dihydropyrimidopyrimidines

Abstract

The present disclosure describes novel dihydropyrimidopyrimidines which are useful as proteinase 3 (PR3) and / or human neutrophil elastase (HNE) inhibitors. The dihydropyrimidopyrimidine compounds of the disclosure can be fused with another heteroaromatic ring. The compounds are believed to be useful for treatment of inflammatory diseases, including chronic obstructive pulmonary disease.

Description

Attorney Docket No.: 064191-501001WO DIHYDROPYRIMIDOPYRIMIDINES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 660,931, filed on June 17, 2024, which is incorporated herein by reference in its entirety for all purposes. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to proteinase 3 (PR3) and / or human neutrophil elastase (HNE) inhibitors, pharmaceutical compositions, and methods of synthesis thereof. The inhibitors are believed to be useful for the treatment of inflammatory diseases, including chronic obstructive pulmonary disease. BACKGROUND OF THE INVENTION

[0003] Neutrophil extracellular traps (NETs) are made of a network of extracellular strings of DNA that bind pathogenic microbes. Histones and several neutrophil granule proteinsassociated with the DNA framework damage entrapped microorganisms. Neutrophil elastase(NE) is a serine protease stored in the azurophilic granules of neutrophils and released into the extracellular milieu during inflammatory response or formation of neutrophil extracellular traps (NETs).

[0004] Human leukocyte elastase (HLE, EC 3.4.21.37), also called human neutrophil elastase (HNE, hNE), belongs to the family of the serine proteases. The proteolytic enzyme is found in the azurophilic granules of polymorphonuclear leukocytes (PMN leukocytes). Intracellular elastase performs an important function in defense against pathogens by breaking down the foreign particles taken by phagocytosis. Activated neutrophilic cells release the HNE from the granules into the extracellular space (extracellular HNE), with some of the released HNE remaining on the outside of the neutrophilic cell membrane (membrane-associated HNE). The highly active enzyme is believed to be capable of breaking down a large number of connective tissue proteins, for example the proteins elastin, collagen and fibronectin. Elastin occurs in high concentrations in many tissue types showing high elasticity, for example in the lung and the arteries. HNE is believed to be involved in the tissue breakdown and transformation (tissue remodeling) associated with a large number ofpathological processes (for example tissue injuries). HNE has also been shown to be a modulator of inflammatory processes. HNE has been shown to induce for example increased interleukin-8 (IL-8) gene expression.

[0005] Accordingly, it is believed that HNE plays an important role in many disorders, injuries and pathological changes whose formation and / or progression are / is associated with inflammatory events and / or proliferative and hypertrophic tissue and vessel transformation. This can be in particular disorders and / or injuries of the lung or the cardiovascular system, or it may be sepsis, cancerous disorders or other inflammatory disorders. HNE inhibitors have been reported. See, e.g., US Patent Nos. 8,569,314 and 9,359,362; and von Nussbaum, F. et al. ChemMedChem 2015; 10(7): 1163-1173.

[0006] Proteinase 3 (PR3) is another neutrophil serine protease whose pathophysiological role is believed to be related to that of HNE. PR3 has also been identified as a potential drug target, suggesting that dual inhibition of both enzymes may be beneficial for a number of pathologies. While a few nonpeptidic inhibitors of PR3 have been reported, none have progressed to clinical trials. The resemblance of the two enzymes in terms of sequence (57% sequence identity) and structure suggests that existing HNE inhibitors could form the basis for dual inhibitors of both HNE and PR3. Nevertheless, successful development of PR3 / HNE dual inhibitors has been challenging. Limited studies have been published in development of PR3 / HNE dual inhibitors. See, e.g., Gartan, et al. Investigating Polypharmacology Through Targeting Known Human Neutrophil Elastase Inhibitors to Proteinase 3. ChemRxiv. 2023; doi:10.26434 / chemrxiv-2023-f32t3.

[0007] There remains a need to develop inhibitors of PR3 and / or HNE for use in treating inflammatory diseases such as chronic obstructive pulmonary disease. BRIEF SUMMARY OF THE INVENTION

[0008] Provided herein are compounds of Formula J:and pharmaceutically acceptable salts thereof, wherein R1is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R1a;each R1ais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; R2is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R2a; each R2ais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; each R3is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; each Raand Rbis independently H, C1-6alkyl, or C3-C8cycloalkyl; or Raand Rbtogether with the nitrogen to which they are connected form a 3- to 8-membered heterocyclyl; each R4is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, thioxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; or two R4on adjacent atoms together with the atoms to which they are connected form a heteroaryl, which is substituted with 0, 1, 2, or 3 R4a; each R4ais independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-15cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1- 8 haloalkyl), -NH(C2-6alkenyl), -NH(C2-6alkynyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10aryl)2, -N(heteroaryl)2, -N(C1-9alkyl)(C1-8haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3- 15 cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(heteroaryl), -C(O)(C1-9alkyl), -C(O)(C1-8haloalkyl), -C(O)(C2-6alkenyl), -C(O)(C2-6alkynyl), -C(O)(C3-15cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10aryl), - C(O)(heteroaryl), -C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(heterocyclyl), - C(O)O(C6-10aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9alkyl)2, -C(O)N(C1-8haloalkyl)2, -C(O)N(C2-6alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(heterocyclyl)2, - C(O)N(C6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6alkenyl), -NHC(O)(C2-6alkynyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), - NHS(O)2(C1-9 alkyl), -N(C1-9 alkyl)(S(O)2(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(C2-6alkenyl), -S(C2-6alkynyl), -S(C3-15cycloalkyl), -S(heterocyclyl), - S(C6-10aryl), -S(heteroaryl), -S(O)N(C1-9alkyl)2, -S(O)(C1-9alkyl), -S(O)(C1-8haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), - S(O)(heterocyclyl), -S(O)(C6-10 aryl), -S(O)(heteroaryl), -S(O)2(C1-9 alkyl), -S(O)2(C1- 8 haloalkyl), -S(O)2(C2-6alkenyl), -S(O)2(C2-6alkynyl), -S(O)2(C3-15cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C1-9alkyl, C1-8haloalkyl, halogen, -OH, -NH2, CO2H,-O(C1-9alkyl), -O(C1-8haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(aryl), - NH(heteroaryl), -N(C1-9alkyl)2, -N(C3-15cycloalkyl)2, -NHC(O)(C1-8haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15cycloalkyl), - NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C3-15 cycloalkyl), - S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; subscript n is 1 or 2; and subscript m is 1 or 2.

[0009] In some embodiments, a pharmaceutical composition of the present invention is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable excipient.

[0010] In some embodiments, a method of the present invention is a method of inhibiting proteinase 3 (PR3) and / or human neutrophil elastase (HNE) in a cell, comprising administering to the cell an effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0011] In some embodiments, a method of the present invention is a method of treating a disease or condition characterized by an elevated level of proteinase 3 (PR3) and / or human neutrophil elastase (HNE) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. In some embodiments, the disease or condition is an inflammatory disease. DETAILED DESCRIPTION OF THE INVENTION I. GENERAL

[0012] The present disclosure describes novel dihydropyrimidopyrimidines, such as a compound of Formula I, which are useful as proteinase 3 (PR3) and / or human neutrophil elastase (HNE) inhibitors. In some embodiments, the dihydropyrimidine compounds of the disclosure can be fused with another heteroaromatic ring, such as in a compound of Formula II described herein. The compounds are believed to be useful for treatment of inflammatory diseases, including chronic obstructive pulmonary disease.II. DEFINITIONS

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0014] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3.

[0015] “Alkyl” is a linear or branched saturated monovalent or divalent hydrocarbon. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C1-10alkyl) or 1 to 8 carbon atoms (i.e., C1-8 alkyl) or 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., (C1- 4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t- Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (- CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).

[0016] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0017] “Alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

[0018] “Cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms. The term “cycloalkyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g. tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non- limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1- cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0019] “Heterocyclyl” or “heterocycle” or “heterocycloalkyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has from 3 to about 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having fromabout 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine,, 2- oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6- azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3- azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4- azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like. The heterocycle can be unsubstituted or substituted.

[0020] “Heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8- naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is to be understood that thepoint of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It also to be understood that when a reference is made to a certain atom-range membered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl-4(3H)-one, phenothiazinyl, and triazolyl. The heteroaryl can be substituted or unsubstituted.

[0021] “Oxo” as used herein refers to the substituent “=O”.

[0022] “Thioxo” as used herein refers to the substituent “=S”.

