HK1134095A - Serine hydrolase inhibitors - Google Patents

Abstract

Provided herein are benzoxazinone compounds of formula (I) and compositions containing the compounds. The compounds and compositions are useful in the methods of inhibiting the action of serine hydrolase, including neutrophil elastase. In certain embodiments, the compounds and compositions are useful in the prevention, amelioration or treatment of serine hydrolase-mediated diseases.

Description

Serine hydrolase inhibitors

1. Field of the invention

The present invention provides compounds, compositions and methods for treating, preventing or ameliorating serine hydrolase mediated diseases, including but not limited to neutrophil elastase mediated diseases. The compounds provided herein are benzoxazinones, which are serine hydrolase inhibitors.

2. Background of the invention

Serine hydrolases are one of the largest and most diverse enzyme families in higher eukaryotes, which include a variety of serine proteases, lipases, esterases and amidases. Human neutrophil elastase is a class of serine hydrolases released from the granules of neutrophils, which occur in infections or inflammatory diseases. Neutrophil elastase is an enzyme that hydrolyzes proteins such as elastin, collagen, mucin, fibronectin and other proteins that make up the interstitium of living connective tissues such as lung, cartilage, blood vessel walls and skin. In addition, neutrophil elastase is known to have effects on other proteins or cells as well.

In an organism, serine hydrolases, such as neutrophil elastase, maintain homeostasis in the organism and their activity is mediated by endogenous inhibitor proteins, such as alpha₁-protease inhibitors, alpha₂Macroglobulin and secretory leukocyte protease inhibitor control. However, when the balance between neutrophil elastase and endogenous inhibitors is lost due to excessive release of neutrophil elastase at the site of inflammation or due to a decrease in the level of inhibition, the activity of neutrophil elastase cannot be controlled, thereby causing tissue damage.

Examples of diseases in which serine hydrolases, including neutrophil elastase, may be involved are: emphysema, acute respiratory distress syndrome, Adult Respiratory Distress Syndrome (ARDS), Idiopathic Interstitial Pneumonia (IIP), cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic sinus lung infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic rheumatoid arthritis, arthroncus, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplants, premature amnion rupture, bullous skin disease, shock, sepsis, Systemic Lupus Erythematosus (SLE), Crohn's disease, Disseminated Intravascular Coagulation (DIC), tissue damage following ischemia reperfusion, corneal scar tissue formation, myelitis, and the like.

Accordingly, there is a need for effective serine hydrolase inhibitors as therapeutic agents for the treatment of serine hydrolase mediated diseases.

3. Summary of the invention

The present invention provides compounds that are inhibitors of serine hydrolases, pharmaceutical compositions comprising the compounds and methods of use thereof. In one embodiment, the compound is an inhibitor of neutrophil elastase (including human neutrophil elastase). The compound is benzoxazinone and pharmaceutically acceptable derivatives thereof. In certain embodiments, the compounds useful in the compositions and methods provided herein are compounds of formula I

Or a pharmaceutically acceptable derivative thereof, wherein the variables are selected such that the resulting compound exhibits elastase inhibitor activity.

The present invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The invention also provides methods of treating, preventing, or ameliorating one or more symptoms of serine hydrolase mediated diseases by administering the compounds and compositions provided herein. In certain embodiments, the serine hydrolase is a neutrophil elastase, e.g., a human neutrophil elastase.

In certain embodiments, the present invention provides methods of inhibiting the action of serine hydrolases, including but not limited to neutrophil elastase, by administering the compounds and compositions provided herein. In other embodiments, the invention provides methods of treating, preventing, or ameliorating one or more symptoms of a disease or disorder, including but not limited to disorders associated with: emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, idiopathic interstitial pneumonia, cystic fibrosis of the lung, chronic interstitial pneumonia, chronic bronchitis, chronic sinus lung infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic rheumatoid arthritis, arthroncus, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplants, premature amnion rupture, bullous skin disease, shock, sepsis, systemic lupus erythematosus, crohn's disease, disseminated intravascular coagulation, tissue injury following ischemia reperfusion, corneal scar tissue formation, and myelitis.

4. Detailed description of the invention

Definition of

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications are herein incorporated by reference in their entirety. Where there are multiple definitions of terms of this invention, those used in this section should be used unless otherwise indicated.

As used herein, an "individual" is an animal, e.g., a mammal, including a human, e.g., a patient.

The term "serine hydrolase mediated disease" or "serine hydrolase mediated disorder" as used herein denotes any disease or other deleterious disorder or condition in which serine hydrolases, including neutrophil elastase or protease-3, are known to have a role. Exemplary diseases or conditions include, but are not limited to: emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, idiopathic interstitial pneumonia, cystic fibrosis of the lung, chronic interstitial pneumonia, chronic bronchitis, chronic sinus lung infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic rheumatoid arthritis, arthroncus, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplants, premature amnion rupture, bullous skin disease, shock, sepsis, systemic lupus erythematosus, crohn's disease, disseminated intravascular coagulation, tissue injury following ischemia reperfusion, corneal scar tissue formation, and myelitis.

Biological activity, as used herein, refers to the in vivo activity or physiological response of a compound produced upon in vivo administration of the compound, composition or other mixture. Thus, biological activity includes the therapeutic effect and pharmacokinetic performance of such compounds, compositions and mixtures. Biological activity can be observed by in vitro systems designed to test this activity.

Pharmaceutically acceptable derivatives of a compound as used herein include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates, nitroxides, or prodrugs of said compound. Such derivatives can be prepared simply by known methods for such derivatization by those skilled in the art. The resulting compounds can be administered to animals or humans without substantial toxic effects, and are pharmaceutically active or prodrugs. Pharmaceutically acceptable salts include, but are not limited to: amine salts such as, but not limited to, N '-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-meglumine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts such as, but not limited to, lithium, potassium, and sodium; alkaline earth metal salts such as, but not limited to, barium, calcium, and magnesium; transition metal salts such as, but not limited to, zinc; and inorganic salts such as, but not limited to, sodium hydrogen phosphate and disodium hydrogen phosphate; also included, but not limited to, salts of inorganic acids such as, but not limited to, hydrochlorides and sulfates; and salts of organic acids such as, but not limited to, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, caseinate, valerate, mesylate, and fumarate. Pharmaceutically acceptable esters include, but are not limited to: acidic groups include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the formula C ═ C (or), where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula C ═ C (oc (o) R), where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of the compound with one or more solvent or water molecules, alternatively 1 to about 100, alternatively 1 to about 10, alternatively 1 to about 2,3 or 4 solvent or water molecules.

Treatment, as used herein, refers to any manner in which one or more symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions of the invention, for example to treat respiratory disorders.

As used herein, ameliorating the symptoms of a particular disorder by administering a particular compound or pharmaceutical composition means that the amelioration can be attributed to the alleviation associated with the administration of that compound or composition, whether permanent or temporary, sustained or transient.

As used herein, unless otherwise indicated, the term "managing" refers to preventing the recurrence of a particular disease or disorder in a patient who has had the disease or disorder and/or extending the time in remission of a patient who has had the disease or disorder. The term encompasses modulating the threshold, development and/or duration of a disease or condition, or altering the way a patient responds to a disease or condition.

IC used in the invention₅₀Refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal response in the assay of the test response.

It is to be understood that the compounds provided herein may have chiral centers. Such chiral centers may be in the (R) or (S) configuration, or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure, or stereoisomerically pure or diastereomeric mixtures. Thus, one skilled in the art will recognize that for a compound that will epimerize in vivo, administration of the (R) form of the compound is equivalent to administration of the (S) form.

The terms alkyl, alkoxy, carbonyl, etc. used in the present specification have the same meaning as commonly understood by those skilled in the art.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if not specified, contain from 1 to 20 carbons, or from 1 to 16 carbons, and are straight or branched. In certain embodiments, alkenyl carbon chains containing 2 to 20 carbon atoms carry 1 to 8 double bonds, and in certain embodiments, alkenyl carbon chains containing 2 to 16 carbons carry 1 to 5 double bonds. In certain embodiments, alkynyl carbon chains containing 2 to 20 carbon atoms have 1 to 8 triple bonds, while in certain embodiments alkynyl carbon chains containing 2 to 16 carbons have 1 to 5 triple bonds. Exemplary alkyl, alkenyl and alkynyl groups of the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, ethylene, propylene, butene, pentene, acetylene and hexyne. Lower alkyl, lower alkenyl and lower alkynyl as used herein refers to carbon chains having about 1 or about 2 carbon atoms up to about 6 carbon atoms. As used herein, "alk (en) (alkynyl) yl" refers to an alkyl group that contains at least one double bond and at least one triple bond.

"heteroalkyl," as used herein, refers to a straight, branched or cyclic, in particular embodiments straight or branched, aliphatic hydrocarbon group having one or more oxygens inserted into the hydrocarbon chain; sulfur, including S (═ O) and S (═ O)₂A group; or substituted or unsubstituted nitrogen atoms, including NR and N⁺An RR group wherein the nitrogen substituent is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or COR ', wherein R' is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, OY, or-NYY ', wherein Y and Y' are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, in one embodiment having from 1 to about 20 atoms in the chain, and in another embodiment from 1 to 12 atoms in the chain.

As used herein, "cycloalkyl" refers to a saturated mono-or polycyclic ring system, in certain embodiments of 3 to 10 carbon atoms, and in other embodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl refer to a mono-or polycyclic ring system comprising at least one double bond and at least one triple bond, respectively. In certain embodiments, cycloalkenyl and cycloalkynyl groups may contain from 3 to 10 carbon atoms, in further embodiments cycloalkenyl groups may contain from 4 to 7 carbon atoms, and in further embodiments cycloalkynyl groups may contain from 8 to 10 carbon atoms. The ring systems of cycloalkyl, cycloalkenyl and cycloalkynyl can be comprised of one ring or two or more rings which can be joined together in a fused, bridged or spiro-linked fashion. As used herein, "cycloalk (ene) (alkynyl) group" refers to a cycloalkyl group that contains at least one double bond and at least one triple bond. "

As used herein, "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted cycloalkyl," "substituted cycloalkenyl" and "substituted cycloalkynyl" refer to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl groups, respectively, substituted with one or more substituents, in certain embodiments one to three or four substituents, as defined herein, typically selected from Q¹。

As used herein, "aryl" refers to an aromatic monocyclic or polycyclic group containing 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl, and substituted naphthyl, wherein said substituents, when present, are one or more substituents as defined herein, typically selected from Q¹。

As discussed herein, "heteroaryl" refers to a mono-or polycyclic aromatic ring system, in particular embodiments of about 5 to about 15 membered, wherein one or more, in one embodiment 1 to 3, of the atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, or sulfur. The heteroaryl group may optionally be fused to a benzene ring. Heteroaryl groups include, but are not limited to: furyl, imidazolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, tetrahydroquinolyl and isoquinolyl.

As used herein, "heteroarylcation" refers to a heteroaryl group that is positively charged at one or more heteroatoms.

As used herein, "heterocyclyl" refers to a mono-or polycyclic non-aromatic ring system, in one embodiment 3 to 10 membered, in another embodiment 4 to 7 membered, and in a further embodiment 5 to 6 membered, mono-or polycyclic non-aromatic ring system, wherein one or more, in particular embodiments 1 to 3, atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, or sulfur. In embodiments where the heteroatom is nitrogen, the nitrogen may optionally be substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternized to form an ammonium group, wherein the substituents are selected from the group consisting of above.

As used herein, "substituted aryl," "substituted heteroaryl," "substituted heterocyclyl" refer to aryl, heteroaryl, and heterocyclyl groups, respectively, substituted with one or more substituents, in certain embodiments one to three or four substituents, wherein the substituents are as defined herein, typically selected from Q¹。

"aralkyl" as used herein refers to an alkyl group in which one hydrogen atom is replaced with an aryl group.

As used herein, "heteroaralkyl" refers to an alkyl group in which one hydrogen atom is replaced with a heteroaryl group.

As used herein, "halo", "halogen" or "halide" refers to F, Cl, Br or I.

Pseudohalogen or pseudohalo groups, as used herein, are groups that exhibit substantial halogen-like behavior. Such compounds can be used in the same manner as halogens and treated in the same manner. Pseudohalogens include, but are not limited to: cyano, thiocyanic acid, selenocyanate, trifluoromethoxy and azide.

"haloalkyl" as used herein refers to an alkyl group wherein one or more hydrogen atoms are replaced with a halogen. Such groups include, but are not limited to: chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.

As used herein, "haloalkoxy" refers to RO, wherein R is a haloalkyl group.

As used herein, "carboxy" refers to the divalent group-C (O) O-.

As used herein, "aminocarbonyl" refers to C (O) NH₂。

As used herein, "alkylaminocarbonyl" refers to C (O) NHR, where R is alkyl, including lower alkyl. "Dialkylaminocarbonyl" as used herein refers to C (O) NR 'R, wherein R' and R are independently alkyl, including lower alkyl; "carboxamide" refers to a group of formula-NR 'COR, wherein R' and R are independently alkyl, including lower alkyl.

As used herein, "aralkylaminocarbonyl" refers to-C (O) NRR ' where one of R ' and R is aryl, including lower aryl, such as phenyl, and the other of R ' and R is alkyl, including lower alkyl.

As used herein, "arylaminocarbonyl" refers to-C (O) NHR where R is aryl, including lower aryl, such as phenyl.

As used herein, "hydroxycarbonyl" refers to COOH.

As used herein, "alkoxycarbonyl" refers to C (O) OR, wherein R is alkyl, including lower alkyl.

As used herein, "aryloxycarbonyl" refers to-C (O) OR, where R is aryl, including lower aryl, such as phenyl.

As used herein, "alkoxy" and "alkylthio" refer to RO and RS, where R is alkyl, including lower alkyl.

As used herein, "aryloxy" and "arylthio" refer to RO-and RS-wherein R is aryl, including lower aryls such as phenyl.

When the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may comprise one or more of the same or different halogens.

As another example, "C_1-3An alkoxyphenyl group "may comprise one or more identical or different alkoxy groups containing one, two or three carbons.

Unless otherwise indicated, the abbreviations for any protecting groups, amino acids and other compounds used in this specification are in accordance with the IUPAC-IUB Commission on common usage, accepted abbreviations or biochemical nomenclature (see, (1972) biochem. 11: 942-944).

Compound (I)

In certain embodiments, the compounds useful in the compositions and methods described herein are compounds of formula I:

or a pharmaceutically acceptable derivative thereof,

wherein a is a 5-10 membered heterocyclyl or heteroaryl ring attached to the benzoxazine core through a carbon atom of the heterocyclyl or heteroaryl ring;

R²is halogeno, pseudohalogeno, alkyl, alkenyl, alkynyl, halogenoalkyl, cycloalkyl, NR^aR^b、-OR^c、-C(O)R^cor-S (O)_mR^c；

R^a、R^bAnd R^cEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R¹is hydrogen, halo, alkyl, -OR³、-SR³、-NO₂Or NR⁴R⁵；

Each R³Independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R⁴and R⁵Selected from the following:

i)R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, with the proviso that R is⁴Or R⁵At least one is not hydrogen; or

ii)R⁴And R⁵Together with the nitrogen atom to which they are substituted form a 5-10 membered substituted or unsubstituted heterocyclyl or heteroaryl ring wherein the substituents, when present, are selected from one or more Q¹；

m is 0 to 2;

each n is independently 0 to 6;

R¹、R²、R³、R⁴and R⁵Optionally substituted with 1, 2,3 or 4 substituents, each substituent independently selected from Q¹Wherein Q is¹Is halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, arylateAlkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aralkyloxycarbonyloxy, and the like, Aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N', N '-dialkylureido, N' -alkyl-N '-arylureido, N', N '-diarylureido, N' -arylureido, N '-dialkylureido, N-alkyl-N' -arylureido, N-aryl-N '-alkylureido, N' -diarylureido, N ', N' -trialkylurea, N '-dialkyl-N' -arylureido, N-alkyl-N ', N' -diarylureido, N '-dialkylaminocarbonyloxy, N' -alkylureido, N-arylureido, N-alkylN ', N' -diarylureido, N, N-aryl-N ', N' -dialkylureido, N '-diaryl-N' -alkylureido, N ', N' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, alkoxycarbonylamino, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,Heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a hydrocarbyleneoxy group (i.e., -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q¹Groups that substitute for the same atoms, together forming a hydrocarbylene group; and

each Q¹Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

each Q²Independently halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylAlkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, triarylcarbonyloxy, and the like, Alkylamino carbonyloxy, dialkylamino carbonyloxy, alkylaryl aminocarbonyloxy, diarylamino carbonyloxy, alkynylalkoxycarbonyl, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N', N '-dialkylureido, N' -alkyl-N '-arylureido, N', N '-diarylureido, N' -arylureido, N '-dialkylureido, N-alkyl-N' -arylureido, N-aryl-N '-alkylureido, N' -diarylureido, N ', N' -trialkylurourea, N '-dialkyl-N' -arylureido, N-alkyl-N ', N' -diarylureido, N '-dialkylaminocarbonyloxy, N' -arylureido, N-alkyl-N ', N' -diarylureido, N '-dialkylureido, N' -, N-aryl-N ', N' -dialkylureido, N '-diaryl-N' -alkylureido, N ', N' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, HeterocyclylsulfonylaminoHeteroaryl thio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q²Groups which substitute for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy group (i.e., -O- (CH)₂)_y-O-), a hydrocarbyleneoxy group (i.e., -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q²Groups that substitute for the same atoms, together forming a hydrocarbylene group;

each Q³Independently selected from the group consisting of halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, substituted aryl carbonyl, substituted aryl alkyl, substituted,Heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, N-alkylureido, N-arylureido, ureido, and the like, N ' -alkylureido, N ', N ' -dialkylureido, N ' -alkyl-N ' -arylureido, N ', N ' -diarylureido, N ' -arylureido, N ' -dialkylureido, N-alkyl-N ' -arylureido, N-aryl-N ' -alkylureido, N ' -diarylureido, N ', N ' -trialkylurourea, N ' -dialkyl-N ' -arylureido, N-alkyl-N ', N ' -diarylureido, N-aryl-N ', N ' -dialkylureido, N ' -diaryl-N ' -alkylureido, N ', N ' -triarylureido, amidino, N ' -dialkylureido, N ' -arylureido, N ' -, Alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Groups which substitute for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy group (i.e., -O- (CH)₂)_y-O-), a hydrocarbyleneoxy group (i.e., -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q³Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q³Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

R⁵⁰is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹Wherein R is⁷⁰And R⁷¹Each independently is hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰And R⁷¹Together form a hydrocarbylene, azahydrocarbylene, oxahydrocarbylene, or thioalkylene group;

R⁵¹、R⁵²and R⁵³Each independently is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl;

R⁶⁰is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; and is

R⁶³Is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹。

In certain embodiments, the compounds of formula I are selected with the proviso that when A is 3-pyridyl and R is²When it is halo or methyl, R¹Is not 2-phenoxy. In one embodiment, the compound of formula I is selected with the proviso that when A is 3-pyridyl and R is²When it is halo or alkoxy, R¹Is not 2-phenoxy. In one embodiment, the compound of formula I is selected with the proviso that when A is 3-pyridyl and R is²When it is halo or alkoxy, R¹Is not a 2-aryloxy group. In one embodiment, the compounds of formula I are selected with the proviso that when a is pyridinyl and R is²When it is halo or alkoxy, R¹Is not a 2-aryloxy group.

