RU2435763C2 - Human protein tyrosine phosphatase inhibitors and application methods thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

where R denotes a thiazolyl group of formula

R² and R³ are selected from: hydrogen, C₁-C₃linear alkyl; R⁴ is selected from: C₁-C₃linear or C₃cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)_n-R¹; R¹ is selected from: i) C₁-C₃linear or branched alkyl, optionally substituted with C₁-C₄alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C₁-C₄alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C₁-C₃alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C₁-C₃alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C₁-C₄alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C₁-C₃alkyl; d) C₁-C₄alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C₁-C₄alkoxy, halogen, methoxycarbonyl or >NHC(O)CH₃; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R^5aR^5b)]_w-; ii) -C(O)[C(R^6aR^6b)]_x-; iii) -C(O)[C(R^7aR^7b)]_yC(O)-; iv) -SO₂[C(R^8aR^8b)]_z-; R^5a, R^5b, R^6a, R^6b, R^7a, R^7b, R^8a and R^8b, each independently denotes: i) hydrogen; ii) C₁-C₃ linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

Description

The present invention relates to compounds effective as beta protein tyrosine phosphatase inhibitors of human protein (HPPT-β) by regulating angiogenesis. The present invention also relates to compositions containing one or more human protein beta-tyrosine phosphatase inhibitors (HPPT-β), and methods for controlling angiogenesis.

Angiogenesis, the development of new blood vessels from a pre-existing vasculature, plays a decisive role in a wide range of physiological and pathological processes (Nguyen LL et al., Int. Rev. Cytol., 204 , 1-48 (2001)). Angiogenesis is a complex process mediated by communication between endothelial cells, which are located on the border between the walls of blood vessels and their liquid contents, and their environment. In the early stages of angiogenesis, tissue or tumor cells produce and secrete pro-angiogenic growth factors in response to environmental stimuli, such as hypoxia. These factors diffuse near endothelial cells and stimulate receptors, which leads to the production and secretion of proteases that destroy the surrounding extracellular matrix. Activated endothelial cells begin to migrate and proliferate into the surrounding tissue in the direction of the source of these growth factors (Bussolino F., Trends Biochem. Sci., 22 , 251-256 (1997)). Endothelial cells then stop the proliferation and differentiation into tubular structures, which represents the first stage in the formation of stable developed blood vessels. Then, pericytoma cells, such as pericytes and smooth muscle cells, are recruited into the newly formed vessel at a further stage in the direction of achieving full development.

Angiogenesis is regulated by the balance of naturally occurring pro-angiogenic and anti-angiogenic factors. Vascular endothelial growth factor, fibroblast growth factor, and angiopoietin are a small number of many potential pro-angiogenic growth factors. Such ligands bind via the tyrosine kinases of their respective receptors to the surface of the endothelial cell and transduce signals that promote cell migration and proliferation. While many regulatory factors have been identified, the molecular mechanisms of this process are still completely incomprehensible.

There are many disease conditions caused by persistently unregulated or improperly regulated angiogenesis. In the case of such disease states, unregulated or improperly regulated angiogenesis can either provoke a specific disease or exacerbate an existing pathological condition. For example, ocular neovascularization is implied as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases. In the case of some previously existing conditions, such as arthritis, newly formed capillary blood vessels penetrate the joints and destroy cartilage. In diabetes, new capillaries formed in the retina penetrate the vitreous humor, causing bleeding and blindness. Both the development and metastasis of solid tumors are also dependent on angiogenesis (Folkman et al., Tumor Angiogenesis, chapter 10, 206-232, in The Molecular Basis of Cancer, Mendelsohn et al., Eds., WB Saunders (1995 )). It has been shown that tumors that grow to more than 2 mm in diameter should receive their own blood supply and, thus, satisfy the requirements by inducing the development of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide the nutrients and growth factors necessary for the development of the tumor, as well as a way for tumor cells to enter the circulatory system and metastasize to distant areas, such as the liver, lung, or bone (Weidner, New Eng. J. Med., 324 , 1, 1-8 (1991)). When used as drugs on tumor-bearing animals, natural angiogenesis inhibitors can prevent the growth of small tumors (O'Reilly et al., Cell, 79 , 315-28 (1994)). According to some protocols, the use of such inhibitors leads to regression and the formation of a “dormant” tumor even after discontinuation of treatment (O'Reilly et al., Cell, 88 , 277-85 (1997)). In addition, satisfactory angiogenesis inhibitors in the case of some tumors can potentiate their response to other treatment regimens (Teischer et al., Int. J. Cancer, 57 , 920-25 (1994)).

Although many disease conditions are triggered by constantly unregulated or improperly regulated angiogenesis, some disease conditions can be treated by increasing angiogenesis. Tissue growth and repair are biological events where cell proliferation and angiogenesis occur. So, an important aspect regarding wound healing is the revascularization of damaged tissue by angiogenesis.

Chronic, non-healing wounds are the main cause of prolonged soreness in the age-determined human population. This is especially true for bedridden or diabetic patients who develop severe, non-healing skin ulcers. In many of these cases, the delay in healing is the result of inadequate blood supply, either as a result of constant pressure or blockage of blood vessels. Insufficient capillary circulation due to small arterial atherosclerosis or venous stasis contributes to the failure to restore damaged tissue. Such tissues are often infected by microorganisms that proliferate undeniably due to the body’s innate defense systems, which require well-vascularized tissue to effectively remove pathogenic organisms. As a result, the greatest therapeutic effect is concentrated on the restoration of blood flow in ischemic tissues, providing nutrients and immunological factors with access to the wound site.

Atherosclerotic lesions in the case of large vessels can provoke tissue ischemia, which can be reduced in intensity by modulating the development of blood vessels in the damaged tissue. For example, atherosclerotic lesions in the coronary arteries can cause angina pectoris and myocardial infarction, which can be prevented if blood flow can be restored by stimulating the development of collateral arteries. Similarly, atherosclerotic lesions in the large arteries that supply the lower limbs can cause ischemia in the skeletal muscle, which limits mobility and, in some cases, necessitates amputation, which can also be prevented by improving blood flow through angiogenic therapy.

Other diseases, such as diabetes and hypertension, are characterized by a decrease in the number and density of small blood vessels, such as arteries and capillaries. These small blood vessels are important for the delivery of oxygen and nutrients. A decrease in the number and density of these vessels contributes to the adverse effects of hypertension and diabetes, including lameness, ischemic ulcers, a progressive variant of hypertensive disease, and renal failure. Such general disorders and many other less common ailments, such as Buerger's disease, can be reduced in intensity by increasing the number and density of small blood vessels using angiogenic therapy.

It has been suggested that one way of regulating angiogenesis is to treat patients with a human protein beta-tyrosine phosphatase inhibitor (HPTP-β) (Kruegar et al., EMBO J., 9 , (1990)), and therefore, to meet this need, obtained compounds of the present invention.

The present invention relates to compounds of formula (I) as shown below:

or their pharmaceutically acceptable salts, where the groups R and Z can be defined according to any of the various alternative descriptions provided below. It has been found that the compounds of formula (I) and / or their pharmaceutically acceptable salts are human protein beta-tyrosine phosphatase inhibitors (HPPT-β) and, therefore, are able to regulate angiogenesis in humans in order to treat various diseases that include, but, not limited to, diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, chronic uve um / vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retroletal fibroplasia, Ils disease, Behcet's disease caused by retinitis or chloroiditis infections, suspected ocular histoplasmosis, Best disease, myopia, congenital fossa in the optic disc, including Stargard disease periphery of the retina and ciliary circle, clinical syndrome, chronic retinal detachment, increased viscosity syndrome, toxoplasmosis, traumatic and post-laser complications associated with disease diversity and proliferative vitreoretinopathy, Crohn’s disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Randu-Osler-Weber disease, hereditary hemorrhagic telangiectasia, solid tumors or “blood tumors” on the scalp of newborns and neoplastic disease, and muscle and myocardial ischemia, stroke, peripheral vascular disease and coronary arterial disease.

The present invention also relates to pharmaceutical compositions containing one or more compounds of formula (I) and their pharmaceutically acceptable salts.

The present invention also relates to methods for controlling angiogenesis and thus providing treatment for diseases caused by angiogenesis, said methods comprising administering to a human an effective amount of one or more compounds of formula (I) and their pharmaceutically acceptable salts, as described herein.

These and other objects, features and advantages will become apparent to a person skilled in the art upon reading the following detailed description and the appended claims. All documents cited in the relevant part are incorporated into this description by reference; reference to any document should not be construed as an admission that the prior art is in accordance with the present invention.

In accordance with this description and the following claims, reference will be made to a number of terms that should be defined as having the following meanings:

All percentages, ratios and proportions in this description are massive, unless otherwise indicated. All temperatures are in degrees Celsius (° C), unless otherwise indicated.

By the term “pharmaceutically acceptable” is meant a substance that is not biologically or otherwise undesirable, that is, the substance can be administered to an individual together with the corresponding active compound without causing clinically unacceptable biological effects or harmful interaction with any of the other components of the pharmaceutical composition, in which it contains.

Throughout the description and claims of this description, the word “include” and other forms of the word, such as “including” and “includes”, means including, but not limited to, and does not imply the exclusion of, for example, other additives, components, whole operations or stages.

As used in the description and the attached claims, the singular forms include the plural indications, unless expressly stated otherwise in this description. For example, a reference to a “composition” includes mixtures of two or more such compositions, a reference to a “phenylsulfamic acid” includes mixtures of two or more such phenylsulfamic acids, a reference to a “compound” includes mixtures of two or more such compounds, etc. P.

The term “optional” or “optional” means that the subsequently described event or event may or may not occur, and that the description includes examples where the event or event occurs and examples where this is not.

Ranges may be expressed, as described herein, from “about” one particular value and / or to “about” another specific value. When such a range is clearly expressed, another aspect includes from one particular value and / or to another specific value. Similarly, when values are expressed as approximations, by using the preceding “about”, it should be understood that the particular value is another aspect. Further, it should be understood that the endpoints of each of the ranges are significant both with respect to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also described herein as “near” the specified specific value in addition to the value itself. For example, if the value "10" is indicated, then the value "about 10" is also indicated. It is also understood that when a value is indicated, then “less than or equal to” the value, “greater than or equal to the value”, and possible ranges between the values are also disclosed, as one of ordinary skill in the art will understand. For example, if the value “10” is indicated, then “less than or equal to 10” as well as “more than or equal to 10” are also disclosed. It is also understood that throughout the description, data is provided by a number of different formats and that this data represents endpoints and reference points and ranges for any combination of values. For example, if a specific value of “10” and a specific value of “15” are indicated, it is understood that directions greater than, greater than or equal to, less than, less than or equal to, or equal to 10 and 15, and also between 10 and 15 are considered disclosed. It is also understood that each unit of measure between two particular units of measure is also disclosed. For example, if 10 and 15 are indicated, then 11, 12, 13 and 14 are also disclosed.

An organic radical may have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms or 1-4 carbon atoms. Organic radicals often have hydrogen bonded to at least some carbon atoms of the organic radical. One example of an organic radical that does not include inorganic atoms is the 5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, the organic radical may contain 1-10 inorganic atoms bonded to or in, including halogen, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino group, disubstituted amino group, acyloxy group, cyano group, carboxyl, carbalkoxy, alkylcarboxylamidoalkylaminoalkylamidoalkylamidoalkylamidoalkylamidoalkylamidoalkylamidoalkylamidoalkylamidoalkylamido , thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic group ppu or substituted heterocyclic group, where the terms are defined elsewhere in this description. Some non-limiting examples of organic radicals that contain heteroatoms include alkoxy groups, trifluoromethoxy groups, acetoxy groups, dimethylamino groups and the like.

Substituted and unsubstituted, linear, branched or cyclic alkyl groups include the following, non-limiting examples: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), cyclopropyl (C ₃ ), n -butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), tert-butyl (C ₄ ), cyclobutyl (C ₄ ), cyclopentyl (C ₅ ), cyclohexyl (C ₆ ), etc. .; whereas substituted linear, branched or cyclic alkyl, non-limiting examples of which include hydroxymethyl (C ₁ ), chloromethyl (C ₁ ), trifluoromethyl (C ₁ ), aminomethyl (C ₁ ), 1-chloroethyl (C ₂ ), 2-hydroxyethyl ( C ₂ ), 1,2-difluoroethyl (C ₂ ), 2,2,2-trifluoroethyl (C ₃ ), 3-carboxypropyl (C ₃ ), 2,3-dihydroxycyclobutyl (C ₄ ) and the like.

Substituted and unsubstituted, linear, branched or cyclic alkenyl includes ethenyl (C ₂ ), 3-propenyl (C ₃ ), 1-propenyl (also 2-methylenethenyl) (C ₃ ), isopropenyl (also 2-methylethen-2-yl) (C ₃ ), buten-4-yl (C ₄ ) and the like; substituted linear or branched alkenyl, non-limiting examples of which include 2-chloroethenyl (also 2-chlorovinyl) (C ₂ ), 4-hydroxybuten-1-yl (C ₄ ), 7-hydroxy-7-methyl-oct-4-en-2- sludge (C ₉ ), 7-hydroxy-7-methyl-octo-3,5-dien-2-yl (C ₉ ) and the like.

Substituted and unsubstituted, linear or branched alkynyl include ethynyl (C ₂ ), prop-2-ynyl (also propargyl) (C ₃ ), propin-1-yl (C ₃ ) and 2-methylhex-4-yn-1-yl (C ₇ ); substituted linear or branched alkynyl, non-limiting examples of which include 5-hydroxy-5-methylhex-3-ynyl (C ₇ ), 6-hydroxy-6-methylhept-3-in-2-yl (C ₈ ), 5-hydroxy- 5-ethylhept-3-ynyl (C ₉ ) and the like.

The term “aryl,” as used herein, means organic rings that consist only of a ring system of conjugated planar carbon atoms with delocalized pi-electrons, non-limiting examples of which include phenyl (C ₆ ), naphthylene-1-yl (C ₁₀ ) , naphthylene-2-yl (C ₁₀ ). Aryl rings may have one or more hydrogen atoms substituted with another organic or inorganic radical. Non-limiting examples of substituted aryl rings include: 4-fluorophenyl (C ₆ ), 2-hydroxyphenyl (C ₆ ), 3-methylphenyl (C ₆ ), 2-amino-4-fluorophenyl (C ₆ ), 2- (N, N- diethylamino) phenyl (C ₆ ), 2-cyanophenyl (C ₆ ), 2,6-di-tert-butylphenyl (C ₆ ), 3-methoxyphenyl (C ₆ ), 8-hydroxynaphthylene-2-yl (C ₁₀ ), 4,5-dimethoxynaphthylene-1-yl (C ₁₀ ) and 6-cyanonaphthylene-1-yl (C ₁₀ ).

The term “heteroaryl” means an aromatic ring system comprising 5-10 atoms. Rings may be a single ring, such as, for example, a ring containing 5 or 6 atoms, where at least one atom of the ring is a heteroatom, but not limited to nitrogen, oxygen or sulfur. Or “heteroaryl” may mean a fused ring system with 8-10 atoms, where at least one of the rings is an aromatic ring, and at least one atom of the aromatic ring is a heteroatom, but not limited to nitrogen, oxygen or sulfur.

The following are non-limiting examples of heteroaryl rings of the present invention:

The term “heterocycle” means a ring system with 3 to 10 atoms, where at least one of the ring atoms is a heteroatom, but not limited to nitrogen, oxygen or sulfur. Rings may be single rings, fused rings or bicycles. Non-limiting examples of heterocycles include:

All of the above heteroaryl rings or heterocyclic rings may optionally be substituted with one or more hydrogen substituents, as described herein below.

Throughout the description of the present description, terms spelling "thiophen-2-yl and thiophen-3-yl" are used to describe heteroaryl residues of the corresponding formula:

whereas in the case of the name of the compounds of the present invention, the chemical nomenclature with respect to these fragments is usually spelled “thiophen-2-yl and thiophen-3-yl”, respectively. In this description, the terms “thiophen-2-yl and thiophen-3-yl” are used in the description of such rings as the groups or fragments that make up the compounds of the present invention, solely in order to make the description of the unambiguous person in this field in relation to rings, on which are referenced in this description.

The term "substituted" is used throughout the description. The term “substituted” is defined herein as “a hydrocarbon fragment, alicyclic or cyclic, which contains one or more hydrogen atoms replaced by a substituent or several substituents, as described hereinbelow”. These groups, when replacing hydrogen atoms, are able to replace one hydrogen atom, two hydrogen atoms or three hydrogen atoms of a hydrocarbon fragment at once. In addition, such substituents can replace two hydrogen atoms at two adjacent carbon atoms to form the above substituent, a new fragment or group. For example, a substituted moiety that requires replacement of one hydrogen atom includes halogen, hydroxyl, and the like. Substitution of two hydrogen atoms includes carbonyl, oxymino group and the like Replacing two hydrogen atoms at two adjacent carbon atoms includes an epoxy group and the like. Substitution of three carbon atoms includes a cyano group and the like. The term “substituted” is used throughout this description to indicate that a hydrocarbon moiety, for example an aromatic ring, an alkyl chain, may include one or more hydrogen atoms replaced by a substituent. When the residue is described as “substituted”, any number of hydrogen atoms can be replaced. For example, 4-hydroxyphenyl represents a “substituted aromatic carbocycle”, (N, N-dimethyl-5-amino) octanyl represents a “substituted C ₈ alkyl”, 3-guanidinopropyl represents a “substituted C ₃ alkyl” and 2-carboxypyridinyl represents “substituted heteroaryl”.

The following are non-limiting examples of groups that can replace hydrogen atoms in a moiety:

i) linear, branched or cyclic C ₁ -C ₁₂ alkyl, alkenyl and alkynyl; e.g. methyl (C ₁ ), ethyl (C ₂ ), ethenyl (C ₂ ), ethynyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), cyclopropyl (C ₃ ), 3-propenyl (C ₃ ), 1-propenyl (also 2-methylethyl) (C ₃ ), isopropenyl (also 2-methylene-2-yl) (C ₃ ), prop-2-ynyl (also propargyl) (C ₃ ), prop-1 -yl (C ₃ ), n-butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), tert-butyl (C ₄ ), cyclobutyl (C ₄ ), buten-4-yl (C ₄ ), cyclopentyl (C ₅ ), cyclohexyl (C ₆ );

ii) substituted or unsubstituted C ₆ - or C ₁₀ aryl; for example phenyl, naphthyl (also referred to herein as naphthylene-1-yl (C ₁₀ ) or naphthylene-2-yl (C ₁₀ );

iii) substituted or unsubstituted C ₁ -C ₉ heterocyclic rings as described herein below;

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl rings as described hereinbelow;

v) - (CR ^14a R ^14b ) _z OR ¹³ ; for example, —OH, —CH ₂ OH, —OCH ₃ , —CH ₂ OCH ₃ , —OCH ₂ CH ₃ , —CH ₂ OCH ₂ CH ₃ , —OCH ₂ CH ₂ CH ₃ and —CH ₂ OCH ₂ CH ₂ CH ₃ ;

vi) - (CR ^14a R ^14b ) _z C (O) R ¹³ ; for example, -COCH _3, -CH ₂ COCH _3, -OCH ₂ CH _3, -CH ₂ COCH ₂ CH _3, -COCH ₂ CH ₂ CH ₃ and -CH ₂ COCH ₂ CH ₂ CH _3;

vii) - (CR ^14a R ^14b ) _z C (O) OR ¹³ ; for example, —CO ₂ CH ₃ , —CH ₂ CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , —CH ₂ CO ₂ CH ₂ CH ₃ , —CO ₂ CH ₂ CH ₂ CH ₃ and —CH ₂ CO ₂ CH ₂ CH ₂ CH ₃ ;

viii) - (CR ^14a R ^14b ) _z C (O) N (R ¹³ ) ₂ ; for example, —CONH ₂ , —CH ₂ CONH ₂ , —CONHCO ₃ , —CH ₂ CONHCO ₃ , —CON (CH ₃ ) _2, and —CH ₂ CON (CH ₃ ) ₂ ;

ix) - (CR ^14a R ^14b ) _z N (R ¹³ ) ₂ ; for example, —NH ₂ , —CH ₂ NH ₂ , —NHCH ₃ , —N (CH ₃ ) ₂ , —NH (CH ₂ CH ₃ ), —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and - CH ₂ NH (CH ₂ CH ₃ );

x) halogen; -F, -Cl, -Br and -I;

xi) - (CR ^14a R ^14b ) _z CN;

xii) - (CR ^14a R ^14b ) _z NO ₂ ;

xiii) -CH _j X _k ; where X is halogen, j is from 0 to 2, j + k = 3; for example, —CH ₂ F, —CHF ₂ , —CF ₃ , —CCl _3, or —CBr ₃ ;

xiv) - (CR ^14a R ^14b ) _z SR ¹³ ; -SH, -CH ₂ SH, -SCH ₃ , -CH ₂ SCH ₃ , -SC ₆ H ₅ and -CH ₂ SC ₆ H ₅ ;

xv) - (CR ^14a R ^14b ) _z SO ₂ R ¹³ ; -SO ₂ H, -CH ₂ SO ₂ H, -SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ C ₆ H ₅ and -CH ₂ SO ₂ C ₆ H ₅ ;

xvi) - (CR ^14a R ^14b ) _z SO ₃ R ¹³ ; -SO ₃ H, -CH ₂ SO ₃ H, -SO ₃ CH ₃ , -CH ₂ SO ₃ CH ₃ , -SO ₃ C ₆ H ₅ and -CH ₂ SO ₃ C ₆ H ₅ ;

where R ¹³ each independently, means hydrogen, substituted or unsubstituted, linear, branched or cyclic C ₁ -C ₄ alkyl, phenyl, benzyl; or two R ¹³ groups taken together can form a ring containing 3-7 atoms; R ^14a and R ^14b each independently is hydrogen or linear or branched C ₁ -C ₄ alkyl; the z index is from 0 to 4.

The present invention is directed to some unmet medical needs, inter alia:

1) the provision of compositions effective as inhibitors of beta-tyrosine phosphatase of human protein (NTR-β); and thus providing a method for regulating angiogenesis in the event of a disorder, disease, disease, or condition where angiogenesis is elevated;

2) the provision of compositions effective as beta protein tyrosine phosphatase inhibitors (HPPT-β); and thus providing a method for regulating angiogenesis in the event of a disorder, disease, disease, or condition; and

3) the provision of compositions effective as inhibitors of beta-tyrosine phosphatase of human protein (NTRP-β); and thus providing a method for regulating angiogenesis in the event of a disorder, disease, disease, or condition where angiogenesis is reduced.

These and other unmet medical needs are met with the human protein beta-tyrosine phosphatase inhibitors (HPTP-β) of the present invention, which are able to control angiogenesis and thus serve as a method of treating increased or decreased angiogenesis in humans or in the treatment of diseases that are triggered inadequate regulation of human protein beta-tyrosine phosphatase (НРТР-β).

The compounds disclosed herein include all pharmaceutically acceptable salt forms, for example, salts of major groups, inter alia, amines, as well as salts of acidic groups, inter alia, sulfamic acids and carboxylic acids. The following are non-limiting examples of anions that can form salts with major groups such as amines: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, etc. The following are non-limiting examples of cations that can form salts with acidic groups, such as carboxylic acid / carboxylate groups: sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.

The compounds of the present invention are ethylamino substituted phenylsulfamic acids or their pharmaceutically acceptable salts having the central structure of compound (I) shown as shown below:

where the groups R and Z can be any of the alternatives defined below and given as examples in the description below. In such compounds of formula (I), the carbon atom carrying the amino group has the absolute stereochemistry (S), as shown in the above figure, which usually corresponds to the (S) configuration of the same carrying the amino group of the carbon atom, but which can be very dependent on the nature replacement group R and the resulting priority changes.

R groups

In some embodiments, the implementation of the R group of compounds of formula (I) can be substituted or unsubstituted heterocycles or heteroaryl rings with an number of atoms in the ring from 3 to 15. The substituted or unsubstituted heterocyclic or heteroaryl rings of group R of compounds of formula (I) can be represented below common ring A as shown below:

These heterocyclic or heteroaryl rings “A” may optionally be substituted with one, two or three independently selected substituents represented by groups of general formula R ¹⁵ . Non-limiting examples of substituent groups R ¹⁵ include:

i) linear, branched or cyclic alkyl, alkenyl and alkynyl; e.g. methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), cyclopropyl (C ₃ ), propylene-2-yl (C ₃ ), propargyl (C ₃ ), n-butyl (C ₄ ), isobutyl (C ₄ ), sec-butyl (C ₄ ), tert-butyl (C ₄ ), cyclobutyl (C ₄ ), n-pentyl (C ₅ ), cyclopentyl (C ₅ ), n-hexyl (C ₆ ) and cyclohexyl (C ₆ );

ii) substituted or unsubstituted aryl; for example, phenyl, 2-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 2-aminophenyl, 3-hydroxyphenyl, 4-trifluoromethylphenyl and biphenyl-4-yl;

iii) substituted or unsubstituted heterocycles, examples of which are given in the description below;

iv) substituted or unsubstituted heteroaryl, examples of which are given in the description below;

v) - (CR ^17a R ^17b ) _q OR ¹⁶ ; for example, —OH, —CH ₂ OH, —OCH ₃ , —CH ₂ OCH ₃ , —OCH ₂ CH ₃ , —CH ₂ OCH ₂ CH ₃ , —OCH ₂ CH ₂ CH ₃ and —CH ₂ OCH ₂ CH ₂ CH ₃ ;

vi) - (CR ^17a R ^17b ) _q C (O) R ¹⁶ ; for example, -COCH _3, -CH ₂ COCH _3, -OCH ₂ CH _3, -CH ₂ COCH ₂ CH _3, -COCH ₂ CH ₂ CH ₃ and -CH ₂ COCH ₂ CH ₂ CH _3;

vii) - (CR ^17a R ^17b ) _q C (O) OR ¹⁶ ; for example, —CO ₂ CH ₃ , —CH ₂ CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , —CH ₂ CO ₂ CH ₂ CH ₃ , —CO ₂ CH ₂ CH ₂ CH ₃ and —CH ₂ CO ₂ CH ₂ CH ₂ CH ₃ ;

viii) - (CR ^17a R ^17b ) _q C (O) N (R ¹⁶ ) ₂ ; for example, —CONH ₂ , —CH ₂ CONH ₂ , —CONHCO ₃ , —CH ₂ CONHCO ₃ , —CON (CH ₃ ) _2, and —CH ₂ CON (CH ₃ ) ₂ ;

ix) - (CR ^17a R ^17b ) _q OC (O) N (R ¹⁶ ) ₂ ; for example, —OC (O) NH ₂ , —CH ₂ OC (O) NH ₂ , —OC (O) NHCH ₃ , —CH ₂ OC (O) NHCH ₃ , —OC (O) N (CH ₃ ) _2, and -CH ₂ OC (O) N (CH ₃ ) ₂ ;

x) - (CR ^17a R ^17b ) _q N (R ¹⁶ ) ₂ ; for example, —NH ₂ , —CH ₂ NH ₂ , —NHCH ₃ , —N (CH ₃ ) ₂ , —NH (CH ₂ CH ₃ ), —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and - CH ₂ NH (CH ₂ CH ₃ );

xi) halogen; -F, -Cl, -Br and -I;

xii) -CH _m X _n ; where X is halogen, m is from 0 to 2, m + n = 3; for example, —CH ₂ F, —CHF ₂ , —CF ₃ , —CCl _3, or —CBr ₃ ;

xiii) - (CR ^17a R ^17b ) _q CN; for example, —CN, —CH ₂ CN and —CH ₂ CH ₂ CN;

xiv) - (CR ^17a R ^17b ) _q NO ₂ ; for example, —NO ₂ , —CH ₂ NO ₂ and —CH ₂ CH ₂ NO ₂ ;

xv) - (CR ^17a R ^17b ) _q SO ₂ R ¹⁶ ; for example, —SO ₂ H, —CH ₂ SO ₂ H, —SO ₂ CH ₃ , —CH ₂ SO ₂ CH ₃ , —SO ₂ C ₆ H ₅ and —CH ₂ SO ₂ C ₆ H ₅ ; and

xvi) - (CR ^17a R ^17b ) _q SO ₃ R ¹⁶ ; for example, —SO ₃ H, —CH ₂ SO ₃ H, —SO ₃ CH ₃ , —CH ₂ SO ₃ CH ₃ , —SO ₃ C ₆ H ₅ and —CH ₂ SO ₃ C ₆ H ₅ ;

where R ¹⁶ each independently, means hydrogen, substituted or unsubstituted linear, branched or cyclic C ₁ -C ₄ alkyl; or two R ¹⁶ groups taken together can form a ring containing 3-7 ring atoms; R ^17a and R ^17b , each independently, is hydrogen or straight or branched C ₁ -C ₄ alkyl; index q is from 0 to 4.