[0023] “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0024] A “compound of the present disclosure” includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formula I, Ia, II, IIa, and IIb, including the compounds of the Examples.

[0025] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0026] “Pharmaceutically effective amount” refers to an amount of the compound of the present disclosure in a formulation or combination thereof, that provides the desired therapeutic or pharmaceutical result.

[0027] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0028] “Treatment” or “treat” or “treating” as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom and / or preventing a worsening of a symptom associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0029] “Therapeutically effective amount” or “effective amount” as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of the compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co- administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0030] “Subject” is any mammal, such as a mouse, a rat, a dog, a cat, including veterinary animals, such as a goat, a pig, a horse, a cow, or a donkey, and primates, such as non-human primates, e.g., a cynomolgous monkey, rhesus monkey, or chimpanzee, as well as humans. In some embodiments, the subject is a human. In some embodiments, a subject is a patient.III. COMPOUNDS

[0031] Provided herein are compounds of Formula J:and pharmaceutically acceptable salts thereof, wherein R1is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R1a; each R1ais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; R2is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R2a; each R2ais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; each R3is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; each Raand Rbis independently H, C1-6alkyl, or C3-C8cycloalkyl; or Raand Rbtogether with the nitrogen to which they are connected form a 3- to 8-membered heterocyclyl; each R4is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, thioxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; or two R4on adjacent atoms together with the atoms to which they are connected form a heteroaryl, which is substituted with 0, 1, 2, or 3 R4a;each R4ais independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-15cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10aryl), -O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C1-8haloalkyl)2, -N(C2-6alkenyl)2, -N(C2-6alkynyl)2, -N(C3-15cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl)2, -N(heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3- 15cycloalkyl), -N(C1-9alkyl)(heterocyclyl), -N(C1-9alkyl)(C6-10aryl), -N(C1-9alkyl)(heteroaryl), -C(O)(C1-9alkyl), -C(O)(C1-8haloalkyl), -C(O)(C2-6alkenyl), - C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10 aryl), - C(O)(heteroaryl), -C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6alkynyl), -C(O)O(C3-15cycloalkyl), -C(O)O(heterocyclyl), - C(O)O(C6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(heterocyclyl)2, - C(O)N(C6-10aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8haloalkyl), -NHC(O)(C2-6alkenyl), -NHC(O)(C2-6alkynyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6alkynyl), -NHC(O)NH(C3-15cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), - NHS(O)2(C1-9alkyl), -N(C1-9alkyl)(S(O)2(C1-9alkyl), -S(C1-9alkyl), -S(C1-8haloalkyl), -S(C2-6alkenyl), -S(C2-6alkynyl), -S(C3-15cycloalkyl), -S(heterocyclyl), - S(C6-10 aryl), -S(heteroaryl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), - S(O)(heterocyclyl), -S(O)(C6-10aryl), -S(O)(heteroaryl), -S(O)2(C1-9alkyl), -S(O)2(C1-8haloalkyl), -S(O)2(C2-6alkenyl), -S(O)2(C2-6alkynyl), -S(O)2(C3-15cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H,-O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(aryl), - NH(heteroaryl), -N(C1-9alkyl)2, -N(C3-15cycloalkyl)2, -NHC(O)(C1-8haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15cycloalkyl), - NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), S(O)2(C1-9alkyl), -S(O)2(C1-8haloalkyl), -S(O)2(C3-15cycloalkyl), - S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; subscript n is 1 or 2; and subscript m is 1 or 2.

[0032] Provided herein is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein R1is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R1a; each R1ais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl; R2is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R2a; each R2ais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl; each R3is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl issubstituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; each Raand Rbis independently H or C1-6 alkyl; each R4is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN, provided that when attached to a carbon, R4is oxo; or alternatively, two R4on adjacent atoms together with the atoms to which they are connected form a heteroaryl, which is substituted with 0, 1, 2, or 3 R4a; each R4ais independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-15cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10aryl), -O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C1-8haloalkyl)2, -N(C2-6alkenyl)2, -N(C2-6alkynyl)2, -N(C3-15cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl)2, -N(heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3- 15cycloalkyl), -N(C1-9alkyl)(heterocyclyl), -N(C1-9alkyl)(C6-10aryl), -N(C1-9alkyl)(heteroaryl), -C(O)(C1-9alkyl), -C(O)(C1-8haloalkyl), -C(O)(C2-6alkenyl), - C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10 aryl), - C(O)(heteroaryl), -C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6alkynyl), -C(O)O(C3-15cycloalkyl), -C(O)O(heterocyclyl), - C(O)O(C6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(heterocyclyl)2, - C(O)N(C6-10aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8haloalkyl), -NHC(O)(C2-6alkenyl), -NHC(O)(C2-6alkynyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15cycloalkyl),-NHC(O)O(heterocyclyl),-NHC(O)O(C6-10aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), - NHS(O)2(C1-9 alkyl), -N(C1-9 alkyl)(S(O)2(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(C2-6alkenyl), -S(C2-6alkynyl), -S(C3-15cycloalkyl), -S(heterocyclyl), - S(C6-10 aryl), -S(heteroaryl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), - S(O)(heterocyclyl), -S(O)(C6-10aryl), -S(O)(heteroaryl), -S(O)2(C1-9alkyl), -S(O)2(C1-8haloalkyl), -S(O)2(C2-6alkenyl), -S(O)2(C2-6alkynyl), -S(O)2(C3-15cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H,-O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(aryl), - NH(heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15cycloalkyl), - NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C3-15 cycloalkyl), - S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; subscript n is 1 or 2; and subscript m is 1 or 2.

[0033] In some embodiments of the compound of Formula J, I or pharmaceutically acceptable salt thereof, each heterocyclyl has three to twelve ring members and has one to four heteroatoms, each independently N, O, or S; and each heteroaryl has five to twelve ring members and one to four heteroatoms, each independently N, O, or S.

[0034] In some embodiments of the compound of Formula J, I or pharmaceutically acceptable salt thereof, the compound has the structure of Formula Ia:

[0035] In some embodiments of the compound or pharmaceutically acceptable salt thereof, two R4on adjacent atoms together with the atoms to which they are connected form a heteroaryl, which is substituted with 0, 1, 2, or 3 R4a.

[0036] In some embodiments of the compound of Formula J, I and / or Ia, or pharmaceutically acceptable salt thereof, the compound has the structure of Formula II:wherein X is N or CR4a.

[0037] In some embodiments of the compound of Formula J, I, Ia, and / or II, or pharmaceutically acceptable salt thereof, R1is C6-C10 aryl, which is substituted with 0, 1, or 2 R1a.

[0038] In some embodiments of the compound of Formula J, I, Ia, and / or II, or pharmaceutically acceptable salt thereof, R2is C6-C10 aryl, which is substituted with 0, 1, or 2 R2a.

[0039] In some embodiments of the compound of Formula J, I, Ia, and / or II, or pharmaceutically acceptable salt thereof, the compound has the structure of Formula IIa:wherein X is N or CR4a; variable p is 0, 1, or 2; and variable q is 0, 1, or 2.

[0040] In some embodiments of the compound of Formula J, I, Ia, II, and / or IIa, each R3is independently H or halogen.

[0041] In some embodiments of the compound of Formula J, I, Ia, II, and / or IIa, subscript n is 0 or 1.

[0042] In some embodiments of the compound of Formula J, I, Ia, II, and / or IIa, or pharmaceutically acceptable salt thereof, the compound has the structure of Formula IIb:wherein X is N or CR4a.

[0043] In some embodiments of the compound of Formula J, I, Ia, and / or II, or pharmaceutically acceptable salt thereof, the compound has the structure of Formula IIc:wherein variable p is 0, 1, or 2; and variable q is 0, 1, or 2.

[0044] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or pharmaceutically acceptable salt thereof, each R1ais independently C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, or -CN. In some embodiments, each R1ais independently halogen. In some embodiments, R1ais Cl.

[0045] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or pharmaceutically acceptable salt thereof, each R2ais independently C1-6alkyl, C2-6alkenyl,C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, or -CN. In some embodiments, each R2ais independently halogen or -CN. In some embodiments, R2ais Br or -CN.

[0046] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or pharmaceutically acceptable salt thereof, X is CR4a.

