CN101137414A - Polycyclic bisamide MMP inhibitors - Google Patents

Abstract

This invention generally relates to drugs containing a diamide group, and more specifically, to polycyclic diamide MMP-13 inhibitor compounds. More specifically, this invention provides a new class of MMP-13 inhibitory compounds containing a pyrimidinyl diamide group and a heterocyclic moiety, which exhibit increased efficacy and solubility compared to currently known MMP inhibitors containing a diamide group.

Description

Polycyclic bisamide MMP inhibitors

field of invention

The present invention relates generally to bisamide-containing MMP inhibitory compounds, and more particularly to polycyclic bisamide MMP-13 inhibitory compounds.

Background of the invention

Matrix metalloproteinases (MMPs) are a family of structurally related zinc-containing enzymes that have been reported to mediate normal physiological processes such as breakdown of connective tissue in embryonic development, reproduction and tissue remodeling. MMP overexpression or MMP imbalance may be a factor in inflammatory, malignant and degenerative disease processes characterized by extracellular matrix or connective tissue degradation. Thus, MMPs are important in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulcers, atherosclerosis, Target for therapeutic inhibitors of neointimal proliferation (leading to restenosis and ischemic heart failure) and tumor metastasis.

It has been reported that the mammalian MMP family includes at least 20 enzymes (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is one of three collagenases that have been identified. Based on the identification of the domain structures of individual members of the MMP family, the catalytic domain of an MMP contains two zinc atoms; one of these zinc atoms performs the catalytic function and is associated with the three histidines contained in the conserved amino acid sequence of the catalytic domain. Acid coordination. MMP-13 is overexpressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast cancer, squamous cell carcinoma of the head and neck, and squamous cell carcinoma of the vagina. The major substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatin, proteoglycans, cytokines and other components of the ECM (extracellular matrix).

Activation of MMPs involves removal of the propeptide moiety, characterized by unpaired cysteine residues with catalytic zinc(II) ions. The X-ray crystal structures of the complexes between the MMP-3 catalytic domain and TIMP-1 and the MMP-14 catalytic domain and TIMP-2 also revealed linkage of the catalytic zinc via the sulfhydryl group of the cysteine residue ( II) Ions. The difficulty in developing potent MMP inhibitory compounds is compounded by several factors, including the selection of selective and broad-spectrum MMP inhibitory activity and making the compound bioavailable via the oral route of administration.

WO02/064568 discloses a series of MMP-13 inhibitory compounds containing a bisamide functional group and a pyridine ring, while WO03/049738 discloses certain bisamide compounds that selectively inhibit MMP-13 enzymes, containing pyridine and pyrimidine rings, And the terminal is substituted by a benzene ring. However, many of these compounds have relatively low potency and thus require higher doses to effectively inhibit MMP-13 for the treatment of MMP-13 mediated conditions and diseases.

Summary of the invention

The present invention relates to a new class of drugs containing polycyclic bisamides. Specifically, the present invention provides a new class of MMP-13 inhibitory compounds containing a pyrimidinylbisamide moiety and a polycyclic moiety, which exhibit potent MMP-13 inhibition compared to currently known MMP inhibitors active and highly selective for MMP-13.

The present invention provides a new class of polycyclic bisamide MMP-13 inhibitory compounds represented by general formula (I) and N-oxides, pharmaceutically acceptable salts and stereoisomers thereof:

In the formula:

R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times;

^R2 is hydrogen;

R ³ is NR ²⁰ R ²¹ ;

^R and ^R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, Alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, hetero Cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R ^{and R} are combined with The nitrogens they are connected together constitute a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times;

^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times;

^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times;

R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl ^, heteroarylalkyl, alkenyl, alkynyl, NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times;

R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;

R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times;

^R and ^R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, Aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, where alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkyl Alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or ^R80 and ^R81 are attached to them The nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O) _x , -NH or -N(alkyl), which is represented by optionally substituted one or more times;

x is selected from 0-2.

The polycyclic bisamide MMP-13 inhibitory compounds of the present invention are useful in the treatment of MMP-13 mediated osteoarthritis and in other MMP-13 mediated conditions characterized by excessive degradation and/or remodeling of the extracellular matrix Inflammatory, malignant and degenerative diseases such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis and chronic obstructive pulmonary disease, and pain such as inflammatory pain, bone pain and joint pain.

The present invention also provides polycyclic bisamide MMP-13 inhibitory compounds useful as active ingredients of pharmaceutical compositions for the treatment or prevention of MMP-13-mediated diseases. The present invention also contemplates the use of such compounds in pharmaceutical compositions for oral or parenteral administration comprising one or more polycyclic bisamide MMP-13 inhibitory compounds described herein.

The present invention also provides methods of inhibiting MMP-13 by administering a formulation by standard methods known in medical practice, including but not limited to: oral, intravenous, parenteral or intraarticular formulations containing polycyclic bis Amide MMP-13 inhibitory compounds for the treatment of diseases or conditions caused by or associated with MMP-13, including prophylactic and therapeutic treatments.

The polycyclic bisamide MMP-13 inhibitory compound of the present invention can be combined with antirheumatic drugs, non-steroidal anti-inflammatory drugs, COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressants, steroids, and biological response modifiers for alleviating diseases Or in combination with other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases.

Detailed description of the invention

The term "alkyl" or "alk" (alone or as part of another group) as used herein refers to optionally substituted straight and branched chain saturated hydrocarbon radicals preferably containing 1 to 10 carbons in the principal chain, most preferably lower alkane base. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-di Methylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. Exemplary substituents may include, but are not limited to, one or more of the following groups: halogen, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g. forming benzyl), cycloalkyl, cyclo Alkenyl, hydroxy or protected hydroxy, carboxyl (-COOH), alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ -CO-), substituted carbamoyl ((R ¹⁰ ) (R ¹¹ )N-CO-, wherein R ¹⁰ or R ¹¹ is as defined below, except that at least one of R ¹⁰ or R ¹¹ is not hydrogen), amino, heterocycle, mono- or dialkylamino or mercapto (-SH).

The term "lower alkane" or "lower alkyl" as used herein refers to an optionally substituted alkyl group as described above having 1 to 4 carbon atoms in the main chain.

The term "alkoxy" refers to an alkyl group as described above bonded through an oxygen linkage (-O-).

The term "alkenyl" (alone or as part of another group) as used herein refers to optionally substituted straight and branched chain hydrocarbon groups having at least one carbon-carbon double bond in the chain, preferably 2 to 10 carbons in the main chain . Exemplary unsubstituted alkenyl groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halogen, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, or protected Hydroxy, carboxyl (-COOH), alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ -CO-), substituted carbamoyl ((R ¹⁰ )(R ¹¹ )N- CO-, wherein R ¹⁰ or R ¹¹ is as defined below, except that at least one of R ¹⁰ or R ¹¹ is not hydrogen), amino, heterocycle, mono- or dialkylamino or mercapto (-SH).

The term "alkynyl" as used herein (alone or as part of another group) refers to optionally substituted straight and branched chain hydrocarbon groups having at least one carbon-carbon triple bond in the chain, preferably 2 to 10 carbons in the main chain . Exemplary unsubstituted alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halogen, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, or protected Hydroxy, carboxyl (-COOH), alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ -CO-), substituted carbamoyl ((R ¹⁰ )(R ¹¹ )N- CO-, wherein R ¹⁰ or R ¹¹ is as defined below, except that at least one of R ¹⁰ or R ¹¹ is not hydrogen), amino, heterocycle, mono- or dialkylamino or mercapto (-SH).

The term "cycloalkyl" (alone or as part of another group) as used herein refers to an optionally substituted saturated cyclic hydrocarbon system, including bridged ring systems, suitably containing 1-3 rings, preferably 3-9 rings per ring. carbon. Exemplary unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include, but are not limited to, one or more of the alkyl groups described above, or one or more of the groups described above as substituents for alkyl groups.

The term "ar" or "aryl" (alone or as part of another group) as used herein refers to an optionally substituted carbocyclic aryl group, preferably containing 1 or 2 rings and 6-12 ring carbons. Exemplary unsubstituted aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more of the nitro groups, the alkyl groups described above, or the groups described above as substituents for alkyl groups.

The term "heterocycle" or "heterocycle system" refers to a heterocyclyl, heterocycloalkenyl or heteroaryl group as described herein, which contains carbon atoms and 1-4 heteroatoms independently selected from N, O or S, Included are any bicyclic or tricyclic groups in which any of the above heterocyclic rings is fused to one or more heterocyclic, aryl or cycloalkyl groups. Optionally, nitrogen and sulfur heteroatoms can be oxidized. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom, resulting in a stable structure. The heterocyclic rings described herein may be substituted on carbon or nitrogen atoms.

Examples of heterocycles include, but are not limited to: 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidone Base, 4aH-carbazole, 4H-quinazinyl, 6H-1,2,5-thiadiazinyl, acridinyl, aziocinyl, benzimidazole, benzofuryl, benzothienyl, Benzothiophenyl, benzoxazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazole Base, benzimidazolone, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5, 2-Dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, di Indolinyl, indolizine, indolyl, isatinoyl, isobenzofuryl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoindolyl Quinolinyl, isothiazolyl, isoxazolyl, morpholinyl, 1,5-diazinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl-rylene Azaphenyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenanthiazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl , Phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidinyl, 4-piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyranyl Azolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridimidazole, pyridothiazole, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, Quinolinyl, 4H-quinolinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2, 5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl , thianthryl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, phenylthio, triazinyl, 1,2,3-triazolyl, 1,2,4 - Triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.

"Heterocycloalkenyl" means a non-aromatic monocyclic or polycyclic hydrocarbon ring system of about 3-10 atoms, preferably about 4-8 atoms, wherein one or more carbon atoms in the ring system are other than carbon A heteroelement, such as a hydrogen, oxygen or sulfur atom, which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The size of the rings in the ring system can include 5-6 ring atoms. Aza, oxa or thia as a prefix to the heterocycloalkenyl defines the presence of at least nitrogen, oxygen or sulfur atoms among the ring atoms, respectively. A heterocycloalkenyl group can be optionally substituted with one or more substituents described herein. Optionally, the nitrogen or sulfur atom of the heterocycloalkenyl group can also be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. "Heterocycloalkenyl" as used herein includes, for example but not limited to, groups described in: Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968) , specifically Chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (The Chemistry of Heterocyclic Compounds, A series of Monographs) (John Wiley&Sons, New York, 1950 to the present), Specifically, Volumes 13, 14, 16, 19 and 28; and "J. Am. Chem. Soc.", 82:5566 (1960), the contents of which are incorporated herein by reference. Exemplary monocyclic azacycloalkenyl groups include, but are not limited to: 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3, 6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, etc. Exemplary oxalenyl groups include, but are not limited to, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary polyoxoheterocycloalkenyl group is 7-oxabicyclo[2.2.1]heptenyl.

"Heterocyclyl" or "heterocycloalkyl" refers to a non-aromatic saturated monocyclic or polycyclic ring system of about 3-10 carbon atoms, preferably 4-8 carbon atoms, wherein one or more carbon atoms in the ring system The atoms are heteroelements other than carbon, such as nitrogen, oxygen or sulfur. The size of the rings in the ring system can include 5-6 ring atoms. Aza, oxa or thia as a prefix to the heterocyclyl limits the presence of at least nitrogen, oxygen or sulfur atoms respectively among the ring atoms. Heterocyclyl can be optionally substituted with one or more of the same or different substituents described herein. Optionally, the nitrogen or sulfur atom of the heterocyclyl can also be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

The term "heterocyclic group" as used herein includes groups such as, but not limited to, those described in: Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), specifically It is Chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (The Chemistry of Heterocyclic Compounds, A series of Monographs) (John Wiley & Sons, New York, 1950 to the present), specifically Volumes 13, 14, 16, 19 and 28; and "J. Am. Chem. Soc.", 82:5566 (1960). Exemplary monocyclic heterocyclyl groups include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1, 4-dioxanyl group, tetrahydrofuryl group, tetrahydrothiophenyl group, tetrahydrothiophenyl group and the like.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system of about 5-10 atoms in which one or more of the carbon atoms in the ring system is a heteroelement other than carbon, such as nitrogen, oxygen or sulfur. The size of the rings in the ring system can include 5-6 ring atoms. "Heteroaryl" can also be optionally substituted with one or more of the same or different substituents described herein. Aza, oxa or thia as a prefix to heteroaryl limits the presence of at least nitrogen, oxygen or sulfur atoms respectively among the ring atoms. Optionally, a nitrogen atom of a heteroaryl can also be oxidized to the corresponding N-oxide. Heteroaryl as used herein includes, for example but not limited to, groups described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (The Chemistry of Heterocyclic Compounds, A series of Monographs) (John Wiley & Sons, New York, 1950 to the present), specifically No. 13 , 14, 16, 19, and 28; and "J. Am. Chem. Soc.", 82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groups include, but are not limited to: pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiol Azolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl , benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzazaindole, 1,2,3-triazinyl, 1, 2,4-triazinyl, 1,3,5-triazinyl, benzothiazolyl, dioxolyl, furyl, imidazolyl, indolyl, indolizyl, isoxazole Base, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, Pyridyl, pyrimidyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazole Base, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thio-1,2,4- Oxadiazolyl, thiomorpholino, phenylthio, thiopyryl, triazolyl and triazolonyl.

The term "amino" refers to a _-NH2 group in which one or two hydrogen atoms may be replaced by an optionally substituted hydrocarbyl group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino, and ethyldimethylamino.

The term "cycloalkylalkyl" refers to a cycloalkyl-alkyl group wherein the aforementioned cycloalkyl group is attached through the aforementioned alkyl group. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl radical, cyclopentylpropyl and cyclohexylpropyl.

The term "arylalkyl" refers to the above-mentioned aryl group linked through the above-mentioned alkyl group.

The term "heteroarylalkyl" refers to the above-mentioned heteroaryl group attached through the above-mentioned alkyl group.

The term "heterocyclylalkyl" or "heterocycloalkylalkyl" refers to the above-mentioned heterocyclyl group attached through the above-mentioned alkyl group.

The terms "halogen", "halo" or "halo" (alone or as part of another group) as used herein refer to chlorine, bromine, fluorine and iodine.

The term "haloalkyl" refers to the above-mentioned halogen attached through the above-mentioned alkyl group. Fluoroalkyl is an exemplary group.

The term "aminoalkyl" refers to the above-mentioned amino group linked through the above-mentioned alkyl group.

The term "bicyclic fused ring system in which at least one ring is partially saturated" refers to an 8-13 membered fused bicyclic group in which at least one ring is non-aromatic. The cyclic group contains carbon atoms and optionally 1-4 heteroatoms independently selected from N, O or S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolinyl, and benzocycloheptyl.

The term "tricyclic fused ring system in which at least one ring is partially saturated" refers to a 9-18 membered fused tricyclic group in which at least one ring is non-aromatic. The cyclic group contains carbon atoms and optionally 1-7 heteroatoms independently selected from N, O or S. Illustrative examples include, but are not limited to: fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene, and 2,2a,7,7a-tetrahydro-1H-cyclobut[a]indene .

The term "pharmaceutically acceptable salt" refers to a derivative of said compound produced by modifying the parent compound by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts prepared from organic acids; The organic acids are such as but not limited to: acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid (pamoic), maleic acid, hydroxymaleic acid , phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 4-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethion Acid etc.

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Suitable salts are listed in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, page 1445, the contents of which are incorporated herein by reference.

The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human or animal tissue without undue toxicity, irritation, allergic reaction or other problems or complications, and having a reasonable benefit. Compounds, materials, compositions and/or dosage forms for risk/risk ratios.

The term "N-oxide" means that a compound of the invention comprising a nitrogen atom (such as that of a pyridyl group) can be reacted in a known manner with hydrogen peroxide or a peracid such as 3-chloroperoxy in an inert solvent such as dichloromethane. -The compound obtained by reacting benzoic acid, the reaction temperature is about -10 to 80°C, preferably about 0°C.

"Substituted" means that one or more hydrogens on the atom indicated in the expression "substituted" is replaced by a group selected from the stated group, as long as the normal valence of the indicated atom is not exceeded and the substitution results in a stable compound . When a substituent is keto (ie, =0), 2 hydrogens on the atom are replaced.

Unless a compound moiety of the invention is defined as unsubstituted, a compound moiety may be substituted. In addition to any of the substituents provided above, moieties of the compounds of the invention may be optionally substituted with one or more groups independently selected from the group consisting of:

C ₁ -C ₄ alkyl;

C ₂ -C ₄ alkenyl;

C ₂ -C ₄ alkynyl;

CF ₃ ;

halogen;

OH;

O-(C ₁ -C ₄ alkyl);

OCH ₂ F;

OCHF ₂ ;

OCF ₃ ;

OC(O)-(C ₁ -C ₄ alkyl);

OC(O)-(C ₁ -C ₄ alkyl);

OC(O)NH-(C ₁ -C ₄ alkyl);

OC(O)N(C ₁ -C ₄ alkyl) ₂ ;

OC(S)NH-(C ₁ -C ₄ alkyl);

OC(S)N(C ₁ -C ₄ alkyl) ₂ ;

SH;

S-(C ₁ -C ₄ alkyl);

S(O)-(C ₁ -C ₄ alkyl);

S(O) ₂ -(C ₁ -C ₄ alkyl);

SC(O)-(C ₁ -C ₄ alkyl);

SC(O)O-(C ₁ -C ₄ alkyl);

_NH2 ;

N(H)-(C ₁ -C ₄ alkyl);

N(C ₁ -C ₄ alkyl) ₂ ;

N(H)C(O)-(C ₁ -C ₄ alkyl);

N(CH ₃ )C(O)-(C ₁ -C ₄ alkyl);

N(H)C(O) _-CF3 ;

N( _CH3 )C(O) _-CF3 ;

N(H)C(S)-(C ₁ -C ₄ alkyl);

N(CH ₃ )C(S)-(C ₁ -C ₄ alkyl);

N(H)S(O) ₂ -(C ₁ -C ₄ alkyl);

N(H)C(O) _NH2 ;

N(H)C(O)NH-(C ₁ -C ₄ alkyl);

N(CH ₃ )C(O)NH-(C ₁ -C ₄ alkyl);

N(H)C(O)N(C ₁ -C ₄ alkyl) ₂ ;

N(CH ₃ )C(O)N(C ₁ -C ₄ alkyl) ₂ ;

N(H)S(O) ₂ NH ₂ );

N(H)S(O) ₂ NH-(C ₁ -C ₄ alkyl);

N(CH ₃ )S(O) ₂ NH-(C ₁ -C ₄ alkyl);

N(H)S(O) ₂ N(C ₁ -C ₄ alkyl) ₂ ;

N(CH ₃ )S(O) ₂ N(C ₁ -C ₄ alkyl) ₂ ;

N(H)C(O)O-(C ₁ -C ₄ alkyl);

N(CH ₃ )C(O)O-(C ₁ -C ₄ alkyl);

N(H)S(O) ₂ O-(C ₁ -C ₄ alkyl);

N(CH ₃ )S(O) ₂ O-(C ₁ -C ₄ alkyl);

N(CH ₃ )C(S)NH-(C ₁ -C ₄ alkyl);

N(CH ₃ )C(S)N(C ₁ -C ₄ alkyl) ₂ ;

N(CH ₃ )C(S)O-(C ₁ -C ₄ alkyl);

N(H)C(S) _NH2 ;

NO ₂ ;

CO ₂ H;

CO ₂ -(C ₁ -C ₄ alkyl);

C(O)N(H)OH;

C(O)N( _CH3 )OH:

C(O)N( _CH3 )OH;

C(O)N(CH ₃ )O-(C ₁ -C ₄ alkyl);

C(O)N(H)-(C ₁ -C ₄ alkyl);

C(O)N(C ₁ -C ₄ alkyl) ₂ ;

C(S)N(H)-(C ₁ -C ₄ alkyl);

C(S)N(C ₁ -C ₄ alkyl) ₂ ;

C(NH)N(H)-(C ₁ -C ₄ alkyl);

C(NH)N(C ₁ -C ₄ alkyl) ₂ ;

C(NCH ₃ )N(H)-(C ₁ -C ₄ alkyl);

C(NCH ₃ )N(C ₁ -C ₄ alkyl) ₂ ;

C(O)-(C ₁ -C ₄ alkyl);

C(NH)-(C ₁ -C ₄ alkyl);

C(NCH ₃ )-(C ₁ -C ₄ alkyl);

C(NOH)-(C ₁ -C ₄ alkyl);

C(NOCH ₃ )-(C ₁ -C ₄ alkyl);

CN;

CHO;

_CH2OH ;

CH ₂ O-(C ₁ -C ₄ alkyl);

_{CH2NH2 ;}

CH ₂ N(H)-(C ₁ -C ₄ alkyl);

CH ₂ N(C ₁ -C ₄ alkyl) ₂ ;

Aryl;

Heteroaryl;

Cycloalkyl; and

heterocyclyl.

In some embodiments of the present invention, the polycyclic bisamide MMP-13 inhibitory compound is represented by general formula (I):

In the formula:

R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times;

^R2 is hydrogen;

R ³ is NR ²⁰ R ²¹ ;

^R and ^R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, Aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, where alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkyl Alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are attached to them The nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times;

^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times;

^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times;

R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl ^, heteroarylalkyl, alkenyl, alkynyl, NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times;

R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;

R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times;

^R and ^R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, Aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, where alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkyl Alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or ^R80 and ^R81 are attached to them The nitrogens of are taken together to form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and said ring is optionally substituted one or more times; and

x is selected from 0-2.

Some embodiments of the present invention include N-oxides, pharmaceutically acceptable salts and stereoisomers of compounds of formula (I).

In some embodiments of the invention, ^R3 may comprise a bicyclic system. According to these embodiments, ^R can be:

In the formula:

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times;

R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein the R ⁹ group is optionally substituted one or more times;

^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl (heterocyclylalkyl) or halogen, wherein alkyl, arylalkyl, cycloalkyl - alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

A and B are independently selected from C, N, O or S;

L, M and T are independently selected from C or N;

g and h are independently selected from 0-2;

m and n are independently selected from 0-3, provided that:

(1) When E exists, m and n are not both 3;

(2) When E is -CH ₂ -W-, m and n are not 3; and

(3) When E is a bond, m and n are not 0;

p is selected from 0-6;

q is selected from 0-4;

r is selected from 0-1;

w is selected from 0-4;

x is selected from 0-2;

y is selected from 1 and 2;

z is selected from 0-2; and

where the dashed line represents an optional double bond.

All other variables are defined as above.

In some embodiments of the present invention, R ¹⁰ and R ¹¹ may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R 10 , OC(O) ^{R 10 ,} OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ and NR ¹⁰ CO ₂ R ¹¹ .

In some embodiments, R ²⁰ together with the nitrogen to which it is attached and L can form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S, or NR ⁵⁰ , wherein the ring can be replaced by Optionally substituted.

More specifically, in this bicyclic embodiment, ^R can be, but is not limited to, the following groups:

In the formula:

R is selected from C(O)NR ¹⁰ R ¹¹ , COR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , CONHCH ₃ or CON(CH ₃ ) ₂ , wherein C(O)NR ¹⁰ R ¹¹ , COR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , CONHCH ₃ and CON(CH ₃ ) ₂ are optionally substituted one or more times;

^R4 is selected from:

^R is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl The radical, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted one or more times;

^R is selected from hydrogen, halogen, hydroxy, alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, haloalkyl, C(O)NR ¹⁰ R ¹¹ or O ₂ NR ¹⁰ R ¹¹ , where alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroaryl alkyl, haloalkyl, C(O)NR ¹⁰ R ¹¹ and O ₂ NR ¹⁰ R ¹¹ are optionally substituted one or more times; and

r is selected from 0-1.

All other variables are defined as above.

In some embodiments of the present invention, when E is present, m and n together may be 1-4, thereby forming a 5-8 membered ring. More preferably, m and n together may be 1-2, thereby forming a 5-6 membered ring.

In other embodiments, when E is a bond, m and n together may be 2-5, thereby forming a 5-8 membered ring. More preferably, m and n together may be 2-3, thereby forming a 5-6 membered ring.

Alternatively, in some embodiments of the invention, ^R3 may comprise a tricyclic ring system. In this embodiment, ^R can be:

In the formula:

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl and heteroaryl, wherein each R ⁹ group is optionally substituted one or more times;

R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl;

A and B are independently selected from C, N, O or S;

L, M and T are independently selected from C or N;

g and h are independently selected from 0-2;

q is selected from 0-4;

r is selected from 0-1;

w is selected from 0-4;

x is selected from 0-2;

y is selected from 1 and 2;

z is selected from 0-2; and

where the dashed line optionally represents a double bond.

All other variables are defined as above.

More specifically, in some tricyclic embodiments, ^R can be:

In the formula:

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-or

All other variables are defined as above.

According to some embodiments of the invention, one or more ^R groups may be heteroaryl. More specifically, in some embodiments, ^R can be independently selected from: dioxole, imidazole, furan, thiazole, isothiazole, isoxazole, morpholine, 1,2,4-oxadio Azole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxirane, oxazole , 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridazine, pyridine , pyrimidine, pyrrole, pyrrolidine, tetrazine, tetrazole, thiazine, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2 , 5-thiadiazole, thiatriazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, 5-thio-1,2,4-oxadiazole, thio Morpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4-triazole, 1,2,3- Triazoles or triazolones, which are optionally substituted.

In some embodiments of the invention, ^R can be:

In the formula:

R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein alkyl, alkynyl and haloalkyl are optionally Optionally replace one or more times;

R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;

B ₁ is selected from NR ¹⁰ , O or S;

D, G, L, M and T are independently selected from C or N; and

Z is a 5-6 membered ring selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted once or more Second-rate.

All other variables are defined as above.

More specifically, ^R can be (but is not limited to) the following groups:

In some embodiments of the invention, R ¹ may comprise a bicyclic system. For example, ^R1 can be:

In the formula:

R ¹² and R ¹³ are independently selected from hydrogen, alkyl or halogen, wherein alkyl is optionally substituted one or more times, or optionally, R ¹² and R ¹³ together form =O, =S or =NR ¹⁰ ;

R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein alkyl, alkynyl and haloalkyl are optionally optionally substituted one or more times, or optionally, two R ¹⁸ groups together form =O, =S or =NR ¹⁰ ;

J and K are independently selected from CR ¹⁰ R ¹¹ , NR ¹⁰ , O or S(O) _x ;

A ₁ is selected from NR ¹⁰ , O or S;

L and M are independently selected from C or N;

q is selected from 0-4; and

x is selected from 0-2.

All other variables are defined as above.

More specifically, ^R can be (but is not limited to) the following groups:

In some embodiments of the invention, ^R can be:

In the formula:

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ¹⁹ is selected from hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein alkyl, alkynyl and haloalkyl are optionally substituted once or repeatedly;

R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl, which are optionally substituted one or more times;

D, G, L, M and T are independently selected from C and N;

B ₁ is selected from NR ¹⁰ , O or S;

X is selected from a bond or (CR ¹⁰ R ¹¹ ) _w E(CR ¹⁰ R ¹¹ ) _w ;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

n is selected from 0-3;

q is selected from 0-4;

w is selected from 0-4;

x is selected from 0-2;

V is a 5-8 membered ring selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, which are optionally substituted one or more times; and

Z is a 5-6 membered ring selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted once or more Second-rate.

All other variables are defined as above.

More specifically, ^R can be (but is not limited to) the following groups:

In the formula:

R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein alkyl, alkynyl and haloalkyl are optionally optionally substituted one or more times, or optionally, two R ¹⁸ groups together form =O, =S or =NR ¹⁰ ;

n is selected from 0-3;

p is selected from 0-6;

q is selected from 0-4; and

x is selected from 0-2.

All other variables are defined as above.

More specifically, ^R can be (but is not limited to) the following groups:

According to some embodiments of the present invention, the polycyclic bisamide MMP-13 inhibitory compound of general formula (I) can be represented by formula (II):

In the formula:

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ₁₀ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times;

R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times;

^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl and halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

L, M and T are independently selected from C or N;

g and h are independently selected from 0-2;

m and n are independently selected from 0-3, provided that:

(1) When E exists, m and n are not both 3;

(2) When E is -CH ₂ -W-, m and n are not 3; and

(3) When E is a bond, m and n are not 0;

p is selected from 0-6;

q is selected from 0-4;

w is selected from 0-4;

x is selected from 0-2;

y is selected from 1 and 2; and

z is selected from 0-2.

All other variables are defined as above.

According to some embodiments of the present invention, the polycyclic bisamide MMP-13 inhibitory compound of general formula (I) can be represented by formula (III):

In the formula:

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times;

^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl and halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl;

L, M and T are independently selected from C or N;

q is selected from 0-4;

w is selected from 0-4;

x is selected from 0-2;

y is selected from 1 and 2; and

z is selected from 0-2.

All other variables are defined as above.

In addition, the polycyclic bisamide MMP-13 inhibitory compound can be represented by formula (IV):

In the formula:

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times;

^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

g and h are independently selected from 0-2;

m and n are independently selected from 0-3, provided that:

(1) When E exists, m and n are not both 3;

(2) when E is -CH2-W-, m and n are not 3; and

(3) When E is a bond, m and n are not 0;

p is selected from 0-6;

x is selected from 0-2; and

where the dashed line optionally represents a double bond.

All other variables are defined as above.

In addition, the polycyclic bisamide MMP-13 inhibitory compound of general formula (I) can be represented by formula (V):

In the formula:

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ¹⁵ and R ¹⁶ form a ring together with the carbon atoms they are bound to, and the ring is selected from a 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5-8 membered cycloalkyl ring, a 5-8 membered heterocyclic ring A base ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl;

g and h are independently selected from 0-2;

x is selected from 0-2; and

where the dashed line optionally represents a double bond.

All other variables are defined as above.

More specifically, compounds of formula (I) may be selected from, but not limited to:

According to some embodiments of the present invention, the polycyclic bisamide MMP-13 inhibitory compound can be represented by general formula (VI):

In the formula:

R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times;

^R2 is hydrogen;

R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , each R ⁴ group may be optionally substituted by one or more R ¹⁴ groups;

R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times;

R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times;

^R and ^R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, Aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, where alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkyl Alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are attached to them The nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , which ring may be optionally substituted one or more times;

^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times;

R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;

R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl;

R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times;

^R and ^R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, Aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, where alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkyl Alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or ^R80 and ^R81 are attached to them The nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH and -N(alkyl), which rings may be optionally substituted one or more times;

R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times;

E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ );

U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ;

Y does not exist or is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or 6 membered aryl;

L, M and T are independently selected from C or N;

g and h are independently selected from 0-2;

q is selected from 0-4;

w is selected from 0-4;

x is selected from 0-2;

y is selected from 1 and 2; and

z is selected from 0-2.

Compounds of formula (VI) may comprise bicyclic or tricyclic ring systems, as defined above. At least one ring in the bicyclic or tricyclic ring system is at least partially saturated.

It is contemplated that the compounds of the invention represented by the above formulas include all diastereoisomers and enantiomers, as well as racemic mixtures. Racemic mixtures can be separated by chiral salt resolution or by chiral column HPLC chromatography.

The present invention also relates to pharmaceutical compositions comprising any of the above polycyclic bisamide MMP-13 inhibitory compounds of the present invention. According to the present invention, some embodiments of the present invention provide a pharmaceutical composition comprising an effective amount of the polycyclic bisamide MMP-13 inhibitory compound of the present invention and a pharmaceutically acceptable carrier.

The invention also relates to methods of inhibiting MMP-13 and methods of treating diseases or conditions mediated by MMP-13 enzymes. Such methods involve administering a polycyclic bisamide MMP-13 inhibitory compound of the invention, such as a compound of formula (I) (described above), or an N-oxide, pharmaceutically acceptable salt or stereoisomer thereof. Examples of diseases or conditions mediated by MMP-13 enzymes include, but are not limited to: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, Eye disease, neuropathy, psychosis, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, aging, dementia, cardiomyopathy, renal tubular injury, diabetes, psychosis, movement disorder, dyschromatosis ( pigmentary abnormality), deafness, inflammatory and fibrotic syndrome, bowel syndrome, allergy, Alzheimer's disease, arterial plaque formation, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma , tissue exposure to chemicals or oxidative damage, pain, inflammatory pain, bone pain and joint pain.

In some embodiments of the present invention, the above-mentioned polycyclic bisamide MMP-13 inhibitory compounds are used for the manufacture of drugs for treating diseases mediated by MMP-13 enzymes.

In some embodiments, the above polycyclic bisamide MMP-13 inhibitory compound can be used in combination with drugs, agents or therapeutic agents, such as but not limited to: (a) antirheumatic drugs for disease relief (b) non-steroidal anti-inflammatory drugs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; (g) biological response modifiers; or (h) Other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases.

Examples of disease-modifying antirheumatic drugs include, but are not limited to: methotrexate, azathioprine luflunomide, penicillamine, gold salts, mycophenolate mofetil, ethyl mofetil, and cyclophosphamide.

Examples of NSAIDs include, but are not limited to: piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.

Examples of COX-2 selective inhibitors include, but are not limited to: rofecoxib, celecoxib, and valdecoxib.

Examples of COX-1 inhibitors include, but are not limited to, piroxicam.

Examples of immunosuppressants include, but are not limited to: methotrexate, cyclosporine, leflunomide, tacrolimus, rapamycin, and sulfasalazine.

Examples of steroids include, but are not limited to: paramethasone, prednisone, cortisone, prednisolone, and dexamethasone.

Examples of biological response modifiers include, but are not limited to: anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, and anti-adhesion molecules.

Examples of anti-inflammatory or therapeutic agents include, but are not limited to: p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, thalidomide, leukotriene inhibitors, and proinflammatory cytokine-producing Other Small Molecule Inhibitors.

According to another embodiment of the present invention, the pharmaceutical composition may comprise an effective amount of the compound of the present invention, a pharmaceutically acceptable carrier and a drug, medicament or therapeutic agent selected from the following group: (a) antirheumatic drugs for relieving diseases; ( b) NSAIDs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; ) Other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases.

In some embodiments of the present invention, compounds of Formula I are synthesized by the general method shown in Scheme 1.

plan 1

Treatment of dimethyl pyrimidine-4,6-dicarboxylate (R ²² =R ²³ =H) with a slight molar excess of R ¹ R ² NH in a suitable solvent and heating gives the desired adduct. Treatment of this compound with a slight molar excess of R ²⁰ R ²¹ NH in a suitable solvent, heating and purification yields the desired final adduct. Alternatively, one skilled in the art can obtain the final adducts by equivalent coupling reactions.