When the groups R ¹⁵ include linear, branched or cyclic C ₁ -C ₁₂ alkyl, alkenyl; substituted or unsubstituted C ₆ - or C ₁₀ aryl; substituted or unsubstituted C ₁ -C ₉ heterocycle; or substituted or unsubstituted C ₁ -C ₉ heteroaryl, R ¹⁵ groups may also have one or more hydrogen atoms substituted by R ¹⁸ groups. Non-limiting examples of R ¹⁸ groups include:

i) linear, branched or cyclic alkyl, alkenyl and alkynyl; e.g. methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), cyclopropyl (C ₃ ), propylene-2-yl (C ₃ ), propargyl (C ₃ ), n -butyl (C ₄ ), isobutyl (C ₄ ), sec-butyl (C ₄ ), tert-butyl (C ₄ ), cyclobutyl (C ₄ ), n-pentyl (C ₅ ), cyclopentyl (C ₅ ), n -hexyl (C ₆ ) and cyclohexyl (C ₆ );

ii) - (CR ^20a R ^20b ) _q OR ¹⁹ ; for example, —OH, —CH ₂ OH, —OCH ₃ , —CH ₂ OCH ₃ , —OCH ₂ CH ₃ , —CH ₂ OCH ₂ CH ₃ , —OCH ₂ CH ₂ CH ₃ and —CH ₂ OCH ₂ CH ₂ CH ₃ ;

iii) - (CR ^20a R ^20b ) _q C (O) R ¹⁹ ; for example, -COCH _3, -CH ₂ COCH _3, -OCH ₂ CH _3, -CH ₂ COCH ₂ CH _3, -COCH ₂ CH ₂ CH ₃ and -CH ₂ COCH ₂ CH ₂ CH _3;

iv) - (CR ^20a R ^20b ) _q C (O) OR ¹⁹ ; for example, —CO ₂ CH ₃ , —CH ₂ CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , —CH ₂ CO ₂ CH ₂ CH ₃ , —CO ₂ CH ₂ CH ₂ CH ₃ and —CH ₂ CO ₂ CH ₂ CH ₂ CH ₃ ;

v) - (CR ^20a R ^20b ) _q C (O) N (R ¹⁹ ) ₂ ; for example, —CONH ₂ , —CH ₂ CONH ₂ , —CONHCO ₃ , —CH ₂ CONHCO ₃ , —CON (CH ₃ ) _2, and —CH ₂ CON (CH ₃ ) ₂ ;

vi) - (CR ^20a R ^20b ) _q OC (O) N (R ¹⁹ ) ₂ ; for example, —OC (O) NH ₂ , —CH ₂ OC (O) NH ₂ , —OC (O) NHCH ₃ , —CH ₂ OC (O) NHCH ₃ , —OC (O) N (CH ₃ ) _2, and -CH ₂ OC (O) N (CH ₃ ) ₂ ;

vii) - (CR ^20a R ^20b ) _q N (R ¹⁹ ) ₂ ; for example, —NH ₂ , —CH ₂ NH ₂ , —NHCH ₃ , —N (CH ₃ ) ₂ , —NH (CH ₂ CH ₃ ), —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and - CH ₂ NH (CH ₂ CH ₃ );

viii) halogen; -F, -Cl, -Br and -I;

ix) -CH _m X _n ; where X is halogen, m is from 0 to 2, m + n = 3; for example, —CH ₂ F, —CHF ₂ , —CF ₃ , —CCl _3, or —CBr ₃ ;

x) - (CR ^20a R ^20b ) _q CN; for example, —CN, —CH ₂ CN and —CH ₂ CH ₂ CN;

xi) - (CR ^20a R ^20b ) _q NO ₂ ; for example, —NO ₂ , —CH ₂ NO ₂ and —CH ₂ CH ₂ NO ₂ ;

xii) - (CR ^20a R ^20b ) _q SO ₂ R ¹⁹ ; for example, —SO ₂ H, —CH ₂ SO ₂ H, —SO ₂ CH ₃ , —CH ₂ SO ₂ CH ₃ , —SO ₂ C ₆ H ₅ and —CH ₂ SO ₂ C ₆ H ₅ ; and

xiii) - (CR ^20a R ^20b ) _q SO ₃ R ¹⁹ ; for example, —SO ₃ H, —CH ₂ SO ₃ H, —SO ₃ CH ₃ , —CH ₂ SO ₃ CH ₃ , —SO ₃ C ₆ H ₅ and —CH ₂ SO ₃ C ₆ H ₅ ;

where R ¹⁹ each independently, means hydrogen, substituted or unsubstituted linear, branched or cyclic C ₁ -C ₄ alkyl; or two R ¹⁹ groups taken together can form a ring containing 3-7 atoms; R ^20a and R ^20b each independently is hydrogen or linear or branched C ₁ -C ₄ alkyl; index q is from 0 to 4.

In the following description, the groups R ¹⁵ and R ¹⁸ can be represented by substituents of a particular ring, such as, for example, the ring included in the definition of R can be given in the form or corresponding to the formula

or corresponding to the formula:

Both of the above formulas are equally fully valid for the optionally substituted thiazolyl ring.

R groups

R groups include a ring containing from 3 to 15 atoms in the ring.

R groups may include 5 membered heteroaryl rings. The following are non-limiting examples of 5 membered heteroaryl rings:

i)

ii)

iii)

iv)

v)

vi)

vii)

viii)

ix)

x)

xi)

xii)

xiii)

xiv)

и xv)

and

xvi)

As described herein, 5-membered heteroaryl rings may be substituted with one or more hydrogen substituents, for example a methyl group:

or a hydrogen substituent, which in itself is also substituted, for example:

Examples of R groups with a 5 membered ring include thiazolyl groups having the formula:

One example of a thiazolyl group R includes thiazol-2-yl groups having the formula:

where R ² and R ³ each independently selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl; or

R ² and R ³ taken together can form a saturated or unsaturated ring containing from 5 to 7 atoms.

One example of such an R group relates to groups of the formula:

where R ³ means hydrogen, and R ² means a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec- butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ).

Another example of the R group relates to groups where R ² is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ); and R ³ means a group selected from methyl (C ₁ ) or ethyl (C ₂ ). Non-limiting examples of this aspect of R include 4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl, 4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yl.

The following example of the group R refers to groups where R ³ means hydrogen and R ² means a substituted alkyl group, and the substituents are selected from:

i) halogen: —F, —Cl, —Br and —I;

ii) -N (R ¹¹ ) ₂ and

iii) -OR ¹¹ ;

where R ¹¹ each independently, is hydrogen or linear or branched C ₁ -C ₄ alkyl. Non-limiting examples of groups including this embodiment R include: —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ CF ₃ , —CH ₂ Cl, —CH ₂ OH, —CH ₂ OCH ₃ , —CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , —CH ₂ NH ₂ , —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and —CH ₂ NH (CH ₂ CH ₃ ).

Another further example of R groups includes groups where R ³ is hydrogen and R ² is phenyl.

Another further example of R groups includes groups where R ³ is hydrogen and R ² is a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5- sludge, [1,2,3] triazol-4-yl, [1,2,3] triazol-5-yl, [1,2,4] triazol-4-yl, [1,2,4] triazol- 5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3- sludge, isoxazol-4-yl, isoxazol-5-yl, [1,2,4] oxadiazol-3-yl, [1,2,4] oxadiazol-5-yl, [1,3,4] oxadiazol-2 -yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl , thiazol-4-yl, thiazol-5-yl, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl and [1,3,4] thiadiazol-2-yl .

One example of R includes groups wherein R ² is thiophen-2-yl or thiophen-3-yl.

Another example of R groups includes thiazol-4-yl groups of the formula:

where R ⁴ represents a group selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl.

One example of R groups includes compounds wherein R ⁴ is hydrogen.

Another example of R groups includes compounds wherein R ⁴ is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ). Non-limiting examples of this aspect of R include 2-methylthiazol-4-yl, 2-ethylthiazol-4-yl, 2- (n-propyl) thiazol-4-yl and 2- (isopropyl) thiazol-4-yl.

A further example of R groups includes compounds wherein R ⁴ is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl and 4-methoxyphenyl.

Another other example of R groups includes compounds wherein R ⁴ is a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5 -yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3 methyl-1,2,4-oxadiazol-5-yl.

The following example of R groups with a 5-membered ring includes substituted or unsubstituted imidazolyl groups of the formula:

One example of thiazolyl groups of R includes imidazol-2-yl groups having the formula:

where R ² and R ³ each independently selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl; or

R ² and R ³ taken together can form a saturated or unsaturated ring containing from 5 to 7 atoms.

One example of R groups includes compounds wherein R groups have the formula:

where R ³ means hydrogen, and R ² means a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec- butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ).

Another example of R groups includes compounds wherein R ² is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ); and R ³ means a group selected from methyl (C ₁ ) or ethyl (C ₂ ). Non-limiting examples of this aspect of R include 4,5-dimethylimidazol-2-yl, 4-ethyl-5-methylimidazol-2-yl, 4-methyl-5-ethylimidazol-2-yl, and 4,5-diethylimidazol-2-yl.

One example of R groups includes compounds wherein R ³ is hydrogen and R ² is a substituted alkyl group, wherein the substituents are selected from:

i) halogen: —F, —Cl, —Br and —I;

ii) -N (R ¹¹ ) ₂ and

iii) -OR ¹¹ ;

where R ¹¹ each independently, is hydrogen or linear or branched C ₁ -C ₄ alkyl. Non-limiting examples of groups including this embodiment R include: —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ CF ₃ , —CH ₂ Cl, —CH ₂ OH, —CH ₂ OCH ₃ , —CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , —CH ₂ NH ₂ , —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and —CH ₂ NH (CH ₂ CH ₃ ).

Another further example of R groups includes groups where R ³ is hydrogen and R ² is phenyl.

Another further example of R groups includes groups where R ³ is hydrogen and R ² is a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5- sludge, [1,2,3] triazol-4-yl, [1,2,3] triazol-5-yl, [1,2,4] triazol-4-yl, [1,2,4] triazol- 5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3- sludge, isoxazol-4-yl, isoxazol-5-yl, [1,2,4] oxadiazol-3-yl, [1,2,4] oxadiazol-5-yl, [1,3,4] oxadiazol-2 -yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl , thiazol-4-yl, thiazol-5-yl, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl and [1,3,4] thiadiazol-2-yl .

One example of R includes groups wherein R ² is thiophen-2-yl or thiophen-3-yl.

Another example of R groups includes imidazol-4-yl groups of the formula:

where R ⁴ represents a group selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl.

One example of this embodiment of R groups relates to compounds wherein R ⁴ is hydrogen.

One example of R groups includes compounds wherein R ⁴ is hydrogen.

Another example of R groups includes compounds wherein R ⁴ is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ). Non-limiting examples of this aspect of R include 2-methylimidazol-4-yl, 2-ethylimidazol-4-yl, 2- (n-propyl) imidazol-4-yl, and 2- (isopropyl) imidazol-4-yl.

A further example of R groups includes compounds wherein R ⁴ is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl and 4-methoxyphenyl.

Another other example of R groups includes compounds wherein R ⁴ is a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5 -yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3 methyl-1,2,4-oxadiazol-5-yl.

The following examples of R groups with a 5-membered ring are substituted or unsubstituted oxazolyl groups of the formula:

One example of oxazolyl groups of R includes oxazol-2-yl groups having the formula:

where R ² and R ³ each independently selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl; or

R ² and R ³ taken together can form a saturated or unsaturated ring containing from 5 to 7 atoms.

One example of R groups includes compounds wherein R groups have the formula:

where R ³ means hydrogen, and R ² means a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec- butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ).

Another example of R groups includes groups where R ² is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ); and R ³ means a group selected from methyl (C ₁ ) or ethyl (C ₂ ). Non-limiting examples of this aspect of R include 4,5-dimethyloxazol-2-yl, 4-ethyl-5-methyloxazol-2-yl, 4-methyl-5-ethyloxazol-2-yl, and 4,5-diethyl-oxazol-2- silt

A further example of R groups includes groups where R ³ is hydrogen and R ² is a substituted alkyl group, wherein the substituents are selected from:

i) halogen: —F, —Cl, —Br and —I;

ii) -N (R ¹¹ ) ₂ and

iii) -OR ¹¹ ;

where R ¹¹ each independently, is hydrogen or linear or branched C ₁ -C ₄ alkyl. Non-limiting examples of groups including this embodiment R include: —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ CF ₃ , —CH ₂ Cl, —CH ₂ OH, —CH ₂ OCH ₃ , —CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , —CH ₂ NH ₂ , —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and —CH ₂ NH (CH ₂ CH ₃ ).

Another further example of R groups includes groups where R ³ is hydrogen and R ² is phenyl.

Another further example of R groups includes groups where R ³ is hydrogen and R ² is a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5- sludge, [1,2,3] triazol-4-yl, [1,2,3] triazol-5-yl, [1,2,4] triazol-4-yl, [1,2,4] triazol- 5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3- sludge, isoxazol-4-yl, isoxazol-5-yl, [1,2,4] oxadiazol-3-yl, [1,2,4] oxadiazol-5-yl, [1,3,4] oxadiazol-2 -yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl , thiazol-4-yl, thiazol-5-yl, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl and [1,3,4] thiadiazol-2-yl .

One example of R includes groups wherein R ² is thiophen-2-yl or thiophen-3-yl.

Another example of R groups includes oxazol-4-yl groups of the formula:

where R ⁴ represents a group selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl.

One example of this embodiment of R groups relates to compounds wherein R ⁴ is hydrogen.

One example of R groups includes compounds wherein R ⁴ is hydrogen.

Another example of R groups includes compounds wherein R ⁴ is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ). Non-limiting examples of this aspect of R include 2-methyloxazol-4-yl, 2-ethyloxazol-4-yl, 2- (n-propyl) oxazol-4-yl, and 2- (isopropyl) -oxazol-4-yl.

A further example of R groups includes compounds wherein R ⁴ is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl and 4-methoxyphenyl.

Another other example of R groups includes compounds wherein R ⁴ is a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5 -yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3 methyl-1,2,4-oxadiazol-5-yl.

A further example of R groups relates to oxazol-5-yl groups of the formula:

where R ⁴ represents a group selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl.

One example of R groups includes compounds wherein R ⁴ is hydrogen.

Another example of R groups includes compounds wherein R ⁴ is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ). Non-limiting examples of this kind of R include 2-methyloxazol-4-yl, 2-ethyloxazol-4-yl, 2- (n-propyl) oxazol-4-yl and 2- (isopropyl) -oxazol-4-yl.

A further example of R groups includes compounds wherein R ⁴ is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl and 4-methoxyphenyl.

Another other example of R groups includes compounds wherein R ⁴ is a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5 -yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3 methyl-1,2,4-oxadiazol-5-yl.

Another other example of R groups with a 5-membered ring includes substituted or unsubstituted [1,2,4] oxadiazolyl groups of the formula:

One example of the [1,2,4] oxadiazolyl groups of R includes [1,2,4] oxadiazol-3-yl groups of the formula:

where R ₂ choose from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl.

One example of R groups includes groups where R ² is hydrogen.

Another example includes R groups, where R ² is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ); and R ³ means a group selected from methyl (C ₁ ) or ethyl (C ₂ ). Non-limiting examples of this aspect of R include 5-methyl [1,2,4] oxadiazol-2-yl, 5-ethyl [1,2,4] oxadiazol-2-yl, 5-propyl [1,2,4] oxadiazole- 2-yl and 5-cyclopropyl [1,2,4] oxadiazol-2-yl.

A further example of R groups includes groups wherein R ² is a substituted alkyl group, wherein the above substituents are selected from:

i) halogen: —F, —Cl, —Br and —I;

ii) -N (R ¹¹ ) ₂ and

iii) -OR ¹¹ ;

where R ¹¹ each independently, is hydrogen or linear or branched C ₁ -C ₄ alkyl. Non-limiting examples of groups including this embodiment R include: —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ CF ₃ , —CH ₂ Cl, —CH ₂ OH, —CH ₂ OCH ₃ , —CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , —CH ₂ NH ₂ , —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and —CH ₂ NH (CH ₂ CH ₃ ).

Another further example of R groups includes groups where R ² is phenyl.

Another further example of R groups includes groups where R ² is a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2 , 3] triazol-4-yl, [1,2,3] triazol-5-yl, [1,2,4] triazol-4-yl, [1,2,4] triazol-5-yl, imidazol- 2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4- sludge, isoxazol-5-yl, [1,2,4] oxadiazol-3-yl, [1,2,4] oxadiazol-5-yl, [1,3,4] oxadiazol-2-yl, furan-2 -yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl thiazole-5- la, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl, and [1,3,4] thiadiazol-2-yl.

Specific examples of R groups include groups where R ² is thiophen-2-yl or thiophen-3-yl.

Another example of R groups includes [1,2,4] oxadiazol-5-yl groups of the formula:

where R ⁴ means a group selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl.

One example of R groups includes compounds wherein R ⁴ is hydrogen.

Another example of R groups includes compounds wherein R ⁴ is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ). Non-limiting examples of this aspect of R include 3-methyl [1,2,4] oxadiazol-5-yl, 3-ethyl [1,2,4] oxadiazol-5-yl, 3- (n-propyl) [1,2, 4] oxadiazol-5-yl and 3- (isopropyl) [1,2,4] oxadiazol-5-yl.

A further example of R groups includes compounds wherein R ⁴ is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl and 4-methoxyphenyl.

Another other example of R groups includes compounds wherein R ⁴ is a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5 -yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3 methyl-1,2,4-oxadiazol-5-yl.

Further, non-limiting examples of 5-membered heteroaryl rings include:

i)

ii)

iii)

iv)

v)

vi)

иvii)

and

viii)

R groups may include 5 membered heterocyclic rings. Non-limiting examples of 5-membered heterocyclic rings include:

i)

ii)

iii)

iv)

v)

иvi)

and

vii)

R groups may include 6 membered heterocyclic rings. Non-limiting examples of 6 membered heterocyclic rings include:

i)

ii)

иiii)

and

iv)

R groups may include 6 membered heteroaryl rings. Non-limiting examples of 6 membered heteroaryl rings include:

i)

ii)

иiii)

and

iv)

An example of 6 membered heteroaryl rings includes pyrimidin-2-yl groups of the formula:

where R ² , R ³ and R ⁴ each independently selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted C ₁ -C ₉ heteroaryl; or

R ² and R ³ or R ³ and R ⁴ taken together can form a saturated or unsaturated ring containing from 5 to 7 atoms.

Another example of R groups includes groups of the formula:

where R ³ and R ⁴ are both hydrogen and R ² is a group selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl ( C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ).

Further examples of R groups include groups where R ² and R ³ are selected from methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), sec -butyl (C ₄ ), isobutyl (C ₄ ) and tert-butyl (C ₄ ); and R ⁴ means hydrogen. Non-limiting examples of this aspect of R include 4,5-dimethylpyrimidin-2-yl, 4,5-diethylpyrimidin-2-yl, 4-methyl-5-ethylpyrimidin-2-yl, and 4-ethyl-5-methylpyrimidin-2-yl.

Another further example of R groups includes groups where R ⁴ is hydrogen, and R ² and R ³ are selected from:

i) halogen: —F, —Cl, —Br and —I;

ii) -N (R ¹¹ ) ₂ and

iii) -OR ¹¹ ;

where R ¹¹ each independently, is hydrogen or linear or branched C ₁ -C ₄ alkyl. Non-limiting examples of groups including this embodiment R include: —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ CF ₃ , —CH ₂ Cl, —CH ₂ OH, —CH ₂ OCH ₃ , —CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , —CH ₂ NH ₂ , —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) _2, and —CH ₂ NH (CH ₂ CH ₃ ).

Another further example of R groups includes groups where R ² or R ³ is substituted phenyl and R ⁴ is hydrogen.

Another further example of R groups includes groups where R ⁴ is hydrogen and R ² or R ³ is a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazole -5-yl, [1,2,3] triazol-4-yl, [1,2,3] triazol-5-yl, [1,2,4] triazol-4-yl, [1,2,4 ] triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazole -3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4] oxadiazol-3-yl, [1,2,4] oxadiazol-5-yl, [1,3,4] oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazo -2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl and [1,3,4] thiadiazol-2-yl.

The following are non-limiting examples of R groups, where R ² is thiophen-2-yl, and where R ² is thiophen-3-yl, thus providing for R groups which are 4- (thiophen-2-yl) pyrimidin-2 -yl, 5- (thiophen-2-yl) pyrimidin-2-yl, 4- (thiophen-3-yl) pyrimidin-2-yl and 5- (thiophen-2-yl) pyrimidin-3-yl.

Non-limiting examples of 6 membered heteroaryl rings include:

иi)

and

.ii)

.

R groups may also include fused ring heteroaryl groups. Non-limiting examples of R groups include:

;i)

;

ii)

iii)

;iv)

;

v)

иvi)

and

vii)

R groups, which are fused heteroaryl rings, may optionally be substituted with one or more independently selected hydrogen substituents, as described above in this description.

Z groups

Z means a group of the formula:

- (L) _n -R ^one ,

where R ¹ choose from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C ₁ -C ₆ alkyl;

iii) substituted or unsubstituted C ₆ or C ₁₀ aryl;

iv) substituted or unsubstituted C ₁ -C ₉ heterocyclic rings, or

v) substituted or unsubstituted C ₁ -C ₉ heteroaryl rings.

One example of R ¹ groups includes substituted or unsubstituted phenyl (C ₆ aryl) groups, where each substituent is independently selected from: halogen, linear, branched or cyclic C ₁ -C ₄ alkyl, —OR ¹¹ , —CN, —N (R ¹¹ ) ₂ , -CO ₂ R ¹¹ , -C (O) N (R ¹¹ ) ₂ , -NR ¹¹ C (O) R ¹¹ , -NO ₂ and -SO ₂ R ¹¹ ; where R ¹¹ each independently represents hydrogen; substituted or unsubstituted, linear, branched or cyclic C ₁ -C ₄ alkyl, alkenyl or alkynyl; substituted or unsubstituted phenyl or benzyl; or two R ¹¹ groups taken together can form a ring containing from 3 to 7 atoms.

Another example of R ¹ groups includes substituted C ₆ aryl groups selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl.

The following example of R ¹ groups includes substituted or unsubstituted C ₆ aryl groups selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2, 6-difluorophenyl, 3,4-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl and 2,4,6-trichlorof nila.

Another other example of R ¹ groups includes substituted C ₆ aryl groups selected from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6- dimethylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2- ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2, 3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3 isopropylphenyl and 4-isopropylphenyl.

Another further example of R ¹ groups includes substituted C ₆ aryl groups selected from 2-aminophenyl, 2- (N-methylamino) phenyl, 2- (N, N-dimethylamino) phenyl, 2- (N-ethylamino) phenyl, 2 - (N, N-diethylamino) phenyl, 3-aminophenyl, 3- (N-methylamino) phenyl, 3- (N, N-dimethylamino) phenyl, 3- (N-ethylamino) phenyl, 3- (N, N- diethylamino) phenyl, 4-aminophenyl, 4- (N-methylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 4- (N-ethylamino) phenyl and 4- (N, N-diethylamino) phenyl.

R ¹ may include heteroaryl groups. Non-limiting examples of heteroaryl groups include:

i)

ii)

iii)

iv)

v)

vi)

vii)

viii)

ix)

x)

xi)

xii)

иxiii)

and

xiv)

The heteroaryl groups of R ¹ may be substituted or unsubstituted. Non-limiting examples of groups that may be a hydrogen substituent include groups selected from:

i) linear, branched and cyclic C ₁ -C ₆ alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted or unsubstituted C ₁ -C ₉ heteroaryl;

iv) —C (O) R ⁹ and

v) -NHC (O) R ⁹ ;

where R ⁹ means a linear or branched C ₁ -C ₆ alkyl; linear or branched C ₁ -C ₆ alkoxy; or —NHCH ₂ C (O) R ¹⁰ ; where R ¹⁰ selected from hydrogen, methyl, ethyl and tert-butyl.

One example of R ¹ relates to groups substituted with an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Another example of R ¹ includes groups that are substituted with substituted or unsubstituted phenyl and benzyl, where phenyl and benzyl substituents are selected from one or more groups, such as:

i) halogen;

ii) C ₁ -C ₃ alkyl;

iii) C ₁ -C ₃ alkoxy;

iv) —CO ₂ R ¹¹ and

v) —NHCOR ¹⁶ ;

where R ¹¹ and R ¹⁶ each independently, means hydrogen, methyl or ethyl.

Another example of R ¹ relates to phenyl and benzyl groups substituted with a carboxy group of the formula —C (O) R ⁹ ; where R ⁹ selected from methyl, methoxy, ethyl and ethoxy.

The following example R ¹ includes phenyl and benzyl groups substituted with an amide group of the formula —NHC (O) R ⁹ ; where R ^{9 is} selected from methyl, methoxy, ethyl, ethoxy, tert-butyl and tert-butoxy.

Another further example of R ¹ includes phenyl and benzyl groups substituted with one or more fluorine or chlorine atoms.

L means a linking group selected from:

i) —C (O) NH [C (R ^5a R ^5b )] _w -;

ii) —C (O) [C (R ^6a R ^6b )] _x -;

iii) —C (O) [C (R ^7a R ^7b )] _y C (O) -;

iv) —SO ₂ [C (R ^8a R ^8b )] _z -;

where R ^5a , R ^5b , R ^6a , R ^6b , R ^7a , R ^7b , R ^8a and R ^8b , each independently, means:

i) hydrogen;

ii) substituted or unsubstituted linear or branched C ₁ -C ₄ alkyl;

iii) substituted or unsubstituted aryl;

iv) substituted or unsubstituted heterocyclic rings;

v) substituted or unsubstituted C ₁ -C ₉ heteroaryl rings;

and the index w, x, y, and z, each independently, is from 1 to 4. A linking group may be present, that is, the index n is 1, or absent when the index n is 0, for example, the linking group is absent in the compounds of category V described later in this description.