[0047] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or pharmaceutically acceptable salt thereof, each R4ais independently C1-9 alkyl, C1-8 haloalkyl, halogen, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C1-9alkyl), -O(C1-8haloalkyl), -NH(C1-9alkyl), -NH(C1-8haloalkyl), -N(C1-9alkyl)2, -N(C1-8haloalkyl)2, -N(C1-9alkyl)(C1-8haloalkyl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)NH2, -C(O)NH(C1-9alkyl), -C(O)NH(C1-8haloalkyl), -C(O)N(C1-9alkyl)2, -C(O)N(C1-8haloalkyl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8haloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -NHS(O)2(C1-9alkyl), -N(C1-9alkyl)(S(O)2(C1-9alkyl), -S(C1-9alkyl), -S(C1-8haloalkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), -S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2. In some embodiments, each R4ais independently oxo, -NH2, -C(O)O(C1-9alkyl), or -NHS(O)2(C1-8haloalkyl). In some embodiments, each R4ais independently oxo, -NH2, -C(O)OCH2CH3, or -NHS(O)2CF3.

[0048] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or pharmaceutically acceptable salt thereof, X is N.

[0049] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or a pharmaceutically acceptable salt thereof, the compound has the structure of any one shown in Table 1.Table 1. Compounds

[0050] In some embodiments of the compound of Formula J, I, Ia, II, IIa, and / or IIb, or a pharmaceutically acceptable salt thereof, the compound has the structure of any one of the following:IV. COMPOSITIONS

[0051] In some embodiments, the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as described herein, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt as described herein, and a pharmaceutically acceptable excipient.

[0052] The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. The compound can also be administered locally, e.g., by inhalation or topical administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day. A. Formulation

[0053] For preparing pharmaceutical compositions from the compound or pharmaceutically acceptable salt of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, cachets, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, binders, preservatives, disintegrating agents, or an encapsulating material. Details on techniques forformulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0054] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% or 10% to 70% of the conjugates of the present invention.

[0055] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0056] Aqueous solutions suitable for oral use can be prepared by dissolving the compound or pharmaceutically acceptable salt of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolality.

[0057] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition tothe active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0058] Oil suspensions can be formulated by suspending the compound or pharmaceutically acceptable salt of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0059] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.

[0060] In another embodiment, the compositions of the present invention can be formulated for parenteral administration into a body cavity. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0061] In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989).

[0062] Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present invention include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®, Capryol®, Capmul®, Captex®, and Peceol®.B. Administration

[0063] The compound or pharmaceutically acceptable salt and compositions of the present invention can be delivered by any suitable means, including oral, parenteral, inhalation, and topical methods.

[0064] A compound or composition of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0065] The dosage or dosing frequency of a compound or composition of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0066] The compound or composition may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0067] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.

[0068] The compounds and compositions of the present invention can be co-administered with other agents. Co-administration includes administering the compound or composition of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the other agent. Co-administration also includes administering simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Moreover, the compounds and compositions of the present invention can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.

[0069] In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including the compounds and compositions of the present invention and any other agent. Alternatively, the various components can be formulated separately.

[0070] The compounds and compositions of the present invention, and any other agents, can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable dosage ranges include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. The composition can also contain other compatible therapeutic agents. V. METHODS

[0071] The compounds and compositions of the present invention, such as a compound of Formula I described herein, is believed to be useful to inhibit PR3 and / or HNE. Accordingly, in some embodiments, a method of the present invention is a method of inhibiting proteinase 3 (PR3) and / or human neutrophil elastase (HNE) in a cell, comprising administering to the cell an effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0072] PR3 and / or HNE are believed to play an important role in many disorders, injuries and pathological changes whose formation and / or progression are / is associated with inflammatory events and / or proliferative and hypertrophic tissue and vessel transformation. This can be in particular disorders and / or injuries of the lung or the cardiovascular system, or it may be sepsis, cancerous disorders or other inflammatory disorders.

[0073] PR3 is classified within the family of “chymotrypsin”-like neutrophil serine proteinase (NSP) which are identified by their highly conserved catalytic triads (His57, Asp102 and Ser195; using chymotrypsinogen numbering) for proteolytic activity and defined by their active site serine residue. PR3 possesses an enlarged binding site with high specificity and differs from neutrophil elastase (NE) by 4 main subsites, S2, S1’, S2’ and S3’. PR3 specificity is further defined by difference in residues which alter subsite specificities.

[0074] PR3 has many functions. Animal transgenic and knockout models have demonstrated that it is able to cleave structural proteins leading to tissue remodelling through diffusing deeper into tissues than the other NSPs. Other functions assist in the defensive immune role of the neutrophil including regulating a variety of cellular processes, cleaving host protein into antibacterial peptides and activating pro-inflammatory cytokines.Dysfunction of these systems has been associated with the development or progression of a number of chronic inflammatory diseases.

[0075] An inflammatory disease can be a skin disease. Inflammatory skin diseases are conditions characterized by redness, swelling, and other signs of inflammation on the skin. Examples include psoriasis, hidradentitis suppurativa, neutrophilic dermatoses, and dermatitis, such as atopic dermatitis or contact dermatitis.

[0076] Psoriasis is a chronic skin condition characterized by inflammation and an accelerated rate of skin cell production, leading to thick, red, scaly patches. This inflammation is caused by an overactive immune system that mistakenly attacks healthy skin cells. There are several types of psoriasis, each of which varies in its signs and symptoms: • Plaque psoriasis. The most common type of psoriasis, plaque psoriasis, causes dry, itchy, raised skin patches (plaques) covered with scales. There may be few or many. They usually appear on the elbows, knees, lower back and scalp. The patches vary in color, depending on skin color. The affected skin might heal with temporary changes in color (post inflammatory hyperpigmentation), particularly on brown or Black skin. • Nail psoriasis. Psoriasis can affect fingernails and toenails, causing pitting, abnormal nail growth and discoloration. Psoriatic nails might loosen and separate from the nail bed (onycholysis). Severe disease may cause the nail to crumble. • Guttate psoriasis. Guttate psoriasis primarily affects young adults and children. It's usually triggered by a bacterial infection such as strep throat. It's marked by small, drop-shaped, scaling spots on the trunk, arms or legs. • Inverse psoriasis. Inverse psoriasis mainly affects the skin folds of the groin, buttocks and breasts. It causes smooth patches of inflamed skin that worsen with friction and sweating. Fungal infections may trigger this type of psoriasis. • Pustular psoriasis. Pustular psoriasis causes clearly defined pus-filled blisters. It can occur in widespread patches, e.g., generalized pustular psoriasis, or on small areas of the palms or soles. • Erythrodermic psoriasis. The least common type of psoriasis, erythrodermic psoriasis can cover the entire body with a peeling rash that can itch or burn intensely. It can be short-lived (acute) or long-term (chronic).

[0077] Dermatitis is a chronic skin inflammation where symptoms include itchiness, scaly skin, a swollen rash, oozing blisters and scaling. Different types of dermatitis include: - Stasis dermatitis occurs when varicose veins or other circulatory conditions cause fluids to build up in the lower legs. The swelling produces pressure beneath the skin and slows the flow of blood and oxygen to the skin. - Allergic contact dermatitis results when the skin touches substances that it is sensitive to, e.g., allergens. The rash often affects only the area that came into contact with an allergen. Common allergens are perfumes, personal care products, poison ivy, ragweed pollen and nickel, used in jewelry and other items. - Irritant contact dermatitis develops when the skin comes into contact with certain things that cause a rash. Irritant contact dermatitis is different from allergic contact dermatitis but shares some features. Some people react to strong irritants after just one exposure. Others may develop a rash after repeated contact with even mild irritants. Common irritants are solvents, bleach, soap and hair products. - Atopic dermatitis, e.g., eczema, has symptoms that can include: dry, cracked skin; itchiness; raw skin from scratching; small, raised bumps; oozing and crusting; and thickened skin. - Perioral dermatitis involves small pus-filled bumps that appear around the mouth. This type of dermatitis also can affect the skin around the nose, cheeks and eyes. Corticosteroid medicine contained in some inhalers, nasal sprays, and creams may play a role in causing perioral dermatitis.

[0078] Hidradenitis suppurativa, also known as acne inversa, is a condition that causes small, painful lumps to form under the skin. The lumps often develop in areas where skin rubs together, such as the armpits, groin, buttocks and breasts. The lumps heal slowly, recur,and can lead to tunnels under the skin and scarring. Hidradenitis suppurativa tends to startafter puberty, often before age 40. It can persist for many years and worsen over time.

