DPP1 inhibitors for use in medicine

Abstract

Provided herein are methods of treating various disorders in a subject comprising administering an effective amount of a compound of Formula (I), NONAHLZYmn(I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof to the subject.

Description

Attorney Docket No.: INMD-221 / 01WO 315953-4549USES OF DPP1 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 745,952, filed on January 16, 2025, the content of which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a type of lysosome cysteine protease capable of removing the dipeptide from the amino terminal of protein substrates. The earliest discovery of DPP1 was by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858); subsequently, its earliest description in human cDNA occurred in 1995 (inmd-213FEBS Lett, 369, 326-330). DPP1 is the only member of the papain-like protease family that has a tetramer effect and is composed of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain and a light chain (J Biol Chem, 270, 21626-21631).

[0003] High levels of DPP1 are expressed by many tissues of the lungs, kidneys, liver and spleen (Biol. Chem. Hoppe Seyler 373: 367-373, 1992). As such it has the same role in activating serine protease in haematopoietic stem cells, and there is also relatively high expression of DPP1 in neutrophils, cytotoxic lymphocytes, natural killer cells, alveolar macrophages and mastocytes. The latest data has shown that, apart from being an important enzyme in lysosomal protein degradation, DPP1 also plays a role as a key enzyme in the activation of the following cell serine protease particles: cytotoxic T lymphocytes and natural killer cells (granzymes A and B; Proc. Nat. Acad. Sci. 96: 8627-8632, 1999), mastocytes (chymotrypsin and fibrinogenase; J Biol. Chem. 276: 18551-18556, 2001), and neutrophils (cathepsin G, elastinase and protease hydrolase 3; J Clin. Invest. 109: 363. 371, 2002). Once activated, these proteases can cause degradation of multiple extracellular matrix components, resulting in tissue damage and chronic inflammation. Due to DPP1 playing a key role in the activation of these proteases, it has become considered to be a type of effective therapeutic target (J Clin Invest, 2002, 109, 363-271; J Immunol, 2004, 173, 7277-7281).

[0004] In light of this, cathepsin C inhibitors exhibit potential for use in treatment in various inflammatory diseases. In view of the effect of DPP1 on certain pro-inflammatory serine proteases, clinical applications that suppress its activity and therefore suppress downstream serine protease activity may have favorable prospects. Currently, there are a number of related patent applications that give reports of synthesis of DPP1 inhibitors, including WO2023243601.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0005] Because DPP1 has been implicated in a number of disease states, and because no DPP1 inhibitors have been approved by a regulatory authority, there remains a need novel use of DPP1 inhibitors in treating various diseases and disorders.SUMMARY

[0006] In one aspect, the present invention provides a method of treating an asthma disorder selected from the group consisting of neutrophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, and drug-induced asthma, or a method of treating a disorder selected from the group consisting of infectious bronchitis, eosinophilic bronchitis, fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicating anti -neoplastic therapy, fibrosis complicating chronic infection, non-cystic fibrosis bronchiectasis (NCFBE), bronchiectasis associated with cystic fibrosis, sarcoidosis, farmer’s lung, hypersensitivity pneumonitis, complications of lung transplantation, vasculitic or thrombotic disorders of the lung vasculature, pulmonary hypertension, antitussive activity, chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, perennial or seasonal allergic rhinitis, rhinitis nervosa (hay fever), nasal polyposis, acute viral infection, common cold, an infection due to a respiratory virus, chronic rhinosinusitis (CRS), Hurley stage I hidradenitis suppurativa (HS), Hurley stage II HS, Hurley stage III HS, cancer, cancer-induced pain, Crohn’s disease, giant cell arteritis, polyarteritis nodosa, anti-glomerular basement membrane (anti-GBM) disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, dermatomyositis / polymyositis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, ventilator-induced lung injury, heart failure, osteoarthritis (OA), ischemia / reperfusion (IR) injury, liver injury, and sepsis in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof to the subject,whereinRing A is heterocyclyl optionally substituted with 1-3 R1;Attorney Docket No.: INMD-221 / 01WO 315953-4549Y is H, alkyl, haloalkyl, NRARB, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein Y is optionally substituted with 1-3 R2;m and n are each independently 1 or 2;L is heterocyclylene, heteroarylene, alkylene, C(=O)-N(Rc), C(=O)-N(Rc)-alkylene, alkylene-O-alkylene or C(=O);Z is a haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, C(=O)-cycloalkyl, or alkylene-aryl, wherein Z is optionally substituted with 1-3 R3;RAand RBare each alkyl, C(=O)alkyl, or S(=O)2alkyl;Rcis H or alkyl;R1is alkyl, OH, halo, Oalkyl, S(alkyl) or S(=O)2alkyl; ortwo R1with the atom they are attached to from a cycloalkyl or heterocyclyl ring;R2is alkyl, halo or OH; andR3is alkyl, halo, haloalkyl or Oalkyl.

[0007] In one embodiment of a method disclosed herein, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:wherein R1, m, n, Y, L and Z are defined above in Formula (I).

[0008] In one embodiment of a method disclosed herein, the compound is a compound of Formula (lb), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:wherein m, n, Y, L and Z are defined above in Formula (I).

[0009] In one embodiment of a method disclosed herein, the compound is any one of the compounds selected from Table 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0010] In one embodiment of a method disclosed herein, a composition comprising the compound or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered to the subject.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0011] In one embodiment of a method disclosed herein, the compound is any one of the compounds disclosed in the patent application having publication number WO2023243601, the entirety of which is incorporated herein.

[0012] In one embodiment of a method disclosed herein, the compound is pharmaceutically acceptable salt, a stereoisomer, or a deuterated form of any one of the compounds disclosed in the patent application having publication number WO2023243601.

[0013] In one embodiment of a method disclosed herein, the compound isAttorney Docket No.: INMD-221 / 01WO 315953-4549(compound 88A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0014] In one embodiment of a method disclosed herein, the asthma disorder is neutrophilic asthma.

[0015] In one embodiment of a method disclosed herein, the disorder is Crohn’s disease, chronic rhinosinusitis (CRS), non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, osteoarthritis (OA), ischemia / reperfusion (IR) injury or liver injury. In one embodiment, the disorder is Crohn’s disease. In one embodiment, the disorder is chronic rhinosinusitis (CRS). In embodiments, the disorder is chronic rhinosinusitis without nasal polyps (CRSsNP) or chronic rhinosinusitis with nasal polyps (CRSwNP). In one embodiment, the disorder is refractory chronic rhinosinusitis. In one embodiment, the disorder is non-CF bronchiectasis (NCFBE). In one embodiment, the disorder is bronchiectasis associated with CF. In one embodiment, the disorder is osteoarthritis (OA). In one embodiment, the disorder isischemia / reperfusion (IR) injury. In one embodiment, the disorder is liver injury. In one embodiment, the liver injury is drug-induced liver injury.DETAILED DESCRIPTIONDefinitions

[0016] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0017] Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0018] The term “about” when immediately preceding a numerical value means a range encompassing said numerical value plus or minus an acceptable amount of variation in the art (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” aAttorney Docket No.: INMD-221 / 01WO 315953-4549value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0019] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0020] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0021] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0022] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene,Attorney Docket No.: INMD-221 / 01WO 315953-4549phenanthrene, pleiadene, pyrene, and triphenylene. In embodiments where “L” is aryl, the aryl radical is a diradical. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0023] “Arylene” refers to a divalent aryl group.

[0024] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0025] “Cycloalkylene” refers to a divalent cycloalkyl group.

[0026] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0027] “Heterocyclyl” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, saturated or partially unsaturated ring radical which consists of two to nineteen carbon ring atoms and from one to six heteroatoms as ring atoms selected from nitrogen, oxygen or sulfur, at least one non-aromatic, saturated or partially unsaturated ring containing at least one heteroatom as a ring atom. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, andAttorney Docket No.: INMD-221 / 01WO 315953-45491,1-dioxo-thiomorpholinyl. In embodiments where “L” is heterocyclyl, the heterocyclyl radical is a diradical. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0028] “Heterocyclyl ene” refers to a divalent heterocyclyl group.

[0029] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising one to nineteen carbon ring atoms, one to six heteroatoms as ring atoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring and at least one heteroatom as a ring atom. For purposes of this disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e. thienyl). In embodiments where “L” is heteroaryl, the heteroaryl radical is a diradical. Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0030] “Heteroarylene” refers to a divalent heteroaryl group.

[0031] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups,Attorney Docket No.: INMD-221 / 01WO 315953-4549sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” can occur when valency allows and to produce a stable compound.

[0032] “ Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NR.gSO2R.i1, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SChRg, -OSChRg, -SChORg, =NSO2Rg, and -SChNRgRh. “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further includes any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.I-I

[0033] As used herein, the symbol “ I ” or “ 1 ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example,“” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0034] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0035] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0036] The compounds of the disclosure, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0037] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0038] The compounds of Formula (I), (la) or (lb), or Table 1, and their pharmaceutically acceptable salts are useful as dipeptidyl peptidase 1 (DPP1 or cathepsin C) inhibitors, and thus may be used in any disease area where DPP1 plays a role. As such, methods of treating various diseases are provided herein. The method of treatment, in one embodiment, comprises, administering to a subject in need of, for an administration period, a composition comprising an effective amount of a compound of Formula (I), (la), or (lb), or Table 1 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In one embodiment, a subject’s symptom(s) or clinical outcome(s) are improved during the administration period or subsequent to the administration period, as compared to the respective symptom(s) or clinical outcome measured prior to the administration period.

[0039] “Prior to the administration period”, as used herein, refers to a time period of from about 28 days prior to the initial administration of the pharmaceutical composition or compound of Formula (I), (la), or (lb) or Table 1 provided herein, to immediately prior to the initial administration of the pharmaceutical composition or compound of Formula(I), (la), or (lb) or Table 1. “Immediately prior to the administration period” in one embodiment, is from about 24 hours prior to about 1 minute prior to the initial administration of the pharmaceutical composition or compound of Formula (I), (la), or (lb) or Table 1 provided herein.

[0040] In one embodiment, prior to the administration period is from about 28 days prior to immediately prior to the administration period. In another embodiment, prior to the administration period is from about 21 days prior to immediately prior to the administration period. In another embodiment, prior to the administration period is from about 14 days prior to immediately prior to the administration period. In even another embodiment, prior to the administration period is from about 10 days prior to immediately prior to the administration period. In yet even another embodiment, prior to the administration period is from about 7 days prior to immediately prior to the administration period. In even yet another embodiment, prior to the administration period is from about 4 days prior to immediately prior to the administration period.

[0041] As used herein, “prior to the administration period”, means a time point prior to a compound of the disclosure being administered to a subject. In one embodiment, “prior to the administration period” is from about 28 days prior to about 1 day prior to the administration period. In another embodiment, prior to the administration period is from about 21 days prior to about 1 day prior to the administration period. In another embodiment, prior to the administration period is from about 14 days prior to about 1 day prior to the administration period. In even another embodiment, prior to the administration period is from about 10 daysAttorney Docket No.: INMD-221 / 01WO 315953-4549prior to about 1 day prior to the administration period. In yet even another embodiment, prior to the administration period is from about 7 days prior to about 1 day prior to the administration period. In even yet another embodiment, prior to the administration period is from about 4 days prior to about 1 day prior to the administration period.

[0042] As used herein, the terms “treatment”, “treating” and variations thereof, are used interchangeably. The terms “treatment” and “treating” as used herein with regard to a patient or a subject, refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. The term “treating” in one embodiment, includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); (3) relieving the condition (for example, by causing regression, or reducing the severity of the state, disorder or condition or at least one of its clinical or subclinical symptoms).

[0043] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to achieve an outcome, for example, to effect beneficial or desired results.

[0044] The terms “subject” “individual” and “patient” are used interchangeably herein to refer to a vertebrate, such as a mammal. The mammal may be, for example, a mouse, a rat, a rabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., cynomolgus monkey, chimpanzee), or a human. A subject’s tissues, cells, or derivatives thereof, obtained in vivo or cultured in vitro are also encompassed. A human subject may be an adult, a teenager, a child (2 years to 14 years of age), an infant (1 month to 24 months), or a neonate (up to 1 month). In some embodiments, the adults are seniors about 65 years or older, or about 60 years or older.Methods of treatment

[0045] The present invention provides a method of treating an asthma disorder selected from the group consisting of neutrophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, and drug-induced asthma, or a method of treating treating a disorder selected from the group consisting of infectious bronchitis,Attorney Docket No.: INMD-221 / 01WO 315953-4549eosinophilic bronchitis, fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicating anti -neoplastic therapy, fibrosis complicating chronic infection, non-cystic fibrosis bronchiectasis (NCFBE), bronchiectasis associated with cystic fibrosis, sarcoidosis, farmer’s lung, hypersensitivity pneumonitis, complications of lung transplantation, vasculitic or thrombotic disorders of the lung vasculature, pulmonary hypertension, antitussive activity, chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, perennial or seasonal allergic rhinitis, rhinitis nervosa (hay fever), nasal polyposis, acute viral infection, common cold, an infection due to a respiratory virus, chronic rhinosinusitis (CRS), Hurley stage I hidradenitis suppurativa (HS), Hurley stage II HS, Hurley stage III HS, cancer, cancer-induced pain, Crohn’s disease, giant cell arteritis, polyarteritis nodosa, anti-glomerular basement membrane (anti-GBM) disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, dermatomyositis / polymyositis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, ventilator-induced lung injury, heart failure, osteoarthritis (OA), ischemia / reperfusion (IR) injury, liver injury, and sepsis in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof to the subject,. •hereinRing A is heterocyclyl optionally substituted with 1-3 R1;Y is H, alkyl, haloalkyl, NRARB, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein Y is optionally substituted with 1-3 R2;m and n are each independently 1 or 2;L is heterocyclylene, heteroarylene, alkylene, C(=O)-N(Rc), C(=O)-N(Rc)-alkylene, alkylene-O-alkylene or C(=O);Z is a haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, C(=O)-cycloalkyl, or alkylene-aryl, wherein Z is optionally substituted with 1-3 R3;RAand RBare each alkyl, C(=O)alkyl, or S(=O)2alkyl;Rcis H or alkyl;R1is alkyl, OH, halo, Oalkyl, S(alkyl), or S(=O)2alkyl; orAttorney Docket No.: INMD-221 / 01WO 315953-4549two R1with the atom they are attached to from a cycloalkyl or heterocyclyl ring;R2is alkyl, halo or OH; andR3is alkyl, halo, haloalkyl or Oalkyl.

[0046] In one embodiment of a method disclosed herein, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:wherein R1, m, n, Y, L and Z are defined above in Formula (I).

[0047] In one embodiment of a method disclosed herein, the compound is a compound of Formula (lb), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:wherein m, n, Y, L and Z are defined above in Formula (I).

[0048] In one embodiment of a method provided herein, Ring A of Formula (I) is 5-10 heterocyclyl optionally substituted with 1-3 R1In embodiments, Ring A is 5-6 monocyclic heterocyclyl optionally substituted with 1-3 R1. In embodiments, Ring A is 7-9 membered polycyclic heterocyclyl optionally substituted with 1-3 R1.

[0049] In one embodiment of a method provided herein, Ring A of FormulaAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0050] In one embodiment of a method provided herein, m of Formula (I), (la) or (lb) is 2 and n is 2.

[0051] In one embodiment of a method provided herein, m of Formula (I), (la) or (lb) is 1 and n is 1.

[0052] In one embodiment of a method provided herein, Y of Formula (I), (la) or (lb) is H, Ci-6 alkyl, haloalkyl, NRARB, C3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Y is optionally substituted with 1-3 R2.

[0054] In one embodiment of a method provided herein, L of Formula (I), (la) or (lb) is 5-6 membered heteroarylene, -C(=O)-N(Rc)-, -C(=O)-N(RC)-CI-6 alkylene-, -C1-6 alkylene-O-Ci-6 alkylene- or -C(=O)-;

[0055] In one embodiment of a method provided herein, L of Formula (I), (la) or (lb) isAttorney Docket No.: INMD-221 / 01WO 315953-4549uherei •n the asterisk (*) represents the point of attachment to Z.

[0057] In one embodiment of a method provided herein, Z of Formula (I), (la) or (lb) is haloalkyl, C3-6 cycloalkyl, phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C(=O)-C3-6 cycloalkyl, C1-6 alkylene-aryl, wherein Z is optionally substituted with 1-3 R3.

[0058] In one embodiment of a method provided herein, Z of formula (I), (la) or (lb) is CF3,

[0059] In one embodiment of a method provided herein, R1of Formula (I), (la) or (lb) is R1is C1-6 alkyl, OH, halo, OC1-6 alkyl, S(Ci-6 alkyl), S(=O)2 C1-6 alkyl. In embodiments, R1is F, OH, SCH3, S(=O)2CH3 or CH3.

[0060] In one embodiment of a method provided herein, two R1of Formula (I), (la) or (lb) with the atom they are attached to form a C3-6 cycloalkyl or 4-6 membered heterocyclyl. In embodiments, two R1with the atom they are attached to form a ring selected from,or , wherein the asterisk (*) represents the point that the two R1are attached to.

[0061] In one embodiment of a method provided herein, R2of Formula (I), (la) or (lb) is C1-6 alkyl or halo. In embodiments, R2is CH3 or F.

[0062] In one embodiment of a method provided herein, RAand RBof Formula (I), (la) or (lb) are each C1-6 alkyl, C(=O) C1-6 alkyl, or S(=O)2C1-6 alkyl. In embodiments, RAand RBare each CH3, C(=O)CH3, or S(=O)2CH3.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0063] In one embodiment of a method provided herein, Rcof Formula (I), (la) or (lb) is H or Cl-6 alkyl. In embodiments, Rcis H or CH3.

[0064] In one embodiment of a method disclosed herein, the compound is any one of the compounds disclosed in the patent application having publication number WO2023243601, the entirety of which is incorporated herein.