One example of L groups includes linking groups of the formula:

-C (O) [C (R ^6a R ^6b )] _x -,

where R ^6a means hydrogen, substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, and the above substituents for phenyl and heteroaryl are selected from:

i) linear, branched and cyclic C ₁ -C ₆ alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted or unsubstituted C ₁ -C ₉ heteroaryl;

iv) —C (O) R ¹⁶ and

v) -NHC (O) R ¹⁶ ;

where R ¹⁶ means a linear or branched C ₁ -C ₆ alkyl; linear and branched C ₁ -C ₆ alkoxy; or —NHCH ₂ C (O) R ¹⁷ ; where R ¹⁷ selected from hydrogen, methyl, ethyl and tert-butyl; index x is 1 or 2.

Another example of L groups includes groups wherein the first R ^6a group is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl; the second group R ^6a represents hydrogen, and the groups R ^6b mean hydrogen. For example, a linking group has the formula:

A further example of L includes a first group R ^6a , as described hereinabove, which is a substituted or unsubstituted heteroaryl group, as described hereinabove.

Another other example of L includes groups of the formula:

-C (O) [C (R ^6a R ^6b )] _x -,

where R ^6a and R ^6b mean hydrogen, and the index x is 1 or 2; the above groups are selected from:

i) -C (O) CH ₂ - and

ii) -C (O) CH ₂ CH ₂ -.

Another example of L groups includes groups of the formula:

-C (O) [C (R ^7a R ^7b )] _y C (O) -,

where R ^7a and R ^7b mean hydrogen, and the index x is 1 or 2; the above groups are selected from:

i) -C (O) CH ₂ C (O) - and

ii) —C (O) CH ₂ CH ₂ C (O) -.

Another other example of L groups includes groups of the formula:

-C (O) NH [C (R ^5a R ^5b )] _w -,

where R ^5a and R ^5b mean hydrogen, and the index w is 0, 1 or 2; the above groups are selected from:

i) -C (O) NH;

ii) -C (O) NHCH ₂ - and

iii) —C (O) NHCH ₂ CH ₂ -.

Another further example of L groups includes groups of the formula:

-SO ₂ [C (R ^8a R ^8b )] _z -,

where R ^8a and R ^8b mean hydrogen, and the index z is 0, 1 or 2; the above groups are selected from:

i) -SO ₂ -;

ii) -SO ₂ CH ₂ and

iii) —SO ₂ CH ₂ CH ₂ -.

The compounds of the present invention described above in this description include all pharmaceutically acceptable salt forms. The compound of the formula:

can form salts, for example, a sulfonic acid salt:

и

and

.

.

The compounds may also be in zwitternized form, for example:

or in the form of a salt of a strong acid, for example:

The analogs (compounds) of the present invention are classified into several categories to help the practitioner in relation to the application of the synthesis strategy to obtain analogues that are not specifically shown in the examples according to this description. Classification by category does not imply increased or decreased effectiveness in relation to any of the compositions described in this description of substances.

The first aspect of category I of the present invention relates to 2- (thiazol-2-yl) compounds of the formula:

where R ¹ , R ² , R ³ and L have the meanings as defined in table I below in this description.

Table I No. L R ^one R ² R ³ one -C (O) CH ₂ - phenyl -CH ₃ -H 2 -C (O) CH ₂ - 2-fluorophenyl -CH ₃ -H 3 -C (O) CH ₂ - 3-fluorophenyl -CH ₃ -H four -C (O) CH ₂ - 4-fluorophenyl -CH ₃ -H 5 -C (O) CH ₂ - 2,3-difluorophenyl -CH ₃ -H 6 -C (O) CH ₂ - 3,4-difluorophenyl -CH ₃ -H 7 -C (O) CH ₂ - 3,5-difluorophenyl -CH ₃ -H 8 -C (O) CH ₂ - 2-chlorophenyl -CH ₃ -H 9 -C (O) CH ₂ - 3-chlorophenyl -CH ₃ -H 10 -C (O) CH ₂ - 4-chlorophenyl -CH ₃ -H eleven -C (O) CH ₂ - 2,3-dichlorophenyl -CH ₃ -H 12 -C (O) CH ₂ - 3,4-dichlorophenyl -CH ₃ -H 13 -C (O) CH ₂ - 3,5-dichlorophenyl -CH ₃ -H fourteen -C (O) CH ₂ - 2-hydroxyphenyl -CH ₃ -H fifteen -C (O) CH ₂ - 3-hydroxyphenyl -CH ₃ -H 16 -C (O) CH ₂ - 4-hydroxyphenyl -CH ₃ -H 17 -C (O) CH ₂ - 2-methoxyphenyl -CH ₃ -H eighteen -C (O) CH ₂ - 3-methoxyphenyl -CH ₃ -H 19 -C (O) CH ₂ - 4-methoxyphenyl -CH ₃ -H twenty -C (O) CH ₂ - 2,3-dimethoxyphenyl -CH ₃ -H 21 -C (O) CH ₂ - 3,4-dimethoxyphenyl -CH ₃ -H 22 -C (O) CH ₂ - 3,5-dimethoxyphenyl -CH ₃ -H 23 -C (O) CH ₂ - phenyl -CH ₂ CH ₃ -H 24 -C (O) CH ₂ - 2-fluorophenyl -CH ₂ CH ₃ -H 25 -C (O) CH ₂ - 3-fluorophenyl -CH ₂ CH ₃ -H 26 -C (O) CH ₂ - 4-fluorophenyl -CH ₂ CH ₃ -H 27 -C (O) CH ₂ - 2,3-difluorophenyl -CH ₂ CH ₃ -H 28 -C (O) CH ₂ - 3,4-difluorophenyl -CH ₂ CH ₃ -H 29th -C (O) CH ₂ - 3,5-difluorophenyl -CH ₂ CH ₃ -H thirty -C (O) CH ₂ - 2-chlorophenyl -CH ₂ CH ₃ -H 31 -C (O) CH ₂ - 3-chlorophenyl -CH2CH3 -H 32 -C (O) CH ₂ - 4-chlorophenyl -CH ₂ CH ₃ -H 33 -C (O) CH ₂ - 2,3-dichlorophenyl -CH ₂ CH ₃ -H 34 -C (O) CH ₂ - 3,4-dichlorophenyl -CH ₂ CH ₃ -H 35 -C (O) CH ₂ - 3,5-dichlorophenyl -CH ₂ CH ₃ -H 36 -C (O) CH ₂ - 2-hydroxyphenyl -CH ₂ CH ₃ -H 37 -C (O) CH ₂ - 3-hydroxyphenyl -CH ₂ CH ₃ -H 38 -C (O) CH ₂ - 4-hydroxyphenyl -CH ₂ CH ₃ -H 39 -C (O) CH ₂ - 2-methoxyphenyl -CH ₂ CH ₃ -H 40 -C (O) CH ₂ - 3-methoxyphenyl -CH ₂ CH ₃ -H 41 -C (O) CH ₂ - 4-methoxyphenyl -CH ₂ CH ₃ -H 42 -C (O) CH ₂ - 2,3-dimethoxyphenyl -CH ₂ CH ₃ -H 43 -C (O) CH ₂ - 3,4-dimethoxyphenyl -CH ₂ CH ₃ -H 44 -C (O) CH ₂ - 3,5-dimethoxyphenyl -CH ₂ CH ₃ -H 45 -C (O) CH ₂ CH ₂ - phenyl -CH ₃ -H 46 -C (O) CH ₂ CH ₂ - 2-fluorophenyl -CH ₃ -H 47 -C (O) CH ₂ CH ₂ - 3-fluorophenyl -CH ₃ -H 48 -C (O) CH ₂ CH ₂ - 4-fluorophenyl -CH ₃ -H 49 -C (O) CH ₂ CH ₂ - 2,3-difluorophenyl -CH ₃ -H fifty -C (O) CH ₂ CH ₂ - 3,4-difluorophenyl -CH ₃ -H 51 -C (O) CH ₂ CH ₂ - 3,5-difluorophenyl -CH ₃ -H 52 -C (O) CH ₂ CH ₂ - 2-chlorophenyl -CH ₃ -H 53 -C (O) CH ₂ CH ₂ - 3-chlorophenyl -CH ₃ -H 54 -C (O) CH ₂ CH ₂ - 4-chlorophenyl -CH ₃ -H 55 -C (O) CH ₂ CH ₂ - 2,3-dichlorophenyl -CH ₃ -H 56 -C (O) CH ₂ CH ₂ - 3,4-dichlorophenyl -CH ₃ -H 57 -C (O) CH ₂ CH ₂ - 3,5-dichlorophenyl -CH ₃ -H 58 -C (O) CH ₂ CH ₂ - 2-hydroxyphenyl -CH ₃ -H 59 -C (O) CH ₂ CH ₂ - 3-hydroxyphenyl -CH ₃ -H 60 -C (O) CH ₂ CH ₂ - 4-hydroxyphenyl -CH ₃ -H 61 -C (O) CH ₂ CH ₂ - 2-methoxyphenyl -CH ₃ -H 62 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl -CH ₃ -H 63 -C (O) CH ₂ CH ₂ - 4-methoxyphenyl -CH ₃ -H 64 -C (O) CH ₂ CH ₂ - 2,3-dimethoxyphenyl -CH ₃ -H 65 -C (O) CH ₂ CH ₂ - 3,4-dimethoxyphenyl -CH ₃ -H 66 -C (O) CH ₂ CH ₂ - 3,5-dimethoxyphenyl -CH ₃ -H 67 -C (O) CH ₂ CH ₂ - phenyl -CH ₂ CH ₃ -H 68 -C (O) CH ₂ CH ₂ - 2-fluorophenyl -CH ₂ CH ₃ -H 69 -C (O) CH ₂ CH ₂ - 3-fluorophenyl -CH ₂ CH ₃ -H 70 -C (O) CH ₂ CH ₂ - 4-fluorophenyl -CH ₂ CH ₃ -H 71 -C (O) CH ₂ CH ₂ - 2,3-difluorophenyl -CH ₂ CH ₃ -H 72 -C (O) CH ₂ CH ₂ - 3,4-difluorophenyl -CH ₂ CH ₃ -H 73 -C (O) CH ₂ CH ₂ - 3,5-difluorophenyl -CH ₂ CH ₃ -H 74 -C (O) CH ₂ CH ₂ - 2-chlorophenyl -CH ₂ CH ₃ -H 75 -C (O) CH ₂ CH ₂ - 3-chlorophenyl -CH ₂ CH ₃ -H 76 -C (O) CH ₂ CH ₂ - 4-chlorophenyl -CH ₂ CH ₃ -H 77 -C (O) CH ₂ CH ₂ - 2,3-dichlorophenyl -CH ₂ CH ₃ -H 78 -C (O) CH ₂ CH ₂ - 3,4-dichlorophenyl -CH ₂ CH ₃ -H 79 -C (O) CH ₂ CH ₂ - 3,5-dichlorophenyl -CH ₂ CH ₃ -H 80 -C (O) CH ₂ CH ₂ - 2-hydroxyphenyl -CH ₂ CH ₃ -H 81 -C (O) CH ₂ CH ₂ - 3-hydroxyphenyl -CH ₂ CH ₃ -H 82 -C (O) CH ₂ CH ₂ - 4-hydroxyphenyl -CH ₂ CH ₃ -H 83 -C (O) CH ₂ CH ₂ - 2-methoxyphenyl -CH ₂ CH ₃ -H 84 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl -CH ₂ CH ₃ -H 85 -C (O) CH ₂ CH ₂ - 4-methoxyphenyl -CH ₂ CH ₃ -H 86 -C (O) CH ₂ CH ₂ - 2,3-dimethoxyphenyl -CH ₂ CH ₃ -H 87 -C (O) CH ₂ CH ₂ - 3,4-dimethoxyphenyl -CH ₂ CH ₃ -H 88 -C (O) CH ₂ CH ₂ - 3,5-dimethoxyphenyl -CH ₂ CH ₃ -H

Compounds included in the first aspect of category I of the present invention can be obtained by the method shown in scheme I and described below in example 1 of this description.

Scheme I

Reagents and conditions: (a) (i) (isobutyl) OSOCl, NMM, DMF; 0 ° C, 20 min; (ii) NH ₃ ; 0 ° C for 30 minutes

Reagents and conditions:

(b) Lawesson's reagent, THF; room temperature, 3 hours.

Reagents and conditions: (c) CH ₃ CN; reflux, 2 hours.

Reagents and conditions: (d) C ₆ H ₄ CO ₂ H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours

Reagents and conditions: (e) (i) H ₂ : Pd / C, CH ₃ OH; (ii) SO ₃ -pyridine, NH ₄ OH, room temperature, 18 hours.

Example 1

{4- [2- (S) - (4-Ethylthiazol-2-yl) -2- (2-phenylacetylamido) ethyl] phenyl} sulfamic acid (5)

(S) tert-Butyl-1-amino-3- (4-nitrophenyl) -1-oxopropan-2-ylcarbamate

Preparation of (S) -tert-butyl 1-amino-3- (4-nitrophenyl) -1-oxopropan-2-ylcarbamate (1):

To a solution of 2- (S) -tert-butoxycarbonylamino-3- (4-nitrophenyl) propionic acid and N-methylmorpholine (1.1 ml, 9.65 mmol) in DMF (10 ml), dropwise cooled to 0 ° C isobutyl chloroformate (1.25 ml, 9.65 mmol) is added. The mixture was stirred at 0 ° C. for 20 minutes, then NH ₃ (gas) was passed through the reaction mixture for 30 minutes at 0 ° C. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed successively with 5% citric acid, water, 5% NaHCO ₃ solution, water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a residue which triturated with ethyl acetate / petroleum ether to give 2.2 g (74% yield) of the desired product as a white solid.

Preparation of [2- (4-nitrophenyl) -1- (S) thiocarbamoylethyl] carbamic acid tert-butyl ester (2):

To a solution of (S) -tert-butyl 1-amino-3- (4-nitrophenyl) -1-oxopropan-2-ylcarbamate 1 (0.400 g, 1.29 mmol) in THF (10 ml), Lawesson's reagent (0.262 g 0.65 mmol). The reaction mixture was stirred for 3 hours and concentrated to give a residue, which was purified using silica to give 0.350 g (83% yield) of the desired product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d , J = 8.4 Hz, 2H), 5.70 (d, J = 7.2 Hz, 1H), 4.85 (d, J = 7.2 Hz, 1H), 3.11-3.30 (m, 1H); 1.21 (s, 9H).

Preparation of 1- (S) -4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamine hydrobromide (3):

A mixture of [2- (4-nitrophenyl) -1- (S) thiocarbamoylethyl] carbamic acid tert-butyl ester 2 (10 g, 30.7 mmol) and 1-bromo-2-butanone (90%, 3.8 ml, 33.8 mmol) in CH ₃ CN (500 ml) was refluxed for 18 hours. The reaction mixture was cooled to room temperature, diethyl ether was added to the solution, and the precipitate formed was removed by filtration to obtain 7.4 7 g of the desired product.

MS (ESI +) MS: 278 (M + 1).

Preparation of N- [1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -2-phenylacetamide (4):

To a solution of 1- (S) -4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamine 3 hydrobromide (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and 1 -hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF (10 ml) at 1 ° C. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (0.268 g, 1.4 mmol) is added, then triethylamine (0.60 ml, 4.2 mmol). The mixture was stirred at 0 ° C. for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase is washed with 1 N. aqueous HCl, 5% aqueous NaHCO ₃ , water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give 0.260 g (60% yield) of the desired product, which was used without further purification.

MS (ESI +): 396 (M + 1).

Preparation of {4- [2- (S) - (4-ethylthiazol-2-yl) -2- (2-phenylacetylamido) ethyl] phenyl} sulfamic acid (5):

N- [1- (4-Ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -2-phenylacetamide 4 (0.260 g) was dissolved in methanol (4 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (0.177 g, 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH (10 ml) was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.136 g of the desired product as an ammonium salt.

¹ H NMR (CD ₃ OD) δ 8.60 (d, 1H, J = 8.1 Hz), 7.33-7.23 (m, 3H), 7.16-7.00 (m, 6H) 5.44-5.41 (m, 1H), 3.28 (1H, A from ABX, masked with solvent), 3.03 (1H, B from ABX, J = 14.1, 9.6 Hz), 2.80 (q, 2H, J = 10.5, 7.8 Hz) 1.31 (t, 3H, J = 4.6 Hz).

The following is a general procedure for isolating the final compound as a free acid.

Reduction of an aryl nitro group to a free amine:

A nitro compound [eg, intermediate 4] (1.0 eq.) And Pd / C (10% Pd per C, 50% humidity, type E101 NE / W, Degussa, 2.68 g, 158) are charged into a Parr hydrogenation vessel % wt.) in the form of solids. Methanol (15 mg / g) was added to give a suspension. The vessel is placed in a Parr hydrogenation apparatus. The vessel is subjected to the process of filling / evacuation of N ₂ (3 × 20 lb / in ² ) until “inert”, then the same process using H ₂ (3 × 40 lb / in ² ). The vessel was filled with _H2 and shaken for about 40 hours at a pressure of H ₂ 40 lb / ^in2. The vessel was evacuated and purged with N ₂ (5 × 20 lb / ^in2). An aliquot is filtered and analyzed by HPLC to determine the completion of the conversion. The suspension is filtered through a CELITE ^™ bed to remove the catalyst, and the yellow homogeneous filtrate is concentrated by evaporation on a rotary evaporator to obtain the desired product, which is used without further purification.

Obtaining free sulfamic acid:

In a 100 ml RBF, free amine (1.0 eq.) Obtained in the step described above is charged. Acetonitrile is added and a yellow suspension, which usually has a yellow to orange color, is stirred at room temperature. In a second 500 ml three-necked RBF, SO ₃ -pyridine (1.4 eq.) And acetonitrile (5 ml / g) were charged and the suspension was stirred at room temperature. Both suspensions are carefully heated until the reaction solution containing the amine is colored from orange to red-orange (usually at a temperature of about 40-45 ° C). The resulting substrate-containing solution was poured in one portion into a stirred suspension of SO ₃ -pyridine at a temperature of 35 ° C. The resulting opaque mixture was stirred vigorously, allowing slow cooling to room temperature. After stirring for 45 minutes or after determining the complete completion of the reaction by HPLC, water (20 ml) was added to the colored suspension to obtain a homogeneous solution having a pH of about 2.4. Concentrated H ₃ PO _{4 was} added slowly to lower the pH to about 1.4. During this pH adjustment, an off-white precipitate usually precipitates and the solution is stirred at room temperature for an additional hour. The suspension is filtered and the filter cake washed with the filtrate. The filter cake was air dried overnight to give the desired product as the free acid.

The following are non-limiting examples according to a first category I aspect of the present invention.

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (2- (2-fluorophenyl) acetamido) ethyl) phenyl) sulfamic acid

¹ H NMR (CD ₃ OD) δ 8.65 (d, 1H, J = 8.4 Hz), 7.29-7.15 (m, 1H), 7.13-7.03 (m, 7H) 5.46-5.42 (m, 1H), 3.64-3.51 (m, 2H), 3.29 (1H), 3.04 (1H, B from ABX, J = 13.8, 9.6 Hz), 2.81 (q, 2H, J = 15.6, 3.9 Hz), 1.31 (t, 3H, J = 7.8 Hz). ¹⁹ F NMR (CD ₃ OD) δ 43.64.

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (2- (3-fluorophenyl) acetamido) ethyl) phenyl) sulfamic acid

¹ H NMR (CD ₃ OD) δ 8.74 (d, 1H, J = 8.4 Hz), 7.32 (q, 1H, J = 6.6, 14.2 Hz), 7.10-6 91 (m, 8H), 5.47-5.40 (m, 1H), 3.53 (s, 2H), 3.30 (1H), 3.11 (1H, B from ABX, J = 9 6, 14.1 Hz), 2.80 (q, 2H, J = 6.6, 15.1 Hz), 1.31 (t, 3H, J = 7.8 Hz). ¹⁹ F NMR δ 47.42.

(S) -4- (2- (2- (2,3-difluorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenyl) sulfamic acid

¹ H NMR (CD ₃ OD) δ 7.16-7.05 (m, 5H), 6.85-6.80 (m, 1H), 5.48-5.43 (m, 1H), 3, 63 (s, 2H), 3.38 (1H, A from ABX, masked by solvent), 3.03 (1H), 2.80 (q, H, J = 15.1, 7.8 Hz), 1, 31 (t, 3H, J = 7.5 Hz).

(S) -4- (2- (2- (3,4-Difluorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenyl) sulfamic acid

¹ H NMR (CD ₃ OD) δ 8.75 (d, 1H, J = 7.8 Hz), 7.23-7.04 (m, 6H), 6.88-6.84 (m, 1H) , 5.44-5.40 (m, 1H), 3.49 (s, 2H), 3.34 (1H), 3.02 (1H, B from ABX, J = 14.1, 9.9 Hz ), 2.80 (q, 2H, J = 15.1, 7.8 Hz), 1.31 (t, 1H, J = 7.5 Hz). ¹⁹ F NMR (CD ₃ OD) δ 22.18, 19.45.

(S) -4- (2- (2- (2-Chlorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenyl) sulfamic acid

¹ H NMR (CD ₃ OD) δ 7.39-7.36 (m, 1H), 7.27-7.21 (m, 2H), 7.15-6.98 (m, 5H), 5, 49-5.44 (m, 1H), 3.69 (d, 2H, J = 11.7 Hz), 3.32 (1H), 3.04 (1H, B from ABX, J = 9.3, 13.9 Hz), 2.80 (q, 2H, J = 7.8, 15.3 Hz), 1.31 (t, 3H, J = 7.5 Hz).

(S) -4- (2- (2- (3-Chlorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenyl) sulfamic acid

¹ H NMR (CD ₃ OD) δ 7.33-7.23 (m, 3H), 7.13-7.03 (m, 5H), 5.43 (q, 1H, J = 5.1, 9 , 6 Hz), 3.51 (s, 2H), 3.29 (1H), 3.03 (1H, V from ABX, J = 9.9, 14.1 Hz), 2.80 (q, 2H , J = 7.5, 15 Hz), 1.31 (t, 3H, J = 7.8 Hz).

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (2- (3-hydroxyphenyl) acetamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.16-7.08 (m, 3H), 7.03-7.00 (m, 3H), 6.70-6.63 (m, 2H), 5, 42-5.40 (m, 1H), 3.44 (s, 2H), 3.28 (1H, A from ABX, masked with solvent), 3.04 (B from ABX, J = 14.1, 9, 6 Hz), 2.89 (q, 2H, J = 15, 7.5 Hz), 1.31 (t, 3H, J = 7.5 Hz).

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (2- (2-methoxyphenyl) acetamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.00 (d, 1H, J = 7.8 Hz), 7.26 (t, 1H, J = 13.2 Hz), 7.09-7.05 (m 4H), 7.01 (s, 1H), 6.91-6.89 (m, 4H), 5.44-5.39 (m, 1H), 3.71 (s, 3H), 3, 52 (s, 2H), 3.26 (1H, A from ABX, J = 14.1, 5.1 Hz), 3.06 (1H B from ABX, J = 13.8, 8.4 Hz), 2.80 (q, 2H, J = 8.1, 15.6 Hz), 1.31 (t, 3H, J = 1.2 Hz).

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [2- (3-methoxyphenyl) acetamido] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.58 (d, 1H, J = 8.1 Hz), 7.21 (t, 1H, J = 7.8 Hz), 7.12-7.02 (m , 4H), 6.81 (s, 2H), 6.72 (d, 1H, J = 7.5 Hz), 5.45-5.40 (m, 1H), 3.79 (s, 3H) 3.50 (s, 2H), 3.29 (1H, A from ABX, masked by solvent), 3.08 (1H, B from ABX, J = 11.8, 5.1 Hz), 2.80 ( q, 2H, J = 15.7.5 Hz), 1.31 (t, 3H, J = 6.6 Hz).

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (3-phenylpropanamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.56 (d, 1H, J = 8.4 Hz), 7.25-6.98 (m, 9H), 5.43-5.38 (m, 1H) , 3.26 (1H, A from ABX, J = 14.1, 9.6 Hz), 2.97 (1H, B from ABX, J = 10.9, 3 Hz), 2.58-2.76 (m, 3H), 2.98 (q, 2H, J = 13.8, 7.2 Hz), 1.29 (t, 3H, J = 8.7 Hz).

(S) -4- (2- (2- (3,4-Dimethoxyphenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.12-7.03 (m, 3H), 6.91 (d, 1H, J = 8.4 Hz), 6.82 (s, 1H), 6.66 (d, 1H, J = 2.1 Hz), 6.63 (d, 1H, J = 2.1 Hz), 5.43 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.45 (s, 2H), 3.30 (1H), 3.03 (1H, B from ABX, J = 14.1, 9.6 Hz), 2.79 (q, 2H, J = 15.1, 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz).

(S) -4- (2- (2- (2,3-Dimethoxyphenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.31 (d, 1H, J = 7.8 Hz), 7.11-6.93 (m, 6H), 6.68 (d, 1H, J = 7, 5 Hz), 5.49-5.40 (m, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 3.55 (s, 2H), 3.26 (1H, A from ABX, masked by solvent), 3.06 (1H, B from ABX, J = 13.9, 9 Hz), 2.80 (q, 2H, J = 14.8, 7.5 Hz), 1, 31 (t, 3H, J = 7.5 Hz).

(S) -4- (2- (3- (3-Chlorophenyl) propanamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.27-7.18 (m, 3H), 7.13-7.08 (m, 5H), 7.01 (s, 1H), 5.39 (q, 1H, J = 5.1, 9.4 Hz), 3.28 (1H, A from ABX, J = 5.1, 14.1 Hz), 2.97 (1H, B from ABX, J = 9, 3, 13.9 Hz), 2.88-2.76 (m, 4H), 2.50 (t, 2H, J = 8.1 Hz), 1.31 (t, 3H, J = 7.8 Hz).

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (3- (2-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.18-7.08 (m, 6H), 6.92 (d, 1H, J = 8.1 Hz), 6.82 (t, 1H, J = 7, 5 Hz), 5.40-5.35 (m, 1H), 3.25 (1H, A from ABX, J = 15, 5.4 Hz), 3.00 (1H, B from ABX, J = 10 5, 7.5 Hz), 2.88-2.76 (m, 4H), 2.47 (q, 2H, J = 9.1, 6 Hz), 1.31 (t, 3H, J = 7.8 Hz).

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (3- (3-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.19-7.00 (m, 5H), 6.75 (s, 1H), 6.73 (s, 1H), 5.42-5.37 (m, 1H), 3.76 (s, 3H), 3.25 (1H, A from ABX, J = 13.9, 5.4 Hz), 2.98 (1H, B from ABX, J = 14.1, 9.6 Hz), 2.86-2.75 (m, 4H), 2.48 (q, 2H, J = 11.7, 1.2 Hz), 1.31 (t, 3H, J = 7 5 Hz).

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (3- (4-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.13-6.99 (m, 7H), 6.82-6.78 (m, 2H), 5.42-5.37 (m, 1H), 3, 33 (s, 3H), 3.23 (1H), 2.97 (1H, B from ABX, J = 13.3, 11.4 Hz), 2.83-2.75 (m, 4H), 2 49 (q, 2H, J = 6.4, 3.3 Hz); 1.31 (t, 3H, J = 7.5 Hz).