In some embodiments, compounds of Formula I are synthesized by the general method shown in Scheme 2.

Scenario 2

Treatment of the dimethyl pyrimidine-4,6-dicarboxylate derivative with 1 equivalent of sodium hydroxide yields the monomethyl pyrimidine-4,6-dicarboxylate derivative. After coupling with R ²⁰ R ²¹ NH by an activated acid such as HOBt/EDCI, HOAt/HATU, PyBroP or ethyl chloroformate in a suitable solvent, purification yields the desired adduct. Treatment of this compound with 1 N NaOH followed by coupling with R ¹ R ² NH via an activated acid (such as HOBt/EDCI, HOAt/HATO, PyBroP, or ethyl chloroformate) yields pyrimidine-4,6-bisamide . The R group can be further manipulated (eg saponification of the COOMe group in R) if desired.

The MMP-13 inhibitory activity of the polycyclic bisamide MMP-13 inhibitory compounds of the invention can be determined by any suitable assay known in the art. Standard in vitro assays for MMP-13 inhibitory activity are described in Example 3000.

The MMP-13 inhibitory activity (IC ₅₀ MMP-13) of the polycyclic bisamide MMP-13 inhibitory compound of the present invention is about 1 nM-20 μM, generally about 8 nM-2 μM. The MMP inhibitory activity of the polycyclic bisamide MMP-13 inhibitory compound of the present invention is preferably in the range of about 1 nM-20 nM. Table 1 lists typical examples of polycyclic bisamide MMP-13 inhibitory compounds of the present invention whose MMP-13 activity is lower than about 1 μM, specifically about 1 nM-300 nM, more specifically about 1 nM-260 nM.

Table 1

SUMMARY OF MMP-13 ACTIVITY OF COMPOUND OF FORMULA I

The synthesis of the polycyclic bisamide MMP-13 inhibitory compounds of the present invention and their biological activity tests are described in the following examples, which are not intended to be limiting in any way.

Examples and methods

All reagents and solvents were obtained from commercial sources and used without further purification. Mass ( ¹ H) spectra were recorded on a 400 MHz NMR spectrometer in deuterated solvents. Flash chromatography was performed on Merck silica gel (grade 60, 70-230 mesh) in a suitable organic solvent, as described in the specific examples. Thin layer chromatography (TLC) was performed on silica gel plates with UV detection.

Preparative Examples 1, 3, 5, 8, 9a, 10-152, 2001-2067 and 2100-2125 relate to intermediate compounds useful in the preparation of compounds of the invention.

Preparation Example 1

Step A

A mixture of 5-bromo-2,3-dihydro-1-indanone (1.76 g), _NH2OH -HCl (636 mg) and NaOAc (751 mg) in MeOH (40 mL) was stirred at 22 °C for 16 h. Water (100 mL) was added and the resulting precipitate was filtered and washed three times with water (20 mL) to yield a colorless solid (1.88 g; >99%). [MH] ⁺ =226.

Step B

1 M lithium aluminum hydride in Et ₂ O (42.4 mL) was slowly added to a mixture of 5-bromo-indan-1-one oxime (1.88 g) in Et ₂ O (20 mL) at -78°C under argon atmosphere middle. The mixture was heated to reflux (40°C) and stirred for 5 hours. The mixture was cooled to 0 °C and water (1.6 mL), 15% aqueous NaOH (1.6 mL) and water (4.8 mL) were added carefully sequentially. The resulting mixture was filtered through Celite and the filtrate was concentrated to yield a clear oil (1.65 g; 94%). [MH] ⁺ =212.

Step C

A THF (10 mL) solution of 5-bromo-indan-1-ylamine (300 mg), di-tert-butyl dicarbonate (370 mg) and triethylamine (237 μL) was stirred at 22°C for 16 hours. The solution was concentrated and the resulting residue was purified by a short silica gel column (4:1 hexane:ethyl acetate, _Rf = 0.3) to yield a clear oil (460 mg; >99%).

Step D

Stir (5-bromo-indan-1-yl)-tert-butyl carbamate (460mg), Pd(PPh ₃ ) ₄ (89mg), Zn(CN) ₂ in a sealed vial under argon atmosphere at 110°C (200 mg) and DMF (5 mL) for 18 hours. The mixture was cooled to 22°C, _Et2O (20 mL) and water (20 mL) were added. The aqueous layer was washed 4 times with _Et2O (10 mL). The combined organic layers were washed 3 times with water (10 mL), once with brine (10 mL), dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography (4:1 hexane:ethyl acetate, _Rf = 0.2) to yield a clear oil (170 mg; 47%). [MH] ⁺ =259.

Step E

4M HCl in dioxane (2 mL) was added to (5-cyano-indan-1-yl)-carbamate tert-butyl ester (170 mg) and the resulting solution was stirred at 22 °C for 3 hours, at which point a precipitate formed . The mixture was concentrated to yield a colorless powder (128 mg; >99%). [M-Cl ⁻ ] ⁺ = 159.

Step F

Triethylamine (67 μL) was added to 5-cyano-indan-1-yl-ammonium chloride (50.6 mg), 6-(4-fluoro-3-methyl-benzyl In a mixture of carbamoyl)-pyrimidine-4-carboxylic acid (62.7 mg), bromotripyrrolidinylphosphonium hexafluorophosphate (124 mg) in THF (2 mL). The mixture was stirred at 22°C for 18 hours. EtOAc (10 mL) and 1N aqueous HCl (10 mL) were added. The aqueous layer was washed twice with EtOAc (10 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ (10 mL), brine (10 mL), dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography (1:1 hexane:ethyl acetate, _Rf = 0.3) to yield an off-white solid (75.8 mg; 81%).

Preparation Example 3

Step A

A THF (10 mL) solution of 5-bromo-indan-1-ylamine (300 mg), di-tert-butyl dicarbonate (370 mg) and triethylamine (237 μL) was stirred at 22°C for 16 hours. The solution was concentrated and the resulting residue was purified by a short silica gel column (4:1 hexane:ethyl acetate, _Rf = 0.3) to yield a clear oil (460 mg; >99%).

Step B

A hot solution of N-acetyl-D-leucine (924 mg) in MeOH (3 mL) was added to a boiling solution of racemic 5-bromo-indan-1-ylamine (1.13 g) in MeOH (2.3 mL) middle. The solution was allowed to cool to 22°C, resulting in a white precipitate. The solid was separated from the supernatant and washed with MeOH (2 mL). The solid was recrystallized twice from MeOH. Aqueous 10% NaOH (20 mL) and _Et2O (20 mL) were added to the resulting solid. Once the solids had dissolved (5 min), the organic layer was removed and the aqueous layer was washed twice with _Et2O . The combined organic layers were dried over _MgSO4 , filtered and concentrated to yield a clear oil (99 mg; 18%). [MH] ⁺ =212.

Step C

Stir (5-bromo-indan-1-yl)-tert-butyl carbamate (460mg), Pd(PPh ₃ ) ₄ (89mg), Zn(CN) ₂ in a sealed vial under argon atmosphere at 110°C (200 mg) and DMF (5 mL) for 18 hours. The mixture was cooled to 22°C and Et2O (20 mL) and water (20 mL) were added. The aqueous layer was washed 4 times with Et2O (10 mL). The combined organic layers were washed 3 times with water (10 mL), once with brine (10 mL), dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography (4:1 hexane:ethyl acetate, _Rf = 0.2) to yield a clear oil (170 mg; 47%). [MH] ⁺ =259.

Step D

4M HCl in dioxane (2 mL) was added to (5-cyano-indan-1-yl)-carbamate tert-butyl ester (170 mg) and the resulting solution was stirred at 22 °C for 3 hours, at which point a precipitate formed . The mixture was concentrated to yield a colorless powder (128 mg; >99%). [M-Cl ⁻ ] ⁺ = 159.

Step E

Triethylamine (67 μL) was added to 5-cyano-indan-1-yl-ammonium chloride (50.6 mg), 6-(4-fluoro-3-methyl-benzylamine prepared in Preparative Example 2120 Formyl)-pyrimidine-4-carboxylic acid (62.7 mg), bromotripyrrolidinylphosphonium hexafluorophosphate (124 mg) in THF (2 mL). The mixture was stirred at 22°C for 18 hours. EtOAc (10 mL) and 1N aqueous HCl (10 mL) were added. The aqueous layer was washed twice with EtOAc (10 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ (10 mL), brine (10 mL), dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by silica gel chromatography (1:1 hexane:ethyl acetate, _Rf = 0.3) to yield an off-white solid (75.8 mg; 81%).

Preparation Example 5

Step A

Commercially available 2,2,2-trifluoro-N-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)acetamide (95 mg) and AlCl ₃ (5 mg) were mixed under aluminum foil Dissolve in 2 mL AcOH. Bromine (23 µL) was added to the solution, and the mixture was stirred at room temperature for 3 hours. 10% Na ₂ S ₂ O ₃ aqueous solution (7 mL) was added to the solution, and the mixture was stirred for 10 min. EtOAc was added to the mixture, the organic layer was washed with brine, dried over _MgSO4 , concentrated in vacuo. The residue was chromatographed on silica gel to yield 87 mg of a brown solid (95%). ¹ HNMR (CDCl ₃ ) δ=2.20-2.38(m, 1H), 2.83-3.15(m, 3H), 5.37(m, 1H), 6.50(s, 1H), 6.89(d, 1H), 7.28(d , 1H). [MH] ⁺ =314/316.

Step B

N-(2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-2,2,2-trifluoroacetamide (87 mg), Pd ₂ (dba) ₃ ( 12.7 mg) and dppf (30.8 mg) were added to anhydrous DMF (6.5 mL). The mixture was heated to 80°C. Zn(CN) ₂ (39 mg) was added in portions. The mixture was stirred for 24 hours. The solvent was evaporated in vacuo. The residue was chromatographed on silica gel to yield 48 mg of a white solid (66%). ¹ HNMR (CDCl ₃ ) δ=2.35-2.40 (m, 1H), 2.95-3.25 (m, 3H), 5.47 (m, 1H), 6.75 (s, 1H), 7.45 (s, 1H). [MH ⁺ ] ^- 259.

Step C

N-(2-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-2,2,2-trifluoroacetamide (47 mg) and K ₂ CO ₃ (142 mg ) was added to MeOH (5 mL) and _H2O (3 mL). The mixture was stirred at room temperature for ₁₆ hours, diluted with _H2O , and extracted with _CH2Cl2 . The organic layer was washed with brine, dried over _MgSO4 , concentrated in vacuo. The residue was chromatographed on silica gel to yield 30 mg of off-white solid (100%). ¹ HNMR (CDCl ₃ ) δ=1.65 (s, 2H), 2.00-2.18 (m, 1H), 2.75-3.15 (m, 3H), 4.35 (m, 1H), 7.44 (s, 1H).

Step D

6-(4-Fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid (79 mg) prepared in Preparative Example 2120, the corresponding cyano-amine (30 mg), EDIC (53 mg) and HOBt (37 mg) was dissolved in THF (5 mL). The mixture was stirred for 16 hours, diluted with EtOAc, washed with NaHCO ₃ and brine. The organic layer was washed with brine, dried over _MgSO4 , concentrated in vacuo. The residue was chromatographed on silica gel to yield 43.8 mg of a white solid (56%). [MH] ⁺ =436.

Preparation Example 8

Step A

If the starting cyano compound (306 mg) from Preparative Example 1 was treated at 0° C. under anhydrous methanol (20 mL) hydrogen chloride gas, the title compound was obtained.

Step B

If the above title compound dissolved in methanol (20 mL) was treated with sodium bicarbonate (336 mg) at room temperature, the title compound was obtained.

Preparation Example 9a

Step A

If the cyano compound of Preparative Example 1 (42 mg) is refluxed overnight with a solution of hydroxylamine (69 mg hydrochloride neutralized with triturated potassium hydroxide in ethanol) in ethanol (3 mL), the desired amidoxime is obtained.

Step B

If the title product of Step A above, dissolved in tetrahydrofuran and cooled to 0°C in an ice bath, is treated sequentially with pyridine and acetyl chloride, the desired compound is obtained.

Step C

If the title product of Step B above is refluxed in chlorobenzene, the desired oxadiazole will be obtained.

Preparation Examples 10-152

If the amines shown in the following Table 2 are coupled with the intermediate (or its enantiomer) of Preparation Example 2119 Step A according to the method described in Example 2300 Step A, according to the method described in Example 1 Step F Coupling with the product of Preparative Example 2120 will give the product shown in Table 2 below.

Table 2

Preparation Example 2001

Step A

Dissolve commercially available 1-bromo-3-ethyl-benzene (1.1 g), zinc cyanide (508 mg), tetrakis-(triphenylphosphine) palladium (333 mg) in anhydrous toluene (8 mL), degas, Stir at 80°C in a sealed pressure tube under argon. After 12 hours, the mixture was concentrated to dryness. The remaining residue was purified by column chromatography (silica, cyclohexane/EtOAc, 95:5) to afford the title compound (470 mg; 62%). [MH] ⁺ =132.

Step B

The title compound of Step A above (470 mg), di-tert-butyl dicarbonate (1.56 g) and nickel(II) chloride hexahydrate (85 mg) were dissolved in anhydrous methanol (30 mL) and cooled to 0°C. Sodium borohydride (948 mg) was then added in small portions. The ice bath was removed and the mixture was stirred vigorously for 4 hours. Diethylenetriamine (385 [mu]L) was then added and the mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate and brine. The organic phase was separated, dried over _MgSO4 , filtered and concentrated. The residue was purified by column chromatography (silica, cyclohexane/EtOAc, 95:5-9:1) to give the intermediate as a colorless oil. (341 mg, 40%). [MH] ⁺ =236.

Step C

A solution of the title compound from Step B above (341 mg) in hydrogen chloride (4M in dioxane) was stirred at room temperature for 1 hour. The solvent was removed to give the title compound (250 mg; quantitative). [M-Cl] ⁺ =136.

Preparation Example 2002-2003

The following compounds were prepared in a similar manner to Preparative Example 2001, except that the compounds of the Preparative Examples shown in Table 3 below were used.

table 3

Preparation Example 2004

Step A

To a commercially available solution of 5-ethyl-thiophene-3-carboxylic acid (3.0 g) in anhydrous dichloromethane (50 mL) was added oxalyl chloride (2.3 mL) at 0° C., followed by DMF (0.4 mL), at 0 The mixture was stirred for 1 hour at °C and then for 3 hours at room temperature. The reaction was then concentrated to an oil. The oil was then dissolved in dichloromethane (3 mL) and slowly added to concentrated aqueous ammonia (30 mL) at about -40°C. The reaction mixture was stirred at about -30°C for 1 hour, then slowly warmed to room temperature (-10 hours). Volatile components in the reaction mixture were removed under reduced pressure to give the intermediate as a tan solid (2.0 g; 68%). [MH] ⁺ =156.

Step B

A solution of the intermediate from Step A above (1.0 g) and tetrabutylammonium borohydride (4.9 g) in anhydrous dichloromethane (30 mL) was stirred vigorously, heated (55-62° C.) for 24 hours, then concentrated to an oil. 1N Hydrochloric acid (15 mL) was slowly added to the cooled (0° C.) oil over 1 hour. The aqueous mixture was then heated at 100 °C for 1 h, cooled to room temperature, washed with diethyl ether (100 mL), and basified to about pH 10 with concentrated aqueous KOH. The aqueous phase was then extracted with diethyl ether (100 mL), the organic phase was separated and dried ( _MgSO4 ), filtered and concentrated to yield the title compound as an oil (0.25 g; 27%). [MH] ⁺ =142.

Preparation of each embodiment 2005

Step A

_BBr3 (1M in dichloromethane, 7.3 mL) was added to a solution of commercially available 3-methoxymonobenzylamine (500 mg) in dichloromethane (5 mL) at 0°C. The mixture was stirred at room temperature for 16 hours. Methanol (5 mL) was then added, and the mixture was stirred for 2 hours, then concentrated to give the title compound (740 mg, quantitative). ¹ H-NMR (CDCl ₃ ) δ=3.90 (brs, 2H), 6.70-6.85 (m, 3H), 7.18 (t, 1H), 8.10 (brs, 3H).

Preparation Example 2006

Step A

Di-tert-butyl dicarbonate (1.10g) was added to commercially available 3-bromo. Benzylamine (938 mg) in anhydrous dichloromethane (10 mL). The resulting clear solution was stirred at room temperature for 15 hours, then concentrated to give the title compound (1.42 g; 99%). [(M-isobutene)H] ⁺ =230/232, [MNa] ⁺ =308/310.

Step B

2,2,2-Trifluoroethanol (719 pL) was carefully added to a suspension of sodium hydride (95%, 303 mg) in dry tetrahydrofuran (10 mL). Copper(I) iodide (2.29 g) and a solution of the title compound from Step A above (572 mg) in anhydrous THF (2 mL) were then added and the resulting suspension was heated at reflux for 17 hours. The mixture was cooled to room temperature, diluted with water (20 mL) and methanol (20 mL), extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried ( _MgSO4 ), filtered, concentrated and purified by flash chromatography (silica, cyclohexane/ethyl acetate) to afford the title compound (330 mg; 54%). [(M-isobutene)H] ⁴ =250, [MNa] ⁺ =328.

Step C

The title compound from Step B above (305 mg) was dissolved in 4M hydrogen chloride in dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (239 mg; 99%).

[M-Cl] ⁺ =206.

Preparation Example 2007

Step A

Commercially available tert-butyl (3-amino-benzyl)-carbamate (222 mg) was suspended in a 4M solution of hydrogen chloride in dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (193 mg; 99%) as the dihydrochloride salt. [M-HCl ₂ ] ⁺ =123.

Preparation Example 2008

Commercially available 3-aminomethyl-benzoic acid methyl ester hydrochloride (500 mg) was dissolved in ammonia water (33%, 50 mL), and stirred at 90° C. for 20 hours in a sealed pressure tube. Removal of the solvent gave the title compound (469 mg; quantitative) as a colorless solid. [M-Cl] ⁺ =151.

Preparation Example 2009

Step A

Commercially available tert-butyl (3-aminobenzyl)-carbamate (400 mg) was dissolved in pyridine (8 mL), cooled to 0° C., and acetyl chloride (154 μL) was added. The reaction mixture was allowed to reach room temperature overnight. The mixture was cooled to 0°C, neutralized with 1M hydrochloric acid, and diluted with water (15 mL). After extraction with dichloromethane (3 x 50 mL), the organic layer was collected, dried ( _MgSO4 ), concentrated, and purified by column chromatography (silica, cyclohexane/EtOAc, 1:1) to give the intermediate as a pale yellow oil (333 mg; 70%). [MNa] ⁺ =287.

Step B

Hydrogen chloride (4M in dioxane, 5 mL) was added to the intermediate from Step A above (333 mg) and the suspension was stirred at room temperature for 1 hour. The reaction mixture was evaporated to give the title compound (251 mg; quantitative) as a colorless solid. [M-Cl] ⁺ =165.

Preparation Example 2010

Step A

Commercially available tert-butyl (3-aminobenzyl)-carbamate (400 mg) was dissolved in pyridine (5 mL), and cooled to 0°C. At this temperature, methanesulfonyl chloride (170 μL) was added and the mixture was allowed to reach room temperature overnight. The reaction mixture was then cooled to 0°C, carefully neutralized with 1M hydrochloric acid and diluted with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 1:1) to give the intermediate as colorless crystals (407mg; 75%) . [MNa] ⁺ = 323.

Step B

Hydrogen chloride (4M in dioxane, 5 mL) was added to the intermediate from Step A above (407 mg) and the suspension was stirred at room temperature for 1 hour. The reaction mixture was evaporated to give the title compound (350 mg; quantitative) as a colorless solid. [M-NH ₃ Cl] ⁺ =184.

Preparation Example 2011

Step A

N,N-Dimethylsulfamoyl chloride (110 μL) was added to a solution of commercially available tert-butyl (3-amino-benzyl)-carbamate (222 mg) in anhydrous pyridine (1 mL). The resulting dark red reaction mixture was stirred at room temperature for 67 hours, then diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with 1M aqueous ammonium chloride (2 x 10 mL). The aqueous layers were combined and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (248 mg; 75%). [(M-isobutene)H] ⁺ =274, [MH] ⁺ =330.

Step B

4M Hydrogen chloride in dioxane (2.8 mL) was added to a solution of the title compound from Step A above (231 mg) in methanol (1.4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (184 mg; 99%). [M-Cl] ⁺ =230.

Preparation Example 2012

Step A

Add isopropanol (100 μL) and trimethylsilyl isocyanate (279 μL) sequentially to a solution of commercially available (3-amino-benzyl)-carbamate tert-butyl ester (222 mg) in anhydrous dichloromethane (1 mL) middle. The resulting reaction mixture was stirred at room temperature for 68 hours, then diluted with methanol (5 mL) and concentrated. The remaining solid was washed with dichloromethane (3x20 mL), dissolved in methanol (20 mL) and concentrated to give the title compound as a colorless solid (187 mg; 70%). [MH] ⁺ = 266, [MNa] ⁺ = 288.

Step B

4M Hydrogen chloride in dioxane (2 mL) was added to a solution of the title compound from Step A above (133 mg) in methanol (1 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (100 mg; 99%). [M-Cl] ⁺ = 166.

Preparation Example 2013

Step A

Di-tert-butyl dicarbonate (2.95 g) was added to a solution of commercially available (3-aminomethyl-phenyl)-methylamine (1.84 g) in anhydrous tetrahydrofuran (40 mL). The mixture was stirred overnight at room temperature and concentrated. The remaining residue was dissolved in tert-butyl methyl ether, washed with saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to afford the title compound (3.19 g; >99%). [MH] ⁺ =237.

Step B

Isopropanol (300 μL) and trimethylsilylisocyanate (836 μL) were added sequentially to a solution of the title compound from Step A above (709 mg) in anhydrous dichloromethane (3 mL). The resulting reaction mixture was stirred at room temperature for 46 hours, then diluted with methanol (15 mL) and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (683 mg; 82%). [MH] ⁺ = 280, [MNa] ⁺ = 302.

Step C

4M Hydrogen chloride in dioxane (9.6 mL) was added to a solution of the title compound from Step B above (672 mg) in methanol (4.8 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (512 mg; 99%). [MH] ⁺ =180.

Preparation of various examples 2014

Step A

Add ethyldiisopropylamine (349 μL) and N-succinimidyl N-methylcarbamate (355 mg) sequentially to commercially available (3-amino-benzyl)-carbamate tert-Butyl ester (222 mg) in anhydrous dichloromethane (1 mL). The resulting reaction mixture was stirred at room temperature for 72 hours, then diluted with ethyl acetate (20 mL) and washed with 0.1 M aqueous sodium hydroxide (3 x 10 mL). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (223 mg; 80%). [MH] ⁺ = 280, [MNa] ⁺ = 302.

Step B

A 4M solution of hydrogen chloride in dioxane (2 mL) was added to a suspension of the title compound from Step A above (140 mg) in methanol (1 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (106 mg; 99%) as the hydrochloride salt. [M-Cl] ⁺ =180, [MNa-HCl] ⁺ =202.

Preparation Example 2015

Step A

N,N-Dimethylcarbamoyl chloride (103 μL) was added to a solution of commercially available tert-butyl (3-amino-benzyl)-carbamate (222 mg) in anhydrous pyridine (1 mL). The resulting dark red reaction mixture was stirred at room temperature for 67 hours, then diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with 1M aqueous ammonium chloride (2 x 10 mL). The aqueous layers were combined and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated to give the title compound (241 mg; 82%). [(M-Boc)H] ⁺ =194, [(M-isobutene)H] ⁺ =238.

Step B

4M Hydrogen chloride in dioxane (2.8 mL) was added to a solution of the title compound from Step A above (205 mg) in methanol (1.4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (159 mg; 99%). [M-Cl] ⁺ =194.

Preparation Example 2016

Step A

A solution of 3-cyano-benzenesulfonyl chloride (1.07 g) in aqueous ammonia (33% in water, 40 mL) was stirred for 1 hour, then evaporated to about 20 mL under reduced pressure and cooled. The precipitate was filtered, washed with water and dried in vacuo to give the intermediate as a colorless solid (722mg; 75%). [MH] ⁺ =183.

Step B

The intermediate of Step A above (722 mg), di-tert-butyl dicarbonate (1.6 g) and nickel(II) chloride hexahydrate (80 mg) were dissolved in anhydrous methanol (20 mL) and cooled to 0°C. Sodium borohydride (1.0 g) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously for 2 hours, then diethylenetriamine (300 μL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated sodium bicarbonate solution, brine, dried ( _MgSO4 ) and concentrated. Purification by column chromatography (dichloromethane/methanol, 96:4-95:5) yielded an amorphous material which was suspended in hydrogen chloride (4M in dioxane, 15 mL) and stirred for 6 hours, evaporated, and dissolved in di A slurry formed in diethyl ether and filtration gave the title compound (590 mg; 67%). [M-Cl] ⁺ =187.

Preparation Example 2017

Step A

N,N-Dimethylsulfamoyl chloride (110 μL) was added to a solution of commercially available tert-butyl (4-amino-benzyl)-carbamate (229 mg) in anhydrous pyridine (1 mL). The resulting dark red reaction mixture was stirred at room temperature for 67 hours, then diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with 1M aqueous ammonium chloride (2 x 10 mL). The aqueous layers were combined and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (269 mg; 82%). [(M-isobutene)H] ⁺ =274.

Step B

4M Hydrogen chloride in dioxane (2.8 mL) was added to a solution of the title compound from Step A above (231 mg) in methanol (1.4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (184 mg; 99%). [M-NH ₃ Cl] ⁺ =213.

Preparation Example 2018

Step A

Add isopropanol (100 μL) and trimethylsilyl isocyanate (154 μL) sequentially to a solution of commercially available (4-amino-benzyl)-tert-butyl carbamate (229 mg) in anhydrous dichloromethane (1 mL) . The resulting reaction mixture was stirred at room temperature for 171/2 hours. Additional trimethylsilyl isocyanate (154 μL) was added and stirring was continued at room temperature for 75 hours. The resulting reaction mixture was diluted with methanol (5 mL) and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (263 mg; 99%). [MH] ⁺ = 266, [MNa] ⁺ = 288.

Step B

The title compound from Step A above (186 mg) was dissolved in 4M hydrogen chloride in dioxane (2.8 mL), and the reaction mixture was stirred at room temperature for 1-hour, then concentrated to give the title compound (139 mg; 99%). [M-Cl] ⁺ = 166.

Preparation Example 2019

Step A

Ethyldiisopropylamine (349 μL) and N-succinimidyl N-methylcarbamate (355 mg) were successively added to a solution of commercially available (4-amino-benzyl)-carbamate tert-butyl ester (229 mg) Anhydrous dichloromethane (1 mL) solution. The resulting reaction mixture was stirred at room temperature for 72 hours, then diluted with ethyl acetate (20 mL) and washed with 0.1 M aqueous sodium hydroxide solution (3 x 10 mL). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated to give the title compound (269mg; 96%). [MH] ⁺ = 280, [MNa] ⁺ = 302.

Step B

A 4M solution of hydrogen chloride in dioxane (2.8 mL) was added to a suspension of the title compound from Step A above (196 mg) in methanol (1.4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (149 mg; 99%). [M-Cl] ⁺ =180, [MNa-HCl] ⁺ =202.

Preparation Example 2020

Step A

N,N-Dimethylcarbamoyl chloride (103 μL) was added to a solution of commercially available tert-butyl (4-amino-benzyl)-carbamate (222 mg) in anhydrous pyridine (1 mL). The resulting dark red reaction mixture was stirred at room temperature for 17_h, then diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with 1M aqueous ammonium chloride (2x10 mL). The aqueous layers were combined and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated to give the title compound (284mg; 97%). [MH] ⁺ = 294, [MNa] ⁺ = 316.

Step B

4M Hydrogen chloride in dioxane (2.8 mL) was added to a solution of the title compound from Step A above (205 mg) in methanol (1.4 mL). The reaction mixture was stirred at room temperature for 1_h, then concentrated to give the title compound (159 mg; 99%). [M-Cl] ⁺ =194.

Preparation Example 2021

Step A

Trimethylsilyl isocyanate (1.9 mL) was added to tert-butyl (3-aminomethyl-4-fluorobenzyl)carbamate (1.63 g) in dry dichloromethane (20 mL) and isopropanol (2 mL ) solution, the mixture was stirred overnight. The solution was concentrated, adsorbed on silica and purified by column chromatography (dichloromethane/methanol, 97:3-9:1) to give the intermediate as a colorless solid (1.43 g; 68%).

Step B

Hydrogen chloride (4M in dioxane, 20 mL) was added to the intermediate from Step A above (1.43 g), stirred for 2.5 hours, evaporated, suspended in diethyl ether, filtered and dried to give the title compound as an off-white solid (1.21 g; quantitative ). [M-NH ₃ Cl] ⁺ = 180.9, [M-Cl] ⁺ = 197.9.

Preparative Example 2022

Step A

Add 3,4-diethoxy-3-cyclobutene-1,2-dione (1.30 g) into commercially available (3-amino-benzyl)-tert-butyl carbamate (1.11 g) in ethanol ( 20mL) solution. The resulting clear solution was heated to reflux for 2-h. The mixture was cooled to room temperature and the solid formed was removed by filtration. The filtrate was concentrated and the remaining solid residue was crystallized from refluxing ethanol to give the title compound (687 mg; 40%). [(M-Boc)H] ⁺ = 247, [MNa] ⁺ = 369.

Step B

The title compound from Step A above (346 mg) was dissolved in ~7N ammonia in methanol (14.3 mL). The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give the title compound (316 mg; 99%). [(M-Boc)H] ⁺ =218, [MNa] ⁺ =340.

Step C

4M hydrogen chloride in dioxane (4 mL) was added to a crude suspension of the title compound from Step B above (312 mg) in methanol (2 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give the title compound (250 mg; 99%). [M-NH ₃ Cl] ⁺ =218.

Preparative Example 2023

Step A

Benzyl chloroformate (1.20 mL) and potassium carbonate (1.16 g) were added to a solution of commercially available 5-amino-2-fluoro-benzonitrile (953 mg) in dry tetrahydrofuran (70 mL). The resulting suspension was stirred at room temperature for 16 hours. Additional benzyl chloroformate (1.20 mL) and potassium carbonate (1.16 g) were added and stirring was continued at room temperature for 7 hours. The mixture was diluted with ethyl acetate (70 mL), washed with water (2x70 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (1.47 g; 78%). [MH] ⁺ =271.

Step B

Di-tert-butyl dicarbonate (2.23 g) and nickel(II) chloride hexahydrate (123 mg) were added to an ice-cold (0-5 °C) solution of the title compound from Step A above (1.35 g) in anhydrous methanol (50 mL) , then sodium borohydride (1.34 g) was added carefully in portions. The resulting black mixture was stirred at 0-5°C (ice bath) for 15 minutes, then the ice bath was removed and stirring was continued at room temperature for 15 hours. Diethylenetriamine (543 μL) was then added and stirring was continued for 15 minutes at room temperature. The mixture was concentrated to dryness, ethyl acetate (50 mL) was added, and the resulting solution was washed with 1M aqueous ammonium chloride (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), dried (MgSO ₄ ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (992 mg; 53%). [(M-Boc)H] ⁺ = 275, [MNa] ⁺ = 397.

Step C

Palladium on carbon (10 wt%, 266 mg) was added to a solution of the title compound from Step B above (936 mg) in dry methanol (50 mL). The resulting black mixture was degassed with hydrogen with a three pump/vent, then stirred under a hydrogen atmosphere at atmospheric pressure at room temperature for 17 hours. Filtration through a plug of ^Celite® , concentration and purification by flash chromatography (silica, cyclohexane/ethyl acetate) afforded the title compound (534 mg; 89%). [(M-Boc)H] ⁺ = 141, [MNa] ⁺ = 263.

Step D

3,4-Diethoxy-3-cyclobutene-1,2-dione (261 mg) was added to a solution of the title compound from Step C above (240 mg) in ethanol (4 mL). The resulting clear solution was heated to reflux for 14 hours, then concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (245 mg; 67%). [(M-Boc)H] ⁺ =265, [MNa] ⁺ =387.

Step E

The title compound from Step D above (219 mg) was dissolved in ~7N ammonia in methanol (8.6 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated to give the title compound (194 mg; 96%). [(M-Boc)H] ⁺ =236, [MNa] ⁺ =358.

Step F

4M hydrogen chloride in dioxane (2.2 mL) was added to a crude suspension of the title compound from Step E above (184 mg) in anhydrous methanol (2.2 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to give the title compound (149 mg; 99%). [M-Cl] ⁺ = 236.

Preparation Example 2024

Step A

Benzyl chloroformate (1.20 mL) and potassium carbonate (1.16 g) were added to a solution of commercially available 3-amino-5-fluoro-benzonitrile (953 mg) in dry tetrahydrofuran (70 mL). The resulting suspension was stirred at room temperature for 16 hours. Additional benzyl chloroformate (1.20 mL) and potassium carbonate (1.16 g) were added and stirring was continued at room temperature for 7 hours. The mixture was diluted with ethyl acetate (70 mL), washed with water (2x70 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (1.76 g; 93%). [MH] ⁺ =271.

Step B

Di-tert-butyl dicarbonate (2.65 g) and nickel(II) chloride hexahydrate (147 mg) were added to an ice-cold (0-5 °C) solution of the title compound (1.62 g) from Step A above in anhydrous methanol (60 mL) , then sodium borohydride (1.60 g) was added carefully in portions. The resulting black mixture was stirred at 0-5°C (ice bath) for 15 minutes, then the ice bath was removed and stirring was continued at room temperature for 15 hours. Diethylenetriamine (652 μL) was then added and stirring was continued for 15 minutes at room temperature. The mixture was concentrated to dryness, ethyl acetate (60 mL) was added and the resulting suspension was washed with 1M aqueous ammonium chloride (60 mL), saturated aqueous sodium bicarbonate (60 mL) and brine (60 mL), dried (MgSO ₄ ), Filter and concentrate. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (1.67 g; 74%). [(M-Boc)H] ⁺ = 275, [MNa] ⁺ = 397.

