Therapeutic compounds and methods

Abstract

The present disclosure provides a compound of Formula I: # imgabs0 # or a salt thereof wherein R1, R2, R4, L1, L2 and A have any of the values described in the specification, and compositions comprising the compound of Formula (I). These compounds are useful as TRPV4 antagonists.

Description

[0001] priority

[0002] This application claims priority to U.S. Provisional Application No. 63 / 359,715 filed on July 8, 2022 and U.S. Provisional Application No. 63 / 385,282 filed on November 29, 2022. The entire contents of these U.S. Provisional Patent Applications are hereby incorporated by reference herein. Technical Field

[0003] The present disclosure relates to pharmaceutical compositions that act as antagonists of both wild-type TRPV4 channels and TRPV4 channels carrying pathogenic activating mutations. Background Art

[0004] 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). 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 including arachidonic acid metabolites. TRPV4 is expressed in many different tissues, including the brain, bladder, skin, heart, lungs, and musculoskeletal tissues.

[0005] TRPV4 channels are widely expressed in different human cell types. In particular, TRPV4 is expressed in epithelial and endothelial cells, fibroblasts, chondrocytes, neurons, and various inflammatory cells (Koivisto et al. 2021NRDD). TRPV4 is directly involved in epithelial and endothelial barrier functions associated with lung injury, and is further associated with respiratory diseases through TRPV4-induced ATP release (Koivisto). Genetic and pharmacological studies have shown that TRPV4 is a therapeutic target for chronic cough, pulmonary edema, chronic obstructive pulmonary disease, and pulmonary fibrosis (Grace et al. 2017, Pharmacology and Therapeutics). TRPV4 gene knockout leads to a decrease in osteoclast function and calcium regulation, and is essential for bone homeostasis, indicating the role of TRPV4 in osteoporosis and other joint diseases. TRPV4 knockout mice have reduced inflammatory hyperalgesia and mechanical pain (J. Neurosci. 2004, 18, 4444-4452, Qu et al., 2016 BioMed Research International) and a variety of functional studies have demonstrated the signaling of TRPV4 in neuropathic pain. TRPV4 is also expressed in the urothelium and detrusor of the bladder, and activation causes muscle contraction (Birder et al. 2007 J. Pharmacol. Exp. Ther.). Consistent with the role of TRPV4 in bladder-related pathologies, it has been shown that inhibition of TRPV4 in cyclophosphamide-induced cystitis mice and rat models can improve bladder function (Prog. Biophys. Mol. Biol. 2010, 1, 2-17). This provides evidence for TRPV4 as a therapeutic target for a variety of diseases, including respiratory diseases, joint diseases, pain and bladder dysfunction.

[0006] Furthermore, pathogenic mutations in activating TRPV4 have been shown to cause a variety of severe Mendelian diseases, including a range of skeletal dysplasias (Nishimura et al. 2012AJMG) and peripheral neuropathy (Landoure et al. Nature Genetics 2009). All disease-causing mutations appear to increase disease risk by increasing calcium influx into cells (Toft-Beterlsen and MacAulay 2021Cells), suggesting therapeutic benefit for TRPV4 inhibitors. These observations suggest that in addition to the many different common diseases caused by activation of the wild-type receptor, inhibition of TRPV4 in genetic diseases due to activating mutations could be beneficial.

[0007] GSK2798745 entered Phase II clinical trials. Further studies have found circulating active metabolites (ACSMed.Chem.Lett.2021,12,9,1498-1502) and a lower safety margin determined in a three-month dog toxicity study, resulting in a 4.8-fold reduction in the maximum clinical dose (Am.J.Cardiovasc.Drugs 2019,19,335-342). GSK2798745 failed to show efficacy for a variety of human disease indications. There is currently a need for drugs that can be used to antagonize TRPV4. Specifically, there is a need for agents with lower toxicity, improved efficacy, improved metabolic stability (e.g., for CYP3A4), lower levels of active circulating metabolites, and / or higher safety margins. Summary of the invention

[0008] In one aspect, the present disclosure provides compounds useful for antagonizing TRPV4.

[0009] In some aspects, the present disclosure provides a compound of Formula I:

[0010]

[0011] or a salt thereof, wherein:

[0012] L 1 Yes CR a R b ;

[0013] L 2 Yes CR c R d ;

[0014] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine;

[0015] R b is H, halo, cyano, (C1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ),

[0016] or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0017] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine;

[0018] R d is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ),

[0019] or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0020] Where R a , R b , R c and R d At least one of is not H;

[0021] R 1 is H, hydroxyl, cyano, halo, methoxycarbonyl, cyclopropyl, (C 1 -C 3 ) alkyl or (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy is optionally substituted by one or more independently selected from hydroxy, (C 1 -C 3 ) substituted with alkoxy, benzyloxy, cyano and fluorine groups,

[0022] or R 1 and R c Together with the atoms to which they are attached, they form a fused cyclopropyl ring;

[0023] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0024] R 4 Yes (C 1-C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace;

[0025] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted by one or more independently selected from halo, cyano, (C 1 -C 5 ) alkyl and hydroxyl groups; and

[0026] A is 0, 1, or 2;

[0027] In some aspects, the present disclosure provides a compound of Formula I:

[0028]

[0029] or a salt thereof, wherein:

[0030] L 1 Yes CR a R b ;

[0031] L 2 Yes CR c R d ;

[0032] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5)cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine;

[0033] R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ),

[0034] or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0035] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine;

[0036] R dis H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ),

[0037] or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0038] R 1 is substituted by one or more fluorines (C 1 -C 3 )alkyl;

[0039] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0040] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace;

[0041] Each Rx are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and

[0042] A is 0, 1 or 2.

[0043] The present disclosure also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0044] The present disclosure also provides a method for treating a condition associated with TRPV4 modulation in an animal, comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0045] The present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

[0046] The present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of a condition associated with TRPV4 modulation.

[0047] The present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition associated with TRPV4 modulation in an animal.

[0048] The present disclosure also provides methods and intermediates disclosed herein for preparing compounds of Formula I or salts thereof.

[0049] Certain compounds of Formula (I) exhibit reduced toxicity, improved potency, improved metabolic stability (eg, towards CYP3A4), lower levels of active circulating metabolites and / or a greater safety margin. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 X-ray powder diffraction (XRPD) data from Example 21 is shown. DETAILED DESCRIPTION

[0052] Unless otherwise indicated, the following definitions apply: Halo or halogen is fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, etc. represent both straight and branched chain groups; however, individual groups (such as propyl) include only straight chain groups, branched chain isomers (such as isopropyl) being specifically mentioned.

[0053] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical (i.e., C 1-5 represents one to five carbon atoms). Examples include (C 1 -C 5 ) alkyl, (C 2 -C 5 ) alkyl, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkyl and (C 3 -C 5 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl and n-pentyl.

[0054] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom (the "oxy").

[0055] The term "carbocycle" refers to a saturated or partially unsaturated (non-aromatic) all-carbon ring having the specified number of carbons.

[0056] The term 6-membered heteroaryl includes the following rings:

[0057]

[0058] As used herein, a wavy line intersecting a bond in a chemical structure Represents the point of attachment of a bond in a chemical structure where a wavy bond meets the rest of the molecule.

[0059] The term "treat, treatment or treating" refers to the extent to which a disease or condition is involved, including suppressing the disease or condition, eliminating the disease or condition and / or alleviating one or more symptoms of the disease or condition. The term "treat, treatment or treating" also refers to therapeutic treatment and / or prophylactic treatment or preventive measures, wherein the purpose is to prevent or slow down (mitigate) undesirable physiological changes or conditions, such as the development or spread of cancer, for example. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction of the degree of disease or condition, stabilization of the disease or condition state (i.e., no deterioration), delay or slowing of disease progression, improvement or alleviation of the disease state or condition and alleviation (whether partial or complete), whether detectable or undetectable. "Treatment" may also refer to prolonged survival compared to expected survival if treatment is not received. Patients in need of treatment include patients who have already suffered from the disease or condition and patients who are prone to suffering from the disease or condition or patients who need to prevent the disease or condition. In some embodiments, "treat, treatment or treating" does not include prevention (preventing or prevention).

[0060] The phrase "therapeutically effective amount" or "effective amount" includes, but is not limited to, an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0061] In one aspect, the compounds of the present disclosure regulate TRPV4. In some embodiments, the regulation is antagonism. In one aspect, the TRPV4 antagonists of the present disclosure can be used to treat conditions associated with TRPV4 overactivation. Such conditions include diseases caused by activating mutations in TRPV4, including, for example, but not limited to, congenital distal spinal motor neuropathy, scapular spinal muscular atrophy, Charcot-Marie-Tooth disease type 2C (CMT2C), displacement dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), spondyloepiphyseal dysplasia, Maroteaux type, pseudo-Morquio syndrome type 2, paratremor dysplasia, autosomal dominant phocomelia and familial phalangeal arthropathy-short limb malformation.

[0062] In one aspect, the TRPV4 antagonists disclosed herein can be used to treat associated conditions associated with increased wild-type TRPV4 and / or overlap with disease symptoms caused by TRPV4 activating mutations. Such conditions include, but are not limited to, skeletal dysplasia, osteodysplasia, osteoarthritis, decreased bone density, osteoporosis, peripheral neuropathy, hereditary neuropathy, spinal muscular atrophy, Charcot-Marie-Tooth disease, bladder diseases (including but not limited to overactive bladder, urinary incontinence, interstitial cystitis, bladder pain syndrome, urinary urgency, and neurogenic bladder.

[0063] In one aspect, the TRPV4 antagonists of the present disclosure can be used to treat other bone disorders, including bone infection, osteogenesis imperfecta, osteonecrosis, Paget's disease of bone, rickets, achondroplasia, dwarfism, short stature, achondroplasia, genetic diseases of the skeleton. In one aspect, TRPV4 antagonists can be used to treat other neuropathies, including spinal muscular atrophy, neuropathic pain, pain, motor neuron disease, chronic pain, intestinal pain, and spasticity. In one aspect, the TRPV4 antagonists of the present disclosure can be used to treat diseases of impaired barrier integrity and vascular permeability regulation disorders, including but not limited to retinal edema, retinal leakage, macular edema of diabetes or other causes, diabetic neuropathy, conditions related to intestinal edema, postoperative abdominal edema, local and systemic edema, fluid retention, congestive heart failure, irritable bowel syndrome (IBS), Crohn's disease, diarrhea, intestinal abnormalities (hyper-responsiveness / hypo-responsiveness), fecal incontinence, constipation, celiac disease, lactose intolerance and bloating, obesity and type II diabetes (T2D), colitis / ulcerative colitis, hypertension, atherosclerosis, diseases with edema as a symptom, congestive heart failure, kidney disease or cirrhosis, kidney infection, urinary tract infection and prostate hypertrophy. In one aspect, the TRPV4 antagonists of the present disclosure can be used to treat pulmonary diseases, including but not limited to pulmonary diseases, chronic obstructive pulmonary disease, ventilator-associated lung injury, ventilator-associated lung parenchymal overexpansion, pulmonary edema caused by high altitude, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis / rhinitis, asthma, cough, chronic cough, bronchiectasis, sarcoidosis and pulmonary hypertension. In one aspect, the TRPV4 antagonists of the present disclosure can be used to treat inflammatory diseases, including but not limited to sepsis, macrophage activation diseases, microglia activation diseases, neuroinflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis and 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 damage, neurodegenerative diseases, tumorigenesis, cardiovascular and metabolic diseases and autoimmune diseases.

[0064] As used herein, the term "mammal" refers to humans, higher non-human primates, rodents, livestock, 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.

[0065] The compounds disclosed herein may exist as tautomers in certain cases. Although only one delocalized resonance structure is depicted, all of these forms are within the scope of the present disclosure.

[0066] It will be understood by those skilled in the art that the present disclosure also includes any compound claimed which may be enriched in one or more isotopes at any or all atoms above the naturally occurring isotopic ratio, such as but not limited to deuterium ( 2 H or deuterium). As a non-limiting example, CH 3 The group can be -CD 3 Substitution. In some embodiments, the compound is enriched in deuterium at one position higher than the naturally occurring deuterium isotope ratio. In some embodiments, the compound is enriched in deuterium at two positions higher than the naturally occurring deuterium isotope ratio. In some embodiments, the compound is enriched in at least about 75% of deuterium at one position. In some embodiments, the compound is enriched in at least about 75% of deuterium at two positions. In some embodiments, the compound is enriched in at least about 95% of deuterium at one position. In some embodiments, the compound is enriched in at least about 95% of deuterium at two positions. The pharmaceutical composition of the present disclosure may include one or more excipients. When used in combination with the pharmaceutical composition of the present disclosure, the term "excipient" generally refers to an additional ingredient combined with a compound of formula (I) or a pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical composition of the present disclosure, the term "excipient" includes, but is not limited to: carriers, binders, disintegrants, lubricants, sweeteners, flavoring agents, coatings, preservatives, and dyes.

[0067] As used herein, the term "about" refers to the amount, value or duration of the amount, value or duration of ± 10% or less. In some embodiments, "about" refers to the amount, value or duration of ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1% or ± 0.5%. In other embodiments, "about" refers to the amount, value or duration of ± 10%, ± 8%, ± 6%, ± 5%, ± 4% or ± 2%. In other embodiments, "about" refers to the amount, value or duration of ± 5%. In some embodiments, "about" refers to the amount, value or duration of ± 2% or ± 1% of the amount, value or duration of the enumeration. For example, in some embodiments, when the term "about" is used when enumerating a temperature or a temperature range, these terms refer to the enumerated temperature or temperature range of ± 5°C, ± 2°C or ± 1°C. In other embodiments, the term "about" refers to the temperature or temperature range of ± 2°C.

[0068] Stereochemical definitions and conventions used herein generally follow those in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present disclosure may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present disclosure (including but not limited to diastereomers, enantiomers, and atropisomers) and mixtures thereof (such as racemic mixtures) are part of the present disclosure.

[0069] Those skilled in the art will appreciate that compounds of the present disclosure having chiral centers can exist and be separated in optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present disclosure includes any racemic, optically active, polymorphic or stereoisomeric forms of compounds of the present disclosure or mixtures thereof, which have the useful properties described herein, and how to prepare optically active forms is well known in the art (e.g., by resolving racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

[0070] When a bond in a compound formula herein is formed in a non-stereochemical manner (e.g., planar), the atoms to which the bond is attached include all stereochemical possibilities. Relative stereochemistry is indicated. Unless otherwise indicated, when bonds in compound formulas herein are drawn as thick or dashed wedges, It should be understood that the atoms connected by the stereochemical bonds are enriched in the absolute stereoisomers depicted. In some embodiments, the compound can be at least 51% of the absolute stereoisomers depicted. In some embodiments, the compound can be at least 60% of the absolute stereoisomers depicted. In some embodiments, the compound can be at least 80% of the absolute stereoisomers depicted. In some embodiments, the compound can be at least 90% of the absolute stereoisomers depicted. In some embodiments, the compound can be at least 95% of the absolute stereoisomers depicted. In some embodiments, the compound can be at least 99% of the absolute stereoisomers depicted.

[0071] The specific values ​​listed below for groups, substituents, and ranges are for illustration only; they do not exclude other determined values ​​of groups and substituents or other values ​​within a determined range. It should be understood that two or more values ​​can be combined. It should also be understood that the values ​​listed below (or a subset thereof) can be excluded.

[0072] It should be understood that 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 may be selected from the groups described herein where applicable, and the groups described herein for the variable L 1 , L 2 , R a , R b , R c , R d , R 1 , R 2 , R 4 and R x Any of the groups in any of the above may be combined, where applicable, with the groups described herein for 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 combination of one or more of them.

[0073] Specifically, (C 1 -C 5 ) alkyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or 3-pentyl; (C 3 -C 6 )cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and (C 1 -C 5 ) The alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy or 3-pentyloxy.

[0074] In some embodiments of the compound of Formula I,

[0075] L 1 Yes CR a R b;

[0076] L 2 Yes CR c R d ;

[0077] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ), or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0078] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5)cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ), or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0079] Where R a , R b , R c and R d At least one of is not H;

[0080] R 1 is H, hydroxyl, cyano, halo, methoxycarbonyl, cyclopropyl, (C 1 -C 3 ) alkyl or (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy is optionally substituted by one or more independently selected from hydroxy, (C 1 -C 3 ) alkoxy, benzyloxy, cyano and fluorine; or R 1 and Rc Together with the atoms to which they are attached, they form a fused cyclopropyl ring;

[0081] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0082] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace;

[0083] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted by one or more independently selected from halo, cyano, (C 1 -C 5 ) alkyl and hydroxyl groups; and

[0084] A is 0, 1 or 2.

[0085] In some embodiments of the compound of Formula I,

[0086] L 1 Yes CR a R b ;

[0087] L 2 Yes CR c Rd ;

[0088] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ), or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0089] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C5 ) alkoxy, (C 3 -C 5 )cycloalkyloxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ), or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0090] R 1 is substituted by one or more fluorines (C 1 -C 3 )alkyl;

[0091] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0092] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace;

[0093] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and

[0094] A is 0, 1 or 2.

[0095] In some embodiments of the compound of Formula I,

[0096] L 1 Yes CR a R b ;

[0097] L 2 Yes CR c R d ;

[0098] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ), or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0099] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ), or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0100] Where R a , Rb , R c and R d At least one of is not H;

[0101] R 1 is H, hydroxyl, cyano, halo, methoxycarbonyl, cyclopropyl, (C 1 -C 3 ) alkyl or (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy is optionally substituted by one or more independently selected from hydroxy, (C 1 -C 3 ) alkoxy, benzyloxy, cyano and fluorine; or R 1 and R c Together with the atoms to which they are attached, they form a fused cyclopropyl ring;

[0102] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0103] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally, one or more (e.g., 1, 2, 3 or 4) R x replace;

[0104] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted by one or more independently selected from halo, cyano, (C 1 -C 5 ) alkyl and hydroxyl groups; and

[0105] A is 0, 1, or 2; or

[0106] L 1 Yes CR a R b ;

[0107] L 2 Yes CR c R d ;

[0108] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ), or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0109] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ), or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl;

[0110] R 1 is substituted by one or more fluorines (C 1 -C 3 )alkyl;

[0111] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0112] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally, one or more (e.g., 1, 2, 3 or 4) R x replace;

[0113] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and

[0114] A is 0, 1 or 2.

[0115] In some embodiments of the compound of Formula I,

[0116] L 1 Yes CR a R b ;

[0117] L 2 Yes CR c R d ;

[0118] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C5 )cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ), or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkylspiro(C 3 -C 5 )cycloalkyl;

[0119] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R d is H, halide, cyano, Rc(C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ), or R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkylspiro(C 3 -C 5 )cycloalkyl;

[0120] Where R a , R b , R c and R d At least one of is not H;

[0121] R 1 is H, hydroxyl, cyano, halo, methoxycarbonyl, cyclopropyl, (C 1 -C 3 ) alkyl or (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy is optionally substituted by one or more independently selected from hydroxy, (C 1 -C 3 ) alkoxy, benzyloxy, cyano and fluorine; or R 1 and R c Together with the atoms to which they are attached, they form a fused cyclopropyl ring;

[0122] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0123] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally, one or more (e.g., 1, 2, 3 or 4) R x replace;

[0124] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted by one or more independently selected from halo, cyano, (C 1 -C 5 ) alkyl and hydroxyl groups; and

[0125] A is 0, 1 or 2.

[0126] In some embodiments of the compound of Formula I,

[0127] L 1 Yes CR a R b ;

[0128] L 2 Yes CR c R d ;

[0129] R a is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH 2 ), or R a and R b Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkylspiro(C 3 -C 5 )cycloalkyl;

[0130] R c is H, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more fluorine; R d is H, halide, cyano, Rc(C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy or (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH 2 ), or R c and R dTogether with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkylspiro(C 3 -C 5 )cycloalkyl;

[0131] R 1 is substituted by one or more fluorines (C 1 -C 3 )alkyl;

[0132] Each R 2 independently selected from halo, cyano, hydroxyl, ethynyl, (C 1 -C 3 ) alkylsulfonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy is optionally substituted with one or more fluorine;

[0133] R 4 Yes (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally, one or more (e.g., 1, 2, 3 or 4) R x replace;

[0134] Each R x are independently selected from hydroxy, halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and

[0135] A is 0, 1 or 2.

[0136] In some embodiments, the compound of formula (I) or a salt thereof is a compound of formula (II):

[0137]

[0138] or a salt thereof, wherein B is 0, 1 or 2.

[0139] In some embodiments of the compound of Formula (II), R 4 Yes (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl.

[0140] In some embodiments, the compound of formula (I) or a salt thereof is a compound of formula (III):

[0141]

[0142] or a salt thereof, wherein B is 0, 1 or 2.

[0143] In some embodiments of the compound of formula (III), R 4 Yes (C 3 -C 7 ) cycloalkyl, phenyl or 6-membered heteroaryl.

[0144] In some embodiments, R a It's H.

[0145] In some embodiments, R a Selected from the group consisting of: halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) The cycloalkyl is optionally substituted with one or more fluorine.

[0146] In some embodiments, R a H, halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF 2 H、(C 1 -C 5) alkyl or (C 3 -C 5 )cycloalkyl.

[0147] In some embodiments, R a It is a halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF 2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0148] In some embodiments, R b It's H.

[0149] In some embodiments, R b is a halide, a cyano group, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) The cycloalkyl is optionally substituted with one or more fluorine.

[0150] In some embodiments, R b H, halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF 2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0151] In some embodiments, R b It is a halide, cyano, CF 3 CF2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF 2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0152] In some embodiments, R c It's H.

[0153] In some embodiments, R c Selected from the group consisting of: halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) The cycloalkyl is optionally substituted with one or more fluorine.

[0154] In some embodiments, R c H, halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF 2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0155] In some embodiments, R c It is a halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH2 CF 2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0156] In some embodiments, R 1 and R c Together with the atoms to which they are attached they form a fused cyclopropyl ring.

[0157] In some embodiments, R d It's H.

[0158] In some embodiments, R d Selected from the group consisting of: halo, cyano, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 )cycloalkyl, wherein any (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy and (C 3 -C 5 ) The cycloalkyl is optionally substituted with one or more fluorine.

[0159] In some embodiments, R d H, halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF 2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0160] In some embodiments, R d It is a halide, cyano, CF 3 CF 2 H.CFH 2 、OCF 3 、OCF 2 H、OCH 2 CF 3 、OCH 2 CF2 H、(C 1 -C 5 ) alkyl or (C 3 -C 5 )cycloalkyl.

[0161] In some embodiments, R c and R d Together with the atoms to which they are attached, they form a spiro 3 -C 5 )cycloalkyl.

[0162] In some embodiments, R 1 Selected from the group consisting of cyano, halo, methoxycarbonyl, cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy, any cyclopropyl, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy is optionally substituted by one or more independently selected from hydroxy, (C 1 -C 3 ) alkoxy, benzyloxy and fluorine groups.