[0065] In one embodiment of a method disclosed herein, the compound is any one of the compounds disclosed in the patent application having publication number WO2023243601, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0066] In one embodiment of a method disclosed herein, the compound is any one of the compounds selected from Table 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0067] In one embodiment of a method disclosed herein, a composition comprising the compound of Formula (I), (la), or (lb) is administered to the subject. In embodiments, the composition is a pharmaceutical composition. In embodiments, the composition further comprises a pharmaceutically acceptable adjuvant, diluent or carrier.Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549Attorney Docket No.: INMD-221 / 01WO 315953-4549>Attorney Docket No.: INMD-221 / 01WO 315953-4549><Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0068] In one embodiment of a method disclosed herein, the compound isAttorney Docket No.: INMD-221 / 01WO 315953-4549(compound 88A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0069] In one embodiment of a method disclosed herein, the asthma disorder is neutrophilic asthma.

[0070] In one embodiment of a method disclosed herein, the disorder is Crohn’s disease, chronic rhinosinusitis (CRS), non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, osteoarthritis (OA), ischemia / reperfusion (IR) injury or liver injury. In one embodiment, the disorder is Crohn’s disease. In one embodiment, the disorder is chronic rhinosinusitis (CRS). In embodiments, the disorder is chronic rhinosinusitis without nasal polyps (CRSsNP) or chronic rhinosinusitis with nasal polyps (CRSwNP). In one embodiment, the disorder is refractory chronic rhinosinusitis. In one embodiment, the disorder is non-CF bronchiectasis (NCFBE). In one embodiment, the disorder is bronchiectasis associated with CF. In one embodiment, the disorder is osteoarthritis (OA). In one embodiment, the disorder isischemia / reperfusion (IR) injury. In one embodiment, the disorder is liver injury. In one embodiment, the liver injury is drug-induced liver injury

[0071] Methods of making the compounds of Formula (I), (la) or (lb) are disclosed in the international patent publication number WO2023243601, the entirety of which is incorporated herein. Further, a person skilled in the art would be capable of preparing the compounds of Formula (I), (la) or (lb) based on known organic synthesis technology, and the starting materials are commercially available chemicals and (or) compounds mentioned in chemical documents. “Commercially available chemicals” are those that can be obtained from actual commercial sources, such suppliers including: Titan, Energy Chemical, Shanghai Demo, Chengdu Chron Chemicals, Accela ChemBio Co., Ltd., Nanjing PharmaBlock, WuXi AppTec and J&K Scientific etc.

[0072] Reference publications and monographs in this field have described in detail the synthesis of the reagents used in preparation of the compounds described in this text, or provide articles that describe such preparation methods for reference. These reference books and monographs include: “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S.R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions”, 2ndEd., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, “Heterocyclic Chemistry”, 2ndEd., John Wiley & Sons, NewAttorney Docket No.: INMD-221 / 01WO 315953-4549York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4thEd., Wiley-Interscience, New York, 1992; Fuhrhop and Penzlin. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2ndEdition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4thEdition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. “Organic Chemistry” 7thEdition (2000)John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2ndEdition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopaedia” (1999) John Wiley & Sons, ISBN:3-527-29645-X, in 8 volumes; “Organic Reactions’^ 1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0073] By accessing the CAS index of known chemical substances prepared by the American Chemical Society, it is possible to selectively identify specific and similar reagents, these indexes are accessible in the majority of public libraries, university libraries and online. Known chemicals in the list that cannot be purchased commercially can alternatively be tailor-made by chemical synthesis laboratories, and many of the standard chemical suppliers (for instance, those listed above) provide a tailor-made synthesis service. The reference publication for preparation and selection of the pharmaceutical salts of the compounds described in this text is P.H. Stahl & C.G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0074] In the methods provided herein, the compounds of Formula (I), (la), or (lb) or Table 1, or pharmaceutically acceptable salts, stereoisomers or deuterated forms thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the Formula (I), (la) or (lb) compound / salt (active ingredient) is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0075] The compounds of Formula (I), (la), or (lb), or Table, or pharmaceutically acceptable salts, stereoisomers or deuterated forms thereof, may be administered to the subject topically (e.g., to the skin or to the lung and / or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HF A) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g., by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

[0076] Administration routes used for the methods herein include oral administration. Administration schedules and administration periods can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration is every other day, every third day, 3* per week or 4* per week.

[0077] For oral administration the compound of Formula (I), (la), or (lb), or Table 1 or pharmaceutically acceptable salts, stereoisomers or deuterated forms thereof, may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, com starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and / or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.

[0078] For the preparation of soft gelatine capsules, the compounds of Formula (I), (la), or (lb) or Table 1, or pharmaceutically acceptable salts thereof, may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the abovementioned excipients for tablets. Additionally, liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules.

[0079] Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally suchAttorney Docket No.: INMD-221 / 01WO 315953-4549liquid preparations may contain coloring agents, flavoring agents, saccharine and / or carboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use.

[0080] The dosage administered will vary with the compound of Formula (I), (la), or (lb) or Table 1, or pharmaceutically acceptable salts thereof employed, the mode of administration, and the treatment outcome desired. For example, in one embodiment, the daily dosage of the compound of Formula (I), (la), or (lb) or Table 1, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (pg / kg) to 100 micrograms per kilogram body weight (pg / kg). Alternatively, in one embodiment, if the composition comprising a compound of Formula (I), (la), or (lb) or Table 1, is administered orally, then the daily dosage of the compound of the disclosure may be in the range from 0.01 micrograms per kilogram body weight (pg / kg) to 100 milligrams per kilogram body weight (mg / kg).

[0081] The compounds of Formula (I), (la), or (lb) or Table 1, or pharmaceutically acceptable salts thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the Formula (I), (la), or (lb) or Table 1, compound / salt (active ingredient) is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0082] Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (percent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

[0083] As discussed herein, in one aspect, the invention provides methods of treating an asthma disorder selected from neutrophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, or drug-induced asthma.

[0084] In embodiments of any one of the methods disclosed herein, the asthma disorder is neutrophilic asthma.

[0085] In another aspect, the invention provides methods of treating a disorder selected from infectious bronchitis, eosinophilic bronchitis, fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicating anti-neoplastic therapy, fibrosis complicating chronic infection, non-cystic fibrosis bronchiectasis (NCFBE), bronchiectasis associated with cystic fibrosis, sarcoidosis, farmer’s lung, hypersensitivity pneumonitis, complications of lung transplantation, vasculitic or thrombotic disorder of the lung vasculature, pulmonaryAttorney Docket No.: INMD-221 / 01WO 315953-4549hypertension, antitussive activity, chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, perennial or seasonal allergic rhinitis, rhinitis nervosa (hay fever), nasal polyposis, acute viral infection, common cold, an infection due to a respiratory virus, chronic rhinosinusitis (CRS), Hurley stage I hidradenitis suppurativa (HS), Hurley stage II HS, Hurley stage III HS, cancer, cancer-induced pain, Crohn’s disease, giant cell arteritis, polyarteritis nodosa, anti-glomerular basement membrane (anti-GBM) disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, dermatomyositis / polymyositis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, ventilator-induced lung injury, heart failure, osteoarthritis (OA), ischemia / reperfusion (IR) injury, liver injury, or sepsis.

[0086] In embodiments of any one of the methods disclosed herein, the disorder is infectious bronchitis or eosinophilic bronchitis. In embodiments, the disorder is infectious bronchitis. In embodiments, the disorder is eosinophilic bronchitis.

[0087] In embodiments of any one of the methods disclosed herein, the disorder is cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicating anti-neoplastic therapy or fibrosis complicating chronic infection

[0088] In embodiments of any one of the methods disclosed herein, the disorder is non-cystic fibrosis bronchiectasis (NCFBE).

[0089] In embodiments of any one of the methods disclosed herein, the disorder is ronchiectasis associated with cystic fibrosis.

[0090] Cystic fibrosis (CF) is caused by abnormalities in the CF transmembrane conductance regulator protein, causing chronic lung infections (particularly with Pseudomonas aeruginosa) and excessive inflammation, and leading to bronchiectasis, declining lung function, respiratory insufficiency and quality of life. The inflammatory process is dominated by neutrophils that produce Neutrophil elastase (NE), as well as other destructive Neutrophil serine proteases (NSPs) including CatG and PR3, that directly act upon extracellular matrix proteins and play a role in the host response to inflammation and infection (Dittrich et al., Eur Respir J.2018;51(3)). The methods provided herein employ reversible inhibitors of DPP1. Without wishing to be bound by theory, it is thought that the compounds of Formula (I), (la), or (lb) administered via the methods provided herein have beneficial effects via inhibiting the activation of NSPs and decreasing inflammation, which in turn leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or anAttorney Docket No.: INMD-221 / 01WO 315953-4549improvement in lung function (e.g., forced expiratory volume in 1 second [FEVi]) in CF subjects.

[0091] Bronchiectasis is considered a pathological endpoint that results from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. The symptoms vary from intermittent episodes of expectoration and infection localized to the region of the lung that is affected to persistent daily expectoration often of large volumes of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. The underlying pathological process of bronchiectasis, without wishing to be bound by theory, has been reported as damage to the airways which results from an event or series of events where inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V. 65(Suppl 1), incorporated by reference herein in its entirety for all purposes).

[0092] The methods provided herein employ reversible inhibitors of DPP1. Without wishing to be bound by theory, it is thought that the compounds of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof administered via the methods provided herein have beneficial effects via decreasing inflammation and mucus hypersecretion, which in some embodiments, leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (cough, sputum production, and forced expiratory volume in 1 second [FEVi]) in bronchiectasis subjects. Without wishing to be bound by theory, it is thought that the methods provided herein modify bronchiectasis progression by reducing the accelerated rate of lung function decline or lung tissue destruction.

[0093] In embodiments of any one of the methods disclosed herein, the disorder is non-cystic fibrosis bronchiectasis (NCFBE) or bronchiectasis associated with CF, and the treating comprises improving the lung function of the subject, as compared to the lung function of the subject prior to treatment. In embodiments, improving lung function of the subject comprises increasing the subject’s forced expiratory volume in 1 second (FEVi), increasing the subject’s forced vital capacity (FVC), increasing the subject’s peak expiratory flow rate (PEFR), or increasing the subject’s forced expiratory flow between 25% and 75% of FVC (FEF (25-75%)), as compared to the respective value for the subject prior to treatment. In embodiments, the lung function is measured by spirometry.

[0094] In embodiments of any one of the methods disclosed herein, the disorder is non-cystic fibrosis bronchiectasis (NCFBE) or bronchiectasis associated with CF, and the treatingAttorney Docket No.: INMD-221 / 01WO 315953-4549comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the subject prior to treatment.

[0095] A pulmonary exacerbation, in one embodiment, is characterized by three or more of the following symptoms exhibited for at least 48 hours by the subject : (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis. In a further embodiment, the three or more symptoms result in a physician’s decision to prescribe an antibiotic(s) to the subject exhibiting the symptoms.

[0096] In embodiments of any one of the methods disclosed herein, the treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated subject. In embodiments, the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the subject : (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis.

[0097] In one embodiment, the treatment methods provided herein comprise improving the lung function of the subject during the administration period, as compared to the lung function of the subject prior to the administration period. In a further embodiment, the compound is administered orally, once daily. The improvement in lung function in one embodiment, is measured by spirometry.

[0098] Improving the lung function of the subject , in one embodiment, comprises increasing the subject’s forced expiratory volume in 1 second (FEVi), increasing the subject’s forced vital capacity (FVC), increasing the subject’s peak expiratory flow rate (PEFR), or increasing the subject’s forced expiratory flow between 25% and 75% of FVC (FEF (25-75%)), as compared to the respective value prior to the administration period. Increasing, in one embodiment, is by about 5%, by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45% or by about 50% of the respective value. Increasing, in one embodiment, is by at least about 5%, by at least about 10%, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45% or by at least about 50%. In yet another embodiment, the increasing is by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30% or by about 5% to about 20%. In even another embodiment, increasing is by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%.

[0099] In embodiments of any one of the methods disclosed herein, the disorder is sarcoidosis.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0100] In embodiments of any one of the methods disclosed herein, the disorder is farmer’s lung.

[0101] In embodiments of any one of the methods disclosed herein, the disorder is hypersensitivity pneumonitis.

[0102] In embodiments of any one of the methods disclosed herein, the disorder is lung transplantation.

[0103] In embodiments of any one of the methods disclosed herein, the disorder is vasculitic or thrombotic disorder of the lung vasculature.

[0104] In embodiments of any one of the methods disclosed herein, the disorder is pulmonary hypertension. In embodiments, the pulmonary hypertension is pulmonary arterial hypertension. In embodiments, the pulmonary hypertension is pulmonary hypertension due to left heart disease. In embodiments, the pulmonary hypertension associated with chronic lung disease.

[0105] In embodiments of any one of the methods disclosed herein, the method comprises treating cough associated with inflammatory and secretory conditions of the airways.

[0106] In embodiments of any one of the methods disclosed herein, the method comprises treating iatrogenic cough.

[0107] In embodiments of any one of the methods disclosed herein, the disorder is acute rhinitis or chronic rhinitis. In embodiments, the disorder is acute rhinitis. In embodiments, the disorder is chronic rhinitis. In embodiments, the disorder is rhinitis medicamentosa. In embodiments, the disorder is vasomotor rhinitis. In embodiments, the disorder is perennial or seasonal allergic rhinitis. In embodiments, the disorder is rhinitis nervosa (hay fever).

[0108] In embodiments of any one of the methods disclosed herein, the disorder is nasal polyposis.

[0109] In embodiments of any one of the methods disclosed herein, the disorder is acute viral infection.

[0110] In embodiments of any one of the methods disclosed herein, the disorder is common cold.[OHl] In embodiments of any one of the methods disclosed herein, the disorder is infection due to a respiratory virus.

[0112] In embodiments of any one of the methods disclosed herein, the disorder is chronic rhinosinusitis (CRS). In embodiments, the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In embodiments, the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In embodiments, the chronic rhinosinusitis is refractory chronic rhinosinusitis.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0113] In embodiments of any one of the methods disclosed herein, the treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS. In embodiments, the one or more symptoms of CRS is nasal congestion; nasal obstruction; nasal discharge; post-nasal drip; facial pressure; facial pain; facial fullness; reduced smell; depression; mucosal edema; mucopurulent discharge; obstruction of the middle meatus; mucosal changes within the ostiomeatal complex and sinuses; or rhinorrhea.

[0114] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) post-nasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (1) obstruction of the middle meatus; (m) mucosal changes within the ostiomeatal complex and sinuses; (n) rhinorrhea; or (o) any combinations thereof. In some embodiments, obstruction of the middle meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0115] In some embodiments, the administration of the compounds of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof or the composition comprising the compounds of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof reduces, diminishes the severity of, delays the onset of, or eliminates one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) post-nasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (1) obstruction of the middle meatus; (m) mucosal changes within the ostiomeatal complex and sinuses; (n) rhinorrhea; (o) or any combinations thereof. In some embodiments, the administration of the pharmaceutical composition enhances sinus drainage.

[0116] In some embodiments, the methods comprise reducing a composite severity score of one or more symptoms of CRS. As used herein, the “composite severity score” is a quantitative measure of all the symptoms of CRS exhibited by the subject. In some embodiments, the composite severity score is a sum total of all the daily symptoms exhibited by the subject. In some embodiments, the composite severity score is reduced during or subsequent to the administration period, as compared to the composite severity score measured prior to the administration period. In some embodiments, the one or more symptoms of CRS exhibited by the subject may be any symptoms described herein or known in the art to be associated with CRS. In some embodiments, the one or more symptoms of CRS are: nasal congestion, reducedAttorney Docket No.: INMD-221 / 01WO 315953-4549smell, rhinorrhea, or any combination thereof. In some embodiments, the rhinorrhea is anterior rhinorrhea. In some embodiments, the rhinorrhea is posterior rhinorrhea.

[0117] In some embodiments, the methods comprise decreasing the Sino-Nasal Outcome Test-22 (SNOT-22) score of the subject during the administration period or subsequent to the administration period, compared to the SNOT-22 score of the subject prior to the administration period. As used herein, “SNOT-22” is a patient-reported measure of outcome developed for use in CRS with or without nasal polyps and contains 22 individual questions. The questions cover a broad range of health and health-related quality of life problems including physical problems, functional limitations and emotional consequences. The theoretical range of the SNOT-22 score is 0-110, with lower scores implying a better health-related quality of life. Further details of SNOT-22 are provided in Hopkins, et al., Clin. Otolaryngol. 2009, 34, 447-454, and Kennedy, et al., Ann Allergy Asthma Immunol. 2013 October; 111(4): 246-251, the contents of which are incorporated herein by reference in its entirety.

[0118] In embodiments of any one of the methods disclosed herein, the disorder is Hurley stage I hidradenitis suppurativa (HS), Hurley stage II HS or Hurley stage III HS.

[0119] Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disorder. The symptoms include skin lesions that are often associated hair follicles, and may be painful, inflamed and / or swollen. In some cases, when the skin lesions heal, they can recur, and may lead to tunnels under the skin and progressive scarring. Since HS is a chronic condition, it can persist for many years and also, worsen over time, with serious effects on quality of life, psychological and emotional well-being. In fact, HS subjects have increased rates of anxiety and depression with a risk of suicide two and a half times that of the general population.

[0120] HS subjects are categorized according to disease severity, termed Hurley staging, as mild (Stage I), moderate (Stage II), or severe (Stage III). Although more than 200,000 cases of HS are diagnosed in the U.S. per year, this disease can be difficult to diagnose and requires specialized care. HS may be mistaken for an infection, an ingrown hair or other conditions. Moreover, current treatment options are limited and lack efficacy.

[0121] In embodiments of any one of the methods disclosed herein, the disorder is cancer. In embodiments, the cancer is bladder cancer, liver cancer, fibroid cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma or Kaposi’s Sarcoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma, acuteAttorney Docket No.: INMD-221 / 01WO 315953-4549myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorders, Natural Killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS), neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma.