In one embodiment, the compound of formula I is selected such that a is a 5-10 membered heterocyclyl or heteroaryl ring that is attached to the benzoxazine core through a carbon atom of the heterocyclyl or heteroaryl ring;

R²is halo, pseudohalo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, NR^aR^b、-OR^c、-C(O)R^cor-S (O)_mR^c；

R^a、R^bAnd R^cEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R¹is alkyl, -OR³、-SR³Or NR⁴R⁵；

Each R³Independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R⁴and R⁵Selected from the following:

i)R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, with the proviso that R is⁴Or R⁵At least one is not hydrogen; or

ii)R⁴And R⁵Together with the nitrogen atom to which they are substituted form a 5-10 membered substituted or unsubstituted heterocyclyl or heteroaryl ring wherein the substituents, when present, are selected from one or more Q¹；

m is 0 to 2; and is

Each n is independently 0 to 6, and the other variables are as described elsewhere herein.

In one embodiment, ring a is a 5-10 or 5-7 membered heterocyclyl or heteroaryl ring. Exemplary heterocyclyl and heteroaryl rings include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, and other heterocyclyl and heteroaryl groups known to those skilled in the art. In one embodiment, ring a is a 5-7 membered heterocyclyl ring, such as pyrrolidinyl or tetrahydrofuranyl. In another embodiment, ring a is a 5-7 membered heteroaryl ring, such as pyridyl, thienyl or pyrrolyl. In one embodiment, ring a is pyridyl. In one embodiment, A is 3-pyridyl. In one embodiment, a is 2-pyridyl. In one embodiment, A is 4-pyridyl. In one embodiment, A is 2-thienyl.

In one embodiment, R²Is halo, alkyl, haloalkyl or alkoxy. In one embodiment, R²Is chlorine, fluorine, bromine, methyl, ethyl, trifluoromethyl or methoxy. In one embodiment, R²Is butyl, propyl, isobutyl or cyclopropyl.

In one embodiment, R¹Is an alkyl group, such as methyl. In one embodiment, R¹is-OR³or-NR⁴R⁵。

In one embodiment, R³Is alkyl, haloalkyl, heteroalkyl, aryl, haloaryl, alkoxyalkyl, alkaryl, or arylsulfonylalkyl. In another embodiment, R³Is methyl, ethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-tolyl, phenylsulfonylethyl, 3, 4-methylenedioxybenzyl or dimethoxyaminoethyl.

In one embodiment, R⁴Is hydrogen, lower alkyl or alkoxyalkyl. In one embodiment, R⁴Is hydrogen, methyl or methoxyethyl.

In one embodiment, R⁵Is an aralkyloxycarbonylalkyl group, a dialkylaminoalkyl group, a heterocyclylalkyl group, an alkylheterocyclyl group or an alkoxyalkyl group. In one embodiment, R⁵Is benzyloxycarbonylmethyl, dimethylaminoethyl, 4-morpholinoethyl, N-methylpyrrolidin-3-yl or methoxyethyl.

In one embodiment, R⁴And R⁵Together with the nitrogen atom on which they are substituted, form a 5-or 6-membered heterocyclyl or heteroaryl ring. In one embodiment, R⁴And R⁵Together with the nitrogen atom it is substituted for, form a 5-membered heterocyclyl or heteroaryl ring. In certain embodiments, the ring is pyrrolyl or pyrrolidinyl.

In certain embodiments, R¹Comprises the following steps:

wherein A is¹Is CR⁶R⁷Or NR⁶；R⁶Is hydrogen, alkyl, alkenyl, alkynyl, phenyl, heteroaryl, alkoxyalkyl, cycloalkylalkyl, hydroxyalkyl, cyanoalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, aminocarbonylalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl, hydroxycarbonylalkyl, heterocyclylcarbonylalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkyl, or imidamidyl; r⁷Is hydrogen or alkyl; q¹Is alkyl, alkoxycarbonyl, phenyl, dialkylamino, alkoxycarbonyl, dialkylaminoalkyl, aralkyl, hydroxycarbonyl, hydroxyalkyl, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, heterocyclyl, heterocyclylalkyl, -N⁺R⁵¹R⁵²R⁵³Alkylsulfinylalkylcarbonyl, cycloalkylaminoalkyl, halo, di (hydroxyalkyl) amino, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, -SO₃H or an alkyl sulfonate; n is₁Is 1 or 2; and n is₂Is 0 to 5.

In certain embodiments, R⁶Is hydrogen, methyl, ethyl, isopropyl, 2-propenyl, 2-propynyl, 3-butynyl, phenyl, cyclopropylmethyl, 2-hydroxyethyl, hydroxycarbonylethyl, hydroxycarbonylpropyl, ethoxycarbonylethyl, methoxymethyl, ethoxymethyl, cyanoethyl, 3-cyanopropyl, dimethylaminomethyl, dimethylaminoethyl, 4-morpholinoethyl, 2-pyrimidinyl, 3-pyrimidinyl, 4-pyrimidinyl, 2-thiazolyl, 4-fluorophenylmethyl, 4-methoxyphenylmethyl, pyrrolidin-1-ylmethyl, tetrahydrofuran-2-ylmethyl, 1, 3-dioxolan-2-ylmethyl, N-methylpiperidin-4-yl, ethoxycarbonylmethyl, hydroxycarbonylmethyl, morpholin-4-ylcarbonylmethyl, Tert-butoxycarbonylaminoethyl, hydroxyethoxyethyl, aminocarbonylmethyl, 2-propynyloxycarbonylaminoethyl or-C (NH) NH₂。

In some embodimentsIn, Q¹Is methyl, ethyl, propyl, isopropyl, phenyl, dimethylamino, diethylamino, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, hydroxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyl, hydroxycarbonylpropyl, hydroxyalkyl, hydroxyalkoxyalkyl, 1-imidazolyl, 4-morpholine, morpholin-4-ylmethyl, morpholin-4-ylethyl, -N (CH)₃)₃ ⁺Methylsulfinylmethylcarbonyl, cycloalkylaminoalkyl, fluorine, bis (hydroxyethyl) amino, dialkylaminoalkylcarbonyl, pyrrolidin-1-ylmethyl, pyrrolidin-1-ylethyl, cyclopropylaminomethyl, 2-oxo-piperazin-4-yl, 1-dioxo-thiomorpholin-4-yl, N-methyl-N- (methoxyethyl) amino, N-methyl-piperazin-4-ylcarbonyl, N-dimethylaminoethylamino (methyl) carbonyl, -SO₃H or- (CH)₂)₃SO₃H。

In certain embodiments, R¹Comprises the following steps:

wherein A is CH or N; and R is⁶、Q¹、n₁And n₂As described elsewhere herein.

In one embodiment, R⁶Is hydrogen, methyl, methoxymethyl or cyclopropylmethyl; r⁷Is hydrogen; q¹Is methyl, dimethylamino, tert-butoxycarbonyl or methoxycarbonyl; n is₁Is 1 or2 and n₂Is 1 or 2.

In certain embodiments, R¹Comprises the following steps:

or

Wherein R is⁶Is hydrogen, alkyl, alkoxyalkyl or cycloalkylalkyl; q¹Is alkyl, dialkylamino or alkoxycarbonyl; and n is₂Is 0 to 5.

In another embodiment, R⁶Is hydrogen, methyl, methoxyethyl or cyclopropylmethyl. In another embodiment, n₂Is 1 and Q¹Is methyl, dimethylamino, tert-butoxycarbonyl or methoxycarbonyl.

In certain embodiments, R¹Is composed of

Wherein Q¹Is alkyl, dialkylamino or alkoxycarbonyl; and n is₂Is 0 to 3.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein X is halogen and the other variables are as defined elsewhere herein. In one embodiment, X is fluorine or chlorine.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Wherein R is²Is alkyl or halo.

In certain embodiments, the compound is

Or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein. In one embodiment, R²Is alkyl, haloalkyl, alkoxy, amino, halo, alkylcarbonyl or alkylsulfinyl. In one embodiment, R²Is methyl, isopropyl, trifluoromethyl, methoxy, hydroxy, amino, chloro, acyl or methylsulfinyl. In one embodiment, R⁸Is alkoxy, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl.

In one embodiment, the compound has the formula (la):

or

Or a pharmaceutically acceptable salt thereof, wherein R^xAnd R^yEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; and the other variables are as defined elsewhere herein. In certain embodiments, R^xAnd R^yEach independently selected from hydrogen and lower alkyl.

In one embodiment, the compound has the formula (la):

or

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In one embodiment, the compound has the formula (la):

or a pharmaceutically acceptable salt thereof, wherein R⁹Is hydrogen or unsubstituted or substituted alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, and n₃Is 1-20. In one embodiment, n₃Is 3 or 4. In one embodiment, R⁹Is hydrogen, methyl, phenyl or 3-carboxypyridin-2-yl.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof, wherein L is a linker and the other variables are as defined elsewhere herein.

In certain embodiments, the linker is characterized by a first covalent bond or chemical functional group connecting one benzoxazinone moiety to a first end of the linker, and a second covalent bond or chemical functional group connecting a second end of the linker to a second benzoxazinone moiety. The first and second functional groups may or may not be present independently.

The linker L may comprise a linear or acyclic moiety, a cyclic moiety, an aromatic ring, or a combination thereof. In certain embodiments, the linker may have 1 to 100 backbone atoms other than hydrogen atoms selected from C, N, O, S, P and Si. In certain embodiments, the linker comprises up to 50, up to 40, up to 30, up to 20, up to 15, up to 10, up to 5, up to 2 backbone atoms other than hydrogen. In certain embodiments, the linker is acyclic.

In certain embodiments, the linker comprises an oligomer of ethylene glycol or alkylene chains or mixtures thereof. In certain embodiments, the two benzoxazinone moieties are linked to the linker through an amide, sulfonamide, or ether linkage.

In other embodiments, the linker in the conjugates provided herein comprises a polyethylene glycol (PEG) chain. The PEG used in the present specification may comprise up to 50 backbone atoms other than hydrogen. In certain embodiments, the PEG comprises 5, 11, 13, 14, 22, or 29 backbone atoms other than hydrogen. In certain embodiments, the PEG comprises 5, 11, 13, or 29 backbone atoms other than hydrogen.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined elsewhere herein.

In certain embodiments, the compound is:

or a pharmaceutically acceptable salt thereof, wherein n₄1-20 and the other variables are as defined elsewhere herein. In one embodiment, n₄Is 4.

In certain embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from:

and

or a pharmaceutically acceptable salt thereof.

Preparation of the Compounds

The compounds provided herein can be prepared by methods known to those skilled in the art and by the following procedures and their routine modifications analogous to those described in the examples section herein.

Some exemplary reaction schemes for the preparation of compounds are shown below:

scheme 1:

the leaving group may be any leaving group known to those skilled in the art, such as Br, Cl and F.

Scheme 2

Exemplary coupling agents for use in the reaction include, but are not limited to: HBTU (2- (1H-benzotriazol-1-yl) -1, 1,3, 3-tetramethylammonium hexafluorophosphate), DCC (N, N' -dicyclohexylcarbodiimide), BOP (benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate), and other coupling agents known to those skilled in the art. Any base known to those skilled in the art may be used, exemplary bases being DBU (diazabicyclo [5.4.0] undec-7-ene), DIEA (diisopropylethylamine), TBAF (tetrabutylammonium fluoride), DIEA (N-ethyl-N, N-di-isopropylamine), and piperidine. Catalysts known to those skilled in the art may also be used, for example HOBt (N-hydroxybenzotriazole).

Scheme 3

In another embodiment, the benzoxazinones provided herein may be prepared by the following method.

Scheme 4

The 2-pyrones in the process of scheme 4 are commercially available or can be prepared by methods known to those skilled in the art. Specific exemplary syntheses of 2-pyrone preparations are set forth below.

Synthesis of 4-hydroxy-2-pyrones from dioxanone (dioxanones):

this method can be found, for example, in j.org.chem., 70: 4854(2005).

Synthesis of 4-hydroxy-2-pyrones from diketoesters (diketoesters):

synthesis of 4-amino-2-pyrone from 4-hydroxy-2-pyrone:

schemes 8 and 9 below show some exemplary syntheses of anthranilic acid preparations:

scheme 5

Scheme 6

Certain benzoxazinone compounds provided by the present invention can be prepared from anthranilic acid by reference to the following methods:

scheme 7

Scheme 8

Scheme 9

Scheme 10

The chiral aminopyrrolidines used in schemes 7, 8, and 9 can be obtained by reaction of j.med.chem.35: 4205(1992) modified procedure to obtain:

in another embodiment, benzoxazinones containing tertiary amines can be further modified, for example, by reaction with R-X to give quaternary amines, where R is selected from alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, haloalkyl, and heterocyclyl groups, and X is a leaving group, such as halo, sulfonate, quaternary ammonium, alkoxycarbonyl, or aryloxycarbonyl:

in another embodiment, the specific benzoxazinone compounds provided herein can be prepared by reference to the following "one-pot" method:

in another embodiment, the alkoxy-substituted benzoxazinones can be prepared by the following method:

the salt of benzoxazinone provided by the invention can be prepared by the following method:

in another embodiment, methane sulfonate, trifluoroacetate, tartrate and other salts can be prepared by similar methods.

Formulation of pharmaceutical compositions

The pharmaceutical compositions provided herein comprise a therapeutically effective amount of one or more compounds provided herein that are useful for preventing, treating, or ameliorating one or more symptoms of a serine hydrolase mediated disease, including but not limited to, neutrophil elastase mediated diseases.

The compositions comprise one or more compounds provided herein. The compounds may be formulated in suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs for oral administration or sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparations and dry powder inhalers. Generally, the compounds described above are formulated into pharmaceutical compositions by techniques and procedures well known in the art (see, e.g., Ansel Introduction to pharmaceutical Dosage Forms, 7 th edition, 1999).

In such compositions, an effective amount of one or more compounds or pharmaceutically acceptable derivatives thereof is combined with a suitable pharmaceutical carrier or vehicle. As noted above, the compounds may be derivatized to the corresponding salts, esters, enol ethers or esters, bases, solvates, hydrates, or prodrugs prior to formulation. The compound is present in the composition at a concentration effective to deliver an amount effective to treat, prevent or ameliorate one or more symptoms of a serine hydrolase mediated disease (including but not limited to neutrophil elastase mediated disease) upon administration.

Typically, the composition is formulated for single dose administration. To formulate a composition, a weight fraction of the compound can be dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at a concentration effective to reduce or ameliorate the condition being treated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any known to those of skill in the art suitable for a particular mode of administration.

Furthermore, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition, or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeting liposomes such as tumor-targeting liposomes, can also be used as pharmaceutically acceptable carriers. These can be prepared by methods known to those skilled in the art. For example, liposomal formulations can be prepared according to methods known in the art. Briefly, liposomes such as multilamellar vesicles (MLVs) are formed by gradually drying egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) in a flask. A solution of the compound provided by the present invention in Phosphate Buffered Saline (PBS) lacking divalent cations was added, and then the flask was shaken until the lipid membrane was dispersed. The resulting vesicles were washed to remove unencapsulated compounds, centrifuged into round spheres, and then resuspended in PBS.

The active compound is included in a pharmaceutically acceptable carrier in an amount effective to exhibit a therapeutically useful effect without producing unwanted side effects in the patient being treated. The therapeutically effective amount concentration can be determined empirically by testing the compound in the in vitro and in vivo systems described herein, and extrapolating therefrom to a human dose.

The concentration of the active compound in the pharmaceutical composition depends on the rate of absorption, inactivation and excretion of the active compound, the physicochemical properties of the compound, the dosing regimen, the amount administered and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of a serine hydrolase mediated disease (including but not limited to a neutrophil elastase mediated disease).

In certain embodiments, a therapeutically effective dose should result in a serum concentration of the active ingredient of about 0.1ng/ml to about 50-100 μ g/ml. In one embodiment, the pharmaceutical composition provides a dose of about 0.001mg to about 2000mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit dosage forms are prepared to provide from about 1mg to about 1000mg, and in certain embodiments, from about 10mg to about 500mg of the essential active ingredient or combination of essential ingredients per dosage unit dosage form.

The active ingredient may be administered immediately or may be divided into a number of smaller dosage forms to be administered at intervals. It will be understood that the exact dosage and treatment time are a function of the condition to be treated and may be determined empirically using known test protocols or inferred from in vivo or in vitro test data. It should be noted that concentrations and dosage values may also vary depending on the severity of the condition that needs to be alleviated. It will be further understood that the specific dosage regimen for any particular individual may be adjusted over time according to the individual's needs or the professional judgment of the person administering the composition or supervising the administration, and that the concentration ranges provided herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acid, base, enol ether or ester, salts, esters, hydrates, solvates and prodrug forms. The derivatives may be selected such that their pharmacokinetic properties are superior to those of the corresponding neutral compounds.

Thus, an effective concentration or amount of one or more compounds or pharmaceutically acceptable derivatives thereof as described herein is combined with an appropriate pharmaceutical carrier or vehicle for systemic, local or topical administration to form a pharmaceutical composition. The compound is included in an amount effective to ameliorate one or more symptoms of, or treat or prevent, a serine hydrolase mediated disorder, including but not limited to, a neutrophil elastase mediated disorder. The concentration of the active compound in the composition will depend on the absorption, inactivation, and excretion rates of the active compound, the dosing regimen, the amount administered, the particular dosage form, and other factors known to those skilled in the art.

The compounds are intended to be administered by appropriate routes including, but not limited to, oral, parenteral, rectal, topical and topical administration. For oral administration, capsules and tablets may be formulated. The compositions are in liquid, semi-liquid or solid form and can be formulated in a form suitable for various routes of administration.

Solutions or suspensions for parenteral, intradermal, subcutaneous or topical application may include any of the following ingredients: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methyl paraben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetate, citrate and phosphate; and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral formulations may be presented in ampoules, disposable syringes or single or multi-dose vials made of glass, plastic or other suitable material.

