.95(d, J=3.6Hz, 3H). LCMS(ESI-MS)m / z=475[M+H] + .

[0327] Example 5. Preparation of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0328] Reaction scheme [ka] [ka]

[0329] Detailed instructions rac-ethyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate [ka] A mixture of diethyl carbonate (94 g, 79.6 mmol) and sodium hydride (60% of the mineral oil, 37.5 g, 93.8 mmol) was heated under reflux in tetrahydrofuran (800 mL). Then, a solution of 1,4-dioxaspiro[4.5]decane-8-one (50.0 g, 32.0 mmol) was added to tetrahydrofuran (230 mL). The resulting mixture was stirred for 3 hours and then cooled to room temperature. The reaction was quenched by adding water (500 mL) and acetic acid (500 mL). The resulting solution was then extracted with ethyl acetate (3 × 500 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain rac-ethyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (52 g, 0.23 mol) as a yellow oil. This was used without further purification. LCMS(ESI-MS)m / z=229.1[M+H] + .

[0330] rac-ethyl 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate [ka] Iodomethane (48.5 g, 341 mmol) was added to a mixture of rac-ethyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (52 g, 228 mmol) and cesium carbonate (149 g, 456 mmol) in acetonitrile (600 mL). The resulting mixture was stirred at room temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography, and eluted with ethyl acetate in 0% to 30% petroleum ether to obtain the product rac-ethyl 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (45 g, 81.5%) as a pale yellow oil. LCMS (ESI-MS) m / z = 243.1 [M + H]+ .

[0331] rac-ethyl 8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-ene-7-carboxylate [ka] To a mixture of rac-ethyl 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (30 g, 124 mmol) in dichloromethane (500 mL), diethylaminosulfur trifluoride (39.9 g, 248 mmol) was added at 0°C. The solution was heated to room temperature and stirred for 5 hours. The mixture was then slowly added to a stirred aqueous solution, and sodium bicarbonate (600 mL) was added at 0°C. The resulting solution was extracted with dichloromethane (3 × 300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain rac-ethyl 8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-ene-7-carboxylate (crude, 35 g). LCMS (ESI-MS) m / z = 245.1 [M + H] + .

[0332] rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methanol [ka] A mixture of rac-ethyl 8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-carboxylate (35 g, 143 mmol) in tetrahydrofuran (600 mL) was mixed with lithium aluminum hydride (115 mL, 286 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours, and then quenched with cold ethanol. The resulting mixture was filtered, and the filtrate was concentrated to obtain the crude product rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methanol (crude, 30 g). LCMS (ESI-MS) m / z = 203.1 [M + H] + .

[0333] rac-2-((8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methyl)isoindoline-1,3-dione [ka] In 300 mL of tetrahydrofuran, a mixture of rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methanol (25 g, 124 mmol), isoindorin-1,3-dione (20 g, 136 mmol), and triphenyl phosphate (48.6 g, 185 mmol) was mixed with diisopropyl azodicarboxylate (37.5 g, 185 mmol). The mixture was stirred overnight at room temperature, and the following morning, the mixture was poured into 200 mL of ice water. The resulting solution was extracted with ethyl acetate (3 × 200 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 40% petroleum ether to obtain the product rac-2-((8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methyl)isoindorin-1,3-dione (18 g, 43.9%) as a yellow oil. LCMS (ESI-MS) m / z = 332.1 [M + H] + .

[0334] rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methaneamine [ka] Hydrazine (17 g, 272 mmol, 80%) was added to a mixture of rac-2-((8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methyl)isoindoline-1,3-dione (18 g, 54 mmol) in ethanol (100 mL). The mixture was stirred overnight at room temperature and then diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3 × 200 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the product rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]deca-8-en-7-yl)methaneamine (crude, 8 g). LCMS (ESI-MS) m / z = 202.1 [M + H] + .

[0335] rac-((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] To a mixture of methanol (80 mL) and rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-8-en-7-yl)methaneamine (8 g, 39.8 mmol), palladium-carbon (4 g, 50 wt%, 10% on carbon) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere (2 atm). The suspension was filtered, and the filtrate was concentrated under vacuum to obtain rac-((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (7.2 g, crude) as a yellow oil. LCMS (ESI-MS) m / z = 204.1 [M + H] + .

[0336] rac-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] Potassium carbonate (9.79 g, 70.8 mmol) was added to a mixture of rac-((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (7.2 g, 35.4 mmol) and 3-fluoro-4-nitrobenzonitrile (5.88 g, 35.4 mmol) in acetonitrile (100 mL), and the resulting mixture was stirred at 50°C for 4 hours. The suspension was filtered, the filtrate was diluted with water (200 mL), and the resulting solution was extracted with dichloromethane (3 × 200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 15% petroleum ether to obtain the product rac-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (6g, 48.4%) as an orange solid. LCMS (ESI-MS) m / z = 350.1 [M+H] + .

[0337] rac-4-amino-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] In ethanol (100 mL) and water (30 mL), a mixture of rac-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (5.5 g, 15.7 mmol) and ammonium chloride (4.21 g, 78.7 mmol) was mixed with iron (4.40 g, 78.7 mmol), and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to obtain rac-4-amino-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (crude, 4.2 g) as a yellow solid. LCMS (ESI-MS) m / z = 320.2 [M + H] + .

[0338] rac-1-(((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] In 20 mL of acetonitrile, a mixture of rac-4-amino-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (4.2 g, 13.2 mmol) and trimethoxymethane (2.09 g, 19.7 mmol) was mixed with formic acid (0.91 g, 19.7 mmol). The mixture was stirred at 80°C for 2 hours, and then cooled to room temperature. The resulting solution was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 45% petroleum ether to obtain the product rac-1-(((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4g, 92.3%) as a yellow solid. LCMS (ESI-MS) m / z = 330.2 [M + H] + .

[0339] rac-1-(((1S,2R)-2-fluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Formic acid (15 mL) was added to rac-1-(((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4 g, 12.1 mmol). The mixture was stirred overnight at 70°C and concentrated to obtain the product rac-1-(((1S,2R)-2-fluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 3.6 g) as a yellow oil. LCMS (ESI-MS) m / z = 286.1 [M + H] + .

[0340] rac-1-(((3S,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((3R,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] To a mixture of trimethylsulfoxonium iodide (5.24 g, 23.8 mmol) in DMSO (50 mL), sodium hydrogen (60% in mineral oil, 1.43 g, 35.7 mmol) was added. The mixture was stirred at 10°C for 10 minutes, then rac-1-(((1S,2R)-2-fluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.4 g, 11.9 mmol) was added, and the mixture was subsequently stirred at room temperature for 10 minutes, then quenched with aqueous ammonium chloride (200 mL). The resulting solution was extracted with ethyl acetate (3 × 100 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. To separate the diastereomers, the residue was purified by reverse-phase chromatography and eluted with 0% to 45% acetonitrile in water to obtain the more polar rac-1-(((3R,5S,6S)-6-fluoro-5-methyl-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg) as a pale yellow solid. Further elution with 55% acetonitrile in water yielded the less polar rac-1-(((3S,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.2 g) as a pale yellow solid. LCMS (ESI-MS) m / z = 300.1 [M + H] + .

[0341] rac-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of ethyl carbamate (1.49 g, 16.7 mmol) and lithium tert-butoxide (401 mg, 5.01 mmol) in N-methylpyrrolidone (10 mL) was stirred at room temperature for 10 minutes. Then, rac-1-(((3S,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.67 mmol) was added, and the mixture was stirred overnight at 100°C. The following day, the mixture was quenched with water (60 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and the crude product was obtained. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 100% petroleum ether to obtain the product rac-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg) as a colorless oil. LCMS (ESI-MS) m / z = 343.1 [M + H] + .

[0342] rac-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Copper(I) iodide (110.46 mg, 0.58 mmol, 1 equivalent) in 1,4-dioxane (2 mL), rac-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.58 mmol, 1 equivalent), 2-(5-chloropyrazine-2-yl)propan-2-ol (100.34 mg, 0.58 mmol, 1 equivalent), N 1 ,N 2The compound was added to a solution of dimethylethane-1,2-diamine (102.08 mg, 1.16 mmol, 2 equivalents) and tripotassium phosphate (246.23 mg, 1.16 mmol, 2 equivalents) under a nitrogen atmosphere. The resulting mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the resulting mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 3% dichloromethane. The fractions having the desired mass signal were combined and concentrated under vacuum to obtain the desired product rac-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, yield 71.43%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 9.18(d,J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.45(s,1H),8.26(d,J=1.5Hz,1H),7.84(d,J=8.4Hz,1H),7.60(dd,J=8.3,1.5Hz,1H),5. 42(s, 1H), 4.67-4.50(m, 1H), 4.38-4.25(m,2H),3.83(d,J=2.0Hz,2H),2.12-1.99(m,2H),1.97-1.88(m,2H),1.80-1.69(m,2H),1.44(d ,J=2.3Hz,6H),1.19(s,3H). LCMS(ESI-MS)m / z=479[M+H] + .

[0343] 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] rac-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.42 mmol, 1 equivalent) under the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm, Mobile phase A: MtBE (0.5% 2M NH3-MeOH) --HPLC, Mobile phase B: EtOH --HPLC, Flow rate: 14 mL / min, Gradient: 30% B at 29 min The sample was separated by preparative chiral HPLC using ~30% B, wavelength: 220 / 254 nm, RT1 (min): 13.529; RT2 (min): 21.063, sample solvent: EtOH--HPLC, injection volume: 0.8 mL. The desired fractions were combined and lyophilized to obtain the product.

[0344] Example 5A (first isomer to elute): 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (77.3 mg, purity 97.0%, 100% ee, yield 38.65%) as a white solid. 11H NMR (400MHz, DMSO-d6)δ 9.18(d,J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.45(s,1H),8.26(d,J=1.5H z, 1H), 7.84(d, J=8.4Hz, 1H), 7.60(dd, J=8.3, 1.5Hz, 1H), 5.42(s, 1H), 4.6 7-4.50(m, 1H), 4.38-4.25(m, 2H), 3.83(d, J=2.0Hz, 2H), 2.12-1.99(m, 2H) , 1.97-1.88(m, 2H), 1.80-1.69(m, 2H), 1.44(d, J=2.3Hz, 6H), 1.19(s, 3H). LCMS(ESI-MS)m / z=479[M+H] + .

[0345] Example 5B (second isomer to elute): 1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (76.5 mg, purity 99.5%, 100% ee, yield 38.25%) as a white solid. 1 1H NMR (400MHz, DMSO-d6)δ 9.18(d,J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.45(s,1H),8.26(d,J=1.5H z, 1H), 7.84(d, J=8.4Hz, 1H), 7.60(dd, J=8.3, 1.5Hz, 1H), 5.42(s, 1H), 4.6 7-4.50(m, 1H), 4.38-4.25(m, 2H), 3.83(d, J=2.0Hz, 2H), 2.12-1.99(m, 2H) , 1.97-1.88(m, 2H), 1.80-1.69(m, 2H), 1.44(d, J=2.3Hz, 6H), 1.19(s, 3H). LCMS(ESI-MS)m / z=479[M+H] + The structure was confirmed by X-ray crystallography.

[0346] Example 6. 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Preparation of dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0347] Detailed instructions rac-N,N-dibenzyl-1-(7-methyl-8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] To a mixture of methyltriphenylphosphonium bromide (70.6 g, 198 mmol) in toluene (600 mL), potassium 2-methylpropane-2-olate (22.2 g, 198 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, rac-7-((dibenzylamino)methyl)-7-methyl-1,4-dioxaspiro[4.5]decan-8-one (50 g, 132 mmol) was added. The mixture was stirred at 100 °C for 4 hours and then cooled to room temperature. The mixture was quenched with water (600 mL), and the resulting solution was extracted with ethyl acetate (3 x 400 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether to obtain rac-N,N-dibenzyl-1-(7-methyl-8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (45 g) as a colorless oil. LCMS (ESI-MS) m / z = 378.2 [M + H] + .

[0348] rac-N,N-dibenzyl-1-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] Dodecane-4-yl)methaneamine [ka] Diethyl zinc (1M in THF, 358mL, 358 mmol) was added at 0°C to a mixture of rac-N,N-dibenzyl-1-(7-methyl-8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (45g, 119 mmol) in diethyl ether (600 mL). The mixture was stirred for 30 minutes, then diiodomethane (95.8g, 358 mmol) was added, and the resulting solution was heated to room temperature and stirred overnight. The mixture was slowly quenched with aqueous ammonium chloride (600 mL), and the resulting solution was extracted with DCM (3 × 200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in petroleum ether containing 0% to 10% ethyl acetate to obtain rac-N,N-dibenzyl-1-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl)methaneamine (5g) was obtained as a colorless oil. LCMS (ESI-MS) m / z = 392.3 [M + H] + .

[0349] rac-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] Dodecane-4-yl)methaneamine [ka] In methanol (100 mL), rac-N,N-dibenzyl-1-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 To a solution of rac-(4-methyl-7,10-dioxadispiro[2.2.4]dodecane-4-yl)methanamine (4 g, 10.2 mmol), palladium (2 g, 50 wt%, 10% carbon) was added. The suspension was stirred under a hydrogen atmosphere for 3 hours and then filtered. The filtrate was concentrated to obtain the crude product rac-(4-methyl-7,10-dioxadispiro[2.2.4] 6 .2 3Dodecane-4-yl)methaneamine (crude 2g) was obtained as a yellow oil. LCMS (ESI-MS) m / z = 212.2 [M + H] + .