[0163] In some embodiments, R 1 is H, methyl, cyclopropyl, CF 3 CF 2 H.CFH 2 、OCF 3 or OCF 2 H.

[0164] In some embodiments, R 1 It is hydroxy, hydroxymethyl or cyanomethyl.

[0165] In some embodiments, R 1 It's methyl.

[0166] In some embodiments, R 1 It's H.

[0167] In some embodiments, the group:

[0168]

[0169] Selected from the group consisting of:

[0170]

[0171] In some embodiments, A is 0.

[0172] In some embodiments, A is 1.

[0173] In some embodiments, R 2 It's cyano.

[0174] In some embodiments, R 2 It is 6-cyano.

[0175] In some embodiments, R 4 is optionally replaced by one or more R x Substituted phenyl.

[0176] In some embodiments, R 4 Selected from the group consisting of:

[0177]

[0178] In some embodiments, R 4 is optionally replaced by one or more R x Substituted pyrimidin-2-yl.

[0179] In some embodiments, R 4 Selected from the group consisting of:

[0180]

[0181] In some embodiments, R 4 is optionally replaced by an R x Replaced (C 1 -C 7 )alkyl.

[0182] In some embodiments, R 4 is optionally replaced by an R x Replaced (C 3 -C 7 )cycloalkyl.

[0183] In some embodiments, R 4 is optionally replaced by an R x Substituted 6-membered heteroaryl.

[0184] In some embodiments, R x is C optionally substituted by one or more groups independently selected from halo, cyano and hydroxy 1 -C 5 alkyl.

[0185] In some embodiments, R x is a C substituted by a hydroxyl group 1 -C 5 alkyl.

[0186] In some embodiments, R x It is 2-hydroxy-2-methylethyl.

[0187] In some embodiments, the compound of formula (I) or a salt thereof is a compound of formula IV or V:

[0188]

[0189] or a salt thereof, wherein B is 0, 1 or 2.

[0190] In some embodiments, the compound of formula (I) or a salt thereof is a compound of formula IV or Va:

[0191]

[0192] or a salt thereof, wherein B is 0, 1 or 2.

[0193] In some embodiments, the compound of formula (I) or a salt thereof is a compound of formula VI or VII:

[0194] or a salt thereof.

[0195] In some embodiments, R c is fluorine, R d It is H or fluorine.

[0196] In some embodiments, the compound or salt is selected from the group consisting of:

[0197]

[0198]

[0199] and its salts.

[0200] In some embodiments, the compound or salt is selected from the group consisting of:

[0201]

[0202] and its salts.

[0203] In some embodiments, the compound or salt is selected from the group consisting of:

[0204] and its salts.

[0205] In some embodiments, the compound or salt is selected from the group consisting of:

[0206]

[0207] and its salts.

[0208] In some embodiments, the compound or salt is selected from the group consisting of:

[0209]

[0210]

[0211] and its salts.

[0212] In some embodiments, the compound or salt is:

[0213]

[0214] or a salt thereof.

[0215] In some embodiments, the compound or salt is:

[0216]

[0217] or a salt thereof.

[0218] In some embodiments, the present disclosure provides 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the present disclosure provides a compound of formula (I) or a salt thereof having lower toxicity than GSK2798745.

[0220] In some embodiments, the present disclosure provides compounds of formula (I) or salts thereof having improved potency compared to GSK2798745.

[0221] In some embodiments, the present disclosure provides compounds of Formula (I) or salts thereof having improved metabolic stability (eg, toward CYP3A4) compared to GSK2798745.

[0222] In some embodiments, the disclosure provides a compound of formula (I) or a salt thereof having lower levels of active circulating metabolites than GSK2798745.

[0223] In some embodiments, the present disclosure provides a compound of formula (I) or a salt thereof having a higher safety maximum than GSK2798745.

[0224] In some embodiments, the disclosure provides compounds of Formula (I) or salts thereof having improved metabolic stability (eg, against CYP3A4) and similar or improved potency compared to GSK2798745.

[0225] In some embodiments, the disclosure provides compounds of Formula (I) or salts thereof having improved metabolic stability (eg, against CYP3A4) and similar or improved potency compared to GSK2798745.

[0226] In some embodiments, the present disclosure provides a solid form of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-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, or about 24.02 degrees 2θ. In some embodiments, the present disclosure provides a solid form of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile having 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 degrees 2θ. With respect to XRPD peaks, the term "about" refers to ±0.01 degrees 2θ.

[0227] In some embodiments, the present disclosure provides a solid form of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile having substantially the same Figure 1 In some embodiments, "substantially the same" refers to an XRPD diffraction pattern having at least three similar signals.

[0228] Processes for preparing compounds of formula I are provided as further embodiments of the present disclosure and are illustrated by the following procedures, wherein general groups have the meanings described above unless otherwise defined.

[0229] In the case where the compound has sufficient alkalinity or acidity, the salt of the compound of formula I can be used as an intermediate for isolating or purifying the compound of formula I. In addition, it may be appropriate to administer the compound of formula I in the form of a pharmaceutically acceptable acid or base salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, malonic acid, tartaric acid, succinic acid, benzoic acid, ascorbic acid, α-ketoglutaric acid and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

[0230] Salts can be obtained using standard methods well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable anion. Alkali metal (e.g. sodium, potassium or lithium) or alkaline earth metal (e.g. calcium) salts of carboxylic acids can also be prepared.

[0231] The compounds of formula I may be formulated into pharmaceutical compositions and administered to a mammalian host, such as a human patient, in various forms suitable for the chosen route of administration, ie, orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

[0232] Therefore, the compounds of the present invention can be combined with a pharmaceutically acceptable vehicle (such as an inert diluent or an absorbable edible carrier) for systemic administration, such as oral administration. They can be enclosed in hard or soft shell gelatin capsules, can be compressed into tablets, or can be directly combined with the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, powder tablets, etc. Such compositions and preparations should contain at least 0.1% active compound. The percentage of the composition and preparation can of course vary and can be preferably between about 2% to about 60% of the weight of a given unit dosage form. The amount of the active compound in such a therapeutically applicable composition is an amount that will obtain an effective dosage level.

[0233] Tablets, lozenges, pills, capsules, etc. may also contain the following: binders such as gum tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame or flavoring agents such as peppermint, wintergreen oil, or cherry flavoring may be added. When the unit dosage form is a capsule, it may also contain a liquid carrier such as a vegetable oil or polyethylene glycol in addition to the above types of substances. Various other substances may be present as coatings or may be present to further improve the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar, etc. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propylparabens as preservatives, a dye, and flavorings, such as cherry or orange flavoring. Of course, any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0234] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts may be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0235] The pharmaceutical dosage form suitable for injection or infusion may include a sterile aqueous solution or dispersion or a sterile powder containing an active ingredient suitable for extemporaneous preparation of a sterile injectable or infusible solution or dispersion, optionally encapsulated in a liposome. In all cases, the final dosage form should be sterile and stable under production and storage conditions. The liquid carrier or vehicle may be a solvent or liquid dispersion medium, including, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), a vegetable oil, or a non-toxic glyceride and a suitable mixture thereof. Preventing the action of microorganisms may be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, it will be preferred to include an isotonic agent, such as sugar, a buffer, or sodium chloride. Prolonging the absorption of the injectable composition may be achieved by using an agent that delays absorption in the composition, such as aluminum monostearate and gelatin.

[0236] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent along with various of the other ingredients enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques which yield a powder of the active ingredient plus any additional desired ingredient present in a previously sterile-filtered solution.

[0237] For topical administration, the compounds of the invention can be applied in pure form, ie when they are liquids. However, it will generally be desirable to combine them with a dermatologically acceptable carrier, which may be a solid or liquid, to administer them to the skin in the form of a composition or formulation.

[0238] Suitable solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silicon dioxide, alumina, and the like. Suitable liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends in which the compounds of the invention may be dissolved or dispersed at effective levels, optionally with the aid of nontoxic surfactants. Adjuvants such as fragrances and other antimicrobial agents may be added to optimize the properties for a given use. The resulting liquid composition may be applied from an absorbent pad, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump sprayer or an aerosol sprayer.

[0239] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified minerals may also be used with the liquid carrier to form spreadable pastes, gels, ointments, soaps, etc. for application directly to the user's skin.

[0240] Examples of useful dermatological compositions that can be used to deliver compounds of Formula I to the skin are known in the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157), and Wortzman (U.S. Pat. No. 4,820,508).

[0241] The effective dosage of the compounds of formula I can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Pat. No. 4,938,949.

[0242] The amount of the compound or its active salt or derivative required for use in therapy will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.

[0243] The desired dose may conveniently be provided in a single dose or in divided doses administered at appropriate intervals, for example in two, three, four or more sub-doses per day. The sub-doses themselves may be further administered, for example, in a number of individual, loosely spaced doses; such as by multiple inhalations from an insufflator or by applying multiple drops to the eye.

[0244] The compounds of the present disclosure may be administered alone or in combination with one or more other therapeutic agents, for example, 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, ionomers, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, antihistamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective adrenergic receptor and alpha 1 adrenergic receptor antagonists, type 5 phosphodiesterase inhibitors, and renin inhibitors.

[0245] Therefore, in some embodiments, the present disclosure also provides a composition 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 present 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 a compound of formula I or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents to an animal for treating a condition associated with TRPV4 modulation.

[0246] The biological activity of the compound can be determined using any suitable assay for evaluating TRPV4 antagonist activity, and using any suitable tissue or in vivo model. For example, the biological activity of the compound can be assessed 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.

[0247] How to use

[0248] In some aspects, the present disclosure provides methods of modulating TRPV4 expression using a compound of the present disclosure or a salt thereof.

[0249] In some aspects, the present disclosure provides methods of modulating TRPV4 expression with a pharmaceutical compound comprising a compound of the present disclosure or a salt thereof.

[0250] In some aspects, the present disclosure provides methods of treating or preventing a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a salt thereof.

[0251] In some aspects, the present disclosure provides methods of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a salt thereof, or a pharmaceutical composition of the present disclosure.

[0252] In some aspects, the present disclosure provides methods of treating or preventing a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a salt thereof.

[0253] In some aspects, the present disclosure provides methods of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a salt thereof, or a pharmaceutical composition of the present disclosure.

[0254] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in modulating TRPV4 expression.

[0255] In some aspects, the present disclosure provides a compound of the present disclosure or a salt thereof, or a pharmaceutical composition of the present disclosure for use in treating or preventing a disease or disorder.

[0256] In some aspects, the present disclosure provides a compound of the present disclosure or a salt thereof for use in treating or preventing a disease or condition disclosed herein.

[0257] In some aspects, the present disclosure provides a compound of the present disclosure or a salt thereof for use in treating a disease or condition disclosed herein.

[0258] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating TRPV4 expression.

[0259] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a salt thereof in the preparation of a medicament for treating or preventing a disease or condition disclosed herein.

[0260] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a salt thereof in the preparation of a medicament for treating a disease or condition disclosed herein.

[0261] In some embodiments, the disease or disorder is associated with the involvement of TRPV4.

[0262] In some aspects, the present disclosure provides a method for treating a condition associated with TRPV4 modulation, comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a solid form thereof.

[0263] In some aspects, the disclosure provides a compound of the disclosure, or a salt thereof, or a solid form thereof, for use in medical therapy.

[0264] In some aspects, the present disclosure provides a compound of the present disclosure, or a salt thereof, or a solid form thereof, for use in the prophylactic or therapeutic treatment of a condition associated with TRPV4 modulation.

[0265] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a salt thereof, or a solid form thereof, in the preparation of a medicament for treating a condition associated with TRPV4 modulation in an animal.

[0266] In some embodiments, the salt thereof is a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the compound is administered to a subject.

[0268] In some embodiments, the compounds are administered to animals.

[0269] In some embodiments, the subject is an animal.

[0270] In some embodiments, the subject is a human.

[0271] In some embodiments, the disease or disorder is a respiratory disease or disorder.

[0272] In some embodiments, the disease or condition is chronic cough, pulmonary edema, chronic obstructive pulmonary disease, or pulmonary fibrosis.

[0273] In some embodiments, the disease or disorder is inflammatory hyperalgesia.

[0274] In some embodiments, the disease or disorder is mechanical pain.

[0275] In some embodiments, the disease or disorder is neuropathic pain.

[0276] In some embodiments, the disease or disorder is a bladder related condition.

[0277] In some embodiments, the disease or condition is a respiratory disease, a joint disease, pain, or bladder dysfunction.

[0278] In some embodiments, the disease or disorder is a joint disease.

[0279] In some embodiments, the disease or condition is pain.

[0280] In some embodiments, the disease or disorder is bladder dysfunction.

[0281] In some embodiments, the disease or disorder is a Mendelian disease.

[0282] In some embodiments, the disease or disorder is skeletal dysplasia.

[0283] In some embodiments, modulation is inhibition.

[0284] In some embodiments, modulation is antagonism.

[0285] Synthesis method

[0286] Formula (I) compounds can be prepared using the synthetic methods and intermediates described in the following examples. Formula (I) compounds can also be prepared using known synthetic methods and intermediate compounds, including, for example, synthetic methods and intermediate compounds described in International Patent Application Publication Nos. WO2012 / 174340, WO2012 / 174342, WO2013 / 012500, and WO2017 / 199199. Schemes 1-6 illustrate intermediates and methods that can be used to prepare compounds of formula (I).

[0287] Solution 1

[0288]

[0289]

[0290] Solution 2

[0291]

[0292]

[0293] Solution 3

[0294]

[0295] Solution 4

[0296]

[0297] Solution 5

[0298]

[0299] Solution 6

[0300]

[0301]

[0302] Solution 7

[0303]

[0304] Solution 8

[0305]

[0306]

[0307] The present disclosure will now be illustrated by the following non-limiting examples.

[0308] Example

[0309] For illustrative purposes, neutral compounds of formula (I) were synthesized and tested in the examples. It should be understood that the conventional techniques in the art (e.g., by saponifying an ester into a carboxylate, or by hydrolyzing an amide to form a corresponding carboxylic acid, which is then converted into a carboxylate) can be used to convert the neutral compound of formula (I) into the corresponding salt of the compound.

[0310] Example 1. Preparation of 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0311]

[0312] Reaction scheme

[0313]

[0314]

[0315] Detailed procedures

[0316] Racemic-4,4-dimethyl-3-(nitromethyl)cyclohexane-1-one

[0317]

[0318] Nitromethane (3.83g, 62.81mmol, 1.2 equivalents) is added to a solution of 4,4-dimethylcyclohex-2-ene-1-one (6.50g, 52.34mmol, 1 equivalent) and benzyltrimethylammonium hydroxide (13.13g, 78.51mmol, 1.5 equivalents) in methanol (60mL). The resulting mixture is stirred at room temperature overnight and concentrated under vacuum to give a crude product. The residue is purified by silica gel column chromatography, eluted with 0% to 10% ethyl acetate / petroleum ether. The fractions are combined and concentrated under vacuum to give the desired product 4,4-dimethyl-3-(nitromethyl)cyclohexane-1-one (6.70g, 46% yield) as a light yellow oil.

[0319] Racemic-8,8-dimethyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane

[0320]

[0321] Ethylene glycol (3.37 g, 54.26 mmol, 1.5 equivalents) is 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 is 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) is added dropwise to the mixture. The resulting mixture is removed from the bath and allowed to warm to room temperature and stirred for 2 hours. The reaction mixture is concentrated under vacuum. The residue is purified by silica gel column chromatography, eluted with 0% to 10% ethyl acetate / petroleum ether. The fractions were combined and concentrated in vacuo to give the desired product, rac-8,8-dimethyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (6 g, 72.3% yield) as a light yellow oil. 1 HNMR (400 MHz, DMSO-d 6 )δ4.73(dd,J=12.6,3.9Hz,1H),4.25(dd,J=12.6,10.1Hz,1H),3.85-3.82(m,4H),2.17( dd,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).

[0322] rac-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0323]

[0324] Palladium on carbon (10%, 0.28 g, 2.62 mmol, 0.1 eq) was added to a solution of racemic-8,8-dimethyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (6.0 g, 26.17 mmol, 1 eq) in methanol (60 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with methanol (3×100 mL). The filtrate was concentrated under reduced pressure to give the crude product racemic-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (6 g crude material) as a colorless oil. LCMS (ESI-MS) m / z=200[M+H]+ .

[0325] rac-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0326]

[0327] Potassium carbonate (8.32 g, 60.21 mmol, 2 equivalents) was added to a solution of racemic-(8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (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 at room temperature overnight. The reaction mixture was diluted 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 give a crude product. The residue was purified by silica gel column chromatography eluting with 0% to 10% ethyl acetate in petroleum ether and concentrated under vacuum to give the desired product, racemic-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (7 g, 67.3% yield) as an orange solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.38-8.31(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] + .

[0328] 4-Amino-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0329]

[0330] Palladium on carbon (10%, 0.22 g, 2.03 mmol, 0.1 eq) was added to a solution of racemic-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (7 g, 20.27 mmol, 1 eq) in methanol (70 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with methanol (3×100 mL). The filtrate was concentrated under reduced pressure to give the crude product racemic-4-amino-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (6 g crude material) as a colorless oil. LCMS (ESI-MS) m / z=316[M+H] + .

[0331] rac-1-((8,8-dimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0332]

[0333] Formic acid (0.88 g, 19.02 mmol, 1 eq) was added to a solution of rac-4-amino-3-(((8,8-dimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (6 g, 19.02 mmol, 1 eq) in trimethoxymethane (58.54 g, 551.64 mmol, 29 eq). The resulting mixture was heated to 80 °C, stirred for 3 hours and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in petroleum ether. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, rac-1-((8,8-dimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4 g, 60.6% yield for 2 steps) as a white solid. LCMS (ESI-MS) m / z=326 [M+H] + .

[0334] rac-1-((2,2-dimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0335]

[0336] A solution of racemic-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 equiv) in formic acid (50 mL) was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (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 give the crude product racemic-1-((2,2-dimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.50 g crude material) as a white solid. LCMS (ESI-MS) m / z=282[M+H] + .

[0337] rac-1-(((3S,5R)-6,6-dimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0338]

[0339] Sodium hydride (60% in oil, 1.19 g, 49.76 mmol, 4 eq) was added to a solution of trimethylsulfoxonium iodide (10.95 g, 49.76 mmol, 4 eq) in dimethyl sulfoxide (100 mL) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of racemic-1-((2,2-dimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.50 g, 12.44 mmol, 1 eq) in dimethyl sulfoxide (35 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 give the crude product, rac-1-(((3S,5R)-6,6-dimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g crude material), as a yellow oil. LCMS (ESI-MS) m / z=296 [M+H] + .

[0340] rac-1-(((5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0341]

[0342] 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, a solution of racemic-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) in N-methylpyrrolidone (10 mL) was added dropwise. The reaction mixture was then 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 (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography eluting with 0% to 2% methanol / dichloromethane and concentrated under vacuum to give the desired product, rac-1-(((5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g, 75.9% yield for 3 steps) as a white solid. LCMS (ESI-MS) m / z=339 [M+H] + .

[0343] rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0344]

[0345] Copper(I) iodide (562.78 mg, 2.95 mmol, 1 eq.) was added to rac-1-(((5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 2.95 mmol, 1 eq.), 2-(5-chloropyrazin-2-yl)propan-2-ol (0.51 g, 2.95 mmol, 1 eq.), N-[(5S,7R)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 2.95 mmol, 1 eq.), 1 ,N 2-dimethylethane-1,2-diamine (0.52g, 5.91mmol, 2 equivalents) and potassium phosphate (1.25g, 5.91mmol, 2 equivalents) in a solution of 1,4-dioxane (10mL). 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, eluted with 0% to 4% methanol / dichloromethane. The fractions were combined and concentrated under vacuum to give the desired product racemic-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 (800mg, 57.1% yield) as a light yellow solid. 1 H NMR(400MHz,DMSO-d6)δ9.10(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] + .

[0346] 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0347]

[0348] Racemic-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (800 mg, 1.68 mmol, 1 eq) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2MNH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 15mL / min; gradient: 50% B to 50% B in 15min; wavelength: 220 / 254nm; RT1(min): 7.11; RT2(min): 11.56; sample solvent: EtOH--HPLC; injection volume: 1mL. The desired fractions were combined and lyophilized to obtain the product:

[0349] First eluting isomer: 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (228.7 mg, 96.6% purity, 100% ee, 28.5% yield) as a white solid. Structure confirmed by X-ray crystallography. 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(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] + .

[0350] Second eluting isomer: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (213.1 mg, 99.9% purity, 100% ee, 26.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(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] + .

[0351] Example 2. Preparation of 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0352]

[0353] Reaction scheme

[0354]

[0355]

[0356] Detailed procedure N,N-dibenzyl-1-methoxymethylamine

[0357]

[0358] Potassium carbonate (47.29g, 342.1mmol, 1.5 equivalents) and sodium sulfate (48.60g, 342.1mmol, 1.5 equivalents) are added to a mixture of dibenzylamine (45g, 228.1mmol, 1 equivalent) and paraformaldehyde (6.78g, 75.27mmol, 0.3 equivalent) in methanol (250mL). The resulting mixture is stirred at room temperature for 12 hours. The resulting mixture is filtered through diatomaceous earth and the filtrate is concentrated under vacuum to obtain a crude product N, N-dibenzyl-1-methoxymethylamine (50g of crude material), which is a yellow oil. 1 HNMR (400 MHz, chloroform-d) δ7.44-7.33 (m, 9H), 7.31 (q, J = 3.1, 2.3 Hz, 1H), 4.08 (s, 2H), 3.88 (s, 4H), 3.29 (s, 3H). LCMS (ESI-MS) m / z = 242 [M+H] + .

[0359] rac-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decan-8-one

[0360]

[0361] (S)-Proline (4.77 g, 41.43 mmol, 0.2 eq) was added to a stirred mixture of N,N-dibenzyl-1-methoxymethylamine (50 g, 207.18 mmol, 1 eq) in dimethyl sulfoxide (500 mL), followed by 1,4-dioxaspiro[4.5]decan-8-one (323.58 g, 2071.82 mmol, 10 eq). The resulting mixture was stirred at 40 °C for 16 hours, then diluted with water (2000 mL) and extracted with diethyl ether (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the crude product. The residue was purified by reverse phase (water containing 0.1% ammonium bicarbonate) in 0% to 50% acetonitrile to give the desired product, rac-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decan-8-one (30 g, 39.6% yield), as a light yellow solid. LCMS (ESI-MS) m / z = 366 [M+H] + .