When a compound exhibits insufficient solubility, a method for solubilizing the compound can be used. Such methods are well known to those skilled in the art and include, but are not limited to, the use of co-solvents, such as dimethyl sulfoxide (DMSO), the use of surfactants, such as TWEENOr dissolved in aqueous sodium bicarbonate.

After mixing or adding the compounds, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture will depend on a variety of factors, including the desired mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration may be sufficient to ameliorate symptoms of the disease, disorder or condition being treated, or determined empirically.

The pharmaceutical compositions can be administered to humans and animals as unit dosage forms, e.g., tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil and water emulsions, containing appropriate amounts of the compounds or their pharmaceutically acceptable derivatives. The pharmaceutically therapeutically active compounds and derivatives thereof are formulated and administered in unit dosage form or multiple dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for human and animal consumption and packaged individually as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with a desired pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets and capsules. The unit dosage form may be administered in portions or in multiple portions. Multiple dosage forms are a plurality of identical unit dosage forms packaged in separate containers for administration as separate unit dosage forms. Exemplary multiple dosage forms include vials, bottles or pints or gallon bottles of tablets or capsules. Thus, a multiple dosage form is a plurality of unit dosage forms that are not separately packaged.

Can also be prepared into sustained release preparation. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methyl methacrylate), or poly (vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRONDEPOT^TM(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid. Polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid are capable of releasing molecules over 100 days, while some hydrogels can release proteins in a shorter time. When encapsulated compounds are left in the body for a long time, they may denature or aggregate by exposure to a humid environment at 37 ℃, resulting in loss of biological activity and possible structural changes thereof. Rational stabilization strategies can be designed according to the mechanism of action involved. For example, if the aggregation mechanism is found to be intermolecular S-S bond formation through sulfur-disulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling water content, using appropriate additives, and forming specific polymer matrix compositions.

Dosage forms or compositions can be prepared containing from 0.005% to 100% of the active ingredient, and which are balanced with a non-toxic carrier. For oral administration, any of the usual excipients, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate or sodium saccharine may be mixed to form a pharmaceutically acceptable non-toxic composition. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release dosage forms such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and others. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may comprise from about 0.001% to 100% active ingredient, and in certain embodiments, from about 0.1-85% or from about 75-95% active ingredient.

The active compound or pharmaceutically acceptable derivative may be formulated with a carrier, such as a time-release formulation or coating, which prevents rapid removal of the compound from the body.

The composition may contain other active compounds to achieve the desired combination of attributes. For therapeutic or prophylactic purposes, the compounds provided herein, or a pharmaceutically acceptable derivative thereof as described herein, may also be beneficially administered with another pharmacological agent known in the art to be therapeutically valuable for one or more diseases or medical conditions contemplated herein, such as serine hydrolase mediated diseases, including but not limited to neutrophil elastase mediated diseases. It will be appreciated that such combination therapy forms a further aspect of the compositions and methods of treatment provided herein.

Lactose-free compositions provided by the present invention may comprise excipients well known in the art and as exemplified in the United States Pharmacopeia (USP) sp (xxi)/nf (xvi). Generally, lactose-free compositions comprise pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredient, binder/filler and lubricant. An exemplary lactose-free dosage form comprises an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

Further included are anhydrous pharmaceutical compositions and dosage forms comprising the compounds provided herein. For example, the addition of water (e.g., 5%) is a widely used method in the pharmaceutical field to simulate long-term storage to measure changes in properties such as shelf life or formulation stability over time. See, for example, Jens t. carstensen, Drug Stability: principles & Practice, 2d.Ed., Marcel Dekker, NY, NY, 1995, pp.379-80. In fact, water and heat can accelerate the decomposition of some compounds. Thus, the action of water can have a very important impact on the formulation, as moisture and/or humidity is commonly encountered during manufacture, handling, packaging, storage, transport and use of the formulation.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture content ingredients and under low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient having a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity occurs during manufacture, packaging, and/or storage.

Anhydrous pharmaceutical compositions should be prepared and stored so as to retain their anhydrous nature. Accordingly, the anhydrous composition is preferably packaged using water resistant materials known in the art so that it is contained in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, sealed foil, plastic, unit dose containers (e.g., vials), blister packs, and strip packs.

4.1.1 oral dosage forms

Oral pharmaceutical dosage forms may be solid, gel or liquid. The solid dosage forms are tablets, capsules, granules and bulk powders. Types of oral tablets include compressed, chewable lozenges as well as tablets which may be enteric-coated, sugar-coated or film-coated. The capsules may be hard or soft gel capsules, while the granules and powders may be provided in non-effervescent or effervescent form, and mixed with other ingredients known to those skilled in the art.

In certain embodiments, the dosage form is a solid dosage form, such as a capsule or tablet. The tablets, pills, capsules, lozenges, and the like may comprise any of the following ingredients or compounds of similar properties: binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents.

Examples of binders include microcrystalline cellulose, gum tragacanth, dextrose solution, acacia syrup, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, for example, any approved certified water-soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended in hydrated alumina. Sweetening agents include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and mixtures of synthetic compounds that produce a pleasant sensation, such as, but not limited to, mint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauric ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. The film coating comprises hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

When oral administration is desired, the compound may be provided in a composition that protects the compound in the acidic environment of the stomach. For example, the composition may be formulated in an enteric coating that maintains integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated with antacids or other such ingredients.

When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain various other materials which modify the physical form of the dosage unit, such as sugar coatings and other enteric agents. The compounds may also be administered as components of elixirs, suspensions, syrups, wafers, sprays (sprinkle), chewing gums and the like. Syrups may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active substance may also be mixed with other active substances which do not impair the desired effect, or with substances which supplement the desired effect, such as antacids, H2 blockers and diuretics. The active ingredient is a compound as described herein or a pharmaceutically acceptable derivative thereof. Higher concentrations, up to about 98% by mass, of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets are resistant to the action of gastric acid due to the enteric coating and dissolve or disintegrate in the neutral or alkaline intestine. Dragees are compressed tablets in which different layers of pharmaceutically acceptable substances are applied. The coated tablet is a compressed tablet coated with a polymer or other suitable coating. A tableted dosage form is a tablet compressed through more than one compression cycle using the aforementioned pharmaceutically acceptable materials. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents may be used in compressed tablets, dragees, double-compressed tablets and chewable tablets. Flavoring and sweetening agents may be used in particular in the formation of chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic formulations. Pharmaceutically acceptable carriers for elixirs include solvents. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. An emulsion is a two-phase system in which one liquid is dispersed throughout the other in the form of fine particles. Pharmaceutically acceptable carriers for emulsions are non-aqueous solutions, emulsifiers and preservatives. Suspensions employ pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable materials for non-effervescent granules that can be reconstituted into liquid oral dosage forms include diluents, sweeteners and wetting agents. Pharmaceutically acceptable materials for effervescent granules that can be reconstituted into liquid oral dosage forms include organic acids and sources of carbon dioxide. Coloring and flavoring agents may be used in all of the above dosage forms.

Solvents include glycerin, sorbitol, ethanol, and syrup. Examples of preservatives include glycerol, methyl and propyl parabens, benzoic acid, sodium benzoate and ethanol. Examples of non-aqueous liquids for emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, gum tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, and gum arabic. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrup, glycerin and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauric ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Colorants include any approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and mixtures of synthetic compounds that produce a pleasant sensation.

For solid dosage forms, the solution or suspension in, for example, propylene carbonate, vegetable oil or triglycerides is packed in gel capsules. Such solutions and their preparation and encapsulation are disclosed in U.S. Pat. Nos. 4,328,245, 4,409,239 and 4,410,545. For liquid dosage forms, the liquid, e.g., dissolved in polyethylene glycol, can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, e.g., water, to facilitate dosing.

Alternatively, liquid or semi-solid oral dosage forms may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycerol, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gel capsule shells. Other useful dosage forms include, but are not limited to: comprising a compound provided by the present invention; dialkylated mono-or multiolefin based glycols including, but not limited to, 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol); and one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

Other dosage forms include, but are not limited to, hydroalcoholic solutions containing pharmaceutically acceptable acetals. The alcohol used in such dosage forms is any pharmaceutically acceptable water miscible solvent having one or more hydroxyl groups, including but not limited to propylene glycol and ethanol. Acetals include, but are not limited to, lower alkyl aldehydes, such as the di (lower alkyl) acetal of acetaldehyde diethyl acetal.

In all embodiments, the tablet and capsule formulations may be coated to modify or maintain the dissolution of the active ingredient by techniques known to those skilled in the art. Thus, for example, they may be coated with conventional enterically digestible coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

4.1.2 injectables, solutions and emulsions

Parenteral administration is also contemplated herein, which is generally characterized by administration by injection or by subcutaneous, intramuscular, or intravenous administration. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for formulation into solutions or suspensions prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, co-solvents, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins, as desired. It is also contemplated herein to implant a slow release system or a sustained release system to maintain a constant dosage level. Briefly, the compounds provided by the present invention are dispersed in a solid phase inner matrix (solid inner matrix) such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethoxylated poly (p-phenylene), natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, carbonate rock silicone copolymers, hydrophilic polymers such as hydrogels of acrylates and methacrylates, collagen, crosslinked polyvinyl alcohol, and partially crosslinked hydrolyzed polyvinyl acetate, which is coated with an outer polymer film such as polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, polyisoprene, polyethylene, styrene, Neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionic polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxy-alcohol copolymers, the outer polymer film being insoluble in body fluids. The compound diffuses through the outer polymer membrane during the release rate controlling step. The proportion of active compound contained in such parenteral compositions is highly dependent on its characteristic properties, as well as the activity of the compound and the needs of the individual.

Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Formulations for parenteral administration include sterile solutions for ready injection, sterile dry soluble products (e.g., lyophilized powders), formulations ready to be mixed with a solvent prior to use (including subcutaneously injectable tablets), sterile suspensions ready for injection, sterile dry soluble products ready to be mixed with a carrier prior to use, and sterile emulsions. The solution may be an aqueous solution or a non-aqueous solution.

For intravenous administration, suitable carriers include saline or Phosphate Buffered Saline (PBS), as well as solutions containing thickening agents and co-solvents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

Pharmaceutically acceptable carriers for parenteral formulations include aqueous carriers, non-aqueous carriers, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include sodium chloride injection, ringer's injection, isotonic dextrose injection, sterile water for injection, dextrose, and lactated ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations, including phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride and benzethonium chloride, should be added to parenteral formulations packaged in multi-dose containers. Isotonic agents include sodium chloride and dextrose. The buffer comprises phosphate and citrate. The antioxidant comprises sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. The emulsifier comprises polysorbateMasking and sequestering of metal ionsThe composition includes EDTA. Pharmaceutically acceptable carriers also include ethanol, polyethylene glycol and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound can be adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dosage will depend upon the age, weight and condition of the patient or animal, as is known in the art.

The unit dose of parenteral formulation is packaged in ampoules, vials or syringes with needles. As known and practiced in the art, all formulations for parenteral administration should be sterilized.

For example, intravenous or intra-arterial infusion of sterile aqueous solutions containing the active compounds is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active substance, injected as required to produce the desired pharmacological activity.

The injectables are designed for local or systemic administration. Typically, a therapeutically effective dose is formulated to comprise a concentration of active compound of at least about 0.1% w/w to about 90% w/w or higher, e.g., more than 1% w/w, against the tissue to be treated. The active ingredient may be administered at one time or may be divided into a number of smaller doses to be administered at regular intervals. It will be understood that the exact dose and treatment time will be related to the function of the tissue to be treated and may be determined empirically through known test protocols or may be extrapolated from in vivo or in vitro test data. It should be noted that concentrations and dosage values may also vary depending on the age of the individual to be treated. It will be further understood that the specific dosage regimen for any particular individual may be adjusted over time according to the individual's needs or the professional judgment of the person administering the composition or supervising the administration, and that the concentration ranges provided herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

The compounds may be suspended in micronized or other suitable form, or derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on a variety of factors, including the desired mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease and can be determined empirically.

4.1.3 Freeze-dried powder

Also of interest herein are lyophilized powders that can be reconstituted into solutions, emulsions, and other mixtures for administration. They may also be reconstituted and formulated as solids or gels.

The sterile lyophilized powder can be prepared by dissolving the compound provided by the present invention or a pharmaceutically acceptable derivative thereof in an appropriate solvent. The solvent may contain an excipient to enhance stability or a pharmacological component of the powder or a reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, or other suitable agents. The solvent may also comprise a buffer, such as citrate, sodium or potassium phosphate or other such buffers known to those skilled in the art, which in one embodiment is about neutral pH. After sterile filtration of the solution, lyophilization is carried out under standard conditions known to those skilled in the art to provide the desired dosage form. Generally, the resulting solution is dispensed into vials for lyophilization. Each vial will contain a single dose (including but not limited to 10-1000mg or 100-500mg) or multiple doses of the compound. The lyophilized powder will be stored under appropriate conditions, for example at about 4 ℃ or room temperature.

Reconstitution of the lyophilized powder with water for injection provides a dosage form for parenteral administration. For reconstitution, about 1-50mg, about 5-35mg, or about 9-30mg of the lyophilized powder can be added per ml of sterile water or other suitable carrier. The exact amount depends on the compound selected. The amount may be determined empirically.

4.1.4 topical application

Topical mixtures can be prepared as described for local and systemic administration. The resulting mixture may be in the form of a solution, suspension, emulsion, etc., and formulated as a cream, gel, ointment, emulsion, solution, elixir, varnish, suspension, tincture, ointment, foam, aerosol, douche, spray, suppository, bandage, skin patch, or any other form suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as inhalation (see, e.g., U.S. Pat. nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of steroids for use in the treatment of inflammatory diseases, particularly asthma). These dosage forms for administration to the respiratory tract may be in the form of an aerosol or solution for nebuliser, or as a fine powder for inhalation, either alone or in admixture with an inert carrier such as lactose. In this case, the particles of the dosage form will have a diameter of less than 50 microns or less than 10 microns.

The compounds may be formulated for topical application, for example, in the form of gels, creams and lotions for topical application to the skin and mucous membranes (e.g., in the eye), and for application to the eye or within the brain pool or within the spinal canal. Topical administration is contemplated in transdermal delivery and administration to the eye or mucosa, or in inhalation therapy. Nasal solutions of the active compounds, either alone or in combination with other pharmaceutically acceptable excipients, may also be administered.

These solutions, particularly for ophthalmic use, can be formulated as 0.01% -10% isotonic solutions at a pH of about 5-7 with appropriate salts.

4.1.5 compositions for other routes of administration

Other routes of administration are also contemplated herein, such as topical application, transdermal patches, and rectal administration.

For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic action. Rectal suppositories, as used herein, mean solids for insertion into the rectum which melt or soften at body temperature to release one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances for rectal suppositories are bases or carriers and agents that increase the melting point. Examples of bases include cocoa butter (cocoa butter), glycerol-gelatin, carbowax (polyethylene glycol) and suitable mixtures of mono-, di-and triglycerides of fatty acids. Combinations of various substrates may be used. Agents used to increase the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared by compression or by molding. An exemplary weight of the rectal suppository is about 2 to 3 grams.

Tablets and capsules for rectal administration may be prepared using the same pharmaceutically acceptable materials by the same methods as those used for preparing formulations for oral administration.

4.1.6 sustained Release compositions

The active ingredients provided herein can be administered by sustained release devices or delivery devices known to those of ordinary skill in the art. Examples include, but are not limited to, those disclosed in U.S. Pat. nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123 and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500, and 6,740,634, the contents of which are each incorporated herein by reference. Such dosage forms may provide sustained or controlled release of one or more active ingredients by providing desired release profiles in varying proportions using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof. Suitable controlled release dosage forms known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

All controlled release drug products share the following common objectives: the curative effect of the medicine is improved to exceed that of the non-released product. In one embodiment, the use of an optimally designed controlled release formulation in medical treatment is characterized by: the disease is cured or controlled in the shortest time with the least amount of medicine. In one embodiment, the advantages of a controlled release formulation include prolonged drug activity, reduced dosing frequency, and improved patient compliance. In addition, controlled release formulations may be used to affect the time at which the effect begins or other characteristics, such as blood levels of the drug, and thereby affect the incidence of side effects (e.g., adverse side effects).

Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously release amounts of other drugs to maintain that level of therapeutic or prophylactic effect over an extended period of time. In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at a rate that will compensate for the amount of drug that is metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

In certain embodiments, the agent can be administered by intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other mode of administration. In one embodiment, a pump may be used (see, e.g., CRC Crit. Ref. biomed. Eng.14: 201 (1987); Buchwald et al, Surgery 88: 507 (1980); Saudek et al, N.Engl. J. Med. 321: 574 (1989)). In another embodiment, a polymeric material may be applied. In another embodiment, a Controlled Release system may be placed in proximity to the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, medical applications of Controlled Release, vol.2, pp.115-138 (1984)).

In some embodiments, the controlled release device is introduced in the vicinity of a site of inappropriate immune activation or tumor in an individual. Other controlled release systems are discussed in the review of Langer (Science 249: 1527) -1533 (1990)). Dispersing the active ingredient in a solid inner matrix (solid inner matrix) such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethoxylated p-phenylene, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, carbonate rock silicone copolymers, hydrophilic polymers such as hydrogels of acrylates and methacrylates, collagen, crosslinked polyvinyl alcohol, and partially crosslinked hydrolyzed polyvinyl acetate, which is coated with an outer polymer film such as polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, neoprene, polyethylene-vinyl acetate copolymer, polyethylene-vinyl acetate, Chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionic polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxy-alcohol copolymers, the outer polymer film being insoluble in body fluids. The active ingredient diffuses through the outer polymer film during the release rate controlling step. The proportion of active ingredient contained in such parenteral compositions is highly dependent on its characteristic properties, as well as the activity of the active ingredient and the needs of the individual.

4.1.7 Targeted dosage forms

The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to target specific tissues, receptors, or other areas of the body of the individual to be treated. Many such targeting methods are known to those skilled in the art. All such targeting methods are contemplated for use in the compositions herein. Non-limiting examples of targeting methods can be found in, for example, U.S. patents 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

In one embodiment, a liposome suspension comprising tissue-targeting liposomes, such as tumor-targeting liposomes, can also be used as a pharmaceutically acceptable carrier. These can be prepared by methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) are formed by gradually drying egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) in a flask. A solution of the compound provided by the present invention in Phosphate Buffered Saline (PBS) lacking divalent cations was added, and then the flask was shaken until the lipid membrane was dispersed. The resulting vesicles were washed to remove unencapsulated compounds, centrifuged into round spheres, and then resuspended in PBS.

