Uses of certain carboxamides as DPP1 inhibitors

Abstract

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

Description

Attorney Docket No.: INMD-208 / 01WO 315953-4452USES OF CERTAIN CARBOXAMIDES AS DPP1 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 659,083, filed on June 12, 2024, the content of which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND OF THE INVENTION

[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 DPP 1 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 downstreamAttorney Docket No.: INMD-208 / 01WO 315953-4452 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 W02014140075, W02014140081, and W02016038007.

[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 OF THE INVENTION

[0006] In one aspect, the present invention provides a method of treating a disease or disorder selected from Crohn’s disease, ulcerative colitis, lupus nephritis, chronic rhinosinusitis (such as chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps), hidradenitis suppurativa (HS), neutrophilic asthma, non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, pulmonary arterial hypertension, acute lung injury, acute respiratory distress syndrome (ARDS), osteoarthritis, ischemia / reperfusion (IR) injury, liver injury, 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, Kaposi’s Sarcoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, medulloblastoma, acute myeloid 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), myelodysplastic syndrome (MDS), neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, Ewing sarcoma or cancer-induced pain, the method comprising administering a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof,whereinAttorney Docket No.: INMD-208 / 01WO 315953-4452

[0010] X3is -NH-, -CH2-NH-, -NH-CH2-, -CH2-CH2-NH- or -NH-CH2-CH2-;

[0011] n is O, 1 or 2;

[0012] each R° is independently selected from halogen, -C1-6 alkyl, -OH, -OC1-6 alkyl, -NH2, - NHC1-6 alkyl, -N(CI-6 alkyl)2 or -NHC(O)CI-6 alkyl; or

[0013] two R° together with the atom they are attached to form a C3-8 cycloalkyl or heterocyclyl ring;

[0014] R3is H or halogen;

[0015] R4is H, halogen, -OH, -C1-6 haloalkyl, C3-8 cycloalkyl, -OC1-6 alkyl, -OC1-6 alkylenearyl, -OC1-6 haloalkyl, -NH2, -NHC1-6 alkyl, -N(CI-6 alkyl)2, -Ci-4 alkylene-NH-Ci-6 alkyl or - Ci-4 alkylene-N(Ci-6 alkyl)2;

[0016] R2is -O-aryl, -O-heterocyclyl, -OC1-4 alkylene-aryl, -OC1-4 alkylene-heterocyclyl, 6-18 membered aryl, 5-12 membered heterocyclyl containing 1-3 heteroatoms selected from N, S or O, or 5-20 membered heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the 6-18 membered aryl or the heterocyclyl is optionally substituted with 1-3 R5and the 5-20 membered heteroaryl is optionally substituted with 1-5 R5;

[0017] or R2and R4together with the atoms they are attached to form a cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

[0018] each R5is independently selected from H, oxo, halogen, -CN, -OH, -NO2, -NH2, - COOH, -C1-6 alkyl, OC1-6 alkyl, -OC3-6 cycloalkyl, -OC2-6 alkenyl, -OC2-6 alkynyl, -C3-6 cycloalkyl, -C2-6 alkenyl, -C2-5 alkynyl, -NHC1-6 alkyl, -N(CI-6 alkyl)2, -COC1-6 alkyl, -COOCi- 6 alkyl, -CONH2, -CONHC1-6 alkyl, -CONHC3-6 cycloalkyl, -CON(CI-6 alkyl)2, -NHCOC1-6 alkyl, -NHCOC3-5 cycloalkyl, -P(O)(Ci-6 alkyl), -S(O)Ci-6 alkyl, -S(O)2Ci-6 alkyl, -S(O)2C3-6 cycloalkyl, -SO2-(3-7 membered heterocyclyl), -S(O)NH2, -S(O)NHCI-6 alkyl, -S(O)N(CI-6 alkyl)2, -S(O)2NH2, -OSO2-C1-6 alkyl, C1-6 alkylene-O-Ci-6 alkyl, C3-8 cycloalkenyloxy, aryl, heteroaryl, 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S and O, and the R5is optionally further substituted with 1-3 groups selected from C1-6 alkyl, C1-6 haloalkyl, Ci-6-alkylene-OH, -CONH2, NH2, C1-6 alkoxy, hydroxyl, -COOH, halogen, or a 5- 7-membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the 5-Attorney Docket No.: INMD-208 / 01WO 315953-44527-membered heterocycle is optionally substituted with 1-2 groups selected from =0, halogen, cyano, Ci-6 alkyl, or Ci-6 haloalkyl.

[0019] In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt thereof:wherein, X1, X2, X3, R°, n, R2, R3and R4are defined above for Formula (I).