(S) -4- {2- [2- (4-Ethyl-2,3-dioxopiperazin-1-yl) acetamido] -2- (4-ethylthiazol-2-yl) ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.14 (s, 4H), 7.08 (s, 1H), 5.56-5.51 (m, 1H), 4.34 (d, 2H, J = 16.2 Hz), 3.88 (d, 2H, J = 17.6 Hz), 3.59-3.40 (m, 3H), 3.26-3.14 (m, 3H), 2, 98 (1H, B from ABX, J = 10.8, 13.9 Hz), 2.82 (q, 2H, J = 6.9, 15 Hz), 1.32 (t, 3H, J = 7, 5 Hz), 1.21 (t, 3H, J = 7.2 Hz).

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [2- (5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) acetamido] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.13 (s, 1H), 7.06-7.02 (m, 4H), 6.95 (s, 1H), 5.42-5.31 (m, 1H), 4.43-4.18 (dd, 2H, J = 16.5 Hz), 3.24-2.93 (m, 2H), 2.74-2.69 (q, 2H, J = 7.3 Hz), 1.79 (s, 3H), 1.22 (t, 3H, J = 7.5 Hz).

(S) -4- [2- (benzo [d] [1,3] dioxol-5-carboxamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.25 (d, 1H, J = 6.5 Hz), 7.13 (s, 1H), 7.06 (d, 2H, J = 8.5 Hz), 7.00 (d, 2H, J = 8.5 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J = 8.1 Hz), 5.90 (s, 2H), 5.48 (q, 1H, J = 5.0 Hz), 3.32-3.24 (m, 2H), 3.07-2.99 (m, 2H), 2.72 (q, 2H, J = 7.5 Hz), 1.21 (t, 3H, J = 7.5 Hz).

(S) -4- {2- [2- (2,5-Dimethylthiazol-4-yl) acetamido] -2- (4-ethylthiazol-2-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.10-7.01 (m, 5H), 5.41 (t, 1H, J = 6.9 Hz), 3.58 (s, 2H), 3.33 -3.01 (m, 2H), 2.82-2.75 (q, 2H, J = 7.5 Hz), 2.59 (s, 3H), 2.23 (s, 3H), 1, 30 (t, 3H, J = 7.5 Hz).

(S) -4- {2- [2- (2,4-Dimethylthiazol-5-yl) acetamido] -2- (4-methylthiazol-2-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.71-8.68 (d, 1H, J = 8.4 Hz), 7.10-7.03 (m, 4H), 7.01 (s, 1H) 5.41 (m, 1H), 3.59 (s, 1H), 3.34-2.96 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H).

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [3- (thiazol-2-yl) propanamido] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.67-7.65 (m, 1H), 7.49-7.47 (m, 1H), 7.14-7.08 (m, 4H), 7, 04 (s, 1H), 5.46-5.41 (q, 1H, J = 5.1 Hz), 3.58 (s, 2H), 3.30-3.25 (m, 3H), 3 02-2.67 (m, 5H); 1.31 (t, 3H, J = 7.5 Hz).

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [2- (4-ethylthiazol-2-yl) acetamido] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.04-6.91 (m, 6H), 5.32 (t, 1H, J = 5.4 Hz), 3.25-2.90 (m, 2H) 2.71-2.61 (m, 4H) 1.93 (s, 2H); 1.22-1.14 (m, 6H).

A second aspect of category I of the present invention relates to 2- (thiazol-4-yl) compounds of the formula:

where R ¹ , R ⁴ and L have the meanings as defined in table II below.

Table II No. L R ^one R ^four 89 -C (O) CH ₂ - phenyl methyl 90 -C (O) CH ₂ - phenyl ethyl 91 -C (O) CH ₂ - phenyl phenyl 92 -C (O) CH ₂ - phenyl thiophen-2-yl 93 -C (O) CH ₂ - phenyl thiazol-2-yl 94 -C (O) CH ₂ - phenyl oxazol-2-yl 95 -C (O) CH ₂ - phenyl isoxazol-3-yl 96 -C (O) CH ₂ - 3-chlorophenyl methyl 97 -C (O) CH ₂ - 3-chlorophenyl ethyl 98 -C (O) CH ₂ - 3-chlorophenyl phenyl 99 -C (O) CH ₂ - 3-chlorophenyl thiophen-2-yl one hundred -C (O) CH ₂ - 3-chlorophenyl thiazol-2-yl 101 -C (O) CH ₂ - 3-chlorophenyl oxazol-2-yl 102 -C (O) CH ₂ - isoxazol-3-yl 103 -C (O) CH ₂ - methyl 104 -C (O) CH ₂ - ethyl 105 -C (O) CH ₂ - phenyl 106 -C (O) CH ₂ - 3-chlorophenyl thiophen-2-yl 107 -C (O) CH ₂ - 3-methoxyphenyl thiazol-2-yl 108 -C (O) CH ₂ - 3-methoxyphenyl oxazol-2-yl 109 -C (O) CH ₂ - 3-methoxyphenyl isoxazol-3-yl 110 -C (O) CH ₂ - 3-fluorophenyl methyl 111 -C (O) CH ₂ - 3-fluorophenyl ethyl 112 -C (O) CH ₂ - 3-fluorophenyl phenyl 113 -C (O) CH ₂ - 3-fluorophenyl thiophen-2-yl 114 -C (O) CH ₂ - 3-fluorophenyl thiazol-2-yl 115 -C (O) CH ₂ - 3-fluorophenyl oxazol-2-yl 116 -C (O) CH ₂ - 3-fluorophenyl isoxazol-3-yl 117 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl methyl 118 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl ethyl 119 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl phenyl 120 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl thiophen-2-yl 121 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl thiazol-2-yl 122 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl oxazol-2-yl 123 -C (O) CH ₂ - 2,5-dimethylthiazol-4-yl isoxazol-3-yl 124 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl methyl 125 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl ethyl 126 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl phenyl 127 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl thiophen-2-yl 128 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl thiazol-2-yl 129 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl oxazol-2-yl 130 -C (O) CH ₂ - 2,4-dimethylthiazol-5-yl isoxazol-3-yl 131 -C (O) CH ₂ - 4-ethylthiazol-2-yl methyl 132 -C (O) CH ₂ - 4-ethylthiazol-2-yl ethyl 133 -C (O) CH ₂ - 4-ethylthiazol-2-yl phenyl 134 -C (O) CH ₂ - 4-ethylthiazol-2-yl thiophen-2-yl 135 -C (O) CH ₂ - 4-ethylthiazol-2-yl thiazol-2-yl 136 -C (O) CH ₂ - 4-ethylthiazol-2-yl oxazol-2-yl 137 -C (O) CH ₂ - 4-ethylthiazol-2-yl isoxazol-3-yl 138 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl methyl 139 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl ethyl 140 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl phenyl 141 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl thiophen-2-yl 142 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl 143 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl 144 -C (O) CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl 145 -C (O) CH ₂ CH ₂ - phenyl methyl 146 -C (O) CH ₂ CH ₂ - phenyl ethyl 147 -C (O) CH ₂ CH ₂ - phenyl phenyl 148 -C (O) CH ₂ CH ₂ - phenyl thiophen-2-yl 149 -C (O) CH ₂ CH ₂ - phenyl thiazol-2-yl 150 -C (O) CH ₂ CH ₂ - phenyl oxazol-2-yl 151 -C (O) CH ₂ CH ₂ - phenyl isoxazol-3-yl 152 -C (O) CH ₂ CH ₂ - 3-chlorophenyl methyl 153 -C (O) CH ₂ CH ₂ - 3-chlorophenyl ethyl 154 -C (O) CH ₂ CH ₂ - 3-chlorophenyl phenyl 155 -C (O) CH ₂ CH ₂ - 3-chlorophenyl thiophen-2-yl 156 -C (O) CH ₂ CH ₂ - 3-chlorophenyl thiazol-2-yl 157 -C (O) CH ₂ CH ₂ - 3-chlorophenyl oxazol-2-yl 158 -C (O) CH ₂ CH ₂ - 3-chlorophenyl isoxazol-3-yl 159 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl methyl 160 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl ethyl 161 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl phenyl 162 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl thiophen-2-yl 163 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl thiazol-2-yl 164 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl oxazol-2-yl 165 -C (O) CH ₂ CH ₂ - 3-methoxyphenyl isoxazol-3-yl 166 -C (O) CH ₂ CH ₂ - 3-fluorophenyl methyl 167 -C (O) CH ₂ CH ₂ - 3-fluorophenyl ethyl 168 -C (O) CH ₂ CH ₂ - 3-fluorophenyl phenyl 169 -C (O) CH ₂ CH ₂ - 3-fluorophenyl thiophen-2-yl 170 -C (O) CH ₂ CH ₂ - 3-fluorophenyl thiazol-2-yl 171 -C (O) CH ₂ CH ₂ - 3-fluorophenyl oxazol-2-yl 172 -C (O) CH ₂ CH ₂ - 3-fluorophenyl isoxazol-3-yl 173 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl methyl 174 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl ethyl 175 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl phenyl 176 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl thiophen-2-yl 177 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl thiazol-2-yl 178 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl oxazol-2-yl 179 -C (O) CH ₂ CH ₂ - 2,5-dimethylthiazol-4-yl isoxazol-3-yl 180 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl methyl 181 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl ethyl 182 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl phenyl 183 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl thiophen-2-yl 184 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl thiazol-2-yl 185 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl oxazol-2-yl 186 -C (O) CH ₂ CH ₂ - 2,4-dimethylthiazol-5-yl isoxazol-3-yl 187 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl methyl 188 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl ethyl 189 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl phenyl 190 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl thiophen-2-yl 191 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl thiazol-2-yl 192 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl oxazol-2-yl 193 -C (O) CH ₂ CH ₂ - 4-ethylthiazol-2-yl isoxazol-3-yl 194 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl methyl 195 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl ethyl 196 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl phenyl 197 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl thiophen-2-yl 198 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl 199 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl 200 -C (O) CH ₂ CH ₂ - 3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl

Compounds included in the second aspect of category I of the present invention can be obtained by the method shown in scheme II and described below in example 2 of this description.

Scheme II

Reagents and conditions: (a) (i) (isobutyl) OSOCl, Et ₃ N, THF; 0 ° C, 20 min; (ii) CH ₂ N ₂ ; room temperature, for 30 hours.

Reagents and conditions: (b) 48% HBr, THF; 0 ° C, 1.5 hours.

Reagents and conditions: (c) CH ₃ CN; reflux, 5 hours.

Reagents and conditions: (d) (3-Cl) C ₆ H ₄ CO ₂ H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (e) (i) H ₂ : Pd / C, CH ₃ OH; (ii) SO ₃ -pyridine, NH ₄ OH, room temperature, 18 hours.

Example 2

4 - ((S) -2- (2- (3-Chlorophenyl) acetamido) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid (10)

Preparation of (S) - [3-diazo-1- (4-nitrobenzyl) -2-oxopropyl] carbamic acid tert-butyl ester (6):

To a solution of 2- (S) -tert-butoxycarbonylamino-3- (4-nitrophenyl) propionic acid (1.20 g, 4.0 mmol) in THF (20 ml) cooled to 0 ° C was added dropwise triethylamine (0 , 61 ml, 4.4 mmol), then isobutyl chloroformate (0.57 ml, 4.4 mmol). The reaction mixture was stirred at 0 ° C. for 20 minutes and filtered. The filtrate is treated with a solution of diazomethane in diethyl ether (approximately 16 mmol) at a temperature of 0 ° C. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed successively with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified using silica (hexane / ethyl acetate in a 2: 1 ratio) to obtain 1.1 g (82% yield) of the desired product as a slightly yellowish solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 5.39 (s, 1H ), 5.16 (d, J = 6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J = 13.8 and 6.6, 1H), 3.06 ( dd, J = 13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).

Preparation of (S) -tert-butyl-4-bromo-1- (4-nitrophenyl) -3-oxobutan-2-ylcarbamate (7):

To a solution of tert-butyl ether (S) - [3-diazo-1- (4-nitrobenzyl) -2-oxopropyl] carbamic acid 6 (0.350 g, 1.04 mmol) in THF (5 ml) cooled to 0 ° C ) 48% aqueous HBr solution (0.14 ml, 1.25 mmol) is added dropwise. The reaction mixture was stirred at 0 ° C. for 1.5 hours, then the reaction was quenched at 0 ° C. with a saturated solution of Na ₂ CO ₃ . The mixture was extracted with ethyl acetate (3 × 25 ml) and the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 0.400 g of the product, which was used in the next step without further purification.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.06 (d, J = 7.8 Hz, 1H), 4.80 (q, J = 6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of (S) -2- (4-nitrophenyl) -1 - [(thiophen-2-yl) thiazol-4-yl] ethanamine hydrobromide (8):

A mixture of (S) -tert-butyl-4-bromo-1- (4-nitrophenyl) -3-oxobutan-2-ylcarbamate 7 (7.74 g, 20 mmol) and thiophene-2-carbothioic acid amide (3.14 g , 22 mmol) in CH ₃ CN (200 ml) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and diethyl ether (50 ml) was added to the solution. The precipitate formed is filtered off. The solid was dried in vacuo to give 7.14 g (87% yield) of the desired product.

MS (ESI +): 322 (M + 1).

Preparation of 2- (3-chlorophenyl) -N - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} acetamide (9):

To a solution of 2- (4-nitrophenyl) -1- (2-thiophen-2-ylthiazol-4-yl) ethylamine 8 (0.41 g, 1 mmol), 3-chlorophenylacetic acid (0.170 g, 1 mmol) and 1 -hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 ml) at 0 ° C add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (0.190 g, 1 mmol), then triethylamine (0.42 ml, 3 mmol). The mixture was stirred at 0 ° C. for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase is washed with 1 N. aqueous HCl, 5% aqueous NaHCO ₃ , water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give 0.290 g (60% yield) of the desired product, which was used without further purification.

MS (ESI-): 482 (M-1).

Preparation of {4- [2- (3-chlorophenyl) acetamino) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl] phenyl} sulfamic acid (10):

2- (3-Chlorophenyl) -N - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} acetamide 9 (0.290 g) is dissolved in methanol (4 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (0.157 g). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.078 g of the desired product as an ammonium salt.

¹ H NMR (CD ₃ OD) δ 7.61 (d, 1H, J = 3.6 Hz), 7.58 (d, 1H, J = 5.1 Hz), 7.41-7.35 (m , 1H), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, 1H, J = 6.6 Hz), 3.70 ( d, 2H, J = 3.9 Hz), 3.23 (1H, A from ABX, J = 6.6, 13.8 Hz), 3.07 (1H, B from ABX, J = 8.1, 13.5 Hz).

The following are non-limiting examples of compounds included in the second category I aspect of the present invention.

4 - ((S) -2- (2- (3-Methoxyphenyl) acetamido) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ 0D) δ 8.35 (d, 1H, J = 8.7 Hz), 7.61-7.57 (m, 2H), 7.25-7.20 (m, 2H) , 7.25-7.20 (m, 2H), 7.09 (s, 1H), 7.05 (d, 2H, J = 4.2 Hz), 6.99 (d, 1H, J = 8 , 7 Hz), 6.81 (d, 1H, J = 7.8 Hz), 6.77 (s, 1H), 5.30-5.28 (m, 1H), 3.76 (s, 3H ), 3.51 (s, 2H), 3.20 (1H, A from ABX, J = 6.3, 13.6 Hz), 3.06 (1H, B from ABX, J = 8.1, 13 , 8 Hz).

4 - {(S) -2- (3-Phenylpropanamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.30 (d, 1H, J = 9 Hz), 7.61-7.56 (m, 2H), 7.26-7.14 (m, 7H), 7 12 (d, 1H, J = 1.5 Hz), 7.09 (d, 1H, J = 2.1 Hz), 6.89 (s, 1H), 5.28-5.26 (m, 1H), 3.18 (1H, A from ABX, J = 6.2, 13.8 Hz), 2.96 (1H, B from ABX, J = 8.4, 13.6 Hz).

4 - {(S) -2- (3- (3-Chlorophenyl) propanamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.61-7.56 (m, 3H), 7.22-7.14 (m, 6H), 7.08 (d, 1H), 7.00 (d, 1H, J = 77.5 Hz), 6.870 (s, 1H), 5.25 (t, 1H, J = 7.8 Hz), 3.18 (1H, A from ABX, J = 6.6, 13 8 Hz), 2.97 (1H, B from ABX, J = 7.8, 13.8 Hz), 2.87 (t, 2H, J = 7.5 Hz), 2.51 (t, 2H , J = 7.2 Hz).

4 - {(S) -2- (2- (3-Fluorophenyl) propanamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.61-7.57 (m, 2H), 7.32-7.28 (m, 1H), 7.19-7.16 (m, 2H), 7, 08 (t, 1H, J = 4.5 Hz), 7.02-6.95 (m, 6H), 5.29 (t, 1H, J = 8.1 Hz), 3.53 (s, 2H ), 3.22 (1H, A from ABX, J = 6.6, 13.9 Hz), 3.06 (1H, B from ABX, J = 8.4, 13.6 Hz).

(S) -4- {2- [2- (3-Methyl-1,2,4-oxadiazol-5-yl) acetamido] -2- (2- (phenylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.98-7.95 (m, 2H), 7.48-7.46 (m, 3H), 7.23 (s, 1H), 7.09-7, 05 (m, 4H), 5.33 (t, 1H, J = 7.2 Hz), 3.33-3.06 (m, 2H), 2.35 (s, 3H).

4 - {(S) -2- [2- (4-Ethyl-2,3-dioxopiperazin-1-yl) acetamido] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.62 (d, 1H, J = 3 Hz), 7.58 (d, 1H, J = 15.6 Hz), 7.27 (s, 1H), 7, 16 (t, 1H, J = 1.5 Hz), 5.42-5.32 (m, 1H), 4.31 (d, 1H, J = 15.6 Hz), 3.91 (d, 1H , J = 15.9 Hz), 3.60-3.50 (m, 4H), 3.30-3.23 (m, 2H), 2.98 (1H, B from ABX, J = 9.9 13.8 Hz); 1.21 (t, 3H, J = 6.9 Hz).

A third aspect of category I of the present invention relates to compounds of the formula:

where the linking group L includes a phenyl group, and the above linking group has the formula:

-C (O) [(CR ^6a H)] [(CH ₂ )] -,

R ^5a means phenyl or substituted phenyl, and non-limiting examples of the groups R ² , R ³ and R ^6a are shown in table III below.

Table III No. R ² R ³ R ^6a 201 methyl hydrogen phenyl 202 methyl hydrogen 2-fluorophenyl 203 methyl hydrogen 3-fluorophenyl 204 methyl hydrogen 4-fluorophenyl 205 methyl hydrogen 3,4-difluorophenyl 206 methyl hydrogen 2-chlorophenyl 207 methyl hydrogen 3-chlorophenyl 208 methyl hydrogen 4-chlorophenyl 209 methyl hydrogen 3,4-dichlorophenyl 210 methyl hydrogen 2-methoxyphenyl 211 methyl hydrogen 3-methoxyphenyl 212 methyl hydrogen 4-methoxyphenyl 213 ethyl hydrogen phenyl 214 ethyl hydrogen 2-fluorophenyl 215 ethyl hydrogen 3-fluorophenyl 216 ethyl hydrogen 4-fluorophenyl 217 ethyl hydrogen 3,4-difluorophenyl 218 ethyl hydrogen 2-chlorophenyl 219 ethyl hydrogen 3-chlorophenyl 220 ethyl hydrogen 4-chlorophenyl 221 ethyl hydrogen 3,4-dichlorophenyl 222 ethyl hydrogen 2-methoxyphenyl 223 ethyl hydrogen 3-methoxyphenyl 224 ethyl hydrogen 4-methoxyphenyl

Compounds included in the third aspect of category I of the present invention can be obtained by the method shown in scheme III and described below in example 3 of this description.

Scheme III

Reagents and conditions: (a) diphenylpropionic acid, EDCI, HOBt, TEA, DMF; temperature from 0 ° C to room temperature, 18 hours.

Reagents and conditions: (b) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH; room temperature, 18 hours.

Example 3

(S) -4- (2- (2,3-diphenylpropanamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid (12)

Preparation of (S) -N- [1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -2,3-diphenylpropanamide (11):

To a solution of 1- (S) - (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamine 3 hydrobromide (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2, 65 mmol) and 1-hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF (10 ml) at 1 ° C, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (0.502 g, 2 62 mmol), then triethylamine (1.1 ml, 7.95 mmol). The mixture was stirred at 0 ° C. for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase is washed with 1 N. aqueous HCl, 5% aqueous NaHCO ₃ , water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give 0.903 g (70% yield) of the desired product, which was used without further purification.

Preparation of (S) -4- (2- (2,3-diphenylpropanamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid (12):

(S) -N- [1- (4-Ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -2,3-diphenylpropanamide 11 (0.903 g) was dissolved in methanol (10 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (30 ml) and treated with SO ₃ -pyridine (0.621 g). The reaction mixture was stirred at room temperature for 5 minutes, then an NH ₄ OH solution was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.415 g of the desired product as an ammonium salt.

¹ H NMR (CD ₃ OD) δ 8.59-8.52 (m, 1H), 7.37-7.04 (m, 9H), 6.97-6.93 (m, 1H), 6, 89-6.85 (m, 2H), 5.36-5.32 (m, 1H), 3.91-3.83 (m, 1H), 3.29 (1H, A from ABX, solvent masked) , 3.15 (1H, B from ABX, J = 5.4, 33.8 Hz), 2.99-2.88 (m, 2H), 2.81-2.69 (m, 2H), 1 32-1.25 (m, 3H).

The precursors of the plurality of Z groups, which includes the third aspect of category I, are readily available. The following procedure illustrates an example of a method that can be used to obtain various R ^6a groups of the present invention. Using the methodology presented in scheme IV and described in example 4, a person skilled in the art will be able to make modifications without undue experimentation to obtain R ^5a groups, with reference to the present description.

Scheme IV

13

Reagents and conditions: (a) methyl 2- (2-methoxyphenyl) acetate, LDA, THF; temperature from 0 ° C to room temperature, 18 hours.

Reagents and conditions: (b)

Example 4

2- (2-Methoxyphenyl) -3-phenylpropanoic acid (14)

Preparation of methyl 2- (2-methoxyphenyl) -3-phenylpropanoate (13):

Methyl 2- (2-methoxyphenyl) acetate (8.496 g, 47 mmol, 1 equiv.) And THF (200 ml) are added to a 500 ml round bottom flask. The homogeneous mixture is cooled to a temperature of 0 ° C in an ice bath. Lithium diisopropylamide (23.5 ml of a 2.0 M solution in heptane / THF mixture) was added, keeping the temperature below 3 ° C. The reaction mixture was stirred for 45 minutes at this reduced temperature. Benzyl bromide (5.6 ml, 47 mmol, 1 eq.) Is added dropwise. The reaction mixture was allowed to gradually warm to room temperature and stirred for 18 hours. The reaction is quenched with 1 N. HCl and extracted 3 times with equal portions of ethyl acetate. The combined extracts were washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using silica to give 4.433 g (35% yield) of the desired compound.

MS (ESI +): 293 (M + Na).

Preparation of 2- (2-methoxyphenyl) -3-phenylpropanoic acid (14):

Methyl 2- (2-methoxyphenyl) -3-phenylpropanoate (4.433 g, 16 mmol, 1 equiv.) Is dissolved in 100 ml of a mixture of THF and methanol in a ratio of 1: 1 (vol./vol.). Sodium hydroxide (3.28 g, 82 mmol, 1 equiv.) Was added and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was then poured into water and the pH was adjusted to 2 by adding 1 N. HCl. A white precipitate formed which was removed by filtration. The resulting solution was extracted with 3 portions of diethyl ether. The extracts are combined, washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified using silica to give 2.107 g (51%) of the desired compound.

MS (ESI-): 255 (M-1); 211 (M-CO ₂ H).

Intermediate 14 can also be obtained in accordance with the procedure presented in scheme III and described in example 3, to obtain the following compounds according to the third aspect of category I.

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [2- (2-methoxyphenyl) -3-phenylpropanamido] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.32-7.12 (m, 7H), 7.05-7.02 (m, 1H), 6.99-6.83 (m, 4H), 6, 80-6.75 (m, 2H), 5.35-5.31 (m, 1H), 4.31-4.26 (m, 1H), 3.75 (s, 3H), 3.20- 2.90 (m, 4H), 2.79-2.74 (m, 2H), 1.32-1.25 (m, 3H).

The following are non-limiting examples of compounds according to the third aspect of category I of the present invention.

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [2- (3-fluorophenyl) -3-phenylpropanamido] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.33-6.87 (m, 14H), 5.39-5.25 (m, 1H), 3.95-3.83 (m, 1H), 3, 31-3.10 (m, 1H), 3.05-2.88 (m, 2H), 2.80-2.70 (m, 2H), 1.32-1.23 (m, 3H). ¹⁹ F NMR δ 47.59.

(S) -4- {2- (4-Ethylthiazol-2-yl) -2- [2- (3-methoxyphenyl) -3-phenylpropanamido] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.85 (d, 1H, J = 8.4 Hz), 7.25-7.20 (m, 1H), 7.11-7.02 (m, 4H) 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H), 4.09 (s, 2H), 3.79 (s , 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

A fourth aspect of category I of the present invention relates to compounds of the formula:

where the linking group L includes a phenyl group, and the above linking group has the formula:

-C (O) [(CR ^6a H)] [(CH ₂ )] -,

R ^5a means substituted or unsubstituted heteroaryl, and examples of the groups R ² , R ³ and R ^5a are shown below in table IV.

Table IV No. R ² R ³ R ^6a 225 methyl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl 226 methyl hydrogen thiophen-2-yl 227 methyl hydrogen thiazol-2-yl 228 methyl hydrogen oxazol-2-yl 229 methyl hydrogen isoxazol-3-yl 230 ethyl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl 231 ethyl hydrogen thiophen-2-yl 232 ethyl hydrogen thiazol-2-yl 233 ethyl hydrogen oxazol-2-yl 234 ethyl hydrogen isoxazol-3-yl 235 ethyl methyl 3-methyl-1,2,4-oxadiazol-5-yl 236 ethyl methyl thiophen-2-yl 237 ethyl methyl thiazol-2-yl 238 ethyl methyl oxazol-2-yl 239 ethyl methyl isoxazol-3-yl 240 thiophen-2-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl 241 thiophen-2-yl hydrogen thiophen-2-yl 242 thiophen-2-yl hydrogen thiazol-2-yl 243 thiophen-2-yl hydrogen oxazol-2-yl 244 thiophen-2-yl hydrogen isoxazol-3-yl 245 isoxazol-3-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl 246 isoxazol-3-yl hydrogen thiophen-2-yl 247 isoxazol-3-yl hydrogen thiazol-2-yl 248 isoxazol-3-yl hydrogen oxazol-2-yl 249 isoxazol-3-yl hydrogen isoxazol-3-yl

Compounds included in the fourth aspect of category I of the present invention can be obtained by the method shown in scheme V and described below in example 5 of this description.

Scheme V

Reagents and conditions: (a) 2-benzyl-3-ethoxy-3-oxopropanoic acid, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (b) CH ₃ C (= NOH) NH ₂ , K ₂ CO ₃ , toluene; reflux, 18 hours.