Article of manufacture

The compounds or pharmaceutically acceptable derivatives thereof may be packaged as articles of manufacture containing packaging materials, the compounds provided herein or pharmaceutically acceptable derivatives thereof useful for treating, preventing or ameliorating one or more symptoms associated with serine hydrolase enzymes, including but not limited to neutrophil elastase activity, and labeling indicating that the compounds or pharmaceutically acceptable derivatives thereof are useful for treating, preventing or ameliorating one or more symptoms of serine hydrolase mediated diseases, including but not limited to neutrophil elastase mediated diseases.

Articles of manufacture provided by the present invention comprise packaging materials. Packaging materials for packaging pharmaceutical products are well known to those skilled in the art. See, for example, U.S. patents 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected dosage form and target mode of administration and treatment. Various combinations of dosage forms are contemplated that include the compounds and compositions provided herein.

Evaluation of Compound Activity

Standard physiological, pharmacological and biochemical methods of testing such compounds to identify compounds having a biological activity of interest already exist. Serine hydrolase activity, including but not limited to neutrophil elastase activity, of the compounds provided herein can be readily determined using the assays described herein as well as assays well known to those of ordinary skill in the art. The following is an illustration of a human neutrophil elastase-mediated condition.

For acute respiratory distress syndrome or adult respiratory distress syndrome, reference may be made to a method using the Human Neutrophil Elastase (HNE) model (AARD, 141-.221-611 (1990)); the endotoxin-induced acute lung injury model in minipigs (AARD, 142: 782-788 (1990)); or a method using a hamster human polymorphonuclear leukocyte elastase-induced pulmonary hemorrhage model (European patent publication 0769498); in ischemia/reperfusion, reference can be made to the method used in a canine model of perfusion injury (J.Clin. invest., 81: 624-629 (1988)).

Methods of use of compounds and compositions

Methods of use of the compounds and compositions are also provided. The methods include both in vitro and in vivo uses of the compounds and compositions.

In certain embodiments, the present invention provides methods of inhibiting the action of serine hydrolases, including but not limited to neutrophil elastase, by administering the compounds and compositions provided herein. In one embodiment, the method comprises contacting the serine hydrolase, including but not limited to neutrophil elastase, with a compound provided herein.

In other embodiments, the invention provides methods of treating, preventing, or ameliorating one or more symptoms of a disease or condition, including but not limited to conditions associated with respiratory distress syndrome, Adult Respiratory Distress Syndrome (ARDS), cystic fibrosis, emphysema, Chronic Obstructive Pulmonary Disease (COPD), and ischemia reperfusion injury. The compounds provided by the present invention may also be used to modulate endogenous and/or exogenous biological stimuli that cause and/or propagate the following diseases by administering the compounds and compositions provided by the present invention: atherosclerosis, diabetes, myocardial infarction; liver diseases including but not limited to cirrhosis, systemic lupus erythematosus, inflammatory diseases of lymphoid origin including but not limited to inflammatory diseases of T lymphocytes, B lymphocytes, thymocytes; autoimmune diseases, bone marrow; arthritis (especially rheumatoid arthritis, osteoarthritis and gout); gastrointestinal inflammation (particularly enteritis, ulcerative colitis, pancreatitis and gastritis); dermatitis (especially psoriasis, eczema, dermatitis); tumor metastasis or invasion; diseases with uncontrolled extracellular matrix degradation, such as osteoarthritis; bone resorption diseases (e.g., osteoporosis, Paget's disease); diseases associated with abnormal angiogenesis; enhanced collagen remodeling associated with diabetes, periodontal disease (e.g., gingivitis), corneal ulceration, dermal ulceration, post-operative conditions (e.g., colonic anastomosis) and skin wound healing; demyelinating diseases of the central and peripheral nervous system (e.g. multiple sclerosis); age-related diseases such as senile dementia, cardiovascular inflammatory diseases; granulomatous disease; kidney diseases including, but not limited to, nephritis and polyarteritis; cancer; pulmonary hypertension, intake of poisons, skin contact, stings, bites; asthma; rhinitis; exacerbation of HIV disease, and also for minimizing organ rejection in organ transplants, including but not limited to human organ transplants; and alternative protease inhibitor therapies.

In other embodiments, the invention provides methods of treating, preventing or ameliorating one or more symptoms of a disease or disorder selected from emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, idiopathic interstitial pneumonia, cystic fibrosis of the lung, chronic interstitial pneumonia, chronic bronchitis, chronic sinus lung infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic rheumatoid arthritis, joint induration, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplants, premature amnion rupture, bullous skin disease, shock, sepsis, systemic lupus erythematosus, crohn's disease, disseminated intravascular coagulation, tissue damage following ischemia reperfusion, pulmonary fibrosis, and pulmonary fibrosis, or pulmonary fibrosis, corneal scar tissue formation and myelitis.

Combination therapy

The compounds provided herein can be administered as a single active ingredient or in combination with other active ingredients. Other active ingredients that may be used in combination with the compounds provided herein include, but are not limited to, compounds known to treat serine hydrolase mediated diseases. In one embodiment, the second active agent used in combination with the compounds provided herein is used to treat, prevent or ameliorate a disease mediated by neutrophils (e.g., human neutrophil elastase). In certain embodiments, the second active agent has serine hydrolase inhibitor activity. In general, various serine hydrolase inhibitors, and in particular inhibitors of neutrophil elastase, are well known in the art. Exemplary serine hydrolase inhibitors are disclosed in U.S. patent 6,001,814, U.S. patent 6,001,813, U.S. patent 6,150,334, U.S. patent 6,001,811, and U.S. application publication 20030203851.

It will be appreciated that each suitable combination of a compound provided by the present invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is contemplated herein.

It should be understood that the detailed description and accompanying examples are intended for purposes of illustration only and are not intended to limit the subject matter described. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, and/or methods of use provided herein, may be made without departing from the spirit and scope thereof. U.S. patents and publications referred to herein are incorporated by reference.

5. Examples of the embodiments

The compounds provided herein can be prepared by synthetic methods known in the art and described herein. Methods for the synthesis of exemplary compounds are described in examples 1-3. Table 1 provides additional examples prepared by similar methods and their conventional modifications. Electrospray mass spectrometry characterization data for various compounds are provided in table 1.

Unless otherwise indicated, all reagents and solvents were obtained from commercial sources, such as Aldrich chemical Company (Milwaukee, Wis.). Wang resin and HOBt were purchased from Novabiochem. CDI and 6-methyl-anthranilic acid were obtained from alfaaaesar. 2-Fluoronicotinic acid was obtained from Matrix Scientific. The compounds were characterized by 1H NMR spectroscopy and/or electrospray ionization mass spectrometry: in deuterated chloroform (CDCl)₃) And water (D)₂O) as residue¹Solvent peak H as internal standard, proton NMR was recorded on a Bruker 400MHz NMR spectrometer: (¹H NMR) spectrum. LC (ES) MS analysis was performed on an Agilent1100Series LC/MSD using ChemStation software. The analysis of LC/MS was carried out on a C18 reverse phase column (Onyx, monolith, 50X 4.6 mm; Phenomenex; Torrance, CA) using a binary system of water and acetonitrile with 0.1% trifluoroacetic acid as a conditioning agent. Preparative HPLC was performed using a C18 reverse phase column (Polaris, 5. mu. column, 150X 21.2 mm; Varian; Torrance, Calif.). Preparative HPLC analysis was performed on Hitachi D-7000Series using a binary system of water and acetonitrile (0.1% acetic acid as the modifier). Flash silica gel column chromatography was performed on either a manually packed column or an SP-4 automated purification system using a pre-filled silica gel cartridge (Biotage; Charlottesville, VA). Blood was collected from the sample and placed into heparin coated tubes containing 5000 kallikrein inhibitor units of aprotinin. Plasma was immediately separated by centrifugation at 4 ℃ and stored at-70 ℃ until analysis.

EXAMPLE 1 preparation of 2- (2-imidazol-l-yl-pyridin-3-yl) -5-methyl-4H-benzo [ d ] [1, 3] oxazin-4-one (A)

A solution of 2-fluoro-nicotinic acid (2.4g, 17mmol) and N, N' -carbonyldiimidazole (CDI, 2.76g, 17.0mmol) in dry acetonitrile (12mL) was stirred at ambient temperature for 30 minutes, then heated to 65 ℃ for 1 hour. To the reaction mixture was added 2-amino-6-methyl-benzoic acid (2.57g, 17mmol) and then stirred at 65 ℃ for 1 hour. To the stirring reaction mixture was added additional CDI (2.76g, 17mmol) and heating continued to 100 ℃ for 1 hour. The reaction mixture was then concentrated by rotary evaporator. The crude material was loaded onto a silica gel column. The impurities were removed in a gradient of 0-60% EtOAc/hexanes and compound 2 was eluted from the column with 100% EtOAc (5% triethylamine as the conditioning agent). Rotary evaporation gave compound a as a yellow powder (2.28g, 44% yield).¹H-NMR δ(CDCl₃)：8.70(dd，1H，J＝4.8Hz，J＝2.0Hz)，8.40(dd，1H，J＝8.0Hz，J＝1.6Hz)，7.94(s，1H)，7.67(t，1H，J＝15.6Hz，J＝8Hz)，7.51(dd，1H，J＝7.6Hz，J＝4.8Hz)，7.33-7.38(m，3H)，7.16(s，1H)，2.83(s，3H).ESMS：305.1[M+H]⁺，327.1[M+Na]⁺。

EXAMPLE 2 preparation of 2- [2- (3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl ] -5-methyl-4H-benzo [ d ] [1, 3] oxazin-4-one (46)

Preparation of 2-Fluoronicotinic acid lipidated Wang resin (B): to a suspension of Wang resin (1.2mmol/g, 15g, 18mmol) in dichloromethane (DCM, 150mL) was added at room temperature a solution of 2-fluoro-nicotinic acid (3.3g, 23.4mmol) and 1-hydroxy-4H-benzotriazole (HOBt, 3.58g, 23.4mmol) in DC (30mL) and N, N '-dimethylformamide (DMF, 15mL), followed by 4-dimethylaminopyridine (DMAP, 286mg, 2.34mmol) and N, N' -diisopropylcarbodiimide (DIC, 3.65g, 23.4 mmol). The mixture was stirred at room temperature for 12 hours. The resin was washed successively with DCM and MeOH, and dried in vacuo to afford resin B (17.54g, 100%).

Preparation of 2- (3-dimethylamino-pyrrolidin-l-yl) -nicotinic acid (C): to a suspension of resin B (1.2mmol/g, 5.0g, 8.0mmol) in pyridine (12mL) at room temperature was added dimethyl-pyrrolidin-3-yl-amine (1.37mL, 12mmol) and 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU, 2.2mL, 14.4 mmol). The mixture was stirred under nitrogen at 100 ℃ for 12 hours. The resin was washed successively with DCM and MeOH (3 ×), and dried in vacuo. Compound C was isolated from the resin by addition of 50% trifluoroacetic acid in DCM. The mixture was stirred at room temperature for 30 minutes. The resin was washed with DCM (3 ×), and the filtrate was concentrated on a rotary evaporator. 1N aqueous HCl (2mL) was added and then lyophilized to give Compound C as a pale pink gum (2.2 g). This compound was used in the next step without further purification.¹H-NMR δ(CDCl₃)：10.85(s，1H)，8.26(dd，1H，J＝4.8Hz，J＝1.6Hz)，7.96(dd，1H，J＝7.2Hz，J＝2.0Hz)，6.81(dd，1H，J＝7.6Hz，J＝4.8Hz)，3.92-3.94(m，1H)，3.70-3.80(m，2H)，3.52-3.54(m，1H)，3.43(m，1H)，2.80(m，6H)，2.20(m，1H)，2.17(m，1H).ESMS：236.0[M+H]⁺。

2- [2- (3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-methyl-4H-benzo [ d][1，3]Preparation of oxazin-4-one (46). A solution of Compound C (133mg, 0.56mmol) and CDI (91mg, 0.56mmol) in dry acetonitrile (1.0mL) was stirred at ambient temperature for 1 hour. 2-amino-6-methyl-benzoic acid (41mg, 0.27mmol) was added and the mixture was stirred at 60 ℃ overnight. The reaction solution was diluted with water (2mL) and DMF (2mL), filtered, and then diluted with C₁₈Purification by reverse phase chromatography afforded compound 46 as a beige powder (11mg, 35% yield).¹H-NMR δ(CDCl₃)：8.32(dd，1H，J＝4.8Hz，J＝2.0Hz)，8.09(dd，1H，J＝8.0Hz，J＝1.6Hz)，7.68(t，1H，J＝15.6Hz，J＝0.8Hz)，7.52(t，1H，J＝4.0Hz，J＝7.6Hz)，7.33(d，1H，J＝7.2Hz)，6.82(dd，1H，J＝8Hz，J＝4.8Hz)，3.95(br s，1H)，3.81(br s，1H)，3.57-3.64(m，2H)，3.48-3.53(m，2H)，2.83(s，3H)，2.64(br s，6H)，2.30(br s，1H).ESMS：351.1[M+H]⁺。

EXAMPLE 3 preparation of 2- [2- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -pyridin-3-yl ] -5-methyl-4H-benzo [ d ] [1, 3] oxazin-4-one (52).

2- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy]-ethoxy } -ethoxy) -nicotinic acid (D) preparation. At ambient temperature and N₂Will be as follows^tBuOK in THF (20% wt, 561.0uL, 1.0mmol) was added to a mixture of 2-fluoronicotinic acid (70.6mg, 0.50mmol) and tetraethylene glycol monomethyl ether (105.5. mu.L, 0.50mmol) dissolved in THF (2.0 mL). The mixture was heated at 100 ℃ for 3 hours. The reaction mixture was diluted with EtOAc. The organic phase is acidified with 1N HCl solution, washed with saturated NaCl solution and then with Na₂SO₄And (5) drying. Filtration and concentration in vacuo afforded compound D (148.1mg, 90%) as a pale yellow liquid, which was used in the next step without further purification. ESMS: 330.0[ M + H]⁺，352.0[M+Na]⁺，368.0[M+K]⁺。

2- [2- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy]-ethoxy } -ethoxy) -pyridin-3-yl]-5-methyl-4H-benzo [ d][1，3]Preparation of oxazin-4-one (52). N, N' -carbonyldiimidazole (CDI, 81.1mg, 0.50mmol) at 65 ℃ and N₂Compound D (164.7mg, 0.50mmol) was treated with CH₃CN (2.0mL) solution for 1 hour. 6-Methylanthranilic acid (75.6mg, 0.50mmol) was added at 25 ℃ and the mixture was then heated at 65 ℃ overnight. Additional CDI (81.1mg, 0.50mmol) was added and the mixture was heated at 65 ℃ for 8 h. Through C₁₈The crude mixture was purified by reverse phase chromatography to give compound 52(120.0mg, 54%) as a colorless gum.¹H-NMR(400mHz，CDCl₃)δ 8.29(dd，1H，J＝5.2Hz，J＝2.0Hz)，8.25(dd，1H，J＝7.6Hz，J＝2.0Hz)，7.66(t，1H，J＝7.8Hz)，7.50(d，1H，J＝7.6Hz)，7.31(d，1H，J＝7.6Hz)，7.01(dd，1H，J＝7.4Hz，J＝5.0Hz)，4.62(m，2H)，3.94(m，2H)，3.78(m，2H)，3.62(m，8H)，3.51(m，2H)，3.34(s，3H)，2.82(s，3H).ESMS：445.0[M+H]⁺，467.0[M+Na]⁺。

EXAMPLE 4 preparation of dimethyl 3-ethyl-5-methoxyphthalate (I)

Compounds D', E and F are commercially available or can be prepared by methods known in the art (e.g., Meyers, A.I. et al, Journal of Organic Chemistry, 1372(1978)),

preparation of 2- (4, 4-dimethyl-4, 5-dihydrooxazol-2-yl) -3-ethyl-5-methoxy-benzoic acid (G). Sec-BuLi (400mL, 1.04mol/L, dissolved in hexane/cyclohexane) was added dropwise to dry Et of compound F (80.0g, 343mmol) and TMEDA (480mL, 3.18mmol) at-78 deg.C (between-70 deg.C and-68 deg.C) and Ar atmosphere (over 30 minutes)₂O solution (1.70L). After stirring at this temperature for 1 hour, with CO₂The reaction is treated with a gas (bubbling for 20 minutes or more, at a temperature of-70 to-55 ℃). After gradually warming to room temperature over 1.5 hours, the reaction mixture was poured into ice water (1.0L). The aqueous layer was washed once with ethyl acetate and acidified (pH 2-3) with concentrated HCl (aq) at 0 ℃. The precipitate was filtered and washed with a small amount of water to give compound G (55.7G, 201mmol) as the desired beige solid. The filtrate was extracted 15 times with ethyl acetate/methanol (10/1), Na₂SO₄The combined organic phases were dried and concentrated in vacuo to afford crude compound G (18.0G) as a beige solid.¹HNMR(DMSO-d₆，400MHz)：δ 1.13(3H，t，J＝7.6Hz)，1.26(6H，s)，2.65(2H，q，J＝7.6Hz)，3.80(3H，s)，3.96(2H，s)，7.04(1H，d，J＝2.4Hz)，7.15(1H，d，J＝2.4Hz).CIMS(+)：278[M+H]⁺。

3-ethyl-5-methoxyPreparation of phthalate (H). Mixing 6.00mol/L H₂SO₄(aqueous) solution (700mL) was added to a solution of compound G (65.7G, 237mmol) in 1, 4-dioxane (700mL) at room temperature. The mixture was heated at 130 ℃ (oil bath temperature) and stirred. After 64 hours, the mixture was concentrated in vacuo and cooled to 0 ℃. The precipitate was filtered and washed with a small amount of water to give compound H (23.8g, 106mmol) as the desired beige solid. The filtrate was extracted twice with ethyl acetate and Na₂SO₄The combined organic phases were dried, filtered, and concentrated in vacuo to afford title compound H (10.8g, 48.2mmol) as a beige solid. (after treatment with NaCl) with CHCl₃/MeOH (4/1) extraction of the aqueous phase with Na₂SO₄The combined organic phases were dried and concentrated in vacuo to recover starting material G (26%).¹HNMR(DMSO-d₆；400MHz)：δ 1.14(3H，t，J＝7.6Hz)，2.60(2H，q，J＝7.6Hz)，3.80(3H，s)，7.04(1H，d，J＝2.4Hz)，7.16(1H，d，J＝2.4Hz).EIMS(+)：224[M]⁺。

Preparation of dimethyl 3-ethyl-5-methoxyphthalate (I). Will K₂CO₃(63.9g, 462mmol) and MeI (28.8mL, 462mmol) were added to a DMF solution (500mL) of compound H (34.6g, 154mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2h and at 40 ℃ for 1h, MeI (28.8mL, 462mmol) was added and the mixture was stirred for 14 h. Additional MeI (28.8mL, 462mmol) was then added to the reaction mixture. After stirring for 8 hours, the mixture was concentrated in vacuo and water was added to the residue. The aqueous phase was extracted 3 times with ethyl acetate, followed by H₂The combined organic phases were washed with O and brine and Na₂SO₄And (5) drying. The organic phase was then concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate: hexane ═ 1:6) to give the title compound I (36.0g, 143mmol) as a pale yellow oil.