[0362] Racemic-N,N-dibenzyl-1-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0363]

[0364] Diethylaminosulfur trifluoride (6,62 g, 41.04 mmol, 1.5 equiv) was added dropwise to a stirred mixture of racemic-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decane-8-one (10 g, 27.36 mmol, 1 equiv) in dichloromethane (100 mL) at 0 ° C under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate 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, eluting with 0% to 10% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give rac-N,N-dibenzyl-1-(8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methanamine (2.8 g, 26.4% yield) as a colorless oil. LCMS (ESI-MS) m / z = 388 [M+H] + .

[0365] rac-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0366]

[0367] Palladium on carbon (10%, 1.0 g, 2.52 mmol, 0.35 equiv) was added to a solution of racemic-N,N-dibenzyl-1-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (2.8 g, 7.23 mmol, 1 equiv) in methanol (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give racemic-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (1.2 g crude material) as a colorless oil. LCMS (ESI-MS) m / z=208[M+H] + .

[0368] rac-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0369]

[0370] Potassium carbonate (2.4 g, 17.37 mmol, 3 eq) was added to a mixture of racemic-(8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (1.2 g, 5.79 mmol, 1 eq) and 3-fluoro-4-nitrobenzonitrile (0.96 g, 5.79 mmol, 1 eq) 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 give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 17% ethyl acetate / petroleum ether. The fractions were combined and concentrated in vacuo to give rac-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-amino)-4-nitrobenzonitrile (840 mg, 32.9% yield for 2 steps) as an orange oil. LCMS (ESI-MS) m / z=354 [M+H] + .

[0371] 4-Amino-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0372]

[0373] Iron powder (1.58 g, 28.3 mmol, 10 equiv) was added to a mixture of racemic-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)-4-nitrobenzonitrile (1 g, 2.83 mmol, 1 equiv) and ammonium chloride (0.61 g, 11.3 mmol, 4 equiv) 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 filter cake was washed with ethanol (30 mL). The filtrate was concentrated under vacuum, and 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 give the crude product, rac-4-amino-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (700 mg crude material) as a yellow solid. LCMS (ESI-MS) m / z=324 [M+H] + .

[0374] rac-1-((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0375]

[0376] Formic acid (185 mg, 4.02 mmol, 2 eq) was added to a mixture of rac-4-amino-3-(((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (650 mg, 2.01 mmol, 1 eq) and triethyl orthoformate (297.92 mg, 2.01 mmol, 1 eq) in tetrahydrofuran (5 mL). The resulting mixture was heated to 80 °C, stirred for 12 hours, and then concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 10% methanol / dichloromethane. The fractions were combined and concentrated in vacuo to give rac-1-((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg, 63.6% yield for 2 steps) as a yellow solid. LCMS (ESI-MS) m / z = 334 [M+H] + .

[0377] rac-1-((2,2-difluoro-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0378]

[0379] A solution of rac-1-((8,8-difluoro-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg, 1.8 mmol, 1 eq) in formic acid (4 mL) was stirred at 70 °C overnight. The resulting mixture was concentrated under vacuum to give the crude product rac-1-((2,2-difluoro-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg crude material) as a yellow solid. LCMS (ESI-MS) m / z = 290 [M+H] + .

[0380] rac-1-(((3S,5S)-6,6-difluoro-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0381]

[0382] A stirred mixture of racemic-1-((2,2-difluoro-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 1.38 mmol, 1 eq) in dimethyl sulfoxide (5 mL) was heated to 35 °C to allow all solids to go into solution. Trimethylsulfoxonium iodide (456.45 mg, 2.07 mmol, 1.5 eq) was added to the above solution followed by potassium tert-butoxide (232.74 mg, 2.07 mmol, 1.5 eq). 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 give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 8% methanol / dichloromethane. The fractions were combined and concentrated in vacuo to give rac-1-(((3S,5S)-6,6-difluoro-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 71.7% yield) as a yellow solid. LCMS (ESI-MS) m / z = 304 [M+H] + .

[0383] rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0384]

[0385] Lithium tert-butoxide (158.36 mg, 1.98 mmol, 2 eq) was added to a mixture of racemic-1-(((3S,5S)-6,6-difluoro-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.99 mmol, 1 eq) and ethyl carbamate (132.18 mg, 1.48 mmol, 1.5 eq) in N-methyl-2-pyrrolidone (5 mL). The reaction mixture was then heated to 75 °C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted 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 give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 10% methanol / dichloromethane. The fractions were combined and concentrated in vacuo to give rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 87.4% yield) as a yellow solid. LCMS (ESI-MS) m / z = 347 [M+H] + .

[0386] rac-1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0387]

[0388] Cuprous iodide (198 mg, 1.03 mmol, 1.2 eq.) was added to rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.87 mmol, 1 eq.), 2-(5-chloropyrazin-2-yl)propan-2-ol (149.5 mg, 0.87 mmol, 1 eq.), N-[(5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.87 mmol, 1 eq.), 1 ,N 2-dimethylethane-1,2-diamine (152.7 mg, 1.73 mmol, 2 equiv) and tripotassium phosphate (441 mg, 2.08 mmol, 2.4 equiv) in a mixture of 1,4-dioxane (5 mL). The reaction mixture was stirred at 100 ° C for 12 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 10% methanol / dichloromethane. The fractions were combined and concentrated in vacuo to give rac-1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 24% yield) as a yellow solid. LCMS (ESI-MS) m / z = 483 [M+H] + .

[0389] 1-(((5R,7R)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0390]

[0391] Racemic-1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-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 NH 3 -methanol)-HPLC, mobile phase B: ethanol-HPLC; flow rate: 20 mL / min; gradient: 45% B to 45% B in 17 min; wavelength: 220 nm. The desired fractions were combined and lyophilized to obtain two products:

[0392] First eluting isomer: 1-(((5R,7R)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (26.4 mg, 96.2% purity, 100% ee, 17.6% yield) as a white solid. Confirmed by X-ray structural analysis. 1 H NMR (300 MHz, DMSO-d 6 )δ9.17(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] + .

[0393] Second eluting isomer: 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (30.5 mg, 98.7% purity, 97.4% ee, 20.3% yield) as a white solid. Confirmed by X-ray structural analysis. 1 H NMR (300 MHz, DMSO-d 6 )δ9.17(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=9.6 Hz,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] + .

[0394] Example 3. 1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3Preparation of 1H-benzo[d]imidazole-6-carbonitrile

[0395]

[0396] Reaction scheme

[0397]

[0398]

[0399] Detailed procedures

[0400] Racemic-N,N-dibenzyl-1-(8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0401]

[0402] Potassium tert-butoxide (6.1 g, 54.72 mmol, 2 eq) was added to a mixture of methyltriphenylphosphonium bromide (11.7 g, 32.83 mmol, 1.2 eq) in toluene (100 mL), followed by the addition of racemic-7-((dibenzylamino)methyl)-1,4-dioxaspiro[4.5]decane-8-one (10 g, 27.36 mmol, 1 eq). The resulting mixture was stirred at 100 °C for 4 hours, diluted with water (200 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 give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 20% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give the desired product, rac-N,N-dibenzyl-1-(8-methylene-1,4-dioxaspiro[4.5]decan-7-yl)methanamine (9.2 g, 92.5% yield), as a yellow solid. LCMS (ESI-MS) m / z = 364 [M+H] + .

[0403] Racemic-N-((7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-N-benzyl-1-benzylamine

[0404]

[0405] Diiodomethane (1.77 mL, 22 mmol, 2 eq) and diethylzinc (22.01 mL, 22 mmol, 2 eq) were added to a mixture of racemic-N,N-dibenzyl-1-(8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (4 g, 11 mmol, 1 eq) in dichloromethane (50 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with saturated aqueous ammonium chloride solution (100 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by reverse phase with 0% to 40% water (containing 0.1% ammonium bicarbonate) / acetonitrile to give the desired product racemic-N-((7,10-dioxabispiro[2.2.4 6 .2 3 ] dodec-4-yl)methyl)-N-benzyl-1-phenylmethanamine (3 g, 72.2% yield) as a yellow solid. LCMS (ESI-MS) m / z=378 [M+H] + .

[0406] Racemic-(7,10-dioxadispiro[2.2.4 6 .2 3 ]Dodecane-4-yl)methylamine

[0407]

[0408] Palladium on carbon (10%, 532.77 mg, 5 mmol, 0.6 equiv) was added to rac-N-((7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methyl)-N-benzyl-1-phenylmethylamine (3 g, 7.94 mmol, 1 equivalent) in methanol (250 mL). The resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to give the crude product racemic-(7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methylamine (1 g, crude material), as a yellow oil. LCMS (ESI-MS) m / z = 198 [M+H] + .

[0409] Racemic-3-(((7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)amino)-4-nitrobenzonitrile

[0410]

[0411] Potassium carbonate (1.12 g, 8.11 mmol, 2 equiv) was added to rac-(7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methylamine (800mg, 4.05mmol, 1 eq) and 3-fluoro-4-nitrobenzonitrile (0.67g, 4.05mmol, 1 eq) in a mixture of acetonitrile (20mL). The resulting mixture was stirred at 50°C for 4 hours, diluted with water (100mL) and extracted with dichloromethane (3×40mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 15% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give the desired product, racemic-3-(((7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)amino)-4-nitrobenzonitrile (1.2 g, 86.3% yield) as a yellow solid. LCMS (ESI-MS) m / z=344 [M+H] + .

[0412] Racemic-1-((7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0413]

[0414] Iron (975.79 mg, 17.47 mmol, 5 equiv) was added to the rac-3-(((7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methyl)amino)-4-nitrobenzonitrile (1.2 g, 3.49 mmol, 1 eq.), trimethoxymethane (370.85 mg, 3.49 mmol, 1 eq.) and formic acid (160.84 mg, 3.49 mmol, 1 eq.) in a mixed solvent of methanol (60 mL) and ethyl acetate (60 mL). 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 give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 50% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give racemic-1-((7,10-dioxadispiro[2.2.4 6 .2 3]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg, 62% yield) as a yellow solid. LCMS (ESI-MS) m / z=324 [M+H] + .

[0415] rac-1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0416]

[0417] The racemic 1-((7,10-dioxadispiro[2.2.4 6 .2 3 A mixture of 1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg, 2.16 mmol, 1 eq.) in formic acid (7 mL) was heated to 70 ° C, stirred overnight and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 70% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give racemic-1-((6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 82.8% yield) as a yellow solid. LCMS (ESI-MS) m / z=280[M+H] + .

[0418] Racemic-1-(((3S,5S)-1-oxadispiro[2.2.2 6 .2 3 ]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0419]

[0420] Sodium hydroxide (60%, 143.2 mg, 3.58 mmol, 2 eq) 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 eq) and trimethylsulfoxonium iodide (787 mg, 3.58 mmol, 2 eq) 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 give the crude product rac-1-(((3S,5S)-1-oxadispiro[2.2.2 6 .2 3]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (470 mg crude material) as a white solid. LCMS (ESI-MS) m / z = 294 [M+H] + .

[0421] Racemic-1-(((4S,6S)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0422]

[0423] A mixture of lithium tert-butoxide (64.13 mg, 0.8 mmol, 0.5 eq) and ethyl carbamate (713 mg, 8 mmol, 5 eq) in N-methyl-2-pyrrolidone (11.75 mL) was stirred at room temperature for 10 min, and then rac-1-(((3S,5S)-1-oxadispiro[2.2.2 6 .2 3 ]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (470 mg, 1.60 mmol, 1 eq.). 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 (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product racemic-1-(((4S,6S)-8-oxo-7-oxa-9-azabisspiro[2.2.4 6 .2 3 ] dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (420 mg crude material) as a white solid. LCMS (ESI-MS) m / z = 337 [M+H] +

[0424] Racemic-1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0425]

[0426] Cuprous iodide (113.23 mg, 0.59 mmol, 0.5 equiv) was added to rac-1-(((4S,6S)-8-oxo-7-oxa-9-azabispiro[2.2.46 .2 3 ] dodecane-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 1.19 mmol, 1 eq), 2-(5-chloropyrazin-2-yl)propan-2-ol (205.25 mg, 1.19 mmol, 1 eq), N 1 ,N 2 -Dimethylethane-1,2-diamine (209.64 mg, 2.38 mmol, 2 equivalents) and tripotassium phosphate (504.80 mg, 2.38 mmol, 2 equivalents) in a mixture of 1,4-dioxane (15 mL). 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 (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 60% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give the desired product, racemic-1-(((4S, 6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-8-oxo-7-oxa-9-azabispivo[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 71.3% yield) as a white solid. LCMS (ESI-MS) m / z=473 [M+H] + .

[0427] 1-(((4R,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0428]

[0429] The racemic 1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro-[2.2.4 6 .2 3The racemate of 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 NH 3 -MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 15mL / min; gradient: 30% B to 30% B in 17min; wavelength: 220 / 254nm; RT1(min): 10.68; RT2(min): 13.184; sample solvent: EtOH--HPLC; injection volume: 0.4mL. The desired fractions were combined and lyophilized to obtain two products:

[0430] First eluting isomer: 1-(((4R,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (173.6 mg, 99.1% purity, 100.0% ee) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.26(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] + .

[0431] Second eluting isomer: 1-(((4S,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3] dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (159.8 mg, 99.1% purity, 99.0% ee) as a white solid. The absolute configuration was confirmed by X-ray crystal structure. 1 H NMR (300 MHz, DMSO-d 6 )δ9.26(d,J=1.5Hz,1H),8.60(d,J=1.5Hz,1H),8.50(s,1H),8.28(d,J=1.5Hz,1 H),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. 0Hz,2H),3.91(q,J=10.3Hz,2H),2.49-2.38(m,1H),2.33-2.20(m,1H),2.15-2. 01(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] + .

[0432] Example 4. Preparation of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0433]

[0434] Reaction scheme

[0435]

[0436]

[0437] Detailed procedures

[0438] 1-Methoxy-5-methylcyclohexa-1,4-diene

[0439]

[0440] Ammonia (1200 mL) was condensed into an evacuated, oven-dried 3-neck round bottom flask equipped with a cold finger containing dry ice acetone at -78°C under an inert atmosphere of nitrogen. Ether (600 mL) containing 1-methoxy-3-methylbenzene (64 g, 524.59 mmol, 1 eq) was added thereto, followed by tert-butyl alcohol (420 mL). Lithium wire (36.41 g, 5245.9 mmol, 10 eq) was then carefully added. After the addition, the reaction mixture was heated to -33°C, after which its color changed to dark blue. The reaction contents were stirred at -33°C for 3 hours, after which ammonium chloride (14.03 g, 2622.95 mmol, 5 eq) was added. The reaction mixture was subsequently removed from the -33°C bath, the cold finger removed and the reaction contents (open to the atmosphere) were warmed to room temperature and stirred for an additional 14 hours. The obtained 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 give the crude product 1-methoxy-5-methylcyclohexa-1,4-diene (60 g crude material) as a yellow oil. LCMS (ESI-MS) m / z=125 [M+H] + .

[0441] 3-Methylcyclohex-3-en-1-one

[0442]

[0443] Oxalic acid (6.53 g, 72.58 mmol, 0.15 eq) was added to a solution of 1-methoxy-5-methylcyclohexa-1,4-diene (60 g, 483.87 mmol, 1 eq) 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 give the crude product 3-methylcyclohex-3-ene-1-one (50 g crude material) as a white solid. LCMS (ESI-MS) m / z=111 [M+H] + .

[0444] 1-Methyl-7-oxabicyclo[4.1.0]heptan-3-one

[0445]

[0446] 3-Chloroperoxybenzoic acid (101.97 g, 590.90 mmol, 1.3 equivalents) was added to a solution of 3-methylcyclohex-3-ene-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, 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 give a crude product of 1-methyl-7-oxabicyclo [4.1.0] heptane-3-one (54 g crude material) as a light yellow oil. 1 H NMR(400MHz,Chloroform-d)δ3.23(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] + .

[0447] 4-((tert-Butyldiphenylsilyl)oxy)-3-methylcyclohex-2-en-1-one

[0448]

[0449] Tert-butyldiphenylsilyl chloride (117.80 g, 428.57 mmol, 1 equivalent) was added to a solution of 1-methyl-7-oxabicyclo [4.1.0] heptane-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 dichloromethane (600 mL) under a nitrogen atmosphere. 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 with water, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography, eluted with 0% to 10% ethyl acetate / petroleum ether. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, 4-((tert-butyldiphenylsilyl)oxy)-3-methylcyclohex-2-en-1-one (60 g, 31.3% yield for 4 steps) as a light yellow oil. LCMS (ESI-MS) m / z=365 [M+H] + .

[0450] rac-(3S,4R)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-3-(nitromethyl)cyclohexane-1-one

[0451]

[0452] Nitromethane (4.01 g, 65.75 mmol, 1.2 eq) was added to a solution of 4-((tert-butyldiphenylsilyl)oxy)-3-methylcyclohex-2-ene-1-one (20 g, 54.94 mmol, 1 eq) and benzyltrimethylammonium hydroxide (13.75 g, 82.41 mmol, 1.5 eq) in methanol (100 mL). The resulting mixture was stirred at room temperature overnight and concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 10% ethyl acetate / petroleum ether. The fractions were combined and concentrated under vacuum to give the desired product, racemic-(3S, 4R)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-3-(nitromethyl)cyclohexane-1-one (18 g, 77.1% yield), as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ7.62-7.49(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] + .

[0453] rac-tert-Butyl(((7S,8R)-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-yl)oxy)diphenylsilane

[0454]

[0455] Ethylene glycol (4.33 g, 69.72 mmol, 1.5 eq) was added to a solution of racemic-(3S, 4R)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-3-(nitromethyl)cyclohexane-1-one (19.8 g, 46.58 mmol, 1 eq) and trimethoxymethane (7.40 g, 69.72 mmol, 1.5 eq) 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 eq) was added dropwise to the mixture. The resulting mixture was removed from the bath and allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 0% to 10% ethyl acetate / petroleum ether. The fractions were combined and concentrated in vacuo to give the desired product, rac-tert-butyl(((7S,8R)-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-yl)oxy)diphenylsilane (18.5 g, 84.7% yield) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ7.62-7.49(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).

[0456] LCMS (ESI-MS) m / z = 470 [M + H] + .

[0457] rac-((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methanamine

[0458]

[0459] Iron powder (21.75 g, 389.4 mmol, 10 equiv) 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 equiv) and ammonium chloride (8.33 g, 155.76 mmol, 4 equiv) 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 filter cake was washed with ethanol (2×200 mL). The filtrate was concentrated under reduced pressure to give the crude product, racemic-((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methanamine (17 g crude material), as a yellow solid. LCMS (ESI-MS) m / z = 440 [M+H] + .

[0460] rac-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0461]

[0462] Potassium carbonate (10.68 g, 77.3 mmol, 2 eq) was added to a solution of rac-((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (17 g, 38.7 mmol, 1 eq) and 3-fluoro-4-nitrobenzonitrile (6.41 g, 38.7 mmol, 1 eq) 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 (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 15% ethyl acetate in petroleum ether. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, rac-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-amino)-4-nitrobenzonitrile (14 g, 61.3% yield for 2 steps) as an orange solid. 1 H NMR (400 MHz, DMSO-d 6)δ8.30-8.26(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),3.59-3.5 7(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] + .

[0463] 4-Amino-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0464]

[0465] Iron powder (13.34 g, 238.91 mmol, 10 equiv) was added to a solution of rac-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-amino)-4-nitrobenzonitrile (14 g, 23.93 mmol, 1 equiv) and ammonium chloride (5.11 g, 95.56 mmol, 4 equiv) 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 filter cake was washed with ethanol (2×200 mL). The filtrate was concentrated under reduced pressure to give the crude product, racemic-4-amino-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (13 g crude material), as a yellow solid. LCMS (ESI-MS) m / z=556 [M+H] + .

[0466] rac-1-(((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0467]

[0468]

[0136] Formic acid (1.08 g, 23.38 mmol, 1 eq) was added to a solution of rac-4-amino-3-((((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (13 g, 23.4 mmol, 1 eq) in trimethoxymethane (71.95 g, 678 mmol, 29 eq). The resulting mixture was heated to 80 °C, stirred for 3 hours and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in petroleum ether. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, rac-1-(((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 73.9% yield for 2 steps) as a pink solid.

[0469] 1 H NMR (400 MHz, DMSO-d 6 )δ8.40-8.35(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] + .

[0470] rac-1-(((1S,2R)-2-((tert-butyldiphenylsilyl)oxy)-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0471]

[0472] A solution of rac-1-(((7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 17.7 mmol, 1 equiv) in formic acid (100 mL) was stirred at 70 °C overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product rac-1-(((1S,2R)-2-((tert-butyldiphenylsilyl)oxy)-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g crude) as a yellow solid. LCMS (ESI-MS) m / z = 522 [M + H] + .

[0473] 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

[0474]

[0475] Sodium hydride (60% in mineral oil, 3.07 g, 76.6 mmol, 4 eq) was added to a solution of trimethylsulfoxonium iodide (16.87 g, 76.6 mmol, 4 eq) in dimethyl sulfoxide (100 mL) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of racemic-1-(((1S, 2R)-2-((tert-butyldiphenylsilyl)oxy)-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10 g, 19.19 mmol, 1 eq) in dimethyl sulfoxide (100 mL) 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 give 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-carbonitrile (10 g crude material), as a yellow solid. LCMS (ESI-MS) m / z=536 [M+H] + .

[0476] rac-1-(((5S,7S,8R)-8-((tert-butyldiphenylsilyl)oxy)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0477]

[0478] Lithium tert-butoxide (2.99 g, 37.32 mmol, 2 eq) was added to a solution of ethyl carbamate (33.21 g, 373.20 mmol, 20 eq) in N-methylpyrrolidone (100 mL). After stirring at room temperature for 5 minutes, a solution of racemic-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 eq) in N-methylpyrrolidone (100 mL) was added dropwise. The reaction mixture was then 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 (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluted with 0% to 2% methanol / dichloromethane. The fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, racemic-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 (5.5 g, 53.8% yield for 3 steps), as a light pink solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.40-8.35(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, 1H),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] + .

[0479] rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0480]

[0481] Racemic-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 (579 mg, 1 mmol, 1 eq) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 1 mL, 1 mmol, 1 eq). The mixture was stirred at room temperature overnight. The next day, calcium carbonate (200.18 mg, 2 mmol, 2 eq) and DOWEX 50WX8-400 (800 mg, 1 eq) were added to the reaction mixture, followed by methanol (2 mL). The resulting mixture was stirred at room temperature for 1 hour and filtered, and the filter cake was washed with methanol (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 10% methanol / dichloromethane. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, racemic-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, 79.4% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.30(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, 1H),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] + .

[0482] rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0483]

[0484] Dess-Martin periodic acid (224.45 mg, 0.53 mmol, 1.2 eq) was added to a solution of rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (150 mg, 0.44 mmol, 1 eq) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 3 hours. The residue was purified by silica gel column chromatography eluting with 0% to 2% methanol in dichloromethane. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (130 mg, 87.18% yield) as a white solid.

[0485] 1 H NMR (400 MHz, DMSO-d 6 )δ8.30(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] + .