[0122] In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is fibroid cancer. In one embodiment, the cancer is oropharyngeal cancer. In one embodiment, the cancer is testicular cancer. In one embodiment, the cancer is thymus cancer. In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is diffuse large B-cell lymphoma. In one embodiment, the cancer is B-cell immunoblastic lymphoma. In one embodiment, the cancer is Natural Killer cell lymphoma. In one embodiment, the cancer is T-cell lymphoma. In one embodiment, the cancer is Burkitt lymphoma or Kaposi’s Sarcoma. In one embodiment, the cancer is astrocytoma. In one embodiment, the cancer is anaplastic astrocytoma. In one embodiment, the cancer is glioblastoma multiforme. In one embodiment, the cancer is oligodendroglioma. In one embodiment, the cancer is ependymoma. In one embodiment, the cancer is meningioma. In one embodiment, the cancer is schwannoma. In one embodiment, the cancer is or medulloblastoma. In one embodiment, the cancer is acute myeloid leukemia (AML). In one embodiment, the cancer is acute lymphoblastic leukemia. In one embodiment, the cancer is acute lymphocytic leukemia. In one embodiment, the cancer is acute promyelocytic leukemia. In one embodiment, the cancer is chronic myeloid leukemia. In one embodiment, the cancer is hairy cell leukemia. In one embodiment, the cancer is myeloproliferative disorders. In one embodiment, the cancer is Natural Killer cell leukemia. In one embodiment, the cancer is blastic plasmacytoid dendritic cell neoplasm. In one embodiment, the cancer is chronic myelogenous leukemia (CML). In one embodiment, the cancer is mastocytosis. In one embodiment, the cancer is chronic lymphocytic leukemia (CLL). In one embodiment, the cancer is multiple myeloma (MM). In one embodiment, the cancer is and myelodysplastic syndrome (MDS). In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is Wilms tumor. In one embodiment, the cancer is rhabdomyosarcoma. In one embodiment, the cancer is retinoblastoma. In one embodiment, the cancer is osteosarcoma. In one embodiment, the cancer is Ewing sarcoma.

[0123] In some embodiments, the breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, the breast cancer comprises ductal carcinoma. In some embodiments, theAttorney Docket No.: INMD-221 / 01WO 315953-4549breast cancer comprises lobular carcinoma. In some embodiments, the breast cancer comprises medullary carcinoma. In some embodiments, the breast cancer comprises colloid carcinoma. In some embodiments, the breast cancer comprises tubular carcinoma. In some embodiments, the breast cancer comprises inflammatory breast cancer.

[0124] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer does not respond to hormonal therapy or therapeutics that target the HER2 protein receptors.

[0125] In some embodiments, the lymphoma is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma or Kaposi’s Sarcoma. In some embodiments, the lymphoma is Hodgkin’s lymphoma. In some embodiments, the lymphoma is non-Hodgkin’s lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is Natural Killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi’s Sarcoma.

[0126] In some embodiments, the brain cancer is astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, the brain cancer is astrocytoma. In some embodiments, the brain cancer is anaplastic astrocytoma. In some embodiments, the brain cancer is glioblastoma multiforme. In some embodiments, the brain cancer is oligodendroglioma. In some embodiments, the brain cancer is ependymoma. In some embodiments, the brain cancer is meningioma. In some embodiments, the brain cancer is schwannoma. In some embodiments, the brain cancer is medulloblastoma.

[0127] In some embodiments, the cancer is liquid tumor. In some embodiments, the liquid tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, a myeloproliferative disorder, Natural Killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or myelodysplastic syndrome (MDS). In some embodiments, the liquid tumor is acute myeloid leukemia (AML). In some embodiments, the liquid tumor is acute lymphoblastic leukemia. In some embodiments, the liquid tumor is acute lymphocytic leukemia. In some embodiments, the liquid tumor is acute promyelocytic leukemia. In some embodiments, the liquid tumor is chronic myeloid leukemia. In someAttorney Docket No.: INMD-221 / 01WO 315953-4549embodiments, the liquid tumor is hairy cell leukemia. In some embodiments, the liquid tumor is a myeloproliferative disorder. In some embodiments, the liquid tumor is Natural Killer cell leukemia. In some embodiments, the liquid tumor is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the liquid tumor is chronic myelogenous leukemia (CML). In some embodiments, the liquid tumor is mastocytosis. In some embodiments, the liquid tumor is chronic lymphocytic leukemia (CLL). In some embodiments, the liquid tumor is multiple myeloma (MM). In some embodiments, the liquid tumor is myelodysplastic syndrome (MDS).

[0128] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer is neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma. In some embodiments, the pediatric cancer is neuroblastoma. In some embodiments, the pediatric cancer is Wilms tumor. In some embodiments, the pediatric cancer is rhabdomyosarcoma. In some embodiments, the pediatric cancer is retinoblastoma. In some embodiments, the pediatric cancer is osteosarcoma. In some embodiments, the pediatric cancer is Ewing sarcoma.

[0129] In embodiments, the cancer is a metastatic cancer. In embodiments, the metastatic cancer is breast to lung metastatic cancer. In embodiments, the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver. In embodiments, the metastatic cancer comprises metastasis of bone cancer to the lung. In embodiments, the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, or the spleen.

[0130] In embodiments, the metastatic cancer comprises metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, or the ovary. In embodiments, the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney. In embodiments, the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

[0131] In embodiments of any one of the methods disclosed herein, the disorder is cancer-induced pain. In some embodiments, the cancer-induced pain is cancer-induced bone pain (CIBP) in a subject having metastasis of a cancer to the bone. In one embodiment of the method disclosed herein, the compound of formula (I), (la), or (lb), or Table 1, or a pharmaceutically acceptable salt thereof is administered to a subj ect in a method for treating cancer-induced bone pain. The disclosure also provides methods of treating cancer-induced bone pain in a subject having cancer, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the subject has metastasis of prostate cancer, breastAttorney Docket No.: INMD-221 / 01WO 315953-4549cancer, lung cancer, or myeloma to the bone. In some embodiments, the subject is identified as having metastasis to the bone by the use of any one of the following methods: plain film radiography, computed tomography, technetium 99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and / or choline positron emission tomography, but is not yet feeling cancer-induced bone pain. In some embodiments, the subject is suffering from cancer-induced bone pain, which is indicative of metastasis of a previously treated or untreated primary tumor to the bone. In some embodiments, the cancer has metastasized to vertebrae, pelvis, long bones, or ribs.

[0132] In some embodiments, administration of the compounds of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof or the composition comprising the compounds of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof diminishes the severity of, delays the onset of, or eliminates a symptom of cancer. In some embodiments, the symptom of cancer is cancer-induced bone pain (CIBP). In some embodiments, the CIBP is neuropathic pain. In some embodiments, the CIBP is inflammatory pain. In some embodiments, the CIBP is spontaneous pain. In some embodiments, the symptom of cancer is nociceptive hypersensitivity. In some embodiments, the symptom of cancer is allodynia. In some embodiments, the allodynia is tactile allodynia. In some embodiments, the tactile allodynia is static mechanical allodynia. In some embodiments, the tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastasis to the bone.

[0133] In embodiments of any one of the methods disclosed herein, the disorder is Crohn’s disease. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0134] In embodiments of any one of the methods disclosed herein, the disorder is giant cell arteritis.

[0135] In embodiments of any one of the methods disclosed herein, the disorder is polyarteritis nodosa.

[0136] In embodiments of any one of the methods disclosed herein, the disorder is anti-glomerular basement membrane (anti-GBM) disease (Goodpasture’s).

[0137] In embodiments of any one of the methods disclosed herein, the disorder is systemic scleroderma.

[0138] In embodiments of any one of the methods disclosed herein, the disorder is diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic retinopathy or diabetic ulcers. In embodiments, the disorder is diabetic nephropathy. In embodiments, the disorder is diabeticAttorney Docket No.: INMD-221 / 01WO 315953-4549neuropathy. In embodiments, the disorder is diabetic retinopathy. In embodiments, the disorder is diabetic ulcers.

[0139] In embodiments of any one of the methods disclosed herein, the disorder is Duchenne muscular dystrophy.

[0140] In embodiments of any one of the methods disclosed herein, the disorder is bronchiolitis obliterans.

[0141] In embodiments of any one of the methods disclosed herein, the disorder is atopic dermatitis.

[0142] In embodiments of any one of the methods disclosed herein, the disorder is pyoderma gangrenosum.

[0143] In embodiments of any one of the methods disclosed herein, the disorder is dermatomyositis or polymyositis. In embodiments, the disorder is dermatomyositis. In embodiments, the disorder is polymyositis.

[0144] In embodiments of any one of the methods disclosed herein, the disorder is thrombosis. In embodiments, the thrombosis is deep vein thrombosis (DVT).

[0145] In embodiments of any one of the methods disclosed herein, the disorder is bronchopulmonary dysplasia.

[0146] In embodiments of any one of the methods disclosed herein, disorder is amyotrophic lateral sclerosis.

[0147] In embodiments of any one of the methods disclosed herein, the disorder is sickle cell anemia.

[0148] In embodiments of any one of the methods disclosed herein, the disorder is psoriasis.

[0149] In embodiments of any one of the methods disclosed herein, the disorder is ventilator-induced lung injury.

[0150] In embodiments of any one of the methods disclosed herein, the disorder is heart failure. In embodiments, the heart failure is heart failure with reduced ejection fraction. In embodiments, the heart failure is heart failure with preserved ejection fraction.

[0151] In embodiments of any one of the methods disclosed herein, the disorder is osteoarthritis (OA). In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0152] Osteoarthritis (OA) is typically not autoimmune in origin and is typically a gradual, degenerative joint disease due to age-related chronic use or injury of the joints leading to cartilage breakdown, bone changes and local non-resolving synovial inflammation. In embodiments, the treating of osteoarthritis (OA) comprises improving weight loss and / orAttorney Docket No.: INMD-221 / 01WO 315953-4549inflamed paw volume of the subject during the administration period, as compared to the weight loss and / or inflamed paw volume of the subject prior reducing weight loss and / or inflamed paw volume of the subject during the administration period, as compared to the weight loss and / or inflamed paw volume of the subject prior to the administration period.

[0153] In embodiments of any one of the methods disclosed herein, the disorder is ischemia / reperfusion (IR) injury. In embodiments, the subject is a heart transplant recipient. In embodiments, the IR injury is due to heart transplantation. The IR injury, in one embodiment, is due to Heart transplantation (HTX). As such, in one embodiment, the subject is a heart transplant recipient. In a further embodiment of the treatment methods disclosed herein, the subject is administered a compound or composition of the present disclosure during heart transplantation or subsequent to heart transplantation. In one embodiment of this method, the subject is administered one of the compounds set forth in Table 1. In yet even a further embodiment, the compound is present in an oral composition and is administered once daily to the subject in need of treatment.

[0154] Treating the IR injury in one embodiment, comprises improving left-ventricular (LV) graft function. Graft function can be measured, in one embodiment, by measuring LV systolic function, e.g., by measuring left-ventricular systolic pressure (LVSP), developed pressure, maximal slope of systolic pressure increment (dP / dtmax), and / or rate pressure product (mmHg*bpm).

[0155] In one embodiment, treating IR injury comprises increasing the subject’s LVSP (mmHg) during or subsequent to the administration period, as compared to the subject’s LVSP (mmHg) prior to the administration period. In one embodiment, treating IR injury comprises increasing the subject’s developed pressure (mmHg) during or subsequent to the administration period, as compared to the subject’s developed pressure (mmHg) prior to the administration period. In yet another embodiment, treating IR injury in a subject in need of treatment comprises increasing the maximal slope of systolic pressure increment (dP / dtmax) for the subject during or subsequent to the administration period, as compared to the maximal slope of systolic pressure increment (dP / dtmax) for the subject prior to the administration period. In even yet another embodiment, treating IR injury in a subject in need of treatment comprises increasing the subject’s rate pressure product during or subsequent to the administration period, as compared to the subject’s rate pressure product prior to the administration period.

[0156] In embodiments of any one of the methods disclosed herein, the disorder is liver injury. In embodiments, the liver injury is drug-induced liver injury. In one embodiment, the liver injury is drug-induced acute liver injury (ALI). In one embodiment, the liver injury isAttorney Docket No.: INMD-221 / 01WO 315953-4549acetaminophen (APAP)-induced acute liver injury. In one embodiment, the liver injury is caused by acetaminophen (APAP) overdose. In embodiment, the liver injury is caused by nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac, and naproxen. In one embodiment, the treatment of ALI is a prophylactic treatment.

[0157] In embodiments, the treatment of liver injury (such as drug-induced acute liver injury) comprises improving the subject’s liver function test (LFT) results during or subsequent to the administration period, as compared to the subject’s LFT results prior to the administration period. In embodiments, LFTs include testing the levels of liver function biomarkers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and bilirubin levels in blood samples. In embodiments, the treatment of liver injury (such as drug-induced acute liver injury) comprises reducing the subject’s levels of one or more liver function biomarkers in blood samples during or subsequent to the administration period, as compared to the subject’s LFT results prior to the administration period.

[0158] In embodiments of any one of the methods disclosed herein, the disorder is sepsis. In one embodiment, the sepsis is a consequence of a subject’s response to overwhelming bacterial infection. In one embodiment, treatment of sepsis prevents organ dysfunction and death of the subject.

[0159] In embodiments of any one of the methods disclosed herein, the effective amount of the compound or composition is administered once daily during an administration period. In embodiments of any one of the methods disclosed herein, effective amount of the compound or composition is administered orally.

[0160] The length of the administration period in any given case may depend on the nature and severity of the condition being treated and / or prevented and be determined by the physician. In one embodiment, the administration period starts at about the time of condition / disease diagnosis and continues for the lifetime of the subject.

[0161] In some embodiments, the administration period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years or about 20 years. In some embodiments, the compounds or compositions disclosed herein may beAttorney Docket No.: INMD-221 / 01WO 315953-4549administered for a period of about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be administered for a period of about 52 weeks. In yet another embodiment, the administration period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years or at least about 20 years.

[0162] In some embodiments, the administration period for the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months or at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years. The administration period for the methods provided herein, in another embodiment, is from about 30 days to about 180 days. In another embodiment, the administration period is from about 30 days to about 36 months, or from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0163] In one embodiment, the administration period is from about 1 year to about 30 years. For example, the administration period, in one embodiment, is from about 1 year to about 25 years, 1 year to about 20 years, from about 1 year to about 15 years, from about 1 year to about 10 years, from about 1 year to about 5 years, from about 1 year to about 3 years, from about 1 year to about 2 years, from about 2 years to about 15 years, from about 2 year to about 10 years, from about 2 years to about 8 years, from about 2 year to about 5 years, from about 2 years to about 4 years, or from about 2 years to about 3 years.

[0164] In one embodiment of the method, the subject is administered the compound of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof once daily during the administration period. In another embodiment, the subjectisAttorney Docket No.: INMD-221 / 01WO 315953-4549administered the compound of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof twice daily, or every other day, or once a week during the administration period. In another embodiment, administration is every other day, every third day, 3* per week or 4 / per week during the administration period.

[0165] In a preferred embodiment, the oral dosage form is administered once daily during the administration period. In a further embodiment, the oral dosage form is administered at approximately the same time every day, e.g., prior to breakfast. In another embodiment, the composition comprising an effective amount of the compound of Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof is administered 2* daily during the administration period. In yet another embodiment, the composition comprising an effective amount of the compound Formula (I), (la), or (lb) or Table 1, or a pharmaceutically acceptable salt, a stereoisomer or a deuterated from thereof is administered 1 x per week, every other day, every third day, 2* per week, 3 x per week, 4x per week, or 5x per week during the administration period.

[0166] Administration, in one embodiment, is via the oral route. In a further embodiment, the composition is administered once daily.EXAMPLES

[0167] Example 1: Synthesis of (7S)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (Intermediate 1)

[0168] Step 1. Synthesis of methyl (3R)-3,4-dihydroxybutanoatestep 1

[0169] To a stirred solution of 1,4-dimethyl (2R)-2-hydroxybutanedioate (60 g, 370.048 mmol, 1.0 equiv) in THF (600 mL) was added Borane dimethyl sulfide complex(lOM) (37.00 mL, 370.048 mmol, 1.0 equiv) dropwise room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added NaBH4 (0.70 g, 18.502 mmol, 0.05 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 16 h. The reaction was quenched with MeOH (100 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicaAttorney Docket No.: INMD-221 / 01WO 315953-4549gel column chromatography, eluted with PE / THF (1:1) to afford methyl (3R)-3,4-dihydroxybutanoate (46 g, 92.68% yield) as a colorless oil. LCMS (ES, m / z . [M+H]+: 135.

[0170] Step 2. Synthesis of methyl 2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]acetatestep 2

[0171] To a stirred solution of methyl (3R)-3,4-dihydroxybutanoate (46 g, 342.948 mmol, 1.0 equiv) and 2,2-dimethoxypropane (107.15 g, 1028.844 mmol, 3.0 equiv) in DCM (500 mL) was added 4-m ethylbenzene- 1 -sulfonate; pyridin-l-ium (8.62 g, 34.295 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford methyl 2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]acetate (42 g, 70.30% yield) as a colorless oil. LCMS (ES, m / z)'. [M+H]+: 175.

[0172] Step 3. Synthesis of 2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]acetaldehydestep 3

[0173] To a stirred solution of methyl 2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]acetate (36 g, 206.664 mmol, 1.0 equiv) in DCM (750 mL) was added DIB AL-H (371.99 mL, 371.995 mmol, 1.8 equiv) dropwise at -85°C under nitrogen atmosphere. The resulting mixture was stirred at -85°C for 1 h under nitrogen atmosphere. To the above mixture was added MeOH (100 mL) dropwise at -85°C. The resulting mixture was slowly warmed to room temperature. The mixture was acidified to pH 5 with IN HC1 (aq.). The resulting mixture was extracted with CH2CI2 (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]acetaldehyde (28 g) was used in the next step directly without further purification. LCMS (ES, m / z '. [M+H]+: 145.