Step C

Palladium on carbon (10 wt%, 458 mg) was added to a solution of the title compound from Step B above (1.61 g) in anhydrous methanol (86 mL). The resulting black mixture was degassed with hydrogen circulating through a three-phase pump/orifice, then stirred under an atmosphere of hydrogen at atmospheric pressure at room temperature for 17 hours. Filtration through a plug of ^Celite® , concentration and purification by flash chromatography (silica, cyclohexane/ethyl acetate) afforded the title compound (834 mg; 81%). [(M-Boc)H] ⁺ = 141, [MNa] ⁺ = 263.

Step D

3,4-Diethoxy-3-cyclobutene-1,2-dione (261 mg) was added to a solution of the title compound from Step C above (240 mg) in ethanol (4 mL). The resulting clear solution was heated to reflux for 14 hours, then concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (294 mg; 81%). [(M-Boc)H] ⁺ =265, [MNa] ⁺ =387.

Step E

The title compound from Step D above (273 mg) was dissolved in ~7N ammonia in methanol (10.7 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated to give the title compound (246 mg; 98%). [(M-Boc)H] ⁺ =236, [MNa] ⁺ =358.

Step F

4M Hydrogen chloride in dioxane (2.8 mL) was added to a crude suspension of the title compound from Step E above (235 mg) in anhydrous methanol (2.8 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to give the title compound (189 mg; 99%). [MH] ⁺ =236.

Preparation Example 2025

Step A

Triethylamine (3.37 mL) and diphenylphosphoryl azide (5.28 mL) were added to a suspension of commercially available 5-bromo-2-fluoro-benzoic acid (4.52 g) in anhydrous toluene (200 mL). The resulting clear solution was heated to reflux for 161/2 hours. Benzyl alcohol (2.51 mL) was then added and heating was continued to reflux for 3 hours. The mixture was concentrated and purified by flash chromatography (silica, cyclohexane/ethyl acetate) to afford the title compound (2.96 g; 46%). [MH] ⁺ = 324/326, [MNa] ⁺ = 346/348.

Step B

The title compound from Step B above (1.62 g), zinc(II) cyanide (479 mg) and tetrakis-triphenylphosphine palladium(0) (292 mg) were suspended in anhydrous N,N-dimethylformamide (10 mL )middle. The resulting mixture was degassed with argon circulation in a three-phase pump/well, then placed in a preheated oil bath (~80°C). After stirring at this temperature for 20 hours, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and saturated aqueous sodium chloride (100 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (761 mg; 56%). [MH] ⁺ =271.

Step C

Di-tert-butyl dicarbonate (1.27 g) and nickel(II) chloride hexahydrate (69 mg) were added to an ice-cold (0-5° C.) solution of the title compound (761 mg) from Step B above in anhydrous methanol (28 mL), Sodium borohydride (752 mg) was then added carefully in portions. The resulting black mixture was stirred at 0-5°C (ice bath) for 20 minutes, then the ice bath was removed and stirring was continued at room temperature for 16-hours. Diethylenetriamine (302 μL) was then added and stirring was continued for 30 minutes at room temperature. The mixture was concentrated to dryness, ethyl acetate (28 mL) was added and the resulting suspension was washed with 1M aqueous ammonium chloride (28 mL), saturated aqueous sodium bicarbonate (28 mL) and brine (28 mL), dried (MgSO ₄ ), Filtration and concentration afforded analytically pure title compound (943 mg; 89%). [(M-Boc)H] ⁺ = 275, [MNa] ⁺ = 397.

Step D

Palladium on carbon (10 wt%, 255 mg) was added to a solution of the title compound from Step C above (898 mg) in dry methanol (48 mL). The resulting black mixture was degassed with hydrogen circulating in a three-phase pump/well, then stirred under a hydrogen atmosphere at atmospheric pressure at room temperature for 16_h. Filtration through a plug of ^Celite® and concentration afforded the analytically pure title compound (554 mg; 96%). [(M-Boc)H] ⁺ = 141, [MNa] ⁺ = 263.

Step E

3,4-Diethoxy-3-cyclobutene-1,2-dione (261 mg) was added to a solution of the title compound from Step D above (240 mg) in ethanol (4 mL). The resulting clear solution was heated to reflux for 24 hours, then concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (259 mg; 71%). [(M-Boc)H] ⁺ =265, [MNa] ⁺ =387.

Step F

The title compound from Step E above (226 mg) was dissolved in ~7N ammonia in methanol (8.7 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated to give the title compound (204 mg; 98%). [(M-Boc)H] ⁺ =236, [MNa] ⁺ =358.

Step G

4M Hydrogen chloride in dioxane (2.4 mL) was added to a crude suspension of the title compound from Step E above (205 mg) in anhydrous methanol (2.4 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to give the title compound (164 mg; 99%). [M-Cl] ⁺ = 236.

Preparation Example 2026

Step A

Triethylamine (675 μL) and diphenylphosphoryl azide (1.06 mL) were added to a suspension of commercially available 3-bromo-2-fluoro-benzoic acid (876 mg) in anhydrous toluene (40 mL). The resulting clear solution was heated to reflux for 16_h. Benzyl alcohol (502 [mu]L) was then added and heating was continued to reflux for 3 hours. The mixture was concentrated and purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (596 mg; 46%). [MH] ⁺ = 324/326, [MNa] ⁺ = 346/348.

Step B

The title compound from Step B above (536 mg), zinc(II) cyanide (151 mg) and tetrakis-triphenylphosphine palladium(0) (92 mg) were suspended in anhydrous N,N-dimethylformamide (3.1 mL )middle. The resulting mixture was degassed with argon circulation in a three-phase pump/well, then placed in a preheated oil bath (~80°C). After stirring at this temperature for 19_h, the mixture was cooled to room temperature, diluted with water (31 mL), extracted with ethyl acetate (3 x 31 mL). The combined organic layers were washed with water (2 x 31 mL) and brine (31 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (234 mg; 55%). [MH] ⁺ =271.

Step C

Di-tert-butyl dicarbonate (390 mg) and nickel(II) chloride hexahydrate (21 mg) were added to an ice-cold (0-5° C.) solution of the title compound (234 mg) from Step B above in anhydrous methanol (9 mL), and then Sodium borohydride (229 mg) was added carefully in portions. The resulting black mixture was stirred at 0-5°C (ice bath) for 20 minutes, then the ice bath was removed and stirring was continued at room temperature for 14 hours. Diethylenetriamine (95 μL) was then added and stirring was continued for 1 hour at room temperature. The mixture was concentrated to dryness, ethyl acetate (9 mL) was added and the resulting suspension was washed with 1M aqueous ammonium chloride (9 mL), saturated aqueous sodium bicarbonate (9 mL) and brine (9 mL), dried (MgSO ₄ ), Filtration and concentration afforded analytically pure title compound (266 mg; 82%). [(M-Boc)H] ⁺ = 275, [MNa] ⁺ = 397.

Step D

Palladium on carbon (10 wt%, 76 mg) was added to a solution of the title compound from Step C above (266 mg) in anhydrous methanol (14 mL). The resulting black mixture was degassed with hydrogen circulating in a three-phase pump/well, then stirred under a hydrogen atmosphere at atmospheric pressure at room temperature for 13_h. Filtration through a plug of ^Celite® and purification by flash chromatography (silica, cyclohexane/ethyl acetate) afforded the title compound (121 mg; 71%). [(M-isobutene)H] ⁺ = 184, [MNa] ⁺ = 263.

Step E

3,4-Diethoxy-3-cyclobutene-1,2-dione (119 mg) was added to a solution of the title compound from Step D above (110 mg) in ethanol (1.8 mL). The resulting clear solution was heated to reflux for 17_h, then concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (90 mg; 54%). [(M-Boc)H] ⁺ =265, [MNa] ⁺ =387.

Step F

The title compound from Step E above (80 mg) was dissolved in ~7N ammonia in methanol (3.1 mL). The reaction mixture was stirred at room temperature for 2_h, then concentrated to give the title compound (73 mg; 99%). [(M-Boc)H] ⁺ =236, [MNa] ⁺ =358.

Step G

4M hydrogen chloride in dioxane (775 [mu]L) was added to a crude suspension of the title compound from Step F above (65 mg) in anhydrous methanol (775 mL). The reaction mixture was stirred at room temperature for 3 hours, then concentrated to give the title compound (52 mg; 99%). [M-Cl] ⁺ = 236.

Preparation Example 2027

Step A

Commercially available 1-(N-Boc-aminomethyl)-3-(aminomethyl)benzene (1.39 g) was added to 3,4-diethoxy-3-cyclobutene-1,2-dione ( 1.3mL) in ethanol (40mL) solution. After 2 hours, aqueous ammonia (28% in water, 40 mL) was added and the mixture was stirred for an additional 2 hours, then evaporated under reduced pressure. The residue was slurried with methanol (20 mL) and filtered to yield the intermediate (1.6 g; 82%).

Step B

A solution of the intermediate from Step A above (400 mg) in hydrogen chloride (4M in dioxane) was stirred for 14 hours, evaporated and dried to give the title compound as an off-white solid (317 mg; 98%). [M-Cl] ⁺ =232.

Preparation Example 2028

Step A

Commercially available 3-bromoacetophenone (4 g) was dissolved in methanol (50 mL). Hydroxylamine hydrochloride (6.9 g) and sodium bicarbonate (8.4 g) were added and the mixture was refluxed for 1.5 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. Drying ( _MgSO4 ) and concentration of the organic layer gave the intermediate as a colorless solid (4.2 g; 98%); [MH] ⁺ = 214/216.

Step B

The intermediate from Step A above (4.2 g) was dissolved in methanol (150 mL). 6N Hydrochloric acid (150 mL) and zinc powder were added in small portions, and the mixture was refluxed for 3 hours. After cooling to room temperature, sodium hydroxide was added, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. Then, the residue was redissolved in water and extracted with ethyl acetate. Drying ( _MgSO4 ) and concentration of the organic layer gave the intermediate as a colorless solid (3 g; 77%). [MH] ⁺ =200/202.

Step C

The intermediate from step B above (3 g) was dissolved in water/THF 1:1 (150 mL). Potassium carbonate (2.5 g) and benzyl chloroformate (4.6 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The organic layer was dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, dichloromethane) to give the intermediate as a colorless solid (3 g; 60%). [MH] ⁺ =334/336.

Step D

The intermediate (3 g) from Step C above, zinc(II) cyanide (800 mg) and tetrakis-triphenylphosphine palladium(0) (520 mg) were suspended in anhydrous N,N-dimethylformamide (40 mL) middle. The resulting mixture was degassed with argon circulation in a three-phase pump/well, then placed in a preheated oil bath (~80°C). After stirring at this temperature for 20 hours, the mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with water (2x100 mL) and brine (100 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by chromatography (silica, dichloromethane) to give the title compound (1.3 g; 52%). [MH] ₊ =281.

Step E

Di-tert-butyl dicarbonate (2 g) and nickel(II) chloride hexahydrate (120 mg) were added to an ice-cold solution of the title compound from Step D above (1.3 g) in anhydrous methanol (40 mL) followed by careful portionwise addition Sodium borohydride (1.2 g). The resulting dark mixture was stirred at 0-5°C (ice bath) for 20 minutes, then the ice bath was removed and stirring was continued at room temperature overnight. Diethylenetriamine (1 mL) was then added and stirring was continued at room temperature for 30 minutes. The mixture was concentrated to dryness, ethyl acetate was added, and the resulting suspension was washed with 1M aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), filtered and concentrated to give the analytically pure title compound (1.3 mg ; 56%). [MH] ⁺ =384.

Step F

Palladium on carbon (10 wt%, 140 mg) was added to a solution of the title compound from Step E above (1.3 g) in anhydrous methanol (40 mL). The resulting black mixture was degassed with hydrogen circulating in a three-phase pump/well, then stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. Filtration through a plug of ^Celite- and concentration yielded the analytically pure title compound (950 mg; 96%). [MH] ⁺ =251.

Step G

Triethylamine (0.7 mL) and 3,4-diethoxy-3-cyclobutene-1,2-dione (782 mg) were added to a solution of the title compound (950 mg) from Step F above in ethanol (4 mL) . The resulting clear solution was heated to reflux overnight. After cooling to room temperature, ammonia water (30% aqueous solution, 30 mL) was added, and the mixture was stirred at room temperature for 2 hours, and concentrated to give the title compound (1.3 g; 91%). [(M-Boc)H] ⁺ =275.

Step H

A 4M solution of hydrogen chloride in dioxane (5 mL) was added to a suspension of the title compound from Step G above (1.3 g) in dioxane (5 mL). The reaction mixture was stirred at room temperature overnight, then concentrated to give the title compound (950 mg; 99%). [M-Cl] ⁺ = 246.

Preparation Example 2029

Step A

A THF/water solution of 5-bromo-2-fluorobenzylamine hydrochloride (5.39 g), potassium carbonate (7.74 g) and benzyl chloroformate (3.8 mL) was stirred for 90 minutes and evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate, brine, dried ( _MgSO4 ), concentrated, and slurried with pentane. Filtration yielded the intermediate as colorless needles (7.74 g; quantitative). [MH] ⁺ =338/340.

Step B

The intermediate of Step A above (7.74 g), zinc(II) cyanide (2.0 g) and tetrakis-(triphenylphosphine)palladium(0) (1.32 g) were dissolved in anhydrous DMF (30 mL), and gas, stirring at 85 °C under argon. After 16 hours, the mixture was evaporated and diluted with ethyl acetate. The solution was washed with saturated ammonium chloride solution and brine, dried ( _MgSO4 ), concentrated, and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1-7:3) to give intermediate body (6.25 g; 98%). ¹ H-NMR (CDCl ₃ ) δ = 4.42 (d, 2H), 5.13 (s, 2H), 5.22 (br s, 1H), 7.1-7.75 (m, 8H).

Step C

The intermediate from Step B above (3.25 g), di-tert-butyl dicarbonate (5.0 g) and nickel(II) chloride hexahydrate (300 mg) were dissolved in methanol (100 mL) and cooled to 0°C. Sodium borohydride (2.6 g) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously for 1 hour, then diethylenetriamine (2 mL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 7:3 -6:4), the intermediate was obtained as a colorless oil (4.09 g; quantitative).

Step D

Palladium on carbon (10 wt%, 600 mg) was added to a solution of the intermediate from Step C above (4.09 g) in ethanol (100 mL), followed by hydrogenation at atmospheric pressure overnight. The catalyst was filtered off and the solvent was evaporated to 20 mL. Then 3,4-diethoxy-3-cyclobutene-1,2-dione (2.22 mL) and triethylamine (1 mL) were added, and the mixture was refluxed for 9 hours. The resulting solution was divided into two portions and used in the next step without further purification. [(M-Boc)H] ⁺ =279, [MNa] ⁺ =401.

Step E

Aqueous ammonia (28% in water, 60 mL) was added to a portion of the intermediate from Step D above and the mixture was stirred for an additional 2 hours before being evaporated under reduced pressure. The precipitate was filtered, washed successively with water and tetrahydrofuran, and dried in vacuo. The remaining solid was suspended in hydrogen chloride (4M in dioxane, 15 mL), stirred overnight, evaporated, suspended in THF, filtered and dried to give the title compound as an off-white solid (1.03 g; 34% including step D). [M-Cl] ⁺ =250.

Preparative Example 2030

Step A

Methylamine (40% in water, 60 mL) was added to a portion of the above intermediate in Preparative Example 2029, Step D, and the mixture was stirred overnight, then evaporated under reduced pressure. The remaining solid was adsorbed on silica and purified by column chromatography (dichloromethane/methanol, 95:5-9:1). The remaining solid was dissolved in hydrogen chloride (4M in dioxane, 20 mL), stirred for 3 hours and evaporated to give the title compound as an off-white solid (414 mg). [M-Cl] ⁺ = 264.

Preparation Example 2031

Step A

The intermediate from Step B of Preparative Example 2029 above (1.1 g) was dissolved in N,N-dimethylformamide (20 mL) and the mixture was cooled to 0°C. After adding sodium hydride (102 mg) and iodomethane (0.5 mL), the reaction mixture was returned to room temperature and stirred overnight. The solvent was removed and the resulting residue was redissolved in water and extracted with ethyl acetate. The organic layer was dried ( _MgSO4 ) and concentrated to give the intermediate (1.02g). [MH] ⁺ =299.

Step B

The intermediate from Step A above (1.02 g) was treated as described in Preparative Example 2029, Step C-Step E, to afford the title compound as an off-white solid (646 mg; 50%). [M-Cl] ⁺ = 264.

Preparative Example 2032

Step A

5-Bromo-2,2-dimethyl-2,3-dihydro-benzofuran (A.M.Bernard et al., Synthesis, 1997, 41-43) (2.32 g) and cuprous cyanide ( I) A suspension of (1.35 g) in N-methylpyrrolidone was heated to 160° C. for 3 days. After evaporation of the solvent, the residue was purified by column chromatography (silica, cyclohexane/EtOAc, 1:0-10:1) to give the intermediate as a colorless oil (1.26 g; 71%).

Step B

The intermediate of Step A above (1.26 g), di-tert-butyl dicarbonate (3.2 g) and nickel(II) chloride hexahydrate (180 mg) were dissolved in anhydrous methanol (30 mL) and cooled to 0°C. Sodium borohydride (2 g) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously overnight, then diethylenetriamine (500 μL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate, brine, dried ( _MgSO4 ) and concentrated. Purification by column chromatography (silica, cyclohexane/EtOAc, 9:1) yielded a clear oil which was dissolved in hydrogen chloride (4M in dioxane, 20 mL) and stirred overnight, filtered and washed with diethyl ether , to obtain the title compound (881 mg; 57%) as colorless fluffy crystals. [M-NH ₃ Cl] ⁺ =161.

Preparative Example 2033

Step A

Commercially available 5-bromo-2-methylbenzothiazole (1.42 g), zinc(II) cyanide (584 mg) and tetrakis-(triphenylphosphine)palladium(0) (360 mg) were dissolved in anhydrous DMF ( 12 mL), degassed and stirred at 80 °C under argon. After 16 hours, the mixture was evaporated and diluted with chloroform. The solution was washed with 1N hydrochloric acid, 1N sodium hydroxide and brine, dried ( _MgSO4 ), and adsorbed on silica. Purification by column chromatography (cyclohexane/EtOAc, 8:2-7:3) yielded the intermediate as pale yellow needles (1.01 g; 93%).

Step B

The intermediate of Step A above (1.01 g), di-tert-butyl dicarbonate (2.54 g) and nickel(II) chloride hexahydrate (140 mg) were dissolved in anhydrous methanol (60 mL) and cooled to 0°C. Sodium borohydride (1.6 g) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously for 5 hours, then diethylenetriamine (500 μL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate, brine, dried ( _MgSO4 ) and concentrated. Purification by column chromatography (silica, cyclohexane/EtOAc, 8:2-6:4) afforded a yellow oil which was suspended in hydrogen chloride (4M in dioxane, 20 mL) and stirred overnight, filtered, Washing with diethyl ether gave the title compound (455 mg; 37%) as a colorless solid. [M-NH ₃ Cl] ⁺ =162; [M-Cl] ⁺ =179.

Preparative Example 2034

Step A

Commercially available 2,2-difluoro-benzo[1,3]dioxol-5-carbonitrile (1.34 g), di-tert-butyl dicarbonate (3.2 g) and nickel chloride hexahydrate ( II) (174 mg) was dissolved in anhydrous methanol (40 mL), cooled to 0°C. Sodium borohydride (1.9 g) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously for 2 hours, then diethylenetriamine (500 μL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 95:5to8 : 2), a colorless oily intermediate (1.44 g; 68%) was obtained, which crystallized after standing.

Step B

A solution of the intermediate in Step A above (1.44 g) in hydrogen chloride (4M in dioxane, 30 mL) was stirred overnight, diluted with diethyl ether, and the colorless precipitate was filtered and washed with diethyl ether to give the title compound as fluffy crystals ( 1.01 g; 90%). [M-NH ₃ Cl] ⁺ =171; [M-Cl] ⁺ =188.

Preparative Example 2035

Step A

A mixture of commercially available 5-methyl-benzoxazole (2.00 g), N-bromosuccinimide (3.48 g) and α, α'-azoisobutyronitrile (49 mg) in chloroform (40 mL) Reflux for 2 hours. The mixture was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1) to afford the title compound as a solid (1.92 g; 61%). [MH] ⁺ =212.

Step B

A mixture of the title compound from Step A above (869 mg) and sodium azide (1.33 g) in DMF (20 mL) was stirred at 60 °C for 16 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated aqueous sodium bicarbonate, dried ( _MgSO4 ) and concentrated to give the title compound as an oil (648mg; 91%). [MH] ⁺ =175.

Step C

A solution of the title compound from Step B above (91 mg) and triphenylphosphine (178 mg) in tetrahydrofuran (2.5 mL) was stirred at room temperature for 3 hours. Water (1 mL) was then added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 85:15) to give the title compound (35 mg; 45%) as a glass. [MH] ⁺ =149.

Preparative Example 2036

Step A

A mixture of commercially available 6-methyl-benzoxazole (1.00 g), N-bromosuccinimide (1.74 g) and α, α'-azisobutyronitrile (25 mg) in chloroform (20 mL) Reflux for 2 hours. The mixture was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1) to give the title compound as a solid (550 mg; 30%). [MH] ⁺ =212.

Step B

A mixture of the title compound from Step A above (473 mg) and sodium azide (725 mg) in DMF (10 mL) was stirred at 60 °C for 16 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate solution, dried ( _MgSO4 ) and concentrated to give the title compound as an oil. [MH] ⁺ =175.

Step C

A solution of the title compound from Step B above (101 mg) and triphenylphosphine (198 mg) in tetrahydrofuran (2.5 mL) was stirred at room temperature for 16 hours. Water (1 mL) was then added and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 85:15) to give the title compound (62 mg; 72%) as a glass. [MH] ⁺ =149.

Preparative Example 2037

Step A

Commercially available 5-chloro-2-methylbenzoxazole (1.5g), potassium cyanide (612mg), dipiperidinemethane (720μL), palladium diacetate (80mg) and 1,5-bis(diphenyl (315 mg) was dissolved in anhydrous toluene (20 mL), degassed, and stirred at 160° C. under argon in a sealed pressure tube. After 24 hours, the mixture was diluted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and brine, dried (MgSO ₄ ), concentrated, and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1 to 7:3) to give the intermediate as a colorless solid (372 mg ; 26%). ¹ H-NMR (CDCl ₃ ) δ = 2.63 (s, 3H), 7.48-7.58 (s, 2H), 7.90 (s, 1H).

Step B

The intermediate of Step A above (372 mg), di-tert-butyl dicarbonate (1.02 g) and nickel(II) chloride hexahydrate (56 mg) were dissolved in anhydrous methanol (25 mL) and cooled to 0°C. Sodium borohydride (400 mg) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously for 14 hours, then diethylenetriamine (300 μL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 7:3 -6:4), the intermediate (413 mg) was obtained as a colorless oil.

Step C

A solution of the intermediate in Step B above (413 mg) in hydrogen chloride (4M in dioxane) was stirred for 2 hours, diluted with diethyl ether, and the precipitate was filtered and washed with diethyl ether to give the title compound (341 mg; two-step Yield 73%). [M-Cl]=163.

Preparative Example 2038

Step A

Reflux commercially available 2-hydroxy-5-methylaniline (5.2 g) and N, N'-carbonyldiimidazole (6.85 g) in anhydrous THF (60 mL) for 6 hours, cool to room temperature, pour on ice, and use 6N hydrochloric acid to adjust to pH4. The precipitate was filtered off, dried and recrystallized from toluene to give the intermediate as a gray solid (4.09 g; 65%).

Step B

The intermediate of Step A above (1.5 g), potassium carbonate (1.7 g) and methyl iodide (6 mL) were dissolved in anhydrous DMF (15 mL) and stirred at 50° C. for 2 hours. The mixture was concentrated to dryness and acidified to pH 4 with 1N hydrochloric acid. The precipitate was filtered off and dried to give the intermediate as an off-white solid (1.48 g; 90%). ¹ H-NMR (CDCl ₃ ) δ=2.40 (s, 3H), 3.38 (s, 3H), 6.77 (s, 1H), 6.90 (d, 1H), 7.05 (s, 1H).

Step C

The intermediate of Step B above (1.1 g), N-bromosuccinimide (1.45 g) and α,α'-azobyronitrile (150 mg) were suspended in carbon tetrachloride (50 mL) and washed with argon Degassed, heated to reflux. After 1 h the mixture was cooled, filtered, evaporated and dissolved in anhydrous DMF (20 mL). Sodium azide (1 g) was then added and the mixture was stirred vigorously for 3 hours, diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄ ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc , 8:2-7:3), a colorless needle intermediate (963 mg; 70%) was obtained. ¹ H-NMR (CDCl ₃ ) δ=3.36 (s, 3H), 4.25 (s, 2H), 6.88 (s, 1H), 6.98 (d, 1H), 7.07 (s, 1H).

Step D

A solution of the intermediate from Step C above (963 mg) and triphenylphosphine (1.36 g) in THF (30 mL) was stirred for 14 hours, then water was added and the mixture was stirred for an additional 2 hours. The mixture was evaporated, co-evaporated twice with toluene and diluted with anhydrous dioxane. After addition of hydrogen chloride (4M in dioxane, 1.5 mL), the precipitate was filtered off and dried to give the intermediate as a colorless solid (529 mg; 52%). [M-Cl] ⁺ =179.

Preparative Example 2039

Step A

5-Methyl-3H-benzoxazol-2-one (1.58 g) in acetic anhydride (20 mL) was heated to 80 °C for 2 hours, evaporated, and co-evaporated with toluene to give the intermediate (2.2 g ; Quantitative). [MH] ⁺ =192.

Step B

The intermediate from Step A above was treated as described in Step C of Preparative Example 2038.

Step C

The intermediate from Step B above (45 mg) was deacetylated in methanol (10 mL) by adding 2N sodium carbonate (10 mL) and heating to 60°C for 30 minutes. The resulting intermediate was worked up as described in Step D of Preparative Example 2038. [M-Cl] ⁺ = 165.

Preparation Example 2040

Step A

A pyridine solution of commercially available 1-(2-hydroxy-4-methyl-phenyl)-ethanone (5.00 g) and acetic anhydride (4.08 g) was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, saturated ammonium chloride solution and brine, dried ( _MgSO4 ) and concentrated to give the title compound as an oil (6.04 g; 95%). [MH] ⁺ =193.

Step B

A mixture of the title compound from Step A above (3.54 g), N-bromosuccinimide (4.27 g) and α,α'-azisobutyronitrile (151 mg) in tetrachloromethane (30 mL) was refluxed for 6 hours . After filtering off the precipitate, the organic layer was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 8:2) to give the title compound (1.70 g; 34%) as an oil. [MH] ⁺ =271/273.

Step C

A mixture of the title compound from Step B above (553 mg) and sodium azide (398 mg) in DMF (8 mL) was stirred at room temperature for 1.5 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate solution, dried (MgSO ₄ ), concentrated, and purified by column chromatography (silica, cycloh

Step D

A mixture of the title compound from Step C above (213 mg), hydroxylamine hydrochloride (507 mg) and sodium bicarbonate (614 mg) in methanol (4 mL) was stirred at 60 °C for 16 hours. The mixture was diluted with ethyl acetate, washed with 0.01M hydrochloric acid, dried ( _MgSO4 ) and concentrated to give the title compound as a colorless solid (165mg; 88%). [MH] ⁺ =207.

Step E

Thionyl chloride (90 mg) was added to a solution of the title compound of Step D above (156 mg) and pyridine (597 mg) in diethyl ether (3 mL) at 0°C, and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with 0.01M hydrochloric acid, extracted with ethyl acetate, dried ( _MgSO4 ) and concentrated to give the title compound as a colorless solid (110 mg; 77%). [MH] ⁺ =189.

Step F

A solution of the title compound from Step E above (105 mg) and triphenylphosphine (191 mg) in tetrahydrofuran (2.5 mL) was stirred at room temperature for 16 hours. Water (1 mL) was then added and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 85:15) to give the title compound (49 mg; 54%) as an oil. ¹ H-NMR (CDCl ₃ ) δ=2.52 (s, 3H), 3.85 (s, 2H), 7.18 (d, 1H), 7.40 (s, 1H), 7.50 (d, 1H).

Preparation Example 2041

Step A

A pyridine solution of commercially available 1-(2-hydroxy-5-methyl-phenyl)-ethanone (5.00 g) and acetic anhydride (4.08 g) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, saturated ammonium chloride solution and brine, dried ( _MgSO4 ) and concentrated to give the title compound as an oil (5.97 g; 95%) which crystallized on standing. [MH] ⁺ =193.

Step B

A mixture of the title compound from Step A above (5.97 g), N-bromosuccinimide (8.30 g) and α,α'-azisobutyronitrile (102 mg) in tetrachloromethane (60 mL) was refluxed for 4 hours . After filtering off the precipitate, the organic layer was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 8:2) to give the title compound (3.16 g; 37%) as a colorless solid. [MH] ⁺ =271/273.

Step C

A mixture of the title compound from Step B above (3.16 g) and sodium azide (398 mg) in DMF (50 mL) was stirred at room temperature for 1.5 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate solution, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 8:2) to give the title compound (639mg; 23%) as an oil. [MH] ⁺ =234.

Step D

A mixture of the title compound from Step C above (630 mg), hydroxylamine hydrochloride (1.50 g) and sodium bicarbonate (1.82 g) in methanol (4 mL) was stirred at 60°C for 16 hours. The mixture was diluted with ethyl acetate, washed with 0.01M hydrochloric acid, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 8:2) to give the title compound (80mg ; 14%). [MH] ⁺ =207.

Step E

Thionyl chloride (34 mg) was added to a solution of the title compound of Step D above (80 mg) and pyridine (285 mg) in diethyl ether (3 mL) at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with 0.01M hydrochloric acid, extracted with ethyl acetate, dried ( _MgSO4 ) and concentrated to give the title compound as an oil (50.1 mg; 74%). [MH] ⁺ =189.

Step F

A solution of the title compound from Step E above (50 mg) and triphenylphosphine (91 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 16 hours. Water (1 mL) was then added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 80:20) to give the title compound (10 mg; 23%) as an oil. ¹ H-NMR (CDCl ₃ ) δ=2.52 (s, 3H), 3.90 (s, 2H), 7.15 (d, 1H), 7.30 (s, 1H), 7.50 (d, 1H).

Preparation Example 2042

Step A

A solution of 4-bromophenol (3.36 g), 3-chloro-butan-2-one (2.2 mL) and potassium carbonate (4 g) in acetone (40 mL) was refluxed for 3 hours. Additional 3-chloro-butan-2-one and potassium carbonate were then added and the mixture was refluxed overnight. The solution was concentrated, dissolved in ethyl acetate and washed with water, 10% aqueous citric acid and brine. The organic phase was dried and evaporated under reduced pressure to obtain the intermediate as a colorless oil (4.88 g; quantitative).

Step B

The intermediate of the above Step A (4.88 g) was added dropwise to a phosphorousoxychloride solution (4.7 mL) at 100°C, and then the mixture was stirred at 100°C for 1 hour. The solution was cooled to room temperature, ice and ethyl acetate were added successively, and the organic layer was washed with brine and saturated aqueous sodium bicarbonate. The solution was concentrated and purified by column chromatography (silica, cyclohexane) to give the intermediate as a pale yellow solid (2.55 g; 58% yield over two steps). ¹ H-NMR (CDCl ₃ ) δδ=2.10 (s, 3H), 2.33 (s, 3H), 7.20-7.30 (m, 2H), 7.50 (s, 1H).

Step C

The intermediate from Step B above (2.55 g), zinc(II) cyanide (1.0 g) and tetrakis-(triphenylphosphine)palladium(0) (653 mg) were dissolved in anhydrous DMF (10 mL) and degassed , stirred under argon at 85°C. After 40 hours, the mixture was evaporated and diluted with ethyl acetate. The solution was washed with 10% citric acid and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 95:5-9:1) to give the intermediate as colorless crystals (1.05 g; 54%). ¹ H-NMR (CDCl ₃ ) δ=2.18 (s, 3H), 2.40 (s, 3H), 7.35-7.50 (m, 2H), 7.72 (s, 1H).

Step D

The intermediate from Step C above (452 mg), di-tert-butyl dicarbonate (1.2 g) and nickel(II) chloride hexahydrate (64 mg) were dissolved in anhydrous methanol (25 mL) and cooled to 0°C. Sodium borohydride (600 mg) was then added in portions, and the ice bath was removed. The mixture was stirred vigorously for 4 hours, then diethylenetriamine (300 μL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated sodium bicarbonate solution, brine, dried ( _MgSO4 ) and concentrated. The solid was suspended in hydrogen chloride (4M in dioxane, 10 mL), stirred overnight, evaporated, slurried with diethyl ether and filtered to afford the title compound (194 mg; 68%).

[M-NH ₃ Cl] ⁺ =159.

Prepare each embodiment 2043

Step A

A THF/water solution of 7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), potassium carbonate (3.6 g) and benzyl chloroformate (2.7 mL) was stirred overnight then evaporated under reduced pressure . The residue was diluted with ethyl acetate, washed successively with 10% citric acid, saturated sodium bicarbonate solution and brine, dried ( _MgSO4 ) and concentrated. The residue was dissolved in methanol (100 mL), and di-tert-butyl dicarbonate (7.6 g) and nickel(II) chloride hexahydrate (400 mg) were added. The solution was allowed to cool to 0°C, then sodium borohydride (2.6 g) was added portionwise. The mixture was allowed to reach room temperature and stirred vigorously overnight, then diethylenetriamine (2 mL) was added and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid, saturated sodium bicarbonate solution and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, dichloromethane/methanol, 1:0 -98:2), the intermediate was obtained as a colorless oil (1.81 g; 26%). [MH] ⁺ =397.

Step B

Palladium on carbon (10 wt%, 200 mg) was added to a solution of the intermediate from Step A above (1.81 g) in ethanol (50 mL), followed by hydrogenation at atmospheric pressure overnight. The catalyst was filtered off and the solvent was evaporated to 20 mL. Then 3,4-diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and triethylamine (0.5 mL) were added and the mixture was refluxed for 4 hours. The solution was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 6:4-1:1) to give the intermediate as a colorless oil which crystallized slowly (1.46 g; 83%).

Step C

Aqueous ammonia (28% in water, 100 mL) was added to a solution of the intermediate from Step B above (1.46 g) in ethanol (20 mL) and the mixture was stirred for 3 hours then evaporated under reduced pressure. The residue was slurried with water, filtered and dried in vacuo. Hydrogen chloride (4M in dioxane, 20 mL) was added to the residue, stirred for 14 hours, evaporated, suspended in diethyl ether, filtered and dried to give the title compound as an off-white solid (1.08 g; 92%). [M-Cl] ⁺ =258.