EXAMPLE 5 Synthesis of protected anthranilic acid, methyl 2-ethyl-4-methoxy-6- (methoxycarbonylamino) benzoate (O)

Preparation of 4-methoxy-6-methyl-2H-pyran-2-one (K). Potassium carbonate (71.2g, 515mmol) and dimethyl sulfate (48.7mL, 515mmol) were added to a solution of Compound J (50.0g, 396mmol) in dry acetone (1.45L). The mixture was heated to reflux for 3 hours and cooled to room temperature. The solids were removed by filtration and the filtrate was concentrated. The oily residue was purified by silica gel chromatography (ethyl acetate: hexane ═ 1:1) to give an oily solid. The oily solid was washed with diisopropyl ether to give compound K (42.3g, 76%) as a yellow powder.¹H NMR(CDCl₃，400MHz)：δ 2.21(3H，s)，3.79(3H，s)，5.41(1H，d，J＝1.8Hz)，5.77-5.78(1H，m).EIMS(+)：140[M]⁺。

Preparation of dimethyl 5-methoxy-3-methylphthalate (L). A mixture of compound K (41.4g, 295mmol) and dimethyl but-2-ynedioate (47.2mL, 384mmol) was stirred at 180 ℃ for 1h and then at 210 ℃ for 30 min. The mixture was cooled to room temperature and purified by silica gel chromatography (ethyl acetate: hexane ═ 20:1-4:1) to give compound L (53.4g, 76%) as a pale yellow oil.¹HNMR(CDCl₃，400MHz)：δ 2.34(3H，s)，3.84(3H，s)，3.88(3H，s)，3.90(3H，s)，6.91(1H，d，J＝2.4Hz)，7.29(1H，d，J＝2.4Hz).EIMS(+)：238[M]⁺

Preparation of 5-methoxy-2- (methoxycarbonyl) -3-methyl-benzoic acid (M). To a solution of compound L (50.0g, 210mmol) in 1, 2-dimethoxyethane (260mL) at 0 deg.C was added 8% aqueous NaOH (262 mL). The mixture was stirred at room temperature for 1 hour, washed with ethyl acetate and acidified to pH 2 with 3 mol/LHCl. The precipitate was filtered and washed with water to give compound M (40.0 g). The filtrate was extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated brine and with anhydrous Na₂SO₄And (5) drying. Filtration and evaporation of the solvent gave compound M as a white powder (5.47, 96% overall yield).¹HNMR(CDCl₃，400MHz)：δ 2.35(3H，s)，3.86(3H，s)，3.90(3H，s)，6.97(1H，d，J＝2.4Hz)，7.39(1H，d，J＝2.4Hz).EIMS(+)：224[M]⁺

Preparation of methyl 4-methoxy-2- (methoxycarbonylamino) -6-methylbenzoate (N). To a suspension of compound M (45.4g, 202mmol) in 1, 4-dioxane (420mL) was added MeOH (40.9mL, 1010mmol) and triethylamine (56.3mL, 404 mmol). The mixture was heated to 100 ℃ and diphenylphosphonic acid azide (65.3mL, 303mmol) was added dropwise to the mixture over 15 minutes. The mixture was stirred at 100 ℃ for 1 hour and concentrated. With saturated NaHCO₃The residue was diluted with aqueous solution and extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated brine and with anhydrous Na₂SO₄And (5) drying. The combined organic layers were then filtered and evaporated. The resulting residue was crystallized from iPrOH to give a white solid. The solid was dissolved in ethyl acetate, and the resulting solution was washed with water and saturated brine, and washed with anhydrous Na₂SO₄And (5) drying. Filtration and evaporation of the solvent gave compound N (33.0 g). Further, the mother liquor was diluted with ethyl acetate, washed with water and saturated brine, and washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The resulting residue was crystallized from iPrOH to give compound N as a white powder (4.29g, 73% overall yield).¹HNMR(CDCl₃，400MHz)：δ 2.45(3H，s)，3.77(3H，s)，3.84(3H，s)，3.90(3H，s)，6.45(1H，d，J＝2.4Hz)，7.84(1H，d，J＝2.4Hz)，9.97(1H，s).EIMS(+)：253[M]⁺

Preparation of methyl 2-ethyl-4-methoxy-6- (methoxycarbonylamino) benzoate (O). A THF solution (600mL) of potassium tert-butoxide (50.7g, 452mmol) and diisopropylamine (63.3mL, 452mmol) was cooled to-78 deg.C under argon and n-butyllithium dissolved in hexane (1.6mol/L, 226mL, 361mmol) was added to the solution over 25 minutes. After stirring at-78 ℃ for 15 min, a solution of the compound N (30.5g, 120mmol) in THF (120ml) was added to the mixture at-78 ℃ over 15 min. The mixture was stirred at-78 ℃ for an additional 20 minutes. Methyl iodide (22.5mL, 361mL) was added in one portion at-78 ℃. After stirring for 10 minutes at-78 ℃,the mixture is injected into saturated NH₄Aqueous Cl solution. THF was removed from the mixture under vacuum and extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated brine and with anhydrous Na₂SO₄And (5) drying. Filtration and evaporation of the solvent gave compound O (32.9g, quantitative) as a yellow oil.

Example 6 an alternative Synthesis of protected anthranilic acid, methyl 2-ethyl-4-methoxy-6- (methoxycarbonylamino) benzoate (O)

Preparation of dimethyl 3-ethyl-5-methoxyphthalate (P). The following is based on the method described by tar, t.f. and Coles p., Synthesis, 383 (1988). 6-Ethyl-4-methoxy-2H-pyran-2-one (40.5g, 263mmol) was placed in a 500mL round bottom flask and dimethyl acetylene dicarboxylate (42mL, 342mmol) was added. The mixture was stirred until the solid was completely dissolved. The flask was connected to a water condenser and placed in a pre-heated oil bath at 180 ℃ for 3 hours. The reaction was cooled to room temperature, diluted with dichloromethane (75mL) and purified by silica gel chromatography gradient using 5-20% ethyl acetate in hexanes. The appropriate fractions were collected and concentrated by rotary evaporation to give compound P as a clear oil (44.16g, 67%).¹H NMR CDCl₃δ：7.30(d，1H，J＝3Hz)，6.95(s，1H，J＝3Hz)，3.90(s，3H)，3.88(s，3H)，3.85(s，3H)，2.64(q，2H，J＝8.0Hz)，1.21(t，3H，J＝8.0Hz).ESMS m/z：221[M-OCH₃]⁺，275[M+Na⁺].

Preparation of 3-ethyl-5-methoxy-2-methoxycarbonylbenzoic acid (Q). NaOH (17.46g, dissolved in 218.0mL H) at 0 deg.C₂O, 436.6mmol) was added dropwise to a solution of compound P (44.06g, 174.7mmol) in 1, 2-dimethoxyethane (218.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The aqueous phase was then washed with dichloromethane (100mL) and acidified to pH 2 with 3N HCl. The acid was extracted with ethyl acetate (3X 400mL)The aqueous layer was combined, the combined organic layers were washed with brine, and then with anhydrous Na₂SO₄And (5) drying. Filtration and concentration by rotary evaporation gave compound Q (40.15g, 96%) as a white powder.¹H NMR(CDCl₃，400MHz)δ：7.41(d，1H，J＝2.0Hz)，7.01(d，1H，J＝3.0Hz)，3.90(s，3H)，3.87(s，3H)，2.65(q，2H，J＝7.5Hz)，1.23(t，3H，J＝7.5Hz).ESMS m/z 261.0[M+Na⁺]，207.0[M-OMe]⁺.

Preparation of methyl 2-ethyl-4-methoxy-6-methoxycarbonylamino-benzoate (O). In N₂To a suspension of compound Q (40.15g, 168.5mmol) in 1, 4-dioxane (360mL) was added MeOH (34mL, 840mmol) and triethylamine (47mL, 340mmol) next. The clear solution was heated to 100 ℃ and diphenylphosphonic acid azide (54.48mL, 252.8mmol) was added dropwise to the reaction. The mixture was stirred at 100 ℃ for a further 1 hour. The reaction mixture was then concentrated and the resulting residue was diluted with saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was extracted with ethyl acetate (1X 600mL and 3X 300mL), and washed with H₂The combined organic layers were washed with O (75mL) and then concentrated by rotary evaporation. Flash column chromatography using 10-15% ethyl acetate in hexanes gradient afforded compound O (34.9g, 78%) as a yellow oil.¹HNMR(CDCl₃，400MHz)δ：9.54(bs，1H)，7.78(d，1H，J＝3.0Hz)，6.48(d，1H，J＝3.0Hz)，3.90(s，3H)，3.84(s，3H)，3.76(s，3H)，2.78(q，2H，J＝7.0Hz)，1.18(t，3H，J＝7.5Hz).ESMS m/z：290.0[M+Na⁺]，236.0[M-OMe]⁺.

Example 7: synthesis of 2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl ] -5-ethyl-7-methoxy-4H-benzo [ d ] [1, 3] oxazin-4-one (132).

[00264]5-Ethyl-2- (2-fluoro-pyridin-3-yl) -7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-ones (S). To a suspension of 2-fluoro-nicotinic acid (13.6g, 96.6mmol) in anhydrous acetonitrile (400mL) was added 1, 1' -carbonyldiimidazole (15.7g, 96.6mmol) and N at room temperature₂The mixture was stirred for 2 hours. Compound R (15.7g, 80.5mmol) was added and the mixture was stirred at room temperature overnight. 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride (30.86g, 161.0mmol) was added in two portions over 30 minutes. The mixture was stirred at room temperature for 1 hour. The precipitate formed during stirring was filtered off, washed with glacial acetonitrile and then dried under high vacuum to give compound S (13.94g) as a white powder. In addition, the filtrate was concentrated and purified by silica gel chromatography gradient with 10-15% ethyl acetate/hexanes to give additional amount of compound S (6.78g, 86% overall yield).¹H NMR(CDCl₃，400MHz)& 8.57(t，1H，J＝1.5Hz)，8.40(q，1H，J＝1.5Hz)，7.37(m，I H)，7.02(d，1H，J＝3.0Hz)，6.94(d，1H，J＝3.0Hz)，3.95(s，3H)，3.22(q，2H，J＝7.5Hz)，1.30(t，3H，J＝7.5Hz).ESMSm/z：301.0[M+H⁺]，323.0[M+Na⁺].

[00265]2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one (132). At 100 ℃ and N₂A solution of compound S (13.9g, 46.4mmol) in dry 1, 4-dioxane (232mL) was next treated with (S) - (-) -3- (dimethylamino) -pyrrolidine (7.50mL, 60.3mmol) for 10 min. The solution was concentrated and the residue was purified on a Biotage40M amine column with a gradient of 20-50% ethyl acetate in hexanes. The fractions containing compound 132 were combined and concentrated by rotary evaporation, dissolved in acetonitrile: water (1: 1, 50mL), then lyophilized to give compound 132(12.81g, 70% yield) as a pale yellow powder.¹H NMR(CDCl₃，400MHz)δ.8.30(dd，1H，J＝1.5Hz)，8.00(dd，1H，J＝1.5Hz)，6.95(d，1H，J＝2.0Hz)，6.88(d，1H，J＝3.0Hz)，6.72(q，1H，J＝4.5Hz)，3.92(s，3H)，3.66(q，1H，J＝4.0Hz)，3.48(m，3H)，3.21(m，2H)，2.78(s，1H)，2.26(s，6H)，2.12(q，1H，J＝6.0Hz)，1.84(m，1H)，1.29(t，3H，J＝7.0Hz)；¹³C NMR(CDCl₃，400MHz)δ：165.5，158.8，158.1，155.7，151.1，151.0，150.6，140.3，117.9，112.2，110.6，107.3，107.1，65.4，55.9，54.4，49.1，44.5，30.3，28.6，15.2；ESMSm/z：395.1[M+H⁺](ii) a Calculating to obtain C₂₂H₂₆N₄O₃: c, 66.99; h, 6.64; n, 14.20; and (3) measuring: c, 66.81; h, 6.66; n, 14.14.

Example 8: 2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-ones(132a) Synthesis of (2)

Preparation of 2-amino-6-ethyl-4-methoxy-benzoic acid (R). At 100 ℃ and N₂The solution was then dissolved in H by treatment with lithium hydroxide (9.80g, 410mmol)₂O, THF and MeOH (3:1:1, 255mL) of Compound O (21.9g, 82.0mmol) for 2 h. The reaction mixture was partially concentrated and the remaining aqueous phase was washed with dichloromethane (50 mL). The aqueous phase was acidified to pH 4-5 with 3N HCl and then extracted with ethyl acetate (3X 400 mL). The combined organic solutions were washed with saturated NaCl solution and anhydrous Na₂SO₄And (5) drying. Filtration and concentration by rotary evaporation gave compound R as a beige powder (15.71g, 98%).¹H NMR(CDCl₃，400MHz)δ：6.18(d，1H，J＝2.0Hz)，6.01(d，1H，J＝2.0Hz)，3.79(s，3H)，2.93(q，2H，J＝7.0Hz)，1.23(t，3H，J＝7.5Hz).ESMS m/z：196.0[M+H]⁺，178.0[M-OH]⁺.

5-Ethyl-2- (2-fluoro-pyridin-3-yl) -7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one (S). TsCl (275mg, 1.44mmol) and N-methylimidazole (285. mu.L, 3.60mmol) were added to 2-fluoro-nicotinic acid (169mg, 1.20mmol) in CH under Ar at 0 deg.C₂Cl₂(3 mL). Mixing the mixture at 0 deg.CStirred for 1 hour. Compound R (195mg, 1.00mmol) was added to the mixture at 0 ℃ over 5 minutes, then the mixture was stirred at 0 ℃ for 30 minutes and at room temperature for the 1 hour. To the mixture were added N-methylimidazole (47.5. mu.L, 0.60mmol) and TsCl (114mg, 0.60mmol) at 0 ℃ and stirred at 0 ℃ for 1 hour. The reaction mixture was poured into ice water and extracted with EtOAc. With saturated NaHCO₃The organic layer was washed with aqueous solution, water (5 times) and brine. Then using anhydrous Na₂SO₄The organic phase was dried and concentrated in vacuo to give compound S (300mg, 1.00mmol) as a white powder.

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one (132). To a solution of compound S (37.60g, 125mmol) and triethylamine (42mL, 301mmol) in anhydrous 1, 4-dioxane (800mL) was added dropwise (S) - (-) -3- (dimethylamino) -pyrrolidine (17.1g, 150mmol) at room temperature Ar. The resulting mixture was stirred for 8 hours. The solution was concentrated and diluted with water (200mL) and EtOAc (50 mL). The resulting solution was basified to pH 9 with saturated sodium bicarbonate and then extracted with ethyl acetate (3X 300 mL). The organic layers were combined, washed with water, brine, and anhydrous Na₂SO₄Dry and then remove EtOAc in vacuo. The crude product was purified by column chromatography (Chromatrex NH-DM2035, fujisissysia Chemical co. ltd.) using a gradient of 20-25% ethyl acetate/hexane to afford compound 132(37.03g, 73%) as a yellow amorphous solid.

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one-HCl (132 a). To a solution of compound 132(120mg, 0.304mmol) in diethyl ether (2.0mL) was added hydrogen chloride (4M in dioxane, 0.0722mL, 0.289mmol) at ambient temperature. After stirring for 30 min a solid formed which was filtered off, washed with diethyl ether and dried in vacuo at room temperature to give compound 132a (114mg), m.p.: 173 ℃ and 180 ℃. [ alpha ] to]_D ²⁴：-308(c 0.53，MeOH).¹H NMR(DMSO-d₆，400MHz)：δ：1.21(3H，t，J＝7.3Hz)2.14-2.21(1H, m), 2.28-2.36(1H, m), 2.72(3H, d, J ═ 4.9Hz), 2.78(3H, d, J ═ 4.9Hz), 3.08-3.17(2H, m), 3.36-3.49(3H, m), 3.68-3.96(2H, m), 3.92(3H, s), 6.89(1H, dd, J ═ 7.4, 4.3Hz), 7.01(1H, d, J-2.4Hz), 7.06(1H, d, J ═ 2.4Hz), 8.05(1H, dd, J ═ 7.4, 1.8Hz), 8.32(1H, dd, J ═ 4.3, 1.8), 10.72(1H, 72 s), 58.45 (6.35% C, 35, C₂₂H₂₆N₄O₃·HCl·H₂O，C 58.86％，H 6.51％，N 12.48％。

EXAMPLE 9 Synthesis of a salt of 2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl ] -5-ethyl-7-methoxy-4H-benzo [ d ] [1, 3] oxazin-4-one

Other salts of 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl ] -5-ethyl-7-methoxy-4H-benzo [ d ] [1, 3] oxazin-4-one (compound 132) may be prepared with reference to the following procedure.