[0020] In one embodiment, the compound, or a pharmaceutically acceptable salt thereof, for use in one of the methods provided herein is selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the compound, or a pharmaceutically acceptable salt thereof, for use in one of the methods provided herein

[0022] In one embodiment, the method of treatment is a method for treating ulcerative colitis, lupus nephritis, chronic rhinosinusitis (such as chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps), hidradenitis suppurativa (HS), neutrophilic asthma, non- CF bronchiectasis (NCFBE), bronchiectasis associated with CF, pulmonary arterial hypertension, acute lung injury, acute respiratory distress syndrome (ARDS), osteoarthritis, ischemia / reperfusion (IR) injury, or liver injury. In one embodiment, the method of treatment is a method for treating ulcerative colitis. In one embodiment, the method of treatment is a method for treating chronic rhinosinusitis. In one embodiment, the method of treatment is a method for treating chronic rhinosinusitis with nasal polyps. In one embodiment, the method of treatment is a method for treating chronic rhinosinusitis without nasal polyps. In one embodiment, the method of treatment is a method for treating hidradenitis suppurativa (HS). In one embodiment, the method of treatment is a method for treating neutrophilic asthma. In one embodiment, the method of treatment is a method for treating non-CF bronchiectasis (NCFBE). In one embodiment, the method of treatment is a method for treating bronchiectasisAttorney Docket No.: INMD-208 / 01WO 315953-4452 associated with CF. In one embodiment, the method of treatment is a method for treating pulmonary arterial hypertension. In one embodiment, the method of treatment is a method for treating acute lung injury. In one embodiment, the method of treatment is a method for treating acute respiratory distress syndrome (ARDS). In one embodiment, the method of treatment is a method for treating osteoarthritis. In one embodiment, the method of treatment is a method for treating ischemia / reperfusion (IR) injury. In one embodiment, the method of treatment is a method for treating liver injury.

[0023] In embodiments, the effective amount of the compound or composition is administered once daily during an administration period. In embodiments, the effective amount of the compound or composition is administered orally.DETAILED DESCRIPTION OF THE INVENTION

[0024] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0025] 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.

[0026] 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” a value 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.

[0027] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0028] “Cyano” refers to the -CN radical.

[0029] “Hydroxy” or “hydroxyl” refers to the -OH radical.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0030] “ Oxo” refers to the =0 substituent.

[0031] “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.

[0032] “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.

[0033] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes Cs alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but alsoAttorney Docket No.: INMD-208 / 01WO 315953-4452 includes Cn and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1 -pentenyl, 2-pentenyl, 3 -pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3 -hexenyl, 4- hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2- undecenyl, 3 -undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11- dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0034] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethene, propene, butene, and the like. The alkenylene 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 alkenylene 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 alkenylene chain can be optionally substituted.

[0035] “ Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0036] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene 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 alkynylene 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 alkynylene chain can be optionally substituted.

[0037] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0038] “Alkylamino” refers to a radical of the formula -NHRa or -NRaRa where each Rais, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0039] “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, phenanthrene, 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.

[0040] “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.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0041] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, 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 cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0042] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, 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 cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0043] “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.

[0044] “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 twelve 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,Attorney Docket No.: INMD-208 / 01WO 315953-4452 tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 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.

[0045] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising one to thirteen 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, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, 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.

[0046] 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, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such asAttorney Docket No.: INMD-208 / 01WO 315953-4452 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.

[0047] “ 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, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SChRg, -OSO2Rg, -SChORg, =NSO2Rg, and -SO2NRgRh. “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 heteroaryl alkyl. “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.-

[0048] As used herein, the symbol “ • or « ” (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.

[0049] 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 forAttorney Docket No.: INMD-208 / 01WO 315953-4452 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] The compounds of Formula (I) or (la), 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 areAttorney Docket No.: INMD-208 / 01WO 315953-4452 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) or (la), or a pharmaceutically acceptable salt thereof. In one embodiment, a subject’s symptom(s) or clinical outcome 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.

[0054] “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) or (la) provided herein, to immediately prior to the initial administration of the pharmaceutical composition or compound of Formula (I) or (la). “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) or (la) provided herein.

[0055] 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.

[0056] 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 days prior 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.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0057] As used herein, the terms “treatment”, “treating,” “ameliorating” and variations thereof, are used interchangeably. These terms 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 patient 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).

[0058] 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. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like.

[0059] 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.

[0060] The present invention provides a method of treating a disease or disorder selected from Crohn’s disease, ulcerative colitis, lupus nephritis, chronic rhinosinusitis (such as chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps), hidradenitis suppurativa (HS), neutrophilic asthma, non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, pulmonary arterial hypertension, acute lung injury, acute respiratory distress syndrome (ARDS), osteoarthritis, ischemia / reperfusion (IR) injury, liver injury, bladder cancer, liver cancer, fibroid cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma,Attorney Docket No.: INMD-208 / 01WO 315953-4452Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma, Kaposi’s Sarcoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, medulloblastoma, acute myeloid 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), myelodysplastic syndrome (MDS), neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, Ewing sarcoma or cancer-induced pain. In one embodiment, the method comprises administering a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof,

[0062] X1is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2-CH2- or -CH2-CH2-O-;

[0063] X2is -CH2- or -CH2-CH2-;

[0064] X3is -NH-, -CH2-NH-, -NH-CH2-, -CH2-CH2-NH- or -NH-CH2-CH2-;