Preparation Example 2044

Step A

Commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (158 mg) was dissolved in acetic anhydride (5 mL). Pyridine (0.2 mL) was added and the mixture was stirred overnight. The mixture was concentrated to dryness and the resulting residue was used in the next step without further purification.

Step B

Di-tert-butyl dicarbonate (436 mg) and nickel(II) chloride hexahydrate (25 mg) were added to an ice-cold solution of the title compound from Step A above (200 mg) in anhydrous methanol (20 mL) followed by the careful addition of boron in portions Sodium hydride (266 mg). The resulting dark mixture was stirred at 0-5°C (ice bath) for 20 minutes, then the ice bath was removed and stirring was continued at room temperature overnight. Diethylenetriamine (0.4 mL) was then added and stirring was continued at room temperature for 30 minutes. The mixture was concentrated to dryness, ethyl acetate was added, and the resulting suspension was washed with aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), filtered and concentrated. The resulting residue (250 mg) was used in the next step without further purification.

Step C

4M hydrogen chloride in dioxane (5 mL) was added to a crude solution of the title compound from Step B above (250 mg) in dioxane (5 mL). The reaction mixture was stirred at room temperature for 5 hours, then concentrated to give the title compound (230 mg; 99%). [M-Cl] ⁺ = 205.

Preparation Example 2045

Step A

A suspension of commercially available 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (1.63g) in anhydrous tetrahydrofuran (20mL) was added to sodium hydride (95%, 278mg) in anhydrous tetrahydrofuran (20mL ) suspension. The resulting suspension was stirred at room temperature for 5 minutes, then N-phenyl-bis(trifluoromethanesulfonimide) (3.97 g) was added and stirring was continued for 21/2 hours at room temperature, at which point the transition from the suspension The resulting mixture turned into a clear solution. The mixture was cooled to 0-5°C (ice bath), hydrolyzed by adding water (40 mL), extracted with ethyl acetate (3x80 mL). The combined organic layers were washed with saturated aqueous sodium chloride (2x80 mL), dried ( _MgSO4 ), filtered and concentrated. Purification of the remaining residue by flash chromatography (silica, cyclohexane/ethyl acetate) afforded the title compound (2.89 g; 98%). [MH] ⁺ =296.

Step B

The title compound from Step A above (2.89 g), zinc cyanide (930 mg) and tetrakis-triphenylphosphine palladium(0) (566 mg) were suspended in anhydrous N,N-dimethylformamide (19.4 mL) . The resulting mixture was degassed with argon circulation in a three-phase pump/well, then placed in a preheated oil bath (~80°C). After stirring at this temperature for 121/2 hours, the mixture was cooled to room temperature, diluted with water (194 mL), extracted with ethyl acetate (3x194 mL). The combined organic layers were washed with water (2x194 mL) and brine (194 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (1.38 g; 83%). [MH] ⁺ =173.

Step C

Lithium aluminum hydride (1.2 g) was added carefully (ice-cooled) to a suspension of the title compound from Step B above (1.34 g) in dry tetrahydrofuran (156 mL). The resulting mixture was heated to reflux for 18_h and then cooled to 0-5 °C (ice bath) carefully by sequentially adding water (1.2 mL), 15% aqueous sodium hydroxide solution (1.2 mL) and water (3.6 mL) hydrolysis. The resulting gray suspension was stirred vigorously at room temperature for 1-h, filtered through a frit and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (740 mg; 58%). [MH] ⁺ =163, [M-NH ₂ ] ⁺ =146.

Step D

Di-tert-butyl dicarbonate (993 mg) was added to a solution of the title compound from Step C above (716 mg) in anhydrous dichloromethane (8.8 mL). The resulting mixture was stirred at room temperature for 16 hours, concentrated and purified by flash chromatography (silica, cyclohexane/ethyl acetate) to afford the title compound (785 mg; 68%). [MH] ⁺ =263.

Step E

If the title compound from Step D above is converted as described in Preparative Example 2025, Step E-Step G, the title compound is obtained.

Preparation Example 2046

Step A

N-methyl-pyrrolidin-2-one of commercially available 6-chloro-4H-benzo[1,4]oxazin-3-one (1.83g) and cuprous(I) cyanide (1.81g) (40 mL) of the suspension was placed in a preheated oil bath (~250 °C). After stirring at this temperature for 20 hours, the mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with water (2x200 mL) and brine (200 mL), dried ( _MgSO4 ), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, cyclohexane/ethyl acetate) to give the title compound (1.08 g; 62%). [MH] ⁺ =175.

Step B

If the title compound from Step A above is converted as described in Preparative Example 2045, Step C-Step E, the title compound is obtained.

Preparation Example 2047

Step A

If the commercially available 3-bromobenzylamine is treated with ethyl bromoacetate and the resulting intermediate is saponified with aqueous hydrochloric acid (as described by A.R. Merrifield et al. (J.Org.Chem. 41, 1976, 2015-2019)), the title compound is obtained .

Step B

If the intermediate of Step A above is treated with thionyl chloride followed by ammonia in a manner similar to that described by Clemo et al. (J. Chem. Soc., 1939, 1958), the title compound will be obtained.

Step C

If the intermediate of Step B above is treated similarly as described in Step C of Preparative Example 2028, the title compound is obtained.

Step D

If the intermediate of Step C above is treated similarly as described in Preparative Example 2028, Step D-Step H, the title compound is obtained.

Preparation Example 2048

Step A

If the intermediate of step C of the above preparative example 2047 is treated with ethanethiol and boron trifluoride·acetic acid complex similarly to that described by T. Hiyama et al. (Angew. Chem. 117, 2005, 218-234), Treatment of the resulting dithioacetal with tetrabutylammonium dihydrotrifluoride and N-iodosuccinimide will give the title compound.

Step B

If the intermediate of Step A above is treated similarly as described in Preparative Example 2028, Step D-Step H, the title compound is obtained.

Preparation Example 2049

Step A

Commercially available 6-bromooxindole (656 mg), zinc cyanide (288 mg) and tetrakis-triphenylphosphine palladium(0) (175 mg) were suspended in anhydrous N,N-dimethylformamide (6 mL) . The resulting mixture was degassed with argon circulation in a three-phase pump/well, then placed in a preheated oil bath (~80°C). After stirring at this temperature for 15 hours, the mixture was cooled to room temperature, diluted with water (60 mL), extracted with ethyl acetate (3x60 mL). The combined organic layers were washed with water (2x60 mL), dried (MgSO4), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (385 mg; 81%). [MH] ⁺ =159.

Step B

If the title compound of Step A above is converted as described in Preparative Example 2045, Step C-Step E, the title compound is obtained.

Preparation Example 2050

Step A

If 6-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one is converted as described in Steps A and B of Preparative Example 2049 (synthesized as described in Atwal et al., J.Med. Chem., 1996, 39, 304-313), the title compound will be obtained.

Preparation Example 2051

Step A

If the commercially available 5-bromo-isoindole-1,3-dione was reduced with lithium aluminum hydride in THF as described in Preparative Example 2045, Step C, the title compound was obtained.

Step B

If the title compound from Step A above is reacted with benzyl chloroformate in THF as described in Preparative Example 2028, Step C, the title compound is obtained.

Step C

If the title compound from Step B above is converted as described in Preparative Example 2028, Step D-Step H, the title compound is obtained.

Preparative Example 2052

Step A

A solution of commercially available 7-bromo-3,4-dihydro-1(2H)-naphthalenone (3.0 g), hydroxylamine hydrochloride (2.8 g) and sodium acetate (3.4 g) in ethanol (60 mL) was refluxed for 2 hours, evaporated, suspended in ethyl acetate, washed with water and brine. The title compound was obtained after evaporation as an off-white solid (3.27 g; quantitative). [MH] ⁺ = 240/242.

Step B

The intermediate from Step A above (1.51 g) was heated in polyphosphoric acid (35 g) at 150°C for 4 hours. The reaction mixture was poured onto ice and extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried and adsorbed on silica. Flash chromatography (cyclohexane/ethyl acetate, 8:2) gave the title compound (1.37 g; 91%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ=2.15-2.37 (m, 4H), 2.74 (t, 2H), 7.06 (d, 1H), 7.18-7.53 (m, 2H), 9.13 (s, 1H); [ MH] ⁺ = 240/242.

Step C

The intermediate from Step B above was treated similarly as described in Step B of Preparative Example 2025 to afford the title compound (38%) as a tan solid. [MH] ⁺ =187.

Step D

The intermediate of Step C above was treated similarly as described in Step C-Step E of Preparative Example 2045 to afford the title compound as an off-white solid. [M-Cl] ⁺ =272.

Preparative Example 2053

Step A

If the commercially available 5-chloro-3H-benzoxazol-2-one is treated similarly as described by J. Sam et al. (J. Pharm. Sci, 60, 1971, 1370-1375), the title compound is obtained.

Step B

If the intermediate in Step A above was treated with cuprous(I) cyanide in a degassed N-methylpyrrolidin-2-one solution at 250°C overnight as described in Step A of Preparative Example 2046, the title compound was obtained.

Step C

If the intermediate of Step B above is treated analogously to Step C-Step E of Preparative Example 2045, the title compound is obtained.

Preparation Example 2054

Step A

If the commercially available 8-hydroxy-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one is treated similarly as described in steps A-step C of the preparation of Example 2045, one will obtain title compound.

Step B

If the intermediate of step A above is treated analogously as described by G.M. Cohen et al. (J. Chem. Soc. Chem. Commun., 1992, 298), the title compound is obtained.

Step C

If the intermediate of Step B above is treated similarly as described in Step E of Preparative Example 2025, the title compound is obtained.

Preparation Example 2055

Step A

Commercially available 5-bromo-2-hydroxybenzonitrile (2.00g), nickel(II) chloride hexahydrate (200mg) in methanol (50mL) solution was cooled to 0°C, and then sodium borohydride (2.25g) was added in batches , to allow the mixture to reach room temperature. After 4 hours, the mixture was cooled to 0 °C and a solution of benzyl chloroformate (1.45 mL) in tetrahydrofuran (3 mL) was added. The mixture was allowed to reach room temperature and stirred for 3 hours. The mixture was concentrated to dryness and the residue was diluted with ethyl acetate, washed with 10% citric acid and brine, dried ( _MgSO4 ), concentrated, and purified by column chromatography (silica, cyclohexane/ethyl acetate, 9:1to8:2), the intermediate was obtained as pale yellow crystals (2.05g; 60%). [MH] ⁺ =336/338.

Step B

The intermediate from Step A above (1.07 g), 1,2-dibromoethane (1.1 mL), Aliquat 336 (0.5 g) and sodium hydroxide (512 mg) were dissolved in anhydrous dichloromethane (15 mL) and anhydrous acetonitrile (15 mL) was refluxed for 2 hours. The mixture was concentrated to dryness and the residue was diluted with ethyl acetate, washed with 10% citric acid and brine, dried ( _MgSO4 ), concentrated, and purified by column chromatography (silica, cyclohexane/ethyl acetate, 9:1-8:2) to yield an oil which was dissolved in anhydrous N,N-dimethylformamide (5 mL). The solution was cooled to 0°C and sodium hydride (60 mg) was added. After stirring overnight, 1N hydrochloric acid was added and the mixture was diluted with ethyl acetate, washed with brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/ethyl acetate, 9:1-8 :2), the intermediate was obtained as a clear oil (162 mg; 14%). [MNa] ⁺ = 384/386.

Step C

The intermediate of Step B above was treated similarly as described in Preparative Example 2028, Step D-Step H, to afford the title compound as a tan solid. [M-Cl] ⁺ =274.

Preparative Example 2056

Step A

If 3-amino-indan-5-carbonitrile was treated similarly as described in preparative example 2043, steps A-step C, the title compound was obtained.

Preparation Example 2057

Step A

If the commercially available 6-Cyano-1,2,3,4-tetrahydro-naphthalen-1-yl-ammonium chloride was treated similarly as described in Preparative Example 2043, Step A - Step C, the title compound was obtained.

Preparation Example 2058

Step A

If a DMF solution of commercially available indole-6-carbonitrile, benzyl chloroformate and sodium hydride is stirred as described by U. Jacquemard et al. (Tetrahedron, 60, 2004, 10039-10048), the title compound is obtained.

Step B

If the intermediate of Step A above, di-tert-butyl dicarbonate, nickel(II) chloride hexahydrate and sodium borohydride in anhydrous methanol are stirred in an ice bath as described in Step E of Preparative Example 2028, one will obtain title compound.

Step C

If the title compound from Step B was stirred with a methanolic solution of palladium on carbon (10 wt %) under an atmosphere of hydrogen as described in Preparative Example 2028, Step F, the title compound was obtained.

Step D

If the title compound of Step C is stirred with 3,4-dichlorocyclobut-3-ene-1,2-bis at room temperature as described by R.M.Anderson et al. A solution of the ketone (synthesized as described by E. Arunkumar et al. (J. Am. Chem. Soc., 126, 2004, 6590-6598)) in pyridine and quenching the reaction mixture with aqueous ammonia will give the title compound.

Step E

If the title compound of Step D above is stirred in a 4M solution of hydrogen chloride in dioxane, the title compound is obtained.

Preparation Example 2059

Step A

A solution of commercially available 1H-indazole-6-carbonitrile (503 mg), benzyl chloroformate (560 μL) and potassium carbonate (650 mg) in aqueous tetrahydrofuran was stirred overnight. The mixture was concentrated to dryness, ethyl acetate was added and the resulting solution was washed with aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine, dried ( _MgSO4 ), filtered and concentrated to give the title compound as a colorless solid (490mg).

Step B

Di-tert-butyl dicarbonate (783 mg) and nickel(II) chloride hexahydrate (43 mg) were added to an ice-cold solution of the title compound from Step A above (490 mg) in anhydrous methanol (40 mL) followed by the careful addition of boron in portions Sodium hydride (470mg). The resulting dark mixture was stirred at 0-5°C (ice bath) for 20 minutes, then the ice bath was removed and stirring was continued at room temperature overnight. Diethylenetriamine (0.4 mL) was then added and stirring was continued at room temperature for 30 minutes. The mixture was concentrated to dryness, ethyl acetate was added and the resulting suspension was washed with aqueous ammonium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried ( _MgSO4 ), filtered and concentrated. The obtained residue was purified by column chromatography (silica, cyclohexane/ethyl acetate=3:2) to obtain the title compound (210 mg; 48%) as a colorless solid. [MH] ⁺ =248.

Step C

If the title compound of Step B is stirred with 3,4-dichlorocyclobut-3-ene-1,2-bis at room temperature as described by R.M.Anderson et al. Ketone (synthesized as described by E.Arunkumar et al. (J.Am.Chem.Soc., 126, 2004, 6590-6598)) in pyridine, the reaction mixture is quenched with ammonia to give [1-(2-amino -3,4-dioxo-cyclobut-1-enyl)-1H-indazol-6-ylmethyl]-tert-butyl carbamate and [2-(2-amino-3,4-dioxo Generation-cyclobut-1-enyl)-2H-indazol-6-ylmethyl]-carbamic acid tert-butyl ester, which can be separated by chromatography.

Step D

If each title compound of Step C is stirred in 4M hydrogen chloride in dioxane, the title compound is obtained as the hydrochloride salt.

Preparative Example 2060

Step A

The intermediate from Preparative Example 2043, Step C (59 mg) and chromium oxide (XI) (15 mg) were suspended in acetic acid (5 mL) and stirred for 2 hours. Isopropanol was then added and the mixture was adsorbed on silica. Flash chromatography (dichloromethane/methanol, 99:1-98:2-96:4) gave the title compound (38.8 mg; 63%) as a tan solid. ¹ H-NMR (CDCl ₃ /CD ₃ OD) δ=1.38(s, 9H), 3.05(t, 2H), 4.25(s, 2H), 4.48(d, 2H), 7.20(d, 1H), 7.43 (d, 2H), 7.89 (s, 1H); [M-isobutene] ⁺ =316, [MNa] ⁺ =394.

Step B

The title compound of Step A above (38.8 mg) was suspended in 4M hydrogen chloride in dioxane (6 mL) and stirred for 3 hours. After evaporation, the title compound was obtained as a yellow solid (44 mg; quantitative). [M-Cl] ⁺ =272.

Preparative Example 2061

Step A

Dimethylammonia (2M in tetrahydrofuran, 30 mL) was added to a solution of the intermediate of Preparative Example 2043 Step B (100 mg) in ethanol (20 mL) and the mixture was stirred overnight then evaporated under reduced pressure. Hydrogen chloride (4M in dioxane, 5 mL) was added to the residue and stirred for 3 hours, evaporated and dried to give the title compound as an off-white solid (117 mg). [M-Cl] ⁺ = 286.

Preparative Example 2062

Step A

Commercially available 4-fluoro-3-methoxybenzaldehyde (2.50 g) was dissolved in anhydrous acetonitrile (35 mL). Tert-butyl carbamate (5.70 g) and triethylsilane (5.66 g) were added to form a suspension. Trifluoroacetic acid (5.55 g) was added over 5 minutes. The resulting clear solution was stirred for 72 hours. The volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (40 mL), washed with water (60 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, concentrated, and the residue was purified by silica column chromatography (hexane/ethyl acetate, 2:1). The Boc group was removed by dissolving the protected amine in 4M hydrogen chloride in dioxane (10 mL) for 1 hour. The resulting slurry was diluted with ether (15 mL) and hexane (15 mL), and the title compound (2.6 g; 80%) was dried under vacuum. [M-NH ₃ Cl] ⁺ =175.

Preparative Example 2063

Step A

A solution of commercially available 5-bromomethyl-benzo[1,2,5]thiadiazole (115 mg) in DMF (1 mL) was added to stirred carbamic acid bis-tert-butylester Potassium salt in DMF (2 mL) (prepared as described in J. Chem. Soc., Perkin Trans. 1, 1983, 2983-2985). Stirring was continued at 50°C for 2 hours. The solvent was removed in vacuo, the residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃ , dried and concentrated. The crude product was used in the next step without further purification. [MH] ⁺ =366.

Step B

The title compound from Step A above (180 mg) was dissolved in trifluoroacetic acid (2 mL). After stirring at room temperature for 1 hour, the solvent was evaporated to give the trifluoroacetate salt of the title compound (180 mg; quantitative). [MH] ⁺ =166.

Preparative Example 2064

Step A

3-Acetyl-benzonitrile (2.1 g), sodium cyanide (1.08 g) and ammonium carbonate (6.95 g) were suspended in ethanol (20 mL) and water (20 mL), heated to 70° C. until completely dissolved. Typical aqueous phase workup and concentration yields intermediates. Hydrogenation with palladium on carbon (10%) in ethanol and acetic acid gave the title compound (2.04 g; 50%).

Preparative Example 2065

Step A

To a solution of 3-cyanobenzaldehyde (263 mg) in 50% aqueous ethanol (12 mL) were added potassium cyanide (130 mg) and ammonium carbonate (769 mg). The reaction mixture was heated to 55°C and maintained at this temperature overnight. The solution was allowed to cool, and the precipitated solid was filtered off. The filtrate was concentrated and extracted with ether (3 x 10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give a crude oil. The crude product was purified by silica gel chromatography to yield the title compound (347 mg; 86%) as a colorless solid. [MH] ⁺ =202.

Step B

The title compound of Step A above (347 mg) was dissolved in ethanol, and palladium on carbon (10%; 200 mg) and 50% aqueous acetic acid (2 mL) were added. The solution was hydrogenated (50 psi) overnight. The solution was filtered and concentrated to give the title compound as a colorless solid foam in quantitative yield. [M-OAc] ⁺ =206.

Preparative Example 2066

Step A

A mixture of 3-cyanobenzaldehyde (262 mg), hydantoin (220 mg), potassium acetate (380 mg) in acetic acid (2 mL) was heated at reflux for 3 hours. The solution was poured onto ice (20 g). The colorless precipitate was collected and washed with ice water. The solid was dried in vacuo to yield the title compound as a yellow solid. [MH] ⁺ =214.

Step B

The title compound from Step A above was treated as described in Step B of Preparative Example 2065. [M-OAc] ⁺ =214.

Preparative Example 2067

Step A

A solution of Boc-aminomethylbenzyl alcohol (237 mg), triphenylphosphine (485 mg) and carbon tetrabromide (491 mg) in dichloromethane (10 mL) was stirred at room temperature overnight, then concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound (200 mg; 67%).

Step B

A mixture of the title compound from Step A above (90 mg), hydantoin (36 mg), potassium carbonate (150 mg) and tetrabutylammonium iodide (1 mg) in N,N-dimethylformamide was stirred at room temperature for 24 hours. The solution was concentrated to dryness, then dissolved in ethyl acetate (20 mL). The solution was washed with water and brine, dried over magnesium sulfate and concentrated to give the title compound (90 mg) as a yellow solid.

Step C

Hydrogen chloride in dioxane (4M, 1 mL) was added to the title compound from Step B above. The solution was stirred for 1 hour and diluted with diethyl ether (10 mL). The precipitate was collected and washed with additional diethyl ether (2 mL) to give the title compound as a colorless solid.

Preparation Example 2100

Step A

3-Bromo-fluoren-9-one (C.F.Koelsch, J.Amer.Chem.Soc., 1944, 1983-1984) (1.08g), sodium bicarbonate (3.5g) and hydroxylamine hydrochloride (3.5g) were stirred at 80°C ) in ethanol (40 mL) overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with brine. Evaporation gave a pale yellow crystalline intermediate (1.13 g; 99%).

Step B

The above intermediate of Step A (1.13 g) was dissolved in anhydrous diethyl ether (30 mL) and cooled to 0°C. Lithium aluminum hydride (1 N in diethyl ether, 20 mL) was then added. After 30 minutes at 0°C, the solution was refluxed for 90 minutes. After adding water (0.8 mL), 15% aqueous sodium hydroxide solution (0.8 mL) and water (2.4 mL), the precipitate was filtered off. The remaining liquid was evaporated under reduced pressure. The oil was dissolved in anhydrous tetrahydrofuran (20 mL) and treated with di-tert-butyl dicarbonate (1.09 g) and triethylamine (0.66 mL). After 16 hours, the mixture was evaporated and diluted with ethyl acetate. The solution was washed with 10% citric acid and brine, dried ( _MgSO4 ) and concentrated. To the residue were added zinc(II) cyanide (350 mg) and tetrakis-(triphenylphosphine)palladium(0) (230 mg) and anhydrous DMF (20 mL). The solution was degassed and stirred at 100°C under argon. After 40 hours, the solution was evaporated and diluted with ethyl acetate. The solution was washed with 10% citric acid and brine, dried (MgSO ₄ ), concentrated, and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1 to 8:2) to give the intermediate (239 mg ; 19%). [MH] ⁺ = 307, [MNa] ⁺ = 329.

Step C

Hydrogen chloride (4M in dioxane, 8 mL) was added to the intermediate from Step B above (127 mg), stirred for 17 hours, filtered and dried to give the title compound as a colorless solid (83 mg; 82%). [M-Cl] ⁺ =207, [MNa] ⁺ =229, [M-NH ₃ Cl] ⁺ =189.

Preparation Example 2101

Step A

A mixture of 4-hydroxy-indan-1-one (125 mg), K ₂ CO ₃ (350 mg), methyl iodide (263 μL) in DMF (4 mL) was stirred at 50° C. for 3 h, then poured into 1 N hydrochloric acid (20 mL ), washed with _Et2O (4 x 10 mL). The combined organic layers were dried over _MgSO4 , filtered and concentrated to give the intermediate as a clear oil (131 mg; 96%). [MH] ⁺ =163.

Step B

A mixture of the intermediate from Step A above (131 mg), _NH2OH -HCl (62 mg) and NaOAc (73.2 mg) in MeOH (4 mL) was stirred at 22 °C for 16 h. Water (10 mL) was added and the resulting precipitate was filtered and washed three times with water (2 mL) to give the intermediate as a colorless solid (133 mg; 91%). [MH] ⁺ =178.

Step C

1M LiAlH in _Et2O (4.0 mL) was slowly added to a mixed solution of the above step B intermediate (133 mg) in Et2O (2 mL) at -78 °C under argon atmosphere. The mixture was heated to reflux (40°C) and stirred for 5 hours. The mixture was cooled to 0 °C and water (0.15 mL), 15% aqueous NaOH (0.15 mL) and water (0.45 mL) were added carefully sequentially. The resulting mixture was filtered through ^Celite® and the filtrate was concentrated to yield the title compound (71.6 mg; 40%) as a clear oil. [M-NH ₂ ] ⁺ =147.

Preparation Example 2102

Step A

A mixture of 5-hydroxy-indan-1-one (125 mg), K ₂ CO ₃ (350 mg), methyl iodide (263 μL) in DMF (4 mL) was stirred at 50° C. for 3 hours and poured into 1N hydrochloric acid (20 mL) , washed with _Et2O (4x10 mL). The combined organic layers were dried over _MgSO4 , filtered and concentrated to give the intermediate as a clear oil (44.7 mg; 33%). [MH] ⁺ =163.

Step B

A mixture of the intermediate from Step A above (44.7 mg), _NH2OH -HCl (21 mg) and NaOAc (25 mg) in MeOH (1 mL) was stirred at 22 °C for 16 h. Water (5 mL) was added and the resulting precipitate was filtered and washed three times with water (1 mL) to give the intermediate as a colorless solid (44 mg; 97%). [MH] ⁺ =178.

Step C

1M LiAlH in Et2O (1.35mL) was slowly added to the above step B intermediate (44.7mg) in _Et2O (1mL) at -78°C under argon atmosphere. The mixture was heated to reflux (40°C) and stirred for 5 hours. The mixture was cooled to 0 °C and water (0.05 mL), 15% aqueous NaOH (0.05 mL) and water (0.15 mL) were added carefully sequentially. The resulting mixture was filtered through ^Celite® and the filtrate was concentrated to yield the title compound (27 mg; 61%) as a clear oil. [M-NH ₂ ] ⁺ =147.

Preparation of various embodiments 2103

Step A

Commercially available 4-bromo-2,3-indan-1-one (514 mg), hydroxylamine hydrochloride (187 mg) and sodium acetate (220 mg) were added to methanol (12 mL), and stirred at room temperature. After 15 h, the mixture was diluted with H2O (50 mL). The intermediate was collected by filtration as a colorless solid (517 mg, 94%). [MH] ⁺ = 226/228.

Step B

The intermediate from Step A above (517 mg) was dissolved in anhydrous diethyl ether (7 mL). The solution was cooled to -78°C and lithium aluminum hydride (1M in _Et2O , 11.5 mL) was added dropwise. The mixture was heated to reflux, stirred for 15 hours, then cooled to -30°C. To the mixture were slowly added water (0.5 mL) and 1M aqueous sodium hydroxide solution (1 mL). The reaction mixture was brought to room temperature and filtered through ^Celite® . The filtrate was concentrated to give the title compound (387 mg) as a solid. [MH] ⁺ = 212/214.

Preparation Example 2104

Step A

A mixture of commercially available 5-bromo-indan-1-one (1.76 g), hydroxylamine hydrochloride (636 mg) and sodium acetate (751 mg) in methanol (40 mL) was stirred at room temperature for 16 hours. Water (100 mL) was added and the resulting precipitate was filtered and washed with water (3x20 mL) to give the title compound as a colorless solid (1.88 g; >99%). [MH] ⁺ = 226/228.

Step B

1M Lithium aluminum hydride in diethyl ether (42.4 mL) was slowly added to a solution of the title compound (1.88 g) in step A above in diethyl ether (20 mL) at -78°C under argon atmosphere. The mixture was heated to reflux (40°C) and stirred for 5 hours. The mixture was cooled to 0 °C and water (1.6 mL), 15% aqueous NaOH (1.6 mL) and water (4.8 mL) were added carefully sequentially. The resulting mixture was filtered through ^Celite® and the filtrate was concentrated to yield the title compound (1.65 g; 94%) as a clear oil. [MH] ⁺ = 212/214.

Step C

A hot solution of commercially available N-acetyl-L-leucine (924 mg) in methanol (3 mL) was added to a boiling solution of the title compound from Step B above (1.13 g) in methanol (2.3 mL). The solution was allowed to cool to room temperature, resulting in a white precipitate. The solid was separated from the supernatant and washed with methanol (2 mL). The solid was recrystallized twice from methanol. 10% Aqueous sodium hydroxide solution (20 mL) and diethyl ether (20 mL) were added to the obtained solid. Once the solids had dissolved, the organic layer was separated and the aqueous layer was washed with diethyl ether. The combined organic layers were dried ( _MgSO4 ), filtered and concentrated to yield the title compound as a clear oil (99mg; 18%). [MH] ⁺ = 212/214.

Step D

A solution of the title compound from Step C above (300 mg), di-tert-butyl dicarbonate (370 mg) and triethylamine (237 μL) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 hours. The solution was concentrated and the remaining residue was purified by chromatography (silica, hexane/ethyl acetate) to yield the title compound (460 mg; >99%) as a clear oil. [(M-isobutene)H] ⁺ = 256/258, [MNa] ⁺ = 334/336.

Step E

In a sealed vial under an argon atmosphere, stir the title compound (460 mg) of the above Step D (460 mg), tetrakis-triphenylphosphine palladium (89 mg), zinc cyanide (200 mg) in N,N-dimethylformamide at 110°C (5 mL) for 18 hours. The mixture was allowed to cool to room temperature, then diethyl ether (20 mL) and water (20 mL) were added. The separated aqueous layer was washed with diethyl ether (4x10 mL). The combined organic layers were washed with water (3x10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated. The resulting residue was purified by chromatography (silica, hexane/ethyl acetate) to give the title compound (170 mg; 47%) as a clear oil. [MH] ⁺ = 259, [MNa] ⁺ = 281.

Step F

A 4M solution of hydrogen chloride in dioxane (2 mL) was added to the title compound from Step E above (170 mg). The resulting solution was stirred at room temperature for 3 hours, at which time a precipitate formed. The mixture was concentrated to yield the title compound (128 mg; >99%). [M-Cl] ⁺ =159.

Preparation Example 2105

Step A

The title compound from Step E of Preparative Example 2104 above (1.0 g) was suspended in 6N hydrochloric acid (50 mL) and heated to 110-112°C for 20 hours, at which point the solution became homogeneous. The solvent was removed under reduced pressure to yield an intermediate. [M-Cl] ⁺ =178.

Step B

The intermediate from Step A above was dissolved in anhydrous MeOH (150 mL) and saturated with anhydrous hydrogen chloride gas. The reaction mixture was then heated to reflux for 20 hours. After cooling to room temperature, the solvent was removed under reduced pressure to yield an oil. The oil was dissolved in dichloromethane and washed with saturated NaHCO ₃ solution. The organic phase was separated, dried over _MgSO4 , filtered and concentrated to yield the title compound as an oil (0.66 g, 89% yield over two steps) which slowly crystallized into a light brown solid.

Preparation Example 2106

Step A

Sodium methoxide (30% by weight in methanol, 7.27 mL) was added to a solution of hydroxylamine hydrochloride (2.78 g) in dry methanol (100 mL). The resulting white suspension was stirred at room temperature for 15 minutes, then a solution of the title compound from Preparative Example 2104, Step E (5.17 g) in anhydrous methanol (100 mL) was added and the mixture was heated to reflux for 20 hours and then cooled to room temperature. The obtained solution of the title compound (complete conversion by HPLC/MS, [MH] ⁺ =292) was used directly in Step B below.

Step B

Diethyl carbonate (48.2 g) and sodium methoxide (30% by weight in methanol, 7.27 mL) were sequentially added to the solution obtained in step A above. The resulting mixture was heated to reflux for 24 hours, then concentrated. To the remaining material was added 1M aqueous ammonium chloride (200 mL), and the resulting aqueous mixture was extracted with methanol/dichloromethane (40:60, 500 mL) and dichloromethane (3x200 mL). The combined organic layers were dried ( _MgSO4 ), concentrated and purified by flash chromatography (silica, dichloromethane/methanol) to yield the title compound as a colorless solid (3.89 g; 61%). [MNa] ⁺ = 340.

Step C

The title compound from Step B above (991 mg) was suspended in 4M hydrochloric acid in dioxane (12.5 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to yield the title compound (785 mg; 99%). [M-Cl] ⁺ =218.

Preparation Example 2107

Step A

A suspension of 2,5-dibromobenzenesulfonyl chloride (1.0 g), sodium sulfite (0.46 g) and sodium hydroxide (0.27 g) in water (10 mL) was heated to 70°C for 5 hours. To the cooled solution was added methyl iodide (4 mL) and methanol. The biphasic system was vigorously stirred overnight at 50°C, then evaporated and suspended in water. Filtration yielded the intermediate as colorless needles (933 mg; 99%). [MH] ⁺ = 313/315/317, [MNa] ⁺ = 335/337/339.

Step B

A solution of the intermediate from Step A above (8.36 g) and cuprous(I) cyanide (7.7 g) in degassed N-methylpyrrolidone (30 mL) was heated to 160° C. overnight in a sealed tube. After evaporation of the solvent, the residue was adsorbed on silica and purified by column chromatography (silica, cyclohexane/EtOAc, 6:4-4:6) to give the intermediate as light brown crystals (1.08 g; 20%) .

Step C

The intermediate from Step B above (980 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.72 mL) were heated under argon in degassed dimethylsulfoxide to 50°C for 45 minutes. To this solution was added ethyl acetate, then washed with 10% citric acid and brine, dried ( _MgSO4 ), concentrated, and purified by column chromatography (silica, cyclohexane/EtOAc, 4:6 to 3:7) to give Pale yellow solid intermediate (694 mg; 71%). ¹ H-NMR (CD ₃ CN) δ=5.70 (s, 2H), 5.75 (br s, 2H), 7.72 (d, 1H), 8.00-8.10 (m, 2H).

Step D

To a DMF (10 mL) solution of the intermediate in Step C above (892 mg) was added palladium on carbon (10% by weight, 140 mg), followed by hydrogenation at normal pressure for 2 hours. The catalyst was filtered off, di-tert-butyl dicarbonate (440 mg) was added to the solvent and stirred overnight. The solvent was evaporated and diluted with ethyl acetate. The solution was washed with 10% citric acid and brine, dried ( _MgSO4 ) and concentrated. Purification by column chromatography (silica, cyclohexane/EtOAc, 6:4) gave a colorless solid which was stirred in hydrogen chloride (4M in dioxane, 20 mL) overnight, evaporated and dried to give colorless crystals Intermediate (69 mg; 8%). [M-Cl] ⁺ =209.