[0174] Step 4. Synthesis of l-{2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-l-hydroxy ethyl } cyclobutane- 1 -carbonitrileAttorney Docket No.: INMD-221 / 01WO 315953-4549step 4

[0175] To a stirred solution of LDA (37.45 g, 349.587 mmol, 1.8 equiv) in THF (300 mL) was added cyclobutanecarbonitrile (31.51 g, 388.430 mmol, 2.0 equiv) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 30 min under N2 atmosphere. To the above mixture was added 2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]acetaldehyde (28 g, 194.215 mmol, 1.0 equiv) in THF(30 mL) dropwise at -78°C. The resulting mixture was stirred at -78°C for additional 1 h. The reaction was quenched with sat. NH4Q (aq.) at -78°C. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (9:1) to afford l-{2-[(4R)-2,2-dimethyl- 1,3 -di oxolan-4-yl]-l -hydroxy ethyl }cy cl obutane-1 -carbonitrile (32 g, 73.14% yield) as a colorless oil. LCMS (ES, m z): [M+H]+: 226.

[0176] Step 5. Synthesis of 1-[1 -(benzyl oxy)-2-[(4R)-2,2-dimethyl- 1,3 -di oxolan-4-y 1 ] ethyl ] cyclobutane- 1 -carb onitril estep 5

[0177] To a stirred solution of NaH (6.82 g, 170.448 mmol, 1.2 equiv, 60%) in DMF (350 mL) was added BnBr (26.72 g, 156.244 mmol, 1.1 equiv) in portions at 0°C under nitrogen atmosphere. To the above mixture was added l-{2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-l-hydroxyethyl} cyclobutane- 1 -carbonitrile (32 g, 142.040 mmol, 1.0 equiv) in DMF(50 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 3 h. The reaction was quenched with sat. NH4Q (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 1 -[ 1 -(benzyloxy)-2-[(4R)-2,2-dimethyl- 1 ,3 -dioxolan-4-yl]ethyl]cyclobutane- 1 -carbonitrile (35 g, 78.1% yield) as a colorless oil. LCMS (ES, m / z . [M+H]+: 316.

[0178] Step 6. Synthesis of l-{l-[l-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutyl}methanamineAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0179] To a stirred solution of l-[l-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutane-l-carbonitrile (30 g, 95.113 mmol, 1.0 equiv) in THF (200 mL) and MeOH (200 mL) was added NaBH4 (7.20 g, 190.226 mmol, 2 equiv) in portions at °C under nitrogen atmosphere. To the above mixture was added dichlorocobalt (2.47 g, 19.023 mmol, 0.2 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 20 h. The reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford l-{l-[l-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutyl}methanamine (15 g, 49.3% yield) as a light yellow oil. LCMS (ES, m z):[M+H]+: 320.

[0180] Step 7. Synthesis of N-({l-[l-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide

[0181] To a stirred solution of l-{l-[l-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutyl}methanamine (15 g, 46.956 mmol, 1.0 equiv) and TEA (9.50 g, 93.912 mmol, 2.0 equiv) in DCM (150 mL) was added 2-nitrobenzenesulfonyl chloride (12.49 g, 56.347 mmol, 1.2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (6:1) to afford N-({1-[1-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutyl}methyl)-2-Attorney Docket No.: INMD-221 / 01WO 315953-4549nitrobenzenesulfonamide (20 g, 84.4% yield) as a light yellow solid. LCMS (ES, m / z '. [M+H]+: 505.

[0182] Step 8. Synthesis of N-({l-[(3R)-l-(benzyloxy)-3,4-dihydroxybutyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide

[0183] To a stirred solution of N-({l-[l-(benzyloxy)-2-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]ethyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide (20 g, 39.635 mmol, 1.0 equiv) in MeOH (200 mL) was added TsOH (20.48 g, 118.905 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred at 60°C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford N-({l-[(3R)-l-(benzyloxy)-3,4-dihydroxybutyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide (15 g, 81.4% yield) as a light yellow oil. LCMS (ES, m / z)'. [M+H]+: 465.

[0184] Step 9. Synthesis of N-({l-[(3R)-l-(benzyloxy)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide

[0185] Tosolution of N-({l-[(3R)-l-(benzyloxy)-3,4-dihydroxybutyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide (15 g, 32.291 mmol, 1.0 equiv) and IH-imidazole (4.40 g, 64.582 mmol, 2.0 equiv) in DCM (160 mL) was added TBSCI (5.35 g, 35.520 mmol, 1.1 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixtureAttorney Docket No.: INMD-221 / 01WO 315953-4549was stirred at room temperature for 16 h. The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8: 1) to afford N-({l-[(3R)-l-(benzyloxy)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide (15 g, 80.2% yield) as a colorless oil. LCMS (ES, m z [M+H]+: 579.

[0186] Step 10. Synthesis of (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(2-nitrobenzenesulfonyl)-6-azaspiro[3.5]nonane

[0187] To a stirred solution of N-({l-[(3R)-l-(benzyloxy)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutyl]cyclobutyl}methyl)-2-nitrobenzenesulfonamide (15 g, 25.916 mmol, 1.0 equiv) and PPh3 (10.20 g, 38.874 mmol, 1.5 equiv) in DCM (200 mL) were added DIAD (7.86 g, 38.874 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(2-nitrobenzenesulfonyl)-6-azaspiro[3.5]nonane (12.8 g, 88.0% yield) as a colorless oil. LCMS (ES, m / z): [M+H]+: 561.

[0188] Step 11. Synthesis of (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-azaspiro[3.5]nonane

[0189] To a stirred solution of (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(2-nitrobenzenesulfonyl)-6-azaspiro[3.5]nonane (12.8 g, 22.825 mmol, 1.0 equiv) in DMF (150 mL) were added K2CO3 (9.46 g, 68.475 mmol, 3.0 equiv) and 4-methoxythiophenol (4.80 g, 34.237 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirredAttorney Docket No.: INMD-221 / 01WO 315953-4549at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3 : 1) to afford (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-azaspiro[3.5]nonane (7.5 g, 87.4% yield) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 376.

[0190] Step 12. Synthesis of (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-azaspiro[3.5]nonanestep 12

[0191] To a stirred solution of (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-azaspiro[3.5]nonane (7.5 g, 19.967 mmol, 1.0 equiv) in DCM (80 mL) were added TEA (6.06 g, 59.901 mmol, 3.0 equiv) and BOC2O (6.54 g, 29.950 mmol, 1.5 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was extracted with CH2CI2 (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (20: 1) to afford tert-butyl (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-azaspiro[3.5]nonane-6-carboxylate (9 g, 94.7% yield) as a colorless oil. LCMS (ES, m z [M+H]+: 476.

[0192] Step 13. Synthesis of tert-butyl (7S)-9-(benzyloxy)-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylatestep 13

[0193] To a stirred solution of tert-butyl (7S)-9-(benzyloxy)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-6-azaspiro[3.5]nonane-6-carboxylate (9 g, 18.918 mmol, 1.0 equiv) in THF (100 mL) was added TBAF (18.92 mL, 18.918 mmol, 1.0 equiv, IN in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 20 h. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purifiedAttorney Docket No.: INMD-221 / 01WO 315953-4549by silica gel column chromatography, eluted with PE / EA (4:1) to afford tert-butyl (7S)-9-(benzyloxy)-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (5.8 g, 84.8% yield) as a colorless oil. LCMS (ES, m z): [M+H]+: 362.

[0194] Step 14. Synthesis of (7S)-9-(benzyloxy)-6-(tert-butoxycarbonyl)-6-azaspiro[3.5]nonane-7-carboxylic acid

[0195] To a stirred solution of tert-butyl (7S)-9-(benzyloxy)-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (4.0 g, 11.066 mmol, 1.0 equiv) and 2, 2,6,6-tetramethylpiperidin-l-olate (0.17 g, 1.107 mmol, 0.1 equiv) in Acetone (60 mL) were added NaBr (0.23 g, 2.213 mmol, 0.2 equiv) and NaHCCh (1.86 g, 22.132 mmol, 2.0 equiv) inH2O(20 mL) dropwise at 0°C under nitrogen atmosphere. To the above mixture was added trichloro-1, 3, 5-triazinane-2, 4, 6-trione (5.14 g, 22.132 mmol, 2.0 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 16 h. The mixture basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was filtered, the filter cake was washed with H2O (2 mL). The aqueous layer was acidified to pH 5 with citric acid. The resulting mixture was extracted with CH2CI2 (10 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (15:1) to afford (7S)-9-(benzyloxy)-6-(tert-butoxycarbonyl)-6-azaspiro[3 ,5]nonane-7-carboxylic acid (2.6 g, 62.5% yield) as a off-white oil. LCMS (ES, m z [M+H]+: 376.

[0196] Step 15. Synthesis of (7S)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acidO OIntermediate 1

[0197] To a stirred solution of (7S)-9-(benzyloxy)-6-(tert-butoxycarbonyl)-6-azaspiro[3.5]nonane-7-carboxylic acid (2.6 g, 6.925 mmol, 1.0 equiv) in MeOH (30 mL) was added Pd / C (0.6 g, 5.638 mmol, 0.81 equiv) in portions. The resulting mixture was stirred at room temperature for 16 h under hydrogen atmosphere (3 atm). The resulting mixture was filtered, the filter cake was washed with MeOH (20 mL). The filtrate was concentrated underAttorney Docket No.: INMD-221 / 01WO 315953-4549reduced pressure. This resulted in (7S)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (1.7 g, 86.0% yield) as a off-white solid. LCMS (ES, m / z . [M+H]+: 286.

[0198] Example 2. Synthesis of (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol- 5-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 1)

[0199] Step 1. Synthesis of (Z)-3,3-difluoro-N'-hydroxycyclobutane-l-carboximidamide

[0200] Into a 100 mL round-bottom flask were added 3, 3 -difluorocy cl obutane-1 -carbonitrile (2.00 g, 17.08 mmol, 1.00 equiv), EtOH (40.00 mL) and hydroxylamine (5.64 g, 170.80 mmol, 10.00 equiv). The resulting mixture was stirred at 80 °C for 3 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with ice water. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (Z)-3,3-difluoro-N'-hydroxycyclobutane-l-carboximidamide (1.40 g, 54.60% yield, 90.00% purity) as off-white solid. LCMS (ES, m z) [M+H]+: 151.

[0201] Step 2. Synthesis of 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-isopropylpiperidine-l,4-dicarboxylateBod

[0202] Into a 40 mL vial were added l-(tert-butoxycarbonyl)-4-isopropylpiperidine-4-carboxylic acid (2.53 g, 9.33 mmol, 1.00 equiv), DMF (20.00 mL), DIEA (2.41 g, 18.65 mmol, 2.00 equiv) and (Z)-3,3-difluoro-N'-hydroxycyclobutane-l-carboximidamide (1.40 g, 9.33 mmol, 1.00 equiv) under nitrogen atmosphere. To the above mixture was added HATU (4.25 g, 11.19 mmol, 1.20 equiv) in portions at 0 °C. The resulting mixture was stirred at roomAttorney Docket No.: INMD-221 / 01WO 315953-4549temperature for additional overnight under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (24%) to afford 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-isopropylpiperidine-l,4-dicarboxylate (1.70 g, crude). The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Cl 8-120 g column, mobile phase, MeCN in Water (0.1% NH3H2O), 45% to 75% gradient in 6 min; detector, UV 254 nm. This resulted in 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-isopropylpiperidine-l,4-dicarboxylate (1.60 g, 42.52% yield, 95.00% purity) as off-white solid. LCMS (ES, m z .[M+H]+: 404.

[0203] Step 3. Synthesis of tert-butyl 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carboxylate

[0204] Into a 40 mL vial were added 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-isopropylpiperidine-l,4-dicarboxylate (650.00 mg, 1.61 mmol, 1.00 equiv), THF (10.00 mL) and TBAF (4.83 mL, 4.83 mmol, 3.00 equiv). The resulting mixture was stirred at 60 °C for overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (4%) to afford tert-butyl 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carboxylate (472.00 mg, 76.01% yield, 90.00% purity) as light yellow oil. LCMS (ES, m z): [M+H]+: 386.

[0205] Step 4. Synthesis of 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidineAttorney Docket No.: INMD-221 / 01WO 315953-4549Bod

[0206] Into a 20 mL vial were added tert-butyl 4-[3 -(3, 3 -difluorocyclobutyl)- 1, 2, 4-oxadiazol-5-yl]-4-isopropylpiperidine-l -carboxylate (200.00 mg, 0.52 mmol, 1.00 equiv) andDCM (3.00 mL). To the above mixture was added HC1 in 1,4-dioxane (4.0 M) (3.00 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine (134.00 mg, 90.51% yield, 95.00% purity) as white solid. LCMS (ES, m / zy. [M+H]+: 286.

[0207] Step 5. Synthesis of tert-butyl (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carb oxy late

[0208] Into a 8 mL vial were added (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (100.00 mg, 0.35 mmol, 1.00 equiv), DMF (2.00 mL), 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine (120.00 mg, 0.42 mmol, 1.20 equiv) and DIEA (135.89 mg, 1.05 mmol, 3.00 equiv). To the above mixture was added HATU (159.91 mg, 0.42 mmol, 1.20 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: C18-120 g column, mobile phase, MeCN in Water (0.1% NH3 H2O), 30% to 70% gradient in 11 min; detector, UV 254 nm. This resulted in tert-butyl (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-Attorney Docket No.: INMD-221 / 01WO 315953-45495-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (65.00 mg, 33.56% yield, 85.00% purity) as light yellow oil. LCMS (ES, mz): [M+H]+: 553.

[0209] Step 6. Synthesis of (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol

[0210] Into a 8 mL vial were added tert-butyl (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (65.00 mg, 0.12 mmol, 1.00 equiv) and ACN (1.00 mL). To the above mixture was added TsOH (60.76 mg, 0.35 mmol, 3.00 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Cl 8-120 g column, mobile phase, MeCN in Water (0.1% NH3H2O), 30% to 55% gradient in 9 min; detector, UV 254 nm. This resulted in (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 1) (7.70 mg, 14.47% yield, 98.8% purity) as white solid. LCMS (ES, m / z . [M+H]+: 453.3. 'H NMR (300 MHz, DMSO-tL) 64.61 (s, 1H), 4.35 -4.21 (m, 1H), 3.94 - 3.50 (m, 4H), 3.17 - 2.95 (m, 2H), 2.98 -2.68 (m, 4H), 2.66 -2.51 (m, 1H), 2.41 -2.22 (m, 3H), 2.05 - 1.64 (m, 6H), 1.66 - 1.46 (m, 3H), 1.46 - 1.30 (m, 3H), 0.76 (d, J= 6.7 Hz, 6H).

[0211] Example 3. Synthesis of (4-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Compound 3)

[0212] Step 1. Synthesis of tert-butyl (Z)-4-(N'-((3,3-difluorocyclobutane-l-carbonyl)oxy)carbamimidoyl)-4-(trifluoromethyl)piperidine-l-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0213] To a stirred solution of 3,3 -difluorocyclobutane- 1 -carboxylic acid (0.84 g, 6.17 mmol, 1.0 equiv) and tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (2.3 g, 7.40 mmol, 1.2 equiv) in DMF (16 mL) was added DIEA (2.3 g, 18.51 mmol, 3.0 equiv) and HATU (3.5 g, 9.25 mmol, 1.50 equiv) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (Z)-4-(N'-((3,3-difluorocyclobutane-l-carbonyl)oxy)carbamimidoyl)-4-(trifluoromethyl)piperidine-l-carboxylate (2.5 g, 95.4% yield) as a light yellow solid. LCMS (ES) [M+Na+H]+m / z: 453.

[0214] Step 2. Synthesis of tert-butyl 4-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)piperidine- 1 -carboxylate

[0215] To a stirred solution of tert-butyl 4-[(Z)-N'-[(Z)-3,3-difluorocyclobutanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (2.4 g, 5.58 mmol, 1.0 equiv) in DMSO (20 mL) was added KOH (0.94 g, 16.76 mmol, 3.0 equiv) at room temperature. The reaction was stirred at room temperature for 18 h. The reaction was monitored by LCMS. The reaction was poured into ice water at 0°C. Then the resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3x60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate wasAttorney Docket No.: INMD-221 / 01WO 315953-4549concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl 4-(5-(3,3-difluorocyclobutyl)- 1.2.4-oxadiazol-3-yl)-4-(trifluoromethyl)piperi dine- 1 -carboxylate (600 mg, 26.0% yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 412.

[0216] Step 3. Synthesis of 5-(3,3-difluorocyclobutyl)-3-(4-(trifluoromethyl)piperidin-4-yl)- 1.2.4-oxadiazole hydrochloride

[0217] To a stirred solution of tert-butyl 4-[5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine-l -carboxylate (300 mg, 0.72 mmol, 1.0 equiv) Dioxane (6.5 mL) was added HC1 in 1,4-di oxane (4.0 M) (6.5 mL) at room temperature. The reaction was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum to afford crude product 5-(3,3-difluorocyclobutyl)-3-(4-(trifluoromethyl)piperidin-4-yl)-l,2,4-oxadiazole hydrochloride (260 mg) as a light yellow solid. LCMS (ES) [M-HC1+H]+m / z: 312.

[0218] Step 4. Synthesis of (7S,9R)-7-(4-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-l-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate

[0219] To a stirred solution of 5-(3,3-difluorocyclobutyl)-3-(4-(trifluoromethyl)piperidin-4-yl)-l,2,4-oxadiazole hydrochloride (105 mg, 0.30 mmol, 1.0 equiv) and (7S)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (Intermediate 1, see Example 1) (112 mg, 0.39 mmol, 1.3 equiv) in DCM (2.1 mL) were added DIEA (156 mg, 1.20 mmol, 4.0 equiv) and at room temperature under nitrogen atmosphere. Then added HATUAttorney Docket No.: INMD-221 / 01WO 315953-4549(172 mg, 0.45 mmol, 1.5 equiv) in portions at 0°C. The reaction was stirred at 0°C for 3 h. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine (1x15 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford (7S,9R)-7-(4-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-l-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (55 mg, 32.4% yield) as a light yellow oil. LCMS (ES) [M+H]+m / z: 580.

