KR20130042590A - Matrix metalloproteinase inhibitors - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to certain hydroxy propionic acid derivatives and methods of their synthesis, and also to pharmacological compositions comprising the compounds of the present invention, and to the overexpression and overactivation of matrix metalloproteinases using the compounds. Asthma, rheumatoid arthritis, COPD, rhinitis, degenerative arthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, restenosis and ischemic heart failure It provides a method for treating causing endovascular hyperplasia, stroke, kidney disease, tumor metastasis and other inflammatory diseases.

Description

Substrate metalloproteinase inhibitors {MATRIX METALLOPROTEINASE INHIBITORS}

The present invention relates to hydroxy propionic acid derivatives and methods of their synthesis. The invention also relates to a pharmacological composition comprising a compound of the invention, and asthma, rheumatoid arthritis, COPD characterized by overexpression and overactivation of matrix metalloproteinases using the compound. , Rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, periodontitis endovascular hyperplasia that causes perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, restenosis and ischemic heart failure Provided are methods for treating neointimal proliferation, stroke, renal disease, tumor metastasis and other inflammatory disorders.

Metalloproteinases (MMPs) are a superfamily of naturally occurring proteinases (enzymes) found in most mammals. The superfamily consists of at least 26 zinc-containing enzymes produced by many cell types, which share structural and functional properties. Proteinases are based on structural and functional considerations, including collagenase (MMP-1, 8 and 13), gelatinase (MMP-2 and 9), metalloelastase. ) (MMP-12), MT-MMP (MMP-14, 15, 16, 17, 24 and 25), matrilysin (MMP-7 and 26), stromelysin (MMP-3) , 10 and 11) and different families and subfamily such as sheddase (TACE and ACE) such as TNF-converting enzymes (Vartak et al., J. Drug Targeting , 15 , p. 1-20 (2007); And Hopper, FEBS , 354 , p. 1-6) (1994)).

Metalloproteinases are thought to be important in physiological and disease processes involved in remodeling such as airway disease, embryonic development, bone formation, and remodeling of the uterus during menstruation. One of the major biological functions of MMP is to catalyze the breakdown of connective tissue or extracellular matrix by its ability to hydrolyze various elements of tissue or matrix. Apart from their role in degrading their connective tissue, MMPs are involved in the activation of the zymogen (progenitor) form of other MMPs, thereby inducing MMP activation. They are also involved in the biosynthesis of TNF-alpha in relation to many pathological conditions.

MMP-9, which belongs to the gelatinase family, plays a major role in chronic inflammatory diseases such as COPD, asthma and rheumatoid arthritis. Concentrations of MMP-9 are reported to increase in diseases such as asthma, interstitial pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD). It became. Because of their proteolytic ability, MMP-9 is involved in tissue remodeling of the airways and lungs in malignant asthma and chronic inflammatory diseases such as COPD. MMP-9 is also likely to be physiologically important because of its ability to modulate the digestion of extracellular matrix elements and the ability of other protease and cytokine activities. MMP-9 is secreted into neutrophils, macrophages and osteoclasts, which are readily induced by cytokines and growth factors, and play a role in various physiological and pathological processes.

MMP-12 is also known as macrophage elastase or metalloelastase and is expressed in activated macrophages, secreted from alveolar macrophages in smokers and secreted from foam cells of atherosclerotic lesions. MMP-12 knockout mouse studies have shown to develop into significant emphysema, thus supporting their role in COPD. MMP-9 (gelatinase B, collagenase of 92 kDa type IV) is a member of the family of MMPs that are secreted as proenzymes and then activated in the body via a protease cascade.

Overexpression or overactivation of MMPs, or the imbalance between MMPs and natural (eg endogenous) tissue inhibitors of matrix metalloproteinases (TIMPs) may be characterized by disruption of the disease characterized by connective tissue or extracellular matrix. It is related to the onset.

Inhibition of the activity of one or more MMPs may be beneficial for the treatment of various inflammations, autologous and allergic diseases such as joint inflammation, GI tract inflammation, skin inflammation, collagen remodeling, wound healing disorders, and the like.

The design and therapeutic applications of MMP inhibitors may require that the requirements of the molecule to be an effective inhibitor of the enzymes of the MMP family are functional groups capable of chelating the active site Zn ⁺² ions (e.g. carboxylic acid, hydroxamic acid or Observe that it has been found that a drill) (Whittaker et al, Chem Rev , 99;.... p 2735-76 (1999)).

WO 2004/014310 discloses methods of preparing peripheral opioid antagonist compounds useful for gastrointestinal motility disorders. WO 02/060888 discloses a process for preparing chromanylbenzoic acid. WO 94/20455 discloses styryl derivatives, for example PDE-IV inhibitors, useful for the prevention and treatment of diseases such as asthma with unwanted inflammatory responses or muscle spasms. WO 2004/110974 discloses compounds and their physiologically functional derivatives as inhibitors of matrix metalloproteinase enzymes. WO 2004/113279 discloses inhibitors of matrix metalloproteinases. WO 2005/026120 discloses compounds described as inhibitors of matrix metalloproteinases. US patent application 2003/0139453 discloses difluorobutyric acid compounds useful for treating diseases associated with zinc metalloproteinase activity. WO 2006/090235 discloses 5-phenyl-pentanoic acid derivatives described as matrix metalloproteinase inhibitors for the treatment of asthma and other diseases. WO 2008/023336 discloses β-hydroxy and amino-substituted carboxylic acids, which act as substrate metalloproteinase inhibitors.

For example, studies have been conducted on the identification of selective inhibitors for several MMP subtypes. MMP inhibitors with improved selectivity will avoid potential side effects associated with the inhibition of MMPs that are independent of the onset of the disease to be treated.

Furthermore, the use of more selective MMP inhibitors can further lower the dosage of inhibitors for the treatment of diseases, which are divided into multiple MMPs in the body after infusion. In addition, the administration of smaller amounts of the compound will improve the range of safety between the dosage of inhibitor required for therapeutic activity and the dosage of inhibitor for which toxicity is observed.

Many drugs exist as asymmetric three-dimensional molecules such as chiral compounds and will therefore have several optical isomers depending on the number of chiral centers present. An important point when evaluating new chemical entities with chiral centers as a single isomer is to understand their effects on pharmacological and toxicological aspects. Often there are pharmadynamics, pharmakinetics and / or toxicological differences between enantiomers / diastereomers. Although natural physiological mediators based on their target environment are achiral, their receptors / enzymes are preferred only for one selectively pure enantiomer of agonist, antagonist and inhibitor. Can be represented. From a pharmacokinetic point of view, chirality can affect drug absorption, distribution, mechanism of action and elimination. Pure single isomers also have advantages in terms of their pharmacodynamic variables, allowing the development of such molecules as drug candidates. Chirality is also known to have an important influence on the physicochemical properties and crystallinity of chiral molecules, which in turn have a major impact on the pharmacodynamics and the likelihood of development. Apart from the foregoing, in order to avoid physiological, pharmacodynamic and toxicological problems arising from the interaction of undesirable target molecules with unwanted isomers, regulatory principles lead to the development of a single isomer, preferably as a drug candidate.

In this context, synthetic strategies to prepare pure single isomers offer advantages over the analytical techniques of isomeric separation, in terms of cost and efficiency, as well as the ability to produce larger amounts of compounds for sophisticated pharmaceutical testing. Thus, compounds which are single chiral isomers according to the present invention have improved efficacy, improved pharmacodynamic and / or improved physicochemical properties compared to racemic compounds.

The present invention is to overcome the problems encountered in the art.

The present invention provides several hydroxy propionic acid derivatives which act as substrate metalloproteinase inhibitors, and pharmacological compositions comprising the compounds according to the invention and their corresponding synthetic methods. The present invention provides a matrix metalloproteinase useful as an effective therapeutic or prophylactic agent for the treatment of various inflammations, autoimmune and allergic diseases and other inflammatory diseases characterized by overexpression and overactivation of metalloproteinases using the compounds. It relates to an inhibitor.

The present invention represents a novel class of compounds which are dual MMP-9 / 12 inhibitors and have a desirable activity profile. Compounds of the invention have advantageous potency and / or selectivity.

A pharmacological composition comprising the compound is provided with a pharmacologically acceptable carrier or diluent, which can be used for the treatment and prevention of inflammatory or autoimmune diseases. The pharmacological composition may be administered or coadministered by a wide range of routes including, for example, oral, topical, rectal, intranasal or parental routes. Can be. The composition may be administered in slow release dosage form or together.

Although specific enantiomers are described by way of example, racemic compounds, diastereomers, pharmacologically acceptable salts and pharmacologically acceptable solvates having the same active form are also provided. Also provided is a pharmacological composition comprising the compound with an optionally included excipient.

An effective therapeutic dose of one or more compounds of the present invention may include one or more other therapeutic agents, such as other anti-inflammatory agents, beta agonists, anti-hypertensive agents, immunosuppressive agents, and anti-infective agents. -infective agent).

Other objects of the present invention will be described by the following detailed description, some of which will become apparent from the detailed description of the invention or be learned by the practice of the invention.

In one aspect, the present invention provides a compound having a structure of Formula 1, wherein the compound comprises a racemic compound thereof, enantiomers and diastereomers or a pharmacologically acceptable salt thereof,

[In Formula 1,

는 페닐, 플루오로페닐, 헤테로아릴 또는 헤테로시클릴로부터 선택될 수 있고;remind

Can be selected from phenyl, fluorophenyl, heteroaryl or heterocyclyl;

U is from a bond, —NH—, —C (═O) —, — (CH ₂ ) _n −, —C (═S) —, —O—, —SO ₂ —, or —S— N may be 0 or an integer between 1 and 2;

V may be selected from a bond, -NH-, -C (= 0)-, -C (= S)-or -S0 _2- ,

W may be selected from a bond, —NH—, —C (═O) —, — (CH ₂ ) _n −, —C (═S) —, —O—, —S— or —S 0 ₂ — ;

는 아릴, 시클로알킬, 헤테로아릴 또는 헤테로시클릴기로부터 선택될 수 있으며, 상기의 각각은 R¹으로부터 독립적으로 선택되는 하나 이상의 치환기에 의하여 추가로 치환될 수 있고;remind

Can be selected from aryl, cycloalkyl, heteroaryl or heterocyclyl groups, each of which can be further substituted by one or more substituents independently selected from R ¹ ;

R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= O) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n- NHC (= 0) -R _f ,-(CH ₂ ) _n -OC (= 0) NR _f R _q , (CH ₂ ) _n -NHC (= 0) -NR _f R _q ,-(CH ₂ ) _n- OC (= O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n S (= O) _m -NR _f R _q (where R _f and R _q is independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is 0 to 2 Is an integer of;

는 헤테로아릴 또는 헤테로시클릴로부터 선택될 수 있음]remind

May be selected from heteroaryl or heterocyclyl]

In another aspect, the present invention provides a compound having a structure of Formula 2, wherein the compound comprises a racemic compound, enantiomers and diastereomers thereof or a pharmacologically acceptable salt thereof:

[In Formula 2,

는 페닐, 플로오로페닐, 헤테로아릴 또는 헤테로시클릴로부터 선택될 수 있고;remind

Can be selected from phenyl, fluorophenyl, heteroaryl or heterocyclyl;