Preparation of various embodiments 2108

Step A

Make 1,1,3-trioxy-2,3-dihydro-1H-1λ ⁶ -benzo[b]thiophene-6-carboxylic acid methyl ester (M.Baumgarth et al., J.Med.Chem., 1998, 41,3736-3747) (286 mg), sodium acetate (490 mg) and hydroxylamine hydrochloride (490 mg) in anhydrous methanol (20 mL) was refluxed for 21/2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with brine. Evaporation yielded the intermediate as an off-white solid (302 mg; 99%). ¹ H-NMR (DMSO): δ=3.90 (s, 3H), 4.57 (s, 2H), 8.04 (d, 1H), 8.25-8.28 (m, 2H), 12.62 (s, 1H).

Step B

The intermediate from Step A above (170 mg) was dissolved in methanol (50 mL) and heated to 60°C. Zinc powder (500 mg) and 6N hydrochloric acid (5 mL) were then added in portions over 30 minutes. The mixture was cooled, filtered and evaporated. After dilution with ethyl acetate, the solution was washed with saturated sodium bicarbonate solution and brine, dried ( _MgSO4 ) and concentrated to give the intermediate as a yellow oil (128mg; 80%). [MH] ⁺ = 242, [MNa] ⁺ = 264.

Preparation Example 2109

Step A

Commercially available methyl 4-bromomethylbenzoate (10.0 g) was dissolved in ethanol (40 mL). Potassium cyanide solution (5.63 g in 8 mL of water) was added dropwise over 15 minutes. The resulting suspension was heated to reflux for 3 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in diethyl ether and water. The organic layer was concentrated to a black oil and purified by column chromatography (5% diethyl ether in dichloromethane) to give the intermediate (6.0 g). [MH] ⁺⁼ 176.

Step B

The intermediate from Step A above (6.0 g) was dissolved in 50% aqueous sulfuric acid (40 mL). The solution was heated at 125°C overnight, upon cooling a tan solid precipitated. The mixture was filtered and the solid recrystallized from hot glacial acetic acid (45 mL). The product was filtered, washed with a small amount of water and dried under vacuum to give the intermediate as an off-white solid (4.15g). [MH] ⁺ =181.

^{Step C}

The intermediate from Step B above (4.15 g) was added in small portions to a mixture of fuming nitric acid (11 mL) and sulfuric acid (15 mL) at 0°C over 4 hours. After the addition was complete, the reaction was warmed to room temperature and poured onto crushed ice. The resulting precipitate was filtered, washed with ice water and dried under vacuum to give the intermediate (4.5g). [MNa] ⁺ = 248.

Step D

The intermediate from Step C above was dissolved in methanol (50 mL) and ammonium hydroxide (5 drops) and water (2 mL) were added. The solution was cooled to 0°C, and palladium on carbon (10 wt%, 250 mg) was added. The flask was filled with a hydrogen balloon and stirred for 2 hours. The balloon was refilled with hydrogen and the reaction was stirred overnight. The resulting precipitate was dissolved by adding 1N sodium hydroxide solution, and the solution was filtered through Celite ^® (Diatomaceous Earth ^® ). The volatiles were removed under reduced pressure to give the intermediate as a brown solid (2.58g). [MH] ⁺ =178.

Step E

The intermediate of Step D was esterified by heating in acidic methanol overnight. The resulting solution was concentrated in vacuo, and the residue was dissolved in hot ethanol (75 mL). Methanol (20 mL) was added to redissolve some material that precipitated as the solution cooled. Sodium nitrite (1.50 g) was added followed by concentrated hydrochloric acid (5 mL). The reaction was stirred for 2 hours, then concentrated hydrochloric acid (2 mL) was added. The reaction was stirred overnight. The volatiles were removed under reduced pressure, water was added and the resulting orange-yellow product was isolated by filtration and dried under vacuum to yield an orange-yellow solid intermediate (2.1 g). [MH] ⁺ =221.

Step F

The intermediate from Step E (1.00 g) was dissolved in methanol (50 mL) and concentrated hydrochloric acid (1 mL). Palladium on carbon (10 wt%, 250 mg) was added as a slurry in methanol (5 mL) and the reaction was placed on a Parr shaker type hydrogenation apparatus (hydrogen 50 psi). After 3 hours, the solution was filtered through ^Celite® and the volatiles were removed under reduced pressure. The resulting brown solid was washed with ether and dried under vacuum to give the intermediate (900 mg). [MH] ⁺ =207.

Preparation Example 2110

Step A

3-Bromo-2-methyl-benzoic acid (20.0 g) was dissolved in anhydrous THF (200 mL) under nitrogen and the reaction vessel was cooled to 0 °C in an ice bath. BH ₃ ·THF complex (1M in THF, 140 mL) was added dropwise to this cooled solution over 3 hours. After gas evolution had subsided, the reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. The mixture was then poured into 1N ice-cooled hydrochloric acid (500 mL), and extracted with _Et2O (3 x 150 mL). The organic extracts were combined, dried over anhydrous _MgSO4 , filtered and concentrated to give the intermediate as a colorless solid (18.1 g; 97%). ¹ H-NMR (CDCl ₃ ) δ=2.40 (s, 3H), 4.70 (s, 2H), 7.10 (t, 1H), 7.30 (d, 1H), 7.50 (d, 1H).

Step B

The intermediate from Step A above (18.1 g) was dissolved in _{anhydrous CH2Cl2} (150 mL) under nitrogen and the reaction vessel was cooled to 0 °C in an ice bath. To this cooled solution was added _PBr3 (5.52 mL) over 10 minutes. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. The mixture was cooled in an ice bath and the reaction was quenched by the dropwise addition of MeOH (20 mL). The organic phase was washed with saturated NaHCO ₃ solution (2×150 mL), dried over anhydrous MgSO ₄ , filtered and concentrated to give a viscous oily intermediate (23.8 g; 97%). ¹ H-NMR (CDCl ₃ ) δ = 2.50 (s, 3H), 4.50 (s, 2H), 7.00 (t, H), 7.25 (d, 1H), 7.50 (d, 1H).

Step C

Tert-butyl acetate (12.7 mL) was dissolved in anhydrous THF (200 mL) under nitrogen and the reaction vessel was cooled to -78 °C in a dry ice/acetone bath. To this cooled solution was added lithium diisopropylamide (1.5 M in cyclohexane, 63.0 mL) dropwise and the mixture was stirred for an additional 1 hour before adding the intermediate from Step B above (23.8 g) in THF ( 30mL) solution. After the addition was complete, the reaction mixture was gradually warmed to room temperature over 12 hours. The mixture was concentrated and the remaining viscous oil was dissolved in _Et2O (300 mL), washed with 0.5N hydrochloric acid (2 x 100 mL), dried over anhydrous _MgSO4 , filtered and concentrated to give a pale yellow viscous oily intermediate ( 21.5 g; 80%). ¹ H-NMR (CDCl ₃ ) δ=1.50(s, 9H), 2.40(s, 3H), 2.50(t, 2H), 3.00(t, 2H), 7.00(t, 1H), 7.25(d, 1H ), 7.50 (d, 1H).

Step D

The intermediate from Step C above (21.5 g) was mixed with polyphosphoric acid (250 g) and placed in an oil bath at 140°C for 10 minutes, mixing the thick slurry occasionally with a spatula. Then, to the mixture was added ice water (1 L) and the mixture was stirred for 2 hours. The mixture was then filtered, the solid was washed with _H2O (2 x 100 mL) and dried to give the intermediate (16.7 g; 96%). ¹ H-NMR (CDCl ₃ ) δ=2.40(s, 3H), 2.65(t, 2H), 3.00(t, 2H), 7.00(t, 1H), 7.20(d, 1H), 7.50(d, 1H ).

Step E

The intermediate from Step D above (11.6 g) was dissolved in anhydrous _CH2Cl2 (100 mL) under nitrogen and _the reaction vessel was cooled to 0 °C in an ice bath. Oxalyl chloride (12.0 mL) was added dropwise to the mixture, and the mixture was stirred for 3 hr, then the mixture was concentrated under reduced pressure. The remaining black residue was dissolved in anhydrous _{CH2Cl2 (} 300 mL), and _AlCl3 (6.40 g) was added to this mixture. After complete addition, the mixture was refluxed for 4 hours, then the mixture was poured into ice water (500 mL), extracted with _CH2Cl2 ( _2x11 mL). The combined extracts were dried over anhydrous MgSO ₄ , filtered and concentrated to give the intermediate as a light brown solid (10.6 g; 98%). ¹ H-NMR (CDCl ₃ ) δ=2.40 (s, 9H), 2.70 (t, 2H), 3.05 (t, 2H), 7.50 (d, 1H), 7.65 (d, 1H).

Step F

A solution of the intermediate from Step E _above (9.66 g) in _CH2Cl2 (70 _mL ) was added to (S) _-2- In a cooled solution of methyl-CBS-oxazaborolidine (1M in toluene, 8.6 mL) and borane·dimethylsulfide complex (1M in _CH2Cl2 , _43.0 mL). After complete addition, the reaction was quenched by addition of MeOH (100 mL) at -20 °C, warmed to room temperature and concentrated. The crude mixture was purified by flash chromatography (10%-30% _Et2O / _{CH2Cl2 gradient} ) to give the intermediate as a colorless solid (8.7 g; 90%). ¹ H-NMR(CDCl ₃ )δ=2.00(m, 1H), 2.35(s, 3H), 2.50(m, 1H), 2.90(m, 1H), 3.10(m, 1H), 5.25(m, 1H ), 7.20(d, 1H), 7.50(d, 1H).

Step G

Triethylamine (15.9 mL) was added to a -78°C cooled solution of the intermediate from Step F above (8.7 g) in _CH2Cl2 (200 mL) followed by _{methanesulfonyl} chloride (4.5 mL) under nitrogen. This mixture was stirred for 90 min, then _NH3 (~150 mL) was condensed into the mixture using a dry ice/acetone cold finger at a rate of ~3 mL/min. After stirring for another 2 h at -78 °C, the mixture was gradually warmed to room temperature to evaporate _NH3 from the reaction mixture. 1N NaOH (200 _mL ) was added and the aqueous layer was extracted with _CH2Cl2 (2 x 100 mL). The combined extracts were dried over anhydrous _MgSO4 , filtered and concentrated to give the crude product as a light brown oil. This oil was dissolved in _Et2O (200 mL), hydrogen chloride (4M in dioxane, 10 mL) was added, the precipitate was collected and dried to give an intermediate (9.0 g; 90%). [M-NH ₃ Cl] ⁺ = 209/211.

Step H

The intermediate from Step G above (5.2 g) was mixed in anhydrous CH ₂ Cl ₂ (50 mL), cooled to 0° C., and to this cooled solution was added di-tert-butyl dicarbonate (5.0 g) followed by Et3N (9.67 mL). After stirring for 3 hours, the mixture was concentrated and redissolved in _Et2O (250 mL). This solution was washed with saturated NaHCO ₃ solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated to give the intermediate as a colorless solid (7.28 g; 97%). ¹ H-NMR (CDCl ₃ , free base) δ=1.80 (m, 1H), 2.30 (s, 3H), 2.60 (m, 1H), 2.80 (m, 1H), 2.90 (m, 1H), 4.30 ( t, 1H), 7.00 (d, 1H), 7.40 (m, H).

Step I

The intermediate from Step H above (7.2 g), zinc(II) cyanide (5.2 g) and Pd( _PPh3 ) ₄ (2.6 g) were mixed under nitrogen and dry DMF (80 mL) was added. The yellow mixture was heated to 100°C for 18 hours, then concentrated under reduced _pressure to yield a crude product, which was purified by flash chromatography (20% _CH2Cl2 /EtOAc) to yield the intermediate as an off-white solid (4.5 g; 75%). ¹ H-NMR (CDCl ₃ ) δ=1.50(s, 3H), 1.90(m, 1H), 2.40(s, 3H), 2.70(m, 1H), 2.80(m, H), 2.95(m, 1H ), 4.75(m, 1H), 5.15(m, 1H), 7.20(d, 1H), 7.50(d, 1H).

Step J

The intermediate from step I above (1.0 g) was suspended in 6N hydrochloric acid (20 mL), heated to 100° C. for 12 hours, then the solution became homogeneous. The solvent was removed under reduced pressure to yield the intermediate as a colorless solid (834 mg; quantitative). [M-NH ₃ Cl] ⁺ =175.

Step K

The intermediate from Step J above (1.0 g) was dissolved in anhydrous MeOH (20 mL), cooled to 0° C., and anhydrous hydrogen chloride was bubbled through the solution for 2-3 minutes. The reaction mixture was then heated to reflux for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure to yield the title compound (880 mg; quantitative) as a colorless solid. [M-NH ₃ Cl] ⁺ =189.

Preparation Example 2111

Step A

Hydrogen chloride solution (4M in dioxane, 2 mL) was added to the intermediate from Step I of Preparative Example 2110 (108 mg) above, and the resulting solution was stirred at 22°C for 6 hours, at which point a precipitate formed. The mixture was concentrated to yield the title compound (83 mg, >99%) as a colorless powder. [M-NH ₃ Cl] ⁺ =156.

Preparation Example 2112

Step A

The hydrochloride salt of the intermediate of Preparative Example 2105, Step B (450 mg) was dissolved in dichloromethane (30 mL). After adding triethylamine (0.3 mL) and di-tert-butyl dicarbonate (480 mg), the reaction mixture was stirred at room temperature for 1.5 hours. Diethylenetriamine (1 mL) was added, and the reaction mixture was washed with water and a saturated solution of ammonium chloride. Drying ( _MgSO4 ) and concentration of the organic layer gave the intermediate (560 mg; 96%) which was used in the next step without further purification. [MNa] ⁺ = 314.

Step B

The intermediate from Step A above (560 mg) was dissolved in anhydrous dichloromethane (10 mL) and cooled with an ice bath. 1M diisobutylaluminum hydride solution (10 mL) was added and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction was quenched with methanol (10 mL). Rochelle salt was added and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, dried ( _MgSO4 ) and the organic layer was concentrated to give an intermediate (420 mg; 83%) which was used in the next step without further purification. [MNa] ⁺ = 286.

Step C

The intermediate from Step B above (420 mg) was dissolved in dichloromethane (20 mL). After adding triethylamine (450 μL) and methanesulfonyl chloride at 0° C., the reaction mixture was stirred for 3 hours. The mixture was then diluted with dichloromethane (20 mL) and washed with brine. Drying ( _MgSO4 ) and concentration of the organic layer gave an intermediate (560mg; crude product) which was used in the next step without further purification. [MNa] ⁺ = 364.

Step D

The crude product from Step C above (560 mg) was dissolved in dimethylacetamide (20 mL). Sodium cyanide (400 mg) was added, and the mixture was stirred at 70°C overnight. Ethyl acetate (80 mL) and brine (100 mL) were added. Dry ( _MgSO4 ) and concentrate the organic layer. The remaining residue was purified by chromatography (silica, dichloromethane/acetone, 9:1) to yield the title compound (327 mg; 75% yield over two steps). [MNa] ⁺ = 295.

Step E

A solution of 4M hydrochloric acid in dioxane (2 mL) was added to a suspension of the title compound from Step D above (110 mg) in dioxane (2 mL). The reaction mixture was stirred at room temperature overnight, then concentrated to give the title compound (90 mg; 99%) as the hydrochloride salt. [M-NH ₃ Cl] ⁺ =156.

Preparation Example 2113

Step A

Commercially available 5-bromo-2,3-indan-1-one (2.10 g) and Mn(OAc) ₃ dihydrate (9.0 g) were added to toluene (100 mL) and acetic acid (10 mL). The mixture was heated to reflux under a Dean-Stark condenser for 1.5 hours. The mixture was diluted with diethyl ether and washed twice with brine. Concentration of the organic layer yielded the racemic intermediate as a yellow solid (2.63 g; 98%). [MH] ⁺ = 269/271.

Step B

The racemic intermediate from Step A above (2.63 g) and PS Amano (1 g) were added to acetonitrile (20 mL) and PBS buffer (200 mL, pH 7). The hydrolysis reaction was monitored by LC/MS. After 1.5 hours, the mixture was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated and purified by column chromatography (silica, hexane/EtOAc) to yield the (S)-enantiomer as a yellow solid (0.84 g; 32%). [MH] ⁺ = 269/271.

Step C

The intermediate from Step B above (179 mg) and Sc(OTf) ₃ (65 mg) were added to methanol (16 mL) and water (4 mL). The mixture was stirred at room temperature for 2 days and extracted _twice with _CH2Cl2 . The combined organic layers were concentrated and purified by column chromatography (silica, hexane/EtOAc) to give the intermediate as a yellow solid (124 mg; 83%). [MH] ⁺ =227/229.

Step D

The intermediate (124 mg) of Step C above, hydroxylamine hydrochloride (42 mg) and sodium acetate (50 mg) were added into methanol (3 mL), and stirred at room temperature. After 15 hours, the mixture was diluted with _H2O and filtered. The collected solid was purified by column chromatography (silica, hexane/EtOAc) to give the intermediate as a colorless solid (117 mg; 1/1 ratio of the two isomers). [MH] ⁺ = 242/244.

Step E

The intermediate from Step D above (103 mg) was dissolved in anhydrous diethyl ether (2 mL). The solution was cooled to -78°C and lithium aluminum hydride (1M in _Et2O , 1.28 mL) was added dropwise. The mixture was heated to reflux and stirred for 15 hours, then cooled to -30°C. To the mixture were slowly added water (0.5 mL) and 1M aqueous sodium hydroxide solution (0.5 mL). The reaction mixture was allowed to warm to room temperature and filtered through ^Celite® . The filtrate was concentrated to give the title compound (62 mg) as a solid. [MH] ⁺ =228/230.

Preparation Example 2114

Step A

Dimethylzinc (1.3M in toluene, 15.5mL) was added to a solution of _TiCl4 (3.54g) in dichloromethane (20ml) at -78°C. After 10 minutes at this temperature, commercially available 6-bromo-indan-1-one (3.58 g) dissolved in dichloromethane (20 mL) was added. After 2 hours at -78°C to -10°C, the mixture was poured onto ice and the aqueous layer was extracted with diethyl ether. The organic layer was dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1) to yield the title compound (2.04 g; 53%) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ=1.25 (s, 6H), 1.94 (t, 2H), 2.82 (t, 2H), 7.05 (d, 1H), 7.20-7.30 (m, 3H).

Step B

A solution of _CrO3 (3.72 g) in 50% aqueous acetic acid (20 mL) was added to an acetic acid solution of the title compound from Step A above (2.10 g) at 55 °C, and the mixture was stirred at this temperature for 30 min. After cooling to 0 °C, 2-propanol (5 mL) was added and the mixture was diluted with ethyl acetate (400 mL), washed with 0.5M NaOH and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (2 Silica, Cyclohexane/EtOAc, 9:1), yielded the title compound (829 mg; 37%) as an oil. [MH] ⁺ = 239/241.

Step C

A mixture of the title compound from Step B above (829 mg), hydroxylamine hydrochloride (963 mg) and sodium bicarbonate (1.17 g) in methanol (5 mL) was stirred at 60°C for 16 hours. The mixture was then concentrated and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried ( _MgSO4 ) and concentrated to give the title compound (898 mg; quantitative) as a foam. [MH] ⁺ =254/256.

Step D

To a solution of the title compound from Step C above (898 mg) in diethyl ether (10 mL) was added lithium aluminum hydride (1M in diethyl ether, 17.7 mL) at -78°C. The resulting mixture was warmed to room temperature and then refluxed for 5 hours. The mixture was then cooled to 0 °C and quenched with water (0.80 mL), 15% aqueous NaOH (2.4 mL) and water (2.4 mL), diluted with chloroform and filtered through ^Celite® . Drying ( _MgSO4 ) and concentration of the organic layer gave the title compound as an oil (687mg) which was used without further purification. [MH] ⁺ = 240/242.

Step E

A solution of the title compound from Step D above (687 mg), (Boc) _2O (812 mg) and triethylamine (376 μL) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 hours. The mixture was then concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1) to yield the title compound (927 mg; 77% yield over two steps) as a colorless oil. ¹ H-NMR(CDCl ₃ )δ=1.20(s, 3H), 1.34(s, 3H), 1.48(s, 9H), 1.76(dd, 2H), 2.45(dd, 1H), 4.70(br d, 1H ), 5.20 (m, 1H), 7.15 (d, 1H), 7.22-7.35 (m, 2H).

Step F

A mixture of the title compound from Step E above (927 mg), Zn(CN) ₂ (192 mg) and Pd(PPh ₃ ) ₄ (157 mg) in DMF (50 mL) was stirred at 100 °C for 16 h. The mixture was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1) to yield the title compound (927 mg; 95%) as a colorless solid. [MH] ⁺ =287.

Step G

A solution of the title compound from Step F above (288 mg) in 4M HCl in dioxane (4 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to yield the title compound (220 mg; quantitative). [M-Cl] ⁺ =187.

Preparation Example 2115

Step A

The intermediate from Step B of Preparative Example 2105 was treated overnight with excess di-tert-butyl carbonate and a catalytic amount of 4-dimethylaminopyridine in acetonitrile. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine, dried and evaporated. Purification by silica gel chromatography (hexane/ethyl acetate) yielded the intermediate as a colorless solid.

Step B

The intermediate from Step A above (954 mg) was dissolved in a mixture of tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL). Sodium hydroxide (1M, 5 mL) was added dropwise. The reaction was stirred overnight. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with aqueous ammonium chloride, dried and evaporated to give the intermediate (789 mg; 86%) which was used without further purification.

Step C

N-Methylmorpholine (0.33 mL) and chloroisobutyl formate (0.16 mL) were added to a solution of the intermediate from Step B above (351 mg) in THF (2 mL) at -10°C. The reaction was kept at the same temperature for 1 hour. Diethyl ether (20 mL) and a saturated solution of sodium bicarbonate (5 mL) were added. The aqueous layer was separated and extracted with diethyl ether (10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to yield an intermediate.

Step D

The above step C intermediate was dissolved in toluene (10 mL) and heated to reflux for 5 h until MS showed no starting material remained (corresponding amine was detected). The reaction mixture was concentrated to afford the intermediate which was used crude in the next step.

Step E

Neat azidetrimethylsilane (1 mL) was added to the intermediate from Step D above and heated to reflux overnight. The mixture was concentrated to dryness. Hydrogen chloride (4M in dioxane, 5 mL) was added to the remaining solid and stirred for 1 hour. Diethyl ether (10 mL) was added and the precipitate was filtered and washed with diethyl ether (10 mL) to yield the title compound as a colorless solid (230 mg, quantified in three steps). [M-Cl] ⁺ =218.

Preparation Example 2116

Step A

Oxalyl chloride (0.17 mL) was added to a solution of commercially available 3-tert-butoxycarbonylamino-indan-1-carboxylic acid (0.5 g) in anhydrous dichloromethane (6 mL) at -20 °C, followed by N, With N-dimethylformamide (0.2 mL), the mixture was stirred at -20°C for 1 hour, then at room temperature for 2 hours. The reaction was then concentrated to an oil. The oil was dissolved in tetrahydrofuran (2 mL), and then slowly added to concentrated aqueous ammonia (about 4 mL) at about -40°C. The reaction mixture was stirred at about -30°C for 1 hour, then slowly warmed to room temperature (-10 hours). Volatile components in the reaction mixture were removed under reduced pressure to yield the title compound as a tan solid (0.15 g; 48%). [MH] ⁺ =177.

Preparation Example 2117

Step A

Commercially available dimethyl pyrimidine-4,6-dicarboxylate (4.91 g) was added to a solution of sodium hydroxide (1.00 g) in dry methanol (50 mL). The resulting suspension was stirred at room temperature for 1 hour. Then 4M hydrochloric acid in dioxane (6.25 mL) was added and stirring was continued at room temperature for 10 minutes. The mixture was concentrated and purified by flash chromatography (silica, dichloromethane/methanol) to yield the title compound (3.48 g; 76%). [MH] ⁺ =183.

Step B

N-Methylmorpholine (720 mL) was added to a suspension of the title compound from Step A above (492 mg) in anhydrous tetrahydrofuran (54 mL). The resulting mixture was placed in an acetone/dry ice bath (-30°C). At this temperature, ethyl chloroformate (265 μL) was added and stirring was continued for 1 hour while keeping the temperature of the acetone/dry ice bath below -25°C. Then, the title compound from Preparative Example 2106, Step C was added and stirring was continued for 16 hours, during which time the acetone/dry ice bath was allowed to warm to ~15°C. The mixture was concentrated and purified by flash chromatography (silica, dichloromethane/methanol) to give a pale yellow solid. This material was washed with dichloromethane (2x20 mL) to give the title compound (703 mg; 68%) as a colorless solid. [MH] ⁺ =382.

Step C

The title compound from Step B above (552 mg) was dissolved in 0.5 M sodium hydroxide in dry methanol (6.2 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to give a beige solid. This material was dissolved in water (6.2 mL) and treated with 1M hydrochloric acid (6.2 mL). The resulting suspension was sonicated for 2 hours, then filtered. The remaining solid was washed with water (2 x 6.2 mL), dissolved in methanol (62 mL), concentrated, and dried under reduced pressure for 24 hours to yield the title compound as a colorless solid (483 mg; 89%). [MH] ⁺ =368.

Preparation Example 2118

Step A

Ethyl chloroformate (361 mg) was added to a solution of the title compound from Preparative Example 2117 Step A (607 mg) and N-methylmorpholine (370 mg) in THF (40 mL) at -30°C. After 1.5 hours at this temperature, a suspension of the title compound (759 mg) and N-methylmorpholine (438 mg) in THF (20 mL) of Preparative Example 2105 Step B was added and the resulting mixture was stirred at -30°C to room temperature. Hour. The mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried ( _MgSO4 ) and concentrated to give the title compound (970 mg; 82%) as an off-white foam. [MH] ⁺ =356.

Step B

Sodium hydroxide (0.5 M in methanol, 6.25 mL) was added to a solution of the title compound from Step A above (920 mg) in methanol (15 mL) at room temperature. After 1 hour at room temperature, the mixture was diluted with 1M hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, chloroform/MeOH 85:15) to yield the title compound (743mg; 83%) as a colorless solid. [MH] ⁺⁼ 342.

Preparation Example 2119

Step A

A solution of the title compound from Preparative Example 2117 Step A (174 mg), the title compound from Preparative Example 2104 Step F (169 mg), PyBroP (470 mg) and N-methylmorpholine (240 μL) in anhydrous DMF (8 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was diluted with ethyl acetate, washed with 10% citric acid, saturated sodium bicarbonate solution, brine, dried ( _MgSO4 ) and concentrated. Purification by column chromatography (silica, cyclohexane/ethyl acetate, 6:4-4:6) afforded the title compound (203 mg; 73%) as a colorless foam. [MH] ⁺⁼ 323.

Step B

Sodium hydroxide (0.5 M in methanol, 1.3 mL) was added to the title compound from Step A above (203 mg) at room temperature. After 5 hours at room temperature, the mixture was evaporated and diluted with 1M hydrochloric acid (0.7 mL). The precipitate was filtered to yield the title compound (157 mg; 81%) as a colorless solid. [MH] ⁺⁼ 309.

Preparation Example 2120

Step A

Ethyl chloroformate (1.19 mL) was added to a solution of the title compound from Preparative Example 2117, Step A (2.29 g) and N-methylmorpholine (3.32 mL) in anhydrous THF (250 mL) at -30°C. After 1 hour at this temperature, 4-fluoro-3-methylbenzylamine (1.75 g) was added and the resulting mixture was stirred for 16 hours, allowing the temperature to rise from -30°C to 10°C. The mixture was concentrated and adsorbed on silica. Purification by column chromatography (silica, cyclohexane/ethyl acetate) gave the title compound (2.39 g; 62%) as a colorless solid. [MH] ⁺⁼ 304.

Step B

Lithium hydroxide (496 mg) was added to a solution of the title compound from Step A above (2.39 g) in tetrahydrofuran (50 mL) and water (50 mL) at room temperature. After 2 hours at room temperature, the mixture was acidified to pH 2 with 1M hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried ( _MgSO4 ) and concentrated to yield the title compound as a colorless solid (2.23 g; 97%). [MH] ⁺⁼ 290.

Preparation Example 2121

Step A

A solution of commercially available pyrimidine-4,6-dicarboxylic acid dimethyl ester (1.96g) and commercially available 3-methoxy-benzylamine (1.38mL) in anhydrous N,N-dimethylformamide (10mL) Place in a preheated oil bath (~80°C). After stirring at this temperature for 18 hours, the mixture was concentrated and subjected to rapid filtration (silica, cyclohexane/ethyl acetate). The obtained material was suspended in anhydrous tetrahydrofuran (10 mL) and treated with a solution of lithium hydroxide (642 mg) in water (15 mL). The resulting mixture was stirred at room temperature for 161/2 hours, diluted with water (35 mL), washed with dichloromethane (3 x 50 mL), and acidified by the addition of 1M hydrochloric acid (20 mL). The formed precipitate was isolated by suction, washed again with water (2 x 50 mL), suspended/dissolved in water (200 mL) and sonicated for 5 min. The remaining precipitate was isolated by suction filtration and dried under reduced pressure to yield the title compound (700 mg; 24%). [MH] ⁺ =288.

Preparation Example 2122

Step A

Following a procedure similar to that described for Preparative Example 2118, except using the title compound from Step A of Preparative Example 2117 and Step K of Preparative Example 2110, the intermediate was obtained in 38% yield. [MH] ⁺ =356.

Preparation Example 2123

Step A

A mixture of 5-bromo-2,3-dihydro-1-indanone (3.04 g), ethylene glycol (10 mL) and toluenesulfonic acid (200 mg) in anhydrous toluene (80 mL) was refluxed with Dean-Stark for 8 Hour. After cooling, potassium carbonate was added and the mixture was adsorbed on silica. Purification by flash chromatography (silica, cyclohexane/ethyl acetate 95:5) gave the title compound (1.41 g; 38%). [MH] ⁺ =254/256.

Step B

To a solution of tert-butyl acetate (840 μL) and lithium dicyclohexylamide (1.38 g) in anhydrous toluene (5 mL) under argon was added the title compound from Step A above (1.44 g), bis(dibenzylideneacetone ) palladium (326 mg) and tri-tert-butylphosphine (0.1 M in anhydrous toluene, 5.6 mL). The mixture was stirred overnight, diluted with ethyl acetate, washed with 10% citric acid, saturated sodium bicarbonate solution and brine, dried, evaporated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1-8 :2), resulting in an oil which was dissolved in acetone (45 mL) and water (5 mL). After addition of pyridinium p-toluenesulfonate (120 mg), the mixture was refluxed for 2 hours, concentrated, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried, evaporated and purified by column chromatography (silica, Cyclohexane/EtOAc, 9:1-8:2), yielded the title compound (980 mg; 66%) as pale yellow crystals. [MH] ⁺ =247.

Step C

A mixture of the title compound from Step B above (891 mg), hydroxylamine hydrochloride (780 mg) and sodium acetate (780 mg) in dry methanol (20 mL) was refluxed for 1.5 hours. The mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried ( _MgSO4 ) and concentrated to give the title compound (980mg; quantitative) as a light yellow oil which crystallized on standing. [MH] ⁺ =262.

Step D

Zinc dust (500 mg) and 2N hydrochloric acid were added to the intermediate from Step C above (296 mg). The mixture was stirred overnight, basified with 1N sodium hydroxide, and extracted with chloroform. Drying (MgSO ₄ ) and concentration of the organic layer gave an oil which was treated with hydrogen chloride (4N in dioxane, 400 μL), evaporated, slurried with diethyl ether and filtered to give the intermediate as a colorless solid (76 mg; twenty four%). [M-NH ₃ Cl] ⁺ =231.

Preparation Example 2124

Step A

If the intermediate from Step I of Preparative Example 2110 is treated similarly as described in Preparative Example 2106, Step A - Step C, the title compound is obtained.

Preparation Example 2125

Step A

The intermediate from Preparative Example 2105, Step B (1.5 g) was mixed in anhydrous _CH2Cl2 (50 mL), cooled to 0 °C, and to this cooled solution was added di _- tert-butyl dicarbonate (1.6 g), followed by _Et3N (1 mL). After stirring for 3 hours, the mixture was concentrated and redissolved in _Et2O (250 mL). The solution was washed with saturated NaHCO ₃ solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated to give the intermediate as a colorless solid (7.28 g; 97%) which was dissolved in THF (60 mL). 1M LiOH aqueous solution (60 mL) was added to the mixture, and the mixture was stirred at 50° C. for 2 hr. The mixture was concentrated to dryness and redissolved in water, acidified to pH=5 with hydrochloric acid and extracted with ethyl acetate. Drying ( _MgSO4 ) and concentration of the organic layer gave the intermediate as a colorless solid (1.87g). [MNa] ⁺ = 314.

Step B

Di-tert-butoxymethyldimethylamine (6.2 mL) was added to a solution of the title compound from Step A above (1.87 g) in anhydrous toluene (15 mL) at 80°C. The mixture was stirred at this temperature for 3 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (silica, dichloromethane) to give the intermediate as a colorless solid (820 mg; 38%). [MNa] ⁺ = 370.

Step C

Sulfuric acid (0.65 mL) was added to a solution of the title compound from Step B above (820 mg) in tert-butyl acetate (40 mL) at room temperature. The mixture was stirred for 5 hours and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine. After drying ( _MgSO4 ), the intermediate was obtained as a colorless solid (640 mg; 99%). [M-NH ₂ ] ⁺ =231.

Step D

Bromotripyrrolidinylphosphonium hexafluorophosphate (1.1 g), the intermediate from Step A of Preparative Example 2117 (310 mg) and N-methylmorpholine (0.5 mL) were added to an anhydrous solution of the title compound (360 mg) from Step C above. Dimethylformamide (5 mL) solution. The mixture was stirred overnight at room temperature and concentrated to dryness. The residue was dissolved in water and extracted with ethyl acetate. After drying ( _MgSO4 ), the solution was concentrated and purified by chromatography (silica, cyclohexene/ethyl acetate) to yield the title compound as a colorless solid (285 mg; 48%). [MNa] ⁺ = 434.