[0486] rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0487]

[0488] Copper(I) iodide (72.37 mg, 0.38 mmol, 1 eq.) was added to rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (130 mg, 0.38 mmol, 1 eq.), 2-(5-chloropyrazin-2-yl)propan-2-ol (65.74 mg, 0.38 mmol, 1 eq.), N-[(5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (130 mg, 0.38 mmol, 1 eq.), 1 ,N 2-dimethylethane-1,2-diamine (66.88 mg, 0.76 mmol, 2 eq.) and tripotassium phosphate (161.32 mg, 0.76 mmol, 2 eq.) in 1,4-dioxane (2 mL). 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, eluting with 0% to 3% methanol / dichloromethane. Fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, rac-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 54.7% yield) as a light yellow solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.27(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] + .

[0489] 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0490]

[0491] Racemic-1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.21 mmol, 1 equiv) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: EtOH--HPLC, mobile phase B: MtBE (0.5% 2M NH 3 -MeOH)--HPLC; flow rate: 13mL / min; gradient: 50% B to 50% B in 13min; wavelength: 220 / 254nm; RT1(min): 8.31; RT2(min): 23.51; sample solvent: EtOH:DCM=1:1--HPLC; injection volume: 2mL. The desired fractions were combined and lyophilized to obtain the product:

[0492] First eluting isomer: 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (25.6 mg, 98.8% purity, 98.5% ee, 25.6% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.27(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] + .

[0493] Second eluting isomer: 1-(((5R,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (22.7 mg, 99.6% purity, 100% ee, 22.7% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.27(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] + .

[0494] Example 5. Preparation of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0495]

[0496] Reaction scheme

[0497]

[0498]

[0499] Detailed procedures

[0500] Racemic 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester

[0501]

[0502] A mixture of diethyl carbonate (94 g, 79.6 mmol) and sodium hydride (60% in mineral oil, 37.5 g, 93.8 mmol) in tetrahydrofuran (800 mL) was heated to reflux, and then a solution of 1,4-dioxaspiro[4.5]decane-8-one (50.0 g, 32.0 mmol) in tetrahydrofuran (230 mL) was added. The resulting mixture was stirred for 3 hours and then cooled to room temperature. Water (500 mL) and acetic acid (500 mL) were added to terminate the reaction. The resulting solution was then extracted with ethyl acetate (3×500 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated to give racemic-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester (52 g, 0.23 mol) as a yellow oil. It was used without further purification. LCMS (ESI-MS) m / z = 229.1 [M+H] + .

[0503] Racemic 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester

[0504]

[0505] Iodomethane (48.5g, 341mmol) is added to a mixture of racemic-8-oxo-1,4-dioxaspiro [4.5] decane-7-ethyl carboxylate (52g, 228mmol) ethyl and cesium carbonate (149g, 456mmol) in acetonitrile (600mL). The resulting mixture is stirred at room temperature for 4 hours. The mixture is filtered and the filtrate is concentrated to give a crude product. The residue is purified by silica gel column chromatography and eluted with 0% to 30% ethyl acetate / petroleum ether to give the product racemic-7-methyl-8-oxo-1,4-dioxaspiro [4.5] decane-7-ethyl carboxylate (45g, 81.5%) as a light yellow oil. LCMS (ESI-MS) m / z=243.1[M+H] + .

[0506] Racemic 8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-ene-7-carboxylic acid ethyl ester

[0507]

[0508] To a mixture of racemic-7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester (30 g, 124 mmol) in dichloromethane (500 mL) was added diethylaminosulfur trifluoride (39.9 g, 248 mmol) at 0°C. The solution was warmed to room temperature and stirred for 5 hours. The mixture was then slowly added to a stirred aqueous sodium bicarbonate solution (600 mL) at 0°C, and the resulting solution was extracted with dichloromethane (3×300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give racemic-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-ene-7-carboxylic acid ethyl ester (35 g crude material). LCMS (ESI-MS) m / z=245.1[M+H] + .

[0509] rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methanol

[0510]

[0511] To a mixture of rac-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-ene-7-carboxylic acid ethyl ester (35 g, 143 mmol) in tetrahydrofuran (600 mL) at 0°C, lithium aluminum hydride (115 mL, 286 mmol) was added, the mixture was stirred at room temperature for 2 hours, and then the mixture was quenched with cold ethanol. The resulting mixture was filtered and the filtrate was concentrated to give the crude product rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-ene-7-yl)methanol (30 g crude material). LCMS (ESI-MS) m / z=203.1[M+H] + .

[0512] rac-2-((8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methyl)isoindoline-1,3-dione

[0513]

[0514] To a mixture of rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-ene-7-yl)methanol (25 g, 124 mmol), isoindoline-1,3-dione (20 g, 136 mmol) and triphenyl phosphate (48.6 g, 185 mmol) in tetrahydrofuran (300 mL) was added diisopropyl azodicarboxylate (37.5 g, 185 mmol). The mixture was stirred at room temperature overnight, and the next morning the mixture was poured into ice water (200 mL). The resulting solution was extracted with ethyl acetate (3×200 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 40% ethyl acetate / petroleum ether to give the product, racemic-2-((8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methyl)isoindoline-1,3-dione (18 g, 43.9%), as a yellow oil. LCMS (ESI-MS) m / z=332.1 [M+H] + .

[0515] rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methanamine

[0516]

[0517] To a mixture of rac-2-((8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methyl)isoindoline-1,3-dione (18 g, 54 mmol) in ethanol (100 mL) was added hydrazine (17 g, 272 mmol, 80%). The mixture was stirred at room temperature overnight and then diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3×200 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated to give the product rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methanamine (8 g crude material). LCMS (ESI-MS) m / z=202.1[M+H] + .

[0518] rac-((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0519]

[0520] To a mixture of rac-(8-fluoro-7-methyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl)methanamine (8 g, 39.8 mmol) in methanol (80 mL) was added palladium on carbon (4 g, 50 wt%, 10% on carbon). 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 give rac-((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (7.2 g crude material) as a yellow oil. LCMS (ESI-MS) m / z=204.1[M+H] + .

[0521] rac-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0522]

[0523] To a mixture of rac-((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (7.2 g, 35.4 mmol) and 3-fluoro-4-nitrobenzonitrile (5.88 g, 35.4 mmol) in acetonitrile (100 mL) was added potassium carbonate (9.79 g, 70.8 mmol) and the resulting mixture was stirred at 50° C. for 4 hours. The suspension was filtered and the filtrate was diluted with water (200 mL), then the resulting solution was extracted with dichloromethane (3×200 mL), the organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 15% ethyl acetate / petroleum ether to give the product, racemic-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (6 g, 48.4%), as an orange solid. LCMS (ESI-MS) m / z=350.1 [M+H] + .

[0524] 4-Amino-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0525]

[0526] To a mixture of rac-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (5.5 g, 15.7 mmol) and ammonium chloride (4.21 g, 78.7 mmol) in ethanol (100 mL) and water (30 mL) was added 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 give rac-4-amino-3-((((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (4.2 g crude material) as a yellow solid. LCMS (ESI-MS) m / z = 320.2 [M+H] + .

[0527] rac-1-(((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0528]

[0529] To a mixture of racemic-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) in acetonitrile (20 mL) was added 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 give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 45% ethyl acetate / petroleum ether to give the product, racemic-1-(((7S,8R)-8-fluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4 g, 92.3%) as a yellow solid. LCMS (ESI-MS) m / z = 330.2 [M+H] + .

[0530] rac-1-(((1S,2R)-2-fluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0531]

[0532] 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 at 70 °C overnight and concentrated to give the product rac-1-(((1S,2R)-2-fluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.6 g crude material) as a yellow oil. LCMS (ESI-MS) m / z = 286.1 [M+H] + .

[0533] rac-1-(((3S,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((3R,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0534]

[0535] To a mixture of trimethylsulfoxonium iodide (5.24 g, 23.8 mmol) in DMSO (50 mL) was added sodium hydrogen (60% in mineral oil, 1.43 g, 35.7 mmol). The mixture was stirred at 10 °C for 10 minutes, then racemic-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 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), and the organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product. To separate the diastereomers, the residue was purified by reverse phase chromatography eluting with 0% to 45% acetonitrile / water to give the more polar racemic-1-(((3R,5S,6S)-6-fluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg) as a light yellow solid. Further elution with acetonitrile / water (55%) gave the less polar racemic-1-(((3S,5S,6R)-6-fluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.2 g) as a light yellow solid. LCMS (ESI-MS) m / z = 300.1 [M+H] + .

[0536] rac-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0537]

[0538] 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 racemic-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 at 100 °C overnight. The next day, the mixture was quenched with water (60 mL) and the solution was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 100% ethyl acetate / petroleum ether to give the product, racemic-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg), as a colorless oil. LCMS (ESI-MS) m / z=343.1 [M+H] + .

[0539] rac-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0540]

[0541] Copper (I) iodide (110.46 mg, 0.58 mmol, 1 eq.) was added to the outer

[0542] 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 eq), 2-(5-chloropyrazin-2-yl)propan-2-ol (100.34 mg, 0.58 mmol, 1 eq), N 1 ,N 2-dimethylethane-1,2-diamine (102.08 mg, 1.16 mmol, 2 equiv) and tripotassium phosphate (246.23 mg, 1.16 mmol, 2 equiv) in 1,4-dioxane (2 mL). 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, eluting with 0% to 3% methanol / dichloromethane. The fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, rac-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 71.43% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.45(s,1H),8.26(d,J=1.5 Hz,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] + .

[0543] 1-(((5S,7S,8R)-8-Fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7R,8S)-8-Fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0544]

[0545] Racemic-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.42 mmol, 1 eq.) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2MNH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 14mL / min; gradient: 30% B to 30% B in 29min; wavelength: 220 / 254nm; RT1(min): 13.529; RT2(min): 21.063; sample solvent: EtOH--HPLC; injection volume: 0.8mL. The desired fractions were combined and lyophilized to obtain the product:

[0546] Example 5A (first eluting isomer): 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (77.3 mg, 97.0% purity, 100% ee, 38.65% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.45(s,1H),8.26(d,J=1.5 Hz,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] + .

[0547] Example 5B (second eluting isomer): 1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (76.5 mg, 99.5% purity, 100% ee, 38.25% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=1.5Hz,1H),8.59(d,J=1.5Hz,1H),8.45(s,1H),8.26(d,J=1.5 Hz,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] + The structure was confirmed by X-ray crystallographic analysis.

[0548] Example 6. 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 Preparation of 1H-benzo[d]imidazole-6-carbonitrile

[0549]

[0550] Detailed procedures

[0551] Racemic-N,N-dibenzyl-1-(7-methyl-8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0552]

[0553] To a mixture of methyltriphenylphosphonium bromide (70.6 g, 198 mmol) in toluene (600 mL) was added potassium 2-methylpropan-2-olate (22.2 g, 198 mmol), the mixture was stirred at room temperature for 10 minutes, and then racemic-7-((dibenzylamino)methyl)-7-methyl-1,4-dioxaspiro[4.5]decane-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 (3×400 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 10% ethyl acetate / petroleum ether to give racemic-N,N-dibenzyl-1-(7-methyl-8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (45 g) as a colorless oil. LCMS (ESI-MS) m / z=378.2 [M+H] + .

[0554] Racemic-N,N-dibenzyl-1-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ]Dodecane-4-yl)methylamine

[0555]

[0556] To a mixture of racemic-N,N-dibenzyl-1-(7-methyl-8-methylene-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (45 g, 119 mmol) in diethyl ether (600 mL) was added diethyl zinc (1 M in THF, 358 mL, 358 mmol) at 0°C. The mixture was stirred for 30 minutes, then diiodomethane (95.8 g, 358 mmol) was added, and the resulting solution was warmed to room temperature and stirred overnight. The mixture was quenched by aqueous ammonium chloride (600 mL), and then the resulting solution was extracted with DCM (3×200 mL), the organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 10% ethyl acetate / petroleum ether to give racemic-N,N-dibenzyl-1-(4-methyl-7,10-dioxaspiro[2.2.4 6 .2 3 ] dodecane-4-yl)methylamine (5 g), as a colorless oil. LCMS (ESI-MS) m / z = 392.3 [M+H] + .

[0557] Racemic-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3]Dodecane-4-yl)methylamine

[0558]

[0559] To racemic-N,N-dibenzyl-1-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 To a solution of 4-(4-(2-(4-(2-(4-methyl-7,10-dioxadispiro[2.2.4-yl)-1-(2 ... 6 .2 3 ] dodecane-4-yl)methylamine (2 g crude product) as a yellow oil. LCMS (ESI-MS) m / z = 212.2 [M+H] + .

[0560] Racemic-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)amino)-4-nitrobenzonitrile

[0561]

[0562] To racemic-(4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methylamine (2.2 g, 10.4 mmol) and 3-fluoro-4-nitrobenzonitrile (1.73 g, 10.4 mmol) in acetonitrile (30 mL) were added potassium carbonate (4.32 g, 31.2 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 give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 18% ethyl acetate / petroleum ether to give racemic-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] dodec-4-yl) methyl) amino) -4-nitrobenzonitrile (3.7 g, 99.4%), as an orange solid. LCMS (ESI-MS) m / z = 358.2 [M+H] + .

[0563] Racemic-4-amino-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ]Dodec-4-yl)methyl)amino)-benzonitrile

[0564]

[0565] To racemic-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl) methyl) amino) -4-nitrobenzonitrile (3.7 g, 10.4 mmol) and ammonium chloride (2.77 g, 51.8 mmol) in ethanol (50 mL) was added iron (2.89 g, 51.8 mmol), the mixture was stirred at 70 ° C for 2 hours, and then cooled to room temperature. The mixture was then filtered, the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL), dried over sodium sulfate, filtered and concentrated to give the product racemic-4-amino-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)amino)benzonitrile (3.3 g, 97.3%), as a yellow solid. LCMS (ESI-MS) m / z = 328.2 [M+H] + .

[0566] Racemic-1-((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0567]

[0568] To racemic-4-amino-3-(((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] dodecane-4-yl) methyl) amino) benzonitrile (3.2 g, 9.77 mmol) in acetonitrile (30 mL) was added 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 cooled to room temperature. The mixture was concentrated to give a crude product, and the residue was purified by silica gel column chromatography and eluted with 0% to 30% ethyl acetate / petroleum ether to give racemic-1-((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 ] dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3 g, 90.9%), as a yellow solid. LCMS (ESI-MS) m / z = 338.2 [M+H] + .

[0569] rac-1-((4-methyl-6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0570]

[0571] Formic acid (20 mL) was added to rac-1-((4-methyl-7,10-dioxadispiro[2.2.4 6 .2 3 The mixture was stirred at 70°C overnight and then cooled to room temperature. The solution was concentrated to give the product, racemic-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] + .

[0572] 1-(5-methyl-1-oxadispiro[2.2.26.23]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0573]

[0574] To a mixture of rac-1-((4-methyl-6-oxospiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2 g, 6.82 mmol) and trimethylsulfoxonium iodide (1.95 g, 8.86 mmol) in methyl sulfoxide (30 mL) was added potassium tert-butoxide (0.99 g, 8.86 mmol). The mixture was stirred at room temperature for 10 minutes and 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 give the crude product, and the residue was purified by silica gel column chromatography and eluted with 0% to 80% ethyl acetate / petroleum ether to give 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] + .

[0575] 1-((6-Hydroxy-6-(hydroxymethyl)-4-methylspiro[2.5]octan-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0576]

[0577] To 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) in N,N-dimethylformamide (10 mL) and water (10 mL) was added trifluoroacetic acid (1.26 g, 11.1 mmol). The mixture was stirred at room temperature overnight 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 give 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] + .

[0578] Racemic-1-(((3S,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 ]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and racemic-1-(((3R,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 ]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0579]

[0580] 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) was added tosyl chloride (1.78 g, 9.31 mmol), 4-dimethylaminopyridine (0.38 g, 3.10 mmol) and triethylamine (1.88 g, 18.6 mmol). 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 give the crude intermediate. The residue was dissolved in acetonitrile (20 mL), potassium carbonate (1.72 g, 12.4 mmol) was added, the mixture was stirred at 50° C. for 3 hours, filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative TLC (EA), Rf = 0.5 to give the product racemic-1-(((3S,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (210 mg, 11%) as a white solid, and Rf = 0.3 to give the product racemic-1-(((3R,5R)-5-methyl-1-oxadispiro[2.2.2 6 .2 3 ]decane-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg, 18.3%), as a white solid. LCMS (ESI-MS) m / z = 308.2 [M+H] + .

[0581] Racemic-1-(((4R,6S)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0582]

[0583] A mixture of ethyl carbamate (1.01 g, 11.4 mmol) and lithium tert-butoxide (182 mg, 2.28 mmol) in 1-methyl-2-pyrrolidone (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). 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 give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 100% ethyl acetate / petroleum ether to give racemic-1-(((4R,6S)-4-methyl-8-oxo-7-oxa-9-azabisspiro[2.2.4 6 .2 3 ] dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (330 mg, 82.7%), as a yellow solid. LCMS (ESI-MS) m / z = 351.2 [M+H] + .

[0584] rac-1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0585]

[0586] To racemic-1-(((4R,6S)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ] dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (330 mg, 0.94 mmol) was added to a mixture of 2-(5-chloropyrazin-2-yl)propan-2-ol (244 mg, 1.41 mmol), N 1 ,N 2 -dimethylethane-1,2-diamine (165 mg, 1.88 mmol), tripotassium phosphate (399 mg, 1.88 mmol) and copper (I) iodide (90 mg, 0.47 mmol). The mixture was stirred at 100 ° C under a nitrogen atmosphere for 16 hours and then cooled to room temperature. The mixture was diluted with water (50 mL), extracted with ethyl acetate (3×30 mL), dried over sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 7% methanol / chloromethane to give racemic-1-(((4R, 6S)-9-(5-(2-hydroxypropan-2-yl)pyrazine-2-yl)-4-methyl-8-oxo-7-oxa-9-azabisspiro[2.2.4 6 .2 3 ] dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg) as a white solid. LCMS (ESI-MS) m / z = 487.2 [M+H] + .

[0587] 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ] dodecane-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((4S,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0588]

[0589] The racemic 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ] dodec-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 NH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 12mL / min; gradient: 20% B to 20% B in 25min; wavelength: 220 / 254nm; RT1(min): 11.542; sample solvent: EtOH--HPLC; injection volume: 0.7mL. The desired fractions were combined and lyophilized to obtain two products:

[0590] First eluting isomer: 1-(((4R,6S)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.4 6 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (113.6 mg, 95.3% purity, 100% ee) as a light yellow solid. 1 HNMR (400 MHz, DMSO-d 6 )δ9.17(d,J=1.5Hz,1H),8.60(d,J=1.5Hz,1H),8.44(s,1H),8.36(d,J=1.5Hz,1 H),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] + .

[0591] Second eluting isomer: 1-(((4S,6R)-9-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methyl-8-oxo-7-oxa-9-azabispiro[2.2.46 .2 3 ]dodec-4-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (111.0 mg, 99.5% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.17(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=1 0.2Hz,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] + .

[0592] Example 7. Preparation of 1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0593]

[0594] Detailed procedures

[0595] (1,4-Dioxaspiro[4.5]dec-6-en-7-yl)methanol

[0596]

[0597] A solution of methyl 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (19.5 g, 98.4 mmol) and lithium aluminum hydride (3.73 g, 98.8 mmol) in tetrahydrofuran (400 mL) was stirred at 0°C for 1 hour. The resulting mixture was quenched with water and aqueous sodium hydroxide solution, then filtered, and the filter cake was washed with tetrahydrofuran (2×100 mL). The filtrate was concentrated under reduced pressure to give a crude product (1,4-dioxaspiro[4.5]dec-6-ene-7-yl)methanol (7 g) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ5.48 (s, 1H), 3.92-3.79 (m, 6H), 1.92-1.83 (m, 2H), 1.71-1.61 (m, 4H).

[0598] 7-(Fluoromethyl)-1,4-dioxaspiro[4.5]dec-6-ene

[0599]

[0600] A solution of (1,4-dioxaspiro [4.5] dec-6-ene-7-yl) methanol (7.0 g, 41.1 mmol) and diethylaminosulfur trifluoride (7.95 g, 49.3 mmol) in dichloromethane (140 mL) was stirred at room temperature overnight. The mixture was quenched with aqueous sodium carbonate (200 mL), and then the resulting mixture was extracted with dichloromethane (3 × 100 mL). The organic layer was dried, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography and eluted with dichloromethane (100%) to give 7-(fluoromethyl)-1,4-dioxaspiro [4.5] dec-6-ene (6.0 g) as a brown oil. 1 H NMR (400 MHz, DMSO-d 6 )δ5.90(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).

[0601] 3-(Fluoromethyl)cyclohex-2-en-1-one

[0602]

[0603] A solution of 7-(fluoromethyl)-1,4-dioxaspiro[4.5]dec-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 0% to 10% ethyl acetate / petroleum ether to give 3-(fluoromethyl)cyclohex-2-ene-1-one (2.0 g) as a colorless oil.

[0604] rac-3-(fluoromethyl)-3-(nitromethyl)cyclohexane-1-one

[0605]

[0606] A solution of 3-(fluoromethyl)cyclohex-2-ene-1-one (2.0 g, 15.6 mmol) and nitromethane (1.14 g, 18.7 mmol) in benzyltrimethylazainium methoxide (3 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 0% to 20% ethyl acetate / petroleum ether to obtain racemic-3-(fluoromethyl)-3-(nitromethyl)cyclohexane-1-one (1.0 g) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ4.69-4.30(m,4H), 2.45-2.21(m,4H), 1.95-1.70(m,4H).

[0607] Racemic-7-(Fluoromethyl)-7-(Nitromethyl)-1,4-dioxaspiro[4.5]decane

[0608]

[0609] A solution of racemic-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) in dichloromethane (20 mL) was stirred 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 and eluted with 0% to 10% ethyl acetate / petroleum ether to give racemic-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] + .

[0610] rac-(7-(Fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0611]

[0612] A solution of racemic-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) in ethanol (10 mL) and water (3 mL) was stirred at 80 ° C for 2 hours. The resulting mixture was filtered and the filter cake was washed with ethanol (3×50 mL). The filtrate was concentrated under reduced pressure to give racemic-(7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (950 mg crude material) as a yellow oil. LCMS (ESI-MS) m / z=204.2[M+H] + .

[0613] rac-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0614]

[0615] A solution of rac-(7-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (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 0% to 50% ethyl acetate / petroleum ether to give 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] + .

[0616] 4-Amino-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0617]

[0618] A solution of rac-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decan-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 give the crude product rac-4-amino-3-(((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (1.0 g) as a yellow oil. LCMS (ESI-MS) m / z=320.3[M+H] + .

[0619] rac-1-((7-(fluoromethyl)-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0620]

[0621] 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 at 80 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate) to give 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] + .