[0065] n is 0, 1 or 2;

[0066] each R° is independently selected from halogen, -C1-6 alkyl, -OH, -OC1-6 alkyl, -NH2, - NHC1-6 alkyl, -N(CI-6 alkyl)2 or -NHC(O)CI-6 alkyl; or

[0067] two R° together with the atom they are attached to form a C3-8 cycloalkyl or heterocyclyl ring;

[0068] R3is H or halogen;

[0069] R4is H, halogen, -OH, -C1-6 haloalkyl, -C3-8 cycloalkyl, -OC1-6 alkyl, -OC1-6 alkylenearyl, -OC1-6 haloalkyl, -NH2, -NHC1-6 alkyl, -N(CI-6 alkyl)2, -Ci-4 alkylene-NH-Ci-6 alkyl or - Ci-4 alkylene-N(Ci-6 alkyl)2;

[0070] R2is -O-aryl, -O-heterocyclyl, -OC1-4 alkylene-aryl, -OC1-4 alkylene-heterocyclyl, 6-18 membered aryl, 5-12 membered heterocyclyl containing 1-3 heteroatoms selected from N, S or O, or 5-20 membered heteroaryl containing 1-3 heteroatoms selected from N, S or O, whereinAttorney Docket No.: INMD-208 / 01WO 315953-4452 the 6-18 membered aryl or the heterocyclyl is optionally substituted with 1-3 R5and the 5-20 membered heteroaryl is optionally substituted with 1-5 R5;

[0071] or R2and R4together with the atoms they are attached to form a cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring; and

[0072] each R5is independently selected from H, oxo, halogen, -CN, -OH, -NO2, -NH2, - COOH, -C1-6 alkyl, OC1-6 alkyl, -OC3-6 cycloalkyl, -OC2-6 alkenyl, -OC2-6 alkynyl, -C3-6 cycloalkyl, -C2-6 alkenyl, -C2-5 alkynyl, -NHC1-6 alkyl, -N(CI-6 alkyl)2, -COC1-6 alkyl, -COOCi- 6 alkyl, -CONH2, -CONHC1-6 alkyl, -CONHC3-6 cycloalkyl, -CON(CI-6 alkyl)2, -NHCOC1-6 alkyl, -NHCOC3-5 cycloalkyl, -P(O)(Ci-6 alkyl), -S(O)Ci-6 alkyl, -S(O)2Ci-6 alkyl, -S(O)2C3-6 cycloalkyl, -SO2-(3-7 membered heterocyclyl), -S(O)NH2, -S(O)NHCI-6 alkyl, -S(O)N(CI-6 alkyl)2, -S(O)2NH2, -OSO2-C1-6 alkyl, C1-6 alkylene-O-Ci-6 alkyl, C3-8 cycloalkenyloxy, aryl, heteroaryl, 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S and O, and the R5is optionally further substituted with 1-3 groups selected from C1-6 alkyl, C1-6 haloalkyl, Ci-6-alkylene-OH, -CONH2, NH2, C1-6 alkoxy, hydroxyl, -COOH, halogen, or a 5- 7-membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the 5- 7-membered heterocycle is optionally substituted with 1-2 groups selected from =0, halogen, cyano, C1-6 alkyl, or C1-6 haloalkyl.

[0073] In one embodiment of a method disclosed herein, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt thereof:wherein, X1, X2, X3, R°, n, R2, R3and R4are defined above for Formula (I).

[0074] In one embodiment of a method provided herein, R2is 6-18 membered aryl optionally substituted with 1-3 R5.

[0075] In one embodiment of a method provided herein, R2is phenyl optionally substituted with 1-3 R5. In embodiments,Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0076] In one embodiment of a method disclosed herein, R2is 5-12 membered heterocyclyl containing 1-3 heteroatoms selected from N, S or O, wherein the heterocyclyl is optionallyAtorney Docket No.: INMD-208 / 01WO 315953-4452Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0077] In one embodiment of a method provided herein, R2is 5-20 membered heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the heteroaryl is optionally substituted with 1-5 R5.

[0078] In one embodiment of a method provided herein, R2is 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R5. In one embodiments,Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0079] In one embodiment of a method disclosed herein, R2is 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl

[0080] In one embodiment of a method disclosed herein, R2is 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R5.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0081] In one embodiment of a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, for use in a method provided herein,VandW are each independently CH or N; D-E is N(H)-C(=O), N(Ci-ealkyl)-C(=O), CH2CH2, C(=O)-O or CH2-O; R6is H, Ci-ealkyl, alkylene-O-alkyl, or heterocyclyl; and i and j are each independently 1, 2 or 3; provided that the sum of i+j is 2, 3 or 4.

[0082] In one embodiment of a method disclosed herein,Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0084] In one embodiment of a method disclosed herein, R2and R4together with the atoms they are attached to form a cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring.

[0085] In one embodiment of a method disclosed herein, R2and R4together with the atoms they are attached to form a monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic aryl, monocyclic heterocyclyl or monocyclic heteroaryl ring.