[0350] rac-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)amino(-4-nitrobenzonitrile) [ka] In acetonitrile (30 mL), rac-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Potassium carbonate (4.32 g, 31.2 mmol) was added to a mixture of dodecane-4-yl)methaneamine (2.2 g, 10.4 mmol) and 3-fluoro-4-nitrobenzonitrile (1.73 g, 10.4 mmol). The mixture was stirred at 50°C for 4 hours and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 18% petroleum ether to obtain rac-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)amino-4-nitrobenzonitrile (3.7g, 99.4%) was obtained as an orange solid. LC-MS (ESI-MS) m / z = 358.2 [M + H] + .

[0351] rac-4-amino-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)amino(benzonitrile) [ka] In ethanol (50 mL), rac-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3A mixture of dodecane-4-yl(methyl)amino-4-nitrobenzonitrile (3.7 g, 10.4 mmol) and ammonium chloride (2.77 g, 51.8 mmol) was mixed with iron (2.89 g, 51.8 mmol), and the mixture was stirred at 70°C for 2 hours, then cooled to room temperature. The mixture was then filtered, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the product rac-4-amino-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)amino(benzonitrile) (3.3g, 97.3%) was obtained as a yellow solid. LC-MS (ESI-MS) m / z = 328.2 [M + H] + .

[0352] rac-1-((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] In acetonitrile (30 mL), rac-4-amino-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 A mixture of dodecane-4-yl(methyl)amino(benzonitrile) (3.2 g, 9.77 mmol) was mixed with trimethoxymethane (1.56 g, 14.7 mmol) and formic acid (0.67 g, 14.7 mmol). The resulting mixture was stirred at 80°C for 2 hours and then cooled to room temperature. The mixture was concentrated to obtain the crude product, and the residue was purified by silica gel column chromatography. Elution was performed with ethyl acetate in 0% to 30% petroleum ether to obtain rac-1-((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (3g, 90.9%) was obtained as a yellow solid. LC-MS (ESI-MS) m / z = 338.2 [M + H]+ .

[0353] rac-1-((4-methyl-6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Formic acid (20 mL) is added to rac-1-((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 The mixture was added to rac-1-((4-methyl-6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g, 8.89 mmol), stirred overnight at 70°C, and then cooled to room temperature. The solution was concentrated to obtain the product rac-1-((4-methyl-6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.3 g) as a yellow oil. LCMS (ESI-MS) m / z = 294.2 [M + H] + .

[0354] 1-(5-methyl-1-oxadispiro[2.2.26.23]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Potassium tert-butoxide (0.99 g, 8.86 mmol) was added to a mixture of rac-1-((4-methyl-6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride (2 g, 6.82 mmol) and trimethylsulfoxonium iodide (1.95 g, 8.86 mmol) in methyl sulfoxide (30 mL). The mixture was stirred at room temperature for 10 minutes, then quenched with aqueous ammonium chloride (50 mL), and the resulting solution was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in petroleum ether containing 0% to 80% ethyl acetate to obtain 1-((5-methyl-1-oxadispiro[2.2.26.23]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.7 g) as a white solid. LCMS (ESI-MS) m / z = 308.2 [M + H] + .

[0355] 1-((6-hydroxy-6-(hydroxymethyl)-4-methylspiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of 1-((5-methyl-1-oxadispiro[2.2.26.23]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.7 g, 5.53 mmol) was added to N,N-dimethylformamide (10 mL) and water (10 mL), to which trifluoroacetic acid (1.26 g, 11.1 mmol) was added. The mixture was stirred overnight at room temperature and diluted with aqueous sodium bicarbonate (50 mL). The resulting solution was extracted with dichloromethane (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product 1-((6-hydroxy-6-(hydroxymethyl)-4-methylspiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.02 g) as a yellow oil. LCMS(ESI-MS)m / z=326.2[M+H] + .

[0356] rac-1-(((3S,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 ]decan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride and rac-1-(((3R,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 Decan-5-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] To a mixture of rac-1-((6-hydroxy-6-(hydroxymethyl)-4-methylspiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.02 g, 6.21 mmol) in dichloromethane (30 mL), tosyl chloride (1.78 g, 9.31 mmol), 4-dimethylaminopyridine (0.38 g, 3.10 mmol), and triethylamine (1.88 g, 18.6 mmol) were added. The mixture was stirred at room temperature for 6 hours and then quenched with water (50 mL). The resulting solution was extracted with dichloromethane (3 × 30 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a crude intermediate. The residue was dissolved in acetonitrile (20 mL), potassium carbonate (1.72 g, 12.4 mmol) was added, and the mixture was stirred at 50°C for 3 hours and filtered. The filtrate was concentrated to obtain the crude product. The residue was purified by preparative TLC (EA), Rf=0.5 to obtain the product rac-1-(((3S,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 ]decan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (210 mg, 11%) yielded a white solid and Rf=0.3, and rac-1-(((3R,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 Decan-5-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg, 18.3%) was obtained as a white solid. LC-MS (ESI-MS) m / z = 308.2 [M + H] + .

[0357] rac-1-(((4R,6S)-4-methyl-8-oxo-7-oxa-9-azadhispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of ethyl carbamate (1.01 g, 11.4 mmol) and lithium tert-butoxide (182 mg, 2.28 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was stirred at room temperature for 10 minutes, and then rac-1-(((3S,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 ]decane-5-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg, 1.14 mmol) was added. The mixture was stirred at 150°C for 6 hours and then cooled to room temperature. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 100% petroleum ether to obtain rac-1-(((4R,6S)-4-methyl-8-oxo-7-oxa-9-azadhispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (330 mg, 82.7%) was obtained as a yellow solid. LC-MS (ESI-MS) m / z = 351.2 [M + H] + .

[0358] rac-1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] 1,4-Dioxane (15 mL) contains rac-1-(((4R,6S)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3A mixture of ]dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (330 mg, 0.94 mmol), with 2-(5-chloropyrazine-2-yl)propan-2-ol (244 mg, 1.41 mmol), N 1 ,N 2 -Dimethylethane-1,2-diamine (165 mg, 1.88 mmol), tribasic potassium phosphate (399 mg, 1.88 mmol), and copper(I) iodide (90 mg, 0.47 mmol) were added. The mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere and then cooled to room temperature. The mixture was diluted with water (50 mL), extracted with ethyl acetate (3 × 30 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 7% chloromethane to obtain rac-1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg) was obtained as a white solid. LC-MS (ESI-MS) m / z = 487.2 [M + H] + .

[0359] 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 ]dodecane-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride and 1-(((4S,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] rac-1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 A mixture of dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg, 0.72 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH) --HPLC; mobile phase B: EtOH --HPLC; flow rate: 12 mL / min; gradient: 20%B to 20%B over 25 mins; wavelength: 220 / 254 nm; RT1 (min): 11.542; sample solvent: EtOH --HPLC; injection volume: 0.7 mL. The desired fractions were combined and lyophilized to obtain two products.

[0360] The first isomer to elute: As a pale yellow solid, 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azadispiro[2.2.4 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (113.6 mg, purity 95.3%, 100% ee). 1 H NMR(400MHz,DMSO-d6)δ 9.17(d,J=1.5Hz,1H),8.60(d,J=1.5Hz,1H),8.44(s,1H),8.36(d,J=1.5Hz,1H) , 7.81(d, J=8.4Hz, 1H), 7.57(dd, J=8.4, 1.5Hz, 1H), 5.41(s, 1H), 4.20-4.06(m, 3H), 3.95(d, J=10.2Hz, 1H), 2.17(d, J=13.9Hz, 1H), 1.97-1.74(m, 4H), 1.52-1. 34(m,7H), 0.91(s,3H), 0.81-0.79(m,1H), 0.59-0.49(m,1H), 0.31-0.17(m,2H). LCMS(ESI-MS)m / z=487.2[M+H] + .

[0361] Secondly, the isomer that elutes is 1-(((4S,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azaspiro[2.2.4], which appears as a white solid. 6 .2 3 Dodecane-4-yl(methyl)-1H-benzo[d]imidazole-6-carbonitrile (111.0 mg, purity 99.5%, 100%ee). 1 H NMR (400MHz, DMSO-d6)δ 9.17(d, J=1.5Hz, 1H), 8.60(d, J=1.6Hz, 1H), 8.44(s, 1H), 8.38-8.33(m, 1H), 7 .81(d, J=8.4Hz, 1H), 7.57(dd, J=8.4, 1.4Hz, 1H), 5.41(s, 1H), 4.20-4.04(m, 3H ), 3.95(d, J=10.2Hz, 1H), 2.17(d, J=13.9Hz, 1H), 2.01-1.71(m, 4H), 1.54-1.37 (m, 7H), 0.91(s, 3H), 0.837-0.77(m, 1H), 0.59-0.47(m, 1H), 0.32-0.17(m, 2H). LCMS(ESI-MS)m / z=487.2[M+H] + .

[0362] Example 7. Preparation of 1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Detailed instructions (1,4-dioxaspiro[4.5]deca-6-en-7-yl)methanol [ka] A solution of methyl 1,4-dioxaspiro[4.5]deca-6-en-7-carboxylate (19.5 g, 98.4 mmol) and lithium aluminum hydride (3.73 g, 98.8 mmol) was stirred at 0°C for 1 hour in tetrahydrofuran (400 mL). The resulting mixture was quenched with aqueous sodium hydroxide solution, and the resulting mixture was filtered. The filtrate was washed with tetrahydrofuran (2 × 100 mL). The filtrate was concentrated under reduced pressure to obtain the crude product (1,4-dioxaspiro[4.5]deca-6-en-7-yl)methanol (7 g) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 5.48 (s, 1H), 3.92-3.79 (m, 6H), 1.92-1.83 (m, 2H), 1.71-1.61 (m, 4H).

[0363] 7-(fluoromethyl)-1,4-dioxaspiro[4.5]deca-6-ene [ka] A solution of (1,4-dioxaspiro[4.5]deca-6-en-7-yl)methanol (7.0 g, 41.1 mmol) and diethylaminosulfur trifluoride (7.95 g, 49.3 mmol) in dichloromethane (140 mL) was stirred overnight at room temperature. The mixture was quenched with aqueous sodium carbonate (200 mL), and the resulting mixture was extracted with dichloromethane (3 x 100 mL). The organic layer was dried, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with dichloromethane (100%) to obtain 7-(fluoromethyl)-1,4-dioxaspiro[4.5]deca-6-ene (6.0 g) as a brown oil. 1 H NMR(400MHz,DMSO-d6)δ 5.90(s,1H),5.08(d,J=4.0Hz,1H),2.52-2.48(m,1H),2.42-2.16(m,5H),2.08-1.84(m,3H),1.73-1.59(m,1H),1.44-1.31(m,1H).

[0364] 3-(fluoromethyl)cyclohexa-2-en-1-one [ka] A solution of 7-(fluoromethyl)-1,4-dioxaspiro[4.5]deca-6-ene (6.0 g, 34.8 mmol) in formic acid (10 mL) was stirred at 80°C for 1 hour. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 10% petroleum ether to obtain 3-(fluoromethyl)cyclohexa-2-en-1-one (2.0 g) as a colorless oil.

[0365] rac-3-(fluoromethyl)-3-(nitromethyl)cyclohexane-1-one [ka] A solution of 3-(fluoromethyl)cyclohexa-2-en-1-one (2.0 g, 15.6 mmol) and nitromethane (1.14 g, 18.7 mmol) in benzyltrimethylazanium methanolate (3 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 20% petroleum ether to obtain rac-3-(fluoromethyl)-3-(nitromethyl)cyclohexane-1-one (1.0 g) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 4.69-4.30 (m, 4H), 2.45-2.21 (m, 4H), 1.95-1.70 (m, 4H).

[0366] rac-7-(fluoromethyl)-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane [ka] A solution of rac-3-(fluoromethyl)-3-(nitromethyl)cyclohexane-1-one (1.0 g, 5.3 mmol), ethylene glycol (0.49 g, 7.9 mmol), and trimethoxymethane (0.84 g, 7.9 mmol) was stirred in 20 mL of dichloromethane at room temperature for 5 minutes. The solution was cooled to 0°C, and methanesulfonic acid (80 mg, 0.79 mmol) was added. The resulting mixture was warmed to room temperature and stirred overnight. The solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography. Elution with ethyl acetate in 0%-10% petroleum ether yielded rac-7-(fluoromethyl)-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (950 mg) as a colorless oil. LCMS (ESI-MS) m / z = 234.2 [M + H] + .

[0367] rac-(7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] A solution of rac-7-(fluoromethyl)-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (950 mg, 4.6 mmol), iron (2.56 g, 46.7 mmol), and ammonium chloride (990 mg, 18.7 mmol) was stirred at 80°C for 2 hours in ethanol (10 mL) and water (3 mL). The resulting mixture was filtered, and the filtrate was washed with ethanol (3 × 50 mL). The filtrate was concentrated under reduced pressure to obtain rac-(7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (crude, 950 mg) as a yellow oil. LCMS (ESI-MS) m / z = 204.2 [M + H] + .

[0368] rac-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] A solution of rac-(7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (950 mg, 4.7 mmol), 3-fluoro-4-nitrobenzonitrile (776 mg, 4.7 mmol), and potassium carbonate (1.29 g, 9.3 mmol) in acetonitrile (15 mL) was stirred overnight at 40°C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 50% petroleum ether to obtain rac-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (1.0 g) as a yellow solid. LCMS (ESI-MS) m / z = 350.3 [M + H] + .

[0369] rac-4-amino-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] A solution of rac-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (1.0 g, 2.9 mmol), iron (1.60 g, 28.6 mmol), and ammonium chloride (0.61 g, 11.4 mmol) in ethanol (12 mL) and water (4 mL) was stirred at 80°C for 2 hours. The resulting mixture was concentrated under vacuum to obtain the crude product rac-4-amino-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (1.0 g) yellow oil. LCMS (ESI-MS) m / z = 320.3 [M + H] + .