[0622] rac-1-((1-(fluoromethyl)-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0623]

[0624] 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 at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (100% ethyl acetate) to give rac-1-((1-(fluoromethyl)-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg) as a white solid. LCMS (ESI-MS) m / z=286.3[M+H]+ .

[0625] rac-1-(((3S,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((3R,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0626]

[0627] A solution of racemic-1-((1-(fluoromethyl)-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.7 mmol) and dimethylmethanesulfinyl iodide (424 mg, 1.9 mmol) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 5 minutes. The solution was cooled to 0 ° C, and potassium tert-butoxide (216 mg, 1.9 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred at 0 ° C for another 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 give rac-1-(((3S,5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octan-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]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (180 mg) as a white solid. LCMS (ESI-MS) m / z = 300.3 [M+H] + .

[0628] rac-1-(((5S,7R)-7-(fluoromethyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0629]

[0630] A solution of ethyl carbamate (1.1 g, 13.3 mmol) and tert-butoxy lithium (107 mg, 1.3 mmol) in N-methyl-2-pyrrolidone (3 mL) was stirred at room temperature for 5 minutes. Racemic-1-(((3S, 5R)-5-(fluoromethyl)-1-oxaspiro[2.5]octane-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 at 75 ° C overnight. The resulting mixture was cooled to room temperature and concentrated under vacuum to give a crude product. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give racemic-1-(((5S,7R)-7-(fluoromethyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a white solid. LCMS (ESI-MS) m / z=343.3 [M+H] + .

[0631] rac-1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0632]

[0633] A solution of rac-1-(((5S,7R)-7-(fluoromethyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.6 mmol), 2-(5-chloropyrazin-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 tripotassium phosphate (248 mg, 1.2 mmol) in dioxane (3 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give racemic-1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (180 mg) as a white solid. LCMS (ESI-MS) m / z=479.2 [M+H] + .

[0634] 1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7S)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0635]

[0636] A mixture of racemic-1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (180 mg, 0.4 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2×25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 19 minutes; wavelength: 220 / 254 nm; RT1 (min): 12.796; RT2 (min): 15.536; sample solvent: MtBE (0.5% 2MNH 3 -MeOH)--HPLC; injection volume: 0.4 mL. The desired fractions were combined and lyophilized to obtain two products:

[0637] First eluting isomer: 1-(((5R,7S)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (62.2 mg, 98.2% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 )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]+ .

[0638] Second eluting isomer: 1-(((5S,7R)-7-(fluoromethyl)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (63.0 mg, 90.9% purity, 100% ee) as a white solid. NMR (400 MHz, DMSO-d 6 )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] + .

[0639] Example 8. Preparation of 1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0640]

[0641] Detailed procedures

[0642] 3-Methoxycyclohexa-1,4-diene-1-carboxylic acid

[0643]

[0644] In a three-necked flask, place m-anisic acid (50.0 g, 0.33 mol) and H 2O (75 mL). The flask was equipped with a mechanical stirrer, an ammonia inlet, and a finger-shaped condenser containing solid carbon dioxide and acetone. Ammonia entered above the solution through a sintered glass filter; about 1 liter of ammonia was collected. The ammonia inlet was replaced by a nitrogen inlet, and a slow stream of nitrogen was introduced above the surface. Vigorous stirring was started (caution: exothermic reaction), and lithium wire (7.0 g, 1.0 mol) was added in batches over 20-30 min for Bitch reduction. Vigorous stirring was continued until the blue color disappeared completely. Stirring was stopped, the condenser was removed, and the ammonia was completely evaporated under a steady stream of nitrogen. Then 1M potassium hydroxide solution (500 mL) was added (thoroughly purged with nitrogen), and stirring was started again. The solution was heated for 2.5 h, with the water bath temperature maintained at 60°C. The water bath was replaced with an ice bath, and the solution was cooled to 10°C. While the ice bath was still in place, concentrated HCl (100 mL) was added, and the temperature was not allowed to exceed 70°C. Stirring was continued until the solution temperature dropped to about 15°C. Remove the ice bath and continue stirring until a homogeneous solution is obtained. Transfer the aqueous solution to a separatory funnel and precipitate with CH 2 Cl 2 (3 x 200 mL) extraction. The combined organic extracts were dried and evaporated on a rotary evaporator under reduced pressure. A sample of the product was recrystallized from toluene. LCMS (ESI-MS) m / z = 155.2 [M+H] + .

[0645] 5-Oxocyclohex-1-ene-1-carboxylic acid

[0646]

[0647] To a solution of 3-methoxycyclohexa-1,4-diene-1-carboxylic acid (14.5 g, 94.1 mmol) in methanol (200 mL) was added oxalic acid (1.27 g, 14.1 mmol) and water (50 mL). The resulting solution was stirred at room temperature for 16 h. The residue was concentrated and purified by silica gel column (EA: PE = 2: 1) to give 5-oxocyclohex-1-ene-1-carboxylic acid (3 g) as a white solid. LCMS (ESI-MS) m / z = 141.0 [M + H] + .

[0648] 5-Oxocyclohex-1-ene-1-carboxylic acid methyl ester

[0649]

[0650] To a solution of 5-oxocyclohex-1-ene-1-carboxylic acid (30 g, 214 mmol) in diethyl ether (300 mL) was added diazomethane (27.0 g, 642 mmol). The resulting solution was stirred at room temperature for 16 h. The residue was concentrated and purified with a silica gel column (EA:PE=1:1) to give the desired product, 5-oxocyclohex-1-ene-1-carboxylic acid methyl ester (11.0 g), as a light yellow oil. LCMS (ESI-MS) m / z=155.1 [M+H] + .

[0651] 1,4-Dioxaspiro[4.5]dec-7-ene-7-carboxylic acid methyl ester

[0652]

[0653] To a solution of 5-oxocyclohex-1-ene-1-carboxylic acid methyl ester (2.3 g, 14.9 mmol) in dichloromethane (50 mL) was added ethylene glycol (1.39 g, 22.4 mmol), trimethyl orthoformate (2.37 g, 224 mmol) and methanesulfonic acid (220 mg, 2.24 mmol). The resulting solution was stirred at room temperature for 16 h. The residue was evaporated and purified with a silica gel column (EA: PE = 1: 1) to give 1,4-dioxaspiro [4.5] dec-7-ene-7-carboxylic acid methyl ester (2.30 g) as a light yellow oil. LCMS (ESI-MS) m / z = 199.0 [M + H] + .

[0654] (1,4-Dioxaspiro[4.5]dec-7-en-7-yl)methanol

[0655]

[0656] To a solution of 1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylic acid methyl ester (2.10 g, 10.6 mmol) in diethyl ether (20 mL) was added lithium aluminum hydride (302 mg, 7.95 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with KOH (15%, 1 mL) and water (1 mL). The mixture was washed with Et 2 The residue was extracted with 1H-4H-2SO4 (20.0 mL x 2). The organic phases were combined, evaporated and purified with a silica gel column (EA:PE = 1:1) to give (1,4-dioxaspiro[4.5]dec-7-en-7-yl)methanol (1.6 g) as a light yellow oil.

[0657] Racemic spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanol

[0658]

[0659] To a solution of 1,4-dioxaspiro[4.5]dec-7-en-7-ylmethanol (1.60 g, 9.40 mmol) in dichloromethane (30 mL) was added diethylzinc (2.90 g, 23.5 mmol), diiodomethane (6.29 g, 23.5 mmol) and trifluoroacetic acid (2.68 g, 23.5 mmol) at 0°C. The resulting solution was stirred at room temperature for 16 h. The residue was evaporated and purified with a silica gel column (EA:PE=1:1) to give racemic-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanol (1.00 g) as a light yellow oil.

[0660] rac-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)isoindoline-1,3-dione

[0661]

[0662] To a solution of rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanol (1.0 g, 5.43 mmol) in tetrahydrofuran (20 mL) was added phthalimide (1.2 g, 8.16 mmol), diisopropyl azodicarboxylate (1.65 g, 8.14 mmol) and triphenylphosphine (2.14 g, 8.14 mmol). The resulting solution was stirred at 60 °C for 5 h. The solution was cooled to room temperature, the residue was concentrated and purified by silica gel column (EA:PE=1:1) to give 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] + .

[0663] rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethanamine

[0664]

[0665] 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 ethanol (20 mL) was added hydrazine hydroxide (830 mg, 16.6 mmol). The resulting solution was stirred at reflux for 5 hours. The mixture was cooled to room temperature, concentrated and purified with a silica gel column (DCM:MeOH=10:1) to give rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethylamine (450 mg) as a light yellow oil.

[0666] 4-Nitro-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile

[0667]

[0668] To a solution of rac-spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethylamine (400 mg, 2.18 mmol) in acetonitrile (5 mL) was added 3-fluoro-4-nitrobenzonitrile (363 mg, 2.18 mmol) and potassium carbonate (649 mg, 6.55 mmol). The resulting solution was stirred at 40 °C for 4 h. The mixture was cooled to room temperature, concentrated and purified with a silica gel column (EA:PE=1:1) to give 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] + .

[0669] 4-Amino-3-((spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)amino)benzonitrile

[0670]

[0671] 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 ethanol (10 mL) and water (3 mL) was added iron (1.02 g, 18.2 mmol) and ammonium chloride (390 mg, 7.29 mmol). The resulting solution was stirred at 80 °C for 4 h. The mixture was cooled to room temperature, concentrated and purified with a silica gel column (DCM:MeOH=10:1) to give 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] + .

[0672] rac-1-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]-1-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile

[0673]

[0674] To 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) was added formic acid (69.2 mg, 1.5 mmol). The resulting solution was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, concentrated and purified with a silica gel column (EA:PE=1:1) to give 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 light yellow solid. LCMS (ESI-MS) m / z=310.1 [M+H] + .

[0675] rac-1-((3-oxobicyclo[4.1.0]hept-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0676]

[0677] Racemic-1-(spiro[bicyclo[4.1.0]heptane-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 mixed in a 25 mL round bottom flask. The resulting solution was stirred at room temperature for 2 h. The mixture was heated to 40 °C with saturated NaHCO 3The reaction was quenched and extracted with EA (20 mL x 2). The organic phases were combined and washed with anhydrous Na 2 SO 4 Drying and evaporation gave rac-1-((3-oxobicyclo[4.1.0]hept-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg) as a light yellow solid. LCMS (ESI-MS) m / z = 266.2 [M+H] + .

[0678] rac-1-(((1R,3S,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxirane]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxirane]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0679]

[0680] To a solution of trimethylsulfoxonium iodide (3.77 mmol) in dimethyl sulfoxide (5 mL) was added iodotrimethyl-λ6-thione (3.77 mmol) at 0°C. After stirring for 30 minutes, racemic-1-((3-oxobicyclo[4.1.0]hept-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 EtOAc (3×5.0 mL). The combined organic layers were washed with brine (3×5.0 mL) and purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a mixture of rac-1-(((1R,3S,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxan]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxan]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (210 mg) as a light yellow solid. LCMS (ESI-MS) m / z=280.1 [M+H] + .

[0681] rac-1-(((1R,3S,6S)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-((1R,3R,6S)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-1-yl)-1H-benzo[d]imidazole-6-carbonitrile

[0682]

[0683] To a solution of a mixture of rac-1-(((1R,3S,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxirane]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-spiro[bicyclo[4.1.0]heptane-3,2'-oxirane]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.716 mmol) in methylpyrrolidone (5 mL) was added ethyl carbamate (319 mg, 3.58 mmol) and tert-butoxylithium (143 mg, 1.79 mmol). The resulting solution was stirred at 100 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with EtOAc (10 mL), washed with brine (3×10 mL), and washed with anhydrous Na 2 SO 4 The mixture was dried, concentrated and purified by silica gel column (DCM: MeOH = 10: 1) to give rac-1-(((1R, 3S, 6S)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R, 3R, 6S)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a light yellow solid. LCMS (ESI-MS) m / z = 323.1 [M+H] + .

[0684] rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0685]

[0686] To a mixture of racemic-1-(((1R,3S,6S)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and racemic-1-(((1R,3R,6S)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile 2-(5-bromopyrazin-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 to a solution of (200 mg, 0.62 mmol) in dioxane (5.0 mL). The resulting solution was stirred at 100 ° C for 16 h. The residue was evaporated and purified with silica gel column (DCM:MeOH=10:1) to give a mixture of rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg) as a light yellow solid. LCMS (ESI-MS) m / z = 459.2 [M+H] + .

[0687] Achiral separation: A mixture of rac-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.22 mmol) was separated by preparative achiral HPLC under the following conditions: Column: CHIRALPAK IF-3, 4.6*50mm, 3μm; mobile phase A: MTBE (0.1% DEA): ethanol = 70:30; flow rate: 1mL / min; gradient: 0% B to 0% B; injection volume: 5μl, the first eluting isomer was obtained: racemic-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazole [d]imidazole-6-carbonitrile (10 mg) as a white solid and the second eluting isomer: rac-1-(((1R,3R,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (15 mg) as a white solid.

[0688] 1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2'-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((1S,3R,6R)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2'-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0689]

[0690] Racemic-1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-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 um; 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:

[0691] First eluting isomer: 1-(((1S,3R,6R)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinyl]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4.10 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.95(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] + .

[0692] Second eluting isomer: 1-(((1R,3S,6S)-3'-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-2'-oxospiro[bicyclo[4.1.0]heptane-3,5'-oxazolidinone]-1-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (3.60 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ8.95(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),2.93-2.9 1(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] + .

[0693] Example 9. Preparation of 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0694]

[0695] Detailed procedures

[0696] 1,4-Dioxaspiro[4.5]decan-7-one

[0697]

[0698] p-Toluenesulfonic acid (13.8 g, 80.3 mmol) was added to cyclohexane-1,3-dione (30 g, 268 mmol), molecular sieves (30g) and magnesium sulfate (30g) in ethylene glycol (300mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (300mL), and the resulting mixture was extracted with ethyl acetate (3×300mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product 1,4-dioxaspiro[4.5]decane-7-one (28g crude material) as a light yellow oil. LCMS (ESI-MS) m / z=157.1[M+H] + .

[0699] Racemic-1,6,9-trioxadispiro[2.1.4 5 .3 3 ]Dodecane

[0700]

[0701] Potassium tert-butoxide (22.1 g, 197 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decane-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 (3×300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product racemic-1,6,9-trioxabispiro[2.1.4 5 .3 3 ] Dodecane (28 g crude material), as a light yellow oil. LCMS (ESI-MS) m / z = 171.1 [M+H] + .

[0702] Racemic-7-(Aminomethyl)-1,4-dioxaspiro[4.5]decan-7-ol

[0703]

[0704] Racemic-1,6,9-trioxadispiro[2.1.4 5 .3 3 ] Dodecane (28 g, 165 mmol) in ammonia methanol solution (7N, 280 mL, 1.96 mol). The resulting mixture was heated to 80 ° C and stirred overnight. The reaction mixture was concentrated under vacuum to give the crude product racemic-7-(aminomethyl)-1,4-dioxaspiro[4.5]decan-7-ol (28 g crude material) as a light yellow oil. LCMS (ESI-MS) m / z = 188.1 [M+H] + .

[0705] rac-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0706]

[0707] Potassium carbonate (41.3 g, 299 mmol) was added to a solution of racemic-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 0% to 15% ethyl acetate / petroleum ether to give the desired product, racemic-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] + .

[0708] 4-Amino-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0709]

[0710] Iron powder (20.1 g, 360 mmol) was added to a solution of racemic-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 filter cake was washed with ethanol (2×200 mL). The filtrate was concentrated under reduced pressure to give the crude product, racemic-4-amino-3-(((7-hydroxy-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (12 g crude material), as a yellow solid. LCMS (ESI-MS) m / z=304.2[M+H] + .

[0711] rac-1-((7-hydroxy-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0712]

[0713] 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 give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 70% ethyl acetate / petroleum ether to give 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] + .

[0714] rac-1-((1-hydroxy-3-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0715]

[0716] 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 aqueous hydrochloric acid (8.66 mL, 8.66 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and then 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 give the crude product. The residue was purified by silica gel column chromatography eluting with 0% to 80% ethyl acetate / petroleum ether to give 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] + .

[0717] rac-1-(((3S,5R)-5-hydroxy-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0718]

[0719] Potassium tert-butoxide (1.37 g, 12.3 mmol) was added to a solution of racemic-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 (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product racemic-1-(((3S,5R)-5-hydroxy-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2 g) as a light yellow oil. LCMS (ESI-MS) m / z = 284.1 [M+H] + .

[0720] rac-1-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0721]

[0722] 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 racemic-1-(((3S, 5R)-5-hydroxy-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2 g, 7.06 mmol) in N-methylpyrrolidone (5 mL) was added dropwise. The reaction mixture was then 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 / water (10 mmol / L NH 4 HCO 3 ), gradient from 0% to 30% in 10 min; detector, UV 254 nm, to give the desired product, racemic-1-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g), as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ9.21(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. 80(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] + .

[0723] rac-1-(((5S,7R)-7-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0724]

[0725] Copper (I) iodide (582 mg, 3.06 mmol) was added to rac-1-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-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-(((5S,7R)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-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), and 1H-benzo[d]imidazole-6-carbonitrile (1 g, 3.06 mmol). 1 ,N 2 -dimethylethane-1,2-diamine (540mg, 6.12mmol) and potassium phosphate (1.3g, 6.12mmol) in a mixture of 1,4-dioxane (10mL). 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 0% to 3% methanol / dichloromethane to obtain the desired product racemic-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 (700mg), which is a light yellow solid. 1 H NMR (300 MHz, DMSO-d 6)δ9.21(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=7.2Hz,2H),4.81(s,2H),4.50(s,1H),4.44(d,J=15.1H z,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=15.1Hz,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=583.3[M+H] + .

[0726] rac-1-(((5S,7R)-7-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0727]

[0728] Methyl iodide (170.33 mg, 1.20 mmol) was added to a mixture of rac-1-(((5S,7R)-7-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-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) in N,N-dimethylformamide (5 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was slowly quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 2% methanol / dichloromethane to give the desired product, rac-1-(((5S,7R)-7-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.21(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=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,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=597.3[M+H] + .

[0729] rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0730]

[0731] 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)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-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 and purified by silica gel column chromatography eluting with 0% to 3% methanol in dichloromethane to give the desired product, rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a yellow oil. 1 H NMR (300 MHz, DMSO-d 6 )δ9.21(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),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=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=477.2[M+H] + .

[0732] 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0733]

[0734] A mixture of racemic-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg, 0.42 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2MNH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 17mL / min; gradient: 10% B to 10% B in 24min; wavelength: 220 / 254nm; RT1(min): 14.661; RT2(min): 20.017; sample solvent: EtOH--HPLC; injection volume: 0.5mL. The desired fractions were combined and lyophilized to obtain the product:

[0735] First eluting isomer: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (44.6 mg, 99.7% purity, 100% ee) as a white solid. 1 H NMR (300 MHz, DMSO-d 6)δ9.21(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),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= 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=477.2[M+H] + .

[0736] Second eluting isomer: 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methoxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (41.0 mg, 98.6% purity, 100% ee) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.21(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),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=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=477.2[M+H] + .

[0737] Example 10. Preparation of 1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0738]

[0739] Detailed procedures

[0740] rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0741]

[0742] Copper (I) iodide (448 mg, 2.35 mmol) was added to rac-1-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-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-(((5S,7S,8R)-8-hydroxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-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), and 1H-benzo[d]imidazole-6-carbonitrile (1000 mg, 2.35 mmol). 1 ,N 2 -dimethylethane-1,2-diamine (414mg, 4.70mmol) and potassium phosphate (996mg, 4.70mmol) in 1,4-dioxane (10mL) solution. The resulting mixture is heated to 100 ° C and stirred overnight. After cooling to room temperature, the resulting mixture is filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography and eluted with 0% to 3% methanol / dichloromethane to obtain the desired product racemic-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 (1g), which is a light yellow solid. LCMS (ESI-MS) m / z = 597.3 [M+H] + .

[0743] rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((5R,7S,8R)-8-hydroxy-3-(6-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0744]

[0745] A mixture of racemic-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 1.68 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2×25 cm, 5 μm; mobile phase A: Hex:DCM=3:1 (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: IPA-HPLC; flow rate: 20mL / min; gradient: 20% B to 20% B in 21min; wavelength: 220 / 254nm; RT1(min): 10.051; RT2(min): 16,651; sample solvent: EtOH--HPLC; injection volume: 1mL. The desired fractions were combined and lyophilized to obtain the product.

[0746] First eluting isomer: rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg) as a light yellow solid. 1 HNMR (400 MHz, DMSO-d 6)δ9.25(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] + .

[0747] Second eluting isomer: rac-1-(((5R,7S,8R)-8-hydroxy-3-(6-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 40.0% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.30(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),6.93–6.8 6(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] + .

[0748] rac-1-(((5S,7S,8R)-8-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0749]

[0750] Methyl iodide (35.5 mg, 0.25 mmol) was added to a solution of rac-1-(((5S,7S,8R)-8-hydroxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-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) at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was slowly quenched with 5 mL of water, and the resulting solution was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 2% methanol / dichloromethane to give the desired product, rac-1-(((5S,7S,8R)-8-methoxy-3-(5-(2-((4-methoxybenzyl)oxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (80 mg) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ9.25(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] + .

[0751] rac-1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0752]

[0753] 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)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-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 give the crude product, rac-1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (70 mg crude material), as a yellow oil. LCMS (ESI-MS) m / z = 491.2 [M+H] + .

[0754] 1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7R,8S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0755]

[0756] A mixture of racemic-1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (70 mg, 0.14 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SC, 2×25 cm, 5 μm; mobile phase A: Hex:DCM=3:1 (0.5% 2M NH 3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 14 min; 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.

[0757] First eluting isomer: 1-(((5R,7R,8S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (14.0 mg, 99.7% purity, 100% ee) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.18(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. 3Hz,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] + .

[0758] Second eluting isomer: 1-(((5S,7S,8R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8-methoxy-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (14.8 mg, 99.6% purity, 99.5% ee) as a white solid. 1 HNMR (300 MHz, DMSO-d 6)δ9.18(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. 3Hz,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] + .

[0759] 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

[0760]

[0761] Detailed procedures

[0762] rac-1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0763]

[0764] To a mixture of rac-1-(((5S,7S)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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) in N,N-dimethylformamide (10 mL) was added sodium hydroxide (347 mg, 8.67 mmol). The reaction mixture was stirred at 100 °C for 3 hours and then 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 give the crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 60% ethyl acetate / petroleum ether to give the product, racemic-1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (200 mg), as a white solid. LCMS (ESI-MS) m / z=417.2 [M+H] + .