[0086] In one embodiment of a method disclosed herein,

[0087] In one embodiment of a method disclosed herein, R2and R4together with the atoms they are attached to form a bicyclic cycloalkyl, bicyclic cycloalkenyl, bicyclic aryl, bicyclic heterocyclyl or bicyclic heteroaryl ring.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0088] In one embodiment of a method disclosed herein,Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0089] In one embodiment of a method disclosed herein, R2is -O-alkyl, -O-heterocyclyl, -OCi-4 alkylene-aryl, or -OC1-4 alkylene-heterocyclyl. In one embodiment,

[0090] In one embodiment of a method disclosed herein, R1is

[0091] In one embodiment of a method disclosed herein, R1isone embodiment of a method disclosedAttorney Docket No.: INMD-208 / 01WO 315953-4452

[0092] In one embodiment of a method disclosed herein, R1embodiment of a method disclosed herein,

[0093] In one embodiment of a method disclosed herein, R1is

[0094] In one embodiment of a method disclosed herein,

[0095] In one embodiment of a method disclosed herein,oneAttorney Docket No.: INMD-208 / 01WO 315953-4452

[0096] In one embodiment of a method disclosed herein, n is 0.

[0097] In one embodiment of a method disclosed herein, R3is H.

[0098] In one embodiment of a method disclosed herein, R3is F, Cl or Br. In one embodiment of a method disclosed herein, R3is F.

[0099] In one embodiment of a method disclosed herein, R4is H, F, Cl, Br or -OCi-6 alkylenearyl.

[0100] In one embodiment of a method disclosed herein,

[0101] 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 thereof.Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0102] In one embodiment of a method disclosed herein, the compound ispharmaceutically acceptable salt thereof.

[0103] In embodiment,pharmaceutically acceptable salt thereof, is administered to treat a disease or disorder is selected from Crohn’s disease, ulcerative colitis, lupus nephritis, chronic rhinosinusitis, hidradenitis suppurativa(HS), neutrophilic asthma, non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, pulmonary arterial hypertension, acute lung injury, acute respiratory distress syndrome (ARDS), osteoarthritis, ischemia / reperfusion (IR) injury, liver injury, deep vein thrombosis (DVT), sepsis, 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,Attorney Docket No.: INMD-208 / 01WO 315953-4452 ependymoma, meningioma, schwannoma, or medulloblastoma, acute myeloid 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 or cancer-induced pain.

[0104] In one embodiment, the disease or disorder is Crohn’s disease, ulcerative colitis, lupus nephritis, chronic rhinosinusitis, hidradenitis suppurativa (HS), neutrophilic asthma, non-CF bronchiectasis (NCFBE) or bronchiectasis associated with CF. In one embodiment, the disease or disorder is Crohn’s disease. In one embodiment, the disease or disorder is ulcerative colitis. In one embodiment, the disease or disorder is chronic rhinosinusitis. In one embodiment, the disease or disorder is hidradenitis suppurativa (HS). In one embodiment, the disease or disorder is non-CF bronchiectasis (NCFBE). In one embodiment, the disease or disorder is bronchiectasis associated with CF.

[0105] A person skilled in the art would be capable of preparing the compounds of Formula (I) or (la) 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.

[0106] 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, New York, 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 IntermediateAttorney Docket No.: INMD-208 / 01WO 315953-4452Text” (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.

[0107] 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.

[0108] In the methods provided herein, the compounds of Formula (I) or (la), 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 compound of Formula (I) or (la), or a pharmaceutically acceptable salts thereof (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.

[0109] The compounds of Formula (I) or (la), or pharmaceutically acceptable salts 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 theAttorney Docket No.: INMD-208 / 01WO 315953-4452Turbuhaler®; 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.

[0110] 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.[OHl] For oral administration the compound of Formula (I) or (la), or pharmaceutically acceptable salts 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.

[0112] For the preparation of soft gelatine capsules, the compounds of Formula (I) or (la), 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.

[0113] 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 such liquid 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.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0114] The dosage administered will vary with the compound of Formula (I) or (la), 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), or (la), 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), or (la), 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).

[0115] The compounds of Formula (I) or (la), 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 compound of Formula (I) or (la), or a pharmaceutically acceptable salts thereof (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.

[0116] Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent 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.

[0117] As discussed herein, in one aspect, the invention provides methods of treating ulcerative colitis, lupus nephritis, chronic rhinosinusitis (such as chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps), hidradenitis suppurativa (HS), neutrophilic asthma, non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, pulmonary arterial hypertension, acute lung injury, acute respiratory distress syndrome (ARDS), 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, acute myeloid 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),Attorney Docket No.: INMD-208 / 01WO 315953-4452 mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS), neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma or cancer-induced pain.

[0118] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating Crohn’s disease.

[0119] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating ulcerative colitis.

[0120] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating lupus nephritis.