L ¹ is a bond,-(CH ₂ ) _n- , -NHCO (CH ₂ ) _n -,-(CH ₂ ) _n C (= 0) NH-, -NHC (= 0) NH-, -SO ₂ NH -, -NHSO _2- , -SO _2- , -NHC (= O) (O)-, -O- (CH ₂ ) _n -,-(CH ₂ ) _n -O-,-(CH ₂ ) _n OC (═O) NH—, —C (═S) NH—, —NHC (═S) — or —NHC (═S) NH—, and n can be 0 or an integer from 1 to 2;

는 아릴, 시클로알킬, 헤테로아릴 또는 헤테로시클릴로부터 선택될 수 있고, 그의 각각은 R¹으로부터 선택되는 하나 이상의 치환기로 치환될 수 있으며;remind

May be selected from aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be substituted with one or more substituents selected from R ¹ ;

R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= O) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n- NHC (= O) -R _f ,-(CH ₂ ) _n -OC (= O) NR _f R _q , (CH ₂ ) _n NHC (= O) -NR _f R _q ,-(CH ₂ ) _n -OC (= O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n -S (= O) _m -NR _f R _q (R _f and R above _q is independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is 0 to 2 Is an integer of;

는 헤테로아릴 또는 헤테로시클릴로부터 선택될 수 있음]remind

May be selected from heteroaryl or heterocyclyl]

However, in another aspect, the invention provides a compound of formula 3, wherein the compound comprises a racemic compound, enantiomers and diastereomers thereof or a pharmacologically acceptable salt thereof,

[In Formula 3,

는 하기의 화학식으로부터 선택되는 모노, 비 또는 폴리시클릭 헤테로아릴 또는 헤테로시클릴로부터 선택될 수 있고;remind

Can be selected from mono, bi or polycyclic heteroaryl or heterocyclyl selected from the following formulas;

R ¹ is as defined above and v may be 0 or an integer from 1 to 4;

R _a may be hydrogen or fluorine;

는 상기에서 정의한 바와 같음]L ¹ and

Is as defined above]

In another aspect, the present invention provides a compound of Formula 4 below, wherein the compound comprises a racemic compound thereof, enantiomers and diastereomers thereof, or a pharmacologically acceptable salt thereof,

[In Formula 4,

L ^1a is selected from S (O) _n , NHCO (CH ₂ ) _n and NHCO (O);

및

는 상기에서 정의한 바와 같음] Ra,

And

Is as defined above]

Enantiomers, diastereomers, rotamers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmacologically acceptable solvates, prodrugs, and the same type of activity of the compounds And metabolites, enantiomers, diastereomers, structural isomers, N-oxides, polymorphs, solvates or pharmacologically thereof, together with pharmacologically acceptable carriers and optionally excipients Provided is a pharmacological composition comprising an acceptable salt.

In one embodiment, the present invention may include a compound of Formula 1, wherein the compound comprises a racemic compound thereof, enantiomers and diastereomers thereof, or a pharmacologically acceptable salt thereof, wherein the compound is an example. For example, it may include, but is not limited to:

(2S) -2-[(S)-{4-[(4-chlorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (Compound 1);

(2S) -2-[(S)-{4-[(4-chlorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (Compound 2);

(2S) -2-[(S)-{4-[(3,4-difluorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 3);

(2S) -2-[(S)-{4-[(2,3-dichlorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 4);

(2S) -2-[(S)-{4-[(2,4-dimethylphenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 5);

(2S) -2-[(S)-{4-[(4-fluorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 6);

(2S) -2-[(S)-{4-[(3,4-difluorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 7);

2- [4-[(2,3-dichlorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) Butanoic acid (compound 8);

(2S) -2-[(S)-{4-[(2,4-dimethylphenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 9);

(2S) -2-[(S)-(4-{[(4-ethylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 10);

(2S) -2-[(S)-(4-{[(4-chlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 11);

(2S) -2-[(S)-(4-{[(3,4-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 12);

(2S) -2-[(S) -hydroxy (4-{[(4-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 13);

(2S) -2-[(S) -hydroxy (4-{[(3-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 14);

(2S) -2-[(S) -hydroxy (4-{[(4-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 15);

(2S) -2-[(S)-(4-{[(4-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 16);

(2S) -2-{(S) -hydroxy [4-({[4-methoxy-3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 17);

(2S) -2-[(S) -hydroxy (4-({[5-methyl-1,2-oxazol-3-yl) carbonyl] amino} phenyl) methyl] -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 18);

(2S) -2-[(S)-(4-{[(3-chloro-4-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1, 2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 19);

(2S) -2-[(S) -hydroxy {4-[(phenylcarbonyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 20);

(2S) -2-[(S) -hydroxy (4-{[(4-propylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 21);

(2S) -2-[(S) -hydroxy {4-[(phenoxycarbonyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 22);

(2S) -2-[(S) -hydroxy {4-[(phenylacetyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H)- I) butanoic acid (compound 23);

(2S) -2-[(S)-(4-{[(2,4-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 24);

(2S) -2-[(S) -hydroxy (4-{[(2-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 25);

(2S) -2-[(S)-(4-{[(2-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 26);

(2S) -2-[(S)-(4-{[(3-chlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 27);

(2S) -2-[(S) -hydroxy (4-{[(3-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 28);

(2S) -2-[(S)-(4-{[(3-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 29);

(2S) -2-[(S)-(4-{[(2,6-dimethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 30);

(2S) -2-[(S)-{4-[(cyclopentylcarbonyl] amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 31);

(2S) -2-[(S) -hydroxy (4-{[(2,4,5-trifluoro-3-methoxyphenyl) carbonyl] amino} phenyl} methyl] -4- (4- Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 32);

(2S) -2-[(S) -hydroxy (4-{[(2,3,4-trifluorophenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 33);

(2S) -2-{(S) -hydroxy [4-({[2- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 34);

(2S) -2-[(S)-(4-{[(3,5-dimethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 35);

(2S) -2-[(S)-(4-{[(2,3-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 36);

(2S) -2-[(S)-(4-{[(3,5-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 37);

(2S) -2-[(S)-(4-{[(2,4-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 38);

(2S) -2-[(S)-(4-{[(2,6-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 39);

(2S) -2-[(S) -hydroxy (4-{[(2-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 40);

(2S) -2-[(S)-{4-[(cyclohexylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 41);

(2S) -2-[(S)-(4-{[(4-ethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 42);

(2S) -2-[(S)-(4-{[(3,4-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 43);

(2S) -2-{(S) -hydroxy [4-({[4- (trifluoromethoxy) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 44);

(2S) -2-{(S) -hydroxy [4-({[3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 45);

(2S) -2-[(S)-[4-({[2-fluoro-4- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] (hydroxy) methyl] -4- (4 Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 46);

(2S) -2-[(S)-(4-{[(3-chloro-2,6-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 47);

(2S) -2-{(S) -hydroxy [4-({[4- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 48);

(2S) -2-[(S)-(4-{[(2,5-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 49);

(2S) -2-[(S)-(4-{[(2,3-difluoro-4-methylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo- 1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 50);

(2S) -2-[(S)-[4-({[4-fluoro-3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] (hydroxy) methyl] -4- (4 Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 51);

(2S) -2-[(S)-{4-[(cyclopropylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 52);

(2S) -2-[(S)-(4-{[(2-ethylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 53);

(2S) -2-[(S) -hydroxy (4-{[(4-methoxyphenyl) acetyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 54);

(2S) -2-[(S)-{4-[(cyclobutylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 55);

(2S) -2-{(S) -hydroxy [4- (4-methoxyphenoxy) phenyl] methyl} -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 56);

(2S) -2-[(S)-[4- (3-chloro-4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 57);

(2S) -2-[(S)-[4- (4-chloro-3-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 58);

(2S) -2-[(S)-[4- (4-chloro-2-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 59);

(2S) -2-[(S)-[4- (4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 ( 4H) -yl) butanoic acid (compound 60);

(2S) -2-[(S)-[4- (3,4-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 61);

(2S) -2-[(S)-[4- (2-chlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 62);

(2S) -2-[(S)-[4- (3-chlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 63);

(2S) -2-[(S)-[4- (2,6-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 64);

(2S) -2-[(S)-[4- (2,5-dichlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 65);

(2S) -2-[(S)-[4- (2-chloro-4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 66);

(2S) -2-{(S) -hydroxy [4- (3-methoxyphenoxy) phenyl] methyl} -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 67);

(2S) -2-[(S)-[4- (2-chloro-4-methoxyphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 68);

(2S) -2-[(S)-[4- (2,4-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 69);

(2S) -2-[(S)-[3-fluoro-4- (4-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 70);

(2S) -2-[(S)-[3-fluoro-4- (3-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 71);

(2S) -2-[(S)-[4- (3,4-dimethylphenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 72);

(2S) -2-[(S)-[4- (3,4-dichlorophenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 73);

(2S) -2-[(S)-[4- (4-tert-butylphenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 74); And

(2S) -2-[(S)-[3-fluoro-4- (4-methoxyphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 75).

In another aspect, provided herein is a pharmacological composition comprising a therapeutically effective amount of one or more compounds described herein and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another aspect, the present disclosure provides a compound according to Formula 1, 2, 3 and 4 above for medical use.

In another aspect, the present disclosure provides a compound according to Formula 1, 2, 3 and 4 for the treatment or prophylaxis of various inflammatory and allergic diseases comprising administering the compound to a mammal in need thereof. .

In another aspect, the present disclosure provides a compound according to Formula 1, 2, 3 and 4, wherein the various inflammatory and allergic diseases are asthma, rheumatoid arthritis, COPD, rhinitis, degenerative arthritis, psoriatic arthritis, psoriasis, lung Fibrosis, pneumonia, acute respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, restenosis and endovascular hyperplasia leading to ischemic heart failure, stroke, kidney disease or tumor metastasis.

In another aspect, the invention relates to a combination of a therapeutically effective amount of a compound of Formula 1, 2, 3, 4 and one or more other therapeutic agents, for use in the treatment of various inflammatory and allergic diseases. Examples of such therapeutic agents include, but are not limited to:

1) Experimental or commercial anti-inflammatory agents, i.e. (i) nonsteroidal anti-inflammatory pyroxicam, diclofenac, propionic acid, penamate, pyrazolone, salicylate ), Phosphodiesterase inhibitors including PDE-4 inhibitors, p38 MAP Kinase / Cathepsin inhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase, and ella Steine inhibitors, beta-2 integrin antagonists, cell adhesion inhibitors (especially ICAMs), adenosine 2a agonists, (ii) leukotriene LTC4 / LTD4 / LTE4 / LTB4-inhibitors, 5-lipox Lipoxygenase inhibitors and PAF-receptor antagonists, (i) Cox-2 inhibitors, (i) other MMP inhibitors, (i) interleukin-I inhibitors, (i) alclometasone, and amcinonide, amelometasone, beclomethasone, betalometasone, beta Betamethasone, budesonide, ciclesonide, clobetasol, cloticasone, cyclomethasone, cyclomethasone, deflazacort, deprodone (deprodone), dexbudesonide, diflorasone, difluprednate, fluticasone, flunisolide, halomethasone, haloferredone (halometasone) haloperedone, hydrocortisone, methylprednisolone, mometasone, prednicarbate, prednisolone, rimexolone, thixocortol, triamcinolone (triamcinolone), ulobetasol, rofleponide, GW 215864, KSR 592, ST-126, dexamethasone, and their pharmacologically acceptable salts, solvates. Preferred corticosteroids include, for example, flunidolide, mometasone, ciclesonide, and dexamethasone.