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one HCl H₂And (4) preparing O. To a solution of compound 132(120mg, 0.304mmol) in diethyl ether (2.0mL) was added hydrogen chloride (4M in dioxane, 0.0722mL, 0.289mmol) at room temperature. After stirring for 30 min, the resulting solid was filtered, washed with diethyl ether and dried in vacuo at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a pale yellow solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one HCl H₂O(114mg)。Mp173-180℃.[α]_D ²⁴-308(c 0.53，MeOH).′H NMR(DMSO-d₆400 MHz): δ 1.21(3H, t, J ═ 7.3Hz), 2.14-2.21(I H, m), 2.28-2.36(1H, m), 2.72(3H, d, J ═ 4.9Hz), 2.78(3H, d, J ═ 4.9Hz), 3.08-3.17(2H, m), 3.36-3.49(3H, m), 3.68-3.96(2H, m), 3.92(3H, s), 6.89(1H, dd, J ═ 7.4, 4.3Hz), 7.01(1H, d, J ═ 2.4Hz), 7.06(1H, d, J ═ 2.4Hz), 8.05(1H, dd, J ═ 7.4, 1.8Hz), 8.32(1H, dd, J ═ 7.4, 1.32, J ═ 2.84%, 10.84%, 6.6H, 6.5H, 6.84%, 6.6.6.6.6.6.6.6.6H, d, J ═ 2.4Hz, 8,3To obtain C₂₂H₂₆N₄O₃·HCl·H₂O，C 58.86％，H 6.51％，N 12.48％。

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one 2HCl 2H₂And (4) preparing O. To a solution of compound 132(120mg, 0.304mmol) in 1, 4-dioxane (2.0mL) was added hydrogen chloride (4M in dioxane, 0.228mL, 0.913mmol) at room temperature. After stirring for 30 min, the resulting solid was filtered, washed with diethyl ether and dried in vacuo at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a pale yellow solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one 2HCl 2H₂O(120mg)。Mp150-159℃.[α]_D ²⁶-272(c 0.52，MeOH).¹H NMR(DMSO-(I₆400 MHz): δ 1.21(3H, t, J ═ 7.3Hz), 2.21-2.36(2H, m), 2.68(3H, d, J ═ 4.3Hz), 2.75(3H, d, J ═ 4.3Hz), 3.06-3.16(2H, m), 3.50-3.55(2H, m), 3.67-3.72(1H, m), 3.84-3.96(2H, m), 3.93(3H, s), 6.92(1H, dd, J ═ 7.4, 4.3Hz), 7.00(1H, d, J ═ 2.4Hz), 7.10(1H, d, J ═ 2.4Hz), 8.10(1H, dd, J ═ 7.4, 1.8, 8.32(1H, dd, 3.11.11H, 11.53%), c.11H, 11.11H, 13, C, 11.11.3 Hz), C, d, C₂₂H₂₆N₄O₃·2HCl·2H₂O，C 52.49％，H 6.41％，N 11.13％。

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one methane sulfonate monohydrate. To a solution of compound 132(120mg, 0.304mmol) in diethyl ether (3.0mL) was added methanesulfonic acid (0.0394mL, 0.608mmol) dissolved in diethyl ether (1.0mL) at room temperature. After stirring for 30 min, the resulting solid was filtered, washed with diethyl ether and dried under vacuum at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a white solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one methanesulfonate monohydrate (141 mg). Mp 43-49 deg.C]_D ²⁵-205(c 0.34，MeOH).¹H NMR(DMSOd₆400 MHz): δ 1.21(3H, t, J ═ 7.3Hz), 2.07-2.12(1H, m), 2.31-2.35(1H, m), 2.33(6H, s), 2.79(3H, d, J ═ 4.9Hz), 2.82(3H, d, J ═ 4.3Hz), 3.07-3.15(2H, m), 3.48(2H, dd, J ═ 8.6, 5.5Hz), 3.68-3.80(2H, m), 3.89-3.96(1H, m), 3.91(3H, s), 6.27(1H, brs), 6.91(1H, dd, J ═ 7.9, 4.9Hz), 7.01(1H, d, J, 2.4Hz), 7.03(1H, br), 6.91(1H, dd, J ═ 7.9, 4.9Hz), 7.01(1H, d, J ═ 2.4, 7.03, 8H, 8, 8.9H, 9H, 9, 1.9, 1H, 8, 9, 1H, 8, 9, 1H, C, 9, C, 9, C₂₂H₂₆N₄O₃·2CH₃SO₃H·H₂O，C 47.67％，H 6.00％，N9.27％.

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one trifluoroacetate. To a solution of compound 132(120mg, 0.304mmol) in diethyl ether (2.0mL) was added trifluoroacetic acid (0.0215mL, 0.289mmol) at room temperature. After stirring for 30 min, the resulting solid was filtered, washed with diethyl ether and dried in vacuo at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a pale yellow solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one trifluoroacetate (112 mg). Mp 117-]_D ²⁵-258(c 0.56，MeOH).¹H NMR(DMSO-(I₆400 MHz): δ 1.21(3H, t, J ═ 7.3Hz), 2.02-2.12(1H, m), 2.28-2.36(1H, m), 2.79(6H, s), 3.08-3.17(2H, m), 3.47(1H, dd, J ═ 8.0, 5.5Hz), 3.67-3.79(2H, m), 3.86-3.91(1H, m), 3.91(3H, s), 6.90(1H, dd, J ═ 7.9, 4.3Hz), 7.00(1H, d, J ═ 2.4Hz), 7.02(1H, d, J ═ 2.4Hz), 8.03(1H, dd, J ═ 7.4, 1.8), 8.33(1H, dd, J ═ 4, 3.91, J ═ 2.4Hz), 8.33(1H, dd, 3.85H, 3.5H, 3.85, 5, 5.85, 5, 2H, 5₂₂H₂₆N₄O₃·CF₃CO₂H，C 56.69％，H 5.35％，N 11.02％.

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Preparation of oxazin-4-one.1.5 trifluoroacetate. To a solution of compound 132(120mg, 0.304mmol) in diethyl ether (2.0mL) was added trifluoroacetic acid (0.0678mL, 0.913mmol) at room temperature. After stirring for 1 hour, the resulting solid was filtered, washed with diethyl ether and dried in vacuo at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a colorless solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one-1.5 trifluoroacetate salt (131 mg). Mp124-125 deg.C]_D ²⁵-235(c 0.58，MeOH).¹HNMR(DMSO-d₆400 MHz): δ 1.21(3H, t, J ═ 7.3Hz), 2.03-2.12(1H, m), 2.30-2.36(1H, m), 2.78(3H, d, J ═ 4.3Hz), 2.81(3H, d, J ═ 4.3Hz), 3.08-3.18(2H, m), 3.47(1H, dd, J ═ 8.6, 5.5Hz), 3.69(1H, dd, J ═ 12.2, 7.3Hz), 3.77(1H, dd, J ═ 11.6, 6.7Hz), 3.91(3H, s), 3.91-3.95(1H, m), 6.89(1H, dd, J ═ 7.4, 4.3), 7.00(1H, d, J ═ 11.6.7 Hz), 3.91(1H, s), 3.91-3.95(1H, m), 6.89(1H, dd, J ═ 7.4, 4.3), 7.00(1H, d, 2, J ═ 8.86, 8H, 8.3.3.3H, 3H, 3.86, 1H, d, 3H, 3.9, H, d, 3.3.6, 3.9, H, 3.9, H, d, H₂₂H₂₆N₄O₃·1.5CF₃CO₂H，C 53.10％，H 4.90％，N 9.91％。

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one 0.5D-tartrate H₂And (4) preparing O. To a solution of compound 132(100mg, 0.254mmol) in methanol (2.0mL) was added D-tartaric acid (19.0mg, 0.127mmol) at room temperature. After stirring for 1 hour, the resulting solid was filtered, washed with methanol and dried under vacuum at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a pale yellow solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]oxazin-4-one-hemi-D-tartrate monohydrate (49.3 mg). Mp144-145 deg.C]_D ²⁵-386(c 0.22，MeOH).¹H NMR(DMSO-d₆，400MHz)：δ 1.20(3H，t，J＝7.3Hz)，1.69-1.79(I H，m)，2.06-2.12(1H，m)，2.20(6H，s)，2.82-2.90(1H，m)，3.09-3.16(2H，m)，3.21-3.31(2H，m), 3.44-3.51(2H, m), 3.90(3H, s), 4.13(1H, s), 6.80(1H, dd, J ═ 8.0, 4.9Hz), 7.01(1H, d, J ═ 3.0Hz), 7.03(1H, d, J ═ 3.0Hz), 7.96(1H, dd, J ═ 8.0, 1.8Hz), 8.28(1H, dd, J ═ 4.9, 1.8Hz), C59.22%, H6.56%, N11.42% were calculated, C59.22%, H6.56%, N11.42% were analyzed₂₂H₂₆N₄O₃·0.5C₄H₆O₆·H₂O，C 59.13％，H 6.41％，N11.49％。

2- [2- ((S) -3-dimethylamino-pyrrolidin-l-yl) -pyridin-3-yl]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one 0.75L-tartrate H₂And (4) preparing O. To a solution of compound 132(100mg, 0.254mmol) in methanol (2.0mL) was added L-tartaric acid (19.0mg, 0.127mmol) at room temperature. After stirring for 1 hour, the resulting solid was filtered, washed with methanol and dried under vacuum at room temperature to give 2- [2- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl as a pale yellow solid]-5-ethyl-7-methoxy-4H-benzo [ d][1，3]Oxazin-4-one 0.75L-tartrate H₂O(86.3mg)。Mp 148-155℃.[α]_D ²⁵-345(c 0.052，MeOH).′H NMR(DMSO-d₆，400MHz)：δ1.20(3H，t，J＝7.3Hz)₅1.71-1.81(1H, m), 2.06-2.14(1H, m), 2.23(6H, s), 2.88-2.94(1H, m), 3.07-3.14(2H, m), 3.33-3.40(2H, m), 3.44-3.50(2H, m), 3.90(3H, s), 4.16(1.5H, s), 6.80(1H, dd, J ═ 8.0, 4.9Hz), 7.00(1H, d, J ═ 3.0Hz), 7.02(1H, d, J ═ 3.0Hz), 7.76(1H, dd, J ═ 8.0, 1.8Hz), 8.28(1H, dd, J ═ 4.9, 1.8Hz), assay 57.59%, assay C29.53%, c.7H, C3H, C7.0, C3, C7, C3, C₂₂H₂₆N₄O₃·0.75C₄H₆O₆·H₂O，C 57.19％，H 6.24％，N 10.67％.

Example 10 Synthesis of Quaternary ammonium with HNE inhibitors

{1- [3- (5-Ethyl-7-methoxy-4-oxo-4H-benzo [ d ]][1，3]Oxazin-2-yl) -pyridin-2-yl]-preparation of pyrrolidin-3-yl } -trimethyl-ammonium acetate (232). To a solution of compound 132(30mg, 0.076mmol) in dichloromethane (380 μ L) was added methyl iodide (14.2 μ L, 0.228mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. The solution was concentrated and the residue was purified by preparative HPLC. The fractions containing the target compound were lyophilized to give compound 232(27.8mg, 89%) as a yellow powder.¹HNMR(CDCl₃，400MHz)δ8.30(dd，1H，J＝4.5Hz)，8.11(dd，1H，J＝1.6Hz)，6.95(d，1H，J＝2.4Hz)，6.89(m，2H)，4.74(m，1H)，4.13(m，1H)，3.94(s，3H)，3.91(m，1H)，3.52(m，2H)，3.43(s，9H)，3.19(m，2H)，2.52(m，1H)，2.33(m，1H)，1.92(s，3H)，1.29(t，3H，J＝7.5Hz).ESMS m/z：409.1[M⁺]

EXAMPLE 11 Synthesis of pyrones

6- (2-cyclopropyl-2-oxo-ethyl) -2, 2-dimethyl- [1, 3]Preparation of dioxin-4-one (S'). To a stirred solution of THF (500mL) and diisopropylamine (32.45mL, 227mmol) at-78 deg.C was added 2M n-butyllithium (126mL, 250 mmol). The reaction was then stirred at-78 ℃ for 30 minutes. HMPA (66.58mL, 383mmol) was added to the mixture at-78 deg.C and the reaction was stirred for an additional 30 minutes. To the cooled mixture was added 2, 2, 6-trimethyl-1, 3-dioxin-4-one (25.3mL, 191mmol) dropwise, and then the reaction was stirred for another 30 minutes under reduced pressure. Cyclopropanecarbonyl chloride (8.76mL, 95.7mmol) was then added dropwise to the reaction. The mixture was warmed to ambient temperature and stirred overnight. The reaction was cooled in an ice bath and 1N HCl was added to reach pH 6. The reaction was extracted with diethyl ether (3X 100 mL). The organic layers were combined, washed with brine (3 × 50mL), dried over sodium sulfate, filtered, and concentrated to a dark brown oil by rotary evaporation. A gradient of 2.5-5% EtOAc in hexanes was used followed by 2.5% EtOAc/dichloromethane, purification of compound S' was achieved by silica gel chromatography. Fractions with the product were pooled and concentrated by rotary evaporation to give compound S' as a clear oil (6.21g, 28%).¹H-NMR CDCl₃ δ：5.40(s，1H)，3.50(s，2H)，2.02(m，2H₅)，1.74(s，6H)，1.15(m，2H，)，1.02(m，2H，).ESMS m/z：211[M+H]⁺，233[M+Na]⁺153[ M-propanone]⁺。

Preparation of 6-cyclopropyl-4-hydroxy-2-pyrone (T). Compound S' (6.21g, 29.5mmol) was dissolved in toluene (35mL) and refluxed for 45 minutes. After the reaction mixture was cooled to ambient temperature, the title compound precipitated, which was filtered off and dried under high vacuum to give compound T as a yellow solid (3.21g, 71%).¹H-NMR CDCl₃ δ：6.07(s，1H)，5.14(s，1H)，1.88(m，1H，)，0.90(m，4H).ESMS m/z：153[M+H]⁺，175[M+Na]⁺.

Preparation of tert-butyl 3, 5-dioxoheptanoate (U). The following method is based on the procedure disclosed in B.Lygo, Tetrahedron, 51, pp.12859-12868 (1995). To an oven-dried 5l flask was added sodium hydride (60% dispersed in mineral oil, 1.21 mmol, 48.55g) under nitrogen. The hydride was washed with hexane (4X 250 mL). The hydride was then suspended in dry Tetrahydrofuran (THF) (2000mL) and the mixture was cooled to 0 ℃ in an ice bath. Tert-butylacetoacetic acid (160g, 1.01mmol) was added dropwise to the solution over 2 hours at 0 ℃ under a constant nitrogen flow through an addition funnel, and after the addition was complete, the reaction was stirred for a further 30 minutes at 0 ℃ under nitrogen. To the mixture was added n-butyllithium (2M in cyclohexane, 556mL, 1.11mmol) dropwise over 3 hours via an addition funnel. After the addition was complete, the reaction was stirred for an additional 30 minutes at 0 ℃. Ethyl propionate (85.94mL, 1.01mmol) was loaded into the addition funnel and added slowly over 1.5 hours to the reactionShould be used. At this time, the reaction was warmed to room temperature and stirred overnight. The reaction was again cooled to 0 ℃ in an ice bath and 2N HCl (1.15 l, cooled to 0 ℃ before addition) was added dropwise after 2 hours via an addition funnel. The reaction pH was checked to ensure neutralization. More 2N HCl was added by pipette if necessary to adjust the solution to pH 7. At this point most of the THF/cyclohexane had been decanted from the aqueous layer and 75% of the organic solvent was removed by rotary evaporation. The aqueous layer was extracted with ethyl acetate (3X 100 mL). The residue obtained after the volume reduction was diluted with ethyl acetate (500mL) and combined with the organic pool extracted from the aqueous phase. The organic pool was washed with saturated sodium chloride (3 × 250mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was then subjected to high vacuum distillation (140 microns, short path distillation head) to afford 131g of crude compound U as a clear oil.¹HNMR CDCl₃O：15.16(bs，1H)，5.59(s，1H)，3.24(s，2H)，3.22(q，2H，J＝8.0Hz)，1.46(s，9H)，1.14(t，3H，J＝8.0Hz).ESMS m/z：237[M+Na⁺]159[ M-/-butyl group]⁺.

Preparation of 6-ethyl-4-hydroxypyran-2-one (V). A solution of 25% (v/v) trifluoroacetic anhydride (TFAA, 1117mL) in trifluoroacetic acid (TFA) was placed in a 2-liter round bottom flask and cooled in an ice bath for 40 minutes. Crude compound U was charged to the addition funnel and slowly added to the stirring mixture over 2 hours. The reaction was warmed to room temperature and held overnight. The TFA/TFAA solution was removed by rotary evaporation. Residual TFA can be removed azeotropically with toluene. The residue was then purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in dichloromethane. The appropriate fractions were collected and concentrated by rotary evaporation to give compound V as a yellow oil (63.15g, 45%).¹H NMR CDCl₃ δ：11.08(bs，1H)，6.00(s，1H)，5.59(s，1H)，2.52(q，2H，J＝8.0Hz)，1.22(t，3H，J＝8.0Hz).ESMS m/z：141.0[M+H⁺].

Preparation of 6-ethyl-4-methoxypyran-2-one (W). The following method is based on the procedure disclosed in Deshopander, V.H. et al, Indian Journal of Chemistry, 35, pp.790-793(1996). Compound V (57.65g, 411mmol) was placed in an oven-dried 2000mL three-necked flask and dissolved in dry acetone (1500 mL). To the solution was added potassium carbonate (74g, 540mmol) and dimethyl sulfate (51ml, 540 mmol). The flask was equipped with a water condenser and a mechanical stirrer. The mixture was heated to reflux for 3.5 hours. LCMS analysis showed the reaction was complete. The reaction was cooled to room temperature and filtered to remove solids. The filtrate was stripped of solvent by rotary evaporation. The remaining yellow oily residue was purified by silica gel chromatography and eluted with a gradient of 10% to 50% ethyl acetate in hexanes. The appropriate fractions were collected and concentrated by rotary evaporation to give compound W as a yellow oil (40.55g, 61%).¹HNMR CDCl₃ δ：5.78(s，1H)，5.42(s，1H)，3.80(s，3H)，2.51(q，2H，J＝8.0Hz)，1.22(t，3H，J＝8.0Hz).ESMS m/z：155[M+H⁺].

Preparation of 4-dimethylamino-6-ethyl-2-pyrone (X). Compound V (4.9g, 35mmol) was dissolved in dichloromethane (50mL) and triethylamine (12.2mL, 87.5mmol) was added. To the resulting solution was added tosyl chloride (6.7g, 35mmol) and the reaction was stirred at 0 ℃ under nitrogen. After 1h dimethylamine (2.0M in tetrahydrofuran, 19.25mL, 38.5mmol) was added and the reaction was stirred for an additional 2h at 0 ℃. The reaction mixture was washed with saturated aqueous sodium bicarbonate, brine and then concentrated by rotary evaporation. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. Fractions with the desired product were collected and concentrated by rotary evaporation to give compound X as a pale yellow solid (3.6g, 62% yield).¹H NMR CDCl₃ δ：5.74(s，1H)，4.92(s，1H)，2.95(s，6H)，2.43(q，2H，J＝20Hz)，1.18(t，3H，J＝12Hz).ESMS m/z：168.1[M+H⁺].