Reagents and conditions: (c) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH; room temperature, 18 hours.

Example 5

4 - {(S) -2- (4-Ethylthiazol-2-yl) -2- [2- (3-methyl-1,2,4-oxadiazol-5-yl) -3-phenylpropanamido] ethyl} phenylsulfamic acid (17)

Preparation of ethyl 2-benzyl-3 - [(S) -1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamino] -3-oxopropanoate (15):

To a solution of 1- (S) - (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamine 3 hydrobromide (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3-oxopropanoic acid (0.277 g) and 1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 ml) at 1 ° C. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (0.240 g, 1.25 mmol) then diisopropylethylamine (DIPEA) (0.306 g). The mixture was stirred at 0 ° C. for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase is washed with 1 N. aqueous HCl, 5% aqueous NaHCO ₃ , water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give 0.169 g (31% yield) of the desired product, which was used without further purification.

Preparation of N - [(S) -1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -2- (3-methyl-1,2,4-oxadiazol-5-yl) - 3-phenylpropanamide (16):

Ethyl 2-benzyl-3 - ((S) -1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamino) -3-oxopropanoate is dissolved in toluene (5 ml) and heated to boiling point with reflux condenser. Potassium carbonate (80 mg) and oxyacetamide (43 mg) were added and 80 mg of potassium carbonate and 43 mg of oxyacetamide were treated at reflux temperature. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was chromatographed using silica to give 0.221 g (94% yield) of the desired product as a yellow oil.

Preparation of 4 - {(S) -2- (4-ethylthiazol-2-yl) -2- [2- (3-methyl-1,2,4-oxadiazol-5-yl) -3-phenylpropanamido] ethyl} phenylsulfamine acids (17):

N - [(S) -1- (4-Ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -2- (3-methyl-1,2,4-oxadiazol-5-yl) -3 -phenylpropanamide 16 (0.221 g) and tin (II) chloride (507 mg, 2.2 mmol) were dissolved in ethanol (25 ml) and the solution was refluxed for 4 hours. The solvent was removed in vacuo and the resulting residue was dissolved in ethyl acetate. Saturated NaHCO ₃ solution (50 ml) was added and the solution was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue, which was dissolved in pyridine (0.143 g) and treated with SO ₃ -pyridine (0.143 g). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.071 g of the desired product as an ammonium salt.

¹ H (CD ₃ OD): δ 7.29-6.87 (m, 10H), 5.38-5.30 (m, 1H), 4.37-4.30 (m, 1H), 3, 42-2.74 (m, 6H), 2.38-2.33 (m, 3H), 1.34-1.28 (m, 3H).

Category II of the present invention relates to 2- (thiazol-2-yl) compounds of the formula:

where R ¹ , R ² , R ³ and L are as defined in table V.

Table v No. R ² R ³ R ^one 250 ethyl hydrogen thiophen-2-yl 251 ethyl hydrogen thiazol-2-yl 252 ethyl hydrogen oxazol-2-yl 253 ethyl hydrogen isoxazol-3-yl 254 ethyl hydrogen thiophen-2-yl 255 ethyl hydrogen thiazol-2-yl 256 ethyl hydrogen oxazol-2-yl 257 ethyl hydrogen isoxazol-3-yl 258 ethyl hydrogen thiophen-2-yl 259 ethyl hydrogen thiazol-2-yl 260 ethyl methyl methyl 261 ethyl methyl ethyl 262 ethyl methyl drank 263 ethyl methyl isopropyl 264 ethyl methyl butyl 265 ethyl methyl phenyl 266 ethyl methyl benzyl 267 ethyl methyl 2-fluorophenyl 268 ethyl methyl 3-fluorophenyl 269 ethyl methyl 4-fluorophenyl 270 phenyl hydrogen methyl 271 phenyl hydrogen ethyl 272 phenyl hydrogen drank 273 phenyl hydrogen isopropyl 274 phenyl hydrogen butyl 275 phenyl hydrogen phenyl 276 phenyl hydrogen benzyl 277 phenyl hydrogen 2-fluorophenyl 278 phenyl hydrogen 3-fluorophenyl 279 phenyl hydrogen 4-fluorophenyl 280 thiophen-2-yl hydrogen methyl 281 thiophen-2-yl hydrogen ethyl 282 thiophen-2-yl hydrogen drank 283 thiophen-2-yl hydrogen isopropyl 284 thiophen-2-yl hydrogen butyl 285 thiophen-2-yl hydrogen phenyl 286 thiophen-2-yl hydrogen benzyl 287 thiophen-2-yl hydrogen 2-fluorophenyl 288 thiophen-2-yl hydrogen 3-fluorophenyl 289 thiophen-2-yl hydrogen 4-fluorophenyl

Compounds included in category II of the present invention can be obtained by the method shown in scheme VI and described below in example 6 of this description.

Scheme VI

Reagents and conditions: (a) 3-benzoylpropionic acid, TsCl, N-methylimidazole, CH ₂ Cl ₂ , room temperature, 18 hours.

Reagents and conditions: (b) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 6

(S) -4- [2- (4-Ethylthiazol-2-yl) -2- (4-oxo-4-phenylbutanamido) ethyl] phenylsulfamic acid (19)

Preparation of (S) -N- [1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -4-oxo-4-phenylbutanamide (18):

3-Benzoylpropionic acid (0.250 g) was dissolved in CH ₂ Cl ₂ (5 ml), N-methylimidazole (0.333 ml) was added and the resulting solution was cooled to 0 ° C, then a solution of p-toluenesulfonyl chloride (0.320 g) was added dropwise to CH ₂ Cl ₂ (2 ml). After 0.5 hours, (S) -1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethanamine 3 (0.388 g) was added. The reaction mixture was stirred for 18 hours at room temperature and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with 1 N. HCl and brine. The solution was dried over Na ₂ SO ₄ , filtered, concentrated and the crude material was purified using silica to give 0.415 g of the desired product.

Preparation of (S) -4- [2- (4-ethylthiazol-2-yl) -2- (4-oxo-4-phenylbutanamido) ethyl] phenylsulfamic acid (19):

(S) -N- [1- (4-Ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] -4-oxo-4-phenylbutanamide 18 (0.2 g) was dissolved in methanol (15 ml) . A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (5 ml) and treated with SO ₃ -pyridine (0.153 g). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.090 g of the desired product as an ammonium salt.

¹ H NMR (CD ₃ OD) δ 8.68 (d, 1H, J = 8.2 Hz), 8.00 (d, 2H, J = 7.2 Hz), 7.80-7.50 (m , 3H), 7.12 (s, 4H), 7.03 (s, 1H), 5.46-5.38 (m, 1H), 3.29-3.14 (m, 2H), 3, 06-2.99 (m, 2H), 2.83 (q, 2H, J = 7.5 Hz), 2.69-2.54 (m, 2H), 1.33 (t, 3H, J = 7.5 Hz).

The following are non-limiting examples of compounds included in category II of the present invention. Intermediate nitro compounds can also be obtained by reacting the corresponding 4-oxocarboxylic acid with intermediate 3 under the conditions described above in this description to obtain intermediate 4 according to Scheme I.

(S) -4- (2- (4-Ethylthiazol-2-yl) -2- (5-methyl-4-oxohexanamido) ethyl) phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.59 (d, 1H, J = 8.1 Hz), 7.14 (s, 4H), 7.08 (t, 1H, J = 13.0 Hz), 5.40-5.35 (m, 1H), 3.37-3.27 (m, 2H), 3.04-2.97 (m, 1H), 2.83-2.61 (m, 4H ), 2.54-2.36 (m, 3H), 1.33 (t, 2H, J = 7.3 Hz), 1.09 (dd, 6H, J = 7.0, 2.2 Hz) .

(S) -4- {2- [4- (3,4-Dihydro-2H-benzo [b] [1,4] dioxepan-7-yl) -4-oxobutanamido] -2- (4-ethylthiazol-2 -yl) ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.64 (d, 1H, J = 8.4 Hz), 7.60 (d, 2H, J = 10.6 Hz), 7.11 (s, 3H), 7.04 (d, 2H, J = 5.5 Hz), 5.42-5.40 (m, 1H), 4.30-4.22 (m, 4H), 3.20-2.98 ( m, 4H), 2.82 (q, 2H, J = 7.3 Hz), 2.67-2.48 (m, 2H), 2.23 (t, 2H, J = 5.5 Hz), 1.32 (t, 3H, J = 7.3 Hz).

(S) -4- {2- [4- (2,3-Dimethoxyphenyl) -4-oxobutanamido] -2- (4-ethylthiazol-2-yl) ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD), δ 8.64, (d, 1H, J = 8.1 Hz), 7.21-7.11 (m, 7H), 7.02 (s, 1H), 5 42 (q, 1H, J = 5.9 Hz), 3.90 (d, 3H, J = 3.3 Hz), 3.88 (d, 3H, J = 2.9 Hz), 3.22 -3.18 (m, 2H), 3.07-2.99 (m, 2H), 2.83 (q, 2H, J = 7.3 Hz), 2.63-2.54 (m, 2H) ), 1.34 (t, 3H, J = 7.69 Hz).

(S) -4- {2- [4-Ethylthiazol-2-yl) -2- [4-oxo-4- (pyridin-2-yl) butanamido] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.60 (d, 1H, J = 12.8 Hz), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H) 7.22-7.21 (m, 1H), 6.99 (s, 3H), 6.91 (s, 1H), 5.30 (q, 1H, J = 5.4 Hz), 3, 36 (q, 2H, J = 7.0 Hz), 3.21-3.15 (m, 1H), 2.91-2.85 (m, 1H), 2.74 (q, 2H, J = 10.4 Hz), 2.57-2.50 (m, 2H), 1.20 (t, 3H, J = 7.5 Hz).

(S) -4- {2- [4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -4-oxobutanamido] -2- (4-ethylthiazol-2-yl) ethyl } phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.52-7.47 (m, 2H), 7.11 (s, 4H), 7.03 (s, 1H), 6.95 (d, 1H, J = 8.4 Hz), 5.41 (q, 1H, J = 3.7 Hz), 4.31 (d, 4H, J = 5.5 Hz), 3.24-3.12 (m, 2H) , 3.06-2.98 (m, 2H), 2.83 (q, 2H, J = 7.3 Hz), 2.62-2.53 (m, 2H), 1.33 (t, 3H , J = 7.3 Hz).

(S) -4- [2- (4-tert-butoxy-4-oxobutanamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid

¹ H NMR (CD ₃ OD), δ 7.10 (s, 4H), 7.02 (s, 1H), 5.41 (q, 1H, J = 3.7 Hz), 3.30-3, 25 (m, 1H), 3.06-2.99 (m, 1H), 2.83 (q, 2H, J = 7.3 Hz), 2.52-2.40 (m, 4H), 1 42 (s, 9H); 1.33 (t, 3H, J = 7.3 Hz).

(S) -4- [2- (4-Ethoxy-4-oxobutanamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 8.62 (d, 1H, J = 8.4 Hz), 7.10 (s, 4H), 7.02 (s, 1H), 5.40 (q, 1H , 3.7 Hz), 4.15 (q, 2H, J = 7.3 Hz), 3.28-3.25 (m, 1H), 3.05-3.02 (m, 1H), 2 82 (q, 2H, J = 4.4 Hz), 2.54-2.48 (m, 2H), 1.33 (t, 3H, J = 7.3 Hz), 1.24 (t, 3H, J = 7.0 Hz).

The first aspect of category III of the present invention relates to 2- (thiazol-2-yl) compounds of the formula:

where non-limiting examples of R ¹ , R ² and R ³ are shown below in table VI of this description.

Table VI No. R ² R ³ R ^one 290 methyl hydrogen phenyl 291 methyl hydrogen benzyl 292 methyl hydrogen 2-fluorophenyl 293 methyl hydrogen 3-fluorophenyl 294 methyl hydrogen 4-fluorophenyl 295 methyl hydrogen 2-chlorophenyl 296 methyl hydrogen 3-chlorophenyl 297 methyl hydrogen 4-chlorophenyl 298 ethyl hydrogen phenyl 299 ethyl hydrogen benzyl 300 ethyl hydrogen 2-fluorophenyl 301 ethyl hydrogen 3-fluorophenyl 302 ethyl hydrogen 4-fluorophenyl 303 ethyl hydrogen 2-chlorophenyl 304 ethyl hydrogen 3-chlorophenyl 305 ethyl hydrogen 4-chlorophenyl 306 thien-2-yl hydrogen phenyl 307 thien-2-yl hydrogen benzyl 308 thien-2-yl hydrogen 2-fluorophenyl 309 thien-2-yl hydrogen 3-fluorophenyl 310 thien-2-yl hydrogen 4-fluorophenyl 311 thien-2-yl hydrogen 2-chlorophenyl 312 thien-2-yl hydrogen 3-chlorophenyl 313 thien-2-yl hydrogen 4-chlorophenyl

Compounds included in category III of the present invention can be obtained by the method shown in scheme VII and described below in example 7 of this description.

Scheme VII

3 twenty

Reagents and conditions: (a) benzyl isocyanate, TEM, CH ₂ Cl ₂ , room temperature, 18 hours.

Reagents and conditions: (b) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 7

(S) -4- (2- (3-Benzylureido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid (21)

Preparation of (S) -1-benzyl-3- [1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] urea (20):

To a solution of 1- (S) - (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethylamine 3 (0.360 g, 1 mmol) hydrobromide and Et ₃ N (0.42 ml, 3 mmol) in 10 ml of CH ₂ Cl ₂ add benzylisocyanate (0.12 ml, 1 mmol). The mixture was stirred at room temperature for 18 hours. The product was isolated by filtration to obtain 0.425 g (96% yield) of the desired product, which was used without further purification.

Preparation of (S) -4- (2- (3-benzylureido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid (21):

(S) -1-Benzyl-3- [1- (4-ethylthiazol-2-yl) -2- (4-nitrophenyl) ethyl] urea, 20, (0.425 g) was dissolved in methanol (4 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (0.220 g). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.143 g of the desired product as an ammonium salt.

¹ H NMR (CD ₃ OD) δ 7.32-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.12-7.00 (m, 4H), 6, 84 (d, 1H, J = 8.1 Hz), 5.35-5.30 (m, 1H), 4.29 (s, 2H), 3.27-3.22 (m, 3H), 3 11-3.04 (m, 3H), 2.81 (q, 2H, J = 10.2, 13.0 Hz), 1.31 (t, 3H, J = 4.5 Hz).

The following are non-limiting examples of compounds included in the first aspect of category III of the present invention.

4 - {[((S) -2- (2-Ethylthiazol-4-yl) -2- (3- (R) -methoxy-1-oxo-3-phenylpropan-2-yl) ureido] ethyl} phenylsulfamic acid

¹ H NMR (CD ₃ OD) δ 7.36-7.26 (m, 3H), 7.19-7.17 (m, 2H), 7.10-7.06 (m, 2H), 6, 90-6.86 (m, 3H), 5.12-5.06 (m, 1H), 4.60-4.55 (m, 1H), 3.69 (s, 3H), 3.12- 2.98 (m, 6H); 1.44-1.38 (m, 3H).

A second aspect of category III of the present invention relates to 2- (thiazol-4-yl) compounds of the formula:

where non-limiting examples of R ¹ and R ⁴ are shown below in table VII of this description.

Table VII No. R ^one R ^four 314 methyl methyl 315 ethyl methyl 316 n-propyl methyl 317 isopropyl methyl 318 phenyl methyl 319 benzyl methyl 320 2-fluorophenyl methyl 321 2-chlorophenyl methyl 322 thiophen-2-yl methyl 323 thiazol-2-yl methyl 324 oxazol-2-yl methyl 325 isoxazol-3-yl methyl 326 methyl ethyl 327 ethyl ethyl 328 n-propyl ethyl 329 isopropyl ethyl 330 phenyl ethyl 331 benzyl ethyl 332 2-fluorophenyl ethyl 333 2-chlorophenyl ethyl 334 thiophen-2-yl ethyl 335 thiazol-2-yl ethyl 336 oxazol-2-yl ethyl 337 isoxazol-3-yl ethyl 338 methyl thiophen-2-yl 339 ethyl thiophen-2-yl 340 n-propyl thiophen-2-yl 341 isopropyl thiophen-2-yl 342 phenyl thiophen-2-yl 343 benzyl thiophen-2-yl 344 2-fluorophenyl thiophen-2-yl 345 2-chlorophenyl thiophen-2-yl 346 thiophen-2-yl thiophen-2-yl 347 thiazol-2-yl thiophen-2-yl 348 oxazol-2-yl thiophen-2-yl 349 isoxazol-3-yl thiophen-2-yl 350 methyl thiazol-2-yl 351 ethyl thiazol-2-yl 352 n-propyl thiazol-2-yl 353 isopropyl thiazol-2-yl 354 phenyl thiazol-2-yl 355 benzyl thiazol-2-yl 356 2-fluorophenyl thiazol-2-yl 357 2-chlorophenyl thiazol-2-yl 358 thiophen-2-yl thiazol-2-yl 359 thiazol-2-yl thiazol-2-yl 360 oxazol-2-yl thiazol-2-yl 361 isoxazol-3-yl thiazol-2-yl 362 methyl oxazol-2-yl 363 ethyl oxazol-2-yl 364 n-propyl oxazol-2-yl 365 isopropyl oxazol-2-yl 366 phenyl oxazol-2-yl 367 benzyl oxazol-2-yl 368 2-fluorophenyl oxazol-2-yl 369 2-chlorophenyl oxazol-2-yl 370 thiophen-2-yl oxazol-2-yl 371 thiazol-2-yl oxazol-2-yl 372 oxazol-2-yl oxazol-2-yl 373 isoxazol-3-yl oxazol-2-yl

Compounds included in the second aspect of category III of the present invention can be obtained by the method described in the description below in scheme VIII and described in example 8.

Scheme VIII

Reagents and conditions: (a) benzyl isocyanate, TEM, CH ₂ Cl ₂ ; room temperature, 18 hours.

Reagents and conditions: (b) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 8

4 - {(S) -2- (3-Benzylureido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid (23)

Preparation of 1-benzyl-3 - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} urea (22):

To a solution of hydrobromide (S) -2- (4-nitrophenyl) -1 - [(2-thiophen-2-yl) thiazol-4-yl) ethanamine 8 and Et ₃ N (0.42 ml, 3 mmol) in 10 benzyl isocyanate (0.12 ml, 1 mmol) is added in ml of dichloromethane. The mixture was stirred at room temperature for 18 hours. The product was isolated by filtration to obtain 0.445 g (96% yield) of the desired product, which was used without further purification.

Preparation of 4 - {(S) -2- (3-benzylureido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid (23):

1-Benzyl-3 - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} urea 22 (0.445 g) is dissolved in methanol (10 ml) and CH ₂ Cl ₂ (5 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (0.110 g). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.080 g of the desired product as an ammonium salt.

¹ H NMR (CD ₃ OD) δ 7.61 (d, 1H, J = 2.1 Hz), 7.58 (d, 1H, J = 6 Hz), 7.33-7.22 (m, 4H ), 7.17-7.14 (m, 1H), 7.09-6.94 (m, 6H), 5.16 (t, 1H, J = 6.6 Hz), 4.13 (s, 2H), 3.14-3.11 (m, 2H).

Category IV of the present invention relates to 2- (thiazol-4-yl) compounds of the formula:

where R ¹ , R ⁴ and L have the meanings as defined below in table VIII of this description.

Table VIII No. R ^four L R ^one 374 methyl -SO ₂ - methyl 375 ethyl -SO ₂ - methyl 376 phenyl -SO ₂ - methyl 377 thiophen-2-yl -SO ₂ - methyl 378 methyl -SO ₂ - trifluoromethyl 379 ethyl -SO ₂ - trifluoromethyl 380 phenyl -SO ₂ - trifluoromethyl 381 thiophen-2-yl -SO ₂ - trifluoromethyl 382 methyl -SO ₂ - ethyl 383 ethyl -SO ₂ - ethyl 384 phenyl -SO ₂ - ethyl 385 thiophen-2-yl -SO ₂ - ethyl 386 methyl -SO ₂ - 2,2,2-trifluoroethyl 387 ethyl -SO ₂ - 2,2,2-trifluoroethyl 388 phenyl -SO ₂ - 2,2,2-trifluoroethyl 389 thiophen-2-yl -SO ₂ - 2,2,2-trifluoroethyl 390 methyl -SO ₂ - phenyl 391 ethyl -SO ₂ - phenyl 392 phenyl -SO ₂ - phenyl 393 thiophen-2-yl -SO ₂ - phenyl 394 methyl -SO ₂ - 4-fluorophenyl 395 ethyl -SO ₂ - 4-fluorophenyl 396 phenyl -SO ₂ - 4-fluorophenyl 397 thiophen-2-yl -SO ₂ - 4-fluorophenyl 398 methyl -SO ₂ - 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl 399 ethyl -SO ₂ - 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl 400 phenyl -SO ₂ - 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl 401 thiophen-2-yl -SO ₂ - 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl 402 methyl -SO ₂ - 1-methyl-1H-imidazol-4-yl 403 ethyl -SO ₂ - 1-methyl-1H-imidazol-4-yl 404 phenyl -SO ₂ - 1-methyl-1H-imidazol-4-yl 405 thiophen-2-yl -SO ₂ - 1-methyl-1H-imidazol-4-yl 406 methyl -SO ₂ - 4-acetamidophenyl 407 ethyl -SO ₂ - 4-acetamidophenyl 408 phenyl -SO ₂ - 4-acetamidophenyl 409 thiophen-2-yl -SO ₂ - 4-acetamidophenyl 410 methyl -SO ₂ CH ₂ - phenyl 411 ethyl -SO ₂ CH ₂ - phenyl 412 phenyl -SO ₂ CH ₂ - phenyl 413 thiophen-2-yl -SO ₂ CH ₂ - phenyl 414 methyl -SO ₂ CH ₂ - (4-methylcarboxyphenyl) methyl 415 ethyl -SO ₂ CH ₂ - (4-methylcarboxyphenyl) methyl 416 phenyl -SO ₂ CH ₂ - (4-methylcarboxyphenyl) methyl 417 thiophen-2-yl -SO ₂ CH ₂ - (4-methylcarboxyphenyl) methyl 418 methyl -SO ₂ CH ₂ - (2-methylthiazol-4-yl) methyl 419 ethyl -SO ₂ CH ₂ - (2-methylthiazol-4-yl) methyl 420 phenyl -SO ₂ CH ₂ - (2-methylthiazol-4-yl) methyl 421 thiophen-2-yl -SO ₂ CH ₂ - (2-methylthiazol-4-yl) methyl 422 methyl -SO ₂ CH ₂ CH ₂ - phenyl 423 ethyl -SO ₂ CH ₂ CH ₂ - phenyl 424 phenyl -SO ₂ CH ₂ CH ₂ - phenyl 425 thiophen-2-yl -SO ₂ CH ₂ CH ₂ - phenyl

Compounds included in category IV of the present invention can be obtained by the method presented in this description below in scheme IX and described in example 9.

Scheme IX

Reagents and conditions: (a) C ₆ H ₄ CH ₂ SO ₂ Cl, DIPEA, CH ₂ Cl ₂ ; 0 ° C, 14 hours.

Reagents and conditions: (b) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 9

{4- (S) - [2-Phenylmethanesulfonylamino-2- (2-thiophen-2-ylthiazol-4-yl) ethyl] phenyl} sulfamic acid (25)

Preparation of (S) -N- {2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} -1-phenylmethanesulfonamide (24):

To a suspension of 2- (4-nitrophenyl) -1- (2-thiophen-2-ylthiazol-4-yl) ethylamine 8 (330 mg, 0.80 mmol) in CH ₂ Cl ₂ (6 ml) at 0 ° C diisopropylethylamine (0.30 ml, 1.6 mmol) was added, followed by phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 14 hours. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ solution, then brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified using silica to give 210 mg of the desired product as a white solid.

Preparation of {4- (S) - [2-phenylmethanesulfonylamino-2- (2-thiophen-2-ylthiazol-4-yl) ethyl] phenyl} sulfamic acid (25):

(S) -N- {2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} -1-phenylmethanesulfonamide 24 (210 mg, 0.41 mmol) is dissolved in methanol (4 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (197 mg, 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.060 g of the desired product as an ammonium salt.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.52-7.63 (m, H), 6.70-7.28 (m, 11H), 4.75 (t, J = 7.2 Hz, 1H), 3.95-4.09 (m, 2H), 3.20 (dd, J = 13.5 and 7.8 Hz, 1H), 3.05 (dd, J = 13.5 and 7.8 Hz, 1H).

Intermediates for use in step (a) of Scheme IX can be prepared by the conventional method described in Scheme X below and described in Example 10.

Scheme X

Reagents and conditions: (a) Na ₂ SO ₃ , H ₂ O; microwave irradiation; 200 ° C, 20 min.

26 27

Reagents and conditions: (b) PCl ₅ , POCl ₃ ; 50 ° C, 3 hours.

Example 10

(2-Methylthiazol-4-yl) methanesulfonyl chloride (27)

Obtaining (2-methylthiazol-4-yl) sodium methanesulfonate (26):

4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) was dissolved in H ₂ O (2 ml) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at a temperature of 200 ° C. The reaction mixture was diluted with H ₂ O (30 ml) and washed with ethyl acetate (2 times 25 ml). The aqueous layer was concentrated to obtain 0.368 g of the desired product as a yellow solid.

LC / MS (ESI +): 194 (M + 1, free acid).

Preparation of (2-methylthiazol-4-yl) methanesulfonyl chloride (27):

(2-Methylthiazol-4-yl) sodium methanesulfonate (357 mg, 1.66 mmol) was dissolved in phosphorus oxychloride (6 ml) and treated with phosphorus pentachloride (345 mg, 1.66 mmol). The reaction mixture was stirred at 50 ° C. for 3 hours, then allowed to cool to room temperature. The solvent was removed under reduced pressure, the residue was redissolved in CH ₂ Cl ₂ (40 ml) and washed with saturated NaHCO ₃ solution and brine. The organic layer was dried over MgSO ₄ , filtered and the solvent was removed in vacuo to give 0.095 g of the desired product as a brown oil.

LC / MS (ESI +): 211 (M + 1).

Intermediates are obtained with a sufficient degree of purity for subsequent use according to Scheme IX without the need for further purification.

(S) - {4- [2- (2-Ethylthiazol-4-yl) -2- (2-methylthiazol-4-sulfonamido) ethyl] phenyl} sulfamic acid

¹ H (CD ₃ OD): δ 7.71-7.66 (m, 2H), 7.27-7.10 (m, 7H), 4.87 (t, 1H, J = 7.3 Hz) 4.30-4.16 (q, 2H, J = 13.2 Hz); 3.34-3.13 (m, 2H); 2.70 (s, 3H).

The following are non-limiting examples of compounds included in category IV of the present invention.

{4- (S) - [2-Phenylmethanesulfonylamino-2- (2-ethylthiazol-4-yl) ethyl] phenyl} sulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.27-7.32 (m, 3H), 7.16-7.20 (m, 3H), 7.05-7.6 (m, 2H ), 6.96 (d, J = 8.4 Hz, 2H), 4.70 (t, J = 9.0 Hz, 1H), 3.91-4.02 (m, 2H), 2.95 -3.18 (m, 4H), 1.41 (t, J = 7.5 Hz, 3H).