2) Experimental or commercial beta agonists, eg (iii) suitable β2-agonists, for example one or more albuterol, salbutamol, biltolterol, pirbuterol ), Levosalbutamol, tulobuterol, terbutaline, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol , Carmoterol, arformoterol, formoterol and their pharmacologically acceptable salts or solvates, one or more β2-agonists are selected from or It was later discovered. (Ii) β2-agonists are described, for example, in US Pat. Nos. 3,705,233, 3,644,353, 3,642,896, 3,700,681, 4,579,985, 3,994,974, 3,937,838, 4,419,364, 5,126,375, 5,243,0,5,243 One or more compounds described in US Pat. Nos. 4,992,474 and 4,011,258.

3) antihypertensives, (i) ACE inhibitors such as enalapril, lisinopril, valsartan, telmisartan, and quinapril, (ii) Angiotensin II receptor antagonists and agonists such as losartan, candesartan, irbesartan, valsartan and eprosartan, ) β-blockers, and (iii) calcium channel blockers;

4) immunosuppressants, such as cyclosporine, azathioprine and methotrexate, anti-inflammatory corticosteroids; And

5) anti-infective agents (eg antibiotics, antiviral agents).

Definition of Terms

As used herein, the following definitions apply to terms.

"Alkyl" refers to a straight or branched, fully saturated hydrocarbon chain having 1 to 20 carbon atoms, optionally substituted with one or more halo atoms. This term refers to functional groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, n-tetradecyl, trifluoromethyl, chloroethyl, etc. Examples can be given.

"Alkenyl" refers to a branched or unbranched unsaturated hydrocarbon group containing at least one double bond, preferably 2 to 20 carbon atoms, unless otherwise indicated as cis or trans structure. Examples of alkenyl groups include ethenyl, 2-propenyl and isopropenyl.

"Cycloalkyl" refers to a non-aromatic ring group having 3 to 20 ring carbon atoms, forming 1 to 3 rings, and optionally comprising one or more olefinic bonds. Polycyclic ring systems are in spiral, fused or bridged alignment. Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, adamantyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2 .2] octane, tricycles [ 3.3.1.1] decane and the like.

"Aryl" refers to an aromatic system having 6 to 14 carbon atoms and having as many as three rings fused or directly linked. Representative examples of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, phenanthrene, atracenyl, azulenyl, and indanyl. Aryl groups also include one or more rings that are not fully aromatic and examples of such systems include indane, indene, 2,3-dihydrobenzofuran and 1,2,3,4-tehydronaphthalene.

"Heteroaryl" refers to an aromatic system having 5 to 14 carbon atoms and as many as 3 rings fused or directly linked and containing 1 to 8 heteroatoms selected from N, 0 and S. Examples of the heteroaryl group include pyridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, thiophenyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, Oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like. Can be.

“Heterocyclyl” is a monocyclic or polycyclic ring system that is fused helical or crosslinked and has 3 to 12 ring atoms and up to 8 hetero atoms selected from N, 0 and S Say Examples of the heterocyclyl ring system include piperidine, morpholine, piperazine, isoquinoline, oxazolidine, tetrahydrofuran, dihydrofuran, dihydropyridine, dihydroisoxazole, dihydrobenzofuran, azabicyclohexane, Dihydroindole, tetrahydroquinoline, pyrrolidine, azepine, azetidine, aziridine, tetrahydropyridine, benzthiazine, benzoxazinyl, isoindolin, azabicyclo [ 3.1.0] hexyl, phenoxazine, tetra Hydropyrans, 1,4-dioxane and the like.

“Cycloalkylalkyl”, “arylalkyl”, “heteroarylalkyl”, and “heterocyclylalkyl” are each cyclo linked to the rest of the molecule through an alkyl group. It refers to an alkyl, aryl, heteroaryl or heterocyclyl group.

"Amino" refers to -NH ₂ .

The term "alkoxy" refers to an O-alkyl group in which the alkyl is as defined above.

"Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

The term "halogeno -C ₁ -C ₆ alkyl, (halogeno-C ₁ -C ₆ alkyl)" is a means for at least one hydrogen is substituted by halogen, C ₁ -C ₆ alkyl.

The term "halogeno -C ₁ -C ₆ alkoxy (halogeno-C ₁ -C ₆ alkoxy)" is refers to a halogen atom is bonded to C ₁ -C ₆ alkoxy. Examples of such functional groups include trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy and the like.

The term "hydroxyl" or "hydroxy" refers to -OH.

"Thiol" means -SH.

"Alkylthio" refers to a thiol group when hydrogen is substituted with alkyl, for example methylthio, ethylthio, propylthio, t-butylthio, cyclopropylthio and the like.

"Cyano" means C≡N.

"Azido" means N = N = N.

The term "leaving group" refers to a functional group that exhibits the property of being liberated under synthetic conditions and easily separating from, or potentially separating from, a synthetic product under defined conditions. Examples of leaving groups include, but are not limited to, halogens (eg, F, Cl, Br, I), triflate, tosylate, mesylate, alkoxy, thioalkoxy or hydroxy radicals and the like.

By “protecting group” is meant a moiety that prevents a chemical reaction at a molecular site intended to remain unaffected during chemical modification of the molecule. Unless otherwise indicated, protecting groups are used for functional groups such as hydroxy, amino or carboxy. Examples of such protecting groups include T.W.Greene and P.G.W. Wuts, “Protectors in Organic Synthesis,” 2nd edition, John Wiley and Sons, New York, N.Y. The kind of carboxyl protecting group, amino protecting group or hydroxy protecting group used is not critical if the derived residues / residues are stable under continuous reaction conditions and can be removed without disrupting the rest of the molecule.

Compounds described herein are produced as diastereomers, including one or more asymmetric carbon atoms. These compounds also exist as morph isomers / roantiomers. All such isomeric forms of these compounds are included herein. Each steric carbon may be of R or S structure. Although certain compounds exemplified herein are described in particular in stereochemical structures, compounds or mixtures thereof having opposite stereochemistry at certain chiral centers are also envisaged.

The term “pharmacologically acceptable salt” forming site of the present invention includes salts of carboxylic acid residues prepared by reacting the compound with a suitable base to provide the base addition salt. Examples of the base include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; And alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. In addition, salts of organic bases such as lysine, arginyl, guanidine, ethanolamine, choline and the like; Also included are inorganic bases, such as ammonium salts or substituted ammonium salts. The compounds of the present invention may also be suitably used as organic or inorganic acids pharmacologically suitable for such compounds, for example hydrohalides such as hydrochloride, hydrobromide, hydroiodide; Other mineral acids and their corresponding salts such as sulfates, nitrates, phosphates and the like; And alkyl and mono-arylsulfonates such as ethane sulfonate, toluene sulfonate and benzene sulfonate; And acid addition salts by treating other organic acids and their corresponding salts such as acetates, tartarate, maleate, succinate, citrate and the like. The salt form differs from the compounds described herein in certain physical properties such as solubility, but otherwise the salts are equivalent for the purposes of the present invention.

The term “pharmacologically acceptable solvates” of the present invention refers to solvates with water (eg hydrates) or pharmacologically acceptable solvents, for example solvates with ethanol. Etc. Such solvates also fall within known categories. Furthermore, the crystalline forms of the compounds described herein exist as polymorphs and are intended to be included within the scope of the present invention per se.

The term "polymorph" includes all crystalline forms as well as amorphous forms of the compounds described herein and is included in the present invention as such.

By “pharmacologically acceptable carrier” is intended to include any type of nontoxic, inert solid, semisolid, or liquid filler, diluent, encapsulating material or formulation aid.

“Pharmacologically acceptable” means approved by the federal or state regulators for use in mammals and more preferably in the human body, or by U.S. By US pharmacopoeia or other commonly recognized pharmacopoeia.

Examples of inflammatory diseases and autoimmune diseases in which the compounds of the present invention have potentially beneficial effects on their treatment methods include asthma (including allergen-induced asthmatic reactions), cystic fibrosis, and bronchitis (including chronic bronchitis). ), Chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), chronic pneumonia, rhinitis and upper respiratory tract inflammatory disorder (URID), ventilator-induced lung injury induced lung injury, silicosis, pulmonary sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, arthritis such as rheumatoid arthritis, degenerative arthritis, infectious arthritis, psoriatic arthritis, traumatic arthritis Arthritis, Rubella Arthritis, Reiter's Syndrome, Gouty Arthritis and Proximal Femur Prosthetic joint failure, gout, acute synovitis, ankylosing spondylitis and non-articular inflammatory conditions, such as herniated / ruptured / prolapsed intervertebral disk syndrome, bursitis, tendonitis, tenosynovitic, fibromyalgic syndrome, and other ligamentous strains and other regional musculoskeletal strains Inflammatory diseases, inflammatory diseases of the gastrointestinal tract such as ulcerative colitis, diverticulitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, and gastritis ( gastritis, multiple sclerosis, systemetic lupus erythematosus, scleroderma, autoimmune exocrinopathy, autoimmune encephalomyelitis (autoimmu) ne encephalomyelitis, diabetes, tumor angiogenesis and metastasis, breast, colon, rectum, lung, kidney, ovary, stomach, uterus, interest, liver, oral cavity, larynx and prostate cancer, including melanoma, melanoma, acute and chronic leukemia, periodontal disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease disease, epilepsy, muscle degeneration, inguinal hernia, retinal degeneration, diabetic retinopathy, macular degeneration, inguinal hernia, eye inflammation (ocular inflammation), bone resorption disease, osteoporosis, osteopetrosis, graft versus host response (graft vs. host reaction, allograft rejection, sepsis, endotoxemia, toxic shock syndrome, tuberculosis, conventional interstitial and idiopathic stromal pneumonia and cryptogenic organizing pneumonia, bacterial meningitis, systemic cachexia, cachexia secondary to infection or malignancy, secondary hydraulic pressure due to congenital immunodeficiency (cachexia secondary to acquired immune deficiency syndrome (AIDS)), malaria, leprosy, leishmaniasis, Lyme disease, glomerulonephritis, glomerulosclerosis, Renal fibrosis, liver fibrosis, pancrealitis, hepatitis, endometriosis, pain such as inflammation and / or trauma-related pain, skin inflammation Diseases such as dermatitis, dermatosis, skin ulcers, psoriasis, eczema, systemic vasculitis, vascular dementia, thrombosis, Atherosclerosis, restenosis, reperfusion injury, plaque calcification, myocarditis, aneurysm, stroke, pulmonary hypertension, left ventricle Left ventricular remodeling and heart failure. It will be apparent to those skilled in the art that the reference herein to treatment extends to prevention as well as treatment of established diseases.

The compounds described herein are well known in, for example, organic synthesis and can be prepared by techniques familiar to those skilled in the art of the present invention. In addition, it is possible to synthesize the compounds of the present invention by the methods described herein. However, these are not the only means by which the compounds described herein are synthesized. Furthermore, the various synthetic steps described herein may be performed in any order to provide the desired compound.

The compounds of the present invention were prepared according to the strategy described below.

Compounds of compounds 10, 11 and 12 can be prepared by Strategy 1 below.

는 상기에서 정의한 바와 같고, X는 O 또는 S이고, R_k는 H, 할로, 알킬, 알콕시, 시아노, 할로게노-C₁-C₆ 알킬 또는 할로게노-C₁-C₆ 알콕시이고, z는 0 내지 4임)은 화학식 6의 화합물과 반응하여 화학식 7의 화합물을 생성할 수 있고, 이는 그 후 화학식 8의 화합물(상기

는 상기에서 정의한 바와 같고, L 및 W는 각각 O 또는 S이고, R_k는 알킬, 아릴 또는 아랄킬임)과 반응하여, 화학식 9의 화합물을 생성한다.Thus, the compound of formula 5 (the

Is as defined above, X is O or S, R _k is H, halo, alkyl, alkoxy, cyano, halogeno-C ₁ -C ₆ alkyl or halogeno-C ₁ -C ₆ alkoxy, z Is 0 to 4) to react with a compound of formula 6 to produce a compound of formula 7, which is then a compound of formula 8

Are as defined above, L and W are each O or S, and R _k is alkyl, aryl or aralkyl to form a compound of formula 9.