[0370] rac-1-((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-4-amino-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (1.0 g, 3.1 mmol) and formic acid (143 mg, 3.1 mmol) in trimethoxymethane (3 mL) was stirred overnight at 80°C. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate) to obtain rac-1-((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (900 mg) as a colorless oil. LCMS (ESI-MS) m / z = 330.3 [M + H] + .

[0371] rac-1-((1-(fluoromethyl)-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-1-((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (900 mg, 2.7 mmol) in formic acid (5 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (100% ethyl acetate) to obtain rac-1-((1-(fluoromethyl)-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg) as a white solid. LC-MS (ESI-MS) m / z = 286.3 [M + H] + .

[0372] rac-1-(((3S,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((3R,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A solution of rac-1-((1-(fluoromethyl)-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitride (500 mg, 1.7 mmol) and dimethylmethanesulfinate iodide (424 mg, 1.9 mmol) was stirred in dimethyl sulfoxide (5 mL) at room temperature for 5 minutes. The solution was cooled to 0°C, and tert-butoxypotassium (216 mg, 1.9 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred at 0°C for a further 1 hour. The reaction was quenched with water at 0°C. The aqueous phase was extracted with ethyl acetate (3 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate = 100%) to obtain rac-1-(((3S,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a white solid, and rac-1-(((3R,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (180 mg) as a white solid. LCMS (ESI-MS) m / z = 300.3 [M + H] + .

[0373] rac-1-(((5S,7R)-7-(fluoromethyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of ethyl carbamate (1.1 g, 13.3 mmol) and tert-butoxylithium (107 mg, 1.3 mmol) in N-methyl-2-pyrrolidone (3 mL) was stirred at room temperature for 5 minutes. rac-1-(((3S,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.7 mmol) was added dropwise over 10 minutes. The resulting mixture was stirred overnight at 75°C. The resulting mixture was cooled to room temperature and concentrated under vacuum to obtain the crude product. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to obtain rac-1-(((5S,7R)-7-(fluoromethyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a white solid. LCMS (ESI-MS) m / z = 343.3 [M+H] + .

[0374] rac-1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-1-(((5S,7R)-7-(fluoromethyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.6 mmol), 2-(5-chloropyrazine-2-yl)propan-2-ol (151 mg, 0.9 mmol), N1,N2-dimethylethane-1,2-diamine (103 mg, 1.1 mmol), copper(I) iodide (111 mg, 0.6 mmol), and tribasic potassium phosphate (248 mg, 1.2 mmol) in dioxane (3 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to obtain rac-1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (180 mg) as a white solid. LCMS (ESI-MS) m / z = 479.2 [M+H] + .

[0375] 1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7S)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of rac-1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (180 mg, 0.4 mmol) was subjected to the following conditions: Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Mobile phase A: MtBE (0.5% 2M NH3-MeOH) -- HPLC; Mobile phase B: EtOH -- HPLC; Flow rate: 20 mL / min; Gradient: 15%B~15%B at 19 min; Wavelength: 220 / 254 nm; RT1 (min): 12.796; RT2 (min): 15.536; Sample solvent: MtBE (0.5% 2M Separation was performed by preparative chiral HPLC using NH3-MeOH)--HPLC with an injection volume of 0.4 mL. The desired fractions were combined and lyophilized to obtain two products.

[0376] The first isomer to elute: 1-(((5R,7S)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (62.2 mg, purity 98.2%, 100% ee) as a white solid. 1 ¹H NMR (400MHz, dimethyl sulfoxide-d6) δ: 9.25 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.85 (d, J=8.0Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 5.42 (s, 1H), 4.55-4.46 (m, 2H), 4.18-3.89 (m, 4H), 2.12-1.76 (m, 6H), 1.46 (s, 8H). LCMS (ESI-MS) m / z=479.2[M+H] + .

[0377] Secondly, the isomer that elutes is 1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (63.0 mg, purity 90.9%, 100% ee) as a white solid. NMR (400MHz, dimethyl sulfoxide-d6) δ: 9.25 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.85 (d, J=8.4Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 5.44 (s, 1H), 4.56-4.46 (m, 2H), 4.19 (s, 1H), 4.07-4.03 (m, 2H), 3.90 (d J=10.0Hz, 1H), 2.12-2.03 (m, 1H), 2.02-1.96 (m, 1H), 1.95-1.89 (m, 1H), 1.89-1.76 (m, 2H), 1.46 (s, 9H). LCMS(ESI-MS)m / z=479.2[M+H] + .

[0378] Example 8. Preparation of 1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0379] Detailed instructions 3-Methoxycyclohexa-1,4-diene-1-carboxylic acid [ka] Place m-anisic acid (50.0 g, 0.33 mol) and H2O (75 mL) into a three-necked flask. Equip the flask with a mechanical stirrer, an ammonia inlet, and a cold finger condenser containing solid carbon dioxide and acetone. Add the ammonia to the solution through a glass filter and collect approximately 1 liter of ammonia. Replace the ammonia inlet with a nitrogen inlet and introduce a slow flow of nitrogen onto the surface. Begin stirring vigorously (Note: this is an exothermic reaction) and gradually add lithium wire (7.0 g, 1.0 mol) over 20-30 minutes to carry out the Birch reduction. Continue vigorous stirring until the blue color completely disappears. Stop stirring, remove the condenser, and allow the ammonia to evaporate completely under a steady flow. Then add 1 M potassium hydroxide solution (500 mL) (thoroughly purged with nitrogen) and start stirring again. Heat the solution in a water bath maintained at 60°C for 2.5 hours. Replace the water bath with an ice bath and cool the solution to 10°C. While maintaining the ice bath, add concentrated HCl (100 mL) without exceeding 70°C. Continue stirring until the solution temperature drops to approximately 15°C. Remove the ice bath and continue stirring until a homogeneous solution is obtained. Transfer the aqueous solution to a separatory funnel and extract with CH2Cl2 (3 x 200 mL). Dry the combined organic extract and deposit it onto a rotary evaporator under reduced pressure. Recrystallize the product sample from toluene. LC-MS (ESI-MS) m / z = 155.2 [M + H] + .

[0380] 5-Oxocyclohexa-1-ene-1-carboxylic acid [ka] To a solution of 3-methoxycyclohexa-1,4-diene-1-carboxylic acid (14.5 g, 94.1 mmol) in methanol (200 mL), oxalic acid (1.27 g, 14.1 mmol) and water (50 mL) were added. The resulting solution was stirred at room temperature for 16 hours. The residue was concentrated and purified by silica gel column chromatography (EA:PE=2:1) ​​to obtain 5-oxocyclohexa-1-ene-1-carboxylic acid (3 g) as a white solid. LC-MS (ESI-MS) m / z = 141.0 [M+H] + .

[0381] 5-Oxocyclohexa-1-ene-1-carboxylate methyl [ka] Diazomethane (27.0 g, 642 mmol) was added to a solution of 5-oxocyclohexa-1-ene-1-carboxylic acid (30 g, 214 mmol) in diethyl ether (300 mL). The resulting solution was stirred at room temperature for 16 hours. The residue was concentrated and purified by silica gel column (EA:PE=1:1) to obtain the desired product, methyl 5-oxocyclohexa-1-ene-1-carboxylic acid (11.0 g), as a pale yellow oil. LCMS (ESI-MS) m / z = 155.1 [M+H] + .

[0382] 1,4-Dioxaspiro[4.5]deca-7-ene-7-carboxylate methyl [ka] To a solution of methyl 5-oxocyclohexa-1-ene-1-carboxylate (2.3 g, 14.9 mmol) in methylene chloride (50 mL), ethylene glycol (1.39 g, 22.4 mmol), trimethyl orthoformate (2.37 g, 224 mmol), and methanesulfonic acid (220 mg, 2.24 mmol) were added. The resulting solution was stirred at room temperature for 16 hours. The residue was evaporated and purified by silica gel column (EA:PE=1:1) to obtain methyl 1,4-dioxaspiro[4.5]deca-7-ene-7-carboxylate (2.30 g) as a pale yellow oil. LCMS (ESI-MS) m / z = 199.0 [M+H] + .

[0383] (1,4-Dioxaspiro[4.5]deca-7-en-7-yl)methanol [ka] To a solution of methyl 1,4-dioxaspiro[4.5]deca-7-en-7-carboxylate (2.10 g, 10.6 mmol) in diethyl ether (20 mL), lithium aluminum hydride (302 mg, 7.95 mmol) was added. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with KOH (15%, 1 mL) and water (1 mL). The residue was extracted with Et2O (20.0 mL × 2). The organic phases were combined, evaporated, and purified by silica gel column (EA:PE = 1:1) to obtain (1,4-dioxaspiro[4.5]deca-7-en-7-yl)methanol (1.6 g) as a pale yellow oil.

[0384] rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanol [ka] To a solution of 1,4-dioxaspiro[4.5]deca-7-en-7-ylmethanol (1.60 g, 9.40 mmol) in methylene chloride (30 mL), diethylzinc (2.90 g, 23.5 mmol), diiodomethane (6.29 g, 23.5 mmol), and trifluoroacetic acid (2.68 g, 23.5 mmol) were added at 0°C. The resulting solution was stirred at room temperature for 16 hours. The residue was evaporated and purified by silica gel column (EA:PE=1:1) to obtain rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanol (1.00 g) as a pale yellow oil.

[0385] rac-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)isoindoline-1,3-dione [ka] In tetrahydrofuran (20 mL), a solution of rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanol (1.0 g, 5.43 mmol) was mixed with phthalimide (1.2 g, 8.16 mmol), diisopropyl azodicarboxylic acid (1.65 g, 8.14 mmol), and triphenylphosphine (2.14 g, 8.14 mmol). The resulting solution was stirred at 60°C for 5 hours. The solution was cooled to room temperature, the residue was concentrated, and purified by silica gel column (EA:PE=1:1) to obtain rac-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)isoindoline-1,3-dione (1.40 g, 60.8%) as a white solid. LCMS(ESI-MS)m / z=314.1[M+H] + .

[0386] rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethaneamine [ka] To a solution of rac-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)isoindole-1,3-dione (1.30 g, 4.15 mmol) in ethyl alcohol (20 mL), hydrazinium hydroxide (830 mg, 16.6 mmol) was added. The resulting solution was stirred under reflux for 5 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel column (DCM:MeOH=10:1) to obtain rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethaneamine (450 mg) as a pale yellow oil.

[0387] rac-4-nitro-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile [ka] To a solution of rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethaneamine (400 mg, 2.18 mmol) in acetonitrile (5 mL), 3-fluoro-4-nitrobenzonitrile (363 mg, 2.18 mmol) and potassium carbonate (649 mg, 6.55 mmol) were added. The resulting solution was stirred at 40°C for 4 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel column (EA:PE=1:1) to obtain rac-4-nitro-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile (650 mg) as a yellow solid. LCMS (ESI-MS) m / z = 330.1 [M+H] + .

[0388] rac-4-amino-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile [ka] To a solution of rac-4-nitro-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile (600 mg, 1.82 mmol) in ethyl alcohol (10 mL) and water (3 mL), iron (1.02 g, 18.2 mmol) and ammonium chloride (390 mg, 7.29 mmol) were added. The resulting solution was stirred at 80°C for 4 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel column (DCM:MeOH=10:1) to obtain rac-4-amino-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile (500 mg) as a yellow oil. LCMS (ESI-MS) m / z = 300.0 [M+H] + .

[0389] rac-1-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] In a solution of rac-4-amino-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile (450 mg, 1.5 mmol) in trimethyl orthoformate (5 mL), formic acid (69.2 mg, 1.5 mmol) was added. The resulting solution was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel column (EA:PE=1:1) to obtain rac-1-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg) as a yellow solid. LCMS (ESI-MS) m / z = 310.1 [M+H] + .

[0390] rac-1-((3-oxobicyclo[4.1.0]heptan-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] rac-1-(spiro[bicyclo[4.1.0]heptan-3,2'-[1,3]dioxolane]-1-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg, 1.13 mmol) and formic acid (5.0 mL, 0.04 mmol) were combined in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 and extracted with EA (20 mL x 2). The organic phases were combined, dried over anhydrous Na2SO4, and evaporated to obtain rac-1-((3-oxobicyclo[4.1.0]heptan-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg) as a pale yellow solid. LCMS (ESI-MS) m / z = 266.2 [M + H] + .

[0391] rac-1-(((1R,3S,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxiran]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxiran]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] To a solution of trimethylsulfoxonium iodide (3.77 mmol) in dimethyl sulfoxide (5 mL), iodotrimethyl-lambda-6-sulfanone (3.77 mmol) was added at 0°C. After stirring for 30 minutes, rac-1-((3-oxobicyclo[4.1.0]heptan-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.77 mmol) was added. The resulting solution was stirred at room temperature for 1 hour, and then quenched with water. The resulting mixture was extracted with RINKAN (3 × 5.0 mL). The combined organic layers were washed with brine (3 x 5.0 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a mixture of rac-1-(((1R,3S,6S)-spiro[bicyclo[4.1.0]heptan-3,2'-oxirane]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-spiro[bicyclo[4.1.0]heptan-3,2'-oxirane]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (210 mg) as a pale yellow solid. LCMS (ESI-MS) m / z = 280.1 [M + H] + .

[0392] rac-1-(((1R,3S,6S)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] To a solution of a mixture of rac-1-(((1R,3S,6S)-spiro[bicyclo[4.1.0]heptan-3,2'-oxiran]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride and rac-1-(((1R,3R,6S)-spiro[bicyclo[4.1.0]heptan-3,2'-oxiran]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride (200 mg, 0.716 mmol), urethane (319 mg, 3.58 mmol) and tert-butoxylithium (143 mg, 1.79 mmol) were added. The resulting solution was stirred at 100°C for 16 hours. The resulting mixture was cooled to room temperature, diluted with SiO(10 mL), washed with brine(3 × 10 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column (DCM:MeOH=10:1) to obtain a mixture of rac-1-(((1R,3S,6S)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a pale yellow solid. LCMS(ESI-MS) m / z=323.1[M+H] + .