(S) - (4- (2- (2- (2-ethylthiazol-4-yl) -2- (3-methoxyphenyl) methylsulfonamido) ethyl) phenyl) sulfamic acid.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.20 (t, J = 8.1 Hz. 1H), 6.94-7.08 (m, 4H), 6.88-6.94 ( m, 3H), 6.75-6.80 (m, 1H), 4.67 (t, J = 7.2 Hz, 1H), 3.90-4.0 (m, 2H), 3.76 (s, 3H), 2.95-3.16 (m, 4H), 1.40 (t, J = 7.5 HZ, 3H).

(S) -4 - {[1- (2-ethylthiazol-4-yl) -2- (4-sulfoaminophenyl) ethylsulfamoyl] methyl} benzoic acid methyl ester

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.90-7.94 (m, 2H), 7.27-7.30 (m, 2H), 7.06-7.11 (m, 3H ), 6.97-7.00 (m, 2H), 4.71 (t, J = 7.2 Hz, 1H), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m, 4H), 1.38-1.44 (m, 3H).

(S) -4- [2- (2-Ethylthiazol-4-yl) -2- (1-methyl-1H-imidazole-4-methylsulfonamido) ethyl] phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.54 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.92-7.00 (m, 4H), 4.62 (t, J = 5.4 Hz, 1H), 3.70 (s, 3H), 2.98-3.14 (m, 3H), 2.79 (dd, J = 9 , 3 and 15.0 Hz, 1H), 1.39 (q, J = 7.5 Hz, 3H).

4 - {(3) -2- [2- (Thiophen-2-yl) thiazol-4-yl] -2- (2,2,2-trifluoroethylsulfonamido] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.62-7.56 (m, 2H), 7.22 (s, 1H), 7.16-7.06 (m, 5H), 4.84 (t, 1H, J = 7.6 Hz), 3.71-3.62 (m, 2H), 3.32-3.03 (m, 2H).

{4- (S) - [2- (Phenylethanesulfonylamino) -2- (2-thiophen-2-ylthiazol-4-yl) ethyl] phenyl} sulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.56-7.62 (m, 2H), 7.04-7.19 (m, 9H), 6.94-6.97 (m, 2H ), 4.78 (t, J = 7.8 Hz, 1H), 3.22-3.30 (m, 2H), 3.11 (dd, J = 13.5 and 7.8 Hz, 1H) 2.78-2.87 (m, 4H).

(S) - (4- (2 (3- (Phenylpropylsulfonamino) -2 - [(2-thiophen-2-yl) thiazol-4-yl} phenyl) sulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.56-7.62 (m, 2H), 6.99-7.17 (m, 10H), 4.72 (t, J = 7.8 Hz, 1H), 3.21 (dd, J = 13.5 and 7.2 Hz, 1H), 3.02 (dd, J = 13.5 and 7.2 Hz, 1H), 2.39-2 64 (m, 4H); 1.65-1.86 (m, 2H).

(S) - {4- [2- (4-Methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-sulfonylamino) -2- (2-thiophen-2-ylthiazol-4-yl ) ethyl] phenyl} sulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.53 (d, J = 5.1 Hz, 1H) 7.48 (d, J = 5.1 Hz, 1H), 7.13-7, 10 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.93-6.88 (m, 3H), 6.75 (d, J = 8.1 Hz, 1H ), 6.54 (d, J = 8.1 Hz, 1H), 4.61 (t, J = 7.5 Hz, 1H), 4.20-4.08 (m, 2H), 3.14 -3.00 (m, 4H); 2.69 (s, 3H).

4 - {(S) -2- (4-Acetamidophenylsulfonamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.67-7.52 (m, 6H), 7.24-7.23 (m, 1H), 7.12-7.09 (m, 3H), 7, 02-6.99 (m, 2H), 4.70 (t, 1H, J = 7.3 Hz), 3.25-3.00 (m, 2H), 2.24 (s, 3H).

The first aspect of category V of the present invention relates to compounds of the formula:

where R ¹ means substituted or unsubstituted heteroaryl, and R ⁴ means a linear, branched or cyclic C ₁ -C ₆ alkyl, as defined below in table IX of this description.

Table IX No. R ^four R ^one 426 -CH ₃ 4- (methoxycarbonyl) thiazol-5-yl 427 -CH ₃ 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 428 -CH ₃ 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 429 -CH ₃ 5- (2-methoxyphenyl) oxazol-2-yl 430 -CH ₃ 5 - [(5) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 431 -CH ₃ 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 432 -CH ₃ 5- (3-methoxybenzyl) oxazol-2-yl 433 -CH ₃ 5- (4-phenyl) oxazol-2-yl 434 -CH ₃ 5- (2-methoxyphenyl) thiazol-2-yl 435 -CH ₃ 5- (3-methoxyphenyl) thiazol-2-yl 436 -CH ₃ 5- (4-fluorophenyl) thiazol-2-yl 437 -CH ₃ 5- (2,4-difluorophenyl) thiazol-2-yl 438 -CH ₃ 5- (3-methoxybenzyl) thiazol-2-yl 439 -CH ₃ 4- (3-methoxyphenyl) thiazol-2-yl 440 -CH ₃ 4- (4-fluorophenyl) thiazol-2-yl 441 -CH ₂ CH ₃ 4- (methoxycarbonyl) thiazol-5-yl 442 -CH ₂ CH ₃ 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 443 -CH ₂ CH ₃ 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 444 -CH ₂ CH ₃ 5- (2-methoxyphenyl) oxazol-2-yl 445 -CH ₂ CH ₃ 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 446 -CH ₂ CH ₃ 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 447 -CH ₂ CH ₃ 5- (3-methoxybenzyl) oxazol-2-yl 448 -CH ₂ CH ₃ 5- (4-phenyl) oxazol-2-yl 449 -CH ₂ CH ₃ 5- (2-methoxyphenyl) thiazol-2-yl 450 -CH ₂ CH ₃ 5- (3-methoxyphenyl) thiazol-2-yl 451 -CH ₂ CH ₃ 5- (4-fluorophenyl) thiazol-2-yl 452 -CH ₂ CH ₃ 5- (2,4-difluorophenyl) thiazol-2-yl 453 -CH ₂ CH ₃ 5- (3-methoxybenzyl) thiazol-2-yl 454 -CH ₂ CH ₃ 4- (3-methoxyphenyl) thiazol-2-yl 455 -CH ₂ CH ₃ 4- (4-fluorophenyl) thiazol-2-yl 456 cyclopropyl 4- (methoxycarbonyl) thiazol-5-yl 457 cyclopropyl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 458 cyclopropyl 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 459 cyclopropyl 5- (2-methoxyphenyl) oxazol-2-yl 460 cyclopropyl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 461 cyclopropyl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 462 cyclopropyl 5- (3-methoxybenzyl) oxazol-2-yl 463 cyclopropyl 5- (4-phenyl) oxazol-2-yl 464 cyclopropyl 5- (2-methoxyphenyl) thiazol-2-yl 465 cyclopropyl 5- (3-methoxyphenyl) thiazol-2-yl 466 cyclopropyl 5- (4-fluorophenyl) thiazol-2-yl 467 cyclopropyl 5- (2,4-difluorophenyl) thiazol-2-yl 468 cyclopropyl 5- (3-methoxybenzyl) thiazol-2-yl 469 cyclopropyl 4- (3-methoxyphenyl) thiazol-2-yl 470 cyclopropyl 4- (4-fluorophenyl) thiazol-2-yl

Compounds according to the first aspect of category V, which include a substituted or unsubstituted thiazol-4-yl group in the case of R ¹ , can be obtained by the method shown in scheme XI and described herein below in example 11.

Scheme XI

Reagents and conditions: (a) CH ₃ CN, refluxing; 24 hours.

Reagents and conditions: (b) thiophosgene, CaCO ₃ , CCl ₄ , H ₂ O; room temperature, 18 hours.

Reagents and conditions: (c) potassium tert-butylate, THF; room temperature, 2 hours.

Reagents and conditions: (d) (i) SnCl ₂ -2H ₂ O, EtOH; reflux, 4 hours; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 11

(S) -4- (2- (2-Phenylthiazol-4-yl) -2- (4-methoxycarbonyl) thiazol-5-ylamino) ethyl) phenylsulfamic acid (31)

Preparation of (S) -2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethanamine hydrobromide (28):

A mixture of (S) -tert-butyl-4-bromo-1- (4-nitrophenyl) -3-oxobutan-2-ylcarbamate 7 (1.62 g, 4.17 mmol) and thiobenzamide (0.63 g, 4, 60 mmol) in CH ₃ CN (5 ml) was refluxed for 24 hours. The reaction mixture was cooled to room temperature and diethyl ether was added to the solution. The precipitate formed is filtered off. The solid was dried in vacuo to give 1.2 g (67% yield) of the desired product.

LC / MS (ESI +): 326 (M + 1).

Preparation of (S) -4- (1-isothiocyanato-2- (4-nitrophenyl) ethyl) -2-phenylthiazole (29):

To a solution of hydrobromide (S) -2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethanamine 28 (726 mg, 1.79 mmol) and CaCO ₃ (716 mg, 7.16 mmol) in H ₂ O (2 ml) was added CCl ₄ (3 ml), then thiophosgene (0.28 ml, 3.58 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH ₂ Cl ₂ and water. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a residue which was purified using silica (CH ₂ Cl ₂ ) to give 480 mg (73% yield) of the desired product as a yellow solid substances.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (d, J = 8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3, 60 (dd, J = 13.8 and 6.0 Hz, 1H); 3.46 (dd, J = 13.8 and 6.0 Hz).

Preparation of (S) -methyl-5- [1- (2-phenylthiazol-4-yl) -2- (4-nitrophenyl) ethylamino] thiazole-4-carboxylate (30):

To a suspension of potassium tert-butoxide (80 mg, 0.75 mmol) in THF (3 ml) was added methyl isocyanoacetate (65 μl, 0.68 mmol), then (S) -2-phenyl-4- (1-isothiocyanato-2 - (4-nitrophenyl) ethyl) thiazole 29 (250 mg, 0.68 mmol). The mixture was extracted with ethyl acetate (3 times 25 ml), the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude residue was purified using silica to give 323 mg (yield about 100%) of the desired product as a slightly yellowish solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09-8.13 (m, 2H), 7.95-7.98 (m, 3H), 7.84 (d, J = 1.2 Hz, 1H), 7.44-7.50 (m, 3H), 7.28-7.31 (m, 2H), 7.96 (d, J = 0.6 Hz, 1H), 4.71-4 78 (m, 1H), 3.92 (s, 3H), 3.60 (dd, J = 13.8 and 6.0 Hz, 1H), 3.45 (dd, J = 13.8 and 6 , 0 Hz, 1H).

Preparation of (S) -4- (2- (2-phenylthiazol-4-yl) -2- (4-methoxycarbonyl) thiazol-5-ylamino) ethyl) phenylsulfamic acid (31):

(S) -Metyl-5- [1- (2-phenylthiazol-4-yl) -2- (4-nitrophenyl) ethylamino] thiazole-4-carboxylate 30 (323 mg, 0.68 mmol) and tin chloride (II ) 612 mg, 2.72 mmol) was dissolved in ethanol and the solution was brought to the boiling point under reflux. The solvent was removed in vacuo and the resulting residue was dissolved in ethyl acetate. Saturated NaHCO ₃ solution was added and the solution was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue, which was dissolved in pyridine (10 ml) and treated with SO ₃ -pyridine (130 mg, 0.82 mmol). The reaction solution was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.071 g of the desired product as an ammonium salt.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7, 03-7.13 (m, 4H), 4.74 (t, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).

Compounds according to the first aspect of category V, which include a substituted or unsubstituted thiazol-2-yl group in the case of R ¹ , can be obtained by the method shown in scheme XII and described in this description below in example 12. Intermediate 32 can be obtained according to scheme II and Example 2 by replacing the thiophene-2-carboxylic acid amide with cyclopropanecarboxylic acid amide.

Scheme XII

Reagents and conditions: (a) thiophosgene, CaCO ₃ , CCl ₄ / H ₂ O; room temperature, 18 hours.

Reagents and conditions: (b)

Reagents and conditions: (c) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 12

4 - {(S) -2- (2-Cyclopropylthiazol-4-yl) -2- [4- (3-methoxyphenyl) thiazol-2-ylamino] ethyl} phenylsulfamic acid (35)

Preparation of (S) -1- (1- (2-cyclopropylthiazol-4-yl) -2- (4-nitrophenyl) ethyl) thiourea (33):

To a solution of (S) -1- (2-cyclopropylthiazol-4-yl) -2- (4-nitrophenyl) ethanamine 32 (4.04 g, 10.9 mmol) and CaCO ₃ (2.18 g, 21, 8 mmol) in a mixture of CCl ₄ / water (25 ml / 20 ml) thiophosgene (1.5 g, 13.1 mmol) is added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH ₂ Cl ₂ and water. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a residue, which was then treated with ammonia (0.5 M solution in 1,4-dioxane, 120 ml) and purified using silica to give 2.90 g of the desired product as a red-brown solid.

LC / MS (ESI-): 347 (M-1).

Preparation of (S) -4- (3-methoxybenzyl) -N- (1- (2-cyclopropylthiazol-4-yl) -2- (4-nitrophenyl) ethyl) thiazol-2-amine (34):

(S) -1- (1- (2-Cyclopropylthiazol-4-yl) -2- (4-nitrophenyl) ethyl) thiourea 33 (350 mg, 1.00 mmol) and 2-bromo-3'-methoxyacetophenone (253 mg, 1.10 mmol) was mixed in 3 ml of CH ₃ CN and refluxed for 24 hours. The mixture was concentrated and chromatographed to give 0.172 g of the product as a yellow solid.

LC / MS (ESI +): 479 (M + 1).

Preparation of 4 - {(S) -2- (2-cyclopropylthiazol-4-yl) -2- [4- (3-methoxyphenyl) thiazol-2-ylamino] ethyl} phenylsulfamic acid (35):

(S) -4- (3-Methoxybenzyl) -N- (1- (2-cyclopropylthiazol-4-yl) -2- (4-nitrophenyl) ethyl) thiazol-2-amine 34 (0.172 g) was dissolved in 10 ml methanol. A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in 5 ml of pyridine and treated with SO ₃ -pyridine (114 mg). The reaction mixture was stirred at room temperature for 5 minutes, then 10 ml of a 7% solution of NH ₄ OH were added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.033 g of the desired product as an ammonium salt.

¹ H (CD ₃ OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80 (m, 2H), 5, 02 (t, 1H, J = 6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J = 7.1 Hz), 2.36 (q, 1H, J = 4 6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

The following are non-limiting examples of compounds included in the first aspect of category V.

(S) -4- (2- (4 - ((2-Methoxy-2-oxoethyl) carbamoyl) thiazol-5-ylamino) -2- (2-ethylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.91 (s, 1H), 7.08-7.10 (m, 3H), 6.99 (d, J = 8.7 Hz, 2H) 4.58 (t, J = 6.9 Hz, 1H), 4.11 (d, J = 2.7 Hz, 2H), 3.78 (s, 3H), 3.14-3.28 ( m, 2H), 3.06 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.5 Hz, 3H).

(S) -4- (2 - ((3 - ((2-Methoxy-2-oxoethyl) carbamoyl) -1-H-indol-2-yl) amino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.63 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.18-7.29 (m, 4H) 7.02-7.16 (m, 4H), 6.85 (s, 1H), 5.04-5.09 (m, 1H), 4.85 (s, 3H), 3.27 (dd , J = 13.5 and 8.1 Hz, 1H), 3.10 (m, J = 13.5 and 8.1 Hz, 1H), 2.69 (s, 3H).

4 - ((S) -2- (5- (2-Methoxyphenyl) oxazol-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) 5 7.52 (dd, J = 7.5 and 1.2 Hz, 1H), 6.95-1.24 (m, 10H), 5.04- 5.09 (m, 1H), 3.92 (s, 3H), 3.26 (dd, J = 13.8 and 8.4 Hz, 1H), 3.10 (dd, J = 13.8 and 8.4 Hz, 1H); 2.72 (s, 3H).

4 - ((S) -2- (5 - ((S) -1- (tert-Butoxycarbonyl) -2-phenylethyl) oxazol-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamine acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.03-7.27 (m, 10H), 6.50 (s, 1H), 4.95-5.00 (m, 1H), 4, 76 (t, J = 6.9 Hz, 1H), 3.22 (dd, J = 14.1 and 6.9 Hz, 1H), 3.00-3.10 (m, 2H), 2.90 (dd, J = 14.1 and 6.9 Hz, 1H), 2.72 (s, 3H), 1.37 (s, 9H).

(S) - {4- {2- [5- (4-Methoxycarbonyl) phenyl] oxazol-2-ylamino} -2- (2-methylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.99 (d, J = 7.5 Hz, 2H), 7.56-7.59 (m, 2H), 7.23-7.24 ( m, 1H), 7.08-7.14 (m, 4H), 6.83 (d, J = 10.2 Hz, 1H), 5.08 (t, J = 6.0 Hz, 1H), 3.91 (s, 3H), 3.25-3.35 (m, 1H), 3.09-3.13 (m, 1H), 2.73 (s, 3H).

(S) -4- (2- (5- (3-Methoxybenzyl) oxazol-2-ylamino} -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.03-7.28 (m, 8H), 6.79-6.83 (m, 1H), 5.70 (s, 1H), 4, 99-5.06 (m, 2H), 4.41 (d, J = 2.1 Hz, 2H), 3.80 (s, 3H), 3.27-3.37 (m, 1H), 3 03-3.15 (m, 1H); 2.71 (s, 3H).

(S) -4- (2- (2-Methylthiazol-4-yl) -2- (5-phenyloxyzol-2-ylamino) ethyl) phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.45 (d, J = 8.7 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.18-7 22 (m, 1H), 7.10-7.14 (m, 6H), 7.04 (s, 1H), 5.04-5.09 (m, 1H), 3.26 (dd, J = 13.8 and 6.3 Hz, 1H), 3.10 (dd, J = 13.8 and 6.3 Hz, 1H), 2.70 (s, 3H).

4 - ((S) -2- (2-Cyclopropylthiazol-4-yl) -2- (4- (3-methoxyphenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80 (m, 2H), 5, 02 (t, 1H, J = 6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J = 7.1 Hz), 2.36 (q, 1H, J = 4 6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

(S) -4- (2- (2-Cyclopropylthiazol-4-yl) -2- (4- (4-fluorophenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.79-7.74 (m, 2H), 7.14-7.03 (m, 7H), 7.21 (s, 1H), 6.79 (s, 1H), 5.08 (t, 1H, J = 6.6 Hz), 3.29-3.12 (m, 2H), 2.40 (q, 2H, J = 5.1 Hz), 1, 23-1.18 (m, 2H); 1.08-1.02 (m, 2H).

4 - ((S) -2- (2-Cyclopropylthiazol-4-yl) -2- (4- (2-methoxyphenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.89-7.87 (d, 1H, J = 7.6 Hz), 7.28 (t, 1H, J = 7.0 Hz), 7.10-6 96 (m, 8H), 5.03 (t, 1H, J = 6.9 Hz), 3.90 (s, 1H), 3.19 (q, 2H, J = 6.6 Hz), 2 38 (q, 1H, J = 4.8 Hz), 1.21-1.14 (m, 2H), 1.06-1.00 (m, 2H).

4 - ((S) -2- (2-Cyclopropylthiazol-4-yl) -2- (4- (2,4-difluorophenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.06-8.02 (q, 2H, J = 6.9 Hz), 7.12-6.95 (m, 7H), 6.88 (s, 1H) 5.11 (t, 1H, J = 6.9 Hz), 3.22-3.15 (m, 2H), 2.38 (q, 1H, J = 4.8 Hz), 1.22- 1.15 (m, 2H); 1.06-1.02 (m, 2H).

(S) -4- (2- (4- (3-Methoxybenzyl) thiazol-2-ylamino) -2- (2-cyclopropylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.22-7.17 (m, 3H), 7.09-6.97 (m, 5H), 6.78-6.66 (m, 3H), 3, 77 (s, 2H), 3.75 (s, 3H), 3.20-3.07 (m, 2H), 2.35 (q, 1H, J = 4.8 Hz), 1.19-1 13 (m, 2H); 1.03-1.00 (m, 2H).

(S) methyl ester - {5- [1- (2-ethylthiazol-4-yl) -2- (4-sulfoaminophenyl) ethylamino] -2-methyl-2H- [1,2,4] triazol-3-yl carbamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 6.97-7.08 (m, 5H), 3.71 (s, 3H), 3.51 (s, 3H), 3.15 (dd, J = 13.5 and 6.3 Hz, 1H), 3.02-3.07 (m, 3H), 1.40 (t, J = 6.6 Hz, 3H).

A second aspect of category V of the present invention relates to compounds of the formula:

where R ¹ means substituted or unsubstituted heteroaryl, and R ⁴ means substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, as described below in table X of this description.

Table X No. R ^four R ^one 471 phenyl 4- (methoxycarbonyl) thiazol-5-yl 472 phenyl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 473 phenyl 5- [1-N- (2-methoxy-2-oxoethyl) -1-N-indol-3-yl] oxazol-2-yl 474 phenyl 5- (2-methoxyphenyl) oxazol-2-yl 475 phenyl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 476 phenyl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 477 phenyl 5- (3-methoxybenzyl) oxazol-2-yl 478 phenyl 5- (4-phenyl) oxazol-2-yl 479 phenyl 5- (2-methoxyphenyl) thiazol-2-yl 480 phenyl 5- (3-methoxyphenyl) thiazol-2-yl 481 phenyl 5- (4-fluorophenyl) thiazol-2-yl 482 phenyl 5- (2,4-difluorophenyl) thiazol-2-yl 483 phenyl 5- (3-methoxybenzyl) thiazol-2-yl 484 phenyl 4- (3-methoxyphenyl) thiazol-2-yl 485 phenyl 4- (4-fluorophenyl) thiazol-2-yl 486 thiophen-2-yl 4- (methoxycarbonyl) thiazol-5-yl 487 thiophen-2-yl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 488 thiophen-2-yl 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 489 thiophen-2-yl 5- (2-methoxyphenyl) oxazol-2-yl 490 thiophen-2-yl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 491 thiophen-2-yl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 492 thiophen-2-yl 5- (3-methoxybenzyl) oxazol-2-yl 493 thiophen-2-yl 5- (4-phenyl) oxazol-2-yl 494 thiophen-2-yl 5- (2-methoxyphenyl) thiazol-2-yl 495 thiophen-2-yl 5- (3-methoxyphenyl) thiazol-2-yl 496 thiophen-2-yl 5- (4-fluorophenyl) thiazol-2-yl 497 thiophen-2-yl 5- (2,4-difluorophenyl) thiazol-2-yl 498 thiophen-2-yl 5- (3-methoxybenzyl) thiazol-2-yl 499 thiophen-2-yl 4- (3-methoxyphenyl) thiazol-2-yl 500 thiophen-2-yl 4- (4-fluorophenyl) thiazol-2-yl 501 cyclopropyl 4- (methoxycarbonyl) thiazol-5-yl 502 cyclopropyl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 503 cyclopropyl 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 504 cyclopropyl 5- (2-methoxyphenyl) oxazol-2-yl 505 cyclopropyl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 506 cyclopropyl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 507 cyclopropyl 5- (3-methoxybenzyl) oxazol-2-yl 508 cyclopropyl 5- (4-phenyl) oxazol-2-yl 509 cyclopropyl 5- (2-methoxyphenyl) thiazol-2-yl 510 cyclopropyl 5- (3-methoxyphenyl) thiazol-2-yl 511 cyclopropyl 5- (4-fluorophenyl) thiazol-2-yl 512 cyclopropyl 5- (2,4-difluorophenyl) thiazol-2-yl 513 cyclopropyl 5- (3-methoxybenzyl) thiazol-2-yl 514 cyclopropyl 4- (3-methoxyphenyl) thiazol-2-yl 515 cyclopropyl 4- (4-fluorophenyl) thiazol-2-yl

Compounds according to the second aspect of category V, which include a substituted or unsubstituted thiazol-4-yl group in the case of R ¹ , can be obtained by the method shown in schemes XIII, XIV and XV and described herein below in examples 13, 14 and 15.

Scheme XIII

Reagents and conditions: (a) (i) (isobutyl) OCOCH ₃ , Et ₃ N, THF; 0 ° C, 20 min .; (ii) CH ₂ N ₂ ; temperature from 0 ° C to room temperature, for 3 hours.

Reagents and conditions: (b) 48% HBr, THF; 0 ° C, 1.5 hours.

Reagents and conditions: (c) CH ₃ CN; reflux, 2 hours.

Reagents and conditions: (d) thiophosgene, CaCO ₃ , CCl ₄ , H ₂ O; room temperature, 18 hours.

Reagents and conditions: (e) (i) CH ₃ C (O) NHNH ₂ , EtOH; refluxing, 2 hours; (ii) POCl ₃ , room temperature, 18 hours; 50 ° C, 2 hours.

Reagents and conditions: (f) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH.

Example 13

(S) -4- (2 - ((5-Methyl-1,3,4-thiadiazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl) phenylsulfamic acid (41)

Preparation of [3-diazo-1- (4-nitrobenzyl) -2-oxopropyl] carbamic acid tert-butyl ester (36):

Triethylamine (dropwise) was added dropwise to a solution of 2- (S) - (tert-butoxycarbonylamino-3- (4-nitrophenyl) propionic acid (1.20 g, 4.0 mmol) in THF (20 ml). 0.61 ml, 4.4 mol), then isobutyl chloroformate (0.57 ml, 4.4 mmol). The reaction mixture was stirred at 0 ° C. for 20 minutes, then filtered. The filtrate was treated with a solution of diazomethane in diethyl ether (approximately 16 mmol) at a temperature of 0 ° C. The reaction mixture was stirred at room temperature for 3 hours and concentrated.The residue was dissolved in ethyl acetate, etc. flushes successively with water and brine, dried (Na2SO _4), filtered and concentrated in vacuo The resultant residue was purified using silica (hexane / ethyl acetate = 2: 1). to give 1.1 g (yield 82%) of the desired product as a slightly yellowish solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 5.39 (s, 1H ), 5.16 (d, J = 6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J = 13.8 and 6.6, 1H), 3.06 ( dd, J = 13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).

Preparation of [3-bromo-1- (4-nitrobenzyl) -2-oxopropyl] carbamic acid tert-butyl ester (37):

A solution of [3-diazo-1- (4-nitrobenzyl) -2-oxopropyl] carbamic acid 36 (0.350 g, 1.04 mmol) in THF (5 ml) was added dropwise 48% aqueous HBr solution (0.14 ml, 1.25 mmol). The reaction mixture was stirred at 0 ° C. for 1.5 hours and quenched at 0 ° C. with a saturated aqueous solution of Na ₂ CO ₃ . The mixture was extracted with ethyl acetate (3 times, 25 ml) and the combined organic extracts washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 0.400 g of the desired product, which was used in the next step without further purification.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.06 (d, J = 7.8 Hz, 1H), 4.80 (q, J = 6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of (S) -2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethanamine hydrobromide (38):

A mixture of [3-bromo-1- (4-nitrobenzyl) -2-oxopropyl] carbamic acid 37 (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol) in CH ₃ CN (5 ml) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added to the solution, and the precipitate formed was filtered off. The solid was dried in vacuo to give 1,059 g (63% yield) of the desired product.