Path A (when X is S): Compound of formula 9 is hydrolyzed to yield compound of formula 10, which is then oxidized to produce compound of formula 11.

Route B (when X is O): Compounds of formula 9 are hydrolyzed to yield compounds of formula 12.

The reaction in which the compound of formula 5 reacts with the compound of formula 6 to produce the compound of formula 7 is carried out in the presence of a base such as potassium carbonate, cesium carbonate, sodium acetate, or potassium acetate, in a solvent such as dimethylformamide, acetonitrile, toluene , Tetrahydrofuran, acetone, dioxane or mixtures thereof.

The reaction for producing the compound of formula 9 by adding asymmetric aldol to the compound of formula 7 with asymmetric aldol is carried out using a base such as tetramethylethylenediamine, diisopropylethylamine, tributylamine, N-ethylpiperidine, 1,4 In the presence of -diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, tetramethylpropylenediamine or (-) spartane, such as a solvent such as dichloromethane Or in diethyl ether, by producing an enolate with titanium tetrachloride, dibutyl boron triflate, dialkyl boron chloride or tin (II) triflate.

The reaction of hydrolyzing a compound of Formula 9 (when Paths A, X is S) to produce a compound of Formula 10 is carried out in the presence of a solvent such as tetrahydrofuran, water, or a mixture thereof, hydrogen peroxide and lithium hydroxide. Can be carried out together.

The reaction to oxidize the compound of formula 10 to produce the compound of formula 11 is carried out in a solvent such as chloroform, dichloromethane, methanol, water, tetrachloromethane or mixtures thereof with an oxidizing agent such as metachloroperbenzoic acid, oxone or hydrogen peroxide. Can be.

The reaction of hydrolyzing the compound of Formula 9 (when Path B, X is O) to produce the compound of Formula 12 may be carried out in a manner similar to the reaction of hydrolyzing the compound of Formula 9 to produce the compound of Formula 10. Can be.

Compounds of Formula 15 may be prepared by Strategy 2 below.

, L, W 및 R_x는 상기에서 정의한 바와 같음)은 화학식 13의 화합물(상기 G는 니트로 또는 C(O)O-벤질 일 수 있음)과 알돌 첨가하여 화학식 14의 화합물을 생성하며, 이는 그 후에 환원되어 화학식 15의 화합물을 생성할 수 있다(G₁가 아미노 또는 COOH일 수 있음).Thus, the compound of formula 8 (the

, L, W and R _x are as defined above, are added to the compound of formula 13 (wherein G may be nitro or C (O) O-benzyl) and aldol to produce the compound of formula 14, It can then be reduced to give the compound of formula 15 (G ₁ may be amino or COOH).

The reaction of producing a compound of formula 14 by adding an aldol to the compound of formula 8 by adding an aldol to the compound of formula 8 may be carried out in a similar manner to the reaction of generating an compound of formula 9 by adding aldol to the compound of formula 8. Can be.

Reduction of the compound of formula 14 to produce the compound of formula 15 may include one or more reducing agents, such as palladium-carbon / hydrogen, Raney nickel / hydrogen, platinum / hydrogen or mixtures thereof, solvents such as tetrahydro It may be carried out in furan, methanol, ethanol, propanol, isopropanol or mixtures thereof.

Compounds of Formula 18 and Formula 21 are prepared by Strategy 3 below.

Thus, the compound of formula 15 (when G ₁ is amino) can react via two routes.

Path C: A compound of Formula 15 is coupled with a compound of Formula 16 (R _k and z are as defined above) to produce a compound of Formula 17, which is then hydrolyzed to produce a compound of Formula 18.

Path D: A compound of Formula 15 is a compound of Formula 19 (X is a leaving group such as halogen, R _j is-(CH ₂ ) _0-1 -CO-, -C (O) O-, -SO _2- , R _k is as defined above to form a compound of formula 20, which is then hydrolyzed to produce a compound of formula 21.

 The reaction of coupling a compound of Formula 15 with a compound of Formula 16 to produce a compound of Formula 17 (path C) comprises a solvent, with a suitable base such as potassium carbonate, sodium carbonate, triethylamine, diisopropylethyl amine, etc. Such as acetonitrile, dimethylformamide, toluene, tetrahydrofuran, acetone or dioxane and the like.

 The reaction of hydrolyzing the compound of formula 17 to produce the compound of formula 18 may be carried out in a similar manner to the reaction of hydrolyzing the compound of formula 14 to produce the compound of formula 15.

The reaction of coupling a compound of Formula 15 with a compound of Formula 19 to produce a compound of Formula 20 (path D) includes bases such as triethylamine (TEA), N-methyl-morpholine (NMM), N, N- It may be carried out on a solvent such as dichloromethane, tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or acetone together with dimethylaminopyridine (DMAP) or N, N-diisopropylethylamine (DIPEA).

The reaction of hydrolyzing the compound of formula 20 to produce the compound of formula 21 may be carried out in a similar manner to the reaction of hydrolyzing the compound of formula 9 to produce the compound of formula 10.

The compound of formula 24 is synthesized by the following strategy 4.

Thus compound 15 (G ₁ is COOH) of compound 15 can be coupled with compound 22, which is then hydrolyzed to yield compound 24.

The reaction of coupling the compound of Formula 15 with the compound of Formula 22 to produce the compound of Formula 23 is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) or N, N'- coupling agent. In the presence of dichlorohexylcarbodiimide (DCC) and optionally activating enzyme HOBT and organic base dimethylaminopyridine, N-methylmorpholine or diisopropylethylamine, in organic solvents such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride Can be implemented. Optionally, the compound of compound 12 is also activated by conversion to the corresponding acid chloride (using thionyl chloride, oxalyl chloride, etc.) or anhydride (pivaloyl chloride, etc.) and coupled with the corresponding aniline.

The reaction of hydrolyzing the compound of Compound 23 to produce the compound of Compound 24 can be carried out in a similar manner to the reaction of hydrolyzing the compound of Compound 14 to the compound of Compound 15.

In the above strategies, when specific reagents such as bases, acids, solvents, condensing agents, hydrolysing agents, enzymes and the like are mentioned, other reagents such as other acids, bases, solvents, known to those skilled in the art, It is understood that condensing agents, reducing agents, deprotectants, hydrolysing agents, enzymes and the like may also be used. Similarly, reaction temperature and duration can be adjusted within the capabilities of one of ordinary skill in the art to meet the desired needs without undue experimentation.

Table 1 lists the types of compounds synthesized using the synthesis method shown in Strategy 1-4 above.

(Formula 2)

The compounds described herein are administered to the animals by oral, topical, rectal, internasal or parenteral routes for treatment. The pharmacological compositions disclosed herein comprise a pharmacologically effective amount of a compound described herein formulated with one or more pharmaceutically acceptable carriers, excipients or diluents.

Solid form preparations for oral administration include capsules, tablets, pills, powders, granules, candy, troche, and cachets. Active compounds for solid preparations include one or more inert, pharmacologically acceptable excipients or carriers such as sodium citrate, dicalcium phosphate, and / or fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol). , Silicic acid, or mixtures thereof); Binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof; Disintegrating agents such as agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate, or mixtures thereof; Absorption accelerators such as quaternary ammonium compounds; Wetting agents such as cetyl alcohol, glycerol mono stearate or mixtures thereof; Absorbers such as kaolin; Lubricating oils such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof.

Capsules, tablets or pills may also include a buffering agent.

Tablets, capsules, pills, or granules may be coated with one or more coatings or shells, eg, enteric coatings or other coatings known to those skilled in the art to control the release of the active ingredient. It can be prepared using the method.

Liquid preparations for oral administration include pharmacologically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid preparations, the active compound is water or one or more non-toxic solvents, solubilizing agents or emulsifiers such as water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzo Eight, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils such as cottonseed oil, peanut oil, grain oil, germ oil, olive oil, castor oil and sesame oil, glycerol, sorbitan fatty acid esters and mixtures thereof Can be. Oral compositions can also include one or more adjuvants such as wetting agents, emulsifiers, suspending agents, sweetnening agents, flavoring agents, perfuming agents, or mixtures thereof.

Injectable preparations, such as sterile injectable and aqueous suspensions, are formulated according to methods known to those skilled in the art, in particular using one or more suitable dispersing or wetting agents and suspending agents. Acceptable vehicles and solvents used include one or more of water, Ringer's solution, isotonic sodium chloride, or mixtures thereof.

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which are solid at room temperature but liquid at body temperature and thus dissolve in the rectum to favor the drug.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound may be mixed under sterile conditions with one or more pharmacologically acceptable carriers and optionally any preservative or buffer, if desired. Ophthalmic formulations, eardrops, eye ointments, powders and solutions may also be included within the scope of the present invention.

The pharmacological agent may be in unit dosage form. In unit dosage form, the formulation may be subdivided into unit dosages containing appropriate amounts of active ingredients. The unit dosage forms may be discrete capsules, preparations containing powders, ointments, capsules, disposable sachets, tablets, gels, creams, or any combination and number of the above packaging forms in vials or ampoules. have.

Experimental Method

Various solvents such as dimethylformamide, benzene, tetrahydrofuran and the like are dried using various drying reagents according to the methods as described in the literature.

Synthesis of Starting Material

3- [4-((4S) -4-benzyl-2-oxo-1,3- Thiazolidine Yl) -4- Oxobutyl ] -3H-benzo [ d] [1,2,3] triazine Synthesis of 4-one

The synthesis of the title compound is described in WO 2008/023336, p. It was carried out according to the reference method described in 54-55.

Synthesis Method of Strategy 1 (Path A)

Example  I: (2S) -2-[(S)-{4-[(4- Chlorophenyl ) Sulfonyl ] Phenyl } (Hydroxy) methyl ] -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 2)

Step 1: 4-[(4- Chlorophenyl ) Sulfanyl ] Benzaldehyde  synthesis

To a solution of 4-chlorothiophenol (1.0 g, 0.0069 mol) in dimethylformamide (5 ml) was added potassium carbonate (2.8 g, 0.0207 mol) and 4-fluorobenzaldehyde (0.904 g, 0.0072 mol) and the reaction mixture. Is heated to about 100 ° C. for about 4 hours. After completion of the reaction, water was added and extracted over ethyl acetate. The organic layer was concentrated and column purified using 7% ethyl acetate / hexanes as eluent to afford the title compound (yield: 0.6 g).

MASS-248

LCMS-M + 1 (248.97)

Step 2: 3-{(3S) -4-[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] -3-[(S)-{4-[(4-chlorophenyl) Sulfanyl ] Phenyl } (Hydroxy) methyl ]-4- Oxobutyl } -1,2,3- Benzotriazine Synthesis of -4 (3H) -one

3- {4-[(4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -4-oxobutyl in dichloromethane (5 ml) cooled to about 0 ° C. under argon atmosphere. } Titanium tetrachloride (0.12 g, 0.00063 mol) was slowly added to a solution of -1,2,3-benzotriazine-4 (3H) -one (0.2 g, 0.00049 mol). After about 30 minutes, tetramethylethylenediamine (0.068 g, 0.00058 mol) was added at about 0 ° C. The reaction mixture was stirred at the same temperature for about 45 minutes, then a solution of 4-[(4-chlorophenyl) sulfanyl] benzaldehyde (0.206 g, 0.00083 mol) in dichloromethane (5 ml) was added slowly. The reaction mixture is again stirred at room temperature for about 5 minutes. At the end, the reaction was quenched with ammonium chloride solution and then with dilute hydrochloric acid solution, then extracted with dichloromethane and water and column purified using 8% ethyl acetate / hexanes as eluent to afford the title compound (yield: 0.150). g).