[0079] Neutrophilic dermatoses are autoinflammatory skin conditions characterized by dense infiltration of inflammatory cells (neutrophils) in the affected tissue. They arise in reaction to an underlying systemic illness. A neutrophilic dermatosis may be seen in isolation or more than one type may occur in the same individual. Neutrophilic dermatoses often arise at the site of injury such as a needle prick, biopsy or insect bite. This reaction to injury isknown as Koebner phenomenon, or isomorphic response. Pathergy refers to papules and pustules appearing at the site of needle stick. Neutrophilic dermatoses include: acute febrile neutrophilic dermatosis (Sweet syndrome), histiocytoid neutrophilic dermatitis, neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, neutrophilic eccrine hidradenitis, erythema elevatum diutinum, Behcet disease, bowel bypass syndrome (bowel-associated dermatitis-arthritis syndrome), neutrophilic urticarial dermatosis, palisading neutrophilic granulomatous dermatitis, and VEXAS syndrome.

[0080] Disorders and injuries of the lung which may be mentioned in this context are in particular chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), cystic fibrosis (CF; also referred to as mucoviscidosis), lung emphysema and acute lung injury (ALI). Other lung disorders include asthma and bronchitis, e.g., chronic bronchitis, interstitial lung disease, and pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis. Disorders and injuries of the cardiovascular system where PR3 and / or HNE are believed to be involved include, for example, tissue transformations during heart failure and reperfusion damage after acute myocardial infarction (AMI), cardiogenic shock, acute coronary syndrome (ACS), and also aneurysms. Other cardiovascular disorders include anti- neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, granulomatosis with polyangiitis (GPA), e.g., Wegener’s granulomatosis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. Disorders associated with sepsis are, for example, systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock and multi-organ failure (MOF; multi-organ dysfunction, MODS) and also disseminated intravascular coagulation (DIC). Examples of tissue breakdown and transformation in cancerous processes are the migration of cancer cells into healthy tissue (formation of metastases) and the formation of new supply blood vessels (neo-angiogenesis). Other inflammatory diseases where PR3 and / or HNE are believed to play a role are rheumatoid disorders, for example rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease (CD) and arteriosclerosis.

[0081] Pulmonary arterial hypertension (PAH) is a progressive lung disorder which, untreated, leads to death on average within 2.8 years after being diagnosed. Particular types of pulmonary hypertension have been specified for example by the World Health Organization (WHO) (Clinical Classification of Pulmonary Hypertension, Venice 2003; G. Simonneau et al., J. Am. Coll. Cardiol. 2004, 43, 5S-12S). An increasing constriction of the pulmonary circulation leads to increased stress on the right heart, which may develop intoright heart failure. By definition, the mean pulmonary aterial pressure (mPAP) in case of chronic pulmonary hypertension is >25 mmHg at rest or >30 mmHg during exertion (normal value<20 mmHg). The pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. In chronic PAH there is neomuscularization of initially unmuscularized pulmonary vessels, and the vascular muscles of the already muscularized vessels increase in circumference. This increasing obliteration of the pulmonary circulation results in progressive stress on the right heart, which leads to a reduced output from the right heart and eventually ends in right heart failure (M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S). PAH is a rare disorder, with a prevalence of 1-2 per million. The average age of the patients has been estimated to be 36 years, and only 10% of the patients were over 60 years of age.

[0082] In some embodiments, pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, formerly also called primary pulmonary hypertension, PPH), familial pulmonary arterial hypertension (FPAH), persistent pulmonary hypertension in neonates and also associated pulmonary arterial hypertension (APAH) which is associated with collagenoses, congenital systemic-pulmonary shunt vitiae, portal hypertension, HIV infections, intake of particular drugs and medicaments (for example anorectics), with disorders having a significant venous / capillary involvement, such as pulmonary venal-occlusive disease and pulmonary capillary hemangiomatosis, or with other disorders such as thyroid disorders, glycogen storage diseases, Gaucher's disease, hereditary teleangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy.

[0083] Other types of pulmonary hypertension include, for example, the pulmonary hypertension associated with left heart disorders, for example with ventricular or valvular disorders, the pulmonary hypertension associated with disorders of the respiratory tract and / or of the lungs, for example with chronic obstructive lung disease, interstitial lung disease or pulmonary fibrosis, the pulmonary hypertension attributable to chronic thrombotic and / or embolic disorders, for example associated with thromboembolic obstruction of pulmonary arteries, and the pulmonary hypertension caused by generally inflammatory disease processes or by special causes (for example associated with schistosomiasis, sarcoidosis and neoplastic diseases).

[0084] Chronic obstructive pulmonary disease (COPD) is a pulmonary disease which progresses slowly and is characterized by obstruction of breathing caused by pulmonaryemphysema and / or chronic bronchitis. First symptoms of the disorder generally appear from the fourth to the fifth decade of life onwards. In the years that follow, the short breath frequently worsens and a cough, associated with extensive and sometimes prolonged discharge and obstructed breathing up to breathlessness (dyspnea), manifests itself. COPD is primarily a smoker's disease: smoking is responsible for 90% of all cases of COPD and 80- 90% of all deaths caused by COPD. COPD is a major medical problem and represents the sixth most frequent cause of death world-wide. About 4-6% of people over the age of 45 are affected.

[0085] Although the obstruction of breathing may only be partial and temporal, COPD cannot be cured. Accordingly, the target of the treatment is to improve the quality of life, to ameliorate the symptoms, to prevent acute worsening and to slow the progressive impairment of pulmonary function. Existing pharmacotherapies, which have hardly changed over the last two to three decades, are the use of bronchodilators to open up blocked respiratory paths, and in certain situations corticosteroids to control the inflammation of the lung. See, P. J. Barnes, N. Engl. J. Med. 343, 269-280 (2000). The chronic inflammation of the lung, caused by cigarette smoke or other irritants, is the force behind the development of the disease. The mechanism on which it is based involves immune cells which, during the course of the inflammatory reaction of the lung, secrete various chemokines. This attracts neutrophilic cells and subsequently alveolar macrophages to the connective tissue of the lung and the lumen. Neutrophilic cells secrete a protease cocktail which contains mainly PR3 and HNE.

[0086] Alpha-1 antitrypsin (AAT) is a small endogenous protein and represents an important endogenous elastase inhibitor. In patients having a genetic deficiency of this protein (AATD), the protease / antiprotease balance is shifted. AADT patients have an increased risk of developing pulmonary emphysema or COPD, and in many AADT patients a lung transplant is indicated.

[0087] Bronchiectasis is understood as an abnormal dilation of the bronchial tree. Two forms may be distinguished: sack-shaped localized bronchiectases and generalized, cylindrical bronchiectases. Bronchiectases may be congenital; however, in most cases they are acquired and are found in particular in smokers. Owing to the dilation, drainage of the bronchial secretions is rendered more difficult, and the retained bronchial secretions promote infections. Frequently, bronchiectases are also encountered in the case of congenital disorders of the mucosa such as mucoviscidosis with abnormal viscosity of the bronchial secretions andin the case of ciliary dyskinesia syndrome. In the case of this syndrome (Kartagener syndrome), the architecture and function of the cilia and thus drainage of the secretions are impaired. Other causes of bronchiectases may be obstructions proximal to the ectasis, for example by tumors or foreign bodies. Recurrent and persisting infections weakening the bronchial walls are also thought to be causal. Furthermore, there are bronchiectasias which can not be connected unambiguously to states of infection or exogenic noxa (idiopathic bronchiectasis).

[0088] Bronchiectasis is characterized by migration of neutrophils into the pulmonary tissue. The patients show a marked imbalance between neutrophilic activity and protective inhibitor proteins, resulting in damage to the pulmonary tissue by the proteases secreted by the neutrophils. See, e.g., Schaaf et al., Respiration 67, 52-59 (2000).

[0089] Bronchiolitis obliterans is an inflammation of the bronchioli with destruction of the epithelium and formation of a fibrin-rich exudate in the bronchioli and the neighbouring alveoli. Organization of the exudate results in plugs of connective tissue reaching from the bronchioli into the alveoli. The disease is characterized by an increased number of neutrophils in the respiratory tract and an imbalance between free elastase and the endogenous elastase inhibitor protein. See, Elssner et al., Transpl. Infect. Dis. 3, 168-176 (2001). Prior infections and medicaments are being discussed as possible causes. The disease may also occur in the context of a transplant rejection.

[0090] Acute lung injury (ALI) and the more pronounced form thereof, acute respiratory distress syndrome (ARDS), are serious disorders associated with a mortality of 50-60%. According to the definition of the North American-European Consensus Conference (NAECC) of 1994, ALI and ARDS are defined by an acute onset, bilateral radiologically visible infiltrates, a PaO2 / FiO2index of ≦300 mmHg (ALI) or ≦200 mmHg (ARDS), a pulmonary capillary wedge pressure of <18 mmHg and no clinical evidence of left atrial hypertension.