[0393] rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] Dioxane (5.0 mL) contains rac-1-(((1R,3S,6S)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitride and rac-1-(((1R,3R,6S)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H- To a solution of benzo[d]imidazole-6-carbonitrile (200 mg, 0.62 mmol), 2-(5-bromopyrazine-2-yl)propan-2-ol (135 mg, 0.62 mmol), N1,N2-dimethylethane-1,2-diamine (109 mg, 1.24 mmol), tripotassium phosphate (263 mg, 1.24 mmol), and copper(I) iodide (118 mg, 0.62 mmol) were added. The resulting solution was stirred at 100°C for 16 hours. The residue was evaporated and purified using a silica gel column (DCM:MeOH=10:1) to obtain a mixture of rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg) as a pale yellow solid. LCMS(ESI-MS)m / z=459.2[M+H] + .

[0394] Achiral separation: A mixture of rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclic[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.22 mmol), conditions: Column: CHIRALPAK IF-3, 4.6*50mm, 3μm, Mobile phase A:MTBE (0.1% DEA):Ethanol = 70:30, Flow rate: 1 mL / min, Gradient: 0% B~0% B; Injection volume: 5 μl to obtain the first isomer:rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 mg) as a white solid, and the second The isomer that elutes: rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (15 mg) was separated by preparative achiral HPLC to obtain it as a white solid.

[0395] 1-(((1R,3S,6S)-3'-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((1S,3R,6R)-3'-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10.0 mg, 0.0220 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IF-3 4.6 × 50 mm, 3 μm, mobile phase A: MTBE (0.1% DEA):ethanol = 70:30, flow rate: 1 mL / min, injection volume: 5 μl. The desired fractions were combined and lyophilized to obtain two products.

[0396] The first isomer to elute is 1-(((1S,3R,6R)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicycle[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4.10 mg) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 8.95(s, 1H), 8.61(s, 1H), 8.48(s, 1H), 8.35(s, 1H), 7.65(d, J=8.4Hz, 1H), 7.32(d , J=10.0Hz, 1H), 5.44(s, 1H), 4.37-4.33(m, 1H), 4.09-4.05(m, 1H), 3.66-3.64(m, 1H), 2.93-2.91(m, 1H), 2.18-2.14(m, 1H), 2.01-1.87(m, 3H), 1.65-1.56(m, 2H), 1 .52(s, 3H), 1.45(s, 3H), 1.43-1.37(m, 1H), 0.97-0.94(m, 1H), 0.68-0.66(m, 1H). LCMS(ESI-MS)m / z=459.2[M+H] + .

[0397] The second isomer that elutes is 1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptan-3,5'-oxazolidine]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.60 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.95(s, 1H), 8.61(s, 1H), 8.48(s, 1H), 8.35(s, 1H), 7.65(d, J=8.4Hz, 1H), 7.32(d , J=10.0Hz, 1H), 5.44(s, 1H), 4.37-4.33(m, 1H), 4.09-4.05(m, 1H), 3.66-3.64(m, 1H), 2.93-2.91(m, 1H), 2.18-2.14(m, 1H), 1.91-1.87(m, 3H), 1.61-1.58(m, 2H), 1 .52(s, 3H), 1.45(s, 3H), 1.43-1.39(m, 1H), 0.97-0.95(m, 1H), 0.71-0.65(m, 1H). LCMS(ESI-MS)m / z=459.3[M+H] + .

[0398] Example 9. Preparation of 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0399] Detailed instructions 1,4-Dioxaspiro[4.5]decane-7-one [ka] p-toluenesulfonic acid (13.8 g, 80.3 mmol) was added to a mixture of cyclohexane-1,3-dione (30 g, 268 mmol), molecular sieve (4 Å) (30 g), and magnesium sulfate (30 g) in ethylene glycol (300 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (300 mL), and the resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product 1,4-dioxaspiro[4.5]decan-7-one (crude, 28 g) as a pale yellow oil. LCMS (ESI-MS) m / z = 157.1 [M + H] + .

[0400] rac-1,6,9-trioxadispiro[2.1.4 5 .3 3 ] Dodecane [ka] Potassium tert-butoxide (22.1 g, 197 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-7-one (28 g, 179 mmol) and trimethylsulfoxonium iodide (39.5 g, 179 mmol) in dimethyl sulfoxide (280 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL), and the resulting solution was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1,6,9-trioxaspiro[2.1.4 5 .3 3 Dodecane (crude, 28g) was obtained as a pale yellow oil. LCMS (ESI-MS) m / z = 171.1 [M+H] + .

[0401] rac-7-(aminomethyl)-1,4-dioxaspiro[4.5]decane-7-ol [ka] In methanol, ammonia (7N, 280 mL, 1.96 mol) contains rac-1,6,9-trioxadispiro[2.1.4 5 .3 3 A solution of dodecane (28 g, 165 mmol) was prepared. The resulting mixture was heated to 80°C and stirred overnight. The reaction mixture was concentrated under vacuum to obtain the crude product rac-7-(aminomethyl)-1,4-dioxaspiro[4.5]decane-7-ol (crude, 28 g) as a pale yellow oil. LCMS (ESI-MS) m / z = 188.1 [M + H] + .

[0402] rac-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] Potassium carbonate (41.3 g, 299 mmol) was added to a solution of rac-7-(aminomethyl)-1,4-dioxaspiro[4.5]decane-7-ol (28 g, 150 mmol) and 3-fluoro-4-nitrobenzonitrile (24.8 g, 150 mmol) in acetonitrile (200 mL). The resulting mixture was heated to 40°C and stirred overnight. After cooling to room temperature, the resulting mixture was purified by silica gel column chromatography and eluted with ethyl acetate in 0%-15% petroleum ether to obtain the desired product, rac-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (12 g), as an orange solid. LCMS (ESI-MS) m / z = 334.1 [M + H] + .

[0403] rac-4-amino-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] Iron powder (20.1 g, 360 mmol) was added to a solution of rac-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (12 g, 36.0 mmol), ammonium chloride (7.7 g, 144 mmol), ethanol (120 mL), and water (40 mL). The resulting mixture was heated to 80°C and stirred for 2 hours. After cooling to room temperature, the resulting mixture was filtered, and the filtrate was washed with ethanol (2 × 200 mL). The filtrate was concentrated under reduced pressure to obtain the crude product rac-4-amino-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (crude, 12 g) as a yellow solid. LCMS (ESI-MS) m / z = 304.2 [M + H] + .

[0404] rac-1-((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Formic acid (1.82 g, 39.6 mmol) was added to a solution of rac-4-amino-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (12 g, 39.6 mmol) in trimethoxymethane (83.9 g, 791 mmol). The resulting mixture was heated to 80°C and stirred for 3 hours. The mixture was cooled to room temperature and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 70% petroleum ether to obtain the desired product, rac-1-((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (9 g), as a white solid. LCMS (ESI-MS) m / z = 314.1 [M + H] + .

[0405] rac-1-((1-hydroxy-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A solution of rac-1-((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (5 g, 17.7 mmol) in acetone (30 mL) and water (10 mL) was treated with 1 M water-soluble hydrochloric acid (8.66 mL, 8.66 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 80% petroleum ether to obtain the desired product rac-1-((1-hydroxy-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g) as a yellow solid. LCMS(ESI-MS)m / z=270.1[M+H] + .

[0406] rac-1-(((3S,5R)-5-hydroxy-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Potassium tert-butoxide (1.37 g, 12.3 mmol) was added to a solution of rac-1-((1-hydroxy-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g, 11.1 mmol) and trimethylsulfoxonium iodide (2.69 g, 12.3 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL), and the resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product rac-1-(((3S,5R)-5-hydroxy-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2 g) as a pale yellow oil. LCMS(ESI-MS)m / z=284.1[M+H] + .

[0407] rac-1-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Lithium tert-butoxide (1.13 g, 14.1 mmol) was added to a solution of ethyl carbamate (12.6 g, 141 mmol) in N-methylpyrrolidone (10 mL). After stirring at room temperature for 5 minutes, a solution of rac-1-(((3S,5R)-5-hydroxy-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2 g, 7.06 mmol) was added dropwise to N-methylpyrrolidone (5 mL). Subsequently, the reaction mixture was heated to 100 °C and stirred overnight. After cooling to room temperature, the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN (10 mmol / LNH4HCO3) in water, 0% to 30% gradient over 10 minutes, detector, UV 254 nm, to obtain the desired product rac-1-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.21(d, J=1.6Hz,1H),8.60(d,J=1.6Hz,1H),8.35(d,J=1.6Hz,1H),8.29(s,1H),6.45(s,1H),4.50(s,1H),3.8 0(dd, J=8.3, 8.3Hz, 2H), 3.10(dd, J=8.1, 8.1Hz, 2H), 2.10-2.00(m,2H),1.60-1.48(m,2H),1.45-1.43(m,4H). LCMS(ESI-MS)m / z=327.1[M+H] + .

[0408] rac-1-(((5S,7R)-7-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Copper(I) iodide (582 mg, 3.06 mmol) in 1,4-dioxane (10 mL), rac-1-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 3.06 mmol), 2-chloro-5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine (896 mg, 3.06 mmol), N 1 ,N 2 -dimethylethane-1,2-diamine (540 mg, 6.12 mmol) and tripotassium phosphate (1.3 g, 6.12 mmol) were added under a nitrogen atmosphere. The resulting mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the resulting mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 3% dichloromethane to obtain the desired product rac-1-(((5S,7R)-7-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ 9.21(d, J=1.6Hz,1H),8.60(d,J=1.6Hz,1H),8.35(d,J=1.6Hz,1H),8.29(s,1H),7.84(d,J=8.3Hz,1H),7.59(dd,J =8.3, 1.5Hz, 1H), 6.89(d, J=7.2Hz, 2H), 6.79(d, J=8.3, 1.5Hz, 1H)7.2Hz, 2H), 4.81(s, 2H), 4.50(s, 1H), 4.44(d, J= 15.1Hz, 1H), 4.36(d, J=15.0Hz, 1H), 3.92(d, J=10.2Hz, 1H), 3.84(d, J=10.2Hz, 1H), 3.79(s, 3H), 2.27(d, J=15.1H) z, 1H), 2.00 (d, J = 13.4Hz, 1H), 1.80 (d, J = 15.1Hz, 1H), 1.69 (t, J = 12.9Hz, 1H), 1.61-1.47 (m, 1H) 1.47-1.43 (m, 9H). LCMS(ESI-MS)m / z=583.3[M+H] + .

[0409] rac-1-(((5S,7R)-7-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Iodomethane (170.33 mg, 1.20 mmol) was added to N,N-dimethylformamide (5 mL) at 0°C to a mixture of rac-1-(((5S,7R)-7-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg, 1.20 mmol) and sodium hydride (60% in mineral oil, 48 mg, 1.20 mmol). The mixture was stirred at 0°C for 1 hour. The mixture was slowly quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 2% dichloromethane to obtain the desired product rac-1-(((5S,7R)-7-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.21(d,J=1.6Hz,1H),8.60(d,J=1.6Hz,1H),8.35(d,J=1.6Hz,1H),8.29(s,1H),7.84(d,J=8.3Hz,1H),7.59(d d, J=8.3, 1.5Hz, 1H), 6.89(d, J=7.2Hz, 2H), 6.79(d, J=7.2Hz, 2H), 4.70(s, 2H), 4.44(d, J=15.1Hz, 1H), 4.36(d , J=15.0Hz, 1H), 3.92(d, J=10.2Hz, 1H), 3.84(d, J=10.2Hz, 1H), 3.79(s, 3H), 3.39(s, 3H), 2.27(d, J=15.1Hz, 1 H), 2.00 (d, J=13.4Hz, 1H), 1.80 (d, J=15.1Hz, 1H), 1.69 (t, J=12.9Hz, 1H), 1.61-1.47 (m, 1H) 1.47-1.43 (m, 9H). LCMS(ESI-MS)m / z=597.3[M+H]+ .

[0410] rac-1-(((5S,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Trifluoroacetic acid (229 mg, 2.01 mmol) was added to a solution of rac-1-(((5S,7R)-7-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 0.67 mmol) in dichloromethane (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, purified by silica gel column chromatography, and eluted with methanol in 0% to 3% dichloromethane to obtain the desired product rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a yellow oil. 1H NMR (300MHz, DMSO-d6)δ 9.21(d, J=1.6Hz, 1H), 8.60(d, J=1.6Hz, 1H), 8.35(d, J=1.6Hz, 1H), 8.29(s, 1H), 7.84(d, J=8.3H) z, 1H), 7.59(dd, J=8.3, 1.5Hz, 1H), 5.40(s, 1H), 4.44(d, J=15.1Hz, 1H), 4.36(d, J=15.0Hz, 1H), 3.92(d, J=10.2Hz, 1H), 3.84(d, J=10.2Hz, 1H), 3.39(s, 3H), 2.27(d, J=15.1Hz, 1H), 2.00(d, J=1 3.4Hz, 1H), 1.80(d, J=15.1Hz, 1H), 1.69(t, J=12.9Hz, 1H), 1.61-1.47(m, 1H)1.47-1.43(m, 9H). LCMS(ESI-MS)m / z=477.2[M+H] + .