[0121] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating chronic rhinosinusitis (CRS). In one embodiment, the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP), or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic rhinosinusitis is refractory chronic rhinosinusitis. In some embodiments, the refractory chronic rhinosinusitis is refractory chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the refractory chronic rhinosinusitis is refractory chronic rhinosinusitis with nasal polyps (CRSwNP).

[0122] 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.

[0123] In some embodiments, the administration of the pharmaceutical composition 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 andAttorney Docket No.: INMD-208 / 01WO 315953-4452 sinuses; (n) rhinorrhea; (o) or any combinations thereof. In some embodiments, the administration of the pharmaceutical composition enhances sinus drainage.

[0124] 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, reduced smell, rhinorrhea, or any combination thereof. In some embodiments, the rhinorrhea is anterior rhinorrhea. In some embodiments, the rhinorrhea is posterior rhinorrhea.

[0125] 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.

[0126] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating hidradenitis suppurativa (HS).

[0127] 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,Attorney Docket No.: INMD-208 / 01WO 315953-4452 psychological and emotional well-being. In fact, HS patients have increased rates of anxiety and depression with a risk of suicide two and a half times that of the general population.

[0128] HS patients 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.

[0129] In one aspect, a method of treating HS in a subject in need thereof is provided. The method comprises in one embodiment, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0130] The HS in one embodiment, is Hurley Stage I HS, Hurley Stage II HS or Hurley Stage III HS. In some embodiments, the HS is Hurley Stage I HS. In some embodiments, the HS is Hurley Stage II HS. In some embodiments, the HS is Hurley Stage III HS.

[0131] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating neutrophilic asthma.

[0132] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating non-cystic fibrosis bronchiectasis (NCFBE).

[0133] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating bronchiectasis associated with CF.

[0134] 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 DPP 1. Without wishing to be bound by theory, it is thought that the compounds of Formula (I), or (la), administered via the methodsAttorney Docket No.: INMD-208 / 01WO 315953-4452 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 an improvement in lung function (e.g., forced expiratory volume in 1 second [FEVi]) in CF patients.

[0135] 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).

[0136] The methods provided herein employ reversible inhibitors of DPP 1. Without wishing to be bound by theory, it is thought that the compounds of Formula (I) or (la), 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 patients. 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.

[0137] In one embodiment, the method for treating non-cystic fibrosis bronchiectasis (NCFBE) or bronchiectasis associated with CF comprises improving lung function of the patient during the administration period, as compared to the lung function of the patient prior to the administration period.

[0138] A pulmonary exacerbation, in one embodiment, is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (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)Attorney Docket No.: INMD-208 / 01WO 315953-4452 hemoptysis. In a further embodiment, the three or more symptoms result in a physician’s decision to prescribe an antibiotic(s) to the patient exhibiting the symptoms.

[0139] In one embodiment of a method for treating non-cystic fibrosis bronchiectasis (NCFBE) or bronchiectasis associated with CF, the method comprises decreasing the rate of pulmonary exacerbation in the subject, compared to the rate of pulmonary exacerbation experienced by the subject prior to the administration period of the composition, or compared to a control subject with bronchiectasis that is not subject to the method of treatment.

[0140] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating pulmonary arterial hypertension.

[0141] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating acute lung injury.

[0142] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating acute respiratory distress syndrome (ARDS).

[0143] In one embodiment, the treatment methods provided herein comprise improving the lung function of the patient during the administration period, as compared to the lung function of the patient 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.

[0144] Improving the lung function of the patient, in one embodiment, comprises increasing the patient’s forced expiratory volume in 1 second (FEVi), increasing the patient’s forced vital capacity (FVC), increasing the patient’s peak expiratory flow rate (PEFR), or increasing the patient’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% toAttorney Docket No.: INMD-208 / 01WO 315953-4452 about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%.

[0145] 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.

[0146] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating osteoarthritis. In embodiments, the treating of osteoarthritis (OA) comprises improving weight loss and / or inflamed paw volume of the patient during the administration period, as compared to the weight loss and / or inflamed paw volume of the patient prior reducing weight loss and / or inflamed paw volume of the patient during the administration period, as compared to the weight loss and / or inflamed paw volume of the patient prior to the administration period.

[0147] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating ischemia / reperfusion (IR) injury. The IR injury, in one embodiment, is due to Heart transplantation (HTX). As such, in one embodiment, the patient is a heart transplant recipient. In a further embodiment, the patient 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 patient is administered one of the compounds set forth in Tables A-C. In yet even a further embodiment, the compound is present in an oral composition and is administered once daily to the patient in need of treatment.

[0148] 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).