[0765] 1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-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]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0766]

[0767] A mixture of racemic-1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-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, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: IPA-HPLC; flow rate: 20mL / min; gradient: 40% B to 40% B in 12min; wavelength: 220 / 254nm; RT1(min): 7.342; RT2(min): 9.486; sample solvent: EtOH--HPLC; injection volume: 0.3mL. The desired fractions were combined and lyophilized to obtain two products:

[0768] First eluting isomer: 1-(((5S,7S)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (76.5 mg, 99.8% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(s,1H),8.31(d,J=1.5Hz,1H),7.83(d,J=8.5Hz,1H),7.61(dd,J=8.4,1.5Hz,1H),4.65(dd,J=14.6,6.1Hz,1H), 4.41(dd,J=14.6,7.7Hz,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] + .

[0769] Second eluting isomer: 1-(((5R,7R)-8,8-difluoro-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (19.9 mg, 99.0% purity, 98.4% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(s,1H),8.31(d,J=1.5Hz,1H),7.83(d,J=8.3Hz,1H),7.61(dd,J=8.4,1.5Hz,1H),4.65(dd,J=14.7,6.0Hz,1H),4.41(dd,J=14. 6,7.7Hz,1H),3.44-3.35(m,2H),2.91-2.80(m,3H),2.16-1.93(m,3H),1.86-1.70(m,3H),0.82(s,9H).LCMS(ESI-MS)m / z=417.2[M+H] + .

[0770] Example 12. Preparation of 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

[0771]

[0772] Detailed procedures

[0773] 1-((3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0774]

[0775] To a diastereomeric 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) in 1,4-dioxane (10 mL) was added N1,N2-dimethylethane-1,2-diamine (255 mg, 2.9 mmol), tripotassium phosphate (615 mg, 2.9 mmol) and copper(I) iodide (139 mg, 0.73 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 5 hours and then 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 give the crude product. The residue was purified by silica gel column chromatography and then eluted with 0% to 55% ethyl acetate / petroleum ether to give 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] + .

[0776] rac-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((5R,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0777]

[0778] A diastereomeric mixture of 1-((3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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, 3×25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: MeOH (0.1% 2M NH 3 -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:

[0779] First eluting isomer: rac-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (240 mg) as a white solid.

[0780] Second eluting isomer: rac-1-(((5R,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (20 mg) as a white solid.

[0781] 1-(((5R,7R)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0782]

[0783] A mixture of racemic-1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH 3-MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20mL / min; gradient: 20% B to 20% B in 23min; wavelength: 220 / 254nm; RT1(min): 11.816; RT2(min): 16.483; sample solvent: EtOH--HPLC; injection volume: 2mL. The desired fractions were combined and lyophilized to obtain two products:

[0784] First eluting isomer: 1-(((5R,7R)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (10.6 mg, 99.5% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(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] + .

[0785] Second eluting isomer: 1-(((5S,7S)-3-(2-chlorophenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (31.6 mg, 99.2% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ8.59(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),2.27-2.1 2(m,3H),2.03-1.89(m,2H),1.89-1.78(m,1H).LCMS(ESI-MS)m / z=457.1[M+H] + .

[0786] Example 13. Preparation of 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

[0787]

[0788] Detailed procedures

[0789] 1-((3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0790]

[0791] To a diastereomeric mixture of 1-((8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (250 mg, 0.72 mmol) and 1-bromo-2-ethoxybenzene (217 mg, 1.08 mmol) in 1,4-dioxane (10 mL) was added N1,N2-dimethylethane-1,2-diamine (127 mg, 1.44 mmol), tripotassium 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 and cooled to room temperature, the mixture was quenched with aqueous ammonium chloride solution (50 mL), the resulting solution was extracted with ethyl acetate (3×30 mL), the organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product, the residue was purified by silica gel column chromatography and eluted with 0% to 58% ethyl acetate / petroleum ether to give 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] + .

[0792] rac-1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((5R,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0793]

[0794] A diastereomeric mixture of 1-((3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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 Na phthyl, 3×25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: MeOH (0.1% 2M NH 3-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 lyophilized to obtain two products.

[0795] First eluting isomer: rac-1-(((5R,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (30 mg) as a white solid.

[0796] Second eluting isomer: rac-1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (140 mg) as a white solid.

[0797] 1-(((5R,7R)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0798]

[0799] A mixture of racemic-1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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, 2×25 cm, 5 μm; mobile phase A: MTBE (2 mM NH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20mL / min; gradient: 8% B to 8% B in 31min; wavelength: 220 / 254nm; RT1(min): 20.16; RT2(min): 26.092; sample solvent: EtOH--HPLC; injection volume: 0.4mL. The desired fractions were combined and lyophilized to obtain two products.

[0800] First eluting isomer: 1-(((5R,7R)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (18.0 mg, 98.9% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(s,1H),8.34(s,1H),7.85(d,J=8.4Hz,1H),7.63(dd,J=8.4,1.5Hz,1H) ,7.32-7.25(m,2H),7.06(d,J=8.4Hz,1H),6.94(t,J=7.6Hz,1H),4.69(dd,J=1 4.7,5.9Hz,1H),4.44(dd,J=14.6,8.0Hz,1H),4.04-3.93(m,2H),3.64(s,2H), 3.01-2.84(m,1H),2.23-2.08(m,3H),1.96-1.78(m,3H),1.17(t,J=6.9Hz,3H). LCMS (ESI-MS) m / z = 467.2 [M+H] + .

[0801] Second eluting isomer: 1-(((5S,7S)-3-(2-ethoxyphenyl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (40.4 mg, 99.8% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(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= 14.6,5.9Hz,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] + .

[0802] Example 14. Preparation of 1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0803]

[0804] Detailed procedures

[0805] 2-Bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide

[0806]

[0807] To a mixture of calcium carbonate (7.15 g, 93.8 mmol) in chloroform (30 mL) at 5 ° C under a nitrogen atmosphere was added water (10 mL) containing 1-amino-3,3-dimethylbutan-2-one hydrochloride (1.8 g, 15.6 mmol). Subsequently, 2-bromoacetyl bromide (5.90 g, 39.1 mmol) was added at 5 ° C. The resulting mixture was allowed to warm to room temperature and then stirred for 6 hours. The reactants were filtered and washed with aqueous sodium carbonate solution (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product of 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] + .

[0808] 5-(tert-Butyl)pyrazin-2-ol

[0809]

[0810] To a mixture of 2-bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide (2.3 g, 9.74 mmol) in ammonia (20 ml, 7N in MeOH) was added sodium iodide (0.26 g, 1.75 mmol). 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 give the crude product 5-(tert-butyl)pyrazine-2-ol (740 mg) as a yellow oil. LCMS (ESI-MS) m / z=153.1[M+H] + .

[0811] 5-(tert-Butyl)pyrazin-2-yl trifluoromethanesulfonate

[0812]

[0813] At 0 ° C under a nitrogen atmosphere, triethylamine (1.46 g, 14.4 mmol) and trifluoromethanesulfonic anhydride (2.03 g, 7.19 mmol) were added to a mixture of 5-tert-butylpyrazine-2-ol (730 mg, 4.80 mmol) in dichloromethane (10 mL), and 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 give a crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 30% ethyl acetate / petroleum ether to give the product trifluoromethanesulfonic acid 5-(tert-butyl) pyrazine-2-yl ester (500 mg) as a yellow oil. LCMS (ESI-MS) m / z=285.0[M+H] + .

[0814] 1-((3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0815]

[0816] To a diastereomeric mixture of 1-((8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (600 mg, 1.73 mmol) and 5-(tert-butyl)pyrazin-2-yl trifluoromethanesulfonate (738 mg, 2.60 mmol) in 1,4-dioxane (10 mL) was added 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 at 90 °C under nitrogen atmosphere overnight and cooled to room temperature. The reaction was quenched with aqueous ammonium chloride (50 mL), extracted with ethyl acetate (3×30 mL), dried over sodium sulfate, filtered and concentrated to give the crude product. The residue was purified by silica gel column chromatography and eluted with 0% to 70% ethyl acetate / petroleum ether to give the product 1-((3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (420 mg) as a light yellow solid. LCMS (ESI-MS) m / z=481.2[M+H] + .

[0817] rac-1-(((5R,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and rac-1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0818]

[0819] A diastereomeric mixture of 1-((3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (420 mg, 0.87 mmol) was separated by preparative chiral SFC under the following conditions: column: DAICEL DCpak P4VP, 3×25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: MeOH (0.1% 2M NH 3 -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 lyophilized to obtain two products:

[0820] First eluting isomer: rac-1-(((5R,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (300 mg) as a white solid.

[0821] Second eluting isomer: rac-1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (50 mg) as a white solid.

[0822] 1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7R)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxa-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0823]

[0824] A mixture of racemic-1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-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, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2MNH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 16mL / min; gradient: 50% B to 50% B in 12min; wavelength: 220 / 254nm; RT1(min): 7.528; RT2(min): 9.869; sample solvent: EtOH; injection volume: 0.4mL. The desired fractions were combined and lyophilized to obtain two products:

[0825] First eluting isomer: 1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (143.5 mg, 98.6% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ9.20(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),4.7 2-4.64(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] +

[0826] Second eluting isomer: 1-(((5R,7R)-3-(5-(tert-butyl)pyrazin-2-yl)-8,8-difluoro-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (51.7 mg, 99.8% purity, 100% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.20(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] + .

[0827] Example 15. Preparation of 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0828]

[0829] Detailed procedures

[0830] 4,4-Difluoro-3-methylcyclohexa-2,5-dien-1-one

[0831]

[0832] To a solution of 4-fluoro-3-methylphenol (25.2 g, 1 eq., 200 mmol) in DCM (1.5 L) was added dropwise pyridine hydrofluoride (20 mL, 70 wt %, 0.78 eq., 156 mmol) at room temperature over 10 min. Then, phenyl diacetate-13-iododiester (77.3 g, 1.2 eq., 240 mmol) was added once and the reaction was stirred at room temperature for 15 min. Potassium carbonate (138 g, 5 eq., 1.00 mol) was added and the resulting mixture was stirred under the same conditions for 10 min. The mixture was filtered and the filtrate was washed with HCl 1M (3x) and brine (1x), and the reaction mixture was stirred for 15 min at room temperature. 2 SO 4 Dry, filter and concentrate under reduced pressure (45°C, not less than 850 mbar, as the product is volatile) to about 200 mL. The crude solution was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 )δ6.80(dt,J=10.2,5.5Hz,1H),6.32–6.26(m,1H),6.15–6.09(m,J=1.5Hz,1H),2.09(dt,J=1.9,1.0Hz,3H). 19 F NMR (376 MHz, CDCl 3 )δ-102.58.

[0833] 4,4-Difluoro-3-methylcyclohex-2-en-1-one

[0834]

[0835] Crude 4,4-difluoro-3-methylcyclohexa-2,5-dien-1-one (28.8 g, 1 eq., 200 mmol) in tert-butyl methyl ether (1.33 liters) was stirred mechanically under reflux overnight at 60° C. in the presence of silica (400 g, 33.3 eq., 6.66 mol). Then, due to incomplete conversion (by aliquoting the crude 19F NMR), 0.2 equivalents of HEH were added, and the mixture was stirred at 60 ° C for another 5h. The mixture was cooled to room temperature and filtered to remove silica, and the filtrate volume was reduced to 400mL with a rotary evaporator. 1.6L pentane was added and the mixture was filtered through a silica pad and concentrated to 200mL (fraction A), the pad was washed with 1L of pentane MTBE 4:1 and concentrated to 250mL (fraction B) (Note: most of the unreacted HEH can be removed by this filtration). NMR showed that there was still HEH impurity in the two fractions stored overnight in the refrigerator. Both fractions precipitated HEH and filtered it out. Each fraction was washed with 5% CuSO4 aqueous solution (x2) (Note: This is done to remove any residues of HEH) and 3M HCl (aqueous solution) (x3) (Note: This is required to remove Hantzsch pyridine). Afterwards, qNMR showed that 4,4-difluoro-3-methylcyclohex-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 (400 MHz, CDCl 3 )δ6.00(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 F NMR (376 MHz, CDCl 3 )δ-100.50(t,J=13.3Hz).

[0836] (S)-4,4-Difluoro-3-methyl-3-(nitromethyl)cyclohexane-1-one

[0837]

[0838] In a 1 L flask, a solution of crude 4,4-difluoro-3-methylcyclohex-2-en-1-one (7.98 g, 210 mL, 0.26 mole, 1 eq, 54.6 mmol) in MTBE was diluted 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 eq, 5.46 mmol) and nitromethane (33.3 g, 29.4 mL, 10 eq, 546 mmol) were added and the mixture was heated under N 2 The mixture was stirred at 50 °C for 2 days. The flask was cooled to room temperature. 4 (3x), saturated NaHCO 3 (3x), H 2The mixture was washed with O (1x) and brine (1x). 2 SO 4 ), filtered and concentrated. The crude product was purified by silica gel chromatography (220 g) using a 0-25% EtOAc / cyclohexane gradient (2CV 0%, 10CV 0-10%, 2CV 10%, 10CV 10-20%, 4CV 20-25%, 2CV 25%) to give (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 (400 MHz, CDCl 3 )δ4.63(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 F NMR (376 MHz, CDCl 3 )δ-110.17(dd,J=24.0,12.9Hz),-110.31(td,J=10.4,3.5Hz).

[0839] (S)-8,8-Difluoro-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane

[0840]

[0841] To a solution of (S)-4,4-difluoro-3-methyl-3-(nitromethyl)cyclohexane-1-one (4.0 g, 1 eq., 19.3 mmol) in anhydrous DCM (3.8 M) was added ethylene glycol (1.59 mL, 1.48 eq., 28.6 mmol) and trimethyl orthoformate (3.2 mL, 1.5 eq., 29.0 mmol). The resulting reaction mixture was stirred at RT for 5 minutes and then cooled to 0 ° C in an ice bath. Methanesulfonic acid (186 μL, 0.148 eq., 2.86 mmol) was added dropwise to the mixture. The reaction mixture was removed from the ice bath and warmed to RT and stirred overnight. The reaction was cooled back to 0 ° C, quenched with 100 mL of water and distributed with 100 mL of DCM. The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave (S)-8,8-difluoro-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (4.2 g, 87%) as a clear orange oil.1 H NMR (400 MHz, CDCl 3 )δ4.82(d,J=11.0Hz,1H),4.51(d,J=11.1Hz,1H),4.02–3.92(m,4H),2.29–2.15(m, 1H),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 F NMR (376 MHz, CDCl 3 )δ-109.08(dddd,J=244.3,20.7,7.2Hz),-110.28(dddd,J=243.9,21.2,7.6,3.0Hz).

[0842] (S)-(8,8-Difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0843]

[0844] To Pd (10% in charcoal; 0.075 eq.) was added a solution of (S)-8,8-difluoro-7-methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (1 eq.) in EtOAc under inert atmosphere. To this mixture was added MeOH (MeOH:EtOAc 2:1, 0.1 M), and the reaction vessel was evacuated and backfilled with H from a balloon. 2 . The reaction was stirred at room temperature overnight. Complete conversion was observed by TLC (TLC: 5% MeOH in DCM showed complete conversion, ninhydrin as colorant). The reaction vessel was evacuated and backfilled with nitrogen. The reaction contents were filtered through celite, washed with EtOAc and concentrated in vacuo to obtain (S)-(8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine (3.7 g, quantitative) as a light yellow clear oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 )δ3.97–3.91(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 F NMR (376 MHz, CDCl 3)δ-106.57–-107.45(m),-111.32–-112.12(m).

[0845] (S)-3-(((8,8-Difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

[0846]

[0847] (S)-(8,8-Difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methanamine (1.00 equiv) was dissolved in MeCN (0.35 M). K 2 CO 3 To the mixture was added (S)-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (5.4 g, 88%). 1 H NMR (400 MHz, CDCl 3 )δ8.41(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 F NMR (376 MHz, CDCl 3 )δ-107.02–-107.96(m),-110.15–-111.12(m).

[0848] (S)-4-Amino-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0849]

[0850] To Pd (10% on charcoal; 0.05 eq.) under inert atmosphere was added a solution of (S)-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (1 eq.) in ethyl acetate. To this mixture was added MeOH (MeOH:AcOEt 2:1, 0.1 M), and the reaction vessel was evacuated and backfilled with H from a balloon. 2 The reaction was stirred at room temperature for 2 hours until complete conversion was observed by TLC (TLC: 100% DCM, ninhydrin as colorant). The reaction vessel was evacuated and backfilled with nitrogen. The reaction contents were filtered through celite, washed with EtOAc and concentrated in vacuo to afford (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 (400 MHz, CDCl 3 )δ7.02(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 F NMR (376 MHz, CDCl 3 )δ-105.99–-106.88(m),-109.87(ddd,J=242.6,19.3,10.3Hz).

[0851] (S)-1-((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0852]

[0853] (S)-4-amino-3-(((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (4.9 g, 1 eq, 15 mmol) was added to trimethyl orthoformate (46 mL, 29 eq, 420 mmol), followed by formic acid (0.56 mL, 1 eq, 15 mmol). The resulting mixture was stirred at room temperature. Additional formic acid (0.56 mL, 1 eq, 15 mmol) was added at t=90 min, 120 min, and 180 min after the start of the reaction, after which the mixture was stirred overnight. The reaction mixture was heated to 40 ℃ for 1 h with 500 mL of EtOAc and 300 mL of saturated NaHCO 3 The reaction contents were partitioned with aqueous solution and the layers were separated. The aqueous layer was back extracted with EtOAc (3 x 150 mL). The combined organics were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Chromatography on silica gel (80 g SiO 2 , 0-70% EtOAc:hexanes) to afford (S)-1-((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (4.4 g, 13 mmol, 87%) as a white solid. 1 HNMR (400MHz, CDCl 3 )δ8.17(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 (376 MHz, CDCl 3 )δ-107.43–-108.46(m),-110.25(ddd,J=243.6,22.9,7.7Hz).

[0854] (S)-1-((2,2-difluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0855]

[0856] To iron(III) chloride (3.27 g, 3.5 eq., 20.2 mmol) and water (2.18 g, 2.18 mL, 21 eq., 121 mmol) was added (S)-1-((8,8-difluoro-7-methyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.00 g, 1 eq., 5.76 mmol) in CH 2 Cl 2 (19.2 mL). The resulting yellow to amber suspension was heated at 50°C and water (2.18 g, 2.18 mL, 21 eq., 121 mmol) containing iron (III) chloride (3.27 g, 3.5 eq., 20.2 mmol) was added at t = 1 hour, 2 hours and 3 hours, keeping the temperature at 50°C throughout the process. The reaction mixture was stirred for 2 h by adding saturated NaHCO 3 The reaction was quenched with aqueous solution. 2 Cl 2 The aqueous layer was extracted three times and the combined organics were washed with brine, purified by Na 2 SO 4 The reaction mixture was dried and concentrated under reduced pressure. NMR showed that the conversion was not complete. At t = 2 hours, 16 hours, 19 hours and 25 hours, the reaction was restarted under the same conditions as before the addition of water (2.18 g, 2.18 mL, 21 eq., 121 mmol) containing iron (III) chloride (3.27 g, 3.5 eq., 20.2 mmol). The conversion was incomplete (70%). The reaction mixture was heated to 40 ℃ and then stirred for 2 hours. The reaction mixture was heated to 40 ℃ and then stirred for 2 hours. The reaction mixture was heated to 40 ℃ and then stirred for 2 hours. The reaction mixture was heated to 40 ℃ and then stirred for 2 hours. 3 The reaction was quenched with aqueous solution. 2 Cl 2 The aqueous layer was extracted three times and the combined organics were washed with brine, purified by Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. Iron chloride hexahydrate (5.4 g, 3.0 mL, 3.5 eq., 20 mmol) was added to restart the reaction. The reaction was heated during 2 h, and then more iron chloride hexahydrate (5.4 g, 3.0 mL, 3.5 eq., 20 mmol) was added, reaching complete conversion after 1 h (determined by LCMS analysis). The mixture was heated to 40 °C by adding saturated NaHCO 3 The reaction was quenched with aqueous solution. 2 Cl 2 The aqueous layer was extracted three times and the combined organics were washed with brine, purified by Na 2 SO 4Drying and concentration under reduced pressure afforded (S)-1-((2,2-difluoro-1-methyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (993 mg, 3.27 mmol, 57%) as a light brown foam. 1 H NMR (400 MHz, CDCl 3 )δ8.07(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 F NMR (376 MHz, CDCl 3 )δ-109.71–-109.83(m),-109.83–-109.94(m).

[0857] (S)-1-((2,2-difluoro-1-methyl-5-methylenecyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0858]

[0859] In N 2 Under atmosphere, NaH (60% in mineral oil) (183 mg, 4.58 mmol, 1.4 equiv) was added in portions to a stirred suspension of methyltriphenylphosphonium bromide (1.64 g, 4.58 mmol, 1.4 equiv) in dry THF (14.6 mL) at 0 °C. The mixture was stirred at 0 °C for 5 minutes, then allowed to warm to room temperature and stirred at this 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) in anhydrous THF (7.28 mL) was slowly added at 0 °C and allowed to reach room temperature overnight. TLC (CyH / EtOAC: 1 / 1) indicated complete conversion. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in saturated NH 4 Cl aqueous solution and extracted 3 times with EtOAc. The combined organic phases were washed with H 2 O and brine, and washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (20 g SiO 2, 10% to 100% EtOAc / cHex) to give (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 (400 MHz, CDCl 3 )δ8.08(s,1H),7.87(d,J=8.3Hz,1H),7.81–7.77(m,1H),7.54(dd,J=8.3,1.5Hz, 1H),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). 19 F NMR (376 MHz, CDCl 3 )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).

[0860] 1-(((3R,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((3S,5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0861]

[0862] To a solution of (S)-1-((2,2-difluoro-1-methyl-5-methylenecyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (327 mg, 1.09 mmol, 1 eq) in DCM (7.2 mL) at 0°C was added m-CPBA (340 mg, 1.52 mmol, 1.4 eq, 77 wt%). The mixture was warmed to room temperature and stirred for 4 hours. LCMS showed that the reaction was incomplete, and m-CPBA (340 mg, 1.52 mmol, 1.4 eq, 77 wt%) was added to the reaction mixture which was stirred overnight at room temperature. The reaction was heated to room temperature with saturated Na 2 S2O 3 The combined organic layers were washed with saturated NaHCO3 and quenched with a 1 / 1 mixture of aqueous solution / saturated NaHCO3 solution and extracted three times with DCM. 3 and washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40 g SiO2, DCM / EtOAc 100 / 0 to 85 / 15 10CV, then for 20CV, 85 / 15, then up to 75 / 25) to give the first diastereomer (undesired) 1-(((3R, 5S)-6,6-difluoro-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (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-carbonitrile (64 mg, 0.2 mmol, 19%). LC-MS: m / z: 318 [M+H] + 1 H NMR (400 MHz, CDCl 3 )δ8.11(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).