[0411] 1-(((5S,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7S)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A mixture of rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.42 mmol) was prepared under the following conditions: Chiralak IE, 2x25 cm, 5 μm, mobile phase A: MTBE (0.5% 2M) Separation was performed by preparative chiral HPLC using NH3-MeOH-HPLC, mobile phase B:EtOH-HPLC, flow rate: 17 mL / min, gradient: 10%B to 10%B over 24 mins, wavelength: 220 / 254 nm, RT1 (min): 14.661, RT2 (min): 20.017, sample solvent:EtOH-HPLC, injection volume: 0.5 mL. The desired fractions were combined and lyophilized to obtain the product.

[0412] The first isomer to elute: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (44.6 mg, purity 99.7%, 100%ee) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 9.21(d, J=1.6Hz,1H),8.60(d,J=1.6Hz,1H),8.35(d,J=1.6Hz,1H),8.29(s,1H),7.84(d,J=8.3H) z, 1H), 7.59(dd, J=8.3, 1.5Hz, 1H), 5.40(s, 1H), 4.44(d, J=15.1Hz, 1H), 4.36(d, J=15.0Hz, 1H), 3.92(d, J=10.2Hz, 1H), 3.84(d, J=10.2Hz, 1H), 3.39(s, 3H), 2.27(d, J=15.1Hz, 1H), 2.00(d, J=1 3.4Hz, 1H), 1.80 (d, J = 15.1Hz, 1H), 1.69 (t, J = 12.9Hz, 1H), 1.61-1.47 (m, 1H) 1.47-1.43 (m, 9H). LCMS(ESI-MS)m / z=477.2[M+H] + .

[0413] Secondly, the isomer that elutes is 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (41.0 mg, purity 98.6%, 100%ee) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 9.21(d, J=1.6Hz,1H),8.60(d,J=1.6Hz,1H),8.35(d,J=1.6Hz,1H),8.29(s,1H),7.84(d,J=8.3H) z, 1H), 7.59(dd, J=8.3, 1.5Hz, 1H), 5.40(s, 1H), 4.44(d, J=15.1Hz, 1H), 4.36(d, J=15.0Hz, 1H), 3.92(d, J=10.2Hz, 1H), 3.84(d, J=10.2Hz, 1H), 3.39(s, 3H), 2.27(d, J=15.1Hz, 1H), 2.00(d, J=1 3.4Hz, 1H), 1.80 (d, J = 15.1Hz, 1H), 1.69 (t, J = 12.9Hz, 1H), 1.61-1.47 (m, 1H) 1.47-1.43 (m, 9H). LCMS(ESI-MS)m / z=477.2[M+H] + .

[0414] Example 10. Preparation of 1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0415] Detailed instructions rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Copper(I) iodide (448 mg, 2.35 mmol) in 1,4-dioxane, rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (800 mg, 2.35 mmol), 2-chloro-5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine (686 mg, 2.35 mmol), N 1 ,N 2 -dimethylethane-1,2-diamine (414 mg, 4.70 mmol) and tripotassium phosphate (996 mg, 4.70 mmol) (10 mL) were added under a nitrogen atmosphere. The resulting mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the resulting mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 3% dichloromethane to obtain the desired product rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g) as a pale yellow solid. LCMS(ESI-MS)m / z=597.3[M+H] + .

[0416] rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((5R,7S,8R)-8-hydroxy-3-(6-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyridine-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A mixture of rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 1.68 mmol) was prepared under the following conditions: Column: CHIRALPAK IE, 2x25cm, 5 μm, Mobile phase A: Hex:DCM=3:1 (0.5% 2M) Separation was performed by preparative chiral HPLC using NH3-MeOH (IPA)-HPLC, mobile phase B: IPA-HPLC, flow rate: 20 mL / min, gradient: 20%B to 20%B in 21 mins, wavelength: 220 / 254 nm, RT1 (min): 10.051, RT2 (min): 16.651, sample solvent: EtOH-HPLC, injection volume: 1 mL. The desired fractions were combined and lyophilized to obtain the product.

[0417] The first isomer to elute is rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 9.25(d, J=1.5Hz,1H),8.56(d,J=1.5Hz,1H),8.35(d,J=15.2Hz,1H),8.23(d,J= 1.6Hz,1H),7.84(d,J=8.4Hz,1H),7.59(dd,J=8.3,1.5Hz,1H),7.29-7.20(m,2H) ,6.94-6.84(m, 2H), 4.35-4.24(m, 1H), 4.27-4.17(m, 2H), 3.88-3.70(m, 2H), 3. 74(s, 3H), 3.36-3.30(m, 3H), 2.08-1.91(m, 4H), 1.65-1.50(m, 8H), 1.11(s, 3H). LCMS(ESI-MS)m / z=597.3[M+H] + .

[0418] Secondly, the isomer that elutes is rac-1-(((5R,7S,8R)-8-hydroxy-3-(6-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyridine-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, yield 40.0%) as a pale yellow solid. 1 1H NMR (400MHz, DMSO-d6)δ 9.30(d, J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.42(s,1H),8.25(s,1H), 7.83(d, J=8.1Hz, 1H), 7.64-7.55(m, 1H), 7.28-7.20(m, 2H), 6.93-6.86 (m, 2H), 4.41-4.32(m, 1H), 4.25(s, 2H), 3.91-3.81(m, 2H), 3.79(s, 3H) , 3.37-3.34(m, 3H), 2.00-1.83(m, 4H), 1.75-1.59(m, 8H), 0.91(s, 3H). LCMS(ESI-MS)m / z=597.3[M+H] + .

[0419] rac-1-(((5S,7S,8R)-8-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Iodomethane (35.5 mg, 0.25 mmol) was added at 0°C to a solution of rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (150 mg, 0.25 mmol) and sodium hydride (60% in mineral oil, 10 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was heated to room temperature and stirred for 2 hours. The mixture was quenched with 5 mL of water, and the resulting solution was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0%-2% dichloromethane to obtain the desired product rac-1-(((5S,7S,8R)-8-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (80 mg) as a white solid. 11H NMR (400MHz, DMSO-d6)δ 9.25(d, J=1.5Hz,1H),8.56(d,J=1.5Hz,1H),8.35(d,J=15.2Hz,1H),8.23(d,J =1.6Hz,1H),7.84(d, J=8.4Hz,1H),7.59(dd, J=8.3,1.5Hz,1H),7.29-7.20(m, 2H),6.94-6.84(m,2H),4.30-4.17(m,4H),3.88-3.70(m,2H),3.74(s,3H),3.3 9(s, 3H), 3.10-3.03(m, 1H), 2.08-1.91(m, 4H), 1.65-1.50(m, 8H), 1.11(s, 3H). LCMS(ESI-MS)m / z=611.3[M+H] + .

[0420] rac-1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Trifluoroacetic acid (44 mg, 0.39 mmol) was added to a solution of rac-1-(((5S,7S,8R)-8-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (80 mg, 0.13 mmol) in dichloromethane (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain the crude product rac-1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (crude, 70 mg) as a yellow oil. LCMS (ESI-MS) m / z = 491.2 [M + H] + .

[0421] 1-(((5S,7S,8R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7R,8S)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A mixture of rac-1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6 carbonitrile (70 mg, 0.14 mmol) was prepared under the following conditions: Column: CHIRAL ART Cellulose-SC, 2x25cm, 5μm, Mobile phase A: Hex:DCM=3:1 (0.5% 2M) Separation was performed by preparative chiral HPLC using NH3-MeOH (EtOH)-HPLC, mobile phase B:EtOH-HPLC, flow rate: 20 mL / min, gradient: 30%B to 30%B in 14 mins, wavelength: 220 / 254 nm, RT1 (min): 9.92, RT2 (min): 12.16, sample solvent:EtOH-HPLC; injection volume: 0.8 mL. The desired fractions were combined and lyophilized to obtain the product.

[0422] The first isomer to elute: 1-(((5R,7R,8S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (14.0 mg, purity 99.7%, 100%ee) as a white solid. 1H NMR(300MHz,DMSO-d6)δ 9.18(d, J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.37(s,1H),8.25-8.20(m,1H),7.84(d,J=8.3 Hz, 1H), 7.60(dd, J=8.3, 1.5Hz, 1H), 5.42(s, 1H), 4.31(d, J=14.5Hz, 1H), 4.21(d, J=14.5Hz, 1H),3.81(q,J=10.3Hz,2H),3.31(s,3H),3.07-3.00(m,1H),2.04(d,J=9.7Hz,2H),1.95(d,J =15.0Hz, 1H), 1.72(d, J=14.6Hz, 1H), 1.65-1.48(m, 2H), 1.44(d, J=2.3Hz, 6H), 1.11(s, 3H). LCMS(ESI-MS)m / z=491.2[M+H] + .

[0423] Secondly, the isomer that elutes is 1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (14.8 mg, purity 99.6%, 99.5% ee) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 9.18(d, J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.37(s,1H),8.25-8.20(m,1H),7.84(d,J=8.3 Hz, 1H), 7.60(dd, J=8.3, 1.5Hz, 1H), 5.42(s, 1H), 4.31(d, J=14.5Hz, 1H), 4.21(d, J=14.5Hz, 1H), 3.81(q, J=10.3Hz,2H),3.31(s,3H),3.07-3.00(m,1H),2.04(d,J=9.7Hz,2H),1.95(d,J =15.0Hz, 1H), 1.72(d, J=14.6Hz, 1H), 1.65-1.48(m, 2H), 1.44(d, J=2.3Hz, 6H), 1.11(s, 3H). LCMS(ESI-MS)m / z=491.2[M+H] + .

[0424] Example 11. Preparation of 1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0425] Detailed instructions rac-1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 2.89 mmol) and 1-iodo-2,2-dimethylpropane (859 mg, 4.34 mmol) was added to N,N-dimethylformamide (10 mL), to which sodium hydroxide (347 mg, 8.67 mmol) was added. The reaction mixture was stirred at 100 °C for 3 hours and cooled to room temperature. The mixture was quenched with aqueous ammonium chloride (50 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 60% petroleum ether to obtain the product rac-1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a white solid. LCMS (ESI-MS) m / z = 417.2 [M + H] + .

[0426] 1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7R)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of rac-1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.48 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IH, 2x25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH) --HPLC; mobile phase B: IPA --HPLC; flow rate: 20 mL / min; gradient: 40%B~40%B at 12 min; wavelength: 220 / 254 nm; RT1 (min): 7.342; RT2 (min): 9.486; sample solvent: EtOH --HPLC; injection volume: 0.3 mL. The desired fractions were combined and freeze-dried to obtain two products.

[0427] The first isomer to elute: 1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (76.5 mg, purity 99.8%, 100%ee) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.4, 1.5 Hz, 1H), 4.65 (dd, J = 14.6, 6.1 Hz, 1H), 4.41 (dd, J = 14.6, 7.7 Hz, 1H), 3.46 - 3.37 (m, 2H), 2.90 - 2.71 (m, 3H), 2.15 - 1.93 (m, 3H), 1.88 - 1.63 (m, 3H), 0.82 (s, 9H). LCMS (ESI-MS) m / z = 417.2 [M + H] + 。

[0428] Second eluted isomer: 1-(((5R,7R)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (19.9 mg, purity 99.0%, 98.4% ee). 1 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.4, 1.5 Hz, 1H), 4.65 (dd, J = 14.7, 6.0 Hz, 1H), 4.41 (dd, J = 14.6, 7.7 Hz,​​​​​​​​​​​​​​​​​1-((3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] To 10 mL of 1,4-dioxane, a diastereomer mixture of 1-((8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.45 mmol) and 1-chloro-2-iodobenzene (519 mg, 2.18 mmol) was mixed with N1,N2-dimethylethane-1,2-diamine (255 mg, 2.9 mmol), tribasic potassium phosphate (615 mg, 2.9 mmol), and copper(I) iodide (139 mg, 0.73 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 5 hours and then cooled to room temperature. The mixture was quenched with hydrated ammonium chloride (50 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and then eluted with ethyl acetate in 0% to 55% petroleum ether to obtain the product 1-((3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg) as a white solid. LCMS (ESI-MS) m / z = 457.1 [M + H] + .

[0431] rac-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((5R,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A diastereomer mixture of 1-((3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 0.88 mmol) was separated by preparative achiral SFC under the following conditions: column: YMC-Actus Triart Diol-HILIC, 3x25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 75 mL / min; gradient: isocratic 24% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 4.26; sample solvent: MeOH--HPLC, injection volume: 3 mL. The desired fractions were combined and lyophilized to obtain two products.

[0432] The first isomer to elute is rac-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (240 mg) as a white solid.

[0433] Secondly, the isomer that elutes is rac-1-(((5R,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (20 mg) as a white solid.

[0434] 1-(((5R,7R)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of rac-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (240 mg, 0.88 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IF, 2x25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH)--HPLC; mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 20%B~20%B at 23 mins; wavelength: 220 / 254 nm; RT1 (min): 11.816; RT2 (min): 16.483; sample solvent: EtOH--HPLC; injection volume: 2 mL. The desired fractions were combined and freeze-dried to obtain two products.

[0435] The first isomer to elute was 1-(((5R,7R)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10.6 mg, 99.5% purity, 100% ee), which was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.59(s,1H),8.35(s,1H),7.85(d,J=8.4Hz,1H),7.63(dd,J=8.4,1.5Hz,1H),7.60-7.51(m,2H),7.45-7.36(m,2H),4.70(dd,J=14.6,5 .9Hz, 1H), 4.45(dd, J=14.6, 8.0Hz, 1H), 3.77-3.66(m,2H),3.02-2.82(m,1H),2.26-2.12(m,3H),2.09-1.93(m,2H),1.91-1.78(m,1H). LCMS(ESI-MS)m / z=457.1[M+H] + .