Example 12 Synthesis of chiral pyrrolidine Compounds

Preparation of (R) -4- (1-benzyl-pyrrolidin-3-yl) -thiomorpholine 1, 1-dioxide (Y). (S) -toluene-4-sulfonic acid 1-benzyl-pyrrolidin-3-ester was prepared as described in J.Med.chem.1992, 35, 4205. (S) -toluene-4-sulfonic acid 1-benzyl-pyrrolidin-3-yl ester (400mg, 1.208mmol, 1eq) and 1, 1-dioxo-thiomorpholine (817mg, 6.042mmol, 5eq) were charged to dioxane and heated at 140 ℃ for 20 hours. The reaction mixture was cooled and the dioxane was removed by rotary evaporation. The resulting residue was purified on a Biotage40M amine column with a gradient of 0-50% ethyl acetate in hexanes to give the title compound as a yellow oil (88mg, 25%).¹HNMR(400MHz)CDCl₃δ7.30-7.20(m，5H)，3.55-3.54(s，2H)，3.19-3.17(m，1H)，3.01-2.91(m，6H)，2.62-2.58(m，2H)，2.51-2.43(m，2H)，2.00-1.97(m，2H)，1.71-1.67(m，2H).ESMS m/z：295.2[M+H]⁺.

Preparation of (R) -4-pyrrolidin-3-yl-thiomorpholine 1, 1-dioxide (Z). Compound Y (88mg, 0.2989mmol, 1eq) was dissolved in EtOH (2.0ml) and 1N HCl (300. mu.l) was added. With N₂The solution was degassed 3 times and a palladium catalyst (10mg, 5% mmol) was added. By H₂(g) Degassed 3 times and hydrogenated for 90 minutes. The catalyst was removed by filtration and 1N HCl (300. mu.l) was added. The solvent was removed in vacuo, poured into water, and lyophilized to give the title compound as a yellow oil (59mg, 82%).¹HNMR(400MHz)D₂O δ 3.88-3.68(dm，2H)，3.57-3.45(m，10H)，3.37-3.29(m，2H)，2.45(m，1H)，2.10(m，1H).205.1[M+H]⁺.

5-Ethyl-2- {2- [3- (1, 1-dioxo-thiomorpholin-4-yl) pyrrolidin-l-yl]Pyridin-3-yl } -7-methoxy-4H-benzo [ d][1，3]And preparing oxazin-4-ketone. At room temperature and N₂To 5-ethyl-2- (2-fluoropyridin-3-yl) -7-methoxy-4H-benzo [ d ] in anhydrous 1, 4-dioxane (850. mu.L)][1，3]Oxazin-4-one (50.0mg, 0.17mmol) Compound Z (52.9mg, 0.22 mmol) was addedL) and diisopropylethylamine (120. mu.L, 0.85mmol), overnight. The solution was concentrated and the resulting residue was purified on a Biotage40M amine column with a gradient of 20-75% ethyl acetate/hexanes to give the title compound. The fractions containing the title compound were combined and concentrated in a speedvac to give the title compound as a yellow oil (19.2mg, 23% yield).¹H NMR(CDCl₃，400MHz)δ：8.33(dd，1H，J＝1.0Hz)，8.1(d，1H，J＝7.0Hz)，6.92(dd，2H，J＝2.5Hz)，6.83(m，1H)，3.93(s，3H)，3.83(m，1H)，3.62(m，2H)，3.39(m，1H)，3.26(m，1H)，3.22(m，4H)，3.17(m，6H)，2.16(m，1H)，1.94(m，1H)，1.29(t，3H，J＝7.5Hz)；ESMS m/z485.2[M+H]⁺.

Example 13 detection of inhibitor IC for human neutrophil elastase₅₀Value of

Human salivary neutrophil elastase (Elastin Products Co.) was diluted in assay buffer A (200mM Tris pH 7.4, 1mg/ml BSA) to give a working concentration of 0.55U/ml. The inhibitor dissolved and diluted 50X in DMSO is added to elastase dissolved in assay buffer A to a final concentration of 1X 10^-4M to 6.95X 10^-12M, and preincubated at room temperature for 20 min. DMSO alone was used as a negative control. The substrate MeOSuc-AAPV-amc (bachem) was dissolved in DMSO to 20mM and further diluted to 1mM with assay buffer a before use. The substrate is heated at 1X 10^-4The final concentration of M was added to the elastase assay. The reaction was allowed to proceed at room temperature for 20 minutes and then stopped with acetic acid at a final concentration of 3% (v/v). Background fluorescence controls were prepared by adding substrate to the pre-terminated elastase. AMC fluorescence was measured by a Wallac (Perkin Elmer) Victor2 plate reader equipped with an excitation/emission filter of 355/460 nm. The fluorescence intensity was plotted against inhibitor concentration and fitted to the Hill equation to determine IC₅₀The value is obtained. Table 1 shows the IC of exemplary compounds₅₀The value is obtained.

[00289] TABLE 1 exemplary Compounds and their Activity

In Table 1, IC vs. human neutrophil elastase₅₀(nM) is as follows: a is less than or equal to 15; b is 16-60; c is 61-150; d>150; ND means no data.

Example 14 neutrophil elastase induced pulmonary hemorrhage assay

The in vivo assay is based on the estimation of lung bleeding volume following intratracheal administration of Human Neutrophil Elastase (HNE). Bleeding can be quantified by measuring the concentration of heme in bronchoalveolar lavage fluid (BALF).

Compounds were dissolved in DMSO or saline and administered intravenously to male bal b/c mice (22-30g) at a fixed volume of 0.01mL/10g or 0.1mL/10g body weight, respectively. DMSO or saline was used as vehicle control. Mice were anesthetized with chloroform and the trachea exposed through a small incision in the neck. Ten minutes after compound administration, mice were administered 7.5 units/animal of HNE (Elastin Products Co.) dissolved in 25mL saline. Three hours after HNE instillation, animals were euthanized with excess urethane. The chest was opened and the lungs were irrigated with 1mL solution consisting of 0.4% trisodium citrate and 0.85% sodium chloride via endotracheal intubation. BALF was collected at a final concentration of 0.2% (v/v) with the addition of Triton X-100 to ensure cell disruption. The hemoglobin concentration in BALF was determined by measuring the absorbance at 405 nm. Results are shown in table 2 and are expressed as% inhibition of HNE-induced bleeding by the compound relative to vehicle-treated controls.

[00294] Table 2: in vivo Activity of Compounds

In table 2, the values of the% inhibition are expressed as follows: a is less than or equal to 10; b is 11-30; c > 30; NI is not inhibited.

Example 15: acute lung injury model (determination of lung permeability)

Adult male Wistar rats (200-250g) were anesthetized by intraperitoneal injection of pentobarbital (30 mg/kg). Under anesthesia, Lipopolysaccharide (LPS) (100. mu.g/100. mu.L/animal) or physiological saline (100. mu.L/animal) was injected intratracheally. The increase in lung permeability following LPS instillation was detected by Evan Blue Dye (EBD) leaking from the blood. EBD (40mg/5ml/kg) was administered via the tail vein 5 hours after LPS challenge. After 6 hours, the animals were bled by cardiac puncture under deep anesthesia and the lung tubes were perfused with 20mL saline to remove the EBD from the vascular space. The lungs were removed and EBD was extracted in 6mL formamide at 65 ℃ overnight. The absorption at 620nm was detected with a spectrophotometer to determine the EBD content. The test compound was dissolved in saline with a small amount of 1N HCl and continued intravenous infusion started at a rate of 10mg/kg/hr for 6 hours after LPS challenge. The results are shown in table 3.

Table 3: in vivo Activity of Compounds (ALI model)

In table 3, the% inhibition is expressed as follows: b is 11-30; c > 30.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (64)

1. A compound having the formula (I):

or a pharmaceutically acceptable derivative thereof,

wherein a is a 5-10 membered heterocyclyl or heteroaryl ring attached to the benzoxazine core through a carbon atom of the heterocyclyl or heteroaryl ring;

R²is halogeno, pseudo-halogeno, alkyl, alkenyl, alkyneAlkyl, haloalkyl, cycloalkyl, NR^aR^b、-OR^c、-C(O)R^cor-S (O)_mR^c；

R^a、R^bAnd R^cEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R¹is-OR³、-SR³、-NO₂Or NR⁴R⁵；

Each R³Independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R⁴and R⁵Selected from the following:

i)R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, with the proviso that R is⁴Or R⁵At least one is not hydrogen; or

ii)R⁴And R⁵Together with the nitrogen atom to which they are substituted form a 5-10 membered substituted or unsubstituted heterocyclyl or heteroaryl ring wherein the substituents, when present, are selected from one or more Q¹；

m is 0 to 2;

each n is independently 0 to 6;

provided that when A is 3-pyridyl and R²Is halo or methyl, then R¹Is not 2-phenoxy;

R¹、R²、R³、R⁴and R⁵Optionally substituted with 1, 2,3 or 4 substituents each independently selected from Q¹Wherein Q is¹Is halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkyleneSilyls, dialkylarylsilyls, alkyldiarylsilyls, triarylsilyls, alkylenes, arylalkylenes, alkylcarbonyls, arylcarbonyls, heteroarylcarbonyls, heterocyclylcarbonyls, alkoxycarbonyls, alkoxycarbonylalkyls, aryloxycarbonyls, aryloxycarbonylalkyls, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyls, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyls, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, alkylene carbonyloxy, aralkylcarbonyloxy, and the like, Dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N ' -alkylureido, N ', N ' -dialkylureido, N ' -alkyl-N ' -arylureido, N ', N ' -diarylureido, N ' -arylureido, N ' -dialkylureido, N-alkyl-N ' -arylureido, N-aryl-N ' -alkylureido, N ' -diarylureido, N ', N ' -trialkylureideoureido, N ' -dialkyl-N ' -arylureido, N-alkyl-N ', N ' -diarylureido, N-aryl-N ', n ' -dialkylureido, N ' -diaryl-N ' -alkylureido, N ', N ' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, Azido group-N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q¹Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q¹Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

each Q²Independently halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyls, mercaptosilyl groups, hydroxy-carbonyl, hydroxycarbonylalkyl, alkyl-haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl, and alkynyl groups containing 1 to 2 double bondsAlkyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, alkoxycarbonyloxy, alkynyl alkoxycarbonyl, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N ' -alkylureido, N ', N ' -dialkylureido, N ' -alkyl-N ' -arylureido, N ', N ' -diarylureido, N ' -arylureido, N ' -dialkylureido, N-alkyl-N ' -arylureido, N-aryl-N ' -alkylureido, N ' -diarylureido, N ', N ' -trialkylurourea, N ' -dialkyl-N ' -arylureido, N-alkyl-N ', N ' -diarylureido, N-aryl-N ', N ' -dialkylureido, N ' -diaryl-N ' -alkylureido, N ' -alkylureido, N, N ', N ' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N ' -triarylamino, arylamidino, aminothiocarbonyl, aminothio, alkylamino, alkylaminothiocarbonyl, arylamino, dialkylamino, haloalkylamino, arylaminocarbonylamino, alkoxycarbonylamino⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q²Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q²Groups that substitute for the same atoms, together forming a hydrocarbylene group;

each Q³Independently selected from halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylcarbonylAlkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N ' -alkylureido, N ' -dialkylureido, N ' -alkyl-N ' -arylureido, N ', n ' -diarylureido, N ' -arylureido, N ' -dialkylureido, N-alkyl-N ' -arylureido, N-aryl-N ' -alkylureido, N ' -diarylureido, N ', N ' -trialkylurourea, N ' -dialkyl-N ' -arylureido, N-alkyl-N ', N ' -diarylureido, N-aryl-N ', N ' -dialkylureido, N ' -diaryl-N ' -alkylureido, N ', N ' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, aminoalkylureido, aminothiocarbonyl, aminothiononyl, aminothio, N ' -trialkylurourea, N ' -dialkylureido, N ' -trialkylur, Dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkyl phosphonyl, alkylaryl phosphonyl, diaryl phosphonyl, hydroxy phosphonyl, alkyl sulfideA group, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isocyanato, alkylsulfinoyloxy, alkylsulfonyloxy, arylsulfinoyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q³Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q³Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

R⁵⁰is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹Wherein R is⁷⁰And R⁷¹Each independently is hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰And R⁷¹Together form a hydrocarbylene, azahydrocarbylene, oxahydrocarbylene, or thioalkylene group;

R⁵¹、R⁵²and R⁵³Each independently is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl;

R⁶⁰is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; and is

R⁶³Is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹。

2. The compound of claim 1, wherein R¹is-OR³、-SR³Or NR⁴R⁵。

3. The compound of claim 1 or2, wherein a is a 5-7 membered heterocyclyl or heteroaryl ring.

4. The compound of claim 1, 2 or 3, wherein a is a 5-7 membered heterocyclyl ring.

5. The compound of claim 1, 2, or 3, wherein a is a 5-7 membered heteroaryl ring.

6. The compound of any one of claims 1-3 or 5, wherein a is pyridyl.

7. The compound of any one of claims 1-3, 5 or 6, wherein a is 3-pyridyl.

8. The compound of any one of claims 1-3, 5 or 6, wherein a is 2-pyridyl.

9. The compound of any one of claims 1-3, 5 or 6, wherein a is 4-pyridyl.

10. The compound of any one of claims 1-3 or 5, wherein a is thienyl.

11. A compound according to any one of claims 1 to 10Wherein R is²Is halo, alkyl, haloalkyl or alkoxy.

12. The compound of any one of claims 1-11, wherein R²Is chlorine, bromine, methyl, ethyl, trifluoromethyl or methoxy.

13. The compound of any one of claims 1-12, wherein R¹is-OR³or-NR⁴R⁵。

14. The compound of any one of claims 1-13, wherein R¹is-NR⁴R⁵。

15. The compound of any one of claims 1-13, wherein R³Is alkyl, haloalkyl, heteroalkyl, aryl, haloaryl, alkoxyalkyl, alkaryl, or arylsulfonylalkyl.

16. The compound of any one of claims 1-13 and 15, wherein R³Is methyl, ethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-tolyl, phenylsulfonylethyl, 3, 4-methylenedioxybenzyl or dimethoxyaminoethyl.

17. The compound of any one of claims 1-14, wherein R⁴Is hydrogen and lowA lower alkyl or alkoxyalkyl group.

18. The compound of any one of claims 1-14, wherein R⁴Is hydrogen, methyl or methoxyethyl.

19. The compound of any one of claims 1-14, wherein R⁵Is an aralkyloxycarbonylalkyl group, a dialkylaminoalkyl group, a heterocyclylalkyl group, an alkylheterocyclyl group or an alkoxyalkyl group.

20. The compound of any one of claims 1-14, wherein R⁵Is benzyloxycarbonylmethyl, dimethylaminoethyl, 4-morpholinoethyl, N-methylpyrrolidin-3-yl or methoxyethyl.

21. The compound of any one of claims 1-14, wherein R⁴And R⁵Together with the nitrogen atom it replaces form a 5 or 6 membered heterocyclyl or heteroaryl ring.

22. The compound of any one of claims 1-14, wherein R⁴And R⁵Together with the nitrogen atom it is substituted for, form a 5 or 6 membered heterocyclyl ring.

23. The compound of any one of claims 1-14, wherein R¹Is composed of

Wherein A is¹Is CR⁶R⁷Or NR⁶；

R⁶Is hydrogen, alkyl, alkenyl, alkynyl, phenyl, heteroaryl, alkoxyalkyl, cycloalkylalkyl, hydroxyalkyl, cyanoalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, aminocarbonylalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl, hydroxycarbonylalkyl, heterocyclylcarbonylalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkyl, or imidamidyl;

R⁷is hydrogen or alkyl;

Q¹is alkyl, alkoxycarbonyl, phenyl, dialkylamino, alkoxycarbonyl, dialkylaminoalkyl, aralkyl, hydroxycarbonyl, hydroxyalkyl, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, heterocyclyl, heterocyclylalkyl, -N⁺R⁵¹R⁵²R⁵³Alkylsulfinylalkylcarbonyl, cycloalkylaminoalkyl, halo, di (hydroxyalkyl) amino, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, -SO₃H or an alkyl sulfonate;

n₁is 1 or 2; and is

n₂Is 0 to 5.

24. The compound of claim 23, wherein R⁶Is hydrogen, methyl, ethyl, isopropyl, 2-propenyl, 2-propynyl, 3-butynyl, phenyl, cyclopropylmethyl, 2-hydroxyethyl, hydroxycarbonylethyl, hydroxycarbonylpropyl, ethoxycarbonylethyl, methoxymethyl, ethoxymethyl, cyanoethyl, 3-cyanopropyl, dimethylaminomethyl, dimethylaminoethyl, 4-morpholinoethyl, 2-pyrimidinyl, 3-pyrimidinyl, 4-pyrimidinyl, 2-thiazolyl, 4-fluorophenylmethyl, 4-methoxyphenylmethyl, pyrrolidin-1-ylmethyl, tetrahydrofuran-2-ylmethyl, 1, 3-dioxolan-2-ylmethyl, N-methylpiperidin-4-yl, ethoxycarbonylmethylA group selected from the group consisting of hydroxycarbonylmethyl, morpholin-4-ylcarbonylmethyl, tert-butoxycarbonylaminoethyl, hydroxyethoxyethyl, aminocarbonylmethyl, 2-propynyloxycarbonylaminoethyl, and-C (NH) NH₂。

25. The compound of claim 23 or 24, wherein Q¹Is methyl, ethyl, propyl, isopropyl, phenyl, dimethylamino, diethylamino, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, hydroxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyl, hydroxycarbonylpropyl, hydroxyalkyl, hydroxyalkoxyalkyl, 1-imidazolyl, 4-morpholino, morpholin-4-ylmethyl, morpholin-4-ethyl, -N (CH)₃)₃ ⁺Methylsulfinylmethylcarbonyl, cycloalkylaminoalkyl, fluorine, bis (hydroxyethyl) amino, dialkylaminoalkylcarbonyl, pyrrolidin-1-ylmethyl, pyrrolidin-1-ethyl, cyclopropylaminomethyl, 2-oxo-piperazin-4-yl, 1-dioxo-thiomorpholin-4-yl, N-methyl-N- (methoxyethyl) amino, N-methyl-piperazin-4-ylcarbonyl, N-dimethylaminoethylamino (methyl) carbonyl, -SO₃H or- (CH)₂)₃SO₃H。

26. The compound of claim 23, wherein R⁶Is hydrogen, methyl, methoxymethyl or cyclopropylmethyl;

R⁷is hydrogen;

Q¹is methyl, dimethylamino, tert-butoxycarbonyl or methoxycarbonyl;

n₁is 1 or 2; and is

n₂Is 1 or 2.

27. The compound of any one of claims 1-14, wherein R¹Is composed of

Or

Wherein R is⁶Is hydrogen, alkyl, alkoxyalkyl or cycloalkylalkyl;

Q¹is alkyl, dialkylamino or alkoxycarbonyl; and is

n₂Is 0 to 5.