[0863] 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

[0864]

[0865] Lithium 2-methyl-2-propoxide (0.51 mL, 1.0 mole in THF, 0.51 mmol, 2.7 equiv) was added to a solution of ethyl carbamate (0.23 g, 2.6 mmol, 13.5 equiv) in NMP (1.3 mL). After stirring at room temperature for 10 min, 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 equiv) in NMP solution (1.3 mL) was added dropwise. The reaction mixture was then heated to 100 °C and stirred at this temperature for 21 h until complete conversion by TLC (100% DCM). The reaction mixture was cooled to room temperature and poured into H 2 O and extracted with EtOAc (x4). The combined organic extracts were washed with NH 4 Cl(x3),H 2 O and brine, dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (4g SiO2, 0% to 7% MeOH / DCM) to give 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, 70%) as a viscous colorless oil. LC-MS: m / z: 361[M+H] +

[0866] 1-(((5S,7S)-8,8-difluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0867]

[0868] To 2-(5-chloropyrazin-2-yl)propan-2-ol (29 mg, 0.17 mmol, 1.25 equiv) was added potassium phosphate (57 mg, 0.27 mmol, 2.0 equiv), 1-(((5S,7S)-8,8-difluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (48 mg, 0.13 mmol, 1 equiv), 1,4-dioxane (0.67 mL), methyl[2-(methylamino)ethyl]amine (12.0 mg, 0.28 mmol, 1.00 equiv) and CuI (26.9 mg, 0.14 mmol, 0.50 equiv) in a sealed tube. The reaction mixture was placed under nitrogen atmosphere and heated to 100 °C for 32 h. The reaction mixture was cooled to room temperature and washed with DCM, water and 7M NH 3 The mixture was diluted with MeOH and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted with DCM (x2). The combined organic extracts were washed with water (2x), dried, filtered and concentrated under reduced pressure to give an orange oil. The residue was purified and concentrated by FCC (MeOH 0-10% in DCM) to give 1-(((5S, 7S)-8,8-difluoro-3-(5-(2-hydroxypropyl-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 (26 mg, 0.13 mmol, 39%), which was an off-white solid. LC-MS: m / z: 497[M+H] + 1 H NMR (400 MHz, CDCl 3 )δ9.37(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). 19 F NMR (376 MHz, CDCl 3)δ-107.42(d,J=242.5Hz),-109.03(ddd,J=242.8,35.6,10.3Hz).

[0869] Example 16. Preparation of 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0870]

[0871] Detailed procedures

[0872] Racemic 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0873]

[0874] Copper (I) iodide (281.87 mg, 1.48 mmol) was added to rac-1-(((5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.48 mmol), 2-(5-chloropyrazin-2-yl)propan-2-ol (254.43 mg, 1.48 mmol, 1 eq), N-[(5S,7S)-7-methyl-2,8-dioxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.48 mmol), 2-(5-chloropyrazin-2-yl)propan-2-ol (254.43 mg, 1.48 mmol, 1 eq), and 1H-benzo[d]imidazole-6-carbonitrile under nitrogen atmosphere. 1 ,N 2 -dimethylethane-1,2-diamine (260.35 mg, 2.96 mmol) and potassium phosphate (628.3 mg, 2.96 mmol) in 1,4-dioxane (5 mL). 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, eluted with 0% to 3% methanol / dichloromethane to give the desired product racemic-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) as a light yellow solid. LCMS (ESI-MS) m / z=475[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)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).

[0875] rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0876]

[0877] Potassium tert-butoxide (106.38 mg, 0.95 mmol) was added to a solution of methyl triphenylphosphonium bromide (337.36 mg, 0.95 mmol) in benzene (3 mL). To the mixture was added dropwise a solution of racemic-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-carbonitrile (300 mg, 0.63 mmol) in benzene (3 mL). The reaction mixture was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography eluting with 0% to 3% methanol / dichloromethane to give rac-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decan-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 (400 MHz, DMSO-d 6)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=14.6Hz,1H),4.4 9(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(ddd,J=2 4.0, 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).

[0878] 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0879]

[0880] Racemic-1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-8,8-dimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.21 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20mL / min; gradient: 20% B to 20% B in 22min; wavelength: 220 / 254nm; RT1(min): 8,922; RT2(min): 16,131; sample solvent: EtOH--HPLC; injection volume: 1.3mL. The desired fractions were combined and lyophilized to obtain the product:

[0881] First eluting isomer: 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (28.0 mg, 99.4% purity, 100% ee, 28.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )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=14.6Hz,1H),4.4 9(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(ddd,J=2 4.0, 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] + .

[0882] Second eluting isomer: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-8-methylene-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (32.2 mg, 99.7% purity, 99.8% ee, 32.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)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=14.6Hz,1H),4.4 9(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(ddd,J=2 4.0, 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] + .

[0883] Example 17. Preparation of 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0884]

[0885] Detailed procedures

[0886] 3,5,5-Trimethylcyclohex-2-en-1-one

[0887]

[0888] To a stirred mixture of ethyl acetoacetate (21 mL, 161.54 mmol) in tert-butanol (170 mL) was added potassium tert-butoxide (0.94 g, 8.38 mmol) and 4-methylpent-3-ene-2-one (15.84 g, 161.54 mmol), and the resulting mixture was stirred at room temperature for 0.5 hours. Another batch of potassium tert-butoxide (3.63 g, 32.31 mmol) was then 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 give a crude product. The residue was purified by silica gel column chromatography with 0% to 15% ethyl acetate / petroleum ether solution to give 3,5,5-trimethylcyclohex-2-ene-1-one (15 g) as a colorless oil. LCMS (ESI-MS) m / z=139[M+H] + .

[0889] Racemic-3,3,5-trimethyl-5-(nitromethyl)cyclohexane-1-one

[0890]

[0891] To a stirred mixture of 3,5,5-trimethylcyclohex-2-ene-1-one (15 g, 108.53 mmol) in methanol (90 mL) was added nitromethane (6,62 g, 108.53 mmol) and pyrrolidine (7.72 g, 108.53 mmol). The resulting mixture was stirred at room temperature for 16 hours and concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 10% ethyl acetate / petroleum ether to give the desired product, racemic-3,3,5-trimethyl-5-(nitromethyl)cyclohexane-1-one (7 g), as a yellow oil. LCMS (ESI-MS) m / z=200 [M+H] + .

[0892] Racemic-7,7,9-trimethyl-9-(nitromethyl)-1,4-dioxaspiro[4.5]decane

[0893]

[0894] To a stirred mixture of racemic-3,3,5-trimethyl-5-(nitromethyl)cyclohexane-1-one (7 g, 35.13 mmol) in dichloromethane (40 mL) was added 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). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography eluting with 0% to 15% ethyl acetate / petroleum ether to give the desired product racemic-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] + .

[0895] rac-7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methanamine

[0896]

[0897] To a stirred mixture of racemic-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) was added iron (5.74 g, 102.75 mmol) and ammonium chloride (3.30 g, 61.65 mmol), and the resulting mixture was heated to 80 ° C and stirred for 2 hours. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (50 mL). The filtrate was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give racemic-(7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (3 g) as a yellow oil. LCMS (ESI-MS) m / z=214[M+H] + .

[0898] 4-Nitro-3-(((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0899]

[0900] To a stirred mixture of racemic-(7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methylamine (3 g, 14.06 mmol) in acetonitrile (60 mL) was added 3-fluoro-4-nitrobenzonitrile (2.34 g, 14.06 mmol) and potassium carbonate (3.89 g, 28.12 mmol). The resulting mixture was heated to 70 ° C and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluted with 0% to 10% ethyl acetate / petroleum ether to give the desired product, racemic-4-nitro-3-(((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzonitrile (5 g), as an orange solid. LCMS (ESI-MS) m / z=360[M+H] + .

[0901] 4-Amino-3-(((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile

[0902]

[0903] To a stirred mixture of rac-4-nitro-3-(((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzonitrile (3 g, 8.34 mmol) in ethanol (60 mL) and water (20 mL) was added iron (2.33 g, 41.73 mmol) and ammonium chloride (2.23 g, 41.73 mmol). The resulting mixture was heated to 80 °C and stirred for 2 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (50 mL). The filtrate 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 concentrated under vacuum to give the desired product, racemic-4-amino-3-(((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)amino)benzotriazole (2.2 g), as a yellow solid. LCMS (ESI-MS) m / z=330[M+H] + .

[0904] rac-1-((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0905]

[0906] To a stirred mixture of rac-4-amino-3-(((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)amino)benzotriazine (2.2 g, 6,67 mmol) in acetonitrile (10 mL) was added formic acid (0.25 mL, 6,67 mmol) and trimethoxymethane (0.73 mL, 6,67 mmol). The resulting mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product, rac-1-((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2 g) as a yellow oil. LCMS (ESI-MS) m / z = 340 [M+H] + .

[0907] rac-1-((1,3,3-trimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0908]

[0909] A mixture of rac-1-((7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane-7-yl)methyl)-1H-benzo]imidazole-6-carbonitrile (2 g, 5.89 mmol) in formic acid (6 mL, 159.04 mmol) was stirred at 80°C overnight. The mixture was cooled to room temperature and concentrated under vacuum to give the crude product rac-1-((1,3,3-trimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.7 g) as a yellow oil. LCMS (ESI-MS) m / z=296[M+H] + .

[0910] rac-1-(((3R,5S)-5,7,7-trimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0911]

[0912] To a stirred mixture of racemic-1-((1,3,3-trimethyl-5-oxocyclohexyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.7 g, 5.75 mmol) in dimethyl sulfoxide (20 mL) was added trimethylsulfoxonium iodide (1.27 g, 5.75 mmol) and potassium tert-butoxide (0.97 g, 8.63 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture 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 concentrated under vacuum to give the crude product racemic-1-(((3R,5S)-5,7,7-trimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.5 g) as a yellow solid. LCMS (ESI-MS) m / z = 310 [M+H] + .

[0913] rac-1-(((5R,7S)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0914]

[0915] A mixture of lithium tert-butoxide (90.56 mg, 1.13 mmol) and ethyl carbamate (1007.80 mg, 11.31 mmol) in 1-methyl-2-pyrrolidone (6 mL) was stirred at room temperature for 5 minutes, and then racemic-1-(((3R,5S)-5,7,7-trimethyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (700 mg, 2.26 mmol) was added. The resulting mixture was heated to 75 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give the crude product, rac-1-(((5R,7S)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg), as a yellow solid. LCMS (ESI-MS) m / z=353 [M+H] + .

[0916] rac-1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0917]

[0918] To a stirred mixture of rac-1-(((5R,7S)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.42 mmol) in dioxane (12 mL) was added 2-(5-chloropyrazin-2-yl)propan-2-ol (244.88 mg, 1.42 mmol), tripotassium phosphate (903.41 mg, 4.25 mmol), methyl[2-(methylamino)ethyl]amine (300.15 mg, 3.41 mmol) and cuprous iodide (270.19 mg, 1.42 mmol) under nitrogen atmosphere and the resulting mixture was heated to 100° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography, eluting with 0% to 10% methanol / dichloromethane to give the desired product, racemic-1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (450 mg), as a yellow solid. LCMS (ESI-MS) m / z=489[M+H] + .

[0919] 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0920]

[0921] The racemate of 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (350 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IA, 3×25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH 3-MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 18mL / min; gradient: 50% B to 50% B in 28min; wavelength: 220 / 254nm; RT1(min): 17.68; RT2(min): 23.745; sample solvent: EtOH--HPLC; injection volume: 0.8mL. The desired fractions were combined and lyophilized to obtain two products:

[0922] First eluting isomer: 1-(((5S,7R)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (109.8 mg, 99.8% purity, 100.0% ee) as a white solid. LCMS (ESI-MS) m / z=489 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 )δ(ppm)9.30(d,J=1.5Hz,1H),8.62(d,J=1.5Hz,1H),8.52(s,1H),8.45(d,J=1.5Hz,1H),7.86(d,J=8. 4Hz,1H),7.62(dd,J=8.4,1.5Hz,1H),4.72(d,J=14.5Hz,1H),4.35(d,J=14.4Hz,2H),4.05–3.91(m,2H) ,2.17(d,J=14.5Hz,1H),1.97(d,J=14.4Hz,1H),1.79(d,J=14.2Hz,1H),1.67(d,J=14.4Hz,1H),1.56( d,J=14.9Hz,1H),1.47(d,J=3.4Hz,6H),1.35(d,J=14.3Hz,1H),1.27(s,3H),1.04(s,3H),0.80(s,3H).

[0923] Second eluting isomer: 1-(((5R,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7,9,9-trimethyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (109.3 mg, 96.5% purity, 98.9% ee) as a white solid. LCMS (ESI-MS) m / z = 489 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6)δ(ppm)9.30(d,J=1.5Hz,1H),8.62(d,J=1.5Hz,1H),8.55(s,1H),8.46(d,J=1.5Hz,1H),7.86(d,J=8. 4Hz,1H),7.63(dd,J=8.4,1.5Hz,1H),4.73(d,J=14.4Hz,1H),4.35(d,J=14.5Hz,1H),4.03–3.95(m,2H) ,2.17(d,J=14.9Hz,1H),1.97(d,J=14.4Hz,1H),1.79(d,J=14.2Hz,1H),1.67(d,J=14.3Hz,1H),1.56( d,J=14.8Hz,1H),1.47(d,J=3.5Hz,6H),1.35(d,J=14.2Hz,1H),1.27(s,3H),1.04(s,3H),0.80(s,3H).

[0924] Example 18. Preparation of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0925]

[0926] Reaction scheme

[0927]

[0928] Detailed procedures

[0929] rac-5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0930]

[0931] Copper (I) iodide (53.3 mg, 0.28 mmol) was added to rac-5-fluoro-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.28 mmol), 2-(5-chloropyrazin-2-yl)propan-2-ol (48.3 mg, 0.28 mmol), N-[(5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.28 mmol), 1 ,N 2-dimethylethane-1,2-diamine (49.4mg, 0.56mmol) and potassium phosphate (119mg, 0.56mmol) in 1,4-dioxane (2mL) solution. 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, eluted with 0% to 2% methanol / dichloromethane. The fractions were combined and concentrated under vacuum to obtain the desired product racemic-5-fluoro-1-(((5S, 7S, 8R)-8-fluoro-3-(5-(2-hydroxypropyl-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 (100mg), as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.50(s,1H),8.33(d,J=5.6Hz,1H),7.81(d,J=10.1Hz,1H),5.42(s,1H),4.69-4.51(m ,1H),4.31(d,J=2.7Hz,2H),3.84(s,2H),2.13-1.96(m,2H),1.95-1.87(m,2H),1.83-1.66(m,2H),1.44(d,J=2.0Hz,6H),1.18(s,3H). LCMS(ESI-MS)m / z=497[M+H] + .

[0932] 5-Fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 5-Fluoro-1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0933]

[0934] Racemic-5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.20 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20ML / MIN mL / min; gradient: isocratic 20; wavelength: 254 / 220nm nm; RT1 (min): 8.262; RT2 (min): 10.453; sample solvent: EtOH--HPLC; injection volume: 1.0mL. The desired fractions were combined and lyophilized to obtain the product:

[0935] First eluting isomer: 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (20.2 mg, 98.3% purity, 100% ee, 20.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.50(s,1H),8.33(d,J=5.6Hz,1H),7.81(d,J=10.1Hz,1H),5.42(s,1H),4.69-4.51(m ,1H),4.31(d,J=2.7Hz,2H),3.84(s,2H),2.13-1.96(m,2H),1.95-1.87(m,2H),1.83-1.66(m,2H),1.44(d,J=2.0Hz,6H),1.18(s,3H). LCMS(ESI-MS)m / z=497[M+H] + .

[0936] Second eluting isomer: 5-fluoro-1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (20.0 mg, 96.4% purity, 99.5% ee, 20.0% yield) as a white solid 1H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=1.5Hz,1H),8.58(d,J=1.6Hz,1H),8.50(s,1H),8.33(d,J=5.6Hz,1H),7.81(d,J=10.1Hz,1H),5.41(s,1H),4.69-4.51(m ,1H),4.31(d,J=2.7Hz,2H),3.84(s,2H),2.13-1.99(m,2H),1.97-1.88(m,2H),1.83-1.67(m,2H),1.44(d,J=2.0Hz,6H),1.17(s,3H). LCMS(ESI-MS)m / z=497[M+H] + .

[0937] Example 19. Preparation of 4-chloro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0938]

[0939] Reaction scheme

[0940]

[0941] Detailed procedures

[0942] rac-4-chloro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0943]

[0944] Copper (I) iodide (51.4 mg, 0.27 mmol) was added to rac-4-chloro-1-(((5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.27 mmol), 2-(5-chloropyrazin-2-yl)propan-2-ol (46.6 mg, 0.27 mmol), N-[(5S,7S,8R)-8-fluoro-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.27 mmol), 1 ,N 2-dimethylethane-1,2-diamine (47.6 mg, 0.54 mmol) and potassium phosphate (114.6 mg, 0.54 mmol) in a solution of 1,4-dioxane (2 mL). 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, eluted with 0% to 2% methanol / dichloromethane. The fractions with the desired mass signal were combined and concentrated under vacuum to obtain the desired product racemic-4-chloro-1-(((5S, 7S, 8R)-8-fluoro-3-(5-(2-hydroxypropyl-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 (100 mg) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.17(d,J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.53(s,1H),8.29(d,J=1.3Hz,1H),7.82(d,J=1.3Hz,1H),5.41(s,1H),4.68-4.50(m,1H ),4.40-4.27(m,2H),3.82(d,J=1.4Hz,2H),2.12-1.98(m,2H),1.96-1.88(m,2H),1.82-1.67(m,2H),1.44(d,J=2.3Hz,6H),1.19(s,3H). LCMS(ESI-MS)m / z=513[M+H] + .

[0945] 4-Chloro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 4-Chloro-1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0946]

[0947] Racemic-4-chloro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.19 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 19ML / MIN mL / min; gradient: isocratic 30; wavelength: 254 / 220nm nm; RT1 (min): 8.246; RT2 (min): 11.53; sample solvent: EtOH--HPLC; injection volume: 0.8mL. The desired fractions were combined and lyophilized to obtain the product:

[0948] First eluting isomer: 4-chloro-1-(((5R,7R,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (42.0 mg, 99.9% purity, 100% ee) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ9.17(d,J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.53(s,1H),8.29(d,J=1.3Hz,1H),7.82(d,J=1.3Hz,1H),5.41(s,1H),4.68-4.50(m,1H ),4.40-4.27(m,2H),3.82(d,J=1.4Hz,2H),2.12-1.98(m,2H),1.96-1.88(m,2H),1.82-1.67(m,2H),1.44(d,J=2.3Hz,6H),1.19(s,3H). LCMS(ESI-MS)m / z=513[M+H] + .

[0949] Second eluting isomer: 4-chloro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (45.3 mg, 98.8% purity, 99.7% ee) as a white solid. 1H NMR (400 MHz, DMSO-d 6 )δ9.17(d,J=1.5Hz,1H),8.58(d,J=1.5Hz,1H),8.53(s,1H),8.29(d,J=1.3Hz,1H),7.82(d,J=1.3Hz,1H),5.41(s,1H),4.68-4.50(m,1H ),4.40-4.27(m,2H),3.82(d,J=1.4Hz,2H),2.12-1.98(m,2H),1.96-1.88(m,2H),1.82-1.67(m,2H),1.44(d,J=2.3Hz,6H),1.19(s,3H). LCMS(ESI-MS)m / z=513[M+H] + .

[0950] Example 20. Preparation of 1-(((5S,7S,8S)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0951]

[0952] The title compound was prepared using procedures analogous to those described herein (see Scheme 7).

[0953] Example 21. Preparation and Characterization of Crystalline Forms of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0954]

[0955] 249.15 mg of 1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile was weighed into a 40 mL glass bottle, 10 mL of anhydrous MeOH was added to the bottle and the mixture was stirred (700 rpm) at 25° C. for 3 days. The suspension was dried in a vacuum oven at 30° C. for 3 hours and then characterized by XRPD ( Figure 1 ).

[0956] The diffraction patterns were obtained at room temperature using a Bruker D8 Advance powder diffractometer using copper Kα radiation (40 kV / 40 mA), a range of 3-40 degrees 0.02θ, a step time of 0.12 seconds and a detector with a 10 degree window. The table below shows selected peaks

[0957] Selected XPRD peaks

[0958] 7.02 10.35 18.89 19.47 24.04 26.55 7.04 10.37 18.91 19.49 24.06 26.59 7.07 15.56 19.20 22.39 25.15 7.09 15.58 19.22 22.41 25.21 7.11 15.60 19.24 22.43 25.23 10.31 18.85 19.42 24.00 26.51 10.33 18.87 19.45 24.02 26.53

[0959] Example 22. Preparation of Additional Compounds

[0960] The following compounds can be prepared using known procedures and intermediates, or using procedures and intermediates analogous to those described in the above examples.

[0961]

[0962] Example 23. TRPV4 calcium assay method

[0963] Transfection

[0964] Human embryonic kidney 293T (HEK293T / 293T) cells were cultured in complete medium (Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 1x penicillin-streptomycin) in T-75 tissue culture flasks. At 90% confluence, cells were incubated with TrypLE TM Express Cell Dissociation Buffer to dissociate cells. Neutralize TrypLE by adding excess culture medium. TM Express buffer. Gently triturate cells and count using trypan blue in a Countess 3 automated cell counter. Transfer cells to a 50 mL conical tube and centrifuge at 1000 revolutions per minute (RPM) for five minutes in a benchtop centrifuge. Aspirate the culture medium containing the dissociation enzyme from the pellet and resuspend to 2 × 10 cells / mL in complete DMEM. 6 The desired concentration of cells / mL.

[0965] 2×10 per need 6 For each cell, the transfection preparation was scaled using a combination of 6 μg TRPV4 wild-type or mutant plasmid DNA, 36 μL Fugene6 transfection reagent, and 1000 μL OptiMEM medium. The transfection mixture was incubated at room temperature for 20 minutes. The total inoculum mixture for one transfection (1000 μL 2×10 61000 μL of the above transfection mixture and 1000 μL of complete DMEM) were combined into a 15 mL conical tube. The cells and transfection plasmid were thoroughly mixed and dispensed into the reservoir. It was plated at a concentration of 25 μL / well on a black 384, black well, clear bottom tissue culture treated plate. This produced approximately 16,000 cells per well. Plasmid DNA constructs were designed by Actio Biosciences in conjunction with Genscript and generated by Genscript for all hTRPV4 wild type and hTRPV4 P / LP (ClinVar) mutations (G78W, P82S, T89I, P97R, R186Q, R232C, R232P, R237G, R237Q, R237L, R269C, R269H, R269S, G270V, R271P, F273L, K276E, E278K, G280S, Y281S, R315G, R315W, R316C, R316H, R316L, R316S, I331F, D333G, S403T, K403T , K407E, S542P, S542Y, L543R, Y591N, R594C, R594H, R594S, G600E, Y602C, R616Q, F617L, L618P, V620I, A716S, A716T, L735R, T740I, R775K, W785R, E797D, E797K, P799A, P799R, P799S, P799L, G800D, K801E, P827H, F471del, N797del). The remaining cells were plated in the same manner on 384, white well, clear bottom, tissue culture treated plates for expression and relative cell number determination. The plates were placed in a 37°C incubator overnight.