[0436] Secondly, the isomer that elutes is 1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (31.6 mg, purity 99.2%, 100%ee) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.59(s, 1H), 8.35(d, J=1.5Hz, 1H), 7.85(d, J=8.3Hz, 1H), 7.63(dd, J=8.3, 1.5Hz, 1H), 7.59-7.50(m, 2H), 7.45-7.34(m, 2H), 4.70(dd, J=14 .6, 5.9Hz, 1H), 4.45(dd, J=14.6, 8.0Hz, 1H), 3.77-3.66(m, 2H), 3.00-2.84(m, 1H), 2.27-2.12(m, 3H), 2.03-1.89(m, 2H), 1.89-1.78(m, 1H). LCMS(ESI-MS)m / z=457.1[M+H] + .

[0437] Example 13. Preparation of 1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0438] Detailed instructions 1-((3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] To 10 mL of 1,4-dioxane, a diastereomer mixture of 1-((8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (250 mg, 0.72 mmol) and 1-bromo-2-ethoxybenzene (217 mg, 1.08 mmol) was mixed with N1,N2-dimethylethane-1,2-diamine (127 mg, 1.44 mmol), tribasic potassium phosphate (305 mg, 1.44 mmol), and copper(I) iodide (69 mg, 0.36 mmol). The resulting mixture was stirred at 100°C for 6 hours under a nitrogen atmosphere, cooled to room temperature, quenched with hydrated ammonium chloride (50 mL), extracted with ethyl acetate (3 × 30 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 58% petroleum ether to obtain 1-((3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (220 mg) as a white solid. LCMS (ESI-MS) m / z = 467.2 [M + H] + .

[0439] rac-1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((5R,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A diastereomer mixture of 1-((3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (220 mg, 0.47 mmol) was separated by preparative achiral SFC under the following conditions: column: GreenSep Naphthyl, 3x25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 75 mL / min; gradient: isocratic 25% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 5.99, RT2 (min): 6.51; sample solvent: MeOH--HPLC; injection volume: 1 mL. The desired fractions were combined and freeze-dried to obtain two products.

[0440] The first isomer to elute is rac-1-(((5R,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (30 mg) as a white solid.

[0441] Secondly, the isomer that elutes is rac-1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (140 mg) as a white solid.

[0442] 1-(((5R,7R)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A mixture of rac-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (140 mg, 0.3 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK ID, 2 x 25 cm, 5 μm; mobile phase A: MTBE (2 mM NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 8% B to 8% B in 31 min; wavelength: 220 / 254 nm; RT1 (min): 20.16, RT2 (min): 26.092; sample solvent: EtOH--HPLC; injection volume 0.4 mL. The desired fractions were combined and lyophilized to give two products.

[0443] The first eluting isomer: 1-(((5R,7R)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (18.0 mg, 98.9% purity, 100% ee). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.34 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.4, 1.5 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 4.69 (dd, J = 14.7, 5.9 Hz, 1H), 4.44 (dd, J = 14.6, 8.0 Hz, 1H), 4.04 - 3.93 (m, 2H), 3.64 (s, 2H), 3.01 - 2.84 (m, 1H), 2.23 - 2.08 (m, 3H), 1.96 -​​​​​Secondly, the isomer that elutes is 1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (40.4 mg, purity 99.8%, 100%ee) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.59(s, 1H), 8.34(s, 1H), 7.85(d, J=8.4Hz, 1H), 7.62(dd, J=8.4, 1.5Hz, 1H), 7 .31-7.24(m, 2H), 7.10-7.04(m, 1H), 6.94(td, J=7.7, 1.3Hz, 1H), 4.69(dd, J=1 4.6, 5.9Hz, 1H), 4.44(dd, J=14.6, 8.1Hz, 1H), 4.01-3.92(m, 2H), 3.64(s, 2H), 3.00-2.82(m, 1H), 2.23-2.12(m, 3H), 1.96-1.82(m, 3H), 1.17(t, J=6.9Hz, 3H). LCMS(ESI-MS)m / z=467.2[M+H] + .

[0445] Example 14. Preparation of 1-(((5S,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0446] Detailed instructions 2-Bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide [ka] To a mixture of calcium carbonate (7.15 g, 93.8 mmol) in chloroform (30 mL), 1-amino-3,3-dimethylbutane-2-onehydrochloride (1.8 g, 15.6 mmol) was added in water (10 mL) at 5°C under a nitrogen atmosphere. Subsequently, 2-bromoacetyl bromide (5.90 g, 39.1 mmol) was added at 5°C. The resulting mixture was heated to room temperature and stirred for 6 hours. The reaction product was diluted with aqueous sodium bicarbonate (30 mL) and filtered. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product 2-bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide (2.4 g) as a yellow oil. LCMS (ESI-MS) m / z = 236.0 [M + H] + .

[0447] 5-(tert-butyl)pyrazine-2-ol [ka] Sodium iodide (0.26 g, 1.75 mmol) was added to a mixture of 2-bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide (2.3 g, 9.74 mmol) in ammonia (20 ml, 7 N in MeOH). The resulting mixture was stirred at room temperature for 3 days. The mixture was quenched with aqueous ammonium chloride (50 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product 5-(tert-butyl)pyrazine-2-ol (740 mg) as a yellow oil. LCMS (ESI-MS) m / z = 153.1 [M + H] + .

[0448] 5-(tert-butyl)pyrazine-2-yltrifluoromethanesulfonate [ka] To a mixture of 5-tert-butylpyrazine-2-ol (730 mg, 4.80 mmol) in dichloromethane (10 mL), triethylamine (1.46 g, 14.4 mmol) and trifluoromethanesulfonic anhydride (2.03 g, 7.19 mmol) were added under a nitrogen atmosphere at 0°C. The mixture was warmed to room temperature and stirred for 6 hours. The mixture was quenched with water (50 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 30% petroleum ether to obtain the product 5-(tert-butyl)pyrazine-2-yltrifluoromethanesulfonate (500 mg) as a yellow oil. LCMS (ESI-MS) m / z = 285.0 [M + H] + .

[0449] 1-((3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] To 1,4-dioxane (10 mL), a diastereomer mixture of 1-((8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrilate (600 mg, 1.73 mmol) and 5-(tert-butyl)pyrazine-2-yltrifluoromethanesulfonate (738 mg, 2.60 mmol) was added, along with BrettPhos (93 mg, 0.173 mmol), BrettPhos Pd G3 (157 mg, 0.173 mmol), and cesium carbonate (1.69 g, 5.19 mmol). The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere and then cooled to room temperature. The reaction mixture was quenched with hydrated ammonium chloride (50 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 70% petroleum ether to obtain the product 1-((3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (420 mg) as a pale yellow solid. LCMS (ESI-MS) m / z = 481.2 [M + H] + .

[0450] rac-1-(((5R,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and rac-1-(((5S,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A diastereomer mixture of 1-((3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (420 mg, 0.87 mmol) was separated by preparative achiral SFC under the following conditions: column: DAIEL DCpak P4VP, 3x25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 60 mL / min; gradient: isocratic 17% B; column temperature (25°C): 35; back pressure (bar): 100; wavelength: 254 nm; RT1 (min): 7.62, RT2 (min): 9; sample solvent: MeOH--HPLC, injection volume: 2.5 mL. The desired fractions were combined and freeze-dried to obtain two products.

[0451] The first isomer to elute was rac-1-(((5R,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg), which was obtained as a white solid.

[0452] The second isomer that eluted was rac-1-(((5S,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (50 mg), which was obtained as a white solid.

[0453] 1-(((5S,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7R)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] A mixture of rac-1-(((5S,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.62 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2x25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH)--HPLC; mobile phase B: EtOH--HPLC; flow rate: 16 mL / min; gradient: 50%B~50%B at 12 min; wavelength: 220 / 254 nm; RT1 (min): 7.528; RT2 (min): 9.869; sample solvent: EtOH; injection volume: 0.4 mL. The desired fractions were combined and freeze-dried to obtain two products.

[0454] The first isomer to elute: 1-(((5S,7S)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (143.5 mg, purity 98.6%, 100%ee) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.20(d, J=1.6Hz,1H),8.56(s,1H),8.45(d,J=1.5Hz,1H),8.30(d,J=1.4Hz,1H),7.83(d,J=8.3Hz,1H) , 7.61(dd, J=8.4, 1.5Hz, 1H), 4.72-4.64(m, 1H), 4.40(dd, J=14.7, 7.7Hz, 1H), 3.91(q, J=10.4Hz, 2H), 3.00-2.80(m, 1H), 2.26-2.02(m, 4H), 2.01-1.89(m, 2H), 1.32(s, 9H). LCMS(ESI-MS)m / z=481.2[M+H] + .

[0455] Secondly, the isomer that elutes is 1-(((5R,7R)-3-(5-(tert-butyl)pyrazine-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (51.7 mg, purity 99.8%, 100% ee) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.20(d, J=1.6Hz,1H),8.56(s,1H),8.45(d,J=1.6Hz,1H),8.35-8.28(m,1H),7.83(d,J=8.4Hz,1H),7.61(dd,J=8.4,1.5Hz,1H),4.67(dd,J= 14.7, 5.9Hz, 1H), 4.40(dd, J=14.7, 7.7Hz, 1H), 3.91(q, J=10.4Hz, 2H), 3.02-2.82(m, 1H), 2.24-2.04(m, 4H), 1.99-1.83(m, 2H), 1.32(s, 9H). LCMS(ESI-MS)m / z=481.2[M+H] + .

[0456] Example 15. Preparation of 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0457] Detailed instructions 4,4-difluoro-3-methylcyclohexa-2,5-dien-1-one [ka] To a solution of 4-fluoro-3-methylphenol (25.2 g, 1 equivalent, 200 mmol) in DCM (1.5 L) at room temperature, pyridine hydrofluoride (20 mL, 70% by weight, 0.78 equivalents, 156 mmol) was added dropwise over more than 10 minutes. Then, phenyl-13-iodanediyl diacetate (77.3 g, 1.2 equivalents, 240 mmol) was added all at once, and the reaction was stirred at room temperature for 15 minutes. Potassium carbonate (138 g, 5 equivalents, 1.00 mol) was added, and the resulting mixture was stirred under the same conditions for 10 minutes. The mixture was filtered, the filtrate was washed with 1 M HCl (3x) and brine (1x), dried over Na2SO4, filtered, and concentrated under reduced pressure (45°C, not below 850 mbar due to the volatility of the product) to approximately 200 mL. The crude solution was used in the next step without further purification. 1 The results were obtained by 1H NMR (400MHz, CDCl3) δ 6.80 (dt, J=10.2, 5.5Hz, 1H), 6.32-6.26 (m, 1H), 6.15-6.09 (m, J=1.5Hz, 1H), and 2.09 (dt, J=1.9, 1.0Hz, 3H). 19 FNMR (376MHz, CDCl3)δ-102.58.

[0458] 4,4-Difluoro-3-methylcyclohexa-2-en-1-one [ka] Crude 4,4-difluoro-3-methylcyclohexa-2,5-dien-1-one (28.8 g, 1 equivalent, 200 mmol) was mechanically stirred in tert-butyl methyl ether (1.33 L) with 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-diethyl ester (HEH; 111 g, 2.2 equivalents, 440 mmol) in the presence of silicon dioxide (400 g, 33.3 equivalents, 6.66 mol) overnight at 60°C until refluxed. Then, no complete conversion occurred (crude aliquots were prepared). 19(By FNMR) 0.2 equivalents of HEH were added, and the mixture was stirred at 60°C for a further 5 hours. The mixture was cooled to room temperature, filtered to remove silica, and the volume of the filtrate was reduced to 400 mL using a Rota Vaporizer. 1.6 L of pentane was added, the mixture was filtered through a silica pad and concentrated to 200 mL (Fraction A), the pad was washed with 1 L of pentane:MTBE 4:1, and concentrated to 250 mL (Fraction B) (Note: Most of the unreacted HEH can be removed through this filtration). NMR showed that the HEH impurity was still present in both fractions after being stored overnight in the freezer. Both fractions had filtered precipitated HEH. Each fraction was washed with 5% CuSO4 aqueous solution (x2) (Note: This was done to remove any residual HEH) and 3 M HCl (x3) (Note: This is necessary to remove Hantsch's pyridine). Subsequently, qNMR showed that 4,4-difluoro-3-methylcyclohexa-2-en-1-one (14.6 g, 100 mmol, 50%) was obtained as a solution in MTBE, which was used in the next step without further purification. 1 H NMR(400MHz, CDCl3)δ 6.00(h,J=1.5Hz,1H),2.63(dd,J=7.2,6.0Hz,2H),2.52-2.41(m,2H),2.05(dt,J=1.5,0.8Hz,3H). 19 FNMR(376MHz, CDCl3)δ-100.50(t,J=13.3Hz).

[0459] (S)-4,4-difluoro-3-methyl-3-(nitromethyl)cyclohexane-1-one [ka] In a 1 L flask, a solution of crude 4,4-difluoro-3-methylcyclohexa-2-en-1-one (7.98 g, 210 mL, 0.26 molar concentration, 1 equivalent, 54.6 mmol) was diluted in MTBE to a total volume of MTBE (546 mL). 1-((1S,2S)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (2.10 g, 0.1 equivalent, 5.46 mmol) and nitromethane (33.3 g, 29.4 mL, 10 equivalents, 546 mmol) were added, and the mixture was stirred at 50°C under N2 for 2 days. The flask was cooled to room temperature. The mixture was washed with saturated KHSO4 solution (3x), saturated NaHCO3 solution (3x), H2O (1x), and brine (1x). The mixture was dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica chromatography (220 g) using a 0-25% siRNA gradient in c-hexane (2CV 0%, 10CV 0-10%, 2CV 10%, 10CV 10-20%, 4CV 20-25%, 2CV 25%) to obtain (S)-4,4-difluoro-3-methyl-3-(nitromethyl)cyclohexane-1-one (4.11 g, 19.8 mmol, 36.3%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.63(d,J=11.1Hz,1H),4.58(d,J=11.1Hz,1H),2.88-2.80(m,1H),2.72- 2.62(m, 1H), 2.56-2.47(m, 2H), 2.45-2.30(m, 2H), 1.28(d, J=1.0Hz, 3H). 19 FNMR(376MHz, CDCl3) δ-110.17(dd,J=24.0,12.9Hz),-110.31(td,J=10.4,3.5Hz).