Step E

The title compound from Step D above (285 mg) was dissolved in a solution of 0.5 M sodium hydroxide in dry methanol (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give a beige solid. This material was dissolved in water (6.2 mL) and treated with 1M hydrochloric acid (2 mL). The resulting suspension was diluted with water and extracted with ethyl acetate. After drying ( _MgSO4 ), the solution was concentrated to yield the title compound as a colorless solid (282 mg; quantitative). [MNa] ⁺ = 420.

Example 1

Step A

In a sealed vial under an argon atmosphere, the pyrimidine-4,6-dicarboxylic acid 4-[(5-cyano-indan-1-yl)-amide] 6-( A mixture of 4-fluoro-3-methyl-benzylamide) (75.8 mg), dibutyltin oxide (9 mg), azidetrimethylsilane (47 μL) and toluene (1.5 mL) for 18 hours. The reaction mixture was concentrated and purified by silica gel chromatography (9: _{1 CH2Cl2} :MeOH, _Rf = 0.2) to yield an off-white solid (30 mg; 36%). [MH ⁺ ] ^- = 471.6.

Example 5

The corresponding nitrile (23.4 mg), Bu ₂ SnO (2.7 mg) and TMSN ₃ (36 μL) were added in dioxane (1 mL). The mixture was heated to 100°C and stirred for 24 hours. The solvent was evaporated in vacuo. The residue was chromatographed on silica gel to yield 20.6 mg of a white solid (80%). [MH] ⁺ = 478.3.

Example 8

If the title compound of Preparative Example 8, Step B, dissolved in N-methylpyrrolidone (5 mL) is heated for 5 hours, the triazolone product is obtained.

Example 9a

If the title compound of Preparative Example 9a, Step C, in hydrazine and methanol is heated, the desired triazole is obtained.

Example 9b

If the procedure described in Preparative Example 9a and Example 9a is followed, but substituting trifluoroacetic anhydride for acetyl chloride in Step B of Preparative Example 9a, the desired trifluoromethyltriazole is obtained.

Examples 10-152

If the nitriles shown in Table 4 below are treated similarly as described in Example 1, the tetrazoles shown will be obtained.

Table 4

Examples 201-230

If the tetrazoles shown in Table 5 below are treated with the appropriate base and methyl iodide, the methylated tetrazoles shown will be obtained.

table 5

Examples 301-330

If a procedure similar to that described in Example 2500, Step A is followed, using starting materials prepared according to Preparative Example 2115 and Preparative Example 2120, the desired compounds in Table 6 below are obtained.

Table 6

Examples 401-430

If a THF solution of the indicated hydroxytetrazoles is heated with a base (ie, aqueous NaOH) and methyl iodide as described in Preparative Example 2500, Step B, the desired methylated tetrazoles in Table 7 below are obtained.

Table 7

Examples 501-530

If the title compounds listed in the table below are heated in a manner similar to that described for the preparation of Example 9a and Example 9a, the desired triazoles are obtained, see Table 8 below.

Table 8

Examples 601-630

If the title compounds listed in the table below are heated in a manner similar to that described for the preparation of Example 9a and Example 9b, the desired triazoles are obtained, see Table 9 below.

Table 9

Examples 701-730

If the title compounds listed in the table below are heated in a manner similar to that described in Preparative Example 8 and Example 8, the desired hydroxytriazoles are obtained, see Table 10 below.

Table 10

Example 2300

Step A

A solution of the above intermediate (60 mg) in Preparative Example 2004, Step B in N,N-dimethylformamide (0.5 mL) was added to the title compound in Preparative Example 2119, Step A, and the mixture was stirred at 80° C. for 15 hours, Concentration followed by column chromatography (silica, diethyl ether/dichloromethane, 3:7) afforded the intermediate as a colorless solid (50 mg; 28%). [MH] ⁺ =420.

Step B

Add SnO(Bu) ₂ (10 mg) and azidotrimethylsilane (55 μL) to a solution of the intermediate (45 mg) of the above step A in anhydrous toluene (1.5 mL) and heat under a nitrogen atmosphere (100-102 °C ) the mixture for 18 hours. The mixture was then concentrated and purified by preparative thin layer chromatography (silica, methanol/dichloromethane, 3:19) to yield the title compound (30 mg; 63%) as a foam. ¹ H-NMR (DMSO) δ=1.25(t, 3H), 2.10-2.30(m, 1H), 2.75(q, 2H), 2.8-3.2(m, 3H), 4.12(d, 2H), 5.64( q, 1H), 6.76(s, 1H), 7.12(s, 1H), 7.20(d, 1H), 7.80(d, 1H), 7.97(s, 1H), 8.52(s, 1H), 9.35(d , 1H), 9.43(s, 1H), 9.64(t, 1H).

Example 2301

Step A

Triethylamine (61 μL) was added to commercially available 6-cyano-1,2,3,4-tetrahydro-naphthalen-1-yl-ammonium chloride (49.6 mg), the title compound from Step B of Preparative Example 2120 ( 57.3 mg), bromotripyrrolidinylphosphonium hexafluorophosphate (113 mg) in THF (2 mL). The mixture was stirred at room temperature for 18 hours. EtOAc (10 mL) and 1N hydrochloric acid (10 mL) were added. The aqueous layer was washed twice with EtOAc (10 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ (10 mL), brine (10 mL), dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to afford the intermediate as an off-white solid (51 mg; 48%). [MH] ⁺ =444.

Step B

In a sealed vial under an argon atmosphere, a mixture of the intermediate from Step A above (51 mg), dibutyltin oxide (7 mg), azidetrimethylsilane (30.5 μL) and toluene (1 mL) was stirred at 110 °C for 18 Hour. The _reaction mixture was concentrated and purified by silica gel chromatography ( _CH2Cl2 /MeOH, 9:1) to yield the title compound (21 mg; 38%) as an off-white solid. [MH] ⁺ =486.

Example 2302-2309

Following a procedure similar to that described in Example 2301, Step A and Step B, except using the acids and amines shown in Table 11 below, the following compounds were prepared.

Table 11

Example 2310

Step A

Boron tribromide (1M in dichloromethane, 468 μL) was added to a solution of the title compound of Example 2308 above (37 mg) in anhydrous dichloromethane (390 μL). The mixture was diluted with dichloromethane (2 mL) and stirred at room temperature for 2 hours. Methanol (5 mL) was added and stirring was continued at room temperature for 1 hour. The mixture was concentrated and purified by flash chromatography (silica, dichloromethane/methanol) to yield the title compound (35 mg; 99%). [MH] ⁺ =457.

Example 2311

Step A

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg), 1-hydroxy-benzotriazole (30 mg), the title compound from Step C of Preparative Example 2043 (58 mg) and N-methylmorpholine (100 μL) were added to a solution of the title compound from Step B of Preparative Example 2119 (51.5 mg) in DMF (3 mL). After stirring at room temperature overnight, the mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, saturated NaHCO ₃ solution and brine. The organic phase was separated, dried over _MgSO4 , filtered and adsorbed on silica. The residue was purified by column chromatography (silica, _CH2Cl2 /MeOH, 97:3-9:1) to yield the title compound (74.6 mg; 82%) as a yellow _solid . [MH] ⁺ =548.

Step B

In a sealed vial, the intermediate of Step A above (74 mg), dibutyltin oxide (35 mg), azidetrimethylsilane (600 μL) and toluene (10 mL) and 1,2-dimethyl A mixture of oxyethane (3 mL) was stirred at 110°C for 2 days. Methanol was added to the reaction mixture and the solution was adsorbed on silica. Purification by silica gel chromatography ( _CH2Cl2 /MeOH, 9:1-85:15) yielded the title compound (17.8 mg; 22% ₎ as an off-white solid. [MH] ⁺ =591.

Example 2312-2327

If a procedure similar to that described in Example 2311, Step A and Step B is followed, except that the amines of the Preparative Examples shown in Table 12 below are used, the following title compounds are obtained.

Table 12

Example 2328-2329

Following a procedure similar to that described in Example 2311, Step A and Step B, except using the acids and amines shown in Table 13 below, the following compounds were prepared.

Table 13

Example 2400

Step A

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (16mg), 1-hydroxy-benzotriazole (11.3mg), 3-methyl-benzylamine hydrochloride (9.6mg ) and N-methylmorpholine (9.3 μL) were added to a solution of the title compound (28 mg) in Preparative Example 2117 Step C in DMF (1 mL). After stirring at room temperature for 12 hours, the mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with saturated NaHCO ₃ , 1N hydrochloric acid and brine. The organic phase was separated, dried over _MgSO4 , filtered and concentrated. The residue was purified by column chromatography (silica, _CH2Cl2 /MeOH, 95:5) to yield the title compound (29 mg; 88%) as a colorless _solid . [MH] ⁺ =471.

Example 2401-2451

Following a method similar to that described in Example 2400, except using commercially available compounds or the compounds of the Preparation Examples shown in Table 14 below, the following compounds were prepared.

Table 14

Example 2452

Step A

A solution of the intermediate of Example 2303 (41 mg, 0.1 mmol) and hydroxylamine (69 mg hydrochloride, neutralized with triturated potassium hydroxide in ethanol) in ethanol (3 mL) was refluxed overnight. The reaction mixture was concentrated to dryness to yield the intermediate as a colorless solid which was used in the next step without further purification. [MH] ⁺ =463.

Step B

The compound from step A above was dissolved in N,N-dimethylformamide (1 mL) and cooled to 0°C in an ice bath. Pyridine (9 μL, 0.11 mmol) was added followed by isobutyl chloroformate (13 μL, 0.105 mmol). The reaction was kept at the same temperature for 30 minutes, then concentrated to dryness to give a brown oily intermediate. [MH] ⁺ =563.

Step C

Chlorobenzene (3 mL) was added to the compound from Step B above and refluxed for 3 hours. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography to obtain the intermediate as an off-white solid (28 mg; 60% yield over 3 steps). [MH] ⁺ =489.

Step D

Trimethylsilyldiazomethane (2M in diethyl ether, 29 μL) was added to a solution of the compound from Step C above (26 mg, 53 μmol) in a mixture of benzene and methanol (1.2 mL, 3:1) and stirred for 1 Hour. The solution was concentrated in vacuo. The tan solid was purified by silica gel chromatography to yield the title compound (24 mg; 90%) as an off-white solid. [MNa] ⁺ = 525.

Example 2453

Step A

The intermediate from Example 2452 Step C (40 mg) was dissolved in acetone (1 mL) and potassium carbonate (12 mg) and 2-bromoacetamide (12 mg) were added. The reaction was stirred at room temperature for several hours, then heated to 55°C. After 4 hours, more 2-bromoacetamide (12 mg) was added and the reaction was heated overnight. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane and water. The organic layer was concentrated in vacuo and purified by column chromatography (5% methanol in dichloromethane) to yield the title compound (33mg) as a colorless solid. [MH] ⁺ =546.

Example 2454

Step A

The intermediate from Example 2452 Step C (35 mg) was dissolved in acetone (0.75 mL) and potassium carbonate (9 mg) and 2-chlorodimethylacetamide (11 mg) were added. The reaction was heated at 55°C overnight. Sodium iodide (10 mg) was added and the reaction was heated overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in aqueous ammonium chloride and dichloromethane. The organic residue was purified by column chromatography (5% methanol in dichloromethane) to yield the title compound (40mg). [MH] ⁺ =574.

Example 2455

Step A

Sodium hydride (790 mg) was added to a solution of commercially available 5-methyl-2-nitro-aniline (5.00 g) in DMF (100 mL) at 0°C, and the mixture was stirred at this temperature for 10 minutes. Then, methyl iodide (18.7 g) was added over 30 minutes, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried ( _MgSO4 ), concentrated and purified by crystallization from ethanol to yield the title compound as red needles (2.83 g; 52%). ¹ H-NMR (DMSO) δ=2.25(s, 3H), 2.92(d, 3H), 6.42(d, 1H), 6.75(s, 1H), 7.90(d, 1H), 8.10(br s, 1H ).

Step B

A mixture of the title compound from Step A above (2.83 g) and palladium on carbon (10 wt%, 1.5 g) in ethanol (20 mL) was stirred at room temperature for 16 h. The mixture was filtered through a ^plug of Celite to yield the title compound as an oil (2.02 g; 87%). ¹ H-NMR(DMSO)δ=2.10(s, 3H), 2.65(s, 3H), 4.32(br s, 3H), 6.20(s, 1H), 6.22(d, 1H), 6.40(d, 1H ).

Step C

A solution of the title compound of Step B above (2.00 g) prepared as described by W. Kantlehner et al. (Liebigs Ann. Chem. 1980, 1448-1454) in trimethoxy-methyl acetate was heated to 100°C for 16 hours. The mixture was cooled to 50°C and diethyl ether was added. The mixture was kept at 0°C for 1 hour and decanted. The residue was concentrated and purified by column chromatography (silica, chloroform/MeOH, 98:2). Crystallization from _Et2O /EtOH gave the title compound as a solid (759 mg; 25%). [MH] ⁺ =205.

Step D

A solution of the title compound from Step C above (309 mg), NBS (351 mg) and AIBN (10 mg) in tetrachloromethane was refluxed for 4 hours. After filtering off the precipitate, the organic layer was concentrated and purified by column chromatography (silica, chloroform/MeOH, 98:2) to yield the title compound (100 mg; 23%). [MH] ⁺ =283.

Step E

A mixture of the title compound from Step D above (1.00 g) and sodium azide (720 mg) in DMF (3 mL) was stirred at room temperature for 16 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 6:4) to yield the title compound (90 mg; 99%) as a colorless solid. [MH] ⁺ =246.

Step F

A solution of the title compound from Step E above (49 mg) and triphenylphosphine (68 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 16 hours. Water (1 mL) was then added, and the mixture was stirred at 50°C for 5 hours. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 80:20) to yield the title compound (23 mg; 50%) as a colorless solid. [MH] ⁺⁼ 220.

Step G

Stir at room temperature the title compound from Step F above (23 mg), the title compound from Step C of Preparative Example 2117 (50 mg), 1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (26 mg), 1 -Hydroxy-benzotriazole (18 mg), DMAP (1 mg) and DIPEA (18 mg) in DMF (2 mL) for 3 days. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with 0.01M hydrochloric acid, 0.01 mM KOH, dried ( _MgSO4 ) and concentrated to give the title compound as a solid (40 mg; 68%). [MH] ⁺ =569.

Step H

A mixture of the title compound from Step G above (22 mg) in 30% aqueous ammonia (40 mL) was heated to 100° C. for 16 hours in a sealed pressure tube. The mixture was concentrated and purified by preparative thin layer chromatography (chloroform/MeOH 90:10) to yield the title compound (2 mg; 10%). [MH] ⁺ =554.

Example 2456-2471

Following a procedure similar to that described for Example 2400, except using the amines of the preparative examples shown in Table 15 below, the following title compounds were obtained.

Table 15

Example 2472-2474

Following a method similar to that described in Example 2400, except using commercially available compounds or the compounds of the Preparation Examples shown in Table 16 below, the following compounds were prepared.

Table 16

Example 2500

Step A

The title compound from Preparative Example 2120, Step B (58 mg) was dissolved in THF and cooled to -10°C. N-methylmorpholine (44 μL) and isobutyl chloroformate (31 μL) were added sequentially. The reaction was kept at the same temperature for 30 minutes. Add a solution of the title compound from Step E of Preparative Example 2115 (230 mg) in N,N-dimethylformamide basified with N-methylmorpholine (44 μL). The reaction was allowed to warm to room temperature over 1 hour and concentrated to dryness. The crude mixture was purified by column chromatography to yield the title compound (58 mg; 63%) as an off-white solid. [MNa] ⁺ = 511.

Step B

Trimethylsilyldiazomethane (2M in diethyl ether, 9.6 μL) was added to a solution of the intermediate from Step A above (8.5 mg) in benzene (0.75 mL) and methanol (0.25 mL) and stirred for 1 hour. The solution was concentrated in vacuo. The tan solid was purified by silica gel chromatography to yield the title compound (8 mg; 90%) as an off-white solid. [MNa] ⁺ = 525.

Example 2501

Step A

PyBop (51 mg) was added to a mixture of the title compound from Preparative Example 2120 Step B (28 mg), the title compound from Preparative Example 2116 Step A (25 mg), triethylamine (138 μL) in tetrahydrofuran (2 mL) and N,N- Dimethylformamide (0.2 mL) solution. The reaction was stirred at room temperature for 2 hours and diluted with ethyl acetate (10 mL). After conventional aqueous workup, the crude product was purified by column chromatography to yield the intermediate as an off-white solid (16 mg; 34%). [MH] ⁺ =545.

Step B

The intermediate from Step A above (5 mg) was dissolved in ammonia (7N in methanol, 3 mL) and kept at room temperature overnight. The solution was concentrated to dryness. The crude product was purified by column chromatography to yield the title compound (4.5 mg; 94%) as an off-white solid. [MH] ⁺ =516.

Example 2502

Step A

The intermediate from Preparative Example 2120, Step B (60 mg) was dissolved in THF (5 mL) and DMF (0.5 mL), cooled to -30 °C, then N-methylmorpholine (23 μL) was added, followed by isochloroformate Butyl ester (27 μL). After stirring at -30°C for 1 hour, commercially available 4-methyl-indan-1-ylamine (62 mg) was added in one portion. The mixture was stirred at -30°C for an additional 1 h, then gradually warmed to room temperature, and the mixture was concentrated under high vacuum to yield an oil. The oil _was purified by flash chromatography with 20% EtOAc/ _CH2Cl2 to yield the title compound as a colorless solid (50 mg; 57%). [MH] ⁺ =419.

Example 2503-2505

Following a procedure similar to that described in Example 2502, except using the amines shown in Table 17 below, the following compounds were prepared.

Table 17

Example 2506

Step A

Triethylamine (52 μL) was added to the title compound (35 mg) of the above-mentioned Preparative Example 2111, the intermediate of the above-mentioned Preparative Example 2120 Step B (48.5 mg), bromotripyrrolidinophosphonium hexafluorophosphate (96 mg) in THF (1.7 mL) in the mixture. The mixture was stirred at 22°C for 18 hours. EtOAc (5 mL) and 1N hydrochloric acid (5 mL) were added. The aqueous layer was washed twice with EtOAc (5 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ (5 mL), brine (5 mL), dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to afford the intermediate as an off-white solid (39.0 mg; 52%). [MH] ⁺ =444.

Step B

In a sealed vial under argon atmosphere, a mixture of the intermediate from Step A above (37.6 mg), dibutyltin oxide (4 mg), azidetrimethylsilane (22 μL) and toluene (0.8 mL) was stirred at 110 °C 30 hours. The reaction mixture was concentrated and purified by silica gel chromatography ( _CH2Cl2 /MeOH ₉ :1) to yield the title compound (7.0 mg; 17%) as an off-white solid. [MH] ⁺ =487.

Example 2507

Step A

Tetrahydrofuran (3 mL) and N-methylmorpholine (0.21 mL) were added to a solution of the intermediate (0.5 g) from Preparative Example 2120 Step B in N,N-dimethylformamide (6 mL) and frozen under nitrogen (-40°C) the mixture. Isobutyl chloroformate (0.25 mL) was then added to the frozen solution, and the mixture was stirred between -40°C and -20°C for 2 hours. To the chilled solution was added the title compound of Preparative Example 2105, Step B (0.43 g) dissolved in tetrahydrofuran (3 mL), and the mixture was stirred at -40°C to -20°C for 2 hours, then slowly warmed to room temperature. Water (2-3 drops) was then added to the mixture and stirred for 1 hour. The mixture was concentrated and the resulting solid was purified by column chromatography (silica, 10% hexane/dichloromethane, then 10% diethyl ether/dichloromethane) to yield an intermediate (0.5 g; 63%). [MH] ⁺ =463.

Step B

1 N KOH (3 mL) was added to the above intermediate of Step A (0.4 g) dissolved in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 15 hours. The mixture was concentrated and the resulting solid was triturated with 10% dichloromethane/diethyl ether and washed with 1N hydrochloric acid. Filtration of the resulting solid yielded the title compound (0.33 g; 86%). ¹ H-NMR (DMSO) δ = 2.2 (s, 3H), 2.9-3.2 (m, 4H), 4.5 (d, 2H), 5.70 (q, 1H), 7.0-7.4 (m, 4H), 7.80 ( d, 1H), 7.85 (s, 1H), 8.50 (s, 1H), 9.40 (m, 2H), 9.65 (t, 1H).

Example 2508-2509

Following a procedure similar to that described in Example 2507, except using the amines shown in Table 18 below, the following compounds were prepared.

Table 18

Example 2510

Step A

The title compound of Preparative Example 2118 Step B (34 mg), the title compound of Preparative Example 2042 Step D, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg), 1 A solution of -hydroxy-benzotriazole (18 mg) and N-methylmorpholine (50 μL) in DMF (4 mL) was stirred at room temperature overnight. The mixture was then concentrated to dryness, and the residue was dissolved in ethyl acetate, washed with saturated NaHCO ₃ , 1N hydrochloric acid and brine. The organic phase was separated, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica, cyclohexane/ethyl acetate 6:4) to yield the title compound (61 mg; quantitative) as a colorless solid. [MH] ⁺ =499.

Step B

0.5N Lithium hydroxide solution (1 mL) was added to the intermediate of the above Step A (61 mg) dissolved in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature overnight. The mixture was concentrated and acidified with 1N hydrochloric acid (0.5 mL). The resulting solid was filtered to yield the title compound (40.7 mg; 84%). [MH] ⁺ =485.

Example 2511-2519

Following a procedure similar to that described in Example 2510, except using the compounds of the Preparation Examples shown in Table 19 below, the following compounds were prepared.

Table 19

Example 2520

Step A

The title compound from Preparative Example 2507 Step B (80 mg) was dissolved in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL) and frozen at -30°C. To the chilled solution was added oxalyl chloride (18 µL), and the mixture was stirred at -30°C to -10°C for 1.5 hours, then at room temperature for 30 minutes. The mixture was then concentrated, the resulting oil was dissolved in tetrahydrofuran (2 mL), the solution was added to concentrated ammonia, and the mixture was stirred at -30°C to -20°C for 10 minutes, then warmed to room temperature over 2 hours. The mixture was evaporated and the resulting solid was purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to yield the title compound (40 mg; 52%). [MH] ⁺ =448.

Example 2521

Step A

The title compound from Preparative Example 2507 Step B (0.15 g) was dissolved in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (0.2 mL) and frozen at -30°C. To this frozen solution was added oxalyl chloride (32 µL), and the mixture was stirred at -30°C to -10°C for 1.5 hours and then at room temperature for 30 minutes. The mixture was then concentrated, the resulting oil was dissolved in tetrahydrofuran (0.5 mL), and the solution was added to a solution of N-methylmorpholine (75 μL) and N,N-dimethylformamide (0.5 mL). In commercially available 2-amino-1-methyl-1,5-dihydro-imidazol-4-one hydrochloride (32 mg), the mixture was stirred at -30°C to -20°C for 10 minutes, then heated to room temperature. The mixture was evaporated and the resulting solid was purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to yield the title compound (34 mg; 41%). [MH] ⁺ =544.

Example 2522

Step A

Oxalyl chloride (17 μL) was added to a solution of the intermediate _from Preparative Example 2120, Step B (28.7 mg) and N,N-dimethylformamide (2 μL) in _CH2Cl2 (1 mL) at 0 °C. The solution was warmed to 22°C and stirred for 2 hours. The solution _was concentrated and the resulting residue was dissolved in _CH2Cl2 (1 mL). The resulting solution was cannulated into a _CH2Cl2 (1 mL) solution of a mixture of the intermediate from Step K of Preparation Example 2110 (20.0 mg) and triethylamine (56 μL) and the _mixture was stirred for 2 hours at which point it into a homogeneous solution. Silica gel (500 mg) was added and the mixture was concentrated and purified by silica gel chromatography (hexane/ethyl acetate 1:1) to afford the intermediate as an off-white solid (29.0 mg; 61%). [MH] ⁺ =477.

^{Step B}

A solution of the intermediate from Step A above (29.0 mg) in THF (240 μL), MeOH (120 μL) and 1N aqueous LiOH (120 μL) was stirred at 50 °C for 1 h. The solution was concentrated to remove all MeOH and the resulting residue was dissolved in THF (200 μL) and acidified with concentrated hydrochloric acid (20 μL). The mixture was concentrated and purified by silica gel chromatography ( _CH2Cl2 /MeOH 9:1) to yield the title compound (15.0 mg; 53%) as an off-white _solid . [MH] ⁺ =463.

Example 2523-2538

Following a procedure similar to that described in Example 2510, Step A and Step B, except using the amines of the preparative examples shown in Table 20 below, the following title compounds were obtained.

Table 20

Example 2539-2555

Following a procedure similar to that described in Example 2510, Step A and Step B, except using the intermediate of Preparative Example 2122 and the amine of the Preparative Example shown in Table 21 below, the following title compounds were obtained.

Table 21

Example 2556

Step A

The title compound from Step E of Preparative Example 2125 above (120 mg) was dissolved in anhydrous dimethylformamide (3 mL). Add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (137 mg), 1-hydroxy-7-azabenzo After triazole (50 mg) and the title compound of Preparative Example 2061 (117 mg) and diisopropylethylamine (150 µL), the mixture was stirred at room temperature (5 hours). The solvent was removed and the residue was dissolved in ethyl acetate and washed with 0.01M hydrochloric acid. Drying ( _MgSO4 ) and concentration of the organic layer gave the title compound as a colorless solid (95mg; 57%). [MH] ⁺ =665.

Step B

Trifluoroacetic acid (1 mL) was added to a solution of the title compound from Step A above (90 mg) in anhydrous dichloromethane (4 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed, the residue was concentrated and purified by column chromatography (silica, chloroform/methanol 9:1) to yield the title compound (28 mg; 33%) as a colorless solid. [MH] ⁺ =609.

Example 2557-2562

Following a procedure similar to that described in Example 2556, Step A and Step B, except using the amines of the preparative examples shown in Table 22 below, the following title compounds were prepared.

Table 22

Example 2563

Step A

A solution of trimethylsilyldiazomethane (8.2 μL, 2M in diethyl ether) in benzene and methanol (0.3 mL, 3:1 ) was added to the intermediate of Preparative Example 2558 (8 mg) at room temperature. After 1 hour, another portion of trimethylsilyldiazomethane (8.2 μL, 2M in diethyl ether) was added. The reaction was stirred for an additional 2 hours until completion. The solution was concentrated and the product was used without further purification.

Step B

The title compound from Step A above was treated similarly as described in Preparative Example 2556, Step B to give the title compound as a colorless solid. [MH] ⁺ =543.

Example 2600

Step A

_BBr3 (30.2 mL) was added to a solution of the title compound of Example 2505 (23.1 mg) in _CH2Cl2 (0.5 _mL ) at 0 °C. The solution was warmed to 22°C and stirred for 1.5 hours. 1N Hydrochloric acid (5 mL) was added and the _aqueous layer was washed with _CH2Cl2 (3 x 5 mL). The combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated, and purified by silica gel chromatography (Hex/EtOAc 1:1) to yield the title compound (17.8 mg; 80%) as a colorless solid. [MH] ⁺ =421.

Example 2601

Step A

The intermediate of Preparative Example 2120 Step B (102 mg), 4-bromo-2,3-dihydro-1H-inden-1-amine (75 mg), 1-ethyl-3-(3-dimethylamino Propyl)-carbodiimide (102 mg), 1-hydroxybenzotriazole (48 mg) and potassium carbonate (224 mg) were dissolved in THF (5 mL) and stirred for 15 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, ammonium chloride and brine, dried ( _MgSO4 ), concentrated and purified by column chromatography (silica, hexane/EtOAc) to yield the title compound as a solid ( 111mg). [MH] ⁺ =483.

Step B

The title compound from Step A above (93 mg), bis(dibenzylideneacetone)palladium (8.8 mg) and 1,1'-bis(diphenylphosphino)propane (21 mg) were dissolved in DMF (5 mL), Heat to 80°C. A solution of zinc(II) cyanide (27 mg) in DMF (1.5 mL) was added dropwise to the reaction mixture. The mixture was stirred for 15 hours, concentrated and purified by column chromatography (silica, hexane/EtOAc) to yield the title compound as a colorless solid (60 mg). [MH] ⁺ =430.

Example 2602

Step A

(5-Bromo-indan-1-yl)-tert-butyl carbamate (1.55 g), benzyl carbamate (904 mg), bis(dibenzylideneacetone) palladium (114 mg), Xantphos (217 mg) and Cesium carbonate (2.281 g) was weighed into a small flask. Anhydrous dioxane (25 mL) was added under an atmosphere of argon and the reaction was heated at 95°C for 18 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate and dry packed on silica. Purification by column chromatography (25% ethyl acetate in hexanes) isolated the product as a colorless solid (930 mg). [MH] ⁺ =383.

Step B

The intermediate from Step A above (930 mg) was dissolved in 4N HCl in dioxane (10 mL) for 16 h. The volatiles were removed under reduced pressure and the residue was washed with diethyl ether and dried under vacuum to give the intermediate as a gray solid (445 mg). [M-Cl] ⁺ =283.

Step C

The intermediate from Preparative Example 2120, Step B (400 mg) was dissolved in DMF (7 mL) and THF (5 mL). N-methylmorpholine (175 mg) was added and the solution was cooled to -40°C. Isobutyl chloroformate (207 mg) was added and the reaction was stirred at -30°C to -40°C for 90 minutes. The intermediate from Step B above (440 mg) and N-methylmorpholine (200 mg) were slurried in THF (7 mL) and transferred to the mixed anhydride by pipette. The reaction was allowed to warm to room temperature over 18 hours. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated and the residue was purified by column chromatography (5% methanol in dichloromethane) to give the intermediate as an off-white solid (200 mg). [MH] ⁺ =554.

Step D

The intermediate from Step C above was slurried in acetic acid (2 mL). Hydrogen bromide (33% in acetic acid, 0.5 mL) was added. After 1.5 hours, an additional amount of hydrogen bromide (33% in acetic acid) was added and the reaction was stirred for 1 hour. Volatile materials were removed under reduced pressure. The residue was washed with diethyl ether (40 mL), then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was concentrated and the residue was purified to give the intermediate as a yellow oil (125 mg). [MH] ⁺ =421.

Step E

The intermediate from Step D above was dissolved in ethanol (2 mL) and dimethyl N-cyanodithioimidocarbonate (150 mg) was added. The reaction was heated at 80°C overnight. The resulting precipitate was filtered, and the solid was washed with a small amount of ethanol and diethyl ether. The crude product was purified by column chromatography (5% methanol in dichloromethane) to yield an off-white solid (50 mg). The resulting solid was heated to 50° C. in ammonia (7N in methanol, 10 mL) for 36 hours. The reaction was dry packed onto silica and purified by column chromatography (5% methanol in dichloromethane) to yield the title compound as an off-white solid (33 mg). [MH] ⁺ =487.

Example 2603

Step A

The intermediate from Example 2602 Step A (650 mg) was dissolved in ethanol (40 mL) and palladium on carbon (10 wt%, 250 mg) was added. The reaction was placed on a Parr shaker type hydrogenation apparatus pressurized with 60 psi hydrogen. After 36 hours, the reaction was filtered and dry packed onto silica. Flash chromatography (25% ethyl acetate in hexanes) gave the intermediate as a colorless oil (300 mg). [MH] ⁺ =249.

Step B

The intermediate from Step A above (150 mg) was dissolved in dichloromethane (3 mL) and triethylamine (122 mg) was added. The solution was cooled to -78°C, and trifluoromethanesulfonic anhydride (164 mg) was added. The reaction was allowed to warm to room temperature over 30 minutes, then diluted with dichloromethane and 0.1N hydrochloric acid. The organic layer was concentrated, and the residue was purified by column chromatography to give a colorless oily intermediate (205mg). [MNa] ⁺ = 403.

Step C

The intermediate from Step B above (205 mg) was dissolved in hydrogen chloride (4N in dioxane, 2 mL). The reaction was stirred for 2 hours, the volatiles were removed under reduced pressure and the residue was washed with diethyl ether to give a solid intermediate (135 mg) whose NMR was consistent with the presence of half an equivalent of dioxane. ¹ H-NMR (DMSO) δ = 8.4 (br, 3H), 7.7 (d, 1H), 7.25 (m, 2H), 4.75 (m, 1H), 3.2 (m, 1H), 2.95 (m, 1H) , 2.40(m, 1H), 2.05(m, 1H).

Step D

The intermediate from Preparative Example 2120, Step B (114 mg) was dissolved in DMF (0.5 mL) and THF (2 mL). N-methylmorpholine (81 mg) was added, and the solution was cooled to -40°C. Isobutyl chloroformate (55 mg) was added and the reaction was stirred at -30°C to -40°C for 90 minutes. The intermediate from Step C above (125 mg) and N-methylmorpholine (161 mg) were slurried in THF (2 mL) and transferred by pipette to the mixed anhydride. The reaction was allowed to warm to room temperature over 18 hours. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was concentrated and the residue was purified by column chromatography (5% methanol in dichloromethane) to yield the title compound (135 mg) as an off-white solid. [MH] ⁺ =552.

Example 2604

Step A

The intermediate of Example 2603 Step A (550 mg) was dissolved in ethanol (2 mL). 3,4-diethoxy-3-cyclobutene-1,2-dione (0.70 g) was added and the reaction was heated at 65°C overnight. The volatiles were removed under reduced pressure, the residue was washed with diethyl ether/hexane (1:1, 10 mL) and dried under vacuum to give a solid intermediate (605 mg). [MNa] ⁺ = 395.

Step B

The intermediate from Step A above (100 mg) was dissolved in hydrogen chloride (4N in dioxane, 5 mL). After 2 hours, the volatiles were removed under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to yield the intermediate as a gray solid (80 mg). [M-NH ₃ Cl] ⁺ =256, [M-Cl] ⁺ =273.

Step C

The intermediate of Preparative Example 2120 Step B (15 mg), 1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (11 mg) and 1-hydroxy-benzotriazole (8 mg) were weighed Weight into flask. DMF (0.5 mL) and THF (0.5 mL) were added, and the mixture was stirred for 1 hour. The intermediate from Step B above (10 mg) was added along with triethylamine. The reaction was stirred overnight, diluted with ethyl acetate, washed with water and dilute hydrochloric acid. The residue was purified by column chromatography (10% methanol in dichloromethane) to give a solid intermediate (14 mg, [MH] ⁺ =544). The purified squarate ester was dissolved in THF (1 mL), and ammonia (7N in methanol, 200 μL) was added. The reaction was stirred for 36 hours and the resulting precipitate was isolated by centrifugation of the reaction mixture followed by decantation of the supernatant to yield the title compound as a solid (8 mg). [MH] ⁺ =515.