28. The compound of claim 27, wherein R⁶Is hydrogen, methyl, methoxyethyl or cyclopropylmethyl.

29. The compound of claim 27, wherein n is₂Is 1, and Q¹Is methyl, dimethylamino, tert-butoxycarbonyl or methoxycarbonyl.

30. The compound of any one of claims 1-14, wherein R¹Is composed of

Wherein Q¹Is alkyl, dialkylamino or alkoxycarbonyl; and is

n₂Is 0 to 3.

31. The compound of any one of claims 1-14, having formula (la)

Or

32. The compound of any one of claims 1-13, having the formula

Or

33. The compound of any one of claims 1-13, having the formula

Or

Wherein X is fluorine or chlorine.

34. The compound of any one of claims 1-14, having formula (la)

Or

35. The compound of claim 23, having formula (la)

Or

36. The compound of claim 35, having formula (la)

37. The compound of claim 35, having formula (la)

Or

38. The compound of claim 30, having formula (la)

Wherein R is⁸Selected from the group consisting of hydrogen, alkoxy, heterocyclyl and heteroaryl.

39. The compound of claim 38, having formula (la)

40. The compound of claim 39, having formula (la)

41. The compound of claim 39 or 40In which R is²Is alkyl, haloalkyl, alkoxy, amino, halo, alkylcarbonyl or alkylsulfinyl.

42. The compound of any one of claims 36-38, wherein R²Is methyl, ethyl, isopropyl, trifluoromethyl, methoxy, hydroxy, amino, chloro, acyl or methylsulfinyl.

43. The compound of claim 40, wherein R⁸Is alkoxy, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl.

44. The compound of any one of claims 1-13, having the formula

Wherein R is⁹Is hydrogen or unsubstituted or substituted alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, and n is₃Is 1-20.

45. The compound of claim 44, wherein n₃Is 3 or 4.

46. The compound of claim 44, wherein R⁹Is hydrogen, methyl, phenyl or 3-carboxypyridin-2-yl.

47. The compound of any one of claims 1-14, having formula (la)

Or

Wherein R is^xAnd R^yEach independently selected from hydrogen or alkyl.

48. The compound of claim 47, having formula (la)

Or

49. A compound having the formula:

wherein L is a linker.

A is a 5-10 membered heterocyclyl or heteroaryl ring attached to the benzoxazine core through a carbon atom;

R²is halogeno, pseudohalogeno, alkyl, alkenyl, alkynyl, halogenoalkyl, cycloalkyl, NR^aR^b、-OR^c、-C(O)R^cor-S (O)_mR^c；

R^a、R^bAnd R^cEach independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R¹is-OR³、-SR³、-NO₂Or NR⁴R⁵；

Each R³Independently selected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R⁴and R⁵Selected from the following:

i)R⁴and R⁵Each independently selected from hydrogen and alkylA group, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, with the proviso that R is⁴Or R⁵At least one is not hydrogen; or

ii)R⁴And R⁵Together with the nitrogen atom to which they are substituted form a 5-10 membered substituted or unsubstituted heterocyclyl or heteroaryl ring wherein the substituents, when present, are selected from one or more Q¹；

m is 0 to 2;

n is 0 to 6;

R¹、R²、R³、R⁴and R⁵Optionally substituted with 1, 2,3 or 4 substituents, each substituent independently selected from Q¹Wherein Q is¹Is halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, mercapto, hydroxycarbonyl, hydroxyalkyl, hydroxycarbonylalkyl, haloalkyl, aminoalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkylalkyl, heteroarylalkyl, and heteroaryl, Alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N' -dibutylaminocarbonylAlkyl ureido, N ' -alkyl-N ' -aryl ureido, N ', N ' -diaryl ureido, N ' -aryl ureido, N ' -dialkyl ureido, N-alkyl-N ' -aryl ureido, N-aryl-N ' -alkyl ureido, N ' -diaryl ureido, N ', N ' -trialkyl ureido, N ' -dialkyl-N ' -aryl ureido, N-alkyl-N ', N ' -diaryl ureido, N-aryl-N ', N ' -dialkyl ureido, N ' -diaryl-N ' -alkyl ureido, N ', N ' -triaryl ureido, amidino, alkyl amidino, aryl amidino, aminothiocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR^60-C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q¹Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q¹Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

each Q²Independently halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonylalkyl, mercapto, hydroxycarbonyl, hydroxyalkyl, hydroxycarbonylalkyl, haloalkyl, aminoalkyl, haloalkenyl, and haloalkenyl, Alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N' -dialkylureido, N '-alkyl-N' -arylureido, N '-diarylureido, N' -arylureido, N, N' -diAlkyl ureido, N-alkyl-N ' -aryl ureido, N-aryl-N ' -alkyl ureido, N ' -diaryl ureido, N ', N ' -trialkyl ureido, N ' -dialkyl-N ' -aryl ureido, N-alkyl-N ', N ' -diaryl ureido, N-aryl-N ', N ' -dialkyl ureido, N ' -diaryl-N ' -alkyl ureido, N ', N ' -triaryl ureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, aminothioalkyl, amino, Alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR^60-C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q²Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q²Groups that substitute for the same atoms, together forming a hydrocarbylene group;

each Q³Independently selected from the group consisting of halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkylalkyl, mercapto, hydroxycarbonyl, hydroxyalkyl, alkyl, haloalkyl, aminoalkyl, haloalkyl, aminoalkyl, arylalkyl, and substituted or substituted arylalkyl, Aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N ' -alkylureido, N ' -dialkylureido, N ' -alkyl-N ' -arylureido, N ' -diarylureido, N ' -arylureido, N ' -arylureido, or a pharmaceutically acceptable salt thereof, N '-arylureido, N' -dialkylureido, N-alkyl-N '-arylureido, N-aryl-N' -alkylureido, N '-diarylureido, N', N '-trialkylurourido, N' -dialkyl-N '-arylureido, N-alkyl-N', N '-diarylureido, N-aryl-N', N '-dialkylureido, N' -dialkyl,N, N '-diaryl-N' -alkylureido, N ', N' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, aryloxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, amidino, arylthiosemicarbazidino, alkylaminocarbonylamino, dialkylaminoalkyl, arylaminocarbonylamino, heteroarylcarbonylamino, arylaminocarbonylamino, and heteroarylcarbonylamino, Azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰-C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q³Radicals, substituted by the same atoms, taken togetherTo an alkylene group; and is

Each Q³Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

R⁵⁰is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹Wherein R is⁷⁰And R⁷¹Each independently is hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰And R⁷¹Together form a hydrocarbylene, azahydrocarbylene, oxahydrocarbylene, or thioalkylene group;

R⁵¹、R⁵²and R⁵³Each independently is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl;

R⁶⁰is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; and is

R⁶³Is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹。

50. The compound of claim 49, having formula (la)

51. The compound of claim 49, having formula (la)

Wherein n is₄Is 1-20.

52. The compound of claim 51, wherein n₄Is 4.

53. A compound according to claim 1 or2, selected from:

54. a compound according to claim 1 or2, selected from:

and

55. a pharmaceutical composition comprising a compound of any one of claims 1-54 and a pharmaceutically acceptable carrier.

56. A method of inhibiting the action of serine hydrolase comprising administering a compound of formula I:

or a pharmaceutically acceptable derivative thereof,

wherein a is a 5-10 membered heterocyclyl or heteroaryl ring attached to the benzoxazine core through a carbon atom of the heterocyclyl or heteroaryl ring;

R²is halogeno, pseudohalogeno, alkyl, alkenyl, alkynyl, halogenoalkyl, cycloalkyl, NR^aR^b、-OR^c、-C(O)R^cor-S (O)_mR^c；

R^a、R^bAnd R^cEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R¹is-OR³、-SR³、-NO₂Or NR⁴R⁵；

Each R³Independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R⁴and R⁵Selected from the following:

i)R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, with the proviso that R is⁴Or R⁵At least one is not hydrogen; or

ii)R⁴And R⁵Together with the nitrogen atom to which they are substituted form a 5-10 membered substituted or unsubstituted heterocyclyl or heteroaryl ring wherein the substituents, when present, are selected from one or more Q¹；

m is 0 to 2;

n is 0 to 6;

R¹、R²、R³、R⁴and R⁵Optionally substituted with 1, 2,3 or 4 substituents each independently selected from Q¹Wherein Q is¹Is halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, arylateAlkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aralkyloxycarbonyloxy, and the like, Aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N', N '-dialkylureido, N' -alkyl-N '-arylureido, N', N '-diarylureido, N' -arylureido, N '-dialkylureido, N-alkyl-N' -arylureido, N-aryl-N '-alkylureido, N' -diarylureido, N ', N' -trialkylurea, N '-dialkyl-N' -arylureido, N-alkyl-N ', N' -diarylureido, N '-dialkylaminocarbonyloxy, N' -alkylureido, N-arylureido, N-alkylN ', N' -diarylureido, N, N-aryl-N ', N' -dialkylureido, N '-diaryl-N' -alkylureido, N ', N' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, Heterocyclyl sulphonyl radicalsAmino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q¹Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q¹Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

each Q²Independently halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkanyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylal(iii) a group diarylsilyl group, triarylsilyl group, alkylene group, arylalkylene group, alkylcarbonyl group, arylcarbonyl group, heteroarylcarbonyl group, heterocyclylcarbonyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, aryloxycarbonyl group, aryloxycarbonylalkyl group, aralkyloxycarbonyl group, aralkyloxycarbonylalkyl group, arylcarbonylalkyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, arylaminocarbonyl group, diarylaminocarbonyl group, aralkylaminocarbonyl group, alkoxy group, aryloxy group, heteroaryloxy group, heteroarylalkoxy group, heterocyclyloxy group, cycloalkoxy group, perfluoroalkoxy group, alkenyloxy group, alkynyloxy group, aralkyloxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, aralkyloxycarbonyloxy group, aminocarbonyloxy group, dialkylaminocarbonyloxy group, alkylarylaminocarbonyloxy group, Diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N', N '-dialkylureido, N' -alkyl-N '-arylureido, N', N '-diarylureido, N' -arylureido, N '-dialkylureido, N-alkyl-N' -arylureido, N-aryl-N '-alkylureido, N' -diarylureido, N ', N' -trialkylurourea, N '-dialkyl-N' -arylureido, N-alkyl-N ', N' -diarylureido, N-aryl-N ', N' -dialkylureido, N, n '-diaryl-N' -alkylureido, N ', N' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothocarbonyl, arylaminothiocarbonyl, alkynylalkoxycarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, substituted arylamino, heteroarylthio, substituted arylamino, arylcarbonylamino, arylaminocarbonylamino, heteroarylcarbonylamino, heteroarylthio, and substituted arylamino, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q²Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q²Groups that substitute for the same atoms, together forming a hydrocarbylene group;

each Q³Independently selected from halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkylalkylcarbonyl, and alkoxycarbonylalkylAralkoxycarbonyl, aralkyloxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N' -dialkylureido, N '-alkyl-N' -arylureido, N ', N ' -diaryl ureido, N ' -aryl ureido, N ' -dialkyl ureido, N-alkyl-N ' -aryl ureido, N-aryl-N ' -alkyl ureido, N ' -diaryl ureido, N ', N ' -trialkyl ureido, N ' -dialkyl-N ' -aryl ureido, N-alkyl-N ', N ' -diaryl ureido, N-aryl-N ', N ' -dialkyl ureido, N ' -diaryl-N ' -alkyl ureido, N ', N ' -triaryl ureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothocarbonyl, arylaminothocarbonyl, amino, aminoalkyl, alkylaminoalkyl, alkylamino, aminothioureido, N ' -dialkyl ureido, N ' -trialkyl ureido, N ' -dialkyl-aryl ureido, N-alkyl-N ' -arylureido, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkyl phosphonyl, alkyl aryl phosphonyl, diArylphosphono, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q³Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q³Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

R⁵⁰is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹Wherein R is⁷⁰And R⁷¹Each independently is hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰And R⁷¹Together form a hydrocarbylene, azahydrocarbylene, oxahydrocarbylene, or thioalkylene group;

R⁵¹、R⁵²and R⁵³Each independently is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl;

R⁶⁰is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; and is

R⁶³Is alkoxy, aralkyloxy, alkyl,Heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹。

57. A method of treating a serine hydrolase mediated disease comprising administering a compound of formula I:

or a pharmaceutically acceptable derivative thereof,

wherein a is a 5-10 membered heterocyclyl or heteroaryl ring attached to the benzoxazine core through a carbon atom of the heterocyclyl or heteroaryl ring;

R²is halogeno, pseudohalogeno, alkyl, alkenyl, alkynyl, halogenoalkyl, cycloalkyl, NR^aR^b、-OR^c、-C(O)R^cor-S (O)_mR^c；

R^a、R^bAnd R^cEach independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R¹is hydrogen, halo, alkyl, -OR³、-SR³、-NO₂Or NR⁴R⁵；

Each R³Independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R⁴and R⁵Selected from the following:

i)R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, with the proviso that R is⁴Or R⁵At least one is not hydrogen; or

ii)R⁴And R⁵Together with the nitrogen atom to which they are substituted form a 5-10 membered substituted or unsubstituted heterocyclyl or heteroaryl ring wherein the substituents, when present, are selected from one or more Q¹；

m is 0 to 2;

n is 0 to 6;

R¹、R²、R³、R⁴and R⁵Optionally substituted with 1, 2,3 or 4 substituents each independently selected from Q¹Wherein Q is¹Is halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkylcarbonylalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, alkylcarbonyl, Aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N ' -alkylureido, N ' -dialkylureido, N ' -alkyl-N ' -arylureido, N ' -diarylureido, N ' -arylureido, N ' -arylureido, or a pharmaceutically acceptable salt thereof, N '-arylureido, N' -dialkylureido, N-alkyl-N '-arylureido, N-aryl-N' -alkylureido, N '-diarylureido, N', N '-trialkylurourido, N' -dialkyl-N '-arylureido, N-alkyl-N', N '-diarylureido, N-aryl-N', N '-dialkylureido, N' -diaryl-N '-alkylureido, N', N '-triarylureido, amidino, alkylamidino, substituted arylureido, N', N '-trialkylhaloureido, amidino, alkylamidino, substituted arylureido, N' -dialkylureido,Arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q¹Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q¹Independently of one another, unsubstituted or substituted by one, two or three radicalsIndependently selected from Q²Substituted with the substituent(s);

each Q²Independently halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkyloxycarbonylalkyl, arylcarbonylalkylalkyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, hydroxyalkyl, alkylcarbonylalkyl, hydroxyalkyl, alkyl, haloalkyl, aminoalkyl, haloalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, alkynylalkoxycarbonyl, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N' -dialkylureido, N '-alkyl-N' -arylureido, N '-diarylureido, N' -arylureido, or a pharmaceutically acceptable salt thereof, N ' -arylureido, N ' -dialkylureido, N-alkyl-N ' -arylureido, N-aryl-N ' -alkylureido, N ' -diarylureido, N ', N ' -trialkylurourea, N ' -dialkyl-N ' -arylureido, N-alkyl-N ', N ' -diarylureido, N-aryl-N ', N ' -dialkylureido, N ' -diaryl-N ' -alkylureido, N ', N ' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonylCarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q²Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q²Groups that substitute for the same atoms, together forming a hydrocarbylene group;

each Q³Independently selected from halo, pseudohalo, hydroxy, oxo, thio, nitrile, nitro, formyl, mercapto, hydroxycarbonylAlkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylene, arylalkylene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylalkyl, cycloalkylalkyl, aralkylaminocarbonyl, aralkylcarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N '-alkylureido, N' -dialkylureido, N '-alkyl-N' -arylureido, N '-diarylureido, N' -arylureido, N '-dialkylureido, N-alkyl-N' -arylureido, or a pharmaceutically acceptable salt thereof, N-aryl-N '-alkylureido, N' -diarylureido, N ', N' -trialkylurourido, N '-dialkyl-N' -arylureido, N-alkyl-N ', N' -diarylureido, N-aryl-N ', N' -dialkylureido, N '-diaryl-N' -alkylureido, N ', N' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, trialkylsimido, substituted alkylamino, N '-dialkylureido, N' -dialkylN '-arylureido, N-alkyl-N', N '-diarylureido, N-aryl-N' -arylureido, N-amidino, alkyl aryl amino, alkyl carbonyl amino,Alkoxycarbonylamino, aralkyloxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N⁺R⁵¹R⁵²R⁵³、P(R⁵⁰)₂、P(＝O)(R⁵⁰)₂、OP(＝O)(R⁵⁰)₂、-NR⁶⁰C(＝O)R⁶³Dialkylphosphono, alkylarylphosphono, diarylphosphono, hydroxyphosphono, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyanato, isothiocyanato, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl; or two Q¹Radicals substituted for the atoms in the 1, 2 or 1,3 positions, together forming an alkylenedioxy radical (i.e. -O- (CH)₂)_y-O-), a thioalkyleneoxy group (i.e. -S- (CH)₂)_y-O-) or hydrocarbylene disulfide group (i.e., -S- (CH)₂)_y-S-), wherein y is 1 or 2; or two Q³Groups that substitute for the same atoms, together forming a hydrocarbylene group; and is

Each Q³Independently is unsubstituted or is independently selected from Q by one, two or three²Substituted with the substituent(s);

R⁵⁰is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹Wherein R is⁷⁰And R⁷¹Each independently is hydrogen, alkyl, aralkyl, arylHeteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰And R⁷¹Together form a hydrocarbylene, azahydrocarbylene, oxahydrocarbylene, or thioalkylene group;

R⁵¹、R⁵²and R⁵³Each independently is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl;

R⁶⁰is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; and is

R⁶³Is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or-NR⁷⁰R⁷¹。

58. The method of claim 56 or 57, wherein R¹is-OR³、-SR³Or NR⁴R⁵。

59. A method of treating a serine hydrolase mediated disease comprising administering a compound of any of claims 1-54.

60. A method of inhibiting the action of serine hydrolase comprising administering a compound of any of claims 1-54.

61. The method of any one of claims 56-60, wherein the serine hydrolase is neutrophil elastase.

62. The method of claim 61, wherein the neutrophil elastase is a human neutrophil elastase.

63. The method of claim 58 or 59, wherein the disease is selected from emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, idiopathic interstitial pneumonia, cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic sinus lung infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic rheumatoid arthritis, joint induration, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplants, premature amnion rupture, bullous skin disease, shock, sepsis, systemic lupus erythematosus, Crohn's disease, disseminated intravascular coagulation, tissue injury following ischemia reperfusion, corneal scar tissue formation, and myelitis.

64. An article of manufacture comprising packaging material, a compound useful for treating, preventing or ameliorating a serine hydrolase mediated disorder or a pharmaceutically acceptable derivative thereof according to any one of claims 1 to 54 contained in the packaging material, and a label indicating that the compound or pharmaceutically acceptable derivative thereof is used for treating, preventing or ameliorating a serine hydrolase mediated disorder.