MASS-657

LCMS-M + 1 (658.02)

Step 3: (2S) -2-[(S)-{4-[(4- Chlorophenyl ) Sulfinyl ] Phenyl } (Hydroxy) methyl ] -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 1)

3-{(3S) -4-[(4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -3- in tetrahydrofuran (5 ml) at 0 ° C. under argon atmosphere. [(S)-{4-[(4-chlorophenyl) sulfanyl] phenyl} (hydroxy) methyl] -4-oxobutyl} -1,2,3-benzotriazine-4 (3H) -one ( To a solution of 0.1 g, 0.0001 mol) is added a hydrogen peroxide solution (0.0102 g, 0.0003 mol) followed by lithium hydroxide (0.006 g, 0.00015 mol). The reaction mixture was stirred at room temperature for about 2 hours. The reaction was quenched by acidifying the reaction mixture with sodium bisulfate and extracting on ethyl acetate and water. The organic layer was thus concentrated and purified by preparative TLC using 10% methanol / dichloromethane as eluent to afford the title compound (yield: 0.090 g).

MS-497.95

LCMS-M1 (496.04)

NMR (DMS0- d ₆ , 400 MHz) δ: 8.04-8.06 (2H, d, J = 8.0 Hz), 7.92-7.93 (1H, d, J = 4.0 Hz), 7.81-7.83 (1H, d, J = 8.0 Hz), 7.67-7.69 (2H, d, J = 8.0 Hz), 7.57-7.59 (4H, d, J = 8 Hz), 7.42-7.44 (2H, d, J = 8 Hz), 4.84 (1H, m), 4.38-4.29 (2H, m), 2.54-2.57 (1H, m), 2.07 (lH, m), 1.89 (1H, m).

The following compounds were prepared following the synthetic route.

(2S) -2-[(S)-{4-[(3,4-difluorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 3);

Mass: 499.48

(2S) -2-[(S)-{4-[(2,3-dichlorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 4);

Mass: 532.39

(2S) -2-[(S)-{4-[(2,4-dimethylphenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 5);

Mass: 491.55

Step 4: (2S) -2-[(S)-{4-[(4- Chlorophenyl ) Sulfonyl ] Phenyl } (Hydroxy) methyl ] -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 2)

(2S) -2-[(S)-{4-[(4-chlorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1 in chloroform (5 ml) at about 0 ° C Metachloroperbenzoic acid (0.124 g, 0.00072 mol) was added to 2,3-benzotriazine-3 (4H) -yl) butanoic acid (0.09 g, 0.00018 mol), and the reaction mixture was allowed to stand at room temperature for 1 hour. Stirred. Upon completion, the reaction mixture was quenched with sodium metabisulfite solution and then extracted in dichloromethane. The organic layer was dried over sodium sulphate, concentrated and purified by preparative TLC, eluting with 10% methanol / dichloromethane to afford the title compound (Yield: 0.04 g).

MS-513.95

LCMS-M-1 (512.00)

NMR (DMSO- d ₆ , 400 MHz) δ: 8.16 (2H, m), 8.08 (1H, m), 7.93-7.95 (4H, d, J = 8.0 Hz), 7.82-7.84 (1H, d, J = 8.0 Hz), 7.68-7.70 (2H, d, J = 8 Hz), 7.53-7.55 (2H, d, J = 8 Hz), 4.90 (1H, m), 4.30-4.40 (2H, m), 2.50 (1H, m), 1.90-2.10 (2H, m).

The following compounds can be prepared along the synthetic route.

(2S) -2-[(S)-{4-[(4-fluorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 6);

Mass: 497.49

(2S) -2-[(S)-{4-[(3,4-difluorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 7);

Mass: 515.48

2- [4-[(2,3-dichlorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) Butanoic acid (compound 8);

Mass: 548.39

(2S) -2-[(S)-{4-[(2,4-dimethylphenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 9);

Mass: 507.55

Synthesis Method of Strategy 1 (Path B)

Example  II: (2S) -2-{(S) -hydroxy [4- (4- Methoxyphenoxy ) Phenyl ] methyl } -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 56)

Step 1: 4- (4- Methoxyphenoxy ) Benzaldehyde  synthesis

To a solution of 4-methoxy phenol (1.0 g, 0.0080 mol) in dimethylformamide (5 ml), potassium carbonate (3.3 g, 0.024 mol) and 4-fluorobenzaldehyde (1.1 g, 0.0088 mol) are added and the reaction The mixture was heated to about 100 ° C. for about 4 hours. At the end of the reaction, water was added thereto and extracted in ethyl acetate. The organic layer was concentrated and column purified using 7% ethyl acetate / hexanes as eluent to afford the title compound (yield: 0.9 g).

Step 2: 3-[(3S) -4-[(4S) -benzyl-2-oxo-1,3- Thiazolidine -3-yl] -3-{(S) -hydroxy [4- (4- Methoxyphenoxy ) Phenyl ] methyl }-4- Oxobutyl ] -1,2,3- Benzotriazine Synthesis of -4 (3H) -one

3- [4-((4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -4-oxobutyl] -3H in dichloromethane (50 ml) at 0 ° C. under argon atmosphere To a solution of benzo [d] [1,2,3-triazin-4-one (5.5 g, 0.013 mol) was added titanium tetrachloride (3.19 g, 0.0169 mol) slowly The reaction mixture was added for about 30 minutes After stirring, tetramethylethylenediamine (3.77 g, 0.0325 mol) was slowly added at 0 ° C., and the reaction mixture was continued to stir at the same temperature for about 45 minutes. Subsequently, 4- (in dichloromethane (20 ml) was added. A solution of 4-methoxyphenoxy) benzaldehyde (5.2 g, 0.022 mol) was added slowly and allowed to stir for about 5 minutes At the end, the reaction was quenched with ammonium chloride solution and then diluted hydrochloric acid, dichloromethane and Extraction with water and column purification using 8% ethyl acetate / hexanes afforded the title compound (Yield: 2.6 g).

Step 3: (2S) -2-{(S) -hydroxy [4- (4- Methoxyphenoxy ) Phenyl ] methyl } -4- (4-oxo-1,2,3-bene Jot Synthesis of Lyazine-3 (4H) -yl) butanoic acid (Compound 56)

3-[(3S) -4-[(4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -3- in tetrahydrofuran (30 ml) at 0 ° C. under argon atmosphere. {(S) -hydroxy [4- (4-methoxyphenoxy) phenyl] methyl} -4-oxobutyl] -1,2,3-benzotriazine-4 (3H) -one (2.6 g, 0.0040 Mole) solution, hydrogen peroxide solution (0.408 g, 0.012 mole) and then lithium hydroxide (0.256 g, 0.0061 mole) were added and the reaction mixture was stirred for about 2 hours. The reaction was quenched by acidification with sodium bisulfate and extraction with ethyl acetate and water. The organic layer was concentrated and column purified using 8% methanol / dichloromethane as eluent to afford the title compound (yield: 0.9 g).

MS-461.46

LCMS-M-1 (460.08)

NMR (DMSO- d ₆ , 400 MHz) δ: 8.19-8.21 (1H, d, J = 8.0 Hz), 8.15-8.17 (1H, d, J = 8.0 Hz), 8.04-8.08 (1H, d, J = 16.0 Hz), 7.89-7.92 (1H, d, J = 12.0 Hz), 7.18-7.20 (2H, d, J = 8 Hz), 6.93 (4H, d), 6.72-6.74 (2H, d, J = 8 Hz), 4.77-4.78 (1H, m, J = 4 Hz), 4.30-4.40 (2H, m), 3.73 (3H, s), 2.59 (1H, m), 2.03-2.07 (2H, m).

The following compounds were prepared following the synthetic route.

(2S) -2-[(S)-[4- (3-chloro-4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 57);

Mass: 482.28

(2S) -2-[(S)-[4- (4-chloro-3-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 58);

Mass: 478.25

(2S) -2-[(S)-[4- (4-chloro-2-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 59);

Mass: 482.28

(2S) -2-[(S)-[4- (4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 ( 4H) -yl) butanoic acid (compound 60);

Mass: 448.29

(2S) -2-[(S)-[4- (3,4-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 61);

Mass: 466.31

(2S) -2-[(S)-[4- (2-chlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 62);

Mass: 464.26

(2S) -2-[(S)-[4- (3-chlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 63);

Mass: 464.26

(2S) -2-[(S)-[4- (2,6-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 64);

Mass: 466.31

(2S) -2-[(S)-[4- (2,5-dichlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 65);

Mass: 498.25 and 500.16

(2S) -2-[(S)-[4- (2-chloro-4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 66);

Mass: 482.28

(2S) -2-{(S) -hydroxy [4- (3-methoxyphenoxy) phenyl] methyl} -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 67);

Mass: 460.30

(2S) -2-[(S)-[4- (2-chloro-4-methoxyphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 68);

Mass: 494.29

(2S) -2-[(S)-[4- (2,4-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 69);

Mass: 466.31

(2S) -2-[(S)-[3-fluoro-4- (4-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 70);

Mass: 462.36

(2S) -2-[(S)-[3-fluoro-4- (3-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 71);

Mass: 462.34

(2S) -2-[(S)-[4- (3,4-dimethylphenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 72);

Mass: 476.46

(2S) -2-[(S)-[4- (3,4-dichlorophenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 73);

Mass: 516.33 and 518.29

(2S) -2-[(S)-[4- (4-tert-butylphenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 74);

Mass: 504.44

(2S) -2-[(S)-[3-fluoro-4- (4-methoxyphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 75);

Mass: 478.38

Synthesis Method of Strategy 2

Example  III: 3-[(3S, 4S) -4- (4- Aminophenyl ) -3-{[(4S) -4-benzyl-2-oxo-1,3- Thiazolyldine -3-yl] carbonyl} -4- Hydroxybutyl ] -1,2,3- Benzotriazine Synthesis of -4 (3H) -one

Step 1: 3-{(3S) -4-[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] -3-[(S) -hydroxy (4- Nitrophenyl ) methyl ]-4- Oxybutyl } -1,2,3- Benzotriazine Synthesis of -4 (3H) -one

3- {4-[(4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -4-oxobutyl} -1,2, in dichloromethane (350 ml) at 0 ° C. To a 3-benzotriazine-4 (3H) -one (20 g, 0.049 mole) solution, titanium tetrachloride (58.8 ml, 0.311 mole) is added and the reaction mixture is brought to room temperature (˜25 ° C.) for about 20 minutes. Stirred. To this, tetramethylethylenediamine (18.5 ml, 0.122 mol) was added at 0 ° C. and the reaction mixture was allowed to stir for about 20 minutes. At the same temperature, 4-nitrobenzaldehyde (12.6 g, 0.083 mole) in dichloromethane (50 ml) was added and allowed to stir at room temperature for about 2 hours. At the end, a saturated solution of ammonium chloride and then diluted hydrochloric acid is added to the reaction mixture. The organic layer was extracted in dichloromethane and purified on silica gel (60-120 mesh) using 25% ethyl acetate: hexane as concentration and eluent to give the desired product (yield: 18.2 g).