[0149] In one embodiment, treating IR injury comprises increasing the patient’s LVSP (mmHg) during or subsequent to the administration period, as compared to the patient’s LVSP (mmHg) prior to the administration period. In one embodiment, treating IR injury comprises increasing the patient’s developed pressure (mmHg) during or subsequent to the administration period, as compared to the patient’ s developed pressure (mmHg) prior to the administration period. In yet another embodiment, treating IR injury in a patient in need of treatment comprises increasingAttorney Docket No.: INMD-208 / 01WO 315953-4452 the maximal slope of systolic pressure increment (dP / dtmax) for the patient during or subsequent to the administration period, as compared to the maximal slope of systolic pressure increment (dP / dtmax) for the patient prior to the administration period. In even yet another embodiment, treating IR injury in a patient in need of treatment comprises increasing the patient’s rate pressure product during or subsequent to the administration period, as compared to the patient’s rate pressure product prior to the administration period.

[0150] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating liver injury. In embodiments, the liver injury is acute liver injury (ALI). In embodiments, the liver injury is drug-induced acute liver injury. In one embodiment, the liver injury is acetaminophen (APAP)-induced acute liver injury. In one embodiment, the liver injury is caused by acetaminophen 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.

[0151] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating deep vein thrombosis (DVT).

[0152] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating sepsis. In one embodiment, sepsis is a consequence of the patient’s response to overwhelming bacterial infection. In one embodiment, the treatment of sepsis prevents organ dysfunction and death of the patient.

[0153] In one embodiment, a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, is administered to a patient for treating a cancer selected from 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 , acute myeloid 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), andAttorney Docket No.: INMD-208 / 01WO 315953-4452 myelodysplastic syndrome (MDS), neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma.

[0154] 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.

[0155] In some embodiments, the cancer is metastatic cancer. In some embodiments, the subject is at a risk for developing metastatic cancer. In some embodiments, the metastatic cancer comprises metastasis of bone cancer to the lung. In some embodiments, the metastatic cancer comprises metastasis of a leukemia to the lymph nodes, the lung, the liver, the hind limb, the brain, the kidney, and / or the spleen. In some embodiments, the metastatic cancer comprises metastasis of liver cancer to the intestine, the spleen, the pancreas, the stomach, the lung, and / orAttorney Docket No.: INMD-208 / 01WO 315953-4452 the kidney. In some embodiments, the metastatic cancer comprises metastasis of a lymphoma to the kidney, the ovary, the liver, the bladder, and / or the spleen.

[0156] In some embodiments, the metastatic cancer comprises metastasis of bladder cancer to the bone, the liver and / or the lung. In some embodiments, the metastatic cancer comprises metastasis of thyroid cancer to the bone, the liver and / or the lung.

[0157] In some embodiments, the methods disclosed herein comprise treating cancer-induced bone pain (CIBP) in a subject having metastasis of a cancer to the bone. In some embodiments, the subject has metastasis of prostate cancer, breast cancer, 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.

[0158] In some embodiments, administration of the composition 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.

[0159] In one embodiment, the invention relates to a method for treating cancer-induced pain. In one embodiment of the method disclosed herein, the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof is administered to a patient 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.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[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 patient.

[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 be administered 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 fromAttorney Docket No.: INMD-208 / 01WO 315953-4452 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) or (la) or a pharmaceutically acceptable salt thereof once daily during the administration period. In another embodiment, the patient is administered the the compound of formula (I) or (la) or a pharmaceutically acceptable salt 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 Formula (I) or (la) is administered 2* daily during the administration period. In yet another embodiment, the composition comprising an effective amount of Formula (I) or (la) is administered l x per week, every other day, every third day, 2x per week, 3x 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. In embodiments, the effective amount of the compound or composition is administered once daily during an administration period. In embodiments, the effective amount of the compound or composition is administered orally.EXAMPLES

[0167] The present disclosure is further illustrated by reference to the following Examples. However, it should be noted that the Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0168] Example 1: IC50 assay

[0169] Mouse DPP1 enzyme IC50 assay: Test articles were applied to active mouse DPP1 enzyme (R&D Systems; Minneapolis, MN) in Assay Buffer (50 mM MES pH 5.5, 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 active mouse DPP1 enzyme at a concentration of 62.5 pg / 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 recombinant active mouse 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. Results are provided in Table 1 below.

[0170] Human DPP1 enzyme IC50 assay: 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 eachAttorney Docket No.: INMD-208 / 01WO 315953-4452Parameter. IC50 was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control. Results are provided in Table 1 below.

[0171] DPP1 Cell IC50 assay: 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 IxlO6cells 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. Results are provided in Table 2 below.Attorney Docket No.: INMD-208 / 01WO 315953-4452

[0172] 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.