[0220] Step 5. Synthesis of (4-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone

[0221] To a stirred solution of tert-butyl 4-[5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine-l -carboxylate (55 mg, 0.13 mmol, 1.0 equiv), MeCN (2 mL) was added TsOH (49 mg, 0.28 mmol, 3.0 equiv) at room temperature. The reaction was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The mixture was basified to pH 8 with saturated NaHCOi (aq.). The resulting mixture was extracted with CH2CI2 (5 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge C1830*150 mm, 5pm; Mobile Phase A: Water (20mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 35 mL / min; Gradient (B%): isocratic 15%-35% 8min; Wave Length: 254nm / 220nm nm; RTl(min): 7.9) to afford (4-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Compound 3) (11.5 mg, 27.6% yield) as a white solid.1H NMR (400 MHz, DMSO-tA) 64.64 - 4.58 (m, 1H), 4.47 - 4.39 (m, 1H), 4.08 - 3.97 (m, 1H), 3.94 - 3.80 (m, 1H), 3.81 - 3.72 (m, 2H), 3.25 - 3.09 (m, 2H), 3.10Attorney Docket No.: INMD-221 / 01WO 315953-4549- 2.90 (m, 3H), 2.81 (t, J= 12.4 Hz, 1H), 2.66 - 2.57 (m, 1H), 2.49 - 2.37 (m, 2H), 2.09 - 1.70 (m, 7H), 1.68 - 1.53 (m, 1H), 1.51 - 1.27 (m, 3H). LCMS (ES) [M+H]+ m / z: 479.

[0222] Example 4. Synthesis of (7S,9R)-7-{4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol- 5-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 12)

[0223] Step 1. Synthesis of (Z)-4, 4-difluoro-N'-hydroxycy cl ohexane-l-carboximidamide

[0224] Into a 250 ml round-bottom flask were added 4,4-difluorocyclohexane-l -carbonitrile (2.00 g, 13.77 mmol, 1.00 equiv) and EtOH (40.00 mL) at room temperature. To the above mixture was added hydroxylamine (4.55 g, 137.75 mmol, 10.00 equiv) in portions at 0°C. The resulting mixture was stirred at 80 °C for additional 3 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (1 :3) to afford (Z)-4,4-difluoro-N'-hydroxycyclohexane-l-carboximidamide (2.30 g, 93.68% yield, 85% purity) as off-white solid. LCMS (ES) [M+H]+m / z: 179.

[0225] Step 2. Synthesis of 4-(Z)-[amino(4,4-difluorocyclohexyl)methylidene]amino 1 -tert-butyl 4-isopropylpiperidine-l,4-dicarboxylateBod

[0226] A solution of l-(tert-butoxycarbonyl)-4-isopropylpiperidine-4-carboxylic acid (1.26 g, 4.64 mmol, 1.00 equiv) in DMF (15.00 mL) was treated with DIEA (1.80 g, 13.92 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere followed by the addition of (Z)-4,4-difluoro-N'-hydroxycyclohexane-l-carboximidamide (1.00 g, 5.61 mmol, 1.21 equiv) and HATU (2.60 g, 6.83 mmol, 1.47 equiv) in portions at 0 °C. The final reaction mixture wasAttorney Docket No.: INMD-221 / 01WO 315953-4549irradiated with microwave radiation at room temperature for 16 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (1:2) to afford 4-(Z)-[amino(4,4-difluorocyclohexyl)methylidene]amino 1-tert-butyl 4-isopropylpiperidine-l,4-dicarboxylate (1.26 g, 62.88% yield, 80% purity) as yellow solid. LCMS (ES) [M+H]+m / z: 432.

[0227] Step 3. Synthesis of tert-butyl 4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carboxylateBoc

[0228] Into a 50 mL round-bottom flask were added 4-(Z)-[amino(4,4-difluorocyclohexyl)methylidene]amino 1-tert-butyl 4-isopropylpiperidine-l,4-dicarboxylate (750.00 mg, 1.73 mmol, 1.00 equiv) and THF (10.00 mL) at room temperature. To the above mixture was added TBAF (5.00 mL, 3.00 equiv) in portions at 0 °C. The resulting mixture was stirred at 60 °C for additional overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (1:1) to afford tert-butyl 4-[3 -(4, 4-difluorocy cl ohexyl)-l, 2, 4-oxadiazol-5-yl]-4-isopropylpiperi dine- 1 -carboxylate (530.00 mg, 73.75% yield, 80% purity) as yellow solid. LCMS (ES) [M+H]+m / z: 414.

[0229] Step 4. Synthesis of 4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidineAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0230] Into a 50 mL round-bottom flask were added tert-butyl 4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carboxylate (360.00 mg, 0.87 mmol, 1.00 equiv) and DCM (2.50 mL) at room temperature. To the above mixture was added HC1 in 1,4-dioxane (4.0 M) (2.50 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 2h. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine (320 mg) as white solid. LCMS (ES) [M+H]+m / z: 314.

[0231] Step 5. Synthesis of tert-butyl (7S,9R)-7-{4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carb oxy late

[0232] Into a 40 mL vial were added 4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine (92.26 mg, 0.29 mmol, 1.20 equiv), DMF (5.00 mL), (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (70.00 mg, 0.24 mmol, 1.00 equiv) and DIEA (95.12 mg, 0.73 mmol, 3.00 equiv) at room temperature. To the above mixture was added HATU (111.94 mg, 0.29 mmol, 1.20 equiv) in portions at 0°C. The resulting mixture was stirred at 0°C for additional 2h. The reaction was quenched with ice water at 0 °C. The aqueous layer was extracted with EtOAc (3x20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel columnAttorney Docket No.: INMD-221 / 01WO 315953-4549chromatography, eluted with PE / EA (3:1) to afford tert-butyl (7S,9R)-7-{4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (75 mg, 52.65% yield, 75% purity) as colorless oil. LCMS (ES) [M+H]+m / z: 581.

[0233] Step 6. Synthesis of (7S,9R)-7-{4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol

[0234] Into a 50 mL round-bottom flask were added tert-butyl (7S,9R)-7-{4-[3-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (65.00 mg, 0.11 mmol, 1.00 equiv) and MeCN (4.00 mL) at room temperature. To the above mixture was added TsOH (57.82 mg, 0.33 mmol, 3.00 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 3h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 30% to 55% gradient in 11 min; detector, UV 254 nm. This resulted in (7S,9R)-7-{4-[3-(4,4-difhiorocyclohexyl)-l,2,4-oxadiazol-5-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 12) (21 mg, 39.04% yield, 98.0% purity) as white solid. LCMS (ES) [M+H]+m / z: 481.3.1HNMR (300 MHz, DMSO-d6) 64.61 (t, J = 4.0 Hz, 1H), 4.37 - 4.21 (m, 1H), 3.93 -3.82 (m, 1H), 3.74 (d, J = 8.7 Hz, 2H), 3.11 - 2.95 (m, 1H), 2.90 - 2.67 (m, 2H), 2.65 - 2.51 (m, 1H), 2.42 - 2.19 (m, 3H), 2.15 - 1.89 (m, 6H), 1.89 - 1.65 (m, 8H), 1.63 - 1.19 (m, 6H), 0.75 (d, J = 6.7 Hz, 6H).

[0235] Example 5. Synthesis of (4-(5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Compound 31)Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0236] Step 1. Synthesis of tert-butyl 4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-carb oxy late

[0237] A solution of 4,4-difluorocyclohexane-l -carboxylic acid (0.63 g, 3.85 mmol, 1.0 equiv), tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (1.20 g, 3.85 mmol, 1.0 equiv), andDIEA (1.5 g, 11.56 mmol, 3.0 equiv) inDMF (20 mL) was treated with HATU (1.76 g, 4.62 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with EtOAc (30 mL). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (4:1) to afford tert-butyl 4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (1.6 g, 90% yield, 90% purity) as a light yellow oil. LCMS (ES, m z . [M+H]+: 458.

[0238] Step 2. Synthesis tert-butyl 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine- 1 -carboxylate

[0239] To a solution of tert-butyl 4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-Attorney Docket No.: INMD-221 / 01WO 315953-4549carboxylate (1.60 g, 3.49 mmol, 1.0 equiv) in DMSO (20 mL), KOH (0.39 g, 6.99 mmol, 2.0 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford tert-butyl 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4- (trifluoromethyl)piperidine-l -carboxylate (600 mg, 39% yield, 90% purity) as a light yellow oil. LCMS (ES, m / z . [M+H]+: 440.

[0240] Step 3. Synthesis of 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine hydrochloride

[0241] A solution of tert-butyl 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4- (trifluoromethyl)piperidine-l -carboxylate (600 mg, 1.36 mmol, 1.0 equiv) in dioxane (3 mL) was treated with HC1 (g) in 1,4-di oxane (4 M) (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without purification. This resulted in 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine hydrochloride (400 mg, 78% yield, 90% purity) as a light yellow solid. LCMS (ES, m / z . [M-HC1+H]+: 340.

[0242] Step 4. Synthesis of tert-butyl (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0243] A solution of 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine hydrochloride (100 mg, 0.26 mmol, 1.0 equiv), (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (98 mg, 0.34 mmol, 1.3 equiv), (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (98 mg, 0.34 mmol, 1.3 equiv), DIEA (103 mg, 0.79 mmol, 3.0 equiv) in DCM (5 mL) was treated with HATU (121 mg, 0.31 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred at 0°C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tertbutyl (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4- (trifluoromethyl)piperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (75 mg, 46% yield, 90% purity) as a light yellow oil. LCMS (ES, m / z . [M+H]+: 607.

[0244] Step 5. Synthesis of (4-(5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone

[0245] Into a 20 mL vial were added tert-butyl (7S,9R)-7-{4-[5-(4,4-difhiorocyclohexyl)-1 ,2,4-oxadiazol-3 -yl]-4-(trifluoromethyl)piperidine- 1 -carbonyl } -9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (75 mg, 0.12 mmol, 1.0 equiv), MeCN (5 mL) and TsOH (63 mg, 0.37 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase flashAttorney Docket No.: INMD-221 / 01WO 315953-4549chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in (4-(5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Compound 31) (18 mg, 29% yield, 97.6% purity) as a white solid. LCMS (ES, m / z . [M+H]+: 507.2. 'H NMR (400 MHz, DMSO-tL): 64.60 (s, 1H), 4.47 - 4.35 (m, 1H), 4.09 - 3.95 (m, 1H), 3.83 - 3.70 (m, 2H), 3.41 -3.34 (m, 1H), 3.03 -2.88 (m, 1H), 2.80 (t, J= 12.3 Hz, 1H), 2.68 - 2.56 (m, 1H), 2.47 - 2.42 (m, 2H), 2.13 - 1.93 (m, 8H), 1.89 - 1.59 (m, 8H), 1.50 - 1.31 (m, 3H).

[0246] Example 6. Synthesis of (7S,9R)-7-{4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 45)

[0247] Step 1. Synthesis of 1 -tert-butyl 4-ethyl 4-(trifluoromethyl)piperi dine- 1,4-di carb oxy late

[0248] Into a 500 mL 3-necked round-bottom flask were added 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (23.48 g, 91.26 mmol, 2.00 equiv) and THF (250.00 mL) at room temperature. To the above mixture was added LDA (8.55 g, 79.85 mmol, 2.00 equiv) dropwise at -40 °C. The resulting mixture was stirred at -40 °C for additional 1 h. To the above mixture was added 4,12-difluoro-8-(trifluoromethyl)-8-thiatricyclo[7.4.0.0A{2,7}]trideca-l(9),2,4,6,10,12-hexaen-8-ium triflate (17.50 g, 39.92 mmol, 1.00 equiv) in portions at -40 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction was quenched with sat. NH4Q (aq.) at -20 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford 1-tert-butyl 4-ethyl 4-Attorney Docket No.: INMD-221 / 01WO 315953-4549(trifluoromethyl)piperidine-l,4-dicarboxylate (8.50 g, 65.44% yield, 90.00% purity) as light yellow oil. LCMS (ES) [M+l]+m / z: 326.

[0249] Step 2. Synthesis of 1 -(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid

[0250] Into a 250 mL round-bottom flask were added 1 -tert-butyl 4-ethyl 4- (trifluoromethyl)piperidine-l,4-dicarboxylate (3.20 g, 9.83 mmol, 1.00 equiv), NaOH (1.18 g, 29.50 mmol, 3.00 equiv), EtOH (60.00 mL) and H2O (15.00 mL) at room temperature. The resulting mixture was stirred at 60 °C for 3 h. The mixture was allowed to cool down to room temperature. The residue was acidified to pH = 4 with HC1 (aq.). The resulting mixture was extracted with CH2CI2 (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in l-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid (2.93 g, crude) as yellow solid. LCMS (ES) [M+l]+m / z:298.

[0251] Step 3. Synthesis of tert-butyl 4-carbamoyl-4-(trifluoromethyl)piperidine-l-carboxylate

[0252] Into a 100 mL round-bottom flask were added 1 -(tert-butoxycarbonyl)-4- (trifluoromethyl)piperidine-4-carboxylic acid (2.80 g, 9.41 mmol, 1.00 equiv), NH4CI (1.51 g, 28.25 mmol, 3.00 equiv) DIEA (2.43 g, 18.83 mmol, 2.00 equiv) and DCM (30.00 mL) at room temperature. To the above mixture was added HATU (3.94 g, 10.36 mmol, 1.10 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with CH2CI2 (3 x 20 mL). The combined organic layers were washed dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate (15 mL). This resulted in tert-butyl 4-carbamoyl-4-Attorney Docket No.: INMD-221 / 01WO 315953-4549(trifluoromethyl)piperidine-l -carboxylate (2.20 g, crude) as white solid. LCMS (ES) [M+l]+m / z: 297.

[0253] Step 4. Synthesis of tert-butyl 4-cyano-4-(trifluoromethyl)piperidine-l -carboxylate<Bc

[0254] Into a 100 mL round-bottom flask were added tert-butyl 4-carbamoyl-4-(trifluoromethyl)piperidine-l -carboxylate (2.10 g, 7.08 mmol, 1.00 equiv), methyl N-[(triethylazaniumyl)sulfonyl]carbamate oxidanide (5.07 g, 21.26 mmol, 3.00 equiv) and DCM (30.00 mL) at room temperature. The resulting mixture was stirred at room temperature for overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl 4-cyano-4-(trifluoromethyl)piperidine-l -carboxylate (1.60 g, 81.12% yield, 90.00% purity) as white solid. LCMS (ES) [M+l]+m / z: 279.

[0255] Step 5. Synthesis of tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-(trifluoromethyl)piperidine- 1 -carboxylate

[0256] Into a 100 mL round-bottom flask were added tert-butyl 4-cyano-4-(trifluoromethyl)piperidine-l -carboxylate (1.45 g, 5.21 mmol, 1.00 equiv), MeOH (15.00 mL) and Hydroxylamine, 50% (15.00 mL) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CH2CI2 (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (1.50 g, crude) as white solid. LCMS (ES) [M+l]+m / z: 312.

[0257] Step 6. Synthesis of tert-butyl 4-[(Z)-N'-[(Z)-3,3-difluoro-l-methylcyclobutanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0258] Into a 100 mL round-bottom flask were added tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (1.40 g, 4.49 mmol, 1.00 equiv), 3, 3 -difluoro- 1 -methylcyclobutane- 1 -carboxylic acid (0.81 g, 5.39 mmol, 1.20 equiv), DIEA (0.87 g, 6.74 mmol, 1.50 equiv) and DMF (15.00 mL) at room temperature. To the above mixture was added HATU (2.22 g, 5.84 mmol, 1.30 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional overnight. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl 4-[(Z)-N'-[(Z)-3,3-difluoro-l-methylcyclobutanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (1.30 g, 65.19% yield, 92.00% purity) as off-white solid. LCMS (ES) [M+l]+m / z: 444.

[0259] Step 7. Synthesis of tert-butyl 4-[5-(3,3-difhioro-l-methylcyclobutyl)-l,2,4-oxadiazol-3 -yl]-4-(trifluoromethyl)piperidine-l -carboxylate

[0260] Into a 40 mL vial were added tert-butyl 4-[(Z)-N'-[(Z)-3,3-difluoro-l-methylcyclobutanecarbonyloxy]carbamimidoyl]-4-(trifluoromethyl)piperidine-l-carboxylate (1.15 g, 2.59 mmol, 1.00 equiv), KOH (0.15 g, 2.59 mmol, 1.00 equiv) andDMSO (10.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8: 1) to affordAttorney Docket No.: INMD-221 / 01WO 315953-4549tert-butyl 4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4- (trifluoromethyl)piperidine-l -carboxylate (900.00 mg, 81.58% yield, 92.00% purity) as light yellow solid. LCMS (ES) [M+l]+m / z: 426.

[0261] Step 8. Synthesis of 4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine

[0262] Into a 40 mL vial were added tert-butyl 4-[5-(3,3-difhioro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine-l -carboxylate (200.00 mg, 0.47 mmol, 1.00 equiv) and DCM (2.00 mL) at room temperature. To the above mixture was added HC1 in 1,4-dioxane (4.0 M) (2.00 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine (180.00 mg) as off-white solid. LCMS (ES) [M+l]+m / z: 326.