[0966] Determination of relative cell number

[0967] Use products from Promega TM Relative cell number was determined using the Cell-Titer Fluor (CTF) assay kit from ELISA. Reagents were prepared according to the manufacturer's instructions. An equal volume of CTF reagent was added to each well. The cell plate was returned to the incubator at 37°C for 30 minutes. After 30 minutes, the plate was read on a BMG CLARIOstar using the EX / EM settings: 380-400nm excitation / 505nm emission.

[0968] Determination of expression

[0969] Prepare according to the manufacturer's instructions HiBiT Lysis Reagent. This assay is identical to the CTF assay described previously. Using the same cell plate from the CTF assay, add an equal volume of HiBiT Lysis Reagent to each well. Allow the reagent and cells to sit at room temperature for 10 minutes before reading luminescence on a BMG CLARIOstar.

[0970] Combination preparations

[0971] Excitement Mode

[0972] TRPV4 agonists were brought to 10 mM in DMSO. During the dilution of any compound, the DMSO concentration was kept constant. DMSO negative controls and concentration-response curves were spotted nanoliters at 6x test concentrations by a PICO8 automated dispenser into 384w clear polypropylene plates containing 1xHBSS+20 mM HEPES buffer.

[0973] Antagonistic Mode

[0974] Compounds were brought to 10 mM in DMSO. DMSO concentration was kept constant during any dilution of compounds. DMSO negative controls and concentration-response curves were spotted nanoliters into 384w clear polypropylene plates containing 1xHBSS+20 mM HEPES buffer at 5x test concentrations by a PICO8 automated dispenser. 80 of predetermined concentrations and loaded into separate 384-well v-bottom polypropylene plates.

[0975] Calcium flux assay

[0976] Approximately 18 hours after transfection, remove the cell plate from the incubator and gently add an equal volume (25uL) of calcium 6 dye. Prepare calcium 6 dye containing probenecid (final 5mM) according to the manufacturer's instructions. Return the cell plate to the 37°C incubator for 1 hour.

[0977] The FLIPR Penta was programmed to add compounds using the following settings

[0978] Pipette tips = 384

[0979] Reading mode 1 excitation wavelength = 470_495

[0980] Read Mode 1 Emission Wavelength = 515_575

[0981] Read Mode 1 Exposure = 0.1000

[0982] Read Mode 1 Gain = 6.50

[0983] Read Mode 1 Excitation Intensity = 20

[0984] Addition volume = 12.5 μL

[0985] Height = 40 μL

[0986] Speed ​​= 15 μL / sec

[0987] Raw data were exported and analyzed as the maximum signal (RFU) after addition of agonist - the average baseline (RFU) for the first 15 seconds in each well. Data were plotted in GraphPad Prism to determine the EC of the molecule. 50 or IC 50 The following table provides data for representative compounds.

[0988] Example 24. CYP3A4 incubation assay

[0989] The compound (final concentration of 1 mM) was incubated in 100 mM phosphate buffer containing 100 pmol / mL recombinant human CYP3A4 enzyme for 0 minutes, 5 minutes, 10 minutes, 15 minutes and 25 minutes. Testosterone was used as a positive control. The reaction was initiated by adding NADPH (final concentration of 1 mM) and terminated at 37 ° C by adding 4 volumes of cold acetonitrile (with 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoprofen as internal standards). The sample was centrifuged at 3,220 g for 40 minutes to precipitate the protein. 70 μL of supernatant was transferred to an analytical plate containing 110 μL of acetonitrile for LC-MS / MS analysis.

[0990] The following table provides data for representative compounds of Formula (I) from the assays of Example 23 and Example 24.

[0991]

[0992]

[0993]

[0994]

[0995] 1) All potency values ​​are the average of at least 3 independent experiments. Potency values ​​are the result of only one experiment.

[0996] Example 25. CYP3A4 incubation

[0997] The following table shows the percentage remaining for the indicated examples after incubation with recombinant human CYP3A4 for 25 minutes under the same conditions as described in Example 23.

[0998]

[0999] Example 26 TRP Selectivity of the Compound of Example 5

[1000] The compound of Example 5 was tested for selectivity against a panel of human TRP family ion channels in the TRP Family FLIPR assay as described below.

[1001] 1. TRPC3 channel (human TRPC3 variant 1 gene, expressed in HEK293 cells).

[1002] 2. TRPC4 channel (human TRPC4 gene, expressed in HEK293 cells).

[1003] 3. TRPC5 channel (human TRPC5 gene, expressed in HEK293 cells).

[1004] 4. TRPC6 channel (human TRPC6 gene, expressed in HEK293 cells).

[1005] 5. TRPM2 channel (human TRPM2 gene, transiently expressed in HEK293 cells).

[1006] 6. TRPM3 channel (human TRPM3 gene, transiently expressed in HEK293 cells).

[1007] 7. TRPM4 channel (human TRPM4 gene, expressed in CHO cells).

[1008] 8. TRPM5 channel (human TRPM5 gene, expressed in CHO cells).

[1009] 9. TRPA1 channel (human TRPA1 gene, expressed in CHO cells).

[1010] 10. TRPV1 channel (human TRPV1 gene, expressed in HEK293 cells).

[1011] 11. TRPV2 channel (human TRPV2 gene, transiently expressed in HEK293 cells).

[1012] 12. TRPV3 channel (human TRPV3 gene, transiently expressed in HEK293 cells).

[1013] 13. TRPV4 channel (human TRPV4 gene, expressed in CHO cells).

[1014] 14. TRPV5 channel (human TRPV5 gene, transiently expressed in HEK293 cells).

[1015] 15. TRPV6 channel (human TRPV6 gene, expressed in HEK293 cells).

[1016] Data acquisition was performed by the FLIPR control software provided with the FLIPR system (MDS-AT), and data were analyzed using Microsoft Excel (Microsoft Corp., Redmond, WA) or GraphPad Prism. Concentration-response data were fitted to a Hill equation of the following form:

[1017]

[1018] Where Base is the response of the test article at low concentration, Max is the maximum response at high concentration, and xhalf is the EC 50 or IC 50 , the concentration of the test article producing half-maximal activation or inhibition, and rate is the Hill coefficient. A nonlinear least squares fit was performed assuming a simple binding model. The fit was weighted by the standard deviation if appropriate. No assumptions were made about the fit parameters; the fit parameters were determined by the algorithm.

[1019] Results and Conclusions

[1020] The effect of each test article was evaluated at eight (8) concentrations (0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM and 10 μM, n≤4 wells / concentration). MAX The results are expressed as % of (for agonists) and % of control (for antagonists). The positive control results confirm the sensitivity of the test system to ion channel activation and inhibition.

[1021] Agonist / antagonist effects of test articles on TRPC3 channels

[1022] In the agonist mode, the reference agonist GSK1702934A was used as an internal control (0-30 μM). MAX The % of response is used to calculate the effect of the test article.

[1023] In antagonist mode, the channel was activated with a positive control agonist (15 μM GSK1702934A). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist verapamil was used as an internal control.

[1024] Agonist / antagonist effects of test articles on TRPC4 and TRPC5 channels

[1025] In the agonist mode, the reference agonist (-) Englerin A was used as an internal control (0-30 μM). MAX The % of response is used to calculate the effect of the test article.

[1026] In antagonist mode, channels were activated with a positive control agonist (0.5 μM (-) Engelin A). Inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist Verapamil was used as an internal control.

[1027] Agonist / antagonist effects of test articles on TRPC6 channels

[1028] In the agonist mode, the reference agonist Na-ATP was used as an internal control (0-100 μM). MAX The % of response is used to calculate the effect of the test article.

[1029] In antagonist mode, channels were activated with a positive control agonist (10 μM Na-ATP). Inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist verapamil was used as an internal control.

[1030] Agonist / antagonist effects of test articles on TRPM2 channels

[1031] In agonist mode, the reference agonist H 2 O 2 Served as internal control (0-1000 μM). 2 O 2 (333μM) triggered by E MAX The % of response is used to calculate the effect of the test article.

[1032] In the antagonist mode, the positive control agonist (300 μM H 2 O 2 ) activated the channel. The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist flufenamic acid (0-1000 μM) was used as an internal control.

[1033] Agonist / antagonist effects of test articles on TRPM3 channels

[1034] In the agonist mode, the reference agonist pregnenolone was used as an internal control (0-100 μM). MAX The % of response is used to calculate the effect of the test article.

[1035] In antagonist mode, the channel was activated with the positive control agonist (pregnenolone 30 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist mefenamic acid (0-200 μM) was used as an internal control.

[1036] Agonist / antagonist effects of test articles on TRPM4 channels

[1037] In the agonist mode, the reference agonist A23187 was used as an internal control (0-30 μM). MAX The % of response calculated the effect of the test article.

[1038] In antagonist mode, the channel was activated with a positive control agonist (A23 1 87 10 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist flufenamic acid (0-200 μM) was used as an internal control.

[1039] Agonist / antagonist effects of test articles on TRPM5 channels

[1040] In the agonist mode, the reference agonist Mg-ATP was used as an internal control (0-100 μM). MAX The % of response is used to calculate the effect of the test article.

[1041] In antagonist mode, channels were activated with a positive control agonist (Mg-ATP 75 μM). Inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist triphenylphosphine oxide (TPPO, 0-300 μM) was used as an internal control.

[1042] Test article agonist / antagonist effect on TRPA1 channels

[1043] In the agonist mode, the reference agonist mustard oil was used as an internal control (0-600 μM). MAX The % of response is used to calculate the effect of the test article.

[1044] In antagonist mode, the channel was activated with a positive control agonist (mustard oil 80 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist ruthenium red (0-30 μM) was used as an internal control.

[1045] Agonist / antagonist effects of test articles on TRPV1 channels

[1046] In the agonist mode, the reference agonist capsaicin was used as an internal control (0-1 μM). MAX The % of response is used to calculate the effect of the test article.

[1047] In antagonist mode, the channel was activated with a positive control agonist (capsaicin 0.1 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist ruthenium red (0-10 μM) was used as an internal control.

[1048] Agonist / antagonist effects of test articles on TRPV2 channels

[1049] In the agonist mode, the reference agonist cannabidiol was used as an internal control (0-300 μM). MAX The % of response is used to calculate the effect of the test article.

[1050] In antagonist mode, the channel was activated with a positive control agonist (capsaicin 100 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist ruthenium red (0-30 μM) was used as an internal control.

[1051] Agonist / antagonist effects of test articles on TRPV3 channels

[1052] In the agonist mode, the reference agonist 2-aminoethoxydiphenyl borate (2-APB) was used as an internal control (0-300 μM). MAX The % of response is used to calculate the effect of the test article.

[1053] In antagonist mode, the channel was activated with a positive control agonist (2-APB 50 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist ruthenium red (0-30 μM) was used as an internal control.

[1054] Agonist / antagonist effects of test articles on TRPV4 channels

[1055] In the agonist mode, the reference agonist GSK1016790A was used as an internal control (0-3 μM). MAX The % of response calculated the effect of the test article.

[1056] In antagonist mode, the channel was activated with a positive control agonist (GSK1016790A 0.3 μM). The inhibition of the signal by the test article was calculated relative to the signal produced by the agonist alone. The reference antagonist ruthenium red (0-10 μM) was used as an internal control.

[1057] Test articles for antagonist effects on TRPV5 channels

[1058] In antagonist mode, the channel was activated with 60 μM cadmium ions. The inhibition of the signal by the test article was calculated relative to the signal generated in the control. The reference antagonist 2-APB (0-300 μM) was used as an internal control.

[1059] Test articles for antagonist effects on TRPV6 channels

[1060] In antagonist mode, the channel was activated with 0.9 mM calcium ions. The inhibition of the signal by the test article was calculated relative to the signal generated in the control. The reference antagonist 2-APB (0-300 μM) was used as an internal control.

[1061] The following table provides data for the compound of Example 5.

[1062]

[1063]

[1064] Example 27. Representative pharmaceutical dosage forms containing a compound of Formula I ("Compound X") for use in human therapy or prevention are illustrated below.

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071] The above preparations can be obtained by conventional procedures well known in the pharmaceutical field.

[1072] All publications, patents and patent documents are incorporated herein by reference, just as if they were individually incorporated herein by reference. The present disclosure has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that within the spirit and scope of the present disclosure, many variations and modifications may be made.

Claims

1. A compound of formula I: or a salt thereof, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; Where R a , R b , R c and R d At least one of is not H; R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl or (C1-C3)alkoxy, wherein any cyclopropyl, (C1-C3)alkyl and (C1-C3)alkoxy is optionally 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 to which they are attached, they form a fused cyclopropyl ring; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyloxy and (C3-C7) cycloalkyl, wherein any of (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyloxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, (C1-C5) alkyl and hydroxy; and A is 0, 1, or 2; or A compound of formula I: or a salt thereof, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R 1 is (C1-C3)alkyl substituted by one or more fluorines; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyloxy and (C3-C7) cycloalkyl, wherein any of (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C5) cycloalkyloxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and A is 0, 1 or 2.

2. The compound or salt of claim 1, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; Where R a , R b , R c and R d At least one of is not H; R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl or (C1-C3)alkoxy, wherein any cyclopropyl, (C1-C3)alkyl and (C1-C3)alkoxy is optionally 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 to which they are attached, they form a fused cyclopropyl ring; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C7) cycloalkyl, wherein any (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, (C1-C5) alkyl and hydroxy; and A is 0, 1 or 2.

3. The compound or salt of claim 1, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R 1 is (C1-C3)alkyl substituted by one or more fluorines; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C7) cycloalkyl, wherein any (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and A is 0, 1 or 2.

4. The compound or salt of claim 1, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; Where R a , R b , R c and R d At least one of is not H; R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl or (C1-C3)alkoxy, wherein any cyclopropyl, (C1-C3)alkyl and (C1-C3)alkoxy is optionally 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 to which they are attached, they form a fused cyclopropyl ring; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C7) cycloalkyl, wherein any (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, (C1-C5) alkyl and hydroxy; and A is 0, 1, or 2; or The compound or salt according to claim 1, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d Together they are oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl; R 1 is (C1-C3)alkyl substituted by one or more fluorines; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C7) cycloalkyl, wherein any (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and A is 0, 1 or 2.

5. The compound or salt of claim 4, wherein L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached form spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, Rc(C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d together is oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached form spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl; Where R a , R b , R c and R d At least one of is not H; R 1 is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3)alkyl or (C1-C3)alkoxy, wherein any cyclopropyl, (C1-C3)alkyl and (C1-C3)alkoxy is optionally 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 to which they are attached, they form a fused cyclopropyl ring; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C7) cycloalkyl, wherein any (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, (C1-C5) alkyl and hydroxy; and A is 0, 1 or 2.

6. The compound or salt of claim 4, wherein: L 1 Yes CR a R b ; L 2 Yes CR c R d ; R a is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R b is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R a and R b Together they are oxo (=O) methylene (=CH2), or R a and R b Together with the atoms to which they are attached form spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl; R c is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; R d is H, halo, cyano, Rc(C1-C5)alkyl, (C1-C5)alkoxy or (C3-C5)cycloalkyl, wherein any of (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted with one or more fluorine; or R c and R 1 Together with the atoms to which they are attached, they form a fused cyclopropyl ring; or R c and R d together is oxo (=O) or methylene (=CH2), or R c and R d Together with the atoms to which they are attached form spiro(C3-C5)cycloalkylspiro(C3-C5)cycloalkyl; R 1 is (C1-C3)alkyl substituted by one or more fluorines; Each R 2 independently selected from halo, cyano, hydroxy, ethynyl, (C1-C3) alkylsulfonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted with one or more fluorine; R 4 is (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl, wherein any R 4 Optionally one or more R x replace; Each R x is independently selected from hydroxy, halo, cyano, (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C7) cycloalkyl, wherein any (C1-C5) alkyl, (C1-C5) alkoxy and (C3-C5) cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano and hydroxy; and A is 0, 1 or 2.

7. The compound or salt according to claim 4, which is a compound of formula (II): or a salt thereof, wherein R 4 is (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl; and B is 0, 1 or 2.

8. The compound or salt according to claim 4, which is a compound of formula (III): or a salt thereof, wherein R 4 is (C3-C7)cycloalkyl, phenyl or 6-membered heteroaryl; and B is 0, 1 or 2.

9. The compound or salt of any one of claims 1 to 8, wherein R a It's H.

10. The compound or salt of any one of claims 1 to 8, wherein R a Selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl, wherein any of the (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted by one or more fluorine.

11. The compound or salt of any one of claims 1 to 8, wherein R a It is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5)alkyl or (C3-C5)cycloalkyl.

12. The compound or salt of any one of claims 1 to 8, wherein R a It is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl or (C3-C5) cycloalkyl.

13. The compound or salt of any one of claims 1 to 12, wherein R b It's H.

14. The compound or salt of any one of claims 1 to 12, wherein R b is halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl, wherein any of the (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl groups are optionally substituted by one or more fluorine groups.

15. The compound or salt of any one of claims 1 to 12, wherein R b It is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5)alkyl or (C3-C5)cycloalkyl.

16. The compound or salt of any one of claims 1 to 12, wherein R b It is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl or (C3-C5) cycloalkyl.

17. A compound or salt as claimed in any one of claims 1 to 16, wherein R c It's H.

18. A compound or salt as claimed in any one of claims 1 to 16, wherein R c Selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl, wherein any of the (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted by one or more fluorine.

19. A compound or salt as claimed in any one of claims 1 to 16, wherein R c It is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5)alkyl or (C3-C5)cycloalkyl.

20. The compound or salt of any one of claims 1 to 16, wherein R c It is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl or (C3-C5) cycloalkyl.

21. A compound or salt as claimed in any one of claims 1 to 16, wherein R 1 and R c Together with the atoms to which they are attached they form a fused cyclopropyl ring.

22. A compound or salt as claimed in any one of claims 1 to 21, wherein R d It's H.

23. A compound or salt as described in any one of claims 1 to 21, wherein R d Selected from the group consisting of halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl, wherein any of the (C1-C5)alkyl, (C1-C5)alkoxy and (C3-C5)cycloalkyl is optionally substituted by one or more fluorine.

24. A compound or salt as described in any one of claims 1 to 21, wherein R d It is H, halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5)alkyl or (C3-C5)cycloalkyl.

25. A compound or salt as described in any one of claims 1 to 21, wherein R d It is halo, cyano, CF3, CF2H, CFH2, OCF3, OCF2H, OCH2CF3, OCH2CF2H, (C1-C5) alkyl or (C3-C5) cycloalkyl.

26. A compound or salt as described in any one of claims 1 to 16, wherein R c and R d Together with the atoms to which they are attached they form a spiro(C3-C5)cycloalkyl.

27. A compound or salt as described in any one of claims 1 to 20 and 22 to 26, wherein R 1 Selected from the group consisting of cyano, halo, methoxycarbonyl, cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy, wherein any cyclopropyl, (C1-C3) alkyl and (C1-C3) alkoxy is optionally substituted by one or more groups independently selected from hydroxy, (C1-C3) alkoxy, benzyloxy and fluorine.

28. A compound or salt as described in any one of claims 1 to 20 and 22 to 26, wherein R 1 It is H, methyl, cyclopropyl, CF3, CF2H, CFH2, OCF3 or OCF2H.

29. A compound or salt as described in any one of claims 1 to 20 and 22 to 26, wherein R 1 It is hydroxy, hydroxymethyl or cyanomethyl.

30. A compound or salt as described in any one of claims 1 to 20 and 22 to 26, wherein R 1 It's methyl.

31. A compound or salt as described in any one of claims 1 to 20 and 22 to 26, wherein R 1 It's H.

32. A compound or salt according to any one of claims 1 to 31, wherein the group: Selected from the group consisting of:

33. A compound or salt as described in any one of claims 1 to 31, wherein A is O.

34. The compound or salt of any one of claims 1 to 31, wherein A is 1.

35. The compound or salt of claim 34, wherein R 2 It's cyano.

36. The compound or salt of claim 34, wherein R 2 It is 6-cyano.

37. A compound or salt as described in any one of claims 1 to 36, wherein R 4 is optionally replaced by one or an R x Substituted phenyl.

38. A compound as described in any one of claims 1 to 36, wherein R 4 Selected from the group consisting of:

39. A compound or salt as described in any one of claims 1 to 36, wherein R 4 is optionally replaced by one or more R x Substituted pyrimidin-2-yl.

40. A compound as described in any one of claims 1 to 36, wherein R 4 Selected from the group consisting of:

41. A compound as described in any one of claims 1 to 36, wherein R 4 is optionally replaced by an R x Substituted (C1-C7) alkyl.

42. A compound as described in any one of claims 1 to 36, wherein R 4 is optionally replaced by an R x Substituted (C3-C7)cycloalkyl.

43. A compound as described in any one of claims 1 to 36, wherein R 4 is optionally replaced by an R x Substituted 6-membered heteroaryl.

44. A compound as described in any one of claims 41 to 43, wherein R x is a C1-C5 alkyl group optionally substituted by one or more groups independently selected from halo, cyano and hydroxy.

45. A compound as described in any one of claims 41 to 43, wherein R x It is a C1-C5 alkyl group substituted by a hydroxy group.

46. ​​A compound as described in any one of claims 41 to 43, wherein R x It is 2-hydroxy-2-methylethyl.

47. The compound or salt of claim 1, which is a compound of formula IV or V: or a salt thereof, wherein B is 0, 1 or 2.

48. The compound or salt of claim 1, which is a compound of formula IV or Va: or a salt thereof, wherein B is 0, 1 or 2.

49. The compound or salt of claim 1, which is a compound of formula VI or VII: or a salt thereof.

50. The compound or salt of claim 1, wherein R c is fluorine, and R d It is H or fluorine.

51. The compound or salt of claim 1 selected from the group consisting of: and its salts.

52. The compound or salt of claim 1 selected from the group consisting of: and its salts.

53. The compound or salt of claim 1 selected from the group consisting of: and its salts.

54. The compound or salt of claim 1 selected from the group consisting of: and its salts.

55. The compound or salt of claim 1, which is: or a salt thereof.

56. The compound or salt of claim 1, which is: or a salt thereof.

57. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

58. A method for treating a condition associated with TRPV4 comprising administering a compound as claimed in any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof.

59. A compound as claimed in any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, for use in treating a condition associated with TRPV4.

60. A compound as claimed in any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of a condition associated with TRPV4.

61. Use of a compound as claimed in any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a condition associated with TRPV4.

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