[0173] 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-208 / 01WO 315953-4452CLAIMS1. A method of treating a disease or disorder selected from Crohn’s disease, ulcerative colitis, lupus nephritis, chronic rhinosinusitis, hidradenitis suppurativa (HS), neutrophilic asthma, non-CF bronchiectasis (NCFBE), bronchiectasis associated with CF, pulmonary arterial hypertension, acute lung injury, acute respiratory distress syndrome (ARDS), osteoarthritis, ischemia / reperfusion (IR) injury, liver injury, 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, Kaposi’s Sarcoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, medulloblastoma, acute myeloid 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), myelodysplastic syndrome (MDS), neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, Ewing sarcoma or cancer-induced pain, the method comprising administering a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof,wherein:X1is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2-CH2- or -CH2-CH2-O-;X2is -CH2- or -CH2-CH2-;X3is -NH-, -CH2-NH-, -NH-CH2-, -CH2-CH2-NH- or -NH-CH2-CH2-; n is 0, 1 or 2;Attorney Docket No.: INMD-208 / 01WO 315953-4452 each R° is independently selected from halogen, -Ci-6 alkyl, -OH, -OCi-6 alkyl, -NH2, -NHC1-6 alkyl, -N(CI-6 alkyl)2 or -NHC(O)CI-6 alkyl; or two R° together with the atom they are attached to form a C3-8 cycloalkyl or heterocyclyl ring;R3is H or halogen;R4is H, halogen, -OH, -C1-6 haloalkyl, -C3-8 cycloalkyl, -OC1-6 alkyl, -OC1-6 alkylenearyl, -OC1-6 haloalkyl, -NH2, -NHC1-6 alkyl, -N(CI-6 alkyl)2, -Ci-4 alkylene-NH-Ci-6 alkyl or - Ci-4 alkylene-N(Ci-6 alkyl)2;R2is -O-aryl, -O-heterocyclyl, -OC1-4 alkylene-aryl, -OC1-4 alkylene-heterocyclyl, 6-18 membered aryl, 5-12 membered heterocyclyl containing 1-3 heteroatoms selected from N, S or O, or 5-20 membered heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the 6-18 membered aryl or the heterocyclyl is optionally substituted with 1-3 R5and the 5-20 membered heteroaryl is optionally substituted with 1-5 R5; or R2and R4together with the atoms they are attached to form a cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring; and each R5is independently selected from H, oxo, halogen, -CN, -OH, -NO2, -NH2, - COOH, -C1-6 alkyl, OC1-6 alkyl, -OC3-6 cycloalkyl, -OC2-6 alkenyl, -OC2-6 alkynyl, -C3-6 cycloalkyl, -C2-6 alkenyl, -C2-5 alkynyl, -NHC1-6 alkyl, -N(CI-6 alkyl)2, -COC1-6 alkyl, -COOCi- 6 alkyl, -CONH2, -CONHC1-6 alkyl, -CONHC3-6 cycloalkyl, -CON(CI-6 alkyl)2, -NHCOC1-6 alkyl, -NHCOC3-5 cycloalkyl, -P(O)(Ci-6 alkyl), -S(O)Ci-6 alkyl, -S(O)2Ci-6 alkyl, -S(O)2C3-6 cycloalkyl, -SO2-(3-7 membered heterocyclyl), -S(O)NH2, -S(O)NHCI-6 alkyl, -S(O)N(CI-6 alkyl)2, -S(O)2NH2, -OSO2-C1-6 alkyl, C1-6 alkylene-O-Ci-6 alkyl, C3-8 cycloalkenyloxy, aryl, heteroaryl, 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S and O, and the R5is optionally further substituted with 1-3 groups selected from C1-6 alkyl, C1-6 haloalkyl, Ci-6-alkylene-OH, -CONH2, NH2, C1-6 alkoxy, hydroxyl, -COOH, halogen, or a 5- 7-membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the 5- 7-membered heterocycle is optionally substituted with 1-2 groups selected from =0, halogen, cyano, C1-6 alkyl, or C1-6 haloalkyl.

2. The method of claim 1, wherein the compound is a compound of Formula (la)Attorney Docket No.: INMD-208 / 01WO 315953-4452 or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein R2is 6-18 membered aryl optionally substituted with 1-3 R5.

4. The method of any one of claims 1-3, wherein R2is phenyl optionally substituted with 1-3 R5.

5. The method of any one of claims 1-4, wherein R2isAtorney Docket No.: INMD-208 / 01WO 315953-44526. The method of claim 1 or 2, wherein R2is 5-12 membered heterocyclyl containing 1-3 heteroatoms selected from N, S or O, wherein the heterocyclyl is optionally substituted with 1- 3 R5.Attorney Docket No.: INMD-208 / 01WO 315953-44528. The method of claim 1 or 2, wherein R2is 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R5.Atorney Docket No.: INMD-208 / 01WO 315953-4452Atorney Docket No.: INMD-208 / 01WO 315953-4452Attorney Docket No.: INMD-208 / 01WO 315953-4452containing 1-3 heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R5.Attorney Docket No.: INMD-208 / 01WO 315953-445212. The method of claim 1 or 2, wherein R2is 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R5.

13. The method of any one of claims 1, 2 and 12, wherein:Attorney Docket No.: INMD-208 / 01WO 315953-4452U, V and W are each independently CH or N;D-E is N(H)-C(=O), N(Ci-6alkyl)-C(=O), CH2CH2, C(=0)-0 or CH2-O;R6is H, Ci-ealkyl, alkylene-O-alkyl, or heterocyclyl; and i and j are each independently 1, 2 or 3; provided that the sum of i+j is 2, 3 or 4.Attorney Docket No.: INMD-208 / 01WO 315953-445215. The method of any one of claims 1, 2 and 12-14, wherein16. The method of claim 1 or 2, wherein R2and R4together with the atoms they are attached to form a cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring.