[0263] Step 9. Synthesis of tert-butyl (7S,9R)-7-{4-[5-(3,3-difhioro-l-methylcyclobutyl)-1 ,2,4-oxadiazol-3 -yl]-4-(trifluoromethyl)piperidine- 1 -carbonyl } -9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate

[0264] Into a 8 mL vial were added (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (50.00 mg, 0.17 mmol, 1.00 equiv), 4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine (62.70 mg, 0.19 mmol, 1.10 equiv), DIEA (33.97 mg, 0.26 mmol, 1.50 equiv) and DMF (2.00 mL) at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3H2O),Attorney Docket No.: INMD-221 / 01WO 315953-454930% to 80% gradient in 12 min; detector, UV 254 nm. This resulted in tert-butyl (7S,9R)-7-{4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluorornethyl)piperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (50.00 mg, 48.15% yield, 89.00% purity) as white solid. LCMS (ES) [M+l]+m / z: 593.

[0265] Step 10. Synthesis of (7S,9R)-7-{4-[5-(3,3-difluoro-l-methylcyclobutyl)-l,2,4-oxadiazol-3-yl]-4-(trifluoromethyl)piperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol

[0266] Into a 8 mL vial were added tert-butyl (7S,9R)-7-{4-[5-(3,3-difluoro-l-methylcy cl obutyl)- 1,2, 4-oxadiazol-3-yl]-4-(trifluoromethyl)piperi dine- 1 -carbonyl} -9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (45.00 mg, 0.07 mmol, 1.00 equiv) and ACN (2.00 mL) at room temperature. To the above mixture was added TsOH (39.23 mg, 0.22 mmol, 3.00 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3H2O), 5% to 65% gradient in 10 min; detector, UV 254 nm. This resulted in (7S,9R)-7-{4-[5-(3,3-difluoro- 1 -methyl cyclobutyl)- 1 ,2,4-oxadiazol-3 -yl]-4-(trifluoromethyl)piperidine- 1 -carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 45) (6.00 mg, 16.04% yield, 97.42% purity) as white solid. LCMS (ES) [M+H]+m / z: 493.2. 'H NMR (300 MHz, DMSO-de) 64.64 - 4.60 (m, 1H), 4.45 - 4.38 (m, 1H), 4.05 - 3.95 (m, 1H), 3.85 - 3.75 (m, 2H), 3.29 - 3.20 (m, 2H), 3.05 - 2.69 (m, 4H), 2.67 - 2.56 (m, 2H), 2.48 - 2.39 (m, 2H), 2.09 - 1.73 (m, 6H), 1.68 (s, 3H), 1.65 - 1.55 (m, 1H), 1.47 - 1.35 (m, 3H).

[0267] Example 7. Synthesis of (4-cy clopropyl-4-(5-(4,4-difluorocyclohexyl)- 1,2,4-oxadiazol-3-yl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Compound 74)

[0268] Step 1. Synthesis of l-benzyl-4-cy cl opropylpiperidine-4-carbonitrileAttorney Docket No.: INMD-221 / 01WO 315953-4549step 1

[0269] To a solution of 2-cyclopropylacetonitrile (1.92 g, 23.69 mmol, 1.1 equiv), benzylbis(2-chloroethyl)amine (5 g, 21.54 mmol, 1.0 equiv) in THF (100 mL) was added NaHMDS (2M in THF) (32.3 mL, 64.61 mmol, 3.0 equiv) dropwise at -10°C within 0.5 h. The reaction was stirred for 2 h with temperature at a temperature range of -10~0°C. The reaction was quenched with NH4Cl(aq) (100 mL), extracted with ethyl acetate (200 mL x 2), the combined organic phase was washed with brine (200 mL). After concentrated under reduced pressure, the residue was purified by reverse HPLC with conditions: silica-C 18-330g, MeCN / ftO (NH4HCO3 0.05%), from 40-100%, within 15 min, Flow rate: 90 mL / min, Detector, 220 nm. The fraction of target was concentrated under reduced pressure. This result in l-benzyl-4-cyclopropylpiperidine-4-carbonitrile (2.0 g, 38% yield, 95% purity) as colorless oil. LCMS (ES) [M+H]+m / z: 241.

[0270] Step 2. Synthesis of tert-butyl 4-cyano-4-cyclopropylpiperidine-l -carboxylate

[0271] To a pressure tank, were added l-benzyl-4-cyclopropylpiperidine-4-carbonitrile (2.0 g, 8.32 mmol, 1.0 equiv), BOC2O (2.54 g, 11.65 mmol, 1.4 equiv) and MeOH (25 mL). This was followed by the addition of Pd(OH)2 / C (0.35 g). The mixture was hydrogenated at room temperature for 4 h with pressure of 1~2 atm. The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without purification. LCMS (ES) [M+H]+m / z: 251.

[0272] Step 3. Synthesis of tert-butyl (Z)-4-cyclopropyl-4-(N'-hydroxycarbamimidoyl)piperidine-l -carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549Bod

[0273] A solution of tert-butyl 4-cyano-4-cyclopropylpiperidine-l -carboxylate (1.8 g, 7.19 mmol, 1.0 equiv) in EtOH (10 mL) was treated with NH3.H2O (10 mL, 50%) at room temperature. The resulting mixture was stirred at 70°C for 12 h. The reaction was cooled to room temperature, the resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without purification. LCMS (ES) [M+H]+m / z: 284.

[0274] Step 4. Synthesis of tert-butyl (Z)-4-cyclopropyl-4-(N'-((4,4-difluorocyclohexane-l-carbonyl)oxy)carbamimidoyl)piperidine- 1 -carboxylateBod

[0275] To a solution of tert-butyl 4-cyclopropyl-4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 -carboxylate (900 mg, 3.17 mmol, 1.0 equiv), 4,4-difluorocyclohexane-l -carboxylic acid (521 mg, 3.17 mmol, 1.0 equiv), DIEA (1.23 g, 9.53 mmol, 3.0 equiv) in DMF (10 mL) was added HATU (1449 mg, 3.81 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (4: 1) to afford tert-butyl 4-cyclopropyl-4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]piperidine-l-carboxylate (1.2 g, 88% yield, 90% purity) as a yellow solid. LCMS (ES) [M+H]+m / z: 430.

[0276] Step 5. Synthesis of tert-butyl 4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3 -yl)piperidine- 1 -carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0277] To a solution of tert-butyl 4-cyclopropyl-4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]piperidine-l-carboxylate (1.2 g, 2.80 mmol, 1.0 equiv) in DMSO (15 mL) was added with KOH (0.39 g, 6.99 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford tert-butyl 4-cyclopropyl-4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]piperidine-l-carboxylate (300 mg, 26% yield, 90% purity) as a white solid. LCMS (ES) [M+H]+m / z: 412.

[0278] Step 6. Synthesis of 3-(4-cyclopropylpiperidin-4-yl)-5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazole hydrochloride

[0279] A solution of tert-butyl 4-cyclopropyl-4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3 -yl]piperidine-l -carboxylate (180 mg, 0.44 mmol, 1.0 equiv) in dioxane (2 mL) was treated with HC1 in 1,4-dioxane (4.0 M) (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue crude product was used in the next step directly without purification. LCMS (ES) [M-HC1+H]+m / z: 312.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0280] Step 7. Synthesis of tert-butyl (7S,9R)-7-(4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)- 1 ,2,4-oxadiazol-3 -yl)piperidine- 1 -carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate

[0281] A solution of 4-cyclopropyl-4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]piperidine hydrochloride (100 mg, 0.29 mmol, 1.0 equiv), (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (107 mg, 0.37 mmol, 1.3 equiv), and DIEA (112 mg, 0.86 mmol, 3.0 equiv) in DCM (2 mL) was treated with HATU (131 mg, 0.34 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred at 0°C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (7S,9R)-7-{4-cyclopropyl-4-[5-(4,4-difluorocyclohexyl)- 1 ,2,4-oxadiazol-3 -yl]piperidine- 1 -carbonyl } -9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (70 mg, 42% yield, 70% purity) as a yellow solid. LCMS (ES) [M+H]+m / z: 239.

[0282] Step 8. Synthesis of (4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl)piperidin-l-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone

[0283] To a solution of tert-butyl (7S,9R)-7-{4-cyclopropyl-4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]piperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (65 mg, 0.11 mmol, 1.0 equiv) in MeCN (2 mL) was added with TsOH (58 mg, 0.34 mmol,Attorney Docket No.: INMD-221 / 01WO 315953-45493.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Column: XBridge Prep RP C18 Column, 19*250 mm, 5 pm; Mobile Phase A: Water (0.05%NH3.H20), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient (B%): isocratic 35%-80% within lOmin. This resulted in (7S,9R)-7-{4-cyclopropyl-4-[5-(4,4-difluorocyclohexyl)- 1 ,2,4-oxadiazol-3 -yl]piperidine- 1 -carbonyl } -6-azaspiro[3.5]nonan-9-ol Compound 74) (20 mg, 37% yield, 99.1% purity) as a white solid. LCMS (ES) [M+H]+m / z: 479.2. 'HNMR (300 MHz, DMSO-fifc) 64.60 (br, 1H), 4.23 (d, J= 13.3 Hz, 1H), 3.84 - 3.73 (m, 3H), 3.30 - 3.23 (m, 1H), 3.00 - 2.87 (m, 1H), 2.85 - 2.75 (m, 1H), 2.65 - 2.56 (m, 1H), 2.25 - 2.00 (m, 7H), 1.99 - 1.69 (m, 8H), 1.69 - 1.51 (m, 2H), 1.49 - 1.24 (m, 4H), 1.08 - 0.99 (m, 1H), 0.35 - 0.29 (m, 2H), 0.19 - 0.12 (m, 2H).

[0284] Example 8. Synthesis of (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 82)

[0285] Step 1. Synthesis of tert-butyl 4-cyano-4-isopropylpiperi dine- 1 -carboxylate

[0286] Into a 250 mL 3-necked round-bottom flask were added tert-butyl 4-cyanopiperidine-1-carboxylate (5.00 g, 23.77 mmol, 1.00 equiv) and THF (50.00 mL) at room temperature. To the above mixture was added LDA (2 M in THF) (5.09 g, 47.55 mmol, 2.00 equiv) dropwise at -70 °C. The resulting mixture was stirred at -70 °C for additional 30 min. To the above mixture was added 2-iodopropane (6.06 g, 35.66 mmol, 1.50 equiv) dropwise at -70 °C. The resulting mixture was stirred at -70 °C for additional 1 h. The reaction was quenched with sat. NH4Q (aq.) at -70 °C. The mixture was allowed to room temperature. The resulting mixture was extracted with EtOAc (50 x mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl 4-cyano-4-isopropylpiperidine-l -carboxylate (4.80 g, 79.99% yield, 89.00% purity) as off-white solid. LCMS (ES) [M+l]+m / z: 253.

[0287] Step 2. Synthesis of tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-isopropylpiperidine-l-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549Bod

[0288] Into a 100 mL round-bottom flask were added tert-butyl 4-cyano-4-isopropylpiperidine-l-carboxylate (3.00 g, 11.88 mmol, 1.00 equiv), MeOH (15.00 mL) and Hydroxylamine, 50% (15.00 mL) at room temperature. The resulting mixture was stirred at 80 °C for overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-isopropylpiperidine-l-carboxylate (3.30 g, crude) as off-white solid. LCMS (ES) [M+l]+m / z: 286.

[0289] Step 3. Synthesis of tert-butyl 4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]-4-isopropylpiperidine-l-carboxylate

[0290] Into a 100 mL round-bottom flask were added 4,4-difluorocyclohexane-l -carboxylic acid (960.00 mg, 5.84 mmol, 1.00 equiv), tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]-4-isopropylpiperidine-l-carboxylate (2002.82 mg, 7.01 mmol, 1.20 equiv), DIEA (1511.73 mg, 11.69 mmol, 2.00 equiv) and DMF (25.00 mL) at room temperature. To the above mixture was added HATU (2668.45 mg, 7.01 mmol, 1.20 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3x15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl 4-[(Z)-N'-[(Z)-4,4-Attorney Docket No.: INMD-221 / 01WO 315953-4549difluorocyclohexanecarbonyloxy]carbamimidoyl]-4-isopropylpiperidine-l-carboxylate (1.70 g, 67.36% yield, 96.00% purity) as light yellow oil. LCMS (ES) [M+l]+m / z: 432.

[0291] Step 4. Synthesis of tert-butyl 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carboxylate

[0292] Into a 100 mL round-bottom flask were added tert-butyl 4-[(Z)-N'-[(Z)-4,4-difluorocyclohexanecarbonyloxy]carbamimidoyl]-4-isopropylpiperidine-l-carboxylate (1.60 g, 3.70 mmol, 1.00 equiv), DMSO (20.00 mL) and KOH (0.21 g, 3.70 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford tert-butyl 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carboxylate (1.30 g, 84.79% yield, 90.0% purity) as light yellow solid. LCMS (ES) [M+l]+ m / z: 414.

[0293] Step 5. Synthesis of 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine

[0294] Into a 20 mL vial were added tert-butyl 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3 -yl]-4-isopropylpiperidine-l -carboxylate (200.00 mg, 0.48 mmol, 1.00 equiv) and DCM (2.00 mL) at room temperature. To the above mixture was added HC1 in 1,4-dioxane (4.0 M) (2.00 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1Attorney Docket No.: INMD-221 / 01WO 315953-4549h. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine (180.00 mg, crude) as white solid. LCMS (ES) [M+l]+ m / z: 314.

[0295] Step 6. Synthesis of tert-butyl (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carb oxy late

[0296] Into a 8 mL vial were added (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (50.00 mg, 0.17 mmol, 1.00 equiv), 4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine (54.92 mg, 0.17 mmol, 1.00 equiv), DIEA (33.97 mg, 0.26 mmol, 1.50 equiv) and DMF (2.00 mL) at room temperature. To the above mixture was added HATU (86.62 mg, 0.22 mmol, 1.30 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3H2O), 40% to 90% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl (7S,9R)-7-{4-[5-(4,4-difhiorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (60.00 mg, 58.96% yield, 93.00% purity) as off-white solid. LCMS (ES) [M+l]+ m / z: 581.

[0297] Step 7. Synthesis of (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-olAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0298] Into a 8 mL vial were added tert-butyl (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (50.00 mg, 0.08 mmol, 1.00 equiv) and ACN (2.00 mL) at room temperature. To the above mixture was added 4-m ethylbenzene- 1 -sulfonic acid hydrate (49.13 mg, 0.25 mmol, 3.00 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 5% to 70% gradient in 14 min; detector, UV 254 nm. This resulted in (7S,9R)-7-{4-[5-(4,4-difluorocyclohexyl)-l,2,4-oxadiazol-3-yl]-4-isopropylpiperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 82) (20.00 mg, 48.33% yield, 97.9% purity) as white solid. LCMS (ES) [M+H]+m / z: 481.3. *HNMR (300 MHz, DMSO-de) 6 4.61 (s, 1H), 4.34 - 4.20 (m, 1H), 3.92 - 3.67 (m, 3H), 3.30 - 3.21 (m, 1H), 2.98 - 2.70 (m, 2H), 2.69 - 2.57 (m, 1H), 2.44 - 2.35 (m, 1H), 2.33 - 1.21 (m, 22H), 0.83 - 0.70 (m, 6H).

[0299] Example 9. Synthesis of (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol

[0300] Step 1. Synthesis of tert-butyl 4-cyano-4-(4-methylphenyl)piperi dine- 1 -carboxylate

[0301] A solution of tolylacetonitrile (4 g, 30.493 mmol, 1.0 equiv), tert-butyl N,N-bis(2-chloroethyl)carbamate (8.93 g, 36.897 mmol, 1.2 equiv) in DMF (50 mL) was treated with NaH (3.05 g, 76.233 mmol, 2.5 equiv, 60%) at 0°C. The resulting mixture was stirred at 80°CAttorney Docket No.: INMD-221 / 01WO 315953-4549for overnight. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford tert-butyl 4-cyano-4-(4-methylphenyl)piperidine-l -carboxylate (6.5 g, 70.96% yield) as a yellow oil. LCMS (ES, m / z):[M+H]+: 301.

[0302] Step 2. Synthesis of 1 -(tert-butoxycarbonyl)-4-(4-methylphenyl)piperidine-4-carboxylic acidBoc

[0303] A solution of tert-butyl 4-cyano-4-(4-methylphenyl)piperidine-l -carboxylate (2 g, 6.658 mmol, 1 equiv) in EtOH (5 mL) was added NaOH (1.07 g, 26.632 mmol, 4 equiv) in H2O (5 mL) at room temperature. The resulting mixture was stirred at 90°C for 48 h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 4 with IN HC1 (aq.). The resulting mixture was extracted with EtOAc, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product l-(tert-butoxycarbonyl)-4-(4-methylphenyl)piperidine-4-carboxylic acid (1.8 g) was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+: 320.

[0304] Step 3. Synthesis of 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-(4-methylphenyl)piperidine- 1 ,4-dicarboxylate

[0305] A solution of l-(tert-butoxycarbonyl)-4-(4-methylphenyl)piperidine-4-carboxylic acid (1.8 g, 5.636 mmol, 1.0 equiv), (Z)-3,3-difluoro-N'-hydroxycyclobutane-l-carboximidamide (1.02 g, 6.763 mmol, 1.2 equiv) , DIEA (2.19 g, 16.908 mmol, 3.0 equiv) in DMF (20 mL) wasAttorney Docket No.: INMD-221 / 01WO 315953-4549treated with HATU (2.57 g, 6.763 mmol, 1.2 equiv) at O°C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-(4-methylphenyl)piperidine-l,4-dicarboxylate (1.0 g, 35.37% yield) as a yellow solid. LCMS (ES, m / zy. [M+H]+: 452.

[0306] Step 4. Synthesis of tert-butyl 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine-l -carboxylate

[0307] A solution of 4-(Z)-[amino(3,3-difluorocyclobutyl)methylidene]amino 1-tert-butyl 4-(4-methylphenyl)piperidine-l,4-dicarboxylate (980 mg, 2.170 mmol, 1.0 equiv) in DMSO (10 mL) was treated with KOH (243 mg, 4.340 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3:1) to afford tert-butyl 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine-l-carboxylate (200 mg, 21.26% yield) as a off-white solid. LCMS (ES, m z) [M+H]+: 434.