[0460] (S)-8,8-difluoro-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane [ka] To a solution of (S)-4,4-difluoro-3-methyl-3-(nitromethyl)cyclohexane-1-one (4.0 g, 1 equivalent, 19.3 mmol) in anhydrous DCM (3.8 M), ethylene glycol (1.59 mL, 1.48 equivalents, 28.6 mmol) and trimethyl orthoformate (3.2 mL, 1.5 equivalents, 29.0 mmol) were added. The resulting reaction mixture was stirred at room temperature for 5 minutes, and then cooled to 0°C in an ice bath. Methanesulfonic acid (186 μL, 0.148 equivalents, 2.86 mmol) was added dropwise to this mixture. The reaction mixture was removed from the ice bath, warmed to room temperature, and stirred overnight. The reaction mixture was cooled back to 0°C, quenched with 100 mL of water, and partitioned with 100 mL of DCM. The layers were separated, and the aqueous layer was extracted with DCM (3 x 50 ml). The combined organic layers were dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain (S)-8,8-difluoro-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (4.2 g, 87%) as a clear orange-yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.82(d,J=11.0Hz,1H),4.51(d,J=11.1Hz,1H),4.02-3.92(m,4H),2.29-2.15(m,1 H), 2.15-2.09(m,1H),2.08-1.95(m,1H),1.91-1.79(m,3H),1.30(d,J=1.4Hz,3H). 19 FNMR(376MHz, CDCl3) δ-109.08(ddd,J=244.3,20.7,7.2Hz),-110.28(dddd,J=243.9,21.2,7.6,3.0Hz).

[0461] (S)-(8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] Under an inert atmosphere, an aqueous solution of (S)-8,8-difluoro-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (1 equivalent) in ethyl acetate was added to 10% phosphate (0.075 equivalents) in charcoal. MeOH (MeOH:ethyl 2:1, 0.1M) was added to this mixture, the reaction vessel was emptied, and H2 was packed in via a balloon. The reaction mixture was stirred overnight at room temperature. Complete conversion was observed by TLC (TLC 5% MeOH / DCM showed complete conversion with ninhydrin as the staining solution). The reaction vessel was emptied and packed with nitrogen. The reaction contents were filtered through Celite, washed with ethyl acetate, and concentrated under vacuum to obtain (S)-(8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (3.7 g, quant.) as a yellowish clear oil, which was used in the next step without further purification. 1 HNMR(400MHz,CDCl3)δ 3.97-3.91(m,4H),2.87(d,J=13.3Hz,1H),2.77(d,J=13.4Hz,1H),2.13- 2.01(m, 2H), 1.84-1.79(m, 3H), 1.64-1.58(m, 1H), 1.12(d, J=1.5Hz, 3H). 19 FNMR (376MHz, CDCl3) δ-106.57--107.45(m),-111.32--112.12(m).

[0462] (S)-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile [ka] (S)-(8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine (1.00 equivalent) was dissolved in MeCN (0.35 M). K2CO3 (2.00 equivalent) and 3-fluoro-4-nitrobenzonitrile (1.00 equivalent) were added, and the resulting orange mixture was stirred at room temperature for 24 hours. The reaction product was filtered through frit, the filtrate was concentrated, and purified on a silica gel column (0-1% MeOH / DCM) to obtain (S)-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (5.4 g, 88%). 1 H NMR(400MHz,CDCl3)δ 8.41(s,1H),8.30-8.22(m,1H),6.85(dd,J=8.7,1.6Hz,1H),4.07-3.90(m,4H),3.56-3.44(m ,2H),2.22-2.09(m,2H),1.93-1.82(m,3H),1.76(dd,J=14.0,2.6Hz,1H),1.30-1.18(m,4H). 19 FNMR (376MHz, CDCl3) δ-107.02~-107.96(m),-110.15~-111.12(m).

[0463] (S)-4-amino-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile [ka] Under an inert atmosphere, a solution of (S)-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (1 equivalent) in ethyl acetate was added to Pd (10% on charcoal; 0.05 equivalents). MeOH (MeOH:AcOEt 2:1, 0.1M) was added to this mixture, the reaction vessel was emptied, and H2 was packed in via balloon. The reaction mixture was stirred at room temperature for 2 hours until complete conversion was observed by TLC (TLC: 100% DCM, ninhydrin as staining agent). The reaction vessel was emptied and packed with nitrogen. The reaction contents were filtered through Celite, washed with ethyl acetate, and concentrated under vacuum to obtain (S)-4-amino-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (4.9 g, 99%). 1 H NMR(400MHz,CDCl3)δ 7.02(dd,J=8.0,1.8Hz,1H),6.89(d,J=1.8Hz,1H),6.67(d,J=7.9Hz,1H),4.02-3.91(m,4H),3.22-3.15(m,2H),2.25- 2.08(m,2H),1.95(dd,J=14.2,2.7Hz,1H),1.85(d,J=6.5Hz,2H)),1.73(dt,J=14.2,2.2Hz,1H),1.27(d,J=1.5Hz,3H). 19 FNMR(376MHz, CDCl3)δ-105.99--106.88(m),-109.87(ddd,J=242.6,19.3,10.3Hz).

[0464] (S)-1-((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] (S)-4-amino-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (4.9 g, 1 equivalent, 15 mmol) was added to trimethyl orthoformate (46 mL, 29 equivalents, 420 mmol), followed by the addition of formic acid (0.56 mL, 1 equivalent, 15 mmol). The resulting mixture was stirred at room temperature. After the start of the reaction, additional formic acid (0.56 mL, 1 equivalent, 15 mmol) was added at t=90 min, 120 min, and 180 min, and the mixture was then stirred overnight. The reaction contents were partitioned with 500 mL of ethyl acetate and 300 mL of saturated NaHCO3 aqueous solution, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3 x 150 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel chromatography (80 g of SiO2, 0-70% SiO2:hexane) to obtain (S)-1-((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4.4 g, 13 mmol, 87%) as a white solid. 1 H NMR (400MHz, CDCl3)δ 8.17(s, 1H), 7.86(dd, J=8.4, 0.7Hz, 1H), 7.80(d, J=1.5Hz, 1H), 7.54(dd, J=8.4, 1.5Hz, 1H), 4.47(d, J=14.8Hz, 1H), 4 .31(d, J=14.9Hz, 1H), 4.04-3.90(m, 4H), 2.29-2.07(m, 2H), 1.97-1.82(m, 3H), 1.73-1.65(m, 1H), 1.13-1.09(m, 3H). 19 F NMR (376MHz, CDCl3) δ-107.43--108.46(m), -110.25(ddd, J=243.6, 22.9, 7.7Hz).

[0465] (S)-1-((2,2-difluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonil [ka] To ferric chloride (3.27 g, 3.5 equivalents, 20.2 mmol) and water (2.18 g, 2.18 mL, 21 equivalents, 121 mmol), a solution of (S)-1-((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.00 g, 1 equivalent, 5.76 mmol) in CH2Cl2 (19.2 mL) was added at room temperature. The resulting yellow to amber suspension was heated to 50 °C, and ferric chloride (3.27 g, 3.5 equivalents, 20.2 mmol) in water (2.18 g, 2.18 mL, 21 equivalents, 121 mmol) was added at t=1, 2, and 3 hours while maintaining the temperature at 50 °C throughout the entire process. The reactants were quenched by adding a saturated aqueous solution of NaHCO3. The aqueous layer was extracted three times with CH2Cl2, the combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. NMR indicated that the conversion was not complete. The reaction was restarted under the same conditions as before, and iron(III) chloride (3.27 g, 3.5 equivalents, 20.2 mmol) was added to water (2.18 g, 2.18 mL, 21 equivalents, 121 mmol) at t=2, 16, 19, and 25 hours. The conversion was not complete (70%). The reactants were quenched by adding a saturated aqueous solution of NaHCO3. The aqueous layer was extracted three times with CH2Cl2, the combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. This time, the reaction was restarted by adding ferric chloride hexahydrate (5.4 g, 3.0 mL, 3.5 equivalents, 20 mmol). The reaction mixture was heated for 2 hours, then more ferric chloride hexahydrate (5.4 g, 3.0 mL, 3.5 equivalents, 20 mmol) was added, and complete conversion was achieved after 1 hour (determined by LC-MS analysis). The reaction was quenched by adding saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with CH2Cl2, the combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain (S)-1-((2,2-difluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (993 mg, 3.27 mmol, 57%) as a pale brown foam. 1H NMR(400MHz,CDCl3)δ 8.07(s,1H),7.89(d,J=8.4Hz,1H),7.75(s,1H),7.56(dd,J=8.3,1.4Hz,1H),4.38(q,J=15.3Hz,2H) , 2.77-2.62(m, 2H), 2.54(d, J=15.7Hz, 1H), 2.50-2.32(m, 2H), 2.25(d, J=14.0Hz, 1H), 1.15(s, 3H). 19 FNMR (376MHz, CDCl3) δ-109.71--109.83(m),-109.83--109.94(m).

[0466] (S)-1-((2,2-difluoro-1-methyl-5-methylenecyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonil [ka] Under an N2 atmosphere, NaH (60% in mineral oil) (183 mg, 4.58 mmol, 1.4 equivalents) was gradually added at 0°C to a stirred suspension of methyltriphenylphosphonium bromide (1.64 g, 4.58 mmol, 1.4 equivalents) in anhydrous THF (14.6 mL). The mixture was stirred at 0°C for 5 hours, then warmed to room temperature and stirred at that temperature for 1 hour. A solution of (S)-1-((2,2-difluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.993 g, 3.27 mmol) was slowly added at 0°C to anhydrous THF (7.28 mL) and allowed to reach room temperature overnight. Complete conversion was demonstrated by TLC (CyH / EtOAC:1 / 1). The reaction mixture was concentrated under reduced pressure, the residue was quenched with saturated NH4Cl aqueous solution, and extracted three times with siRNA. The combined organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g SiO2, 10-100% siRNA in cHex) to obtain (S)-1-((2,2-difluoro-1-methyl-5-methylenecyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (473 mg, 3.27 mmol, 48%) as a white crystalline solid. LC-MS: m / z: 302 [M+H] + 1 H NMR (400MHz, CDCl3)δ 8.08(s, 1H), 7.87(d, J=8.3Hz, 1H), 7.81-7.77(m, 1H), 7.54(dd, J=8.3, 1.5Hz, 1 H), 4.92(p, J=1.2Hz, 1H), 4.76(t, J=1.7Hz, 1H), 4.42(d, J=15.1Hz, 1H), 4.29(d, J=15.1Hz, 1H), 2.44-2.33(m, 3H), 2.15-2.05(m, 2H), 2.02-1.91(m, 2H), 1.42(d , J=1.3Hz, 1H), 1.34(d, J=15.1Hz, 1H), 1.02(s, 4H), 0.95(dd, J=8.1, 6.2Hz, 1H). 19F NMR (376MHz, CDCl3) δ-105.09--105.83(m), -105.86--106.80(m), -108.95(dd, J=32.0, 11.1Hz), -109.60(dd, J=31.7, 11.4Hz).

[0467] 1-(((3R,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((3S,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] In 7.2 mL of DCM, at 0°C, m-CPBA (340 mg, 1.52 mmol, 1.4 equivalents, 77% by weight) was added to an aqueous solution of (S)-1-((2,2-difluoro-1-methyl-5-methylenecyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. The mixture was warmed to room temperature and stirred for 4 hours. LC-MS indicated that the reaction was not complete, so m-CPBA (340 mg, 1.52 mmol, 1.4 equivalents, 77% by weight) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was quenched with a 1 / 1 mixture of saturated Na2S2O3 aqueous solution and saturated NaHCO3 aqueous solution, and extracted three times in DCM. The combined organic layers were washed with saturated NaHCO3 and brine, dried to (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40 g of SiO2, 10 CV at DCM / siRNA100 / 0~85 / 15, then 20 CV at 85 / 15, then max 75 / 25) to obtain the first diastereomer (undesirable) 1-(((3R,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel (96 mg, 0.3 mmol, 28%) and the second diastereomer (desired) 1-(((3S,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel (64 mg, 0.2 mmol, 19%). LC-MS:m / z:318[M+H] + 1 H NMR (400MHz, CDCl3)δ 8.11(s, 1H), 7.88(d, J=8.4Hz, 1H), 7.76(d, J=1.3Hz, 1H), 7.60-7.54(m, 1H), 4.42(d, J=15.2Hz, 1H), 4.30(d, J=15.2Hz, 1H), 2.61(t, J=4.3Hz, 1H), 2.57(d, J=4.4Hz, 1H), 2.38-2.22(m, 4H), 1.37(dt, J=11.8, 2.6Hz, 2H), 1.30(s, 3H), 1.07(ddd, J=13.8, 5.4, 2.6Hz, 1H).

[0468] 1-(((5S,7S)-8,8-difluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Lithium 2-methyl-2-propanoate (0.51 mL, 1.0 molar concentration in THF, 0.51 mmol, 2.7 equivalents) was added to a solution of ethyl aminoformate (0.23 g, 2.6 mmol, 13.5 equivalents) in NMP (1.3 mL). After stirring at room temperature for 10 minutes, a solution of 1-(((3S,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (60 mg, 0.46 mmol, 1.00 equivalent) in NMP (1.3 mL) was added dropwise. Subsequently, the reaction mixture was heated to 100°C and stirred at that temperature for 21 hours until it was completely converted by TLC (100% DCM). The reaction mixture was cooled to room temperature and poured into H2O and extracted with ELISA (x4). The combined organic extracts were washed with NH4Cl(x3), H2O, and brine, dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography (4 g of SiO2, 0-7% MeOH in DCM) to obtain 1-(((5S,7S)-8,8-difluoro-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (48 mg, 0.13 mmol, 70%) as a viscous, colorless oil. LC-MS: m / z: 361[M+H] + .