17. The method of claim 1 or 16, wherein R2and R4together with the atoms they are attached to form a monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic aryl, monocyclic heterocyclyl or monocyclic heteroaryl ring.

18. The method of any one claims 1, 16, and 17, whereinFormula (I) is19. The method of claim 1 or 16, wherein R2and R4together with the atoms they are attached to form a bicyclic cycloalkyl, bicyclic cycloalkenyl, bicyclic aryl, bicyclic heterocyclyl or bicyclic heteroaryl ring.Atorney Docket No.: INMD-208 / 01WO 315953-4452Attorney Docket No.: INMD-208 / 01WO 315953-445221. The method of claim 1 or 2, wherein R2is -O-alkyl, -O-heterocyclyl, -OC1-4 alkylene- aryl, or -OCi-4 alkylene-heterocyclyl.

22. The method of any one of claims 1, 2 and 21, wherein R2is23. The method of any one of claims 1 and 3-22, wherein R1is24. The method of any one of claims 1-23, wherein R1isThe method of any one of claims 1-24, wherein R1isAttorney Docket No.: INMD-208 / 01WO 315953-445227. The method of any one of claims 1 and 3-22, wherein28. The method of any one of claims 1, 3-22 and 27, wherein29. The method of claim 28, wherein R130. The method of any one of claims 1-27, wherein n is 0.

31. The method of any one of claims 1-28, wherein R3is H.

32. The method of any one of claims 1-28, wherein R3is F, Cl or Br.

33. The method of any one of claims 1-28 and 30, wherein R3is F.

34. The method of any one of claims 1-33, wherein R4is H, F, Cl, Br or -OCi-6 alkylenearyl.

36. The method of claim 1, wherein37. The method of claim 1, wherein the compound is any one of the compounds selected from Table 1, or a pharmaceutically acceptable salt thereof.Attorney Docket No.: INMD-208 / 01WO 315953-445238. The method of claim 1, wherein the compound ior a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 1-38, wherein the disease or disorder is Crohn’s disease.

40. The method of any one of claims 1-38, wherein the disease or disorder is ulcerative colitis.

41. The method of any one of claims 1-38, wherein the disease or disorder is lupus nephritis.

42. The method of any one of claims 1-38, wherein the disease or disorder is chronic rhinosinusitis.

43. The method of claim 42, wherein the disease or disorder is chronic rhinosinusitis with nasal polyps.

44. The method of claim 42, wherein the disease or disorder is chronic rhinosinusitis without nasal polyps.

45. The method of any one of claims 1-38, wherein the disease or disorder is hi dradenitis suppurativa (HS).

46. The method of any one of claims 1-38, wherein the disease or disorder is neutrophilic asthma.

47. The method of any one of claims 1-38, wherein the disease or disorder is non-CF bronchiectasis (NCFBE).

48. The method of any one of claims 1-38, wherein the disease or disorder is bronchiectasis associated with CF.

49. The method of any one of claims 1-38, wherein the disease or disorder is pulmonary arterial hypertension.

50. The method of any one of claims 1-38, wherein the disease or disorder is acute lung injury.

51. The method of any one of claims 1-38, wherein the disease or disorder is acute respiratory distress syndrome (ARDS).

52. The method of any one of claims 1-38, wherein the disease or disorder is osteoarthritis.

53. The method of any one of claims 1-38, wherein the disease or disorder is ischemia / reperfusion (IR) injury.Attorney Docket No.: INMD-208 / 01WO 315953-445254. The method of claim 53, wherein the subject is a heart transplant recipient.

55. The method of claim 53 or 54, wherein the IR injury is due to heart transplantation.

56. The method of any one of claims 53-55, wherein the treating comprises improving left- ventricular (LV) graft function of the patient.

57. The method of claim 56, wherein improving left-ventricular (LV) graft function comprises improving LV systolic function of the patient.

58. The method of claim 57, wherein improving left-ventricular (LV) systolic function of the patient comprises improving LV systolic pressure (LVSP), developed pressure, maximal slope of systolic pressure increment (dP / dtmax), the rate pressure product (mmHg*bpm) of the patient, or a combination thereof.

59. The method of any one of claims 1-38, wherein the disease or disorder is liver injury.

60. The method of claim 59, wherein the liver injury is acute liver injury.

61. The method of claim 59, wherein the liver injury is drug-induced acute liver injury.

62. The method of any one of claims 1-38, wherein the disease or disorder 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 , acute myeloid 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.

63. The method of any one of claims 1-38, wherein the disease or disorder is cancer- induced pain.

64. The method of claim 63, wherein the disease or disorder is cancer-induced bone pain.

65. The method of any one of claims 1-64, wherein the effective amount of the compound or composition is administered once daily during an administration period.

66. The method of any one of claims 1-64, wherein the effective amount of the compound or composition is administered orally.

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