[0091] A central role in the development of these disorders is played by the massive inflammatory changes in the lung, which are triggered by a widely branched system of mediators. An important role in the development of lung injury is also played by neutrophilic granulocytes, the number of which increases permanently during the inflammatory process See, Chollet-Martin et al., Am. J. Respir. Crit. Care Med. 154, 594-601 (1996). The action of the mediators causes damage to the alveolocapillary membranes, and this results in anincreased permeability of the alveolar capillary barrier. Owing to the increased permeability, protein-rich fluid can permeate into the alveolae and also into the interstitial space; a low- pressure pulmonary edema develops. Characteristic for ALI / ARDS, this is a noncardiogenic edema. The edema fluid contains mainly fibrin, erythrocytes, leukocytes, hyaline membranes and other proteins. Together with the products of activated neutrophils, the protein-rich exudate leads to dysfunction of the surfactant. The inflammatory processes cause damage and loss of pneumocytes of type II, which form surfactant, resulting in a reduced surfactant production. The surfactant deficit increases the surface tension in the alveolae; the alveolae collapse and atelectases are formed. With perfusion being maintained, there is thus a ventilation / perfusion imbalance resulting in an increase of the pulmonary right-left shunt. Furthermore, compliance is reduced, and in contrast the alveolar dead space is increased because there are areas which are ventilated but, owing to pulmonary hypertension, no longer sufficiently perfused.

[0092] An increased elastase activity, which correlates to the severity of the lung injury, could be measured in the bronchoalveolar lavage fluid (BALF) of ARDS patients. In animal models where the lung is injured (for example by administration of LPS), this effect can be reproduced. Treatment with elastase inhibitors (for example sivelestat or elafin) can reduce the elastase activity in the BALF and improve lung function.

[0093] An elastase inhibitor sivelestat has been approved in Japan and South Korea for the treatment of acute lung injury associated with SIRS. The reversible, but reactive compound has only a relatively weak effect on HNE (Ki200 nM) and also acts on the pancreas elastase (IC505.6 μM). The active compound is administered intravenously.

[0094] Elafin and structural analogs have also been investigated as therapeutic elastase inhibitors. Elafin is an endogenous small protein which inhibits both elastase and proteinase 3. However, owing to the proteinergic character, oral administration of elafin has not been achieved.

[0095] WO 2004 / 024700, WO 2004 / 024701, WO 2005 / 082863, WO 2005 / 082864 and WO 2008 / 003412 disclose various 1,4-diaryldihydropyrimidin-2-one derivatives as HNE inhibitors for the treatment of chronic obstructive pulmonary disease, acute coronary syndrome, myocardial infarction, heart failure and pulmonary hypertension. WO 2007 / 129060 and WO 2008 / 135537 claim tetrahydro-pyrrolopyrimidinediones as HNEinhibitors. WO 01 / 40231 describes heterocyclically fused dihydropyrimidines as potassium channel inhibitors for the treatment of atrial arrhythmias.

[0096] Accordingly, in some embodiments, the method of the present invention is a method of treating a disease or condition characterized by an elevated level of proteinase 3 (PR3) and / or human neutrophil elastase (HNE) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention. In some embodiments, the disease or condition is an inflammatory disease. In some embodiments, the disease or condition is an inflammatory lung disease. In some embodiments, the disease or condition is chronic obstructive pulmonary disease. VI. EXAMPLES

[0097] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7thedition, Wiley-Interscience, 2013.)

[0098] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. For example, disclosed compounds can be purified via silica gel chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0099] Compounds were characterized using standard instrumentation methods. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum (1H-NMR) and mass spectrum (MS).1H-NMR was measured at 400 MHz, unless otherwise specified. In some cases, exchangeable hydrogen could not be clearly observed depending on the compound and measurement conditions. The designation br. or broad, used herein, refers to a broad signal. HPLC preparative chromatography was carried out by a commercially available ODS column in a gradient mode using water / methanol (containing formic acid) as eluents, unless otherwise specified.

[0100] The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

[0101] In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure.

[0102] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.

[0103] Abbreviations. Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, contains a list of many of these abbreviations and acronyms. Table 2. List of abbreviations and acronyms.

[0104] General LCMS conditions used throughout the Examples: LC: the gradient was 5%B in 0.40min and 5-95% B in 2.60 min , hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml / min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C182.1*50mm, 5um. Detection methods were diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000. Example 1. Synthesis of 4-(4-bromophenyl)-1-(3-chlorophenyl)-3,4- dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0105] Preparation of compound 2-2

[0106] To a solution of 4-chloro-5-iodo-pyrimidine (25 g, 103.98 mmol, 1 eq) in THF (750 mL) was added n-BuLi (2.5 M, 83.18 mL, 2 eq) at -78°C and stirred at -70°C for 1h under N2. Then 4-bromo-N-methoxy-N-methylbenzamide (25.38 g, 103.98 mmol, 1 eq) in THF (50 mL) was added to the mixture at -70°C. Then the reaction mixture was stirred at -70°C for 2 h. Another one batch (25 g) was set up in parallel. The combined mixture was quenched into HCl solution (1000 mL, 0.5 N). The aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic phase was washed with brine (150 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a crude product which was purified by silica gel chromatography eluted with Petroleum ether / Ethyl acetate=100:1 to 10:1 to give 2-2 (25 g, 79.82 mmol, 38.38% yield) as yellow solid:1H NMR (400 MHz, CHLOROFORM-d) δ 9.21 - 9.14 (m, 1H), 8.74 (s, 1H), 7.69 (s, 4H).

[0107] Preparation of compound 2-3

[0108] To a mixture of 2-2 (12.5 g, 39.91 mmol, 1 eq) and 3-chloroaniline (5.60 g, 43.90 mmol, 4.67 mL, 1.1 eq) in MeCN (125 mL) was added TEA (8.08 g, 79.82 mmol, 11.11 mL, 2 eq) dropwise at 20°C under N2. Then the mixture was stirred at 80°C for 12 h. Another one batch (12.5 g) was set up in parallel. The mixture was purified by re-crystallized from MeCN (250mL) to give the pure product 2-3 (25 g, 45.03 mmol, 56.41% yield) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.00 - 7.96 (m, 1H), 7.83 - 7.79 (m, 2H), 7.73 - 7.67 (m, 2H), 7.59 - 7.54 (m, 1H), 7.40 (t,J= 8.1 Hz, 1H), 7.23 - 7.18 (m, 1H).

[0109] Preparation of compound 2-4

[0110] To a solution of 2-3 (12.5 g, 22.51 mmol, 1 eq) in MeOH (120 mL) was added NH2OH.HCl (9.39 g, 135.08 mmol, 6 eq) and KOH (2.53 g, 22.51 mmol, 120 mL, 50% in H2O) at 20°C. The mixture was stirred at 70°C for 2 h. Another one batch (12.5 g) was set up in parallel. The mixture was poured into ice-water (300 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (500 mL). The combined organic phase was washed with brine (50 mL), concentrated under reduced pressure to give 2-4 (21 g, 41.62 mmol, 92.43% yield) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.44 (m, 1H), 7.99 - 7.91 (m, 1H), 7.87 - 7.74 (m, 2H), 7.61 - 7.52 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.42 - 7.29 (m, 2H), 7.03 - 6.94 (m, 1H).

[0111] Preparation of compound 2-5

[0112] To a solution of 2-4 (7 g, 13.87 mmol, 1 eq) in EtOH (70 mL) and HOAc (70 mL) was added Zn (27.21 g, 416.19 mmol, 30 eq) at 20°C. The mixture was stirred at 20°C for 12 h. Another two batches (7 g) were set up in parallel. All the reactions were filtered, the filtrate was poured into H2O (400 mL), extracted with DCM (300 mL × 3). The combined organic phase was washed with aq. NaHCO3(100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2-5 (15 g, 26.95 mmol, 64.74% yield) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.17 (s, 1H), 8.04 - 7.94 (m, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.50 - 7.44 (m, 3H), 7.35 (t, J = 8.1 Hz, 1H), 7.10 - 7.06 (m, 1H).