[0308] Step 5. Synthesis of 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine hydrochlorideAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0309] To a stirred solution of tert-butyl 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]- 4-(4-methylphenyl)piperidine-l -carboxylate (200 mg, 0.461 mmol, 1 equiv) in Dioxane (2 mL) was added HC1 in 1,4-dioxane (4.0 M) (2 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine hydrochloride (150 mg, 87.91% yield) as a white solid. LCMS (ES, m / z)'. [M+H]+: 334.

[0310] Step 6. Synthesis of tert-butyl (7S)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol- 5-yl]-4-(4-methylphenyl)piperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carb oxy late

[0311] To a stirred solution of (7S)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (Intermediate 1, see Example 1) (90 mg, 0.315 mmol, 1.0 equiv) and 4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine hydrochloride (116 mg, 0.315 mmol, 1.0 equiv) inDCM (2 mL) were added DIEA (122 mg, 0.945 mmol, 3.0 equiv) and HATU (179 mg, 0.473 mmol, 1.5 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for 3 h. The mixture was purified by silica gel column chromatography, eluted with PE / THF (25%) to afford tertbutyl (7S)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine-l-carbonyl}-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (60 mg, 31.67% yield) as an off-white solid. LCMS (ES, m / z)'. [M+H]+: 601.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0312] Step 7. Synthesis of (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4- (4-methylphenyl)piperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol

[0313] To a stirred solution of tert-butyl (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine- 1 -carbonyl } -9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (60 mg, 0.100 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (51 mg, 0.300 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 2 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in (7S,9R)-7-{4-[3-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)piperidine-l-carbonyl}-6-azaspiro[3.5]nonan-9-ol (Compound 83) (15 mg, 30.00% yield) as a white solid. 'H NMR. (400 MHz, DMSO-tA) 67.25 (t, J= 7.6 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.62 (d, J= 3.8 Hz, 1H), 4.13 (dd, J= 37.0, 13.5 Hz, 1H), 3.97 - 3.70 (m, 3H), 3.59 (pd, J= 8.5, 2.9 Hz, 1H), 3.30 -3.11 (m, 1H), 3.11 -2.99 (m, 2H), 2.98 -2.77 (m, 4H), 2.70 -2.55 (m, 3H), 2.27 (s, 3H), 2.24 -2.14 (m, 1H), 2.09 - 1.99 (m, 1H), 1.88 - 1.67 (m, 5H), 1.68 - 1.54 (m, 1H), 1.49 - 1.32 (m, 3H). LCMS (ES, m / zy. [M+H]+: 501.

[0314] Example 10. Synthesis of N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methyl-l-[(4R,7S)-l-oxa-6-azaspiro[3.5]nonane-7-carbonyl]azetidine-3-carboxamide (Compound 88)

[0315] Step 1. Synthesis of (5S)-5-{[(tert-butyldimethylsilyl)oxy]methyl}pyrrolidin-2-one >0°C-rt, 1 hstep 1

[0316] Into a 250 mL 3-necked round-bottom flask were added (5S)-5-(hydroxymethyl)pyrrolidin-2-one (20.00 g, 173.71 mmol, 1.00 equiv), DMF (100.00 mL) andAttorney Docket No.: INMD-221 / 01WO 315953-4549IH-imidazole (23.65 g, 347.43 mmol, 2.00 equiv). To the above mixture was added TBSC1 (36.65 g, 243.20 mmol, 1.40 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EA (3 x 110 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (50%) to afford (5S)-5-{[(tert-butyldimethylsilyl)oxy]methyl}pyrrolidin-2-one (38.00 g, 95.36% yield, 90.00% purity) as light yellow solid. LCMS (ES, m / z): [M+H]+: 230.

[0317] Step 2. Synthesis of benzyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopyrrolidine- 1 -carboxylate>step 2

[0318] Into a 500 mL 3-necked round-bottom flask were added (5S)-5-{[(tert-butyldimethylsilyl)oxy]methyl}pyrrolidin-2-one (15.00 g, 65.39 mmol, 1.00 equiv) and THF (300.00 mL) under nitrogen atmosphere. To the above mixture was added NaHMDS (78.47 mL, 78.47 mmol, 1.20 equiv) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for additional 1 h. To the above mixture was added CbzCI (13.39 g, 78.47 mmol, 1.20 equiv) dropwise at -78 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with sat. NH4Q (aq.) at 0 °C. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (6%) to afford benzyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopyrrolidine-l-carboxylate (19.30 g, 81.19% yield, 88.00% purity) as light yellow oil. LCMS (ES, m / z): [M+H]+: 364.

[0319] Step 3. Synthesis of benzyl N-[(2S)-l-[(tert-butyldimethylsilyl)oxy]-6-[dimethyl(oxo)-lambda6-sulfanylidene]-5-oxohexan-2-yl]carbamatestep 3Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0320] Into a 250 mL 3-necked round-bottom flask were added trimethyl(oxo)-lambda6-sulfanylium iodide (89.29 g, 405.75 mmol, 2.50 equiv) and DMSO (150.00 mL) under nitrogen atmosphere. To the above mixture was added t-BuOK (45.53 g, 405.75 mmol, 2.50 equiv) in portions at 15 °C. The resulting mixture was stirred at room temperature for additional 1 h. To the above mixture was added benzyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopyrrolidine-1 -carboxylate (59.00 g, 162.23 mmol, 1.00 equiv) dropwise at 15 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (45%) to afford benzyl N-[(2S)-1-[(tert-butyldimethylsilyl)oxy]-6-[dimethyl(oxo)-lambda6-sulfanylidene]-5-oxohexan-2-yl]carbamate (45.00 g, 60.85% yield, 80.00% purity) as light yellow oil. LCMS (ES, m z .[M+H]+: 456.

[0321] Step 4. Synthesis of benzyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopiperidine- 1 -carboxylateCbz!step 4 Cbz

[0322] Into a 100 mL round-bottom flask were added benzyl N-[(2S)-l-[(tert-butyldimethylsilyl)oxy]-6-[dimethyl(oxo)-lambda6-sulfanylidene]-5-oxohexan-2-yl]carbamate (45.00 g, 98.75 mmol, 1.00 equiv), toluene (50.00 mL) and bis((lZ,5Z)-cycloocta-l,5-diene); bis(chloroiridium) (0.66 g, 0.99 mmol, 0.01 equiv). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (5%) to afford benzyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopiperidine-l-carboxylate (20.00 g, 53.64% yield, 90.00% purity) as light yellow oil. LCMS (ES, m z .[M+H]+: 378.

[0323] Step 5. Synthesis of benzyl (7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549step 5

[0324] Into a mL 3 -necked round-bottom flask were added trimethyl(oxo)-lambda6-sulfanylium iodide (29.14 g, 132.43 mmol, 2.50 equiv), t-BuOH (40.00 mL) and t-BuOK (14.86 g, 132.43 mmol, 2.50 equiv). The resulting mixture was stirred at 50 °C for 1 h under nitrogen atmosphere. To the above mixture was added benzyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopiperidine-l-carboxylate (20.00 g, 52.97 mmol, 1.00 equiv) dropwise at 50 °C. The resulting mixture was stirred at 50 °C for additional overnight. The mixture was allowed to cool down to room temperature. The reaction was quenched with ice water. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (5%) to afford benzyl (7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (crude). The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Column: welch xtimate XB-C 18(50* 150); Mobile Phase A: Water (20mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 90mL / min mL / min; Gradient (B%): isocratic 48%-78% 10 min; Wave Length: 254 nm / 220 nm; RTl(min): 10. This resulted in benzyl (7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (10.00 g, 46.54% yield, 95.00% purity) as light yellow oil. LCMS (ES, m / z): [M+H]+: 406.

[0325] Step 6. Synthesis of benzyl (4R,7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate

[0326] The benzyl (7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (7.00 g, 17.26 mmol, 1.00 equiv) was purified by reversed-phase flash chromatography with the following conditions: Column: XA CHIRAL ART Amylose-C NEO, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: Hex=l: 1; Flow rate: 80 mL / min; Gradient (B%): isocratic 25% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 2.59; RT2(min): 3.82; Sample Solvent:Attorney Docket No.: INMD-221 / 01WO 315953-4549ACN; Injection Volume: 2 mL. This resulted in benzyl (4R,7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (620.00 mg, 8.86% yield, 95.00% purity) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 406.

[0327] Step 7. Synthesis of benzyl (4R,7S)-7-(hydroxymethyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate

[0328] Into a 20 mL vial were added benzyl (4R,7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (1.00 g, 2.47 mmol, 1.00 equiv), THF (5.00 mL) and TBAF (1.00 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (20%) to afford benzyl (4R,7S)-7-(hydroxymethyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (510.00 mg, 71.00% yield, 80.00% purity) as light yellow oil. LCMS (ES, m / z): [M+H]+: 292.

[0329] Step 8. Synthesis of (4R,7S)-6-[(benzyloxy)carbonyl]-l-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid"<>

[0330] Into a 20 mL vial were added benzyl (4R,7S)-7-(hydroxymethyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (300.00 mg, 1.03 mmol, 1.00 equiv), acetone (9.00 mL), NaBr (21.19 mg, 0.21 mmol, 0.20 equiv) and NaHCCh (173.00 mg, 2.06 mmol, 2.00 equiv) in ELO (3.00 mL). To the above mixture was added trichloro-1, 3, 5-triazinane-2, 4, 6-trione (478.60 mg, 2.06 mmol, 2.00 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction was quenched with sat. NaHCCh (aq.). The filtrate were collected by filtration and washed with H2O. The resulting mixture was extracted with DCM / MeOH (10:1) (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (4R,7S)-6-[(benzyloxy)carbonyl]-l-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid (250.00 mg, 79.52% yield, 88.00% purity) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 306.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0331] Step 9. Synthesis of benzyl (4R,7S)-7-(3-{[(4,4-difluorocyclohexyl)methyl](methyl)carbamoyl}-3-isopropylazetidine-l-carbonyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate

[0332] Into a 8 mL vial were added (4R,7S)-6-[(benzyloxy)carbonyl]-l-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid (166.76 mg, 0.55 mmol, 1.05 equiv), DMF (2.00 mL), DIEA (201.68 mg, 1.56 mmol, 3.00 equiv) and N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methylazetidine-3-carboxamide (150.00 mg, 0.52 mmol, 1.00 equiv). To the above mixture was added HATU (237.33 mg, 0.62 mmol, 1.20 equiv) in portions at 0 °C. The resulting mixture was stirred at 0 °C for additional 1 h. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Column: welch xtimate XB-C18(50*150); Mobile Phase A: Water(10% FA), Mobile Phase B: ACN; Flow rate: 90mL / min mL / min; Gradient (B%): isocratic 30%-78% 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 10. This resulted in benzyl (4R,7S)-7-(3-{[(4,4-difluorocyclohexyl)methyl](methyl)carbamoyl}-3-isopropylazetidine-l-carbonyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (145.00 mg, 48.42% yield, 70.00% purity) as light yellow oil. LCMS (ES, m / z . [M+H]+: 576.

[0333] Step 10. Synthesis of N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methyl-l-[(4R,7S)-l-oxa-6-azaspiro[3.5]nonane-7-carbonyl]azetidine-3-carboxamide

[0334] Into a 8 mL vial were added benzyl (4R,7S)-7-(3-{[(4,4-difluorocyclohexyl)methyl](methyl)carbamoyl}-3-isopropylazetidine-l-carbonyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (130.00 mg, 0.16 mmol, 1.00 equiv, 70.00%), DCM (4.00Attorney Docket No.: INMD-221 / 01WO 315953-4549mL), TEA (31.99 mg, 0.32 mmol, 2.00 equiv), EtsSiH (2.00 mL) and PdCh (2.80 mg, 0.02 mmol, 0.10 equiv). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: C18-120 g column, mobile phase, MeCN in Water (0.1% NH3H2O), 25% to 55% gradient in 10 min; detector, UV 254 nm. This resulted in N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methyl-l-[(4R,7S)-l-oxa-6-azaspiro[3.5]nonane-7-carbonyl]azetidine-3-carboxamide (Compound 88) (27.7 mg, 39.69% yield, 99.4% purity) as off-white solid. LCMS (ES, m / z . [M+H]+: 442.3. 'H NMR (300 MHz, DMSO-tL) 64.38 - 4.02 (m, 4H), 3.97 - 3.75 (m, 2H), 3.24 - 2.97 (m, 4H), 2.79 - 2.73 (m, 3H), 2.55 - 2.51 (m, 1H), 2.22 - 1.91 (m, 6H), 1.89 - 1.71 (m, 3H), 1.71 - 1.48 (m, 4H), 1.48 - 1.34 (m, 2H), 1.25 - 1.07 (m, 2H), 0.94 - 0.78 (m, 6H).

[0335] Example 11. Synthesis of N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methyl-l-[(4S,7S)-l-oxa-6-azaspiro[3.5]nonane-7-carbonyl]azetidine-3-carboxamide (Compound 88A)

[0336] Step 1. Synthesis of benzyl (4S,7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate

[0337] The benzyl (7 S)-7- { [(tert-butyl dimethyl silyl)oxy ]methyl } - 1 -oxa-6-azaspiro[3.5]nonane-6-carboxylate (7.00 g, 17.26 mmol, 1.00 equiv) was purified by reversed-phase flash chromatography with the following conditions: Column: XA CHIRAL ART Amylose-C NEO, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: Hex=l: 1; Flow rate: 80 mL / min; Gradient (B%): isocratic 25% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 2.59; RT2(min): 3.82; Sample Solvent: ACN; Injection Volume: 2 mL. This resulted in benzyl (4S,7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (620.00 mg, 8.86% yield, 95.00% purity) as light yellow oil. LCMS (ES, m / z): [M+H]+: 406.

[0338] Step 2. Synthesis of benzyl (4S,7S)-7-(hydroxymethyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0339] Into a 20 mL vial were added benzyl (4S,7S)-7-{[(tert-butyldimethylsilyl)oxy]methyl}-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (620.00 mg, 1.53 mmol, 1.00 equiv), THF (10.00 mL) and TBAF (2.00 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (23%) to afford benzyl (4S,7S)-7-(hydroxymethyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (310.00 mg, 69.61% yield, 90.00% purity) as light yellow oil. LCMS (ES, m / z)'. [M+H]+: 292.

[0340] Step 3. Synthesis of (4S,7S)-6-[(benzyloxy)carbonyl]-l-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid<

[0341] Into a 20 mL vial were added benzyl (4S,7S)-7-(hydroxymethyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (300.00 mg, 1.03 mmol, 1.00 equiv), acetone (9.00 mL), NaBr (21.19 mg, 0.21 mmol, 0.20 equiv) and NaHCCh (173.00 mg, 2.06 mmol, 2.00 equiv) in H2O (3.00 mL). To the above mixture was added trichloro-1, 3, 5-triazinane-2, 4, 6-trione (478.60 mg, 2.06 mmol, 2.00 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction was quenched with sat. NaHCCh (aq.). The filtrate were collected by filtration and washed with H2O. The resulting mixture was extracted with DCM / MeOH (10:1) (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (4S,7S)-6-[(benzyloxy)carbonyl]-l-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid (250.00 mg, 79.52% yield, 90.00% purity) as light yellow oil. LCMS (ES, m / z)'. [M+H]+: 306.

[0342] Step 4. Synthesis of benzyl (4S,7S)-7-(3-{[(4,4-difluorocyclohexyl)methyl](methyl)carbamoyl}-3-isopropylazetidine-l-carbonyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylateAttorney Docket No.: INMD-221 / 01WO 315953-4549

[0343] Into a 8 mL vial were added (4S,7S)-6-[(benzyloxy)carbonyl]-l-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid (250.00 mg, 0.82 mmol, 1.00 equiv), DMF (2.00 mL), DIEA (317.48 mg, 2.46 mmol, 3.00 equiv) and N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methylazetidine-3-carboxamide (236.12 mg, 0.82 mmol, 1.00 equiv). To the above mixture was added HATU (373.60 mg, 0.98 mmol, 1.20 equiv) in portions at 0 °C. The resulting mixture was stirred at 0 °C for additional 1 h. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Column: welch xtimate XB-C18(50*150); Mobile Phase A: Water(10% FA), Mobile Phase B: ACN; Flow rate: 90mL / min; Gradient (B%): isocratic 30%-78% 10 min; Wave Length: 254nm / 220nm; RTl(min): 10. This resulted in benzyl (4S,7S)-7-(3-{[(4,4-difluorocyclohexyl)methyl](methyl)carbamoyl}-3-isopropylazetidine-l-carbonyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (210.00 mg, 44.55% yield, 80.00% purity) as light yellow oil. LCMS (ES, m / z . [M+H]+: 575.