MS: 560.15 (M + 1)

Step 2: 3-[(3S, 4S) -4- (4- Aminophenyl ) -3-{[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] carbonyl} -4- Hydroxybutyl ] -1,2,3- Benzotriazine Synthesis of -4 (3H) -one

3-{(3S) -4-[(4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -3- [in tetrahydrofuran (100 ml) and methanol (100 ml) To a solution of (S) -hydroxy (4-nitrophenyl) methyl] -4-oxobutyl} -1,2,3-benzotriazine-4 (3H) -one (18 g, 0.032 mol) at room temperature (˜25) 10% Pd / C (6.0 g) was added and H ₂ was fed in a Parr apparatus for about 1 hour. The reaction mixture was filtered through celite and the residue was washed with 100% methanol / dichloromethane. The filtrate was concentrated and column purified on silica gel (60-120 mesh) using 60% ethyl acetate: hexane as eluent to give the desired product (yield: 14.57 g).

MS: 512.02 (M-18)

Synthesis Method of Strategy 3

Example  IV: (2S) -2-[(S)-[4-({[2- Fluoro -4- (trifluoromethyl) Phenyl ] Carbonyl} amino) Phenyl ] (Hydroxy) methyl ] -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 46)

Step 1: N- {4-[(1S, 2S) -2-{[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] carbonyl} -1-hydroxy-4- (4-oxo-1,2,3- Benzotriazine -3 (4H) -yl) butyl] Phenyl }-2- Influenza Oro-4- ( Trifluoromethyl ) Benzamide  synthesis

3-[(3S, 4S) -4- (4-aminophenyl) -3-{[(4S) -4-benzyl-2-oxo-1,3-thiazolidine in dichloromethane (40 ml) at 0 ° C -3-yl] carbonyl} -4-hydroxybutyl] -1,2,3-benzotriazine-4 (3H) -one (0.3 g, 0.00057 mol) triethylamine (0.24 ml, 0.0017 mol) Was added. To the reaction mixture, 2-fluoro-4-trifluoromethyl benzoyl chloride (0.19 g, 0.00086 mol) was added under a nitrogen atmosphere, and the reaction mixture was allowed to stir at room temperature for about 2 hours. At the end of the reaction, water was added, and the organic layer was extracted and concentrated to give the desired product (yield: 153 mg).

Step 2: (2S) -2-[(S)-[4-({[2- Fluoro -4-( Trifluoromethyl ) Phenyl ] Carbonyl} amino) Phenyl ] (Hydroxy) methyl ] -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 46)

N- {4-[(1S, 2S) -2-{[(4S) -4 - benzyl-2-oxo-1,3-thiazolidin-3-yl] carbonyl} in tetrahydrofuran (20 ml)} -1-hydroxy-4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butyl] phenyl} -2-fluoro-4- (trifluoromethyl) benzamide Hydrogen peroxide (0.022g, 0.00064mol), lithium hydroxide (0.0134g, 0.000032mol) and water (2ml) were added to the solution (0.153g, 0.000213mol), and the reaction mixture was stirred at room temperature for about 1 hour. . The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to afford the crude product. Purification was carried out on preparative TLC using 10% methanol: dichloromethane as eluent to afford the title product (yield: 61.0 mg).

MS: 545.16 (M + 1)

_{NMR (DMSO- d 6, 400 MHz} ), δ: 10.56 (1H, s), 8.22-8.17 (2H, m), 8.07 (1H, t, J = 7.44Hz), 7.92-7.87 (3H, m), 7.73 (1H, d, J = 8.04 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 4.82 (1H, d, J = 6.04 Hz), 4.40-4.32 (2H, m), 2.75-2.60 (1H, m), 2.30-2.0 (2H, m)

Example  V: (2S) -2-[(S)-(4-{[(4- Ethylphenyl ) Carbonyl] amino} Phenyl Synthesis of (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 10)

Step 1: 3-{(3S) -4-[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] -3-[(S) -hydroxy (4- Nitrophenyl ) methyl ]-4- Oxobutyl } -1,2,3- Benzotriazine Synthesis of -3 (4H) -one

3- {4-[(4S) -4 - benzyl-2-oxo-1,3-thiazolidin-3-yl] -4-oxobutyl} -1,2, in dichloromethane (20 ml) at 0 ° C. Titanium tetrachloride (2.94 ml, 0.0029 mol) was added dropwise to a 3-benzotriazine-3 (4H) -yl (1 g, 0.0025 mol) solution, and the reaction mixture was stirred at room temperature (˜25 ° C.) for about 40 minutes. Stirred. To this, tetramethylethylenediamine (0.712 g, 0.0061 mol) was added at about 0 ° C. and the reaction mixture was allowed to stir for an additional 30 minutes. At the same temperature, nitrobenzaldehyde (0.64 g, 0.0042 moles) in dichloromethane (50 ml) was added to the reaction mixture and stirred at room temperature (˜25 ° C.) for about 2 hours. At the end of the reaction, a saturated solution of ammonium chloride was added and the reaction mixture was worked up with dichloromethane and water. Purification was carried out on silica gel (60-120 mesh) using 30% ethyl acetate: hexane as eluent to give the title product (yield: 0.62 g).

MS: 559.91 (M + 1)

Step 2: 3-[(3S, 4S) -4- (4- Aminophenyl ) -3-{[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] carbonyl} -4- Hydroxybutyl ] -1,2,3- Benzotriazine Synthesis of -3 (4H) -one

3-{(3S) -4-[(4S) -4-benzyl-2-oxo-1,3-thiazolidin-3-yl] -3 in tetrahydrofuran (20 ml) at room temperature (˜25 ° C.) 10% in-[(S) -hydroxy (4-nitrophenyl) methyl] -4-oxobutyl} -1,2,3-benzotriazine-3 (4H) -yl (0.61 g, 0.0011 mol) solution Pd / C (0.5 g) was added and H ₂ was fed using a balloon for about 2 hours. The reaction mixture was filtered through celite and the residue was washed with 10% methanol: dichloromethane. The filtrate was concentrated to give the desired compound (yield: 0.6 g).

MS: 511.94 (M-18)

Step 3: N- {4-[(1S, 2S) -2-{[(4S) -4-benzyl-2-oxo-1,3- Thiazolidine -3-yl] carbonyl} -1-hydroxy-4- (4-oxo-1,2,3- Benzotriazine -3 (4H) -yl) butyl] Phenyl Synthesis of 4-ethylbenzamide

3-[(3S, 4S) -4- (4-aminophenyl) -3-{[(4S) -4-benzyl-2-oxo-1,3-thiazolidine in dichloromethane (20 ml) at 0 ° C 3-ethyl] carbonyl} -4-hydroxybutyl] -1,2,3-benzotriazine-4 (3H) -one (0.6 g, 0.0011 mol) in a solution of triethylamine (0.47 ml, 0.0034 mol) ) Is added. Then 4-ethyl benzoyl chloride (0.29 g, 0.0017 mol) was added and the reaction mixture was stirred at 0 ° C. for about 30 minutes. The reaction was worked up with dichloromethane and water to give the crude product (yield: 680 mg).

MS: 662.04 (M + 1)

Step 4: (2S) -2-[(S)-(4-{[(4- Ethylphenyl ) Carbonyl] amino} Phenyl ) (Hydroxy) methyl ] -4- (4-oxo-1,2,3- Benzotriazine Synthesis of -3 (4H) -yl) butanoic Acid (Compound 10)

N- {4-[(1S, 2S) -2-{[(4S) -benzyl-2-oxo-1,3-thiazolidin-3-yl] carbonyl} -1 in tetrahydrofuran (10 ml) Hydrogen peroxide (0.3 ml) in hydroxy-4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butyl] phenyl} -4-ethylbenzamide (0.35 g, 0.00053 mol) , 2.65 mol) was added and the reaction mixture was stirred at 0 ° C for about 15 minutes. Lithium hydroxide (0.033 g, 0.00079 mol) and water (5 ml) were then added thereto and again stirred at room temperature for about 2 hours. At the end, the reaction was quenched by addition of water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified as preparative TLC using 10% methanol: dichloromethane as eluent to afford the title product (yield: 84.0 mg).

MS: 485.17 (M-1)

NMR (DMSO- d ₆ , 400 MHz), δ: 10.06 (1H, s), 8.20-8.15 (2H, m), 8.06-8.02 (1H, m), 7.89-7.85 (3H, m), 7.61 (2H , d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 4.80-4.78 (1H, m), 4.40-4.32 (2H, m) , 2.70-2.65 (3H, m), 2.20-2.00 (2H, m).

The following compounds were prepared by this synthetic route.

(2S) -2-[(S)-(4-{[(4-chlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 11);

Mass: 492.91

(2S) -2-[(S)-(4-{[(3,4-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 12);

Mass: 528.84

(2S) -2-[(S) -hydroxy (4-{[(4-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 13);

Mass: 489.97

(2S) -2-[(S) -hydroxy (4-{[(3-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 14);

Mass: 489.97

(2S) -2-[(S) -hydroxy (4-{[(4-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 15);

Mass: 473.01

(2S) -2-[(S)-(4-{[(4-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 16);

Mass: 477.96

(2S) -2-{(S) -hydroxy [4-({[4-methoxy-3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 17);

Mass: 557.94

(2S) -2-[(S) -hydroxy (4-{[(5-methyl-1,2-oxazol-3-yl) carbonyl] amino} phenyl) methyl] -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 18);

Mass: 464.96

(2S) -2-[(S)-(4-{[(3-chloro-4-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1, 2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 19);

Mass: 510.80

(2S) -2-[(S) -hydroxy {4-[(phenylcarbonyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 20);

Mass: 459.95

(2S) -2-[(S) -hydroxy (4-{[(4-propylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 21);

Mass: 501.92

(2S) -2-[(S) -hydroxy {4-[(phenoxycarbonyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 22);

Mass: 475.92

(2S) -2-[(S) -hydroxy {4-[(phenylacetyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H)- I) butanoic acid (compound 23);

Mass: 473.94

(2S) -2-[(S)-(4-{[(2,4-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 24);

Mass: 526.84

(2S) -2-[(S) -hydroxy (4-{[(2-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 25);

Mass: 472.92

(2S) -2-[(S)-(4-{[(2-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 26);

Mass: 476.88

(2S) -2-[(S)-(4-{[(3-chlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 27);

Mass: 492.85

(2S) -2-[(S) -hydroxy (4-{[(3-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 28);

Mass: 472.92

(2S) -2-[(S)-(4-{[(3-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 29);

Mass: 476.88

(2S) -2-[(S)-(4-{[(2,6-dimethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 30);

Mass: 518.92

(2S) -2-[(S)-{4-[(cyclopentylcarbonyl] amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 31);

Mass: 450.94

(2S) -2-[(S) -hydroxy (4-{[(2,4,5-trifluoro-3-methoxyphenyl) carbonyl] amino} phenyl} methyl] -4- (4- Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 32);

Mass: 543.09

(2S) -2-[(S) -hydroxy (4-{[(2,3,4-trifluorophenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 33);

Mass: 513.06

(2S) -2-{(S) -hydroxy [4-({[2- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 34);

Mass: 527.11

(2S) -2-[(S)-(4-{[(3,5-dimethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 35);

Mass: 519.13

(2S) -2-[(S)-(4-{[(2,3-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 36);

Mass: 495.04

(2S) -2-[(S)-(4-{[(3,5-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 37);