[0113] To a solution of 2-5 (0.2 g, 359.27 μmol, 1 eq) in DMF (6 mL) was added TEA (109.06 mg, 1.08 mmol, 150.02 μL, 3 eq) and CDI (116.51 mg, 718.55 μmol, 2 eq) at 20°C. The mixture was stirred at 60°C for 1 h. The mixture was filtered. The filtrate was purified by prep-HPLC to give Example 1 (10.9 mg, 22.78 μmol, 6.34% yield, 94.5% purity, HCl) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.49 (d, J= 2.8 Hz, 1H), 8.42 (s, 1H), 7.69 - 7.61 (m, 2H), 7.53 - 7.42 (m, 5H), 7.35 - 7.24 (m, 1H), 5.86 (d, J = 2.4 Hz, 1H); LCMS: m / z 415.0 / 417.0, (M+H (79Br)+ / (M+H (81Br)+, RT: 2.403 min. Example 2. Synthesis of 4-(1-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimido[4,5- d]pyrimidin-4-yl)benzonitrile

[0114] To a solution of Example 1 (128.57 mg, 216.52 μmol, 1 eq) in DMF (2 mL) was added and Zn(CN)2 (20.34 mg, 173.21 μmol, 0.8 eq) and Pd(PPh3)4 (75.06 mg, 64.96 μmol, 0.3 eq) at 20°C in glove box. The mixture was stirred at 80°C for 12 h under Ar. The mixture was filtrated. The filtrate was purified by prep-HPLC to give Example 2 (10.5 mg, 28.41 μmol, 13.12% yield, 97.9% purity, HCl) as off white solid:1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.60 (m, 1H), 8.57 (d, J = 2.6 Hz, 1H), 8.47 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.55 - 7.45 (m, 3H), 7.36 - 7.25 (m, 1H), 5.99 (d, J = 2.5 Hz, 1H); LCMS: m / z 362.0, (M+H)+, RT: 2.204 min.Example 3. Synthesis of 5-(4-bromophenyl)-10-(3-chlorophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidin-3 -one

[0115] Preparation of compound 10-2

[0116] To a solution of 2-5 (5 g, 8.98 mmol, 1 eq) in DMF (150 mL) was added di(imidazol-1-yl)methanethione (3.20 g, 17.96 mmol, 2 eq) and TEA (2.73 g, 26.95 mmol, 3.75 mL, 3 eq) at 20°C. The mixture was stirred at 60°C for 2 h. Another two batches (5 g) were set up in parallel. The mixture was poured into water (400 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with brine (100 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 10-2 (16 g, 25.94 mmol, 96.28% yield) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.29 (br d, J = 2.9 Hz, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.53 - 7.39 (m, 5H), 7.24 (br d, J = 5.5 Hz, 1H), 5.94 (d, J = 2.9 Hz, 1H); LCMS: m / z 430.9 / 432.9, (M+H)+ / (M+H,81Br)+, RT: 2.687 min.

[0117] Preparation of compound 10-3

[0118] To a solution of 10-2 (8 g, 12.97 mmol, 1 eq) in DMF (80 mL) was added K2CO3(5.38 g, 38.91 mmol, 3 eq) and MeI (2.76 g, 19.46 mmol, 1.21 mL, 1.5 eq) at 0°C, the mixture was stirred at 20°C for 3 hrs. Another one batch (8 g) was set up in parallel. The mixture was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give crude product which was triturated with Petroleum: ethyl acetate=5:1 (30 mL) to give 10-3 (9 g, 18.17 mmol, 70.05% yield, 90% purity) as off white solid:1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.26 (s, 1H), 7.68 - 7.51 (m, 5H), 7.46 - 7.37 (m, 3H), 6.10 (s, 1H), 2.24 (s, 3H); LCMS: m / z 445.0 / 446.9, (M+H)+ / (M+H,81Br)+, RT: 2.908 min.

[0119] Preparation of compound 10-4

[0120] To a solution of 10-3 (2 g, 4.04 mmol, 1 eq) in EtOH (20 mL) was added TsOH.H2O (1.92 g, 10.10 mmol, 2.5 eq) and NH2NH2.H2O (505 mg, 10.09 mmol, 489.34 μL, 2.5 eq) at 20°C，the mixture was stirred at 90°C for 16 hrs. The majority of the solution was concentrated under reduced pressure to give crude 10-4 (2 g, 2.33 mmol, 57.63% yield) as yellow solid. A small sample of the solution was purified by prep-HPLC to give 10-4 (25.2 mg, 51.14 μmol, 1.27% yield, 94.6% purity) as light-yellow solid:1H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.69 (m, 1H), 8.59 (s, 1H), 7.72 - 7.59 (m, 6H), 7.54 (br d, J = 8.5 Hz, 2H), 7.50 - 7.39 (m, 3H), 7.11 (br d, J = 7.9 Hz, 1H), 6.13 (s, 1H), 2.28 (s, 2H); LCMS: m / z 429.0 / 431.0, (M+H)+ / (M+H,81Br)+, RT: 2.029 min.

[0121] Preparation of compound 10-5

[0122] To a solution of 10-3 (0.5 g, 785.17 μmol, 1 eq) in EtOH (10 mL) was added TsOH (135.21 mg, 785.17 μmol, 1 eq) and ethyl N-aminocarbamate (163.49 mg, 1.57 mmol, 2 eq) at 20°C, the mixture was stirred at 80°C for 12 hrs. LCMS one peak with desired Ms was detected. The residue was poured into aq.NaHCO3 (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, the filtrate was concentrated in vacuum to give crude product. The crude was purified by silica gel chromatography eluted with Petroleum ether / Ethyl acetate=100:1 to 0:1 to afford 10-5 (0.32 g, 573.98 μmol, 73.10% yield) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.46 (br s, 1H), 10.16 - 9.82 (m, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 7.80 (br s, 1H), 7.75 - 7.64 (m, 4H), 7.61 - 7.51 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.26 (s, 1H), 4.07 (br d, J = 6.8 Hz, 2H), 2.28 (s, 1H); LCMS: m / z 501.0 / 503.0, (M+H)+ / (M+H,81Br)+, RT: 2.135 min.

[0123] Preparation of Example 3

[0124] To a solution of 10-5 (30 mg, 53.81 μmol, 1 eq) in NMP (0.3 mL), the solution was kept at 180°C for 10 min in stop flow. Another two batches (30 mg) were set up in parallel. All the mixture was filtrated. The filtrate was purified by prep-HPLC to give Example 3 (7.4mg, 16.13 μmol, 9.99% yield, 99.3% purity, HCl) as off white solid:1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 7.77 (s, 1H), 7.64 - 7.59 (m, 4H), 7.57 - 7.53 (m, 1H), 7.48 (d, J = 8.5 Hz, 2H), 6.44 (s, 1H); LCMS: m / z 455.0 / 457.0, (M+H)+ / (M+H,81Br)+, RT: 2.392 min. Example 4. Synthesis of 4-(10-(3-chlorophenyl)-3-oxo-2,3,5,10-tetrahydropyrimido[4,5- d] triazolo[4,3-a]pyrimidin-5-yl)benzonitrile

[0125] To a solution of Example 3 (100.00 mg, 219.45 μmol, 1 eq) in NMP (1 mL) was added Zn(CN)2(20.61 mg, 175.56 μmol, 0.8 eq) and Pd(PPh3)4(25.36 mg, 21.94 μmol, 0.1 eq) in glove box. The mixture was stirred at 80°C for 12 h under Ar. The mixture was poured into H2O (2ml), filtrated, the filtrate cake was triturated with EtOH (10 ml) to give crude product. The crude product was purified by prep-TLC to give Example 4 (6 mg, 14.22 μmol, 6.48% yield, 95.2% purity) as off white solid:1H NMR (400 MHz, CHLOROFORM- d) δ 8.73 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.59 - 7.45 (m, 5H), 7.39 - 7.33 (m, 1H), 6.31 (s, 1H); LCMS: m / z 402.1, (M+H)+, RT: 2.160 min. Example 5. Synthesis of 4-(3-amino-10-(3-chlorophenyl)-5,10-dihydropyrimido[4,5- d][1,2,4]triazolo[4,3-a]pyrimidin-5-yl)benzonitrile

[0126] To a solution of Example 5 (100 mg, 197.93 μmol, 1 eq) in DMF (1 mL) was added Zn(CN)2 (50 mg, 197.93 μmol,1 eq) and Pd(PPh3)4 (22.87 mg, 19.79 μmol, 0.1 eq) at 20°C in glove box, the mixture was stirred at 80°C for 12 hr under Ar. The mixture was poured into H2O (2ml), filtrated, the filtrate cake was triturated with EtOH (10 ml) to give crude product. The crude product was purified by preparatory HPLC to give Example 6 (4.7 mg, 10.49 μmol, 5.30% yield, 97.6% purity, HCl) as off white solid:1H NMR (400 MHz, DMSO-d6) δ 8.72 (br d, J = 19.9 Hz, 2H), 8.64 (br s, 2H), 7.95 (br d, J = 8.0 Hz, 2H), 7.89 - 7.78 (m, 3H), 7.64 (br s, 2H), 7.59 (br s, 1H), 7.10 (s, 1H); LCMS: m / z 401.1, (M+H)+, RT: 1.963 min. Example 6. Synthesis of N-(5-(4-bromophenyl)-10-(3-chlorophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-1,1,1- trifluoromethanesulfonamide