Example 2605

Step A

The intermediate of Preparative Example 2120 Step B (196 mg), (2S)-1-amino-5-bromo-2,3-dihydro-1H-inden-2-ol (154 mg), 1-ethyl-3- (3-Dimethylaminopropyl)-carbodiimide (195 mg), 1-hydroxybenzotriazole (91 mg) and potassium carbonate (214 mg) were dissolved in THF (5 mL) and stirred for 15 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, ammonium chloride and brine, dried (MgSO ₄ ), concentrated, and purified by column chromatography (silica, hexane/EtOAc) to give a colorless solid of (1R,2S)-configuration of the title compound (80 mg, J _1,2 = 4.9 Hz, [MH] ⁺ =449/451) and (1S, 2S)-configuration of the title compound (76 mg, J _1,2 = 6.2 Hz, [MH] ⁺ = 449/451).

Example 2606

Step A

The title compound of Example 2605 (1R,2S) (8.8 mg), Pd( _PPh3 ) ₄ (2.0 mg) and triethylamine (24 μL) were added to ethanol (1 mL) and DMSO (1 mL). The mixture was stirred under carbon monoxide (1 atm) for 15 hours and diluted with ethyl acetate. The mixture was washed with brine, concentrated and purified by column chromatography (silica, hexane/EtOAc) to yield the title compound as a colorless solid (8.0 mg). [MH] ⁺ =499.

Step B

The title compound from Step A above (8.0 mg) was added to 1 M aqueous sodium hydroxide solution (2 mL) and THF (1 mL). The mixture was stirred at room temperature for 15 hours, acidified to pH ₂ with 1M hydrochloric acid, and extracted twice with _CH2Cl2 . The combined organic layers were dried over _MgSO4 , concentrated and purified by column chromatography (silica) to yield the title compound as a colorless solid (4.1 mg). [MH] ⁺ =465.

Example 2607

Step A

The title compound of EXAMPLE 2605 (1R,2S) (80 mg), DIAD (39 mg), triphenylphosphine (63 mg) and benzoic acid (29 mg) were added to THF (3 mL). The mixture was stirred at room temperature for 24 hours, concentrated and purified by column chromatography (silica, hexane/EtOAc) to give the intermediate as a colorless solid (85 mg). [MNa] ⁺ = 625/627.

Step B

The intermediate from Step A above (40 mg), Pd( _PPh3 ) ₄ (10 mg) and triethylamine (120 μL) were added to ethanol (2 mL) and DMSO (2 mL). The mixture was stirred under carbon monoxide (1 atm) for 15 hours and diluted with ethyl acetate. The mixture was washed with brine, concentrated and purified by column chromatography (silica, hexane/EtOAc) to give the intermediate as a colorless solid (31 mg). [MH] ⁺ = 597/599.

Step C

The intermediate from Step B above (5.4 mg) was added to 1 M aqueous sodium hydroxide solution (2 mL) and THF (1 mL). The mixture was stirred _at room temperature for 15 hours, acidified to pH 2 with 1M hydrochloric acid, and extracted twice with _CH2Cl2 . The combined organic layers were dried over _MgSO4 , concentrated and purified by column chromatography (silica) to yield the title compound as a colorless solid (3.1 mg). [MH] ⁺ = 465/467.

Example 2608

Step A

The above-mentioned intermediate (90 mg) of Preparation Example 2112 Step E, the intermediate (124 mg) of Preparation Example 2120 Step B, 1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (100 mg ) and 1-hydroxy-benzotriazole (70 mg) were dissolved in N,N-dimethylformamide (10 mL). After addition of N-methylmorpholine (240 μL), the reaction mixture was stirred overnight. The solvent was evaporated and the resulting residue was purified by column chromatography (silica, dichloromethane/acetone 95:5) to yield the title compound (127 mg; 67%). [MH] ⁺ =444.

Step B

Dibutyltin(IV) oxide (5 mg) and trimethylsilyl azide (130 μL) were added to a solution of the title compound from Step A above (50 mg) in anhydrous toluene (5 mL). The resulting mixture was heated to reflux for 19 hours. The mixture was allowed to cool to room temperature and methanol (5 mL) was added. Concentration and flash chromatography (silica, chloroform/methanol, 85:15) afforded the title compound (53 mg; 99%). [MNa] ⁺ = 509.

Example 2609

Step A

The above intermediate from Preparative Example 2123 Step D (38.2 mg), the intermediate from Preparative Example 2120 Step B (43 mg), PyBroP (75 mg) were dissolved in N,N-dimethylformamide (3 mL). After addition of N-methylmorpholine (40 μL), the reaction mixture was stirred overnight. The solvent was evaporated and the resulting residue was purified by column chromatography (silica, cyclohexane/ethyl acetate 7:3-6:4) to yield the title compound (50.7 mg; 72%) as an oil. [MH] ⁺ =519.

Step B

To a solution of the title compound from Step A above (42.8 mg) in trifluoroacetic acid (3 mL) was added water (3 drops). The resulting mixture was stirred for 3 hours and then adsorbed on silica. Purification by flash chromatography (silica, dichloromethane/methanol, 95:5) afforded the title compound (35.2 mg; 92%) as a colorless foam. [MNa] ⁺ = 463.

Example 2610

Step A

The hydrochloride salt of the intermediate of Preparative Example 2105, Step B (450 mg) was mixed in anhydrous _CH2Cl2 (30 mL), cooled to 0 °C, and to this cooled solution was added di _- tert-butyl dicarbonate (480 mg), Then Et3N ( _0.3 mL) was added. After stirring for 3 hours, the mixture was washed with saturated NaHCO ₃ solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous _MgSO4 , filtered and concentrated to give the title compound (560 mg; 96%) as a colorless solid. [MNa] ⁺ = 314.

Step B

1 M diisobutyl-aluminum hydride solution (15 mL) was added to a solution of the title compound from Step A above (560 mg) in dichloromethane (30 mL) at 0°C. The mixture was stirred overnight and the reaction was quenched with methanol. After addition of Rochelle salt, the mixture was stirred for an additional 2 hours. The organic layer was extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated to yield the title compound (820 mg; 83%) [MNa] ⁺ =286.

Step C

The intermediate from Step B above (420 mg) was dissolved in anhydrous _CH2Cl2 (20 mL), cooled to 0 °C, and to _this cooled solution was added _Et3N (0.45 mL) followed by methanesulfonyl chloride (0.25 mL ). After stirring for 3 hours, the mixture was diluted with dichloromethane, washed with saturated _NH4Cl solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated to give a colorless solid intermediate which was dissolved in N,N-dimethylacetamide (20 mL). After adding sodium cyanide (400 mg), the mixture was stirred at 70°C overnight. Diethyl ether (80 mL) and brine (100 mL) were added, the organic layer was separated, dried (MgSO ₄ ), filtered and concentrated, and chromatographed (silica, dichloromethane/acetone) to yield the title compound (327 mg; 75%). [MNa] ⁺ = 295.

Step D

The intermediate from Step C above (210 mg) was suspended in 6N hydrochloric acid (20 mL) and heated to 100°C for 12 hours, at which point the solution became homogeneous. The solvent was removed under reduced pressure to yield a colorless solid, which was redissolved in methanol (20 mL), cooled to 0 °C, and anhydrous hydrogen chloride was bubbled through the solution for 10 min. The reaction mixture was then heated to reflux for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure to yield the title compound (145 mg; 92%) as a colorless solid. [M-NH ₃ Cl] ⁺ =189.

Step E

Bromotripyrrolidinophosphonium hexafluorophosphate (246 mg), the intermediate from Step A of Preparative Example 2117 (310 mg) and N-methylmorpholine (0.5 mL) were added to anhydrous di Methylformamide (5 mL) solution. The mixture was stirred overnight at room temperature and concentrated to dryness. The residue was dissolved in water and extracted with ethyl acetate. After drying ( _MgSO4 ), the solution was concentrated and chromatographed (silica, dichloromethane/acetone) to yield the title compound as a colorless solid (285 mg; 48%). [MH] ⁺ =370.

Step F

The title compound from Step E above (51 mg) was dissolved in a solution of 0.5M sodium hydroxide in dry methanol (0.3 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to give a beige solid. This material was dissolved in water (6.2 mL) and treated with 1M hydrochloric acid (2 mL). The resulting suspension was diluted with water and extracted with ethyl acetate. After drying ( _MgSO4 ), the solution was concentrated to yield the title compound as a colorless solid (40 mg; 82%). [MNa] ⁺ = 378.

Step G

Bromotripyrrolidinophosphonium hexafluorophosphate (34 mg), the product from Preparative Example 2043 Step C (38 mg) and N-methylmorpholine (0.06 mL) were added to anhydrous dimethylformamide of the title compound from Step F above (40 mg) in methyl formamide (5 mL) solution. The mixture was stirred overnight at room temperature and concentrated to dryness. The residue was dissolved in water and extracted with ethyl acetate. After drying ( _MgSO4 ), the solution was concentrated to give the crude title compound as a colorless solid which was used without further purification. [MH] ⁺ =595.

Step H

The crude intermediate from Step G above was dissolved in tetrahydrofuran (5 mL) and 1M aqueous lithium hydroxide was added. The reaction mixture was then stirred at room temperature (4 hours), concentrated and purified by chromatography (dichloromethane/methanol 9:1) to yield the title compound as a colorless solid (5 mg, 13% yield over two steps). [MH] ⁺ =581.

Example 2700

Step A

2-Chloro-3-nitro-benzoic acid (1.24 g) was dissolved in anhydrous THF (7.5 mL) under nitrogen and the reaction vessel was cooled to 0 °C in an ice bath. BH ₃ ·THF complex (1M in THF, 11.2 mL) was added dropwise to this cooled solution over 1 h. Once gas evolution subsided, the reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. Then, the mixture was poured into 1N ice-cold hydrochloric acid (50 mL), and extracted with _Et2O (3x15 mL). The organic extracts were combined, dried over anhydrous MgSO ₄ , filtered and concentrated to give the intermediate as a colorless solid (1.15 g; >99%). ¹ H-NMR (CDCl ₃ ) δ=4.90 (s, 2H), 7.48 (t, 1H), 7.76 (d, 1H), 7.82 (d, 1H).

Step B

The intermediate from Step A above (1.15 g) was dissolved in anhydrous _CH2Cl2 (20 mL) under nitrogen and _the reaction vessel was cooled to 0 °C in an ice bath. _PBr3 (390 μL) was added to this cooled solution over 10 minutes. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours. The mixture was cooled in an ice bath and the reaction was quenched by dropwise addition of MeOH (1 mL). The organic phase was washed with saturated NaHCO ₃ solution (2×15 mL), dried over anhydrous MgSO ₄ , filtered and concentrated to give a viscous oily intermediate (1.35 g; 88%). ¹ H-NMR (CDCl ₃ ) δ=4.66 (s, 2H), 7.42 (t, 1H), 7.70 (d, 1H), 7.78 (d, 1H).

Step C

Dimethyl malonate (1.24 mL) was added dropwise to a mixed solution of NaH (60% in oil, 475 mg) in THF (30 mL) over 10 min. The mixture was stirred at 60°C for 1 hour, then cooled to 22°C, at which time a solution of the intermediate from Step B above (1.35 g) in THF (20 mL) was added dropwise over 20 minutes, and the resulting mixture was stirred for 1.5 hours. 10% _H2SO4 (50 _mL ) was added and the aqueous layer was washed with _Et2O (3 x 50 mL). The combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated to yield an oil. The oil was added to 10% NaOH (30 mL), stirred at reflux (110° C.) for 18 hours. The aqueous layer was washed with _Et2O (3 x 15 mL), and the organic layer was discarded. The aqueous layer was acidified with concentrated HCl (10 mL), then washed with _Et2O (3 x 20 mL). The combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated to yield an oil. The resulting oil was stirred with _H2SO4 (0.9 _mL ), _H2O (4.5 mL) and AcOH (6.4 mL) at 120 °C for 18 h. The reaction was cooled to 22 °C, diluted with water (20 mL), the resulting aqueous layer was washed with EtOAc (3x20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO ₄ , filtered and concentrated to give an oily intermediate body (1.21 g; 93%). [MH] ⁺ =230.

Step D

A solution of the intermediate from Step C above (1.21 g) and acetyl chloride (355 μL) in methanol (50 mL) was stirred at 65 °C in a sealed vessel for 18 h, then concentrated to give the intermediate as an oil (1.28 g; >99%). [MH] ⁺ =244.

Step E

A mixture of the intermediate from Step D above (1.28 g) and iron powder (325 mesh, 724 mg) in EtOH (7 mL) and AcOH (7 mL) was stirred at 90 °C for 30 min. The mixture was filtered through ^Celite® , then concentrated. The resulting mixture was mixed with saturated Na ₂ CO ₃ solution (30 mL) and EtOAc (30 mL) for 30 min, then filtered through ^Celite® . The layers were separated and the aqueous layer was washed with EtOAc (30 mL). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated to give the intermediate as a clear oil (1.07 g; >99%). [MH] ⁺ =214.

Step F

Acetyl chloride (393 μL) was added to a solution of the intermediate from Step E above (1.07 g) and _{triethylamine} (767 μL) in _CH2Cl2 (30 mL). The solution was stirred for 3 hours, concentrated and purified by silica gel chromatography (Hex/EtOAc, 4:1) to afford the intermediate (800 mg; 63%). [MH] ⁺ = 256.1.

Step G

BBr3 (650 μL) _was added to a solution of the intermediate from Step F above (800 mg) in _CH2Cl2 (20 mL). The resulting solution was stirred at 22°C for 24 hours, and 1N hydrochloric acid (30 mL) was carefully added. The aqueous layer was washed with _CH2Cl2 (2 x 20 mL), the combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated to give the intermediate (704 _mg ; 99%). [MH] ⁺ =242.

Step H

A mixture _of the intermediate from Step G above (611 mg), _Na2CO3 (268 mg) and thionyl chloride (368 μL) in _CH2Cl2 (15 _mL ) was stirred under nitrogen atmosphere for 6 h. The mixture was filtered and the supernatant was concentrated to yield an off-white solid. The solid was dissolved in _CH2Cl2 (15 mL), and to _this solution was added _AlCl3 (675 mg). The resulting mixture was stirred at reflux (45°C) for 18 hours, then poured onto ice (40 g) and allowed to warm to 22°C. The layers were separated and the _aqueous layer was washed with _CH2Cl2 (2x30 mL). The combined organic layers were dried over anhydrous _MgSO4 , filtered, concentrated and purified by silica gel chromatography (Hex/EtOAc, 1:1) to afford the intermediate as an off-white solid (377.5 mg; 67%). [MH] ⁺ =224.

Step I

A mixed solution of the intermediate from Step H above (377.5 mg) in 3N aqueous LiOH (3 mL), THF (6 mL) and MeOH (6 mL) was stirred at 50 °C for 1 h. The resulting solution was _concentrated , diluted with water (15 mL), and washed with _CH2Cl2 (3 x 15 mL). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated to yield the intermediate (284 mg; 93%). [MH] ⁺ =182.

Step J

A solution of NaNO ₂ (42 mg) in water (1 mL) was added dropwise to a mixed solution of the intermediate of Step I above (106 mg) in 2N hydrochloric acid (2 mL) at 0° C. for 5 min. The mixture was stirred at 0°C for 15 minutes at which time all solids had dissolved. Solid _Na2CO3 ( ₂₅₀ mg) was added carefully which turned the mixture dark red. This mixture was pipetted into CuCN solution which was premixed by stirring CuCl (72 mg) and NaCN (92 mg) in water (2 mL) for 1 h. Once the reddish mixture was transferred into the CuCN solution, the resulting mixture was stirred at 0°C for 1 hour, then warmed to 22°C over 30 minutes, then heated to 50°C for 15 minutes. A saturated solution of NaHCO ₃ (10 mL) was added and the resulting aqueous layer was washed with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous _MgSO4 , filtered, concentrated and purified by silica gel chromatography (Hex/EtOAc, 3:1) to afford the intermediate as an off-white solid (50 mg; 43%). [MH] ⁺ = 191.9. ¹ H-NMR (CDCl ₃ ) δ = 2.81 (dd, 2H), 3.22 (dd, 2H), 7.76 (m, 2H).

Step K

The intermediate from Step J above (133 mg, solution in 1 mL _CH2Cl2 ) was added to (S)-2-methyl-CBS-oxazoboron with a syringe pump over _1.5 h at -20 °C (internal temperature) alkane (1M in toluene, 700 μL) and borane·dimethylsulfide complex (1M in CH ₂ Cl ₂ , 700 μL) in an ice-cold solution. After complete addition, the mixture was quenched by addition of MeOH (1 mL) at -20 °C, warmed to room temperature and concentrated. The crude mixture was purified by silica gel chromatography (hexane/EtOAc, 3:1) to give the intermediate as a colorless solid (98.5 mg; 73%). [MH] ⁺ =194.

Step L

Diisopropyl azadicarboxylate (20 μL) was added to the intermediate from Step K above (14 mg), _PPh (26.6 mg), and phthalimide (15 mg) in THF (800 μL) at 0 °C in solution. The reaction solution was warmed to 22°C, stirred for 2 hours, then concentrated and purified by silica gel chromatography (hexane/EtOAc, · 5:1) to give the intermediate as a colorless solid (16 mg; 69%). [MH] ⁺ =323.

Step M

A solution of the intermediate from Step L above (32 mg) and hydrazine (55% in water, 17 μL) in EtOH (1 mL) was stirred for 4 h, then concentrated to a colorless solid. The solid was mixed with conc. HCl (5 mL), stirred at 105 °C for 48 h, then concentrated to a colorless solid. To this solid was added HCl in MeOH (5 mL, anhydrous hydrogen chloride was bubbled through MeOH for 5 min) and the mixture was stirred at 65° C. for 18 h in a sealed vessel. The solution was concentrated to a white solid which analysis revealed to be 4-chloro-5-cyano-indan-1-yl-ammonium chloride and 4-chloro-5-methoxycarbonyl-indan-1- base-ammonium chloride mixture, the two species are separated in the final step. Oxalyl chloride (26 μL) was added to a solution of the intermediate from Preparative Example 2120, Step B (43 mg) and N,N-dimethylformamide (5 μL) in _CH2Cl2 (1.5 _mL ) at 0 °C. The solution was allowed to warm to 22°C and stirred for 2 hours. The solution was concentrated and the resulting residue was dissolved in _CH2Cl2 ( _1.5 mL). The resulting solution was added via cannula to the above 4-chloro-5-cyano-indan-1-yl-ammonium chloride and 4-chloro-5-methoxycarbonyl-indan-1-yl-ammonium chloride and In a mixture of triethylamine (56 μL) in _CH2Cl2 (1.5 mL), the mixture was stirred _for 2 hours, at which point it became a homogeneous solution. Silica gel (500 mg) was added and the mixture was concentrated and purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to yield an off-white solid which was pyrimidine-4,6-dicarboxylic acid 4-[(4-chloro-5 -cyano-indan-1-yl)-amide] 6-(4-fluoro-3-methyl-benzylamide) and 4-chloro-1-{[6-(4-fluoro-3-methyl -Benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-indane-5-carboxylic acid methyl ester. This mixture was dissolved in THF (200 μL), MeOH (200 μL) and 3N aqueous LiOH (100 μL), and stirred at 50° C. for 1 hour. The solution was concentrated to remove all methanol and the resulting residue was dissolved in THF (200 μL) and acidified with concentrated hydrochloric acid (30 μL). The mixture was concentrated and purified by silica gel chromatography (Hexane/EtOAc, 1:1 to remove pyrimidine-4,6-dicarboxylic acid 4-[(4-chloro-5-cyano-indan-1-yl)- Amide] 6-(4-Fluoro-3-methyl-benzylamide), followed by _CH2Cl2 / _MeOH , 9:1), yielded the title compound as an off-white solid (15.0 mg; 31%). [MH] ⁺ =483.

Example 2701

Step A

The intermediate from Preparative Example 2109, Step F (250 mg) and carbonyldiimidazole (140 mg) were dissolved in DMF (5 mL) and stirred for 1 hour. The intermediate from Preparative Example 2120, Step B (210 mg) was dissolved in DMF (3 mL) and triethylamine (105 mg) was added. The resulting mixture was transferred to the acid solution by pipette and stirred for 1 hour. The volatiles were removed under reduced pressure and the crude product was dissolved in ethyl acetate and dry packed onto silica. Purification by column chromatography (10% methanol in dichloromethane) isolated the title compound as a pale orange solid (175 mg). [MH] ⁺ =478.

Example 2702

Step A

Sodium hydroxide solution (1.3 g in 5 mL of water) was added to a solution of commercially available 4,6-dimethyl-pyrimidin-2-ylamine (6.0 g) in water (400 mL) and heated at 80° C. for 10 minutes. Potassium permanganate (15 g) was then added and heated at 85°C-90°C for 1 hour. Potassium permanganate (15 g) was added again and the mixture was heated for a further 2 hours. The mixture was cooled to room temperature, filtered through ^Celite® , then acidified to pH~2. The mixture was concentrated to 20% of the original volume, the solid was filtered and dried. The solid was dissolved in methanol (200 mL) and saturated with dry hydrogen chloride gas, and the mixture was heated to reflux for 24 hours. The mixture was concentrated to an oil, then dissolved in dichloromethane, and the organic phase was washed with a saturated solution of NaHCO ₃ , then dried over MgSO ₄ , filtered and concentrated to give a solid, which was analyzed by column chromatography (silica, 10% methanol/di (chloromethane) to give the intermediate (0.41 g). [MH] ⁺ =212.

Step B

4-Fluoro-3-methyl-benzylamine (0.15 g) dissolved in N,N-dimethylformamide (1 mL) was added to N,N-dimethyl In formamide (3 mL), the mixture was stirred at 80°C for 15 hours, concentrated, and purified by column chromatography (silica, 10% methanol/dichloromethane) to give a colorless foamy intermediate (0.15 g; 28% ). [MH] ⁺ =319.

Step C

1N Potassium hydroxide solution (2 mL) was added to a solution of the intermediate from Step B above (0.15 g) in THF (2 mL) and stirred for 24 hours. The mixture was concentrated and purified by column chromatography (silica, 10% methanol/dichloromethane) to give the intermediate (60 mg; 42%). [MH] ⁺ =305.

Step D

N-Methylmorpholine (15 μL) was added to a solution of the intermediate from Step C above (20 mg) in N,N-dimethylformamide (0.5 mL) and the solution was frozen (-40° C.) under nitrogen. Isobutyl chloroformate (10 μL) was then added to the chilled solution, and the mixture was stirred at -40°C to -20°C for 1.5 hours. To the frozen solution was added the intermediate of Preparative Example 2105, Step B (13 mg) dissolved in tetrahydrofuran (0.5 mL), and the mixture was stirred at -40°C to -20°C for 1 hour and then slowly warmed to room temperature. Water (1-2 drops) was then added to the mixture and stirring was continued for 1 hour. The mixture was concentrated and the resulting solid was purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to yield the intermediate (20 mg; 64%). [MH] ⁺ =478.

Step E

1N Potassium hydroxide solution (40 µL) and water (100 µL) were added to the intermediate (20 mg) of the above Step D dissolved in tetrahydrofuran (0.4 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was concentrated, and then 1N hydrochloric acid (0.3 mL) was added to the obtained solid, which was then concentrated to a solid. The solid was purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to yield the title compound (9 mg; 47%). [MH] ⁺ =464.

Example 2703

Step A

Benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate (51 mg), the intermediate from Step K of Preparative Example 2110 (22 mg) and triethylamine (50 μL) and tetrahydrofuran (0.3 mL ) was added to a solution of the intermediate of Example 2702 Step C (25 mg) in N,N-dimethylformamide (0.3 mL), and the mixture was stirred at room temperature for 24 hours. The mixture was then concentrated and purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to afford the intermediate (14 mg; 35%). [MH] ⁺⁼ 492.

Step B

1N LiOH (0.5 mL) and methanol (0.3 mL) were added to the above intermediate of Step B (14 mg) dissolved in tetrahydrofuran (0.5 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated, and the resulting solid was acidified with 1N hydrochloric acid, then concentrated to a solid. The solid was purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to yield the title compound (10 mg; 73%). [MH] ⁺ =478.

Example 2704

Step A

Dissolve commercially available methyl 2-chloro-6-methyl-pyrimidine-4-carboxylate (9.38 g) and selenium dioxide (8.93 g) in dioxane (50 mL) in a round bottom flask under argon Stir at 105°C. After 12 hours, the mixture was filtered twice through ^Celite® , washing well with dioxane (2 x 100 mL). The filtrate was then evaporated to give the intermediate as a viscous orange oil (8.0 g; 74%). [MH] ⁺ =217.

Step B

The intermediate from Step A above (0.9 g) was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0°C. Then oxalyl chloride (0.87 mL) was added slowly, followed by 2-3 drops of N,N-dimethylformamide, and the cooling operation was stopped. After gas evolution was complete, the mixture was concentrated, dissolved in dichloromethane, pyridine (0.34 mL) was added followed by 4-fluoro-3-methylbenzylamine (0.53 mL) and the reaction was stirred for 30 minutes. MS analysis showed the product to be present ([MH] ^{+ =} 338). The mixture was filtered and evaporated onto silica. The product was eluted by column chromatography with 30% ethyl acetate/hexanes. This provided the intermediate as a yellow solid (0.67g).

Step C

A solution of the intermediate (670 mg) in Step B above in THF (20 mL) was cooled to 0°C, 1M lithium hydroxide aqueous solution (3.98 mL) was added slowly, and the reaction was stirred at 0°C for 2 hours. Analysis of the reaction by MS showed the product to be an acid ([MH] ⁺ = 324). The mixture was quenched with 1M hydrochloric acid (4.0 mL) and allowed to warm to room temperature. The mixture was reduced to dryness in vacuo and the product was extracted by trituration with tetrahydrofuran and filtration. The filtrate was evaporated to give the intermediate as an orange solid (1.1 g).

Step D

Dimethylamine (2M in THF, 0.6 mL) was added to a solution of the intermediate from Step C above (0.1 g) in THF (1 mL), and the mixture was stirred for 15 hours. The mixture was concentrated, then acidified with 1N hydrochloric acid, followed by filtration. The solid was purified by column chromatography (silica, 40% diethyl ether/dichloromethane) to give the intermediate (54 mg; 54%). [MH] ⁺ =333.

Step E

Benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate (85 mg), the intermediate of Preparative Example 2105 Step B (31 mg), triethylamine (40 μL) and dichloromethane ( 0.5 mL) was added to a solution of the intermediate (54 mg) in step D above in N,N-dimethylformamide (1 mL), and stirred at room temperature for 24 hours. The mixture was then concentrated and purified by column chromatography (silica, 30% diethyl ether/dichloromethane) to give the intermediate (70 mg; 86%). [MH] ⁺ =506.

Step F

1N Aqueous sodium hydroxide solution (0.3 mL) and methanol (0.3 mL) were added to a solution of the intermediate (70 mg) from Step E above in tetrahydrofuran (0.3 mL), and the mixture was stirred at room temperature for 24 hours. The mixture was concentrated and purified by column chromatography (silica, 30% methanol/dichloromethane) to yield the title compound (22 mg; 32%). [MH] ⁺ =492.

Example 2705

Step A

Sodium methoxide (0.5M in methanol, 2 mL) was added to a solution of the intermediate from Example 2704, Step C (80 mg) in THF (1 mL) and stirred for 15 hours. The mixture was concentrated, then acidified with 1N hydrochloric acid, followed by filtration to give the intermediate (50mg). [MH] ⁺ =320.

Step B

Benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate (82 mg), the intermediate from Preparative Example 2105 Step B (35 mg), triethylamine (50 μL) and dichloromethane ( 1 mL) was added to a solution of the intermediate from Step A above (50 mg) in N,N-dimethylformamide (1 mL). After stirring at room temperature for 24 hours, the mixture was concentrated and purified by column chromatography (silica, 30% diethyl ether/dichloromethane) to give the intermediate (40 mg; 50%). [MH] ⁺ =493.

Step C

1N Aqueous sodium hydroxide solution (0.3 mL) and methanol (0.3 mL) were added to a solution of the intermediate (40 mg) of the above Step B in tetrahydrofuran (0.3 mL), and the mixture was stirred at room temperature for 24 hr. The mixture was concentrated and purified by column chromatography (silica, 10% methanol/dichloromethane) to yield the title compound (26 mg; 67%). [MH] ⁺ =479.

Example 2706

Step A

The intermediate from _Example 2704 Step C (0.92 g) was dissolved in _CH2Cl2 (20 mL) and DMF (0.2 mL) and cooled to 0 °C. Oxalyl chloride (0.81 mL) was added dropwise. After stirring for 1 h, gas evolution had subsided and a solution of the intermediate from Preparative Example 2105, Step B (0.60 g) and _{triethylamine} (0.44 mL) in _CH2Cl2 (5 mL) was added dropwise. After stirring at room temperature for 3 hours, the mixture was concentrated under high vacuum to give the crude product, which _was purified by flash chromatography in 20% EtOAc/ _CH2Cl2 to give the intermediate as a colorless solid (0.95 g; 67%). [MH] ⁺ =497.

Step B

The intermediate from Step A above (50 mg) was dissolved under nitrogen in a solution containing 0.4N _Na2CO3 aqueous solution (0.50 mL), 3-thiophenyl boronic acid ( ₁₄ mg) and tetrakis-triphenylphosphine palladium (0) (12 mg) in dimethoxyethane (5 mL). After heating the reaction mixture to 100°C and stirring for 8 hours, LC/MS showed complete disappearance of starting material. After cooling to room temperature, the mixture was concentrated under high vacuum to give the crude product, _which was purified by flash chromatography in 25% MeOH/ _CH2Cl2 to yield the title compound as a colorless solid (47 mg; 53%). [MH] ⁺ =531.

Example 2707-2709

Following a procedure similar to that described in Example 2706, Step B, except using the boronic acids shown in Table 23 below, the following compounds were prepared.

Table 23

Example 2710

Step A

A solution of the intermediate from Example 2706 Step A (0.24 g), Zn(CN) ₂ (112 mg) and Pd(PPh ₃ ) ₄ (139 mg) was mixed under nitrogen and dry DMF (5 mL) was added. The yellow mixture was heated to 105°C for 18 hours, then concentrated. The mixture was purified by column chromatography (30% diethyl ether/dichloromethane) to give an intermediate (0.15 g; 64%). [MH] ^- =486.

Step B

Dibutyltin oxide (11 mg) and azidetrimethylsilane (55 μL) were added to a solution of the intermediate (50 mg) from Step A above in anhydrous toluene (1 mL), and the mixture was heated to 105° C. for 3 hours, Then concentrate. The residue was purified by column chromatography (30% diethyl ether/dichloromethane) to give the intermediate (50 mg; 92%). [MH] ^- =529.

Step C

1N Aqueous sodium hydroxide solution (0.5 mL) and methanol (0.3 mL) were added to a solution of the intermediate (50 mg) of the above Step B in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 24 hr. The mixture was concentrated and purified by preparative thin layer chromatography (silica, 20% methanol/dichloromethane) to yield the title compound (25 mg; 51%). [MH] ^- =515.

Example 2711

Step A

The intermediate from Example 2710, Step A (25 mg) was dissolved in anhydrous MeOH (20 mL), cooled in an ice bath, then bubbled with anhydrous hydrogen chloride gas for 1 min. Then, the reaction mixture was sealed and placed in the refrigerator (4°C) overnight. The mixture was warmed to room temperature and concentrated to give an off-white, colorless oil, to which was added ammonia (6N in MeOH, 5 mL) and the mixture was stirred at room temperature for 10 hours. After evaporation under high vacuum, the crude product was purified by flash chromatography in 5% MeOH/ _CH2Cl2 to afford the intermediate as _a colorless solid (15 mg; 53%). [MH] ⁺ =505.

Step B

The title compound from Step A above (15 mg) was dissolved in THF (2 mL) and MeOH (2 mL) containing lithium hydroxide (20 mg) and heated to 50°C for 5 hours. The reaction mixture was then concentrated under high vacuum to give a crude product which was collected, washed with water (3 x 3 mL) and dried to yield the title compound as a colorless solid (10 mg; 68%). [MH] ⁺ =493.

Example 2712

Step A

The intermediate of Example 2706 Step A (50 mg), methylhydrazine (5 mg) and triethylamine (12 mg) were heated in DMF (0.25 mL) at 40 °C for 1 h. The mixture was diluted with ethyl acetate and washed with water. The crude product was purified by column chromatography (5% methanol in dichloromethane), saponified (2 mL THF/MeOH 1:1, 0.33 mL 1N NaOH) overnight. The resulting acid was purified by chromatography (10% methanol in dichloromethane) to yield the title compound as a colorless solid (20 mg; 40%). [MH] ⁺ =493.

Example 2713

Step A

Following a procedure similar to that described in Example 2712, except using N,N-dimethylhydrazine, the title compound was obtained at 12%. [MH] ⁺ =507.

Example 2714 and Example 2715

Step A

PyBop (550 mg) was added to a solution of the intermediate from Step C of Example 2704 (323 mg), the intermediate from Step B of Preparative Example 2105 (191 mg), triethylamine (0.35 mL) in THF (5 mL) at room temperature. The reaction mixture was stirred for 1 hour, then concentrated to dryness. The solid was dissolved in ethyl acetate (20 mL), and the resulting solution was washed with 1M hydrochloric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The solution was dried over magnesium sulfate and concentrated in vacuo. The crude mixture was purified by silica gel chromatography to give two intermediates: 2-OBt product (300 mg; 50%, [MH] ⁺ = 596) and 2-indanylamino product (163 mg; 28%, [MH] ⁺ = 652 ).

Step B

Aqueous 1 M sodium hydroxide solution (0.3 mL) was added to a solution of the first title compound (2-OBt product) (36.5 mg) from Step A above in tetrahydrofuran (1 mL). After 1 hour at 40°C, the solution was neutralized with 2M aqueous sodium bisulfate (0.3 mL). The resulting solution was concentrated to dryness. The solid was triturated with tetrahydrofuran (5 mL), dried over magnesium sulfate and concentrated in vacuo to yield the title compound (21 mg; 70%) as a colorless solid. [MH] ⁺ =465.