Mass: 526.99

(2S) -2-[(S)-(4-{[(2,4-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 38);

Mass: 495.04

(2S) -2-[(S)-(4-{[(2,6-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 39);

Mass: 495.10

(2S) -2-[(S) -hydroxy (4-{[(2-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 40);

Mass: 489.16

(2S) -2-[(S)-{4-[(cyclohexylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 41);

Mass: 465.20

(2S) -2-[(S)-(4-{[(4-ethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 42);

Mass: 503.20

(2S) -2-[(S)-(4-{[(3,4-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 43);

Mass: 495.16

(2S) -2-{(S) -hydroxy [4-({[4- (trifluoromethoxy) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 44);

Mass: 545.15

(2S) -2-{(S) -hydroxy [4-({[3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 45);

Mass: 527.15

(2S) -2-[(S)-(4-{[(3-chloro-2,6-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 47);

Mass: 529.13

(2S) -2-{(S) -hydroxy [4-({[4-trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 48);

Mass: 527.16

(2S) -2-[(S)-(4-{[(2,5-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 49);

Mass: 495.15

(2S) -2-[(S)-(4-{[(2,3-difluoro-4-methylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo- 1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 50);

Mass: 509.18

(2S) -2-[(S)-[4-({[4-fluoro-3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] (hydroxy) methyl] -4- (4 Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 51);

Mass: 545.15

(2S) -2-[(S)-{4-[(cyclopropylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 52);

Mass: 423.19

(2S) -2-[(S)-(4-{[(2-ethylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 53);

Mass: 485.19

(2S) -2-[(S) -hydroxy (4-{[(4-methoxyphenyl) acetyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 54);

Mass: 503.20

(2S) -2-[(S)-{4-[(cyclobutylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 55);

Mass: 437.21

temperament To metalloproteinase (MMP)  Analysis

The novel chemicals of the present invention and the corresponding reference materials used in the present invention were prepared in 100% DMSO (stock 10 mM) and then MMP assay buffer solutions [50 mM HEPES, 10 mM CaCl ₂ , 150 nM NaCl, 1 μM zinc acetate, 600 μM CHAPS (pH 7.4)]. Human MMPs used in the assay are expressed in either full lenght or catalytic domains. Collagenase (MMP-1), gelatinase (MMP-9), elastase (MMP-12) and membrane type-1 (MMP-14) are cut off and reagent APMA (4-amino phenyl mercury acetate) Was activated using to obtain an active catalytic domain. In a conventional 100 μl reaction assay mixture, 1.0 μl of the desired MMP enzyme was incubated in buffer solution for 30 minutes in the presence or absence of 1.0 μl of NCE / standard. The reaction is initiated with fluorescent substrate-FAM-TAMRA (FAM-Thr-Pro-Gly-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-Arg-Lys-TAMRA-NH2) at the final concentration of 10 μM per well desired. The process proceeded for 45 minutes and the rate was monitored (increased in RFU) at excitation wavelength 495 nm and emission 525 nm. The blank reaction rate (no enzyme) is reduced at each value. Percent control was calculated using the following formula.

Percent Active = (Repression Rate / Control Speed) × 100

IC ₅₀ values were calculated using a minimum square regression analysis by Graph-Pad prism version 4.2 software and a 5-6 point dose response curve in the presence of inhibitors. IC ₅₀ values were averaged over duplicate analysis data and values to be presented in the table.

The present invention relates to compounds which act as dual MMP-9 / 12 inhibitors with preferred activity profiles.

The MMP-9 activity of the compounds described herein is about 10 μM to about 1 nM, or about 1 μM to about 3.2 nM, or about 650 nM to about 1 nM, in marimastat compared to about 1.4 nM to 3.2 nM, or An IC ₅₀ value of about 300 nM to about 1 nM, or about 100 nM to about 1 nM, or about 50 nM to about 1 nM, or about 30 nM to about 1 nM, or about 20 nM to about 1 nM, or about 12 nM to about 1 nM.

The MMP-12 activity of the compounds described herein is about 10 μM to about 1 nM, or about 1 μM to about 1 nM, or about 300 nM to about 1 nM, or about 100 nM to about 100 nM, relative to 0.2 nM to 0.9 nM for marimastat. An IC ₅₀ value of 1 nM, or about 50 nM to about 1 nM, or about 30 nM to about 1 nM, or about 20 nM to about 1 nM, or about 15 nM to about 1 nM, or about 7 nM to about 1 nM.

Claims (12)

In the compound of Formula 1,
Compounds comprising racemic compounds thereof, enantiomers and diastereomers thereof, or pharmacologically acceptable salts thereof:
(Formula 1)

[In the formula 1,
remind

Is phenyl, fluorophenyl, heteroaryl or heterocyclyl;
U is a bond, —NH—, —C (═O) —, — (CH ₂ ) _n −, —C (═S) —, —O—, —SO ₂ — or —S—, wherein n is 0 or an integer from 1 to 2;
V is a bond, —NH—, —C (═O) —, —C (═S) — or —SO ₂ —;
W is a bond, —NH—, —C (═O) —, — (CH ₂ ) _n —, —C (═S) —, —O—, —S— or —SO ₂ —;
remind

Is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be further substituted with one or more substituents independently selected from R ¹ below;
R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ Alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= 0) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n -NHC (= O) -R _f ,-(CH ₂ ) _n -OC (= O) -NR _f R _q , (CH ₂ ) _n NHC (= O ) NR _f R _q ,-(CH ₂ ) _n -OC (= O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n S (= O ) _m -NR _f R _q (where R _f and R _q are independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is an integer from 0 to 2);
remind

Is selected from heteroaryl or heterocyclyl] The method of claim 1,
A compound having the structure of Formula 2 and comprising a racemic compound, enantiomers and diastereomers thereof, or a pharmacologically acceptable salt thereof:
(2)

[In Formula 2,
remind

Is phenyl, fluorophenyl, heteroaryl or heterocyclyl;
L ¹ is a bond,-(CH ₂ ) _n- , -NHCO (CH ₂ ) _n -,-(CH ₂ ) _n C (= 0) NH-, -NHC (= 0) NH-, -SO ₂ NH -, -NHSO _2- , -SO _2- , -NHC (= O) (O)-, -O- (CH ₂ ) _n -,-(CH ₂ ) _n -O-,-(CH ₂ ) _n OC (= O) NH-, -C (= S) NH-, -NHC (= S)-or -NHC (= S) NH-, n is 0 or an integer from 1 to 2;
remind

Is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be further substituted with one or more substituents independently selected from R ¹ below;
R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= O) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n- NHC (= 0) -R _f ,-(CH ₂ ) _n -OC (= 0) NR _f R _q , (CH ₂ ) _n NHC (= 0) NR _f R _q ,-(CH ₂ ) _n -OC ( = O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n S (= O) _m -NR _f R _q (where R _f and R _q are Independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is an integer from 0 to 2 )ego;
remind

Is heteroaryl or heterocyclyl] The method of claim 1,
A compound having the structure of Formula 3 and comprising a racemic compound thereof, an enantiomer and diastereomer thereof, or a pharmacologically acceptable salt thereof:
(Formula 3)

[In Formula 3,
remind

Is mono, bi or polycyclic heteroaryl or heterocyclyl selected from the following compounds;

V is 0 or an integer from 1 to 4;
Ra is hydrogen or fluorine;
R ¹ and L ¹ And

As defined in paragraph 1] The method of claim 1,
A compound having the structure of Formula 4 and comprising a racemic compound, enantiomers and diastereomers thereof, or a pharmacologically acceptable salt thereof:
(Formula 4)