MS (ESI +): 326 (M + 1).

Preparation of (S) -4- [1-isothiocyanato-2- (4-nitrophenyl) ethyl] -2-phenylthiazole (39):

To a solution of hydrobromide (S) -2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethanamine 38 (2.03 g, 5 mmol) and CaCO ₃ (1 g, 10 mmol) in a mixture of CCl ₄ / water (10 ml: 7.5 ml) thiophosgene (0.46 ml, 6 mmol) is added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH ₂ Cl ₂ and water. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a residue, which was purified using silica (CH ₂ Cl ₂ ) to give 1.71 g (93% yield) of the desired product.

MS (ESI +): 368 (M + 1).

Preparation of (S) -5-methyl-N- [2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethyl] -1,3,4-thiadiazol-2-amine (40):

A solution of (S) -4- [1-isothiocyanato-2- (4-nitrophenyl) ethyl] -2-phenylthiazole 39 (332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in ethanol (5 ml) is boiled under reflux for 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in POCl ₃ (3 ml) and the resulting solution was stirred at room temperature for 18 hours, then the solution was heated at 50 ° C for 2 hours. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (40 ml), and the resulting solution was treated with 1N. NaOH solution until a pH of approximately 8 is reached. The solution is extracted with ethyl acetate. The combined aqueous layers were washed with ethyl acetate, the organic layers were combined, washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 0.345 g (93% yield) of the desired product as a yellow solid.

¹ H NMR (CDCl ₃ ) 8.09 (d, J = 8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H), 3.59 (m, 2H), 2.49 (s, 3H). ESI + MS 424 (M + 1).

Preparation of (S) -4- (2- (5-methyl-1,3,4-thiadiazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl] phenylsulfamic acid (41):

(S) -5-Methyl-N- [2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethyl] -1,3,4-thiadiazol-2-amine 40 (0.404 g, 0.954 mmol) was dissolved in methanol (5 ml). Pd / C (50 mg, 10% w / w) was added and the mixture was stirred under a hydrogen atmosphere until complete completion of the reaction. The reaction mixture was filtered through a CELITE ™ pad and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (4 ml) and treated with SO ₃ -pyridine (0.304 g, 1.91 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH (50 ml) was added. The mixture was then concentrated and the resulting residue was purified by preparative reverse phase HPLC to give 0.052 g (11% yield) of the desired product as the ammonium salt.

¹ H (CD ₃ OD): δ 8.00-7.97 (m, 2H), 7.51-7.47 (m, 3H), 7.23 (s, 1H), 7.11-7, 04 (q, 4H, J = 9.0 Hz), 5.18 (t, 1H, J = 7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H ) ESI-MC 472 (M-1).

Reagents and conditions: (a) thiophosgene, CaCO ₃ , CCl ₄ / H ₂ O; room temperature, 18 hours.

Reagents and conditions: (b) CH ₃ CN; reflux, 5 hours.

Reagents and conditions: (c) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH; room temperature, 18 hours.

Example 14

(S) - [4- (2 - {[4- (3-Methoxyphenyl) thiazol-2-ylamino] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid (44 )

Preparation of (S) -1- [1- (thiophen-2-ylthiazol-4-yl) -2- (4-nitrophenyl) ethyl] thiourea (42):

To a solution of (S) -2- (4-nitrophenyl) -1- (thiophen-2-ylthiazol-4-yl) ethanamine 8 (1.23 g, 2.98 mmol) and CaCO ₃ (0.597 g, 5, 96 mmol) in a mixture of CCl ₄ / water (10 ml / 5 ml), thiophosgene (0.412 g, 3.58 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH ₂ Cl ₂ and water. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a residue, which was then treated with ammonia (0.5 M solution in 1,4-dioxane, 29.4 ml, 14.7 mmol) and purified using silica to give 0.490 g of the desired product as a red-brown solid.

MS (ESI +): 399 (M + 1).

Preparation of 4- (2-methoxyphenyl) -N - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} thiazol-2-amine ( 43):

(S) -1- [1- (Thiophen-2-ylthiazol-4-yl) -2- (4-nitrophenyl) ethyl] thiourea 42 (265 mg, 0.679 mmol) are treated with bromo-2′-methoxyacetophenone (171 mg, 0.746 mmol) to give 0.221 g of the product as a yellow solid.

MS (ESI +): 521 (M + 1).

Preparation of (S) - [4- (2 - {[4- (3-methoxyphenyl) thiazol-2-ylamino] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid ( 44):

4- (2-Methoxyphenyl) -N - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} thiazol-2-amine 43 ( 0.229 g) was dissolved in 12 ml of methanol. A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through CELITE ^™ and the solvent was removed under reduced pressure. The crude product was dissolved in 6 ml of pyridine and treated with SO ₃ -pyridine (140 mg). The reaction mixture was stirred at room temperature for 5 minutes, then 10 ml of a 7% solution of NH ₄ OH were added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.033 g of the desired product as an ammonium salt.

¹ H (CD ₃ OD): δ 7.96-7.93 (m, 1H), 7.60-7.55 (m, 2H), 7.29-7.23 (m, 1H), 7, 18-6.95 (m, 9H), 5.15 (t, 1H, J = 6.9 Hz), 3.90 (s, 3H), 3.35-3.24 (m, 2H).

Compounds according to the second aspect of category V, which include a substituted or unsubstituted oxazol-2-yl group in the case of R ¹ , can be obtained by the method shown in scheme XV and described in the description below in example 15. Intermediate 39 can be obtained in accordance with scheme XIII and example 13.

Scheme XV

Reagents and conditions: (a) 1-azido-1- (3-methoxyphenyl) ethanone, PPh ₃ , dioxane, 90 ° C, 20 minutes.

Reagents and conditions: (b) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH; room temperature, 18 hours.

Example 15

4 - {(S) -2- [5- (3-Methoxyphenyl) oxazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid (46)

Preparation of [5- (3-methoxyphenyl) oxazol-2-yl] - [2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethyl] amine (45):

A mixture of (S) -4- (1-isothiocyanato-2- (4-nitrophenyl) ethyl) -2-phenylthiazole 39 (300 mg, 0.81 mmol), 1-azido-1- (3-methoxyphenyl) ethanone (382 mg, 2.0 mmol) and PPh ₃ (0.8 g bound to the polymer, about 3 mmol / g) in dioxane (6 ml) are heated at 90 ° C. for 20 minutes. The reaction solution was cooled to room temperature and the solvent was removed in vacuo and the resulting residue was purified using silica to give 300 mg (yield 74%) of the desired product as a yellow solid.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.02 (d, J = 7.2 Hz, 2H), 7.92-7.99 (m, 2H), 7.42-7.47 ( m, 3H), 7.22-7.27 (m, 3H), 6.69-7.03 (m, 4H), 6.75-6.78 (m, 1H), 5.26 (t, J = 6.3 Hz, 1H), 3.83 (s, 4H), 3.42-3.45 (m, 2H).

Preparation of 4 - {(S) -2- [5- (3-methoxyphenyl) oxazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid (46):

[5- (3-Methoxyphenyl) oxazol-2-yl] - [2- (4-nitrophenyl) -1- (2-phenylthiazol-4-yl) ethyl] amine 45 (300 mg, 0.60 mmol) is dissolved in methanol (15 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through CELITE ^™ and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (10 ml) and treated with SO ₃ -pyridine (190 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give 0.042 g of the desired product as an ammonium salt.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.99 (d, J = 7.5 Hz, 2H), 7.46-7.50 (m, 3H), 7.23-7.29 ( m, 3H), 7.04-7.12 (m, 6H), 6.78 (dd, J = 8.4 and 2.4 Hz, 1H), 5.16 (t, J = 6.6 Hz , 1H), 3.81 (s, 3H), 3.29-3.39 (m, 1H), 3.17 (dd, J = 13.8 and 8.1 Hz, 1H).

Further, in the case of obtaining compounds that are included in category V of the present invention, compounds of the present invention, including R ¹ groups having groups not illustrated by example, can be obtained by modifying the methods described herein above. For example, Category V compounds, including substituted or unsubstituted [1,2,4] triazol-3-yl groups, can be prepared by s .......

The following are non-limiting examples according to a second category V aspect of the present invention.

(S) -4- (2- (5-Phenyl-1,3,4-thiadiazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.97-7.94 (m, 2H), 7.73-7.70 (m, 2H), 7.44-7.39 (m, 6H), 7, 25 (s, 1H), 7.12 (s, 4H), 5.29 (t, 1H, J = 6.9 Hz), 3.35-3.26 (m, 2H).

4 - ((S) -2- (5-Propyl-1,3,4-thiadiazol-2-ylamino) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.59-7.54 (m, 2H), 7.17-7.03 (m, 6H), 5.13 (t, 1H, J = 7.2 Hz) 3.32-3.13 (m, 2H), 2.81 (t, 2H, J = 7.4 Hz), 1.76-1.63 (t, 6H, J = 7.4 Hz), 0.97 (t, 3H, J = 7.3 Hz).

4 - ((S) -2- (5-Benzyl-1,3,4-thiadiazol-2-ylamino) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ (m, 2H), 7.49-7.45 (m, 2H), 7.26-7.16 (m, 5H), 7.05-6.94 (m 6H), 5.04 (t, 1H, J = 7.1 Hz), 4.07 (s, 2H), 3.22-3.04 (m, 2H).

4 - ((S) -2- (5- (Naphthalen-1-ylmethyl) -1,3,4-thiadiazol-2-ylamino) -2- (2- (thiophen-2-yl) thiazol-4-yl ) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.08-8.05 (m, 1H), 7.89-7.80 (m, 2H), 7.55-7.43 (m, 6H), 7, 11-7.00 (m, 6H), 5.08 (t, 1H, J = 7.1 Hz), 4.63 (s, 2H), 3.26-3.08 (m, 2H).

4 - ((S) -2- (5 - ((Methoxycarbonyl) methyl) -1,3,4-thiadiazol-2-ylamino) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.48-7.44 (m, 2H), 7.03-6.92 (m, 6H), 5.02 (t, 1H, J = 7.2 Hz) 4.30 (s, 2H); 3.55 (s, 3H); 3.22-3.02 (m, 2H).

4 - ((S) -2- (5 - ((2-Methylthiazol-4-yl) methyl) -1,3,4-thiadiazol-2-ylamino) -2- (2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.60-7.56 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m, 2H), 7.09-7, 03 (q, 4H, J = 8.7 Hz), 5.14 (t, 1H, J = 7.2 Hz), 4.28 (s, 2H), 3.33-3.14 (m, 2H ), 2.67 (s, 3H).

4 - {(S) -2- [4- (2,4-Difluorophenyl) thiazol-2-ylamino] - [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.06-8.02 (q, 1H, J = 6, 8 Hz), 7.59-7.54 (m, 2H), 7.16-7.08 ( m, 6H), 7.01-6.88 (m, 4H), 5.20 (t, 1H, J = 7.0 Hz), 3.36-3.17 (m, 2H).

(S) -4- {2- [4- (Ethoxycarbonyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.02-7.99 (m, 2H), 7.54-7.45 (m, 4H), 7.26 (s, 1H), 7.08 (s, 4H), 5.26 (t, 1H, J = 6, 9 Hz), 4.35-4.28 (q, 2H, J = 6.9 Hz), 3.38-3.18 (m, 2H ), 1.36 (t, 3H, J = 7.2 Hz).

(S) -4- {2- [4- (2-Ethoxy-2-oxoethyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.96 (m, 2H), 7.50-7.46 (m, 3H), 7.21 (s, 1H), 7.10-7.04 (m, 4H), 6.37 (s, 1H), 5.09 (t, 1H, J = 6.9 Hz), 4.17-4.10 (q, 2H, J = 7.1 Hz), 3, 54 (s, 2H), 3.35-3.14 (m, 2H), 1.22 (t, 3H, J = 7.1 Hz).

(S) -4- {2- [4- (4-Acetamidophenyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.11 (m, 2H), 7.82-7.80 (m, 2H), 7.71-7.61 (m, 6H), 7.40 (s, 1H), 7.23 (s, 4H), 5.32 (t, 1H, J = 7.0 Hz), 3.51-3.35 (m, 2H), 2.28 (s, 3H).

(S) -4- [2- (4-Phenylthiazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl] phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.03-7.99 (m, 2H), 7.75-7.72 (d, 2H, J = 8.4 Hz), 7.53-7.48 ( m, 3H), 7.42 (m, 4H), 7.12 (s, 4H), 6.86 (s, 1H), 5.23 (t, 1H, J = 7.2 Hz), 3, 40-3.27 (m, 2H).

(S) -4- {2- [4- (4- (Methoxycarbonyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 8.04-8.00 (m, 4H), 7.92-7.89 (d, 2H, J = 9.0 Hz), 7.53-7.49 ( m, 3H), 7.30 (s, 1H), 7.15 (s, 4H), 7.05 (s, 1H), 5.28 (t, 1H, J = 6.9 Hz), 3, 93 (s, 3H); 3.35-3.24 (m, 2H).

4 - {(S) -2- [4- (Ethoxycarbonyl) thiazol-2-ylamino] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H (CD ₃ OD): δ 7.43-7.38 (m, 2H), 7.26 (s, 1H), 7.00-6.94 (m, 3H), 6.89 (s, 4H), 5.02 (t, 1H, J = 7.0 Hz), 4.16-4.09 (q, 2H, J = 7.1 Hz), 3.14-2.94 (m, 2H ), 1.17 (t, 3H, J = 7.1 Hz).

(S) -4- [2- (4- (Methoxycarbonyl) thiazol-5-ylamino) -2- (2-phenylthiazol-4-yl) ethyl] phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7, 03-7.13 (m, 4H), 4.74 (t, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).

(S) -4- [2- (5-Phenyloxazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl] phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.94-7.96 (m, 2H), 7.45-7.49 (m, 5H), 7.32 (t, J = 7.8 Hz, 2H), 7.12 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.12 (s, 4H), 7.05 (s, 1H), 5, 15 (t, J = 6.4 Hz, 1H), 3.34 (dd, J = 14.1 and 8.4 Hz, 1H), 3.18 (dd, J = 14.1 and 8.4 Hz , 1H).

(S) -4- {2- [5- (4-Acetamidophenyl) oxazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.92-7.94 (m, 2H), 7.55-7.58 (m, 2H), 7.39-7.50 (m, 5H ), 7.26 (s, 1H), 7.12 (s, 4H), 7.02 (s, 1H0), 5.14 (t, J = 7.8 Hz, 1H), 3.13-3 38 (m, 2H); 2.11 (s, 3H).

4 - ((S) -2- (5- (2,4-Difluorophenyl) oxazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl) phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.97-7.99 (m, 2H), 7.54-7.62 (m, 1H), 7.45-7.50 (m, 3H ), 7.28 (s, 1H), 7.12 (s, 4H), 6.97-7.06 (m, 3H), 5.15-5.20 (m, 1H), 3.28- 3.40 (m, 1H); 3.20 (dd, J = 13.8 and 8.4 Hz, 1H).

4 - {(S) -2- [5- (3-Methoxyphenyl) oxazol-2-ylamino] -2 - [(2-thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.55-7.60 (m, 2H), 7.26 (t, J = 8.1 Hz, 1H), 7.21 (s, 1H) 7.04-7.15 (m, 8H), 6.77-6.81 (m, 1H), 5.10 (t, J = 6.3 Hz, 1H), 3.81 (s, 3H ), 3.29-3.36 (m, 1H), 3.15 (dd, J = 14.1 and 8.4 Hz, 1H).

(S) -4- [2- (4,6-Dimethylpyrimidin-2-ylamino] -2- (2-methylthiazol-4-yl) ethyl] phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.00-7.10 (m, 5H), 6.44 (s, 1H), 5.50 (t, J = 7.2 Hz, 1H) 3.04-3.22 (m, 2H); 2.73 (s, 3H); 2.27 (s, 6H).

(S) -4- [2- (4-Hydroxy-6-methylpyrimidin-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl] phenylsulfamic acid

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.44 (d, J = 8.4 Hz, 2H), 6.97-7.10 (m, 4H), 5.61 (s, 1H) 5.40-5.49 (m, 1H); 3.10-3.22 (m, 2H); 2.73 (s, 3H); 2.13 (s, 3H).

The first aspect of category VI of the present invention relates to compounds of the formula:

where R ¹ means heteroaryl, and R ⁴ has the meanings as described further below in table XI of this description.

Table XI No. R ^four R ^one 516 phenyl 4- (methoxycarbonyl) thiazol-5-yl 517 phenyl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 518 phenyl 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 519 phenyl 5- (2-methoxyphenyl) oxazol-2-yl 520 phenyl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 521 phenyl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 522 phenyl 5- (3-methoxybenzyl) oxazol-2-yl 523 phenyl 5- (4-phenyl) oxazol-2-yl 524 phenyl 5- (2-methoxyphenyl) thiazol-2-yl 525 phenyl 5- (3-methoxyphenyl) thiazol-2-yl 526 phenyl 5- (4-fluorophenyl) thiazol-2-yl 527 phenyl 5- (2,4-difluorophenyl) thiazol-2-yl 528 phenyl 5- (3-methoxybenzyl) thiazol-2-yl 529 phenyl 4- (3-methoxyphenyl) thiazol-2-yl 530 phenyl 4- (4-fluorophenyl) thiazol-2-yl 531 thiophen-2-yl 4- (methoxycarbonyl) thiazol-5-yl 532 thiophen-2-yl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 533 thiophen-2-yl 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 534 thiophen-2-yl 5- (2-methoxyphenyl) oxazol-2-yl 535 thiophen-2-yl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 536 thiophen-2-yl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 537 thiophen-2-yl 5- (3-methoxybenzyl) oxazol-2-yl 538 thiophen-2-yl 5- (4-phenyl) oxazol-2-yl 539 thiophen-2-yl 5- (2-methoxyphenyl) thiazol-2-yl 540 thiophen-2-yl 5- (3-methoxyphenyl) thiazol-2-yl 541 thiophen-2-yl 5- (4-fluorophenyl) thiazol-2-yl 542 thiophen-2-yl 5- (2,4-difluorophenyl) thiazol-2-yl 543 thiophen-2-yl 5- (3-methoxybenzyl) thiazol-2-yl 544 thiophen-2-yl 4- (3-methoxyphenyl) thiazol-2-yl 545 thiophen-2-yl 4- (4-fluorophenyl) thiazol-2-yl 546 cyclopropyl 4- (methoxycarbonyl) thiazol-5-yl 547 cyclopropyl 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl 548 cyclopropyl 5- [1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl] oxazol-2-yl 549 cyclopropyl 5- (2-methoxyphenyl) oxazol-2-yl 550 cyclopropyl 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl 551 cyclopropyl 5- [4- (methylcarboxy) phenyl] oxazol-2-yl 552 cyclopropyl 5- (3-methoxybenzyl) oxazol-2-yl 553 cyclopropyl 5- (4-phenyl) oxazol-2-yl 554 cyclopropyl 5- (2-methoxyphenyl) thiazol-2-yl 555 cyclopropyl 5- (3-methoxyphenyl) thiazol-2-yl 556 cyclopropyl 5- (4-fluorophenyl) thiazol-2-yl 557 cyclopropyl 5- (2,4-difluorophenyl) thiazol-2-yl 558 cyclopropyl 5- (3-methoxybenzyl) thiazol-2-yl 559 cyclopropyl 4- (3-methoxyphenyl) thiazol-2-yl 560 cyclopropyl 4- (4-fluorophenyl) thiazol-2-yl

Compounds according to the first aspect of category VI can be obtained by the method shown in scheme XVI and described in the description below in example 16.

Scheme XVI

Reagents and conditions: (a) CH ₃ CN; reflux, 2 hours.

Reagents and conditions: (b) (3-Cl) C ₆ H ₄ CO ₂ H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (c) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH, room temperature, 18 hours.

Example 16

4 - ((S) -2- (2- (3-Chlorophenyl) acetamido) -2- (2- (thiophen-2-yl) oxazol-4-yl) ethyl) phenylsulfamic acid (49)

Preparation of (S) -2- (4-nitrophenyl) -1 - [(thiophen-2-yl) oxazol-4-yl] ethanamine hydrobromide (47):

A mixture of (S) -tert-butyl-4-bromo-1- (4-nitrophenyl) -3-oxobutan-2-ylcarbamate 7 (38.7 g, 100 mmol) and thiophene-2-carboxamide (14 g, 110 mmol ) (available from Alfa Aesar) in CH ₃ CN (500 ml) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and diethyl ether (200 ml) was added to the solution. The precipitate formed is filtered off. The solid is dried in vacuo to give the desired product, which can be used in the next step without further purification.

Preparation of 2- (3-chlorophenyl) -N - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) oxazol-4-yl] ethyl} acetamide (48):

To a solution of (S) -2- (4-nitrophenyl) -1 - [(thiophen-2-yl) oxazol-4-yl] ethanamine. HBR 47 (3.15 g, 10 mmol) of 3-chlorophenylacetic acid (1, 70 g, 10 mmol) and hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 ml) at 1 ° C. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.90 g 10 mmol), then triethylamine (4.2 ml, 30 mmol). The mixture was stirred at 0 ° C. for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase is washed with 1 N. aqueous HCl, 5% aqueous NaHCO ₃ , water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give the desired product, which was used without further purification.

Preparation of 4 - ((S) -2- (2- (3-chlorophenyl) acetamido) -2- (2- (thiophen-2-yl) oxazol-4-yl) ethyl) phenylsulfamic acid (49):

2- (3-Chlorophenyl) -N - {(S) -2- (4-nitrophenyl) -1- [2- (thiophen-2-yl) oxazol-4-yl] ethyl} acetamide 48 (3 g) is dissolved in methanol (4 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (0.157 g). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH was added. The mixture was then concentrated and the resulting residue could be purified by reverse phase chromatography to give the desired product as the ammonium salt.

A second aspect of category VI of the present invention relates to compounds of the formula:

where R ¹ means aryl, and R ² and R ³ have the meanings as defined below in table XII of this description.

Table xii No. R ² R ³ R ^one 561 methyl hydrogen phenyl 562 methyl hydrogen benzyl 563 methyl hydrogen 2-fluorophenyl 564 methyl hydrogen 3-fluorophenyl 565 methyl hydrogen 4-fluorophenyl 566 methyl hydrogen 2-chlorophenyl 567 methyl hydrogen 3-chlorophenyl 568 methyl hydrogen 4-chlorophenyl 569 ethyl hydrogen phenyl 570 ethyl hydrogen benzyl 571 ethyl hydrogen 2-fluorophenyl 572 ethyl hydrogen 3-fluorophenyl 573 ethyl hydrogen 4-fluorophenyl 574 ethyl hydrogen 2-chlorophenyl 575 ethyl hydrogen 3-chlorophenyl 576 ethyl hydrogen 4-chlorophenyl 577 thien-2-yl hydrogen phenyl 578 thien-2-yl hydrogen benzyl 579 thien-2-yl hydrogen 2-fluorophenyl 580 thien-2-yl hydrogen 3-fluorophenyl 581 thien-2-yl hydrogen 4-fluorophenyl 582 thien-2-yl hydrogen 2-chlorophenyl 583 thien-2-yl hydrogen 3-chlorophenyl 584 thien-2-yl hydrogen 4-chlorophenyl

Compounds according to the second aspect of category VI can be obtained by the method shown in scheme XVII and described in this description below in example 17.

Scheme XVII

Reagents and conditions: (a) CH ₃ CN; reflux, 2 hours.

Reagents and conditions: (b) C ₆ H ₄ CO ₂ H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (c) (i) H ₂ : Pd / C, MeOH; (ii) SO ₃ -pyridine, NH ₄ OH, room temperature, 18 hours.

Example 17

{4- [2- (S) - (4-Ethyloxazol-2-yl) -2-phenylacetylaminoethyl] phenyl} sulfamic acid (52)

Preparation of (S) -1- (4-ethyloxazol-2-yl) -2- (4-nitrophenyl) ethanamine (50):

A mixture of [1- (S) -carbamoyl-2- (4-nitrophenyl) ethylcarbamic acid tert-butyl ester 1 (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1 ml, 36 mmol) in CH ₃ CN (500 ml) was refluxed for 18 hours. The reaction mixture was cooled to room temperature, diethyl ether was added to the solution, and the precipitate formed was removed by filtration and used without further purification.

Preparation of N- [1- (4-ethyloxazol-2-yl) -2- (4-nitrophenyl) ethyl] -2-phenylacetamide (51):

To a solution of (S) -1- (4-ethyloxazol-2-yl) -2- (4-nitrophenyl) ethanamine 50 (2.9 g, 11 mmol), phenylacetic acid (1.90 g, 14 mmol) and 1 -hydroxybenzotriazole (HOBt) (0.94 g, 7.0 mmol) in DMF (100 ml) at 1 ° C. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (2.68 g, 14 mmol) is added ), then triethylamine (6.0 ml, 42 mmol). The mixture was stirred at 0 ° C. for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase is washed with 1 N. aqueous HCl, 5% aqueous NaHCO ₃ , water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give the desired product, which was used without further purification.

Preparation of {4- [2- (S) - (4-ethyloxazol-2-yl) -2-phenylacetylaminoethyl] phenyl} sulfamic acid (52):

N- [1- (4-Ethyloxazol-2-yl) -2- (4-nitrophenyl) ethyl] -2-phenylacetamide 51 (0.260 g) was dissolved in methanol (4 ml). A catalytic amount of Pd / C (10% w / w) was added and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a CELITE ^™ layer and the solvent was removed under reduced pressure. The crude product was dissolved in pyridine (12 ml) and treated with SO ₃ -pyridine (0.177 g, 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then a 7% solution of NH ₄ OH (10 ml) was added. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography to give the desired product as the ammonium salt.

Regulation of HPPT-β provides a method for modulating the activity of the angiopoietin receptor tyrosine kinase type Tie-2, and thus, to mediate, influence, or otherwise control disease conditions associated with angiogenesis, where angiogenesis is not properly regulated by the human body. The compounds of the present invention serve as a means of regulating angiogenesis. As such, the present invention addresses some unmet medical needs, inter alia:

1) the provision of compositions effective as inhibitors of beta-tyrosine phosphatase of human protein (NTR-β); and, thus, ensuring the implementation of the method of regulation of angiogenesis in violation, where angiogenesis is increased;

2) the provision of compositions effective as beta protein tyrosine phosphatase inhibitors (HPPT-β); and, thus, ensuring the implementation of the method of regulation of angiogenesis in violation;

3) the provision of compositions effective as inhibitors of beta-tyrosine phosphatase of human protein (NTRP-β); and, thus, ensuring the implementation of the method of regulation of angiogenesis in violation, where angiogenesis is reduced.