[0127] To a solution of Example 5 (0.2 g, 395.86 μmol, 1 eq) in DCM (4 mL) was added TEA (120.17 mg, 1.19 mmol, 165.30 μL, 3 eq) and Tf2O (134.02 mg, 475.03 μmol, 78.38 μL, 1.2 eq) at 0°C, the mixture was stirred at 0°C for 1 hr. he mixture was filtrated. The filtrate was purified by Preparatory TLC to give Example 7 (5.2 mg, 7.37 μmol, 1.86% yield, 83.2% purity) as light-yellow solid:1H NMR (400 MHz, CHLOROFORM-d) δ 8.75 (s, 1H), 8.43 (s, 1H), 7.62 - 7.51 (m, 4H), 7.40 (s, 1H), 7.33 - 7.28 (m, 3H), 6.30 (s, 1H);19F NMR (377 MHz, CHLOROFORM-d) δ -72.29 (s, 3F); LCMS: m / z 585.9 / 587.9, (M+H)+ / (M+H,81Br)+, RT: 2.924 min. Example 7. Synthesis of N-(10-(3-chlorophenyl)-5-(4-cyanophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-1,1,1- trifluoromethanesulfonamide

[0128] To a solution of Example 6 (65 mg, 129.73 μmol, 1 eq) in DCM (3 mL) was added TEA (65.64 mg, 648.66 μmol, 90.29 μL, 5 eq), the mixture was undissolved, then Tf2O (73.21 mg, 259.47 μmol, 42.81 μL, 2 eq) in DCM (1 mL) was added to the mixture at 0°C continued for 0.25 min, the mixture was dissolved. TLC showed one new spot was detected. The mixture was purged with N2 to about 1 mL. The crude was purified by Preparatory TLC, silica was washed with CHCl3(5 ml) to remove crude, then washed with MeCN (5 ml) to give Example 8 (1.5 mg, 2.34 μmol, 1.81% yield, 83.2% purity) as yellow solid:1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (s, 1H), 8.42 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.58 - 7.54 (m, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.40 (s, 1H), 7.34 - 7.29 (m, 1H), 7.08 (br s, 1H), 6.27 (s, 1H);19F NMR (376 MHz, CHLOROFORM-d) δ -72.38 (s, 3F); LCMS: m / z 533.0, (M+H)+, RT: 2.794 min. Example 8. Synthesis of 9-(4-bromophenyl)-4-(3-chlorophenyl)-4,9- dihydropyrimido[4,5-d]tetrazolo[1,5-a]pyrimidine

[0129] To a solution of 10-4 (50 mg, 81.45 μmol, 1 eq) in HOAc (0.1 mL) and H2O (0.9 mL) was added NaNO2(16.86 mg, 244.36 μmol, 3 eq) at 0°C, the mixture was stirred at 20°C for 2 hrs. The mixture was filtrated. The filtration was purified by prep-HPLC to give Example 9 (9.8 mg, 17.61 μmol, 21.62% yield, 99.7% purity, TFA) as light-yellow solid:1HNMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.39 (s, 1H), 7.89 - 7.78 (m, 1H), 7.74 - 7.57 (m, 7H), 7.29 (s, 1H); LCMS: m / z 440.0 / 442.0, (M+H)+ / (M+H,81Br)+, RT: 2.546 min. Example 9. Synthesis of 4-(4-(3-chlorophenyl)-4,9-dihydropyrimido[4,5-d]tetrazolo[1,5- a]pyrimidin-9-yl)benzonitrile

[0130] To a solution of Example 9 (50 mg, 90.77 μmol, 1 eq) in DMF (1 mL) was added Zn(CN)2 (8 mg, 90.77 μmol, 1 eq) and Pd(PPh3)4 (31.47 mg, 27.23 μmol, 0.3 eq) in glove box. The mixture was stirred at 80°C for 12 h under Ar. The mixture was filtrated. The filtration was purified by prep-HPLC to give Example 10 (8.7 mg, 20.43 μmol, 22.51% yield, 99.4% purity, HCl) as white solid:1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.40 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.89 - 7.81 (m, 3H), 7.69 - 7.60 (m, 3H), 7.40 (s, 1H); LCMS: m / z 387.1, (M+H)+, RT: 2.306 min. Example 10. Synthesis of 5-(4-bromophenyl)-10-(3-chlorophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine

[0131] To a solution of Example 13 (10 mg, 17.59 μmol, 1 eq) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (1.48 mg, 35.17 μmol, 2 eq) at 20°C, the mixture was stirred at 20°C for 12 hrs. Another one batch (40 mg) was set up in parallel. The mixture wasfiltrated. The filtrate was purified by prep-HPLC to give Example 11 (5.5 mg, 12.46 μmol, 14.1% yield, 99.6% purity, HCl) as off white solid.column:1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.39 (d, J = 12.6 Hz, 2H), 7.81 - 7.74 (m, 1H), 7.70 - 7.55 (m, 5H), 7.50 (d, J = 8.5 Hz, 2H), 6.99 - 6.93 (m, 1H); LCMS: m / z 439.0 / 441.0, (M+H,79Br)+ / (M+H,81Br)+, RT: 2.230 min. Example 11. Synthesis of 4-(10-(3-chlorophenyl)-5,10-dihydropyrimido[4,5- d] triazolo[4,3-a]pyrimidin-5-yl)benzonitrile

[0132] To a solution of Example 11 (100 mg, 204.69 μmol, 1 eq) in DMF (1 mL) was added Zn(CN)2(20 mg, 204.69 μmol, 1eq) and Pd(PPh3)4(70.96 mg, 61.41 μmol, 0.3 eq) in glove box. The mixture was stirred at 80°C for 12 h under Ar The mixture was poured into H2O (2 ml), filtrated. The filtrate cake was purified by prep-TLC to give Example 12 (5.2 mg, 13.20 μmol, 6.45% yield, 97.9% purity) as white solid:1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.80 - 7.76 (m, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.65 - 7.54 (m, 3H), 7.05 (s, 1H); LCMS: m / z 386.1, (M+H)+, RT: 1.996 min. Example 12. Synthesis of ethyl 5-(4-bromophenyl)-10-(3-chlorophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate

[0133] To a solution of 10-3 (100 mg, 157.03 μmol, 1 eq) in EtOH (2 mL) was added ethyl 2-hydrazino-2-oxo-acetate (82.99 mg, 628.14 μmol, 4 eq) and TsOH (27.04 mg, 157.03 μmol, 1 eq) at 20°C, the mixture was stirred at 80°C for 12 hrs. The mixture was filtrated, the filtrate was purified by twice prep-HPLC (NH4CO3 then HCl) to give Example 13 (5.5 mg, 10.01 μmol, 6.38% yield, 99.8% purity, HCl) as off white solid:1H NMR (400 MHz, CHLOROFORM-d) δ 8.77 (s, 1H), 8.66 (s, 1H), 7.86 - 7.80 (m, 1H), 7.68 - 7.63 (m, 2H), 7.62 - 7.57 (m, 3H), 7.45 - 7.33 (m, 3H), 4.34 - 4.18 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); LCMS: m / z 511.0 / 513.0, (M+H)+ / (M+H,81Br)+, RT: 2.669 min. Example 13. Synthesis of ethyl 10-(3-chlorophenyl)-5-(4-cyanophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate

[0134] To a solution of Example 13 (200 mg, 351.73 μmol, 1 eq) in DMF (2 mL) was added Zn(CN)2(33 mg, 351.73 μmol, 1 eq) and Pd(PPh3)4(121.93 mg, 105.52 μmol, 0.3 eq) in glove box. The mixture was stirred at 80°C for 12 h under Ar. The mixture was poured into H2O (2 mL), filtrated, the filtrate cake was triturated with EtOH (10 ml) to give crude product. The crude product was purified by prep-HPLC to give Example 14 (6.8 mg, 13.76 μmol, 3.91% yield, 100% purity, HCl) as white solid:1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.66 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.84 - 7.80 (m, 1H), 7.69 - 7.58 (m, 5H), 7.46(s, 1H), 4.25 (t, J = 7.3 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H); LCMS: m / z 458.1, (M+H)+, RT: 2.296 min. Example 14. Synthesis of 5-(4-bromophenyl)-10-(3-chlorophenyl)-5,10- dihydropyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidin-3-amine