[In Formula 4,
L ^la is S (O) _n , NHCO (CH ₂ ) _n and NHCO (O);
Ra,

And

Is as defined in paragraph 1] In the compound of Formula 1,
Racemic compounds, enantiomers and diastereomers thereof, or pharmacologically acceptable salts thereof, including:
(2S) -2-[(S)-{4-[(4-chlorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (Compound 1);
(2S) -2-[(S)-{4-[(4-chlorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (Compound 2);
(2S) -2-[(S)-{4-[(3,4-difluorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 3);
(2S) -2-[(S)-{4-[(2,3-dichlorophenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 4);
(2S) -2-[(S)-{4-[(2,4-dimethylphenyl) sulfinyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 5);
(2S) -2-[(S)-{4-[(4-fluorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 6);
(2S) -2-[(S)-{4-[(3,4-difluorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 7);
2-[{4-[(2,3-dichlorophenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl ) Butanoic acid (compound 8);
(2S) -2-[(S)-{4-[(2,4-dimethylphenyl) sulfonyl] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 9);
(2S) -2-[(S)-(4-{[(4-ethylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 10);
(2S) -2-[(S)-(4-{[(4-chlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 11);
(2S) -2-[(S)-(4-{[(3,4-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 12);
(2S) -2-[(S) -hydroxy (4-{[(4-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 13);
(2S) -2-[(S) -hydroxy (4-{[(3-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 14);
(2S) -2-[(S) -hydroxy (4-{[(4-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 15);
(2S) -2-[(S)-(4-{[(4-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 16);
(2S) -2-{(S) -hydroxy [4-({[4-methoxy-3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 17);
(2S) -2-[(S) -hydroxy (4-{[(5-methyl-1,2-oxazol-3-yl) carbonyl] amino} phenyl) methyl] -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 18);
(2S) -2-[(S)-(4-{[(3-chloro-4-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1, 2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 19);
(2S) -2-[(S) -hydroxy {4-[(phenylcarbonyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 20);
(2S) -2-[(S) -hydroxy (4-{[(4-propylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 21);
(2S) -2-[(S) -hydroxy {4-[(phenoxycarbonyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 22);
(2S) -2-[(S) -hydroxy {4-[(phenylacetyl) amino] phenyl} methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H)- I) butanoic acid (compound 23);
(2S) -2-[(S)-(4-{[(2,4-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 24);
(2S) -2-[(S) -hydroxy (4-{[(2-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 25);
(2S) -2-[(S)-(4-{[(2-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 26);
(2S) -2-[(S)-(4-{[(3-chlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 27);
(2S) -2-[(S) -hydroxy (4-{[(3-methylphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine- 3 (4H) -yl) butanoic acid (compound 28);
(2S) -2-[(S)-(4-{[(3-fluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 29);
(2S) -2-[(S)-(4-{[(2,6-dimethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 30);
(2S) -2-[(S)-{4-[(cyclopentylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 31);
(2S) -2-[(S) -hydroxy (4-{[(2,4,5-trifluoro-3-methoxyphenyl) carbonyl] amino} phenyl} methyl] -4- (4- Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 32);
(2S) -2-[(S) -hydroxy (4-{[(2,3,4-trifluorophenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 33);
(2S) -2-{(S) -hydroxy [4-({[2- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 34);
(2S) -2-[(S)-(4-{[(3,5-dimethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 35);
(2S) -2-[(S)-(4-{[(2,3-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 36);
(2S) -2-[(S)-(4-{[(3,5-dichlorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 37);
(2S) -2-[(S)-(4-{[(2,4-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 38);
(2S) -2-[(S)-(4-{[(2,6-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 39);
(2S) -2-[(S) -hydroxy (4-{[(2-methoxyphenyl) carbonyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 40);
(2S) -2-[(S)-{4-[(cyclohexylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 41);
(2S) -2-[(S)-(4-{[(4-ethoxyphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 42);
(2S) -2-[(S)-(4-{[(3,4-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 43);
(2S) -2-{(S) -hydroxy [4-({[4- (trifluoromethoxy) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 44);
(2S) -2-{(S) -hydroxy [4-({[3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2, 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 45);
(2S) -2-[(S)-[4-({[2-fluoro-4- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] (hydroxy) methyl] -4- (4 Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 46);
(2S) -2-[(S)-(4-{[(3-chloro-2,6-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo -1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 47);
(2S) -2-{(S) -hydroxy [4-({[4-trifluoromethyl) phenyl] carbonyl} amino) phenyl] methyl} -4- (4-oxo-1,2,3 -Benzotriazine-3 (4H) -yl) butanoic acid (compound 48);
(2S) -2-[(S)-(4-{[(2,5-difluorophenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2 , 3-benzotriazine-3 (4H) -yl) butanoic acid (compound 49);
(2S) -2-[(S)-(4-{[(2,3-difluoro-4-methylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo- 1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 50);
(2S) -2-[(S)-[4-({[4-fluoro-3- (trifluoromethyl) phenyl] carbonyl} amino) phenyl] (hydroxy) methyl] -4- (4 Oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 51);
(2S) -2-[(S)-{4-[(cyclopropylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (Compound 52);
(2S) -2-[(S)-(4-{[(2-ethylphenyl) carbonyl] amino} phenyl) (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 53);
(2S) -2-[(S) -hydroxy (4-{[(4-methoxyphenyl) acetyl] amino} phenyl) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 54);
(2S) -2-[(S)-{4-[(cyclobutylcarbonyl) amino] phenyl} (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 55);
(2S) -2-{(S) -hydroxy [4- (4-methoxyphenoxy) phenyl] methyl} -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 56);
(2S) -2-[(S)-[4- (3-chloro-4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 57);
(2S) -2-[(S)-[4- (4-chloro-3-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 58);
(2S) -2-[(S)-[4- (4-chloro-2-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 59);
(2S) -2-[(S)-[4- (4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 ( 4H) -yl) butanoic acid (compound 60);
(2S) -2-[(S)-[4- (3,4-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 61);
(2S) -2-[(S)-[4- (2-chlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 62);
(2S) -2-[(S)-[4- (3-chlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H ) -Yl) butanoic acid (Compound 63);
(2S) -2-[(S)-[4- (2,6-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 64);
(2S) -2-[(S)-[4- (2,5-dichlorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -yl) butanoic acid (compound 65);
(2S) -2-[(S)-[4- (2-chloro-4-fluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 66);
(2S) -2-{(S) -hydroxy [4- (3-methoxyphenoxy) phenyl] methyl} -4- (4-oxo-1,2,3-benzotriazine-3 (4H) -Yl) butanoic acid (compound 67);
(2S) -2-[(S)-[4- (2-chloro-4-methoxyphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 68);
(2S) -2-[(S)-[4- (2,4-difluorophenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotriazine -3 (4H) -yl) butanoic acid (compound 69);
(2S) -2-[(S)-[3-fluoro-4- (4-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 70);
(2S) -2-[(S)-[3-fluoro-4- (3-methylphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzotri Azine-3 (4H) -yl) butanoic acid (compound 71);
(2S) -2-[(S)-[4- (3,4-dimethylphenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 72);
(2S) -2-[(S)-[4- (3,4-dichlorophenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 73);
(2S) -2-[(S)-[4- (4-tert-butylphenoxy) -3-fluorophenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3- Benzotriazine-3 (4H) -yl) butanoic acid (compound 74); And
(2S) -2-[(S)-[3-fluoro-4- (4-methoxyphenoxy) phenyl] (hydroxy) methyl] -4- (4-oxo-1,2,3-benzo Triazine-3 (4H) -yl) butanoic acid (compound 75). In the pharmaceutical composition,
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5 together with a pharmaceutically acceptable carrier, excipient or diluent. 6. The method according to any one of claims 1 to 5,
Compounds for use in the treatment or prophylaxis of animals or humans with inflammatory or allergic diseases. The method of claim 7, wherein
The inflammatory or allergic diseases include asthma, rheumatoid arthritis, COPD, rhinitis, degenerative arthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, restenosis And vascular endometrial hyperplasia, stroke, kidney disease or tumor metastasis associated with ischemic heart failure. The method according to claim 6,
A pharmacological composition further comprising one or more additional active ingredients selected from:
a) anti-inflammatory agents (i) nonsteroidal anti-inflammatory pyroxicam, diclofenac, propionic acid, fenamate, pyrazolone, salicylate, PDE Phosphodiesterase inhibitors, including -4 inhibitors, p38 MAP Kinase / Cathepsin inhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 Integrin antagonists, cell junction inhibitors (especially ICAMs), adenosine 2a agonists, (ii) leukotriene LTC4 / LTD4 / LTE4 / LTB4-inhibitors, 5-lipoxygenase inhibitors and PAF-receptor antagonists, (x) Cox- 2 inhibitors, (iii) other MMP inhibitors, (iii) interleukin-I inhibitors, (iii) alclometasone, amcinonide, amelometasone, beclomethasone ), Betamethasone, budesonide, ciclesonide (ci clesonide, clobetasol, cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesonide, diflorasone ), Difluprednate, fluticasone, flunisolide, halomethasone, haloperedone, hydrocortisone, methylprednisolone, methylprednisolone, Mometasone, prednicarbate, prednisolone, premisolone, rimexolone, thixocortol, triamcinolone, ulobetasol, rofleponide ), GW 215864, KSR 592, ST-126, dexamethasone, and their pharmacologically acceptable salts and solvates, preferred corticosteroids are for example flunisolide, beclomethasone, triamcinolone, Sony to DE, fluticasone, mometasone, ciclesonide, and a dexamethasone;
b) beta agonists, suitable β2-agonists for example one or more albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol , Tulobuterol, terbutaline, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, ar Formoterol, formoterol and their pharmacologically acceptable salts, or solvates of one or more of the above β2-agonists;
c) antihypertensives, (i) ACE inhibitors such as enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists such as losarartan, candesartan, irbesartan, valsartan and eprosartan, (ⅲ) β-blockers , And (iii) calcium channel blockers;
d) immunosuppressive agents, such as cyclosporine, azathioprine and methotrexate, anti-inflammatory corticosteroids; And
e) anti-infective agents. Compound of formula 11 (wound A is phenyl, U is -S0 _2- , and V and W are bonded) and compound of formula 12 (ring A is phenyl, U is -O-, V And in the method of producing formula (1) when W is bonded,
A method comprising the steps of:
Formula 11

(Formula 12)

a) reacting a compound of formula 5 with a compound of formula 6 to produce a compound of formula 7;
(Formula 5)

(Formula 6)

(Formula 7)

b) reacting the compound of Formula 7 with the compound of Formula 8 to produce a compound of Formula 9;
(Formula 8)

(Formula 9)

c) hydrolyzing the compound of Formula 9 (when X is S) to produce a compound of Formula 10;
(Formula 10)

d) oxidizing the compound of Formula 10 to produce a compound of Formula 11; or
e) hydrolyzing the compound of formula 9 (when X is O) to produce a compound of formula 12:
[In the above formula,
remind

Is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is further substituted by one or more substituents independently selected from R ¹ ,
R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= O) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n- NHC (= O) -R _f ,-(CH ₂ ) _n -OC (= O) -NR _f R _q , (CH ₂ ) _n NHC (= O) NR _f R _q ,-(CH ₂ ) _n -OC (= O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n S (= O) _m -NR _f R _q (where R _f and R _q Is independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is 0 to 2 Integer);
remind

Is selected from heteroaryl or heterocyclyl;
X is O or S;
Rk is H, halo, alkyl, alkoxy, cyano, halogeno-C ₁ -C ₆ alkyl or halogeno-C ₁ -C ₆ alkoxy;
Z is 0-4;
L and W are each O or S;
Rx is alkyl, aryl or aralkyl] The compound of formula 18 (wound A is phenyl, U is -NH-, V is -CO-, and W is -NH-) and the compound of formula 21 (ring A is phenyl, U is In the method for producing formula (1) in which -NH-, and V and W are bonded together to be Rj,
A method comprising the steps of:
Formula 18

Formula 21

a) adding an aldol compound of formula 13 and a compound of formula 8 to produce a compound of formula 14;
(Formula 13)

(Formula 8)

(Formula 14)

b) reducing the compound of Formula 14 to produce a compound of Formula 15;
(Formula 15)

c) coupling a compound of Formula 15 (when G ₁ is amino) with a compound of Formula 16 to produce a compound of Formula 17;
Formula 15 when G ₁ is NH ₂

(Formula 16)

(Formula 17)

d) hydrolyzing the compound of formula 17 to produce a compound of formula 18; or
e) coupling the compound of Formula 15 with the compound of Formula 19 to produce a compound of Compound 20; And
(Formula 19)

(Formula 20)

f) hydrolyzing the compound of formula 20 to produce a compound of formula 21:
[In the above formula,
remind

Is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is further substituted by one or more substituents independently selected from R ¹ ,
R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= O) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n- NHC (= O) -R _f ,-(CH ₂ ) _n -OC (= O) NR _f R _q ,-(CH ₂ ) _n NHC (= O) NR _f R _q ,-(CH ₂ ) _n -OC (= O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n S (= O) _m -NR _f R _q (where R _f and R _q Is independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is 0 to 2 Integer);
remind

Is selected from heteroaryl or heterocyclyl;
Rk is H, halo, alkyl, alkoxy, cyano, halogeno-C ₁ -C ₆ alkyl or halogeno-C ₁ -C ₆ alkoxy;
Z is 0-4;
L and W are each O or S;
Rx is alkyl, aryl or aralkyl;
G is nitro or C (O) O-benzyl;
G ₁ is amino or COOH;
X is, for example, a leaving group such as halogen;
Rj is-(CH ₂ ) _0-1 -CO-, -C (O) O-, -SO _2- ] In the method for the preparation of a compound of formula 24 (Formula 1 when ring A is phenyl, U is -CO-, V is -NH- and W is a bond),
A method comprising the steps of:
(Formula 24)

a) coupling a compound of Formula 15 (when G ₁ is COOH) and a compound of Formula 22 to produce a compound of Formula 23; And
(Formula 22)

(Formula 15)

(Formula 23)

b) hydrolyzing the compound of formula 23 to produce a compound of formula 24:
[In the above formula,
remind

Is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is further substituted by one or more substituents independently selected from R ¹ ,
R ¹ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-C ₁ -C ₆ alkyl, halogeno-C ₁ -C ₆ alkoxy, azido, thiol, alkylthiol,-(CH ₂ ) _n -OR _f , -C (= O) -R _f , -COOR _f , -NR _f R _q ,-(CH ₂ ) _n -C (= O) NR _f R _q ,-(CH ₂ ) _n- NHC (= 0) -R _f ,-(CH ₂ ) _n -OC (= 0) -NR _f R _q ,-(CH ₂ ) _n NHC (= 0) NR _f R _q ,-(CH ₂ ) _n- OC (= O) -R _f ,-(CH ₂ ) _n -NH-C (= O) -R _f or-(CH ₂ ) _n S (= O) _m -NR _f R _q (where R _f and R _q is independently selected from halogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is 0 to 2 Is an integer of;
remind

Is selected from heteroaryl or heterocyclyl;
Rk is H, halo, alkyl, alkoxy, cyano, halogeno-C ₁ -C ₆ alkyl or halogeno-C ₁ -C ₆ alkoxy;
Z is 0-4;
L and W are each O or S;
Rx is alkyl, aryl or aralkyl]