Step C

Aqueous 1M sodium hydroxide solution (0.16 mL) was added to a solution of the second title compound (2-indanylamino product) (35 mg) from Step A above in THF (2 mL) and stirred overnight. The solution was neutralized with 2M aqueous sodium bisulfate (0.2 mL). The resulting solution was concentrated to dryness. The solid was triturated with tetrahydrofuran (5 mL), dried over magnesium sulfate and concentrated in vacuo to yield the title compound (29 mg; 87%) as a colorless solid. [MH] ⁺ =624.

Example 2716

Step A

Hydrazine (1 M in THF, 2 mL) was added to a stirred solution of the title compound from Step A of Example 2714 above (100 mg) in anhydrous THF (5 mL) and stirring was continued at room temperature for 2 hours. The solvent was then evaporated in vacuo. The crude product was purified by flash chromatography (10% acetone in dichloromethane) to afford the intermediate (77 mg; 85%). [MH] ⁺ =533.

Step B

A solution of the title compound from Step A above (30 mg) in MeOH (1 mL) and THF (2 mL) was treated with 1 N aqueous lithium hydroxide (0.5 mL) and stirred at room temperature overnight. The reaction mixture was acidified to pH 4.5 with 2N hydrochloric acid and stirred at room temperature for 15 minutes. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over _MgSO4 and evaporated. The resulting residue was purified by column chromatography (10% methanol in dichloromethane) to yield the title compound (2.2 mg; 8%). [MH] ⁺ =519.

Example 2717

Step A

Sodium tert-butoxide (14 mg) and benzenesulfonamide (24 mg) were added to a solution of the intermediate (70 mg) of Step A of Example 2714 in dioxane (1 mL), and the mixture was stirred at room temperature for 1 hour, then at 70° C. for 10 Hour. The mixture was concentrated and purified by column chromatography (silica, 30% diethyl ether/dichloromethane) to give the intermediate (40 mg; 55%). [MH] ⁺ =618.

Step B

1N Aqueous sodium hydroxide solution (0.5 mL) and methanol (0.3 mL) were added to a solution of the intermediate (40 mg) of the above Step A in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 24 hr. The mixture was concentrated and purified by preparative thin layer chromatography (silica, 15% methanol/dichloromethane) to yield the title compound (26 mg; 66%). [MH] ⁺ =604.

Example 2718

Step A

Commercially available (R)-2-amino-1-propanol (12 μL) was added to a solution of the intermediate (46 mg) of Example 2714 Step A in N,N-dimethylformamide (0.2 mL) and tetrahydrofuran (1 mL) , the mixture was stirred at room temperature for 48 hours, then concentrated to give the intermediate (50 mg). [MH] ⁺ =536.

Step B

1N Aqueous lithium hydroxide solution (0.5 mL) and methanol (0.3 mL) were added to a solution of the intermediate (50 mg) of the above Step A in tetrahydrofuran (0.3 mL), and the mixture was stirred at room temperature for 12 hr. The mixture was concentrated, acidified with 1N hydrochloric acid, and concentrated again. The mixture was purified by preparative thin layer chromatography (silica, 10% methanol/dichloromethane) to yield the title compound (20 mg; 50% yield over two steps). [MH] ⁺ =522.

Example 2719

Step A

Following a procedure similar to that described in Example 2718, except using (S)-2-amino-1-propanol, the title compound was obtained in 40% yield over two steps. [MH] ⁺ =522.

Example 2720

Step A

The intermediate from Example 2714, Step A (50 mg) was mixed with azetidine (5 mg) in anhydrous THF (1 mL) under nitrogen, and the mixture was stirred at room temperature. TLC analysis showed complete disappearance of starting material after 1 h, then MeOH (1 mL) was added followed by NaOH (1M in _H2O , 0.5 mL). The reaction mixture was further stirred at room temperature for 12 hours. The solvent was removed under reduced pressure and the remaining residue was partitioned between EtOAc (10 mL) and 1M hydrochloric acid (10 mL). The organic layer was dried over _MgSO4 , filtered and concentrated to give the crude product, which was purified by flash chromatography in 20% MeOH/ _CH2Cl2 to give the title compound (18 mg; 43%) as _a colorless solid. [MH] ⁺ =504.

Example 2721-2724

Following a procedure similar to that described in Example 2720, except using the amines shown in Table 24 below, the following compounds were prepared.

Table 24

Example 3000

Assays for Determining MMP-13 Inhibition

A typical assay for MMP-13 activity is performed in assay buffer consisting of 50 mM Tris, pH 7.5, 150 mM NaCl, ₅ mM CaCl2 and 0.05% Brij-35. 50 [mu]L aliquots of various concentrations of test compounds were prepared in assay buffer. 10 μL of 40 nM MMP-13 enzyme stock solution was added to the compound solution. Mix the mixture of enzyme and compound in assay buffer thoroughly and incubate for 20 min at room temperature. After the incubation was complete, the assay was started by adding 40 μL of 12.5 μM MMP-13 Fluorescent Substrate Stock Solution (Calbiochem Cat# 444235). A time-dependent increase in fluorescence was measured using an automatic plate multireader with excitation at 325 nm and emission at 393 nm. _IC50 values were calculated from the initial reaction rate. In Table 1 the inhibitory activity of highly potent compounds of formula I is summarized. Selectivity assays were performed in a similar manner with MMP-1, MMP-14 and TACE.

Claims (139)

1. A compound of formula (I) and its N-oxide, pharmaceutically acceptable salts and stereoisomers:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ³ is NR ²⁰ R ²¹ ; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkenyl, ^alkynyl , NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane Alkylkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or ^R80 and ^R81 are attached to them The nitrogens of are taken together to form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and said ring is optionally substituted one or more times; x is selected from 0-2. 2. The compound of claim 1, wherein ^R is selected from:

In the formula: R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; A and B are independently selected from C, N, O or S; L, M and T are independently selected from C or N; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; q is selected from 0-4; r is selected from 0-1; w is selected from 0-4; x is selected from 0-2; y is selected from 1 and 2; z is selected from 0-2; and where the dashed line optionally represents a double bond. 3. The compound of claim 2, wherein each of the R ¹⁰ and R ¹¹ groups is optionally substituted by one or more substituents independently selected from the group consisting of halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN ^, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R 11, SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC (O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , and NR ¹⁰ CO ₂ R ¹¹ . 4. The compound of claim 2, wherein ^R20 together with the nitrogen and L to which it is attached forms a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or ^NR50 , and the ring is optionally substituted. 5. The compound of claim 2, wherein when E exists, the sum of m and n is 1-4. 6. The compound of claim 2, wherein when E exists, the sum of m and n is 1-2. 7. The compound of claim 2, wherein when E is a bond, the sum of m and n is 2-5. 8. The compound according to claim 2, wherein when E is a bond, the sum of m and n is 2-3. 9. The compound of claim 2, wherein ^R is selected from:

In the formula: R is selected from C(O)NR ¹⁰ R ¹¹ , COR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , CONHCH ₃ or CON(CH ₃ ) ₂ , wherein C(O)NR ¹⁰ R ¹¹ , COR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , CONHCH ₃ and CON(CH ₃ ) ₂ are optionally substituted one or more times; ^R4 is selected from

^R is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl The radical, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted one or more times; ^R is selected from hydrogen, halogen, hydroxy, alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, haloalkyl, C(O)NR ¹⁰ R ¹¹ or O ₂ NR ¹⁰ R ¹¹ , where alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroaryl alkyl, haloalkyl, C(O)NR ¹⁰ R ¹¹ and O ₂ NR ¹⁰ R ¹¹ are optionally substituted one or more times; and r is selected from 0-1. 10. The compound of claim 2, wherein at least one ^R4 is heteroaryl. 11. compound as claimed in claim 10, it is characterized in that, ^R Selected from dioxole, imidazole, furan, thiazole, isothiazole, isoxazole, morpholine, 1,2,4-_ Oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxirane, _ Azole, 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridazine, Pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazine, tetrazole, thiazine, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1, 2,5-thiadiazole, thiatriazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, 5-thio-1,2,4-oxadiazole, sulfur Morpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4-triazole, 1,2,3 - triazoles or triazolones, which are optionally substituted. 12. The compound of claim 1, wherein ^R is selected from: In the formula: R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times; R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl; R ^a and R ^b are independently selected from hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and Haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; A and B are independently selected from C, N, O or S; L, M and T are independently selected from C or N; g and h are independently selected from 0-2; q is selected from 0-4; r is selected from 0-1; w is selected from 0-4; x is selected from 0-2; y is selected from 1 and 2; z is selected from 0-2; and where the dashed line optionally represents a double bond. 13. The compound of claim 12, wherein R ³ comprises:

14. The compound of claim 13, wherein R is selected from the group consisting of dioxole, imidazole, ^furan , thiazole, isothiazole, isoxazole, morpholine, 1,2,4-_ Oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxirane, _ Azole, 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridazine, Pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazine, tetrazole, thiazine, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1, 2,5-thiadiazole, thiatriazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, 5-thio-1,2,4-oxadiazole, sulfur Morpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4-triazole, 1,2,3 - triazoles or triazolones, which are optionally substituted. 15. The compound of claim 1, wherein R ^is selected from:

In the formula: R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein the alkyl, alkynyl and haloalkyl groups are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; B ₁ is selected from NR ¹⁰ , O or S; D, G, L, M and T are independently selected from C or N; and Z is a 5-6 membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times. 16. The compound of claim 15, wherein ^R is selected from: 17. The compound of claim 1, wherein R ^is selected from:

In the formula: R ¹² and R ¹³ are independently selected from hydrogen, alkyl or halogen, wherein the alkyl group is optionally substituted one or more times, or optionally, R ¹² and R ¹³ together form =O, =S or =NR ¹⁰ ; R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein alkyl, alkynyl and haloalkyl are optionally optionally substituted one or more times, or optionally, two R ¹⁸ groups together form =O, =S or =NR ¹⁰ ; J and K are independently selected from CR ¹⁰ R ¹¹ , NR ¹⁰ , O or S(O) _x ; A ₁ is selected from NR ¹⁰ , O or S; L and M are independently selected from C or N; q is selected from 0-4; and x is selected from 0-2. 18. The compound of claim 17, wherein ^R is selected from:

19. The compound of claim 1, wherein R ^is selected from:

In the formula: R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein the alkyl, aryl and arylalkyl is optionally substituted one or more times; R ¹⁹ is selected from hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein the alkyl, alkynyl and haloalkyl are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein said alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; D, G, L, M and T are independently selected from C or N; B ₁ is selected from NR ¹⁰ , O or S; X is selected from a bond or (CR ¹⁰ R ¹¹ ) _w E(CR ¹⁰ R ¹¹ ) _w ; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; n is selected from 0-3; q is selected from 0-4; w is selected from 0-4; x is selected from 0-2; V is a 5-8 membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl or heteroaryl, which are optionally substituted one or more times; and Z is a 5-6 membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times. 20. The compound of claim 19, wherein ^R is selected from:

In the formula R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkynyl, OH, halogen, CN, C(O)NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , OR ¹⁰ , OCF ₃ , OCHF ₂ , NR ¹⁰ CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , NR ¹⁰ SO ₂ NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , wherein the alkyl, alkynyl and haloalkyl groups are optionally substituted one or more times, or optionally, two R ¹⁸ groups together form =O, =S or =NR ¹⁰ ; and p is selected from 0-6. 21. The compound of claim 20, wherein ^R is selected from:

22. The compound of claim 1, which is a compound of formula (II):

in: R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; L, M and T are independently selected from C or N; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; q is selected from 0-4; w is selected from 0-4; x is selected from 0-2; y is selected from 1 and 2; and z is selected from 0-2. 23. The compound of claim 1 which is a compound of formula (III): In the formula: R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; L, M and T are independently selected from C or N; q is selected from 0-4; w is selected from 0-4; x is selected from 0-2; y is selected from 1 and 2; and z is selected from 0-2. 24. A compound of formula (IV) and N-oxides, pharmaceutically acceptable salts and stereoisomers thereof:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ⁰ -C ⁶ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with the carbon atoms they are bound to, and the ring is selected from a 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5-8 membered cycloalkyl ring, a 5-8 membered heterocyclic ring A base ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; F ⁸⁰ and R ⁸¹ are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; x is selected from 0-2; where the dashed line optionally represents a double bond. 25. A compound of formula (V) and N-oxides, pharmaceutically acceptable salts and stereoisomers thereof:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with the carbon atoms they are bound to, and the ring is selected from a 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5-8 membered cycloalkyl ring, a 5-8 membered heterocyclic ring A base ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R ⁸⁰ and R ⁸¹ are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; g and h are independently selected from 0-2; q is selected from 0-4; x is selected from 0-2; where the dashed line optionally represents a double bond. 26. The compound of claim 1 selected from the group consisting of:

27. The compound of claim 1, comprising: 28. The compound of claim 1, comprising:

29. The compound of claim 1, comprising:

30. The compound of claim 1, comprising:

31. The compound of claim 1, comprising:

32. The compound of claim 1, comprising:

33. The compound of claim 1, comprising:

34. The compound of claim 1, comprising:

35. The compound of claim 1, comprising:

36. The compound of claim 1, comprising:

37. The compound of claim 1, comprising:

38. The compound of claim 1, comprising: 39. The compound of claim 1, comprising: 40. The compound of claim 1, comprising:

41. The compound of claim 1, comprising:

42. The compound of claim 1, comprising: 43. The compound of claim 1, comprising:

44. The compound of claim 1, comprising:

45. The compound of claim 1, comprising:

46. The compound of claim 1, comprising:

47. The compound of claim 1, comprising:

48. The compound of claim 1, comprising:

49. The compound of claim 1, comprising:

50. The compound of claim 1, comprising:

51. The compound of claim 1, comprising: 52. A compound of formula (VI) and N-oxides, pharmaceutically acceptable salts and stereoisomers thereof:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ⁹ is selected from hydrogen, alkyl, CH(CH ₃ )CO ₂ H, halogen, (C ₀ -C ₆ )-alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-alkyl-C (O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)NH-CN, O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S (O) _y -alkyl-C(O)OR ¹⁰ , S(O) _z -alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-NR ¹⁰ R ¹¹ , C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, C(O)NR ¹⁰ -(C ₀ - C ₆ )-alkyl-aryl, CH ₂ NR ¹⁰ R ¹¹ , (CH ₂ ) _y NR ¹⁰ C(O)-alkyl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)-(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)O-alkyl , (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ C(O)O-(C ₀ -C ₆ )-alk base-heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)ONR ¹⁰ R ¹¹ , (CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl, ( CH ₂ ) _w NR ¹⁰ S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ -NR ¹⁰ -alkyl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, (CH ₂ ) _w NR ¹⁰ S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl -heteroaryl, (CH ₂ ) _w NR ¹⁰ C(O)NR ¹⁰ -SO ₂ -R ³⁰ , S(O) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-aryl, S(O ) ₂ NR ¹⁰ -(C ₀ -C ₆ )-alkyl-heteroaryl, S(O) ₂ NR ¹⁰ -alkyl, S(O) ₂ -(C ₀ -C ₆ )-alkyl-aryl , S(O) ₂ -(C ₀ -C ₆ )-alkyl-heteroaryl, O-heteroaryl or heteroaryl, wherein each R ⁹ group is optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ³⁰ is selected from alkyl or (C ₀ -C ₆ )-alkyl-aryl; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Y does not exist or is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or 6 membered aryl; L, M and T are independently selected from C or N; g and h are independently selected from 0-2; q is selected from 0-4; w is selected from 0-4; x is selected from 0-2; y is selected from 1 and 2; z is selected from 0-2. 53. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 54. A method of inhibiting MMP-13, said method comprising administering a compound of formula (I) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer thereof:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ³ is NR ²⁰ R ²¹ ; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl ^, heteroarylalkyl, alkenyl, alkynyl, NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; x is selected from 0-2. 55. A method of inhibiting MMP-13, said method comprising administering a compound of formula (IV) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer thereof:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with the carbon atoms they are bound to, and are selected from 6-membered aromatic rings, 5- or 6-membered heteroaryl rings, 5-8 membered cycloalkyl rings, 5-8 membered heterocyclyl rings, A 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; x is selected from 0-2; where the dashed line optionally represents a double bond. 56. A method of inhibiting MMP-13, said method comprising administering a compound of formula (V) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer thereof:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with the carbon atoms they are bound to, and are selected from 6-membered aromatic rings, 5- or 6-membered heteroaryl rings, 5-8 membered cycloalkyl rings, 5-8 membered heterocyclyl rings, A 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; g and h are independently selected from 0-2; q is selected from 0-4; x is selected from 0-2; where the dashed line optionally represents a double bond. 57. A method for treating a disease mediated by MMP-13, said method comprising administering an effective amount of a compound of formula (I) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer thereof to a patient in need of treatment :

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ³ is NR ²⁰ R ²¹ ; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl ^, heteroarylalkyl, alkenyl, alkynyl, NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and said ring is optionally replaced one or more times; x is selected from 0-2. 58. A method for treating a disease mediated by MMP-13, said method comprising administering an effective amount of a compound of formula (IV) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer thereof to a patient in need of treatment :

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; x is selected from 0-2; where the dashed line optionally represents a double bond. 59. A method for treating a disease mediated by MMP-13, said method comprising administering an effective amount of a compound of formula (V) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer thereof to a patient in need of treatment : In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; g and h are independently selected from 0-2; q is selected from 0-4; x is selected from 0-2; where the dashed line optionally represents a double bond. 60. The method of claim 57, wherein the disease is rheumatoid arthritis. 61. The method of claim 57, wherein the disease is osteoarthritis. 62. The method of claim 57, wherein the disease is abdominal aortic aneurysm. 63. The method of claim 57, wherein the disease is cancer. 64. The method of claim 57, wherein the disease is inflammation. 65. The method of claim 57, wherein the disease is atherosclerosis. 66. The method of claim 57, wherein the disease is multiple sclerosis. 67. The method of claim 57, wherein the disease is chronic obstructive pulmonary disease. 68. The method of claim 58, wherein the disease is rheumatoid arthritis. 69. The method of claim 58, wherein the disease is osteoarthritis. 70. The method of claim 58, wherein the disease is abdominal aortic aneurysm. 71. The method of claim 58, wherein the disease is cancer. 72. The method of claim 58, wherein the disease is inflammation. 73. The method of claim 58, wherein the disease is atherosclerosis. 74. The method of claim 58, wherein the disease is multiple sclerosis. 75. The method of claim 58, wherein the disease is chronic obstructive pulmonary disease. 76. The method of claim 59, wherein the disease is rheumatoid arthritis. 77. The method of claim 59, wherein the disease is osteoarthritis. 78. The method of claim 59, wherein the disease is abdominal aortic aneurysm. 79. The method of claim 59, wherein the disease is cancer. 80. The method of claim 59, wherein the disease is inflammation. 81. The method of claim 59, wherein the disease is atherosclerosis. 82. The method of claim 59, wherein the disease is multiple sclerosis. 83. The method of claim 59, wherein the disease is chronic obstructive pulmonary disease. 84. Use of a compound of formula (I) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer in the manufacture of a medicament for treating diseases mediated by MMP-13 enzymes:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ³ is NR ²⁰ R ²¹ ; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl ^, heteroarylalkyl, alkenyl, alkynyl, NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; x is selected from 0-2. 85. Use of a compound of formula (IV) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer in the manufacture of a medicament for treating diseases mediated by MMP-13 enzymes:

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; x is selected from 0-2; where the dashed line optionally represents a double bond. 86. Use of a compound of formula (V) or its N-oxide, a pharmaceutically acceptable salt or a stereoisomer in the manufacture of a medicament for treating diseases mediated by MMP-13 enzymes: In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; g and h are independently selected from 0-2; q is selected from 0-4; x is selected from 0-2; where the dashed line optionally represents a double bond. 87. A use of a compound of formula (I):

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ³ is NR ²⁰ R ²¹ ; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R and ^R are independently selected from hydrogen, halogen, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, heteroaryl, arylalkyl ^, heteroarylalkyl, alkenyl, alkynyl, NO ₂ , NR ¹⁰ R ¹¹ , NR ¹⁰ NR ¹⁰ R ¹¹ , NR ¹⁰ N=CR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ R ¹¹ , CN, C(O)OR ¹⁰ or fluoroalkyl, where alkyl, ring Alkyl, alkoxy, alkenyl, alkynyl and fluoroalkyl are optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; x is selected from 0-2; Wherein the drug, medicament or therapeutic agent is used in combination with the compound of formula I, and the medicament, medicament or therapeutic agent is selected from: (a) antirheumatic drugs for disease relief; (b) non-steroidal anti-inflammatory drugs; (c) COX -2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; (g) biological response modifiers; or (h) for the treatment of chemokine-mediated diseases other anti-inflammatory or therapeutic agents. 88. A use of a compound of formula (IV):

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁷ is selected from hydrogen, alkyl, cycloalkyl, halogen, R ⁴ or NR ¹⁰ R ¹¹ , wherein alkyl and cycloalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , and said ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R ⁸⁰ and R ⁸¹ are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; g and h are independently selected from 0-2; m and n are independently selected from 0-3, provided that: (1) When E exists, m and n are not both 3; (2) When E is -CH ₂ -W-, m and n are not 3; and (3) When E is a bond, m and n are not 0; p is selected from 0-6; x is selected from 0-2; wherein the dashed line optionally represents a double bond; Wherein the drug, medicament or therapeutic agent is used in combination with the compound of formula I, and the medicament, medicament or therapeutic agent is selected from: (a) antirheumatic drugs for disease relief; (b) non-steroidal anti-inflammatory drugs; (c) COX -2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; (g) biological response modifiers; or (h) for the treatment of chemokine-mediated diseases other anti-inflammatory or therapeutic agents. 89. A use of a compound of formula (V):

In the formula: R ¹ is selected from alkyl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl or CHR ²⁵ R ²¹ , wherein alkyl, cycloalkyl-alkyl, arylalkyl and heteroarylalkyl The group is optionally substituted one or more times; ^R2 is hydrogen; R ⁴ is selected from R ¹⁰ , hydrogen, alkyl, aryl, heteroaryl, halogen, CF ₃ , COR ¹⁰ , OR ¹⁰ , NR ¹⁰ R ¹¹ , NO ₂ , CN, SO ₂ OR ¹⁰ , CO ₂ R ¹⁰ , C(O)NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , SO ₂ R ¹⁰ , OC(O)R ¹⁰ , OC(O)NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(=NR ^a )NHR ^b , (C ₀ -C ₆ )-alkyl-NHC(=NR ^a )NHR ^b , (C ₀ -C ₆ ) -Alkyl-C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-C(O)-NH-CN , O-(C ₀ -C ₆ )-Alkyl-C(O)NR ¹⁰ R ¹¹ , S(O) _x -(C ₀ -C ₆ )-Alkyl-C(O)OR ¹⁰ , S(O ) _x -(C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-alkyl-C(O)NR ¹⁰ -(C ₀ -C ₆ )-alkane Group-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)R ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)OR ¹⁰ , (C ₀ -C ₆ )-Alkyl-NR ¹⁰ -C(O)-NR ¹⁰ R ¹¹ , (C ₀ -C ₆ )-Alkyl- NR ¹⁰ -SO ₂ NR ¹⁰ R ¹¹ , wherein each R ⁴ group is optionally substituted by one or more R ¹⁴ groups; R ⁵ is selected from hydrogen, alkyl, C(O)NR ¹⁰ R ¹¹ , aryl, arylalkyl, SO ₂ NR ¹⁰ R ¹¹ , C(O)OR ¹⁰ or CN, wherein alkyl, aryl and aryl Alkyl is optionally substituted one or more times; R ⁸ is selected from hydrogen, alkyl, OR ¹⁰ , NR ¹⁰ R ¹¹ , CN, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, aryl ylalkyl, cycloalkyl-alkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; ^R and ^R are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S or NR ⁵⁰ , wherein the ring is optionally substituted one or more times; ^R is selected from hydrogen, alkyl, arylalkyl, cycloalkyl-alkyl, heteroarylalkyl, heterocyclylalkyl or halogen, wherein alkyl, arylalkyl, cycloalkyl-alkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R ¹⁵ and R ¹⁶ form a ring together with their bonded carbon atoms, and the ring is selected from 6-membered aromatic ring, 5- or 6-membered heteroaryl ring, 5-8 membered cycloalkyl ring, 5-8 membered heterocyclic group ring, a 5-8 membered cycloalkenyl ring or a 5-8 membered heterocycloalkenyl ring, wherein the ring is optionally substituted by one or more ^R groups; ^R is selected from hydrogen or alkyl, wherein alkyl is optionally substituted one or more times; ^R is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, wherein said bicyclic or tricyclic fused ring system is optionally substituted one or more times; R ²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR ¹⁰ R ¹¹ or haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; R ⁵⁰ is selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R ⁸⁰ , C(O)NR ⁸⁰ R ⁸¹ , SO ₂ R ⁸⁰ or SO ₂ NR ⁸⁰ R ⁸¹ , wherein alkyl, aryl and heteroaryl is optionally substituted one or more times; ^R80 and ^R81 are independently selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl , aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkane alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and aminoalkyl are optionally substituted one or more times, or ^R and ^R are combined with their The attached nitrogens together form a 3-8 membered ring containing carbon atoms and optionally containing heteroatoms selected from O, S(O) _x , -NH or -N(alkyl), and the ring is optionally replace one or more times; R ^a and R ^b are independently selected from: hydrogen, CN, alkyl, haloalkyl, S(O) _x NR ¹⁰ R ¹¹ , S(O) _x R ¹⁰ or C(O)NR ¹⁰ R ¹¹ , wherein alkyl and haloalkyl is optionally substituted one or more times; E is selected from the group consisting of bond, CR ¹⁰ R ¹¹ , O, NR ⁵ , S, S=O, S(=O) ₂ , C(=O), N(R ¹⁰ )(C=O), (C=O) N(R ¹⁰ ), N(R ¹⁰ )S(=O) ₂ , S(=O) ₂ N(R ¹⁰ ), C=N-OR ¹¹ , -C(R ¹⁰ R ¹¹ )C(R ¹⁰ R ¹¹ )-, -CH ₂ -W- or

W is selected from O, NR ⁵ , S, S=O, S(=O) ₂ , N(R ¹⁰ )(C=O), N(R ¹⁰ )S(=O) ₂ or S(=O) ₂ N(R ¹⁰ ); U is selected from C(R ⁵ R ¹⁰ ), NR ⁵ , O, S, S=O or S(=O) ₂ ; Q is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl or 6 membered aryl; g and h are independently selected from 0-2; q is selected from 0-4; x is selected from 0-2; wherein the dashed line optionally represents a double bond; Wherein the drug, medicament or therapeutic agent is used in combination with the compound of formula I, and the medicament, medicament or therapeutic agent is selected from: (a) antirheumatic drugs for disease relief; (b) non-steroidal anti-inflammatory drugs; (c) COX -2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; (g) biological response modifiers; or (h) for the treatment of chemokine-mediated diseases other anti-inflammatory or therapeutic agents. 90. The application according to claim 87, wherein the antirheumatic drug for relieving the disease is selected from methotrexate, azathioprine, leflunomide, penicillamine, gold salt, mycophenolate mofetil, Ethyl motil or cyclophosphamide. 91. The use according to claim 87, wherein the non-steroidal anti-inflammatory drug is selected from piroxicam, ketoprofen, naproxen, indomethacin or ibuprofen. 92. The use according to claim 87, wherein the COX-2 selective inhibitor is selected from rofecoxib, celecoxib or valdecoxib. 93. The use according to claim 87, wherein the COX-1 inhibitor is piroxicam. 94. The application according to claim 87, wherein the immunosuppressant is selected from methotrexate, cyclosporin, leflunomide, tacrolimus, rapamycin or sulfasalazine pyridine. 95. The use according to claim 87, wherein the steroid is selected from paramethasone, prednisone, cortisone, prednisolone or dexamethasone. 96. The application according to claim 87, wherein the biological response modifier is selected from anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10 or anti- Adhesive molecules. 97. The application according to claim 87, wherein said other anti-inflammatory agents or therapeutic agents are selected from: p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, Thalidomide amines, leukotriene inhibitors, or other small molecule inhibitors of pro-inflammatory cytokine production. 98. The application according to claim 88, wherein the antirheumatic drug for relieving the disease is selected from methotrexate, azathioprine, leflunomide, penicillamine, gold salt, mycophenolate mofetil ethyl ester or cyclophosphamide. 99. The use according to claim 88, wherein the non-steroidal anti-inflammatory drug is selected from piroxicam, ketoprofen, naproxen, indomethacin or ibuprofen. 100. The use according to claim 88, wherein the COX-2 selective inhibitor is selected from rofecoxib, celecoxib or valdecoxib. 101. The use according to claim 88, wherein the COX-1 inhibitor is piroxicam. 102. The use according to claim 88, wherein the immunosuppressant is selected from methotrexate, cyclosporine, leflunomide, tacrolimus, rapamycin or sulfasalazine pyridine. 103. The use of claim 88, wherein the steroid is selected from paramethasone, prednisone, cortisone, prednisolone or dexamethasone. 104. The application according to claim 88, wherein the biological response modifier is selected from anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10 or anti- Adhesive molecules. 105. The application according to claim 88, wherein said other anti-inflammatory agents or therapeutic agents are selected from: p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, Thalidomide amines, leukotriene inhibitors, or other small molecule inhibitors of pro-inflammatory cytokine production. 106. The application according to claim 89, wherein the antirheumatic drug for relieving diseases is selected from methotrexate, azathioprine, leflunomide, penicillamine, gold salt, mycophenolate mofetil ethyl ester or cyclophosphamide. 107. The use according to claim 89, wherein the non-steroidal anti-inflammatory drug is selected from piroxicam, ketoprofen, naproxen, indomethacin or ibuprofen. 108. The use according to claim 89, wherein the COX-2 selective inhibitor is selected from rofecoxib, celecoxib or valdecoxib. 109. The use according to claim 89, wherein the COX-1 inhibitor is piroxicam. 110. The use according to claim 89, wherein the immunosuppressant is selected from methotrexate, cyclosporine, leflunomide, tacrolimus, rapamycin or sulfasalazine pyridine. 111. The use according to claim 89, wherein the steroid is selected from paramethasone, prednisone, cortisone, prednisolone or dexamethasone. 112. The application according to claim 89, wherein the biological response modifier is selected from anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10 or anti- Adhesive molecules. 113. The application according to claim 89, wherein said other anti-inflammatory agents or therapeutic agents are selected from: p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, Thalidomide amines, leukotriene inhibitors, or other small molecule inhibitors of pro-inflammatory cytokine production. 114. A pharmaceutical composition, which contains an effective amount of the compound of claim 1, a pharmaceutically acceptable carrier and a drug, medicament or therapeutic agent selected from the group consisting of: (a) antirheumatic drugs for disease relief; ( b) NSAIDs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; ) Other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases. 115. The pharmaceutical composition according to claim 114, wherein the COX-2 selective inhibitor is selected from rofecoxib, celecoxib or valdecoxib. 116. The pharmaceutical composition of claim 114, wherein the COX-1 inhibitor is piroxicam. 117. A pharmaceutical composition, which contains an effective amount of the compound of claim 24, a pharmaceutically acceptable carrier and a drug, medicament or therapeutic agent selected from the group consisting of: (a) antirheumatic drugs for disease relief; ( b) NSAIDs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; ) Other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases. 118. The pharmaceutical composition according to claim 117, wherein the COX-2 selective inhibitor is selected from rofecoxib, celecoxib or valdecoxib. 119. The pharmaceutical composition of claim 117, wherein the COX-1 inhibitor is piroxicam. 120. A pharmaceutical composition, which contains an effective amount of the compound of claim 25, a pharmaceutically acceptable carrier and a drug, medicament or therapeutic agent selected from the group consisting of: (a) antirheumatic drugs for disease relief; ( b) NSAIDs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; ) Other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases. 121. The pharmaceutical composition of claim 114, wherein the COX-2 selective inhibitor is selected from rofecoxib, celecoxib or valdecoxib. 122. The pharmaceutical composition of claim 114, wherein the COX-1 inhibitor is piroxicam. 123. Use of a compound selected from the following group or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating MMP-13 enzyme-mediated diseases:

124. The use of the compound according to claim 123, wherein a drug, medicament or therapeutic agent is used in combination with the compound, and the drug, medicament or therapeutic agent is selected from: (a) disease-modifying (b) NSAIDs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressants; (f) steroids; (g) biological response modifiers or (h) other anti-inflammatory or therapeutic agents for the treatment of chemokine-mediated diseases. 125. The method of claim 57, wherein the disorder is pain. 126. The method of claim 57, wherein the disease is inflammatory pain. 127. The method of claim 57, wherein the disorder is bone pain. 128. The method of claim 57, wherein the disorder is arthralgia. 129. The method of claim 58, wherein the disorder is pain. 130. The method of claim 58, wherein the disease is inflammatory pain. 131. The method of claim 58, wherein the disorder is bone pain. 132. The method of claim 58, wherein the disorder is arthralgia. 133. The method of claim 59, wherein the disorder is pain. 134. The method of claim 59, wherein the disease is inflammatory pain. 135. The method of claim 59, wherein the disorder is bone pain. 136. The method of claim 59, wherein the disorder is arthralgia. 137. The method of claim 57, wherein the disease is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic Obstructive pulmonary disease, eye disease, neuropathy, psychosis, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, aging, dementia, cardiomyopathy, renal tubular damage, diabetes mellitus, psychosis, movement disorders, Dyschromatosis, deafness, inflammatory and fibrotic syndrome, bowel syndrome, allergy, Alzheimer's disease, arterial plaque formation, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, Trauma, chemical or oxidative tissue exposure, pain, inflammatory pain, bone or joint pain. 138. The method of claim 58, wherein the disease is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic Obstructive pulmonary disease, eye disease, neuropathy, psychosis, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, aging, dementia, cardiomyopathy, renal tubular damage, diabetes mellitus, psychosis, movement disorders, Dyschromatosis, deafness, inflammatory and fibrotic syndrome, bowel syndrome, allergy, Alzheimer's disease, arterial plaque formation, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, Trauma, chemical or oxidative tissue exposure, pain, inflammatory pain, bone or joint pain. 139. The method of claim 59, wherein the disease is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic Obstructive pulmonary disease, eye disease, neuropathy, psychosis, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, aging, dementia, cardiomyopathy, renal tubular damage, diabetes mellitus, psychosis, movement disorders, Dyschromatosis, deafness, inflammatory and fibrotic syndrome, bowel syndrome, allergy, Alzheimer's disease, arterial plaque formation, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, Trauma, chemical or oxidative tissue exposure, pain, inflammatory pain, bone or joint pain.