[0469] 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] In a sealed tube, 2-(5-chloropyrazine-2-yl)propan-2-ol (29 mg, 0.17 mmol, 1.25 equivalents) was mixed with tripotassium phosphate (57 mg, 0.27 mmol, 2.0 equivalents), 1-(((5S,7S)-8,8-difluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (48 mg, 0.13 mmol, 1 equivalent), 1,4-dioxane (0.67 mL), methyl[2-(methylamino)ethyl]amine (12.0 mg, 0.28 mmol, 1.00 equivalent), and CuI (26.9 mg, 0.14 mmol, 0.50 equivalents). The reaction mixture was placed under a nitrogen atmosphere and heated at 100°C for 32 hours. The reaction mixture was cooled to room temperature and diluted with DCM, water, and 7M NH3 in MeOH, and stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (×2). The combined organic extracts were washed with water (2x), dried, filtered, and concentrated under reduced pressure to obtain orange oil. The residue was purified by FCC (0-10% MeOH in DCM) and concentrated to obtain 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (26 mg, 0.13 mmol, 39%) as an off-white solid. LC-MS:m / z:497[M+H] + 1 H NMR (400MHz, CDCl3)δ 9.37(d, J=1.6Hz, 1H), 8.43(d, J=1.6Hz, 1H), 8.37(s, 1H), 7.90(dd, J=8.4, 0.7Hz, 1H) , 7.80(d, J=1.3Hz, 1H), 7.57(dd, J=8.4, 1.4Hz, 1H), 4.46(d, J=15.2Hz, 1H), 4.35(d, J= 15.2Hz, 1H), 3.99(d, J=10.8Hz, 1H), 3.91(d, J=10.8Hz, 1H), 2.45(dddd, J=35.7, 18.0, 9.0, 3.9Hz, 1H), 2.30-2.10(m, 2H), 2.09-1.93(m, 3H), 1.63-1.57(m, 6H), 1.43(s, 3H). 19F NMR (376MHz, CDCl3) δ -107.42 (d, J=242.5Hz), -109.03 (ddd, J=242.8, 35.6, 10.3Hz).

[0470] Example 16. Preparation of 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0471] Detailed instructions rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Copper(I) iodide (281.87 mg, 1.48 mmol) is mixed with rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.48 mmol), 2-(5-chloropyrazine-2-yl)propan-2-ol (254.43 mg, 1.48 mmol), 1 equivalent) in 1,4-dioxane (5 mL), N 1 ,N 2The compound was added to a solution of -dimethylethane-1,2-diamine (260.35 mg, 2.96 mmol) and tripotassium phosphate (628.3 mg, 2.96 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100°C and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with methanol in 0%-3% dichloromethane to obtain the desired product rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg) as a pale yellow solid. LCMS (ESI-MS) m / z = 475 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ(ppm)9.27(s, 1H), 8.64(d, J=4.0Hz, 1H), 8.32(d, J=10.1Hz, 2H ), 7.86-7.79(m, 1H), 7.60(t, J=5.6Hz, 1H), 5.44(d, J=3.3Hz, 1H), 4.85(d, J=14.7Hz, 1H) ), 4.60(d, J=14.9Hz, 1H), 4.16(d, J=10.1Hz, 1H), 4.05(d, J=10.5Hz, 1H), 3.19(s, 1H), 2.58(d, J=12.4Hz, 2H), 2.46-2.19(m, 3H), 1.47(t, J=3.2Hz, 6H), 0.95(d, J=3.6Hz, 3H).

[0472] rac-1-(((5S,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] Potassium tert-butoxide (106.38 mg, 0.95 mmol) was added to a solution of methyltriphenylphosphonium bromide (337.36 mg, 0.95 mmol) in benzene (3 mL). To this mixture, a solution of rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.63 mmol) was added dropwise to benzene (3 mL). The reaction mixture was stirred overnight at 80°C. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with methanol in 0% to 3% dichloromethane to obtain rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg) as a yellow solid. LCMS (ESI-MS) m / z = 473 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.28 (d, J=1.5Hz, 1H), 8.64 (d, J=1.5Hz, 1H), 8.37 (d, J=1.4Hz, 1H), 8.21 (s, 1H), 7.80(d, J=8.3Hz, 1H), 7.57(dd, J=8.3, 1.4Hz, 1H), 5.44(s, 1H), 5.00(s, 1H), 4.76(d, J=14.6H) z, 1H), 4.49(s, 1H), 4.44(d, J=14.6Hz, 1H), 4.03-3.92(m, 2H), 2.97(dd, J=15.2, 11.1Hz, 1H), 2.40(dd d, J=24.0, 14.3, 3.4Hz, 2H), 2.28(d, J=13.1Hz, 1H), 1.86-1.74(m, 2H), 1.50-1.45(m, 6H), 0.90(s, 3H).

[0473] 1-(((5S,7R)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel and 1-(((5R,7S)-3-(5-(2-hydroxypropane-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitriel [ka] rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.21 mmol) was synthesized under the following conditions: Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm, Mobile phase A: MtBE (0.5% 2M) Separation was performed by preparative chiral HPLC using NH3-MeOH (H3-MeOH)--HPLC, mobile phase B:EtOH--HPLC, flow rate: 20 mL / min, gradient: 20%B to 20%B in 22 mins; wavelength: 220 / 254 nm; RT1 (min): 8.922, RT2 (min): 16.131, sample solvent:EtOH--HPLC, injection volume: 1.3 mL. The desired fractions were combined and lyophilized to obtain the product.

[0474] The first isomer to elute: 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (28.0 mg, purity 99.4%, 100% ee, yield 28.0%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.28 (d, J=1.5Hz, 1H), 8.64 (d, J=1.5Hz, 1H), 8.37 (d, J=1.4Hz, 1H), 8.21 (s, 1H), 7.80(d, J=8.3Hz, 1H), 7.57(dd, J=8.3, 1.4Hz, 1H), 5.44(s, 1H), 5.00(s, 1H), 4.76(d, J=14.6H) z, 1H), 4.49(s, 1H), 4.44(d, J=14.6Hz, 1H), 4.03-3.92(m, 2H), 2.97(dd, J=15.2, 11.1Hz, 1H), 2.40(dd d, J=24.0, 14.3, 3.4Hz, 2H), 2.28(d, J=13.1Hz, 1H), 1.86-1.74(m, 2H), 1.50-1.45(m, 6H), 0.90(s, 3H). LCMS(ESI-MS)m / z=473[M+H] + .

[0475] Secondly, an isomer elutes as a white solid: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (32.2 mg, purity 99.7%, 99.8% ee, yield 32.2%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.28 (d, J=1.5Hz, 1H), 8.64 (d, J=1.5Hz, 1H), 8.37 (d, J=1.4Hz, 1H), 8.21 (s, 1H), 7.80(d, J=8.3Hz, 1H), 7.57(dd, J=8.3, 1.4Hz, 1H), 5.44(s, 1H), 5.00(s, 1H), 4.76(d, J=14.6H) z, 1H), 4.49(s, 1H), 4.44(d, J=14.6Hz, 1H), 4.03-3.92(m, 2H), 2.97(dd, J=15.2, 11.1Hz, 1H), 2.40(dd d, J=24.0, 14.3, 3.4Hz, 2H), 2.28(d, J=13.1Hz, 1H), 1.86-1.74(m, 2H), 1.50-1.45(m, 6H), 0.90(s, 3H). LCMS(ESI-MS)m / z=473[M+H] + .

[0476] Example 17. Preparation of 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile [ka]

[0477] Detailed instructions 3,5,5-Trimethylcyclohexa-2-en-1-one [ka] To a stirred mixture of 170 mL of tert-butanol and 21 mL of ethyl acetoethyl (161.54 mmol), potassium tert-butoxide (0.94 g, 8.38 mmol) and 4-methylpenta-3-en-2-one (15.84 g, 161.54 mmol) were obtained, and the resulting mixture was stirred at room temperature for 0.5 hours. Next, another batch of potassium tert-butoxide (3.63 g, 32.31 mmol) was added, and the resulting mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0%-15% petroleum ether to obtain 3,5,5-trimethylcyclohexa-2-en-1-one (15 g) as a colorless oil. LCMS (ESI-MS) m / z = 139 [M + H] + .

[0478] rac-3,3,5-trimethyl-5-(nitromethyl)cyclohexane-1-one [ka] To a stirred mixture of methanol (90 mL) containing 3,5,5-trimethylcyclohexa-2-en-1-one (15 g, 108.53 mmol), nitromethane (6.62 g, 108.53 mmol) and pyrrolidine (7.72 g, 108.53 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0%-10% petroleum ether to obtain the desired product, rac-3,3,5-trimethyl-5-(nitromethyl)cyclohexane-1-one (7 g), as a yellow oil. LCMS (ESI-MS) m / z = 200 [M + H] + .

[0479] rac-7,7,9-trimethyl-9-(nitromethyl)-1,4-dioxaspiro[4.5]decane [ka] To a stirred mixture of rac-3,3,5-trimethyl-5-(nitromethyl)cyclohexane-1-one (7 g, 35.13 mmol) in dichloromethane (40 mL), ethane-1,2-diol (2.18 g, 35.13 mmol), trimethoxymethane (3.73 g, 35.13 mmol), and methanesulfonic acid (0.51 g, 5.27 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography and eluted with ethyl acetate in 0% to 15% petroleum ether to obtain the desired product, rac-7,7,9-trimethyl-9-(nitromethyl)-1,4-dioxaspiro[4.5]decane (5 g), as a yellow oil. LCMS (ESI-MS) m / z = 244 [M + H] + .

[0480] rac-7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methaneamine [ka] To a stirred mixture of rac-7,7,9-trimethyl-9-(nitromethyl)-1,4-dioxaspiro[4.5]decane (5 g, 20.55 mmol) in ethanol (75 mL) and water (15 mL), iron (5.74 g, 102.75 mmol) and ammonium chloride (3.30 g, 61.65 mmol) were added. The resulting mixture was heated to 80°C and stirred for 2 hours. The resulting mixture was cooled to room temperature, filtered, and the filtered cake was washed with ethanol (50 mL). The filtrate was diluted with water (50 mL), extracted with dichloromethane (3 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentra...

Claims

1. 5-Fluoro-1-(((5S,7S,8R)-8-Fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile 【Chemistry 1】 The solid form.

2. The aforementioned configurations are approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, 15.58, 15.60, 18.85, 18.87, 18.89, 18.91, 19.20, 19.22, 19.24, 19.42, 19.45, 19.47, 19.49, and 22.

3. The solid form according to claim 1, exhibiting an X-ray powder diffraction pattern having one or more signals represented by 2θ°, selected from the group consisting of 9, approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.

59.

3. The aforementioned configurations are approximately 7.02, 7.04, 7.07, 7.09, 10.31, 10.33, 10.35, 10.37, 15.56, 15.58, 15.60, 18.85, 18.87, 18.89, 18.91, 19.20, 19.22, 19.24, 19.42, 19.45, 19.47, 19.49, and 22.

3. The solid form according to claim 1, exhibiting an X-ray powder diffraction pattern having at least three signals represented by 2θ°, selected from the group consisting of approximately 22.41, approximately 22.43, approximately 24.00, approximately 24.02, approximately 24.04, approximately 24.06, approximately 25.15, approximately 25.21, approximately 7.11, approximately 25.23, approximately 26.51, approximately 26.53, approximately 26.55, and approximately 26.

59.

4. Approximately 7.02, approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.31, approximately 10.33, approximately 10.35, approximately 10.37, approximately 15.56, approximately 15.58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately The solid form according to claim 1, exhibiting an X-ray powder diffraction pattern having at least six signals represented by 2θ°, selected from the group consisting of 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.

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5. Approximately 7.02, approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.31, approximately 10.33, approximately 10.35, approximately 10.37, approximately 15.56, approximately 15.58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately The solid form according to claim 1, exhibiting an X-ray powder diffraction pattern having at least nine signals represented by 2θ°, selected from the group consisting of 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.

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6. Approximately 7.02, approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.31, approximately 10.33, approximately 10.35, approximately 10.37, approximately 15.56, approximately 15.58, approximately 15.60, approximately 18.85, approximately 18.87, approximately 18.89, approximately 18.91, approximately 19.20, approximately 19.22, approximately 19.24, approximately 19.42, approximately 19.45, approximately 19.47, approximately 19.49, approximately 22.39, approximately 2 The solid form according to claim 1, exhibiting an X-ray powder diffraction pattern having at least 12 signals represented by 2θ°, selected from the group consisting of 2.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.

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7. The solid form according to claim 1, exhibiting an X-ray powder diffraction pattern having signals represented by 2θ° at approximately 7.04, approximately 7.07, approximately 7.09, approximately 10.33, approximately 10.35, approximately 18.87, and approximately 24.

02.

8. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 7, and a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.

9. A method for treating a condition associated with TRPV4, comprising administering to a subject the solid form described in any one of claims 1 to 7 or the pharmaceutical composition described in claim 8.

10. A solid form according to any one of claims 1 to 7 for the preventive or therapeutic treatment of a condition associated with TRPV4.

11. Use of a solid form according to any one of claims 1 to 7 for the manufacture of a drug for treating a condition associated with TRPV4.

12. Use of the solid form according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 for the treatment of conditions related to TRPV4.

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