[0135] To a solution of 10-4 (1.5 g, 1.75 mmol, 1 eq) in MeOH (450 mL) was added molecular sieve (1.5 g) and CNBr (739.50 mg, 6.98 mmol, 512.48 μL, 4 eq) at 20°C, the mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by Preparatory HPLC to give a solution. A small sample of the solution was under lyophilization to give Example 5 (5.9 mg, 11.70 μmol, 0.67% yield, 97.4% purity, HCl) as light yellow solid. The remainder of the solution was poured into aq.NaHCO3(10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give Example 5 (200 mg, 395.86 μmol, 22.68% yield, 90% purity) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 6.4 Hz, 2H), 8.50 (br s, 2H), 7.80 (s, 1H), 7.69 - 7.63 (m, 5H), 7.61 - 7.56 (m, 3H), 6.90 (s, 1H); LCMS: m / z 454.0 / 456.0, (M+H)+ / (M+H,81Br)+, RT: 2.142 min. Example 15. Additional Compounds

[0136] The following compounds can also be produced by the methods and procedures described herein.Example 16. Biological Data

[0137] Elastin cleavage was examined using a SensoLyte Green Elastase Assay Kit (AnaSpec, Fremont, CA USA). Human neutrophil proteinase 3 was obtained from Athens Research & Technology (Athens, GA USA). Human neutrophil elastase was obtained from Enzo Biochem, Inc (Farmingdale, NY USA). PR3 biochemical data is summarized in Table 3. HNE biochemical data is summarized in Table 4. Table 3. PR3 ActivityTable 4. HNE Activity

[0138] Although the foregoing invention has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

1. WHAT IS CLAIMED IS:

1. A compound of Formula J:or a pharmaceutically acceptable salt thereof, wherein R1is C6-C10 aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R1a; each R1ais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; R2is C6-C10aryl or heteroaryl, which is substituted with 0, 1, 2, or 3 R2a; each R2ais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -S(O)0-2Ra, -NRaRb, -NO2, -CN, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; each R3is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; each Raand Rbis independently H, C1-6 alkyl, or C3-C8 cycloalkyl; or, alternatively, Raand Rbtogether with the nitrogen to which they are connected form a 3- to 8-membered heterocyclyl; each R4is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, thioxo, -NO2, or -CN, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -ORa, -S(O)0-2Ra, -NRaRb, oxo, -NO2, and -CN; or alternatively, two R4on adjacent atoms together with the atoms to which they are connected form a heteroaryl, which is substituted with 0, 1, 2, or 3 R4a; each R4ais independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, - NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6alkenyl), -O(C2-6alkynyl), -O(C3-15cycloalkyl), -O(heterocyclyl), -O(C6-10aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), - NH(C6-10aryl), -NH(heteroaryl), -N(C1-9alkyl)2, -N(C1-8haloalkyl)2, -N(C2-6alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl)2, -N(heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9alkyl)(C2-6alkynyl), -N(C1-9alkyl)(C3-15cycloalkyl), -N(C1-9alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6alkynyl), -C(O)(C3-15cycloalkyl), -C(O)(heterocyclyl), - C(O)(C6-10aryl), -C(O)(heteroaryl), -C(O)O(C1-9alkyl), -C(O)O(C1-8haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C6-10 aryl), -C(O)O(heteroaryl), - C(O)NH2, -C(O)NH(C1-9alkyl), -C(O)NH(C1-8haloalkyl), -C(O)NH(C2-6alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), - C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9alkyl)2, -C(O)N(C1-8haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C6-10 aryl)2, - C(O)N(heteroaryl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8haloalkyl), -NHC(O)(C2-6alkenyl), -NHC(O)(C2-6alkynyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9alkyl), -NHC(O)NH(C1-8haloalkyl), -NHC(O)NH(C2-6alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C1-9alkyl), -N(C1-9alkyl)(S(O)(C1-9alkyl), -NHS(O)2(C1-9alkyl), -N(C1-9alkyl)(S(O)2(C1-9alkyl), -S(C1-9alkyl), - S(C1-8 haloalkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), - S(heterocyclyl), -S(C6-10 aryl), -S(heteroaryl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8haloalkyl), -S(O)(C2-6alkenyl), -S(O)(C2-6alkynyl), -S(O)(C3-15cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10aryl), - S(O)(heteroaryl), -S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C1-9alkyl, C1-8haloalkyl, halogen, -OH, -NH2, CO2H,-O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), - O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(aryl), - NH(heteroaryl), -N(C1-9alkyl)2, -N(C3-15cycloalkyl)2, -NHC(O)(C1-8haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), - NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15cycloalkyl), - NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), - NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), - S(O)(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; subscript n is 1 or 2; and subscript m is 1 or 2.

2. The compound or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound has the structure of Formula Ia:

3. The compound or pharmaceutically acceptable salt thereof, of claim 1, wherein two R4on adjacent atoms together with the atoms to which they are connected form a heteroaryl, which is substituted with 0, 1, 2, or 3 R4a.

4. The compound or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound has the structure of Formula II:wherein X is N or CR4a.

5. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 4, wherein R1is C6-C10aryl, which is substituted with 0, 1, or 2 R1a.

6. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 5, wherein R2is C6-C10aryl, which is substituted with 0, 1, or 2 R2a.

7. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 6, wherein the compound has the structure of Formula IIa:wherein X is N or CR4a; variable p is 0, 1, or 2; and variable q is 0, 1, or 2.

8. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 7, wherein each R3is independently H or halogen.

9. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 8, wherein subscript n is 0 or 1.

10. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 9, wherein the compound has the structure of Formula IIb:(IIb), wherein X is N or CR4a.

11. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 10, wherein each R1ais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, or -CN.

12. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 11, wherein each R1ais independently halogen.

13. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 12, wherein R1ais Cl.

14. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 13, wherein each R2ais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -ORa, -S(O)0-2Ra, -NRaRb, -NO2, or -CN.

15. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 14, wherein each R2ais independently halogen or -CN.

16. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 15, wherein R2ais Br or -CN.

17. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 16, wherein X is CR4a.

18. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, wherein each R4ais independently C1-9 alkyl, C1-8 haloalkyl, halogen, oxo, -OH, -CN, - NO2, -NH2, -N3, -SH, -O(C1-9alkyl), -O(C1-8haloalkyl), -NH(C1-9alkyl), - NH(C1-8haloalkyl), -N(C1-9alkyl)2, -N(C1-8haloalkyl)2, -N(C1-9alkyl)(C1-8haloalkyl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)O(C1-9 alkyl), - C(O)O(C1-8 haloalkyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)N(C1-9alkyl)2, -C(O)N(C1-8haloalkyl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), - NHS(O)(C1-9alkyl), -N(C1-9alkyl)(S(O)(C1-9alkyl), -NHS(O)2(C1-9 alkyl), -N(C1-9 alkyl)(S(O)2(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), - S(O)2(C1-9alkyl), -S(O)2(C1-8haloalkyl), -S(O)(NH)(C1-9alkyl), -S(O)2NH(C1-9alkyl), or -S(O)2N(C1-9alkyl)2.

19. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 18, wherein each R4ais independently oxo, -NH2, -C(O)O(C1-9alkyl), or -NHS(O)2(C1-8haloalkyl).

20. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 19, wherein each R4ais independently oxo, -NH2, -C(O)OCH2CH3, or -NHS(O)2CF3.

21. The compound or pharmaceutically acceptable salt thereof, of any one of claims 1 to 16, whereinX is N.

22. The compound or pharmaceutically acceptable salt thereof of any one.

23. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, and a pharmaceutically acceptable excipient.

24. A method of inhibiting proteinase 3 (PR3) and / or human neutrophil elastase (HNE) in a cell, comprising administering to the cell an effective amount of a compound of any one of claims 1 to 22, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23.

25. A method of treating a disease or condition characterized by an elevated level of proteinase 3 (PR3) and / or human neutrophil elastase (HNE) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 22, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23.

26. The method of claim 25, wherein the disease or condition is an inflammatory disease.

27. The method of claim 25 or 26, wherein the disease or condition is an inflammatory lung disease.

28. The method of any one of claims 25 to 27, wherein the disease or condition is chronic obstructive pulmonary disease.

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