[0344] Step 5. Synthesis of N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methyl-l-[(4S,7S)-l-oxa-6-azaspiro[3.5]nonane-7-carbonyl]azetidine-3-carboxamide

[0345] Into a 8 mL vial were added benzyl (4S,7S)-7-(3-{[(4,4-difluorocyclohexyl)methyl](methyl)carbamoyl}-3-isopropylazetidine-l-carbonyl)-l-oxa-6-azaspiro[3.5]nonane-6-carboxylate (190.00 mg, 0.33 mmol, 1.00 equiv), DCM (4.00 mL), TEA (66.79 mg, 0.66 mmol, 2.00 equiv), EtsSiH (2.00 mL) and PdCh (5.85 mg, 0.03 mmol, 0.10 equiv). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reactionAttorney Docket No.: INMD-221 / 01WO 315953-4549solution was purified by reversed-phase flash chromatography with the following conditions: C18-120 g column, mobile phase, MeCN in Water (0.1% NH3H2O), 25% to 55% gradient in 10 min; detector, UV 254 nm. This resulted in N-[(4,4-difluorocyclohexyl)methyl]-3-isopropyl-N-methyl-l-[(4S,7S)-l-oxa-6-azaspiro[3.5]nonane-7-carbonyl]azetidine-3-carboxamide (Compound 88A) (30.00 mg, 20.59% yield, 98.20% purity) as off-white solid. LCMS (ES, m / zy. [M+H]+: 442.3. 'HNMR (300 MHz, DMSO-t / e)64.42 - 4.05 (m, 4H), 3.97 - 3.77 (m, 2H), 3.21 (d, J= 7.4 Hz, 2H), 3.10 (t, J= 9.8 Hz, 2H), 2.78 (s, 3H), 2.49 - 2.35 (m, 2H), 2.28 (dt, J= 10.6, 7.9 Hz, 1H), 2.21 - 1.91 (m, 4H), 1.89 - 1.71 (m, 2H), 1.71 - 1.58 (m, 4H), 1.56 - 1.40 (m, 1H), 1.36 - 1.07 (m, 3H), 0.89 (t, J= 6.2 Hz, 6H).

[0346] Example 12. Human DPP1 enzyme IC50 assay

[0347] Recombinant human DPP1 enzyme (R&D Systems; Minneapolis, MN) was first proteolytically processed into its mature form using recombinant human cathepsin L (R&D Systems) in a buffer consisting of 20 mM citric acid pH 4.5, 150 mM NaCl, 1 mM EDTA and 10 mM DTT. Test articles were applied to activated human DPP1 enzyme in Assay Buffer (25 mM MES pH 6.0, 50 mM NaCl, 5 mM DTT) in a total reaction volume of 125 pL. 25 pL of compound in Assay Buffer plus 5% DMSO was first added to 50 pL of activated human DPP1 enzyme at a concentration of 1 ng / pL and allowed to pre-incubate for 10 minutes at 37 °C after which 50 pL of 1000 pM H-Gly-Arg-AMC substrate (Bachem; St. Torrance, CA) was added, giving final substrate concentration of 400 pM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37 °C, with fluorescence at Excitation / Emission 350 / 450 nm measured every 5 minutes. DPP1 concentration was interpolated based on its activity relative to a standard curve of activated human recombinant DPP1 enzyme. IC50 values for each compound were calculated via the XLFit (IDBS Version 5.3.1.3) Add-On to Microsoft Excel using the four parameter fit equation y = {A+[(B-A)] / [l+((C / x)AD)]}, which appears as equation number 205 (4 Parameter Logistic Model or Sigmoidal Dose-Response Model) in XLFit. Default constraints were used for each Parameter. IC50 was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control.

[0348] Results are provided in Table 1 below. In Table 1, *** represents average IC50 < 5 nM, ** represents average IC50 in the range of 5-15 nM, and * represents average IC50 > 15 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0349] Example 13. DPP1 Cell IC50 assay

[0350] HL-60 cells (ATCC; Manassas, VA) were maintained in RPMI-1640 supplemented with 20% heat-inactivated FBS and IX Antibiotic Antimycotic (Cytiva; Marlborough, MA). Media was changed every three to four days and cells were not allowed to exceed 1x106cells per mL. Prior to assay, cells were collected by centrifugation at 500 ref for 3 minutes, resuspended in PBS and counted. Cells were diluted in PBS to a concentration of 5xl05live cells per mL and transferred to black 96-well plates for assay, 60 pL per well. Test articles were diluted in PBS plus 0.5% DMSO, and 20 pL was added to each assay well. Compound was allowed to pre-incubate with cells with gentle shaking at 100 rpm for 60 minutes at 37 °C in a cell culture incubator maintained at 5% CO2, after which 20 pL of 500 pM H-Gly-Phe-AFC substrate (MP Biomedicals; Solon, OH) was added to each well. Plates were returned to the incubator with shaking at 100 rpm for 30 minutes, after which fluorescence was measured at Excitation / Emission 400 / 505 nm. % Inhibition was calculated from RFU values compared to control cell wells that received only PBS plus 0.5% DMSO. IC50 values for each compound were calculated via the XLFit (IDBS Version 5.3.1.3) Add-On to Microsoft Excel using the four parameter fit equation y = (A+((B-A) / (l+((C / x)AD)))), which appears as equation number 205 (4 Parameter Logistic Model or Sigmoidal Dose-Response Model) in XLFit. IC50 was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control.

[0351] Results are provided in Table 2 below. In Table 2, *** represent average IC50 < 1 nM, ** represents average IC50 in the range of 1-2.5 nM, and * represents average IC50 in the range of > 2.5 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.Attorney Docket No.: INMD-221 / 01WO 315953-4549

[0352] All, documents, patents, patent applications, publications, product descriptions, and protocols which are cited throughout this application are incorporated herein by reference in their entireties for all purposes.

[0353] The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Modifications and variation of the above-described embodiments of the invention are possible without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims

Attorney Docket No.: INMD-221 / 01WO 315953-4549CLAIMS1. A method of treating an asthma disorder selected from the group consisting of neutrophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, and drug-induced asthma, in a subject in need of treatment, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof to the subject,whereinRing A is heterocyclyl optionally substituted with 1-3 R1;Y is H, alkyl, haloalkyl, NRARB, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein Y is optionally substituted with 1-3 R2;m and n are each independently 1 or 2;L is heterocyclylene, heteroarylene, alkylene, C(=O)-N(Rc), C(=O)-N(Rc)-alkylene, alkylene-O-alkylene or C(=O)-;Z is a haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, C(=O)-cycloalkyl or alkylene-aryl, wherein Z is optionally substituted with 1-3 R3;RAand RBare each alkyl, C(=O)alkyl, or S(=O)2alkyl;Rcis H or alkyl;R1is alkyl, OH, halo, Oalkyl, S(alkyl), or S(=O)2alkyl; ortwo R1with the atom they are attached to from a cycloalkyl or heterocyclyl ring; R2is alkyl, halo or OH; andR3is alkyl, halo, haloalkyl or Oalkyl.

2. A method of treating a disorder selected from the group consisting of infectious bronchitis, eosinophilic bronchitis, fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicating anti-neoplastic therapy, fibrosis complicating chronic infection, non-cystic fibrosis bronchiectasis (NCFBE), bronchiectasis associated with cystic fibrosis, sarcoidosis, farmer’ s lung, hypersensitivity pneumonitis, complications of lung transplantation, vasculitic or thrombotic disorder of the lung vasculature, pulmonary hypertension, antitussive activity, chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, perennial or seasonal allergic rhinitis, rhinitis nervosa (hay fever), nasal polyposis, acute viralAttorney Docket No.: INMD-221 / 01WO 315953-4549infection, common cold, an infection due to a respiratory virus, chronic rhinosinusitis (CRS), Hurley stage I hidradenitis suppurativa (HS), Hurley stage II HS, Hurley stage III HS, cancer, cancer-induced pain, Crohn’s disease, giant cell arteritis, polyarteritis nodosa, anti -glomerular basement membrane (anti-GBM) disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, dermatomyositis / polymyositis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, ventilator-induced lung injury, heart failure, osteoarthritis (OA), ischemia / reperfusion (IR) injury, liver injury, and sepsis in a subject in need of treatment, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof to the subject,whereinRing A is heterocyclyl optionally substituted with 1-3 R1;Y is H, alkyl, haloalkyl, NRARB, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein Y is optionally substituted with 1-3 R2;m and n are each independently 1 or 2;L is heterocyclylene, heteroarylene, alkylene, C(=O)-N(Rc), C(=O)-N(Rc)-alkylene, alkylene-O-alkylene or C(=O)-;Z is a haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, C(=O)-cycloalkyl or alkylene-aryl, wherein Z is optionally substituted with 1-3 R3;RAand RBare each alkyl, C(=O)alkyl, or S(=O)2alkyl;Rcis H or alkyl;R1is alkyl, OH, halo, Oalkyl, S(alkyl), or S(=O)2alkyl; ortwo R1with the atom they are attached to from a cycloalkyl or heterocyclyl ring; R2is alkyl, halo or OH; andR3is alkyl, halo, haloalkyl or Oalkyl.Attorney Docket No.: INMD-221 / 01WO 315953-45493. The method of claim 1 or 2, wherein the compound is a compound of Formula (la):pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

4. The method of claim 1 or 2, wherein the compound is a compound of Formula (lb):pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,6. The method of any one of claims 1-5, wherein the m is 2 and n is 2.

7. The method of any one of claims 1-5, wherein the m is 1 and n is 1.Attorney Docket No.: INMD-221 / 01WO 315953-45499. The method of any one of claims 1-8, wherein L is, wherein the asterisk (*) represents the point of attachment to Z.

11. The method of any one of claims 1-10, wherein12. The method of any one of claims 1-3, wherein R1is F, OH, SCH3, S(=O)2CH3 or CH3.Attorney Docket No.: INMD-221 / 01WO 315953-454913. The method of any one of claims 1-3, wherein two R1together with the atom to whicheach are attached form a ring selected from, wherein the asterisk (*) represents the atom to which the two R1are attached.

14. The method of any one of claims 1-13, wherein R2is CH3 or F.

15. The method of any one of claims 1-14, wherein RAand RBare each CH3, C(=0)CH3, or S(=O)2CH3.

16. The method of any one of claims 1-8, wherein Rcis H or CH3.

17. The method of any one of claims 1-16, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

18. The method of any one of claims 1-17, wherein the compound is(compoun ),Attorney Docket No.: INMD-221 / 01WO 315953-4549(compound 88A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

19. The method of any one of claims 1-18, wherein a composition comprising the compound or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered to the subject.

20. The method of claim 19, wherein the composition further comprises a pharmaceutically acceptable adjuvant, diluent or carrier.

21. The method of any one of claims 1 and 3-20, wherein the asthma disorder is neutrophilic asthma.

22. The method of any one of claims 2-20, wherein the disorder is non-cystic fibrosis bronchiectasis (NCFBE) or bronchiectasis associated with cystic fibrosis (CF).

23. The method of claim 22, wherein the disorder is non-cystic fibrosis bronchiectasis (NCFBE).

24. The method of claim 22, wherein the disorder is bronchiectasis associated with cystic fibrosis.

25. The method of any one of claims 2-20, wherein the disorder is Crohn’s disease.

26. The method of any one of claims 2-20, wherein the disorder is chronic rhinosinusitis (CRS).

27. The method of claim 26, wherein the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

28. The method of claim 26, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

29. The method of any one of claims 2-20, wherein the disorder is osteoarthritis (OA).

30. The method of any one of claims 2-20, wherein the disorder is ischemia / reperfusion (IR) injury.

31. The method of any one of claims 2-20, wherein the disorder is liver injury.

32. The method of any one of claims 31, wherein the liver injury is drug-induced liver injury.

33. The method of any one of claims 2-20, wherein the disorder is infectious bronchitis or eosinophilic bronchitis.Attorney Docket No.: INMD-221 / 01WO 315953-454934. The method of any one of claims 2-20, wherein the disorder is idiopathic interstitial pneumonia, fibrosis complicating anti -neoplastic therapy or fibrosis complicating chronic infection.

35. The method of any one of claims 2-20, wherein the disorder is fibrosing alveolitis.

36. The method of claim 35, wherein the fibrosing alveolitis is cryptogenic fibrosing alveolitis.

37. The method of claim 23 or 24, wherein treating comprises improving the lung function of the subject, as compared to the lung function of the subject prior to treatment.

38. The method of claim 37, wherein improving lung function of the subject comprises increasing the subject’s forced expiratory volume in 1 second (FEVi), increasing the subject’s forced vital capacity (FVC), increasing the subject’s peak expiratory flow rate (PEFR), or increasing the subject’s forced expiratory flow between 25% and 75% of FVC (FEF (25-75%)), as compared to the respective value for the subject prior to treatment.

39. The method of claim 37 or 38, wherein the lung function is measured by spirometry.

40. The method of any one of claims 23, 24, and 37-39, wherein the treating comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the subjectprior to treatment.

41. The method of any one of claims 23, 24, and 37-39, wherein treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated subject.

42. The method of claim 40 or 41, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the subject: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis.

43. The method of any one of claims 2-20, wherein the disorder is sarcoidosis.

44. The method of any one of claims 2-20, wherein the disorder is farmer’s lung.

45. The method of any one of claims 2-20, wherein the disorder is hypersensitivity pneumonitis.

46. The method of any one of claims 2-20, wherein the disorder is complications of lung transplantation.

47. The method of any one of claims 2-20, wherein the disorder is vasculitic or thrombotic disorder of the lung vasculature.

48. The method of any one of claims 2-20, wherein the disorder is pulmonary hypertension.Attorney Docket No.: INMD-221 / 01WO 315953-454949. The method of claim 48, wherein the pulmonary hypertension is pulmonary arterial hypertension.

50. The method of claim 48, wherein the pulmonary hypertension is pulmonary hypertension due to left heart disease.

51. The method of claim 48, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

52. The method of any one of claims 2-20, wherein the disorder is chronic cough associated with inflammatory and secretory conditions of the airways.

53. The method of any one of claims 2-20, wherein the disorder is iatrogenic cough.

54. The method of any one of claims 2-20, wherein the disorder is acute rhinitis.

55. The method of any one of claims 2-20, wherein the disorder is chronic rhinitis.

56. The method of any one of claims 2-20, wherein the disorder is rhinitis medicamentosa.

57. The method of any one of claims 2-20, wherein the disorder is vasomotor rhinitis.

58. The method of any one of claims 2-20, wherein the disorder is perennial or seasonal allergic rhinitis.

59. The method of any one of claims 2-20, wherein the disorder is rhinitis nervosa (hay fever).

60. The method of any one of claims 2-20, wherein the disorder is treating nasal polyposis.

61. The method of any one of claims 2-20, wherein the disorder is acute viral infection.

62. The method of any one of claims 2-20, wherein the disorder is common cold.

63. The method of any one of claims 2-20, wherein the disorder is an infection due to a respiratory virus.

64. The method of any one of claims 26-28, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

65. The method of any one of claims 26-28 and 64, wherein treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

66. The method of claim 65, wherein the one or more symptoms of CRS is nasal congestion; nasal obstruction; nasal discharge; post-nasal drip; facial pressure; facial pain; facial fullness; reduced smell; depression; mucosal edema; mucopurulent discharge; obstruction of the middle meatus; mucosal changes within the ostiomeatal complex and sinuses; or rhinorrhea.

67. The method of any one of claims 2-20, wherein the disorder is cancer.

68. The method of claim 67, wherein the cancer is a metastatic cancer.Attorney Docket No.: INMD-221 / 01WO 315953-454969. The method of claim 68, wherein the metastatic cancer is breast to lung metastatic cancer.

70. The method of claim 68, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

71. The method of claim 68, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

72. The method of claim 68, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, or the spleen.

73. The method of claim 68, wherein the metastatic cancer comprises metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, or the ovary.

74. The method of claim 68, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney.

75. The method of claim 68, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

76. The method of any one of claims 2-20, wherein the disorder is giant cell arteritis.

77. The method of any one of claims 2-20, wherein the disorder is polyarteritis nodosa.

78. The method of any one of claims 2-20, wherein the disorder is anti-glomerular basement membrane (anti-GBM) disease (Goodpasture’s).

79. The method of any one of claims 2-20, wherein the disorder is systemic scleroderma.

80. The method of any one of claims 2-20, wherein the disorder is diabetic nephropathy.

81. The method of any one of claims 2-20, wherein the disorder is diabetic neuropathy.

82. The method of any one of claims 2-20, wherein the disorder is diabetic retinopathy.

83. The method of any one of claims 2-20, wherein the disorder is diabetic ulcers.

84. The method of any one of claims 2-20, wherein the disorder is Duchenne muscular dystrophy.

85. The method of any one of claims 2-20, wherein the disorder is bronchiolitis obliterans.

86. The method of any one of claims 2-20, wherein the disorder is atopic dermatitis.

87. The method of any one of claims 2-20, wherein the disorder is pyoderma gangrenosum.

88. The method of any one of claims 2-20, wherein the disorder is dermatomyositis or polymyositis.

89. The method of any one of claims 2-20, wherein the disorder is thrombosis.

90. The method of claim 89, wherein the thrombosis is deep vein thrombosis (DVT).Attorney Docket No.: INMD-221 / 01WO 315953-454991. The method of any one of claims 2-20, wherein the disorder is bronchopulmonary dysplasia.

92. The method of any one of claims 2-20, wherein the disorder is amyotrophic lateral sclerosis.

93. The method of any one of claims 2-20, wherein the disorder is sickle cell anemia.

94. The method of any one of claims 2-20, wherein the disorder is psoriasis.

95. The method of any one of claims 2-20, wherein the disorder is ventilator-induced lung injury.

96. The method of any one of claims 2-20, wherein the disorder is heart failure.

97. The method of claim 96, wherein the heart failure is heart failure with reduced ejection fraction.

98. The method of claim 96, wherein the heart failure is heart failure with preserved ejection fraction.

99. The method of claim 30, wherein the subject is a heart transplant recipient.

100. The method of claim 30 or 99, wherein the IR injury is due to heart transplantation.

101. The method of any one of claims 30, 99, and 100, wherein the treating comprises improving left-ventricular (LV) graft function of the subject.

102. The method of claim 101, wherein improving left-ventricular (LV) graft function comprises improving LV systolic function of the subject.

103. The method of claim 101 or 102, wherein improving left-ventricular (LV) systolic function of the subjectcomprises improving LV systolic pressure (LVSP), developed pressure, maximal slope of systolic pressure increment (dP / dtmax), the rate pressure product (mmHg*bpm) of the subject, or a combination thereof.

104. The method of any one of claims 2-20, wherein the disorder is sepsis.

105. The method of any one of claims 1-104, wherein the effective amount of the compound or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once daily during an administration period.

106. The method of any one of claims 1-105, wherein the effective amount of the compound or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered orally.

107. The method of claim 106, wherein the compound or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered orally.

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