For the purposes of the present invention, the term “regulate” is defined as including, but not limited to, regulation in relation to increase or regulation in relation to decrease, for fixing, bringing “in order” or to uniformity, direction or targeting by various means. In one aspect, the antibody can be used in a method of treating a “disorder with increased angiogenesis” or “a disorder with reduced angiogenesis.” As used herein, a “disorder with increased angiogenesis” is a disorder in which unwanted or increased angiogenesis is involved in a pathological process in the event of a biological manifestation of a disease, disorder and / or condition; in the case of a biological cascade leading to a violation; or as a symptom of a disorder. Similarly, a “disorder with reduced angiogenesis” is a disorder in which unwanted or reduced angiogenesis is involved in the pathological process in the case of biological manifestations of the disease. This “involvement in the pathological process” of angiogenesis in the case of a disorder with increased / decreased angiogenesis includes, but is not limited to, the following:

1) angiogenesis as the “cause” of the disorder or biological manifestation of the disease, the level of angiogenesis is increased or decreased genetically, due to infection, autoimmunity, trauma, biomechanical reasons, lifestyle or some other reasons;

2) angiogenesis as part of the observed manifestation of a disease or disorder. That is, a disease or disorder is defined in terms of increased or decreased angiogenesis. From a clinical point of view, angiogenesis indicates a disease; however, angiogenesis should not be a “hallmark” of a disease or disorder;

3) angiogenesis is part of a biochemical or cellular cascade that leads to a disease or disorder. In this regard, due to the regulation of angiogenesis, the cascade can be interrupted and the disease can be controlled. Non-limiting examples of disorders with controlled angiogenesis that can be treated using the present invention are described herein below.

Preparations

The present invention also relates to compositions or preparations that contain one or more human protein beta-tyrosine phosphatase inhibitors (HPPT-β), as described herein. Typically, compositions according to the invention comprise:

a) an effective amount of one or more phenylsulfamic acids or their salts of the present invention, which are effective as inhibitors of human beta protein tyrosine phosphatase (HPPT-β); and

b) one or more excipients.

For the purposes of the present invention, the terms “excipient” and “carrier” are used interchangeably throughout the description of the present invention, and the above terms in this description are defined as “ingredients that are used in the practice of preparing a safe and effective pharmaceutical composition”.

It will be understood by a person skilled in the art of pharmaceutical technology that excipients are used primarily to fulfill the function of delivering a safe, stable and functional pharmaceutical, and they serve not only as part of the total excipient for delivery, but also as a means to achieve effective absorption by the recipient active ingredient. The excipient can also act as a simple and direct inert filler, or the excipient, as used herein, can be part of a pH-stabilizing system or coating to “insure” delivery of safe ingredients to the stomach. The person skilled in the art of pharmaceutical preparations can also take advantage of the fact that the compounds of the present invention improve cell potency, pharmacokinetic properties, and also improve oral bioavailability.

In non-limiting examples, the compositions according to the invention comprise:

a) from about 0.001 mg to 1000 mg of one or more phenylsulfamic acids or their salts of the present invention; and

b) one or more excipients.

In another example, the compositions according to the invention contain:

a) from about 0.01 mg to 100 mg of one or more phenylsulfamic acids or their salts of the present invention; and

b) one or more excipients.

In the following example, the compositions according to the invention contain:

a) from about 0.1 mg to 10 mg of one or more phenylsulfamic acids or their salts of the present invention; and

b) one or more excipients.

The term "effective amount", as used herein, means "the amount of one or more phenylsulfamic acids, effective at doses and for the period of time necessary to achieve the desired therapeutic result." The effective amount may vary in accordance with factors known in the art, such as the condition of the disease, age, gender and weight of the person or animal being treated. Although specific dosage regimens may be described in the examples provided herein, one skilled in the art will recognize that the dosage regimens may be modified to provide an optimal therapeutic response. Thus, it is not necessary to indicate the exact “effective amount”. For example, several separate doses may be administered daily or the dose may be proportionally reduced as required due to the urgent need for a therapeutic situation. In addition, the compositions of the present invention can be administered as often as necessary to achieve a therapeutic amount.

Mode of application

The present invention relates to methods for regulating angiogenesis in humans, comprising administering to the human one or more compounds of the invention.

One example of a method according to the invention includes a method for treating a disorder with controlled angiogenesis in a subject, wherein the disorder with controlled angiogenesis is a disorder with increased angiogenesis, and the aforementioned disorder is selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, elastikum pseudoxanthoma, Paget's disease, venous occlusion, carotid obstructive disease, chronic uveitis / vitritis, mycobacterial infections, Lyme disease, systemic red chunks, retroletal fibroplasia, Ilse’s disease, Behcet’s disease, causing retinitis or chorioditis infections, suspected ocular histoplasmosis, Best’s disease, myopia, congenital fossae in the optic disc, Stargardt’s disease, including inflammation of the periphery of the retina and ciliary circle of clinical retinal syndrome, chronic high viscosity syndrome, toxoplasmosis, traumatic and post-laser complications associated with reddening of diseases and proliferative vitreoretinopathy.

Another example of the methods of the invention includes a method of treating a disorder with controlled angiogenesis in a subject, wherein the disorder with controlled angiogenesis is a disorder with increased angiogenesis, and the aforementioned disorder is selected from inflammatory intestinal diseases such as Crohn’s disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Randu-Osler-Weber disease or hereditary hemorrhagic telangiectasia, solid tumors or “blood tumors” on the head in newborns and syndrome ma acquired immunodeficiency.

A further example of the methods of the invention includes a method of treating a disorder with controlled angiogenesis in a subject, wherein the disorder with controlled angiogenesis is a disorder with reduced angiogenesis, and the aforementioned disorder is selected from skeletal muscle ischemia and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease.

Another other example of the methods of the invention includes a method for vascularizing ischemic tissue. As used herein, the term “ischemic tissue” means tissue that has lost adequate blood flow. Examples of ischemic tissue include, but are not limited to, tissue that lacks adequate blood supply resulting from myocardial infarction or stroke, mesenteric ischemia or limb ischemia, or is the result of vascular occlusion or stenosis. According to one example, interruption in the supply of oxygenated blood may be caused by vascular occlusion. Such vascular occlusion can be triggered by arteriosclerosis, trauma, surgery, disease and / or other etiologies. Also included in the methods of treatment of the present invention is the treatment of skeletal muscle ischemia and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease.

Another other example of the methods of the invention includes a tissue repair method. As used herein, “tissue repair” means the promotion of tissue repair, regeneration, growth and / or maintenance, including, but not limited to wound healing or tissue engineering. A person skilled in the art will understand that tissue repair requires the formation of new blood vessels. In turn, tissue can be damaged, including, but not limited to, due to traumatic injuries or conditions, including arthritis, osteoporosis and other skeletal disorders and burns. Tissue can also be damaged due to damage due to surgery, radiation, tearing, toxic chemicals, viral or bacterial infections or burns. Tissue in need of repair also includes non-healing wounds. Examples of non-healing wounds include non-healing skin ulcers resulting from diabetic pathology, or fractures that are difficult to treat.

The compounds of the invention are also suitable for use in performing tissue repair in the context of directed tissue regeneration (GTR) methods. Such methods are currently used by specialists in this field to accelerate wound healing after invasive surgery.

Another further example of the methods of the invention includes a method for promoting tissue repair characterized by enhanced tissue growth during a tissue engineering process. As used in this description, the term "tissue engineering" is defined as the formation, design and manufacture of biological prostheses in combination with synthetic or natural materials for the growth or replacement of tissues and organs of the body. Thus, these methods can be used to enhance the design and growth of human tissues outside the body for the purpose of implantation performed later to restore or replace diseased tissues. For example, antibodies may be useful when promoting the development of substitute grafts that are used as therapy in the treatment of burns.

Of other examples of tissue engineering, an example of the methods of the invention includes cell-containing or cell-free “devices” that induce the regeneration of functional human tissues when they are implanted in a site requiring regeneration. As discussed herein, tissue-guided tissue regeneration can be used to promote the resumption of bone growth, for example, in the case of periodontal disease. Thus, antibodies can be used to promote the growth of reconstructed tissues introduced in three-dimensional configurations to a site of wound or other tissue in need of such restoration.

According to yet another example of tissue engineering, an example of the methods of the invention, the compounds disclosed herein can be incorporated into external or internal “devices” containing human tissues designed to replace the function of diseased internal tissues. This method involves the isolation of cells from the body, their placement in structural matrices and the implantation of a new system inside the body or the use of the system outside the body. For example, antibodies can be included in a vascular graft of a cell line to promote the development of cells contained in the graft. It is contemplated that the methods of this invention can be used to enhance tissue repair, regeneration, and engineering in “products,” such as cartilage and bone, central nervous system tissues, muscle, liver, and islets of Langerhans islet (insulin producing cells).

The present invention also relates to the use of the phenylsulfamic acids according to the invention for the manufacture of a medicament in order to promote the development of substitute grafts.

The present invention also relates to the use of the phenylsulfamic acids of the invention in accordance with the present invention for the manufacture of a medicament for use in the implementation of tissue repair in the context of directed tissue regeneration (GTR) methods.

The compounds of the invention can be used to produce one or more drugs, non-limiting examples of which are:

drugs for treating a disorder with controlled angiogenesis in a subject, wherein the disorder with controlled angiogenesis is a disorder with increased angiogenesis;

drugs for treating a disorder with controlled angiogenesis in a subject where the disorder with controlled angiogenesis is a disorder with increased angiogenesis selected from Crohn’s disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Randu-Osler-Weber disease, or hereditary hemorrhagic body , solid tumors and "blood tumors" on the head of newborns and acquired immunodeficiency syndrome;

drugs suitable for tissue engineering, thus inducing enhanced tissue development;

drugs for treating a disorder with controlled angiogenesis in a subject, where the disorder with controlled angiogenesis is a disorder with reduced angiogenesis.

Methods

Screening tests using in vitro and in vivo models of angiogenesis

Antibodies of the compounds of this invention can be screened for angiogenesis tests that are known in the art. Such tests include in vitro assays, which determine the development of blood vessel substitutes in cultured cells or the formation of vascular structures from tissue explants, and in vivo assays, which determine the development of blood vessels directly or indirectly (Auerbach R. et al., Clin Chem., 49 , 32-40 (2003); Vailhe B. et al., Lab. Invest., 81 , 439-452 (2001)).

1. In vitro models of angiogenesis

In the case of in vitro models that are suitable for the application of the present invention, cultured endothelial cells or tissue explants are used and the effects of agents on “angiogenic” cell responses or on the formation of blood capillary-like structures are determined. Non-limiting examples of in vitro angiogenesis tests include, but are not limited to, migration and proliferation of endothelial cells, capillary formation, endothelial "germination", aortic ring explant analysis, and chicken aortic arch analysis.

2. In vivo models of angiogenesis

In vivo agents or antibodies that are suitable for the use of the present invention were administered locally or systemically in the presence or absence of growth factors (e.g., VEGF or angiopoietin), and the development of a new blood vessel was determined by direct observation or by determining a surrogate marker, such as hemoglobin content or fluorescent indicator. Non-limiting examples of in vivo angiogenesis tests include, but are not limited to, chicken chorioallantoid membrane analysis, corneal angiogenesis test, and MATRIGEL ^™ cork test.

3. Methods for determining vascularization of ischemic tissue

Standard routine methods are useful in determining whether a tissue is inherently at risk of ischemic damage from unwanted vascular occlusion. For example, in myocardial disease, such methods include a variety of imaging techniques (e.g., radioactive labeling methodologies, x-rays and MRI) and physiological tests. Therefore, the induction of angiogenesis as an effective means of preventing or attenuating ischemia in tissues damaged or at risk of damage due to vascular occlusion can be easily determined.

A person skilled in the art using standard methods will be able to determine tissue vascularization. Non-limiting examples of determining vascularization in a subject include SPECT (computed tomography of single proton emission), PET (tomography of positron emission), MRI (magnetic resonance imaging), and a combination thereof, by determining blood flow in tissue before and after treatment. Angiography can be used as an assessment of the macroscopic presence of blood vessels. A histological assessment can be used to count the presence of blood vessels at the level of small vessels. These and other methods are discussed by Simons et al., "Clinical trials in coronary angiogenesis", Circulation, 102 , 73-86 (2000).

The following are non-limiting examples of activity with respect to HPTP-β (IC ₅₀ , μM) and PTP1B (IC ₅₀ , μM), shown below in table A of this description.

Table a Compound НРТР-β IC _fifty μm RTR1V IC _fifty μm

(S)-{4-[2-(4-этилтиазол-2-ил)-2-(фенилацетиламидо)этил]фенил}сульфаминовая кислота

(S) - {4- [2- (4-ethylthiazol-2-yl) -2- (phenylacetylamido) ethyl] phenyl} sulfamic acid 0.05 22.9

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (2-fluorophenyl) acetamido) ethyl) phenylsulfamic acid 0.012 5.36

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (3-fluorophenyl) acetamido) ethyl) phenylsulfamic acid 0,0003 2.85

(S) -4- (2- (2- (2,3-difluorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0,028 5.36

(S) -4- (2- (2- (3,4-difluorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0,075 23.9

(S) -4- (2- (2- (2-chlorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0.056 22.8

(S) -4- (2- (2- (3-chlorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0,033 13.6

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (3-hydroxyphenyl) acetamido) ethyl) phenylsulfamic acid 0.04 6.57

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (2-methoxyphenyl) acetamido) ethyl) phenylsulfamic acid 0.014 11.7

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (3-methoxyphenyl) acetamido) ethyl) phenylsulfamic acid 0.008 4.05

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3-phenylpropanamido) ethyl) phenylsulfamic acid 0.002 10,4

(S) -4- (2- (2- (3,4-dimethoxyphenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0,028 15,5

(S) -4- (2- (2- (2,3-dimethoxyphenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0,037 25,4

(S) -4- (2- (3- (3-chlorophenyl) propanamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid 0,0002 15.3

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3- (2-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid 0.003 16.9

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3- (3-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid 0.01 20.6

(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3- (4-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid 0.006 16,0

(S) -4- {2- [2- (4-ethyl-2,3-dioxopiperazin-1-yl) acetamido] -2- (4-ethylthiazol-2-yl) ethyl} phenylsulfamic acid 0.002 0.53

(S) -4- {2- (4-ethylthiazol-2-yl) -2- [2- (5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) acetamide] ethyl} phenylsulfamic acid 0.002 0.254

(S) -4- [2- (benzo [d] [1,3] dioxol-5-carboxamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid 0,042 19

The values and values given in this description should not be understood as strictly limited to the listed exact numerical values. Instead, unless otherwise indicated, it is understood that each such value represents both the indicated value and the functionally equivalent range surrounding the given value. For example, it is meant that a value indicated as “40 mm” means “about 40 mm”.

All documents cited in the detailed description of the invention, in the relevant part, are incorporated into this description by reference; the citation of any document should not be construed as an admission that it is a prior art in relation to the present invention. To the extent that any meaning or definition of a term in this description contradicts any meaning or definition of the same term in a document incorporated by reference, one should be guided by the meaning or definition intended for that term in this document.

Although specific embodiments of the present invention are illustrated and described, it will be apparent to one skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, it is intended to include in the appended claims all such changes and modifications that are within the scope of this invention.

Claims (15)

1. The compound of the formula:

where R means a substituted or unsubstituted thiazolyl group of the formula:

or

R ² and R ³ each independently selected from:
i) hydrogen; or
ii) C ₁ -C ₃ linear alkyl;
R ⁴ means a group selected from:
i) C ₁ -C ₃ linear or C ₃ cyclic alkyl;
ii) phenyl; and
iii) thiophenyl;
Z means a group of the formula:

R ¹ choose from:
i) C ₁ -C ₃ linear or branched alkyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl, halogen;
ii) unsubstituted phenyl or substituted with one, two substituents selected from halogen, methoxy or hydroxy, C ₁ -C ₄ alkoxycarbonyl;
iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl substituted with C ₁ -C ₃ alkyl; or
iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo (1,4) dioxepanyl, pyridine, pyrimidine, 1H-indole and 2,3 -dihydrobenzo [b] [1,4] dioxinyl, which may be substituted by one or two substituents selected from:
a) hydroxy;
b) C ₁ -C ₃ alkyl, which may be substituted with one or two substituents selected from:
i) phenyl;
ii) C ₁ -C ₄ alkoxycarbonyl;
iii) naphthalenyl;
iv) 2-methylthiazolyl;
c) NHC (O) C ₁ -C ₃ alkyl;
d) C ₁ -C ₄ alkoxycarbonyl;
e) 1- (tert-butoxycarbonyl) -2-phenylethyl;
f) methoxybenzyl;
g) phenyl, which may be substituted with C ₁ -C ₄ alkoxy, halogen, methoxycarbonyl or NHC (O) CH ₃ ;
h) (methoxy-2-oxoethyl) carbamoyl;
L means a linking group selected from:
i) —C (O) NH [C (R ^5a R ^5b )] _w -;
ii) —C (O) [C (R ^6a R ^6b )] _x -;
iii) —C (O) [C (R ^7a R ^7b )] _y C (O) -;
iv) —SO ₂ [C (R ^8a R ^8b )] _z -;
R ^5a , R ^5b , R ^6a , R ^6b , R ^7a , R ^7b , R ^8a and R ^8b each independently mean:
i) hydrogen;
ii) C ₁ -C ₃ linear alkyl which may be substituted with 1 or 2 halogen atoms;
iii) phenyl, which may be substituted with 1-2 substituents selected from halogen and lower alkoxy;
iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo (1,4) oxazinyl and oxadiazolyl substituted with methyl;
index n is 0 or 1; the indices w, x, y and z, each independently, are from 1 to 3,
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where R ² and R ³ each means hydrogen or C ₁ -C ₃ linear alkyl. 3. The compound according to claim 1, where R ⁴ means phenyl. 4. The compound according to claim 1, where R ⁴ means thiophenyl. 5. The compound according to claim 1, where L has the formula:
-C (O) [C (R ^6a R ^6b )] _x -,
R ^6a means hydrogen, substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl; index x is 1 or 2. 6. The compound according to claim 5, where R ^{1 is} selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2 , 3-dimethoxyphenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl. 7. The compound according to claim 1 of the formula:
i)

where R ² means methyl or ethyl, R ³ means hydrogen, R ^6a selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2 -chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4 dimethoxyphenyl and 3,5-dimethoxyphenyl;
ii)

where R ⁴ means methyl, ethyl, phenyl or thiophen-2-yl, R ^6a selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl;
iii)

where R ² selected from methyl, ethyl, R ³ means hydrogen or methyl; R ^{1 is} selected from phenyl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and isoxazol-3-yl. 8. The compound according to claim 1, where R represents:

and where Z is a substituted or unsubstituted heteroaryl group selected from:
i) imidazol-2-yl and imidazol-4-yl corresponding to the formulas:

ii) oxazol-2-yl, oxazol-4-yl and oxazol-5-yl corresponding to the formulas:

iii) isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, corresponding to the formulas:

iv) [1,2,4] oxadiazol-3-yl and [1,2,4] oxadiazol-5-yl corresponding to the formulas:

v) [1,3,4] oxadiazol-2-yl of the formula:

vi) thiazol-2-yl, thiazol-4-yl and thiazol-5-yl corresponding to the formulas:

vii) [1,2,4] thiadiazol-3-yl and [1,2,4] thiadiazol-5-yl corresponding to the formulas:

9. The compound of claim 8, where Z is selected from 4- (methoxycarbonyl) thiazol-5-yl, 4 - [(2-methoxy-2-oxoethyl) carbamoyl] thiazol-5-yl, 5- (2-methoxyphenyl) oxazol-2-yl, 5 - [(S) -1- (tert-butoxycarbonyl) -2-phenylethyl] oxazol-2-yl, 5- [4- (methoxycarbonyl) phenyl] oxazol-2-yl, 5- ( 3-methoxybenzyl) oxazol-2-yl, 5- (4-phenyl) oxazol-2-yl, 5- (2-methoxyphenyl) thiazol-2-yl, 5- (3-methoxyphenyl) thiazol-2-yl, 5 - (4-fluorophenyl) thiazol-2-yl, 5- (2,4-difluorophenyl) thiazol-2-yl, 5- (3-methoxybenzyl) thiazol-2-yl, 4- (3-methoxyphenyl) thiazol-2 -yl and 4- (4-fluorophenyl) thiazol-2-yl. 10. A compound selected from:
{4- [2 (S) - (4-ethylthiazol-2-yl) -2-phenylacetylamido) ethyl] phenyl} sulfamic acid;
(S) - (4- (2- (4-ethylthiazol-2-yl) -2- (2- (2-fluorophenyl) acetamido) ethyl) phenylsulfamic acid;
(S) - (4- (2- (4-ethylthiazol-2-yl) -2- (2- (3-fluorophenyl) acetamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (2- (2,3-difluorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (2- (3,4-difluorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (2- (2-chlorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (2- (3-chlorophenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (3-hydroxyphenyl) acetamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (2-methoxyphenyl) acetamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (2- (3-methoxyphenyl) acetamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3-phenylpropanamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (2- (3,4-dimethoxyphenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (2- (2,3-dimethoxyphenyl) acetamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (3- (3-chlorophenyl) propanamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3- (2-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3- (3-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (3- (4-methoxyphenyl) propanamido) ethyl) phenylsulfamic acid;
(S) -4 {2- [2- (4-ethyl-2,3-dioxopiperazin-1-yl) acetamide] -2- (4-ethylthiazol-2-yl) ethyl} phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [2- (5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) acetamide] ethyl} phenylsulfamic acid;
(S) -4- [2- (benzo [d] [1,3] dioxol-5-carboxamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid;
4 - ((S) -2- (2- (3-chlorophenyl) acetamido) -2- (2-thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid;
4 - ((S) -2- (2- (3-methoxyphenyl) acetamido) -2- (thiophen-2-yl) thiazol-4-yl) ethyl) phenylsulfamic acid;
4 - {(S) -2- (3-phenylpropanamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
4 - {(S) -2- (3- (3-chlorophenyl) propanamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
4 - {(S) -2- (2- (3-fluorophenyl) acetamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
(S) -4- {2- [2- (2,5-dimethylthiazol-4-yl) acetamido] -2- (4-ethylthiazol-2-yl] ethyl} phenylsulfamic acid;
(S) -4- {2- [2- (2,4-dimethylthiazol-5-yl) acetamido] -2- (4-methylthiazol-2-yl) ethyl} phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [3- (thiazol-2-yl) propanamido] ethyl} phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [2- (4-ethylthiazol-2-yl) acetamido] ethyl} phenylsulfamic acid;
(S) -4- {2- [2- (3-methyl-1,2,4-oxadiazol-5-yl) acetamide] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid;
4 - {(S) -2- [2- (4-ethyl-2,3-dioxopiperazin-1-yl) acetamido] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
(S) -4- (2- (2,3-diphenylpropanamido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [2- (2-methoxyphenyl) -3-phenylpropanamido] ethyl} phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [2- (3-fluorophenyl) -3-phenylpropanamido] ethyl} phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [2- (3-methoxyphenyl) -3-phenylpropanamido] ethyl} phenylsulfamic acid;
4 - {(S) -2- (4-ethylthiazol-2-yl) -2- [2- (3-methyl-1,2,4-oxadiazol-5-yl) -3-phenylpropanamido] ethyl} phenylsulfamic acid ;
(S) -4- [2- (4-ethylthiazol-2-yl) -2- (4-oxo-4-phenylbutanamido) ethyl] phenylsulfamic acid;
(S) -4- (2- (4-ethylthiazol-2-yl) -2- (5-methyl-4-oxohexanamido) ethyl) phenylsulfamic acid;
(S) -4- {2- [4- (3,4-dihydro-2H-benzo [b] [1,4] dioxepin-7-yl) -4-oxobutanamido] -2- (4-ethylthiazol-2 -yl) ethyl} phenylsulfamic acid;
(S) -4- {2- [4- (2,3-dimethoxyphenyl) -4-oxobutanamido] -2- (4-ethylthiazol-2-yl) ethyl} phenylsulfamic acid;
(S) -4- {2- (4-ethylthiazol-2-yl) -2- [4-oxo-4- (pyridin-2-yl) butanamido] ethyl} phenylsulfamic acid;
(S) -4- {2- [4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -4-oxobutanamido] -2- (4-ethylthiazol-2-yl) ethyl } phenylsulfamic acid;
(S) -4- [2- (4-tert-butoxy-4-oxobutanamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid;
(S) -4- [2- (4-ethoxy-4-oxobutanamido) -2- (4-ethylthiazol-2-yl) ethyl] phenylsulfamic acid;
(S) -4- (2- (3-benzylureido) -2- (4-ethylthiazol-2-yl) ethyl) phenylsulfamic acid;
4 - {(S) -2- (3-benzylureido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
4 - {(S) -2 - [(2-methylthiazol-4-yl) methylsulfonamido] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
{4- (S) - [2-phenylmethanesulfonylamino-2- (2-ethylthiazol-4-yl) ethyl] phenyl} sulfamic acid;
{4- (S) - [2- (3-methoxyphenyl) methanesulfonylamino-2- (2-ethylthiazol-4-yl) ethyl] phenyl} sulfamic acid;
(S) -4 - {[1- (2-ethylthiazol-4-yl) -2- (4-sulfaminophenyl) ethylsulfamoyl] methyl} benzoic acid methyl ester;
(S) -4- [2- (2-ethylthiazol-4-yl) -2- (1-methyl-1H-imidazole-4-sulfonamido) ethyl] phenylsulfamic acid;
4 - {(S) -2- [2- (thiophen-2-yl) thiazol-4-yl] -2- (2,2,2-trifluoroethylsulfonamido) ethyl} phenylsulfamic acid;
{4- (S) - [2- (phenylethanesulfonylamino) -2- (2-thiophen-2-ylthiazol-4-yl) ethyl] phenyl} sulfamic acid;
{4- (S) - [3- (phenylpropanesulfonylamino) -2- (2-thiophen-2-ylthiazol-4-yl) ethyl] phenyl} sulfamic acid;
(S) - {4- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-sulfonylamino) -2- (2-thiophen-2-ylthiazol-4-yl ) ethyl] phenyl} sulfamic acid;
4 - {(S) -2- (4-acetamidophenylsulfonamido) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
4 - {(S) -2- (2-cyclopropylthiazol-4-yl) -2- [4- (3-methoxyphenyl) thiazol-2-ylamino] ethyl} phenylsulfamic acid;
(S) -4- (2- (4 - ((2-methoxy-2-oxoethyl) carbamoyl) thiazol-5-ylamino) -2- (2-ethylthiazol-4-yl) ethyl) phenylsulfamic acid;
4 - ((S) -2- (5- (1-N- (2-methoxy-2-oxoethyl) -1-H-indol-3-yl) oxazol-2-ylamino) -2- (2-methylthiazole -4-yl) ethyl) phenylsulfamic acid;
4 - ((S) -2- (5- (2-methoxyphenyl) oxazol-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamic acid;
4 - ((S) -2- (5 - ((S) -1- (tert-butoxycarbonyl) -2-phenylethyl) oxazol-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamine acids;
(S) -4- (2- (5- (4-methoxycarbonyl) phenyl) oxazol-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (5- (3-methoxybenzyl) oxazol-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl) phenylsulfamic acid;
(S) -4- (2- (2-methylthiazol-4-yl) -2- (5-phenyloxazol-2-ylamino) ethyl) phenylsulfamic acid;
4 - ((S) -2- (2-cyclopropylthiazol-4-yl) -2- (4- (3-methoxyphenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid;
(S) -4- (2- (2-cyclopropylthiazol-4-yl) -2- (4- (4-fluorophenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid;
4 - ((S) -2- (2-cyclopropylthiazol-4-yl) -2- (4- (2-methoxyphenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid;
4 - ((S) -2- (2-cyclopropylthiazol-4-yl) -2- (4- (2,4-difluorophenyl) thiazol-2-ylamino) ethyl) phenylsulfamic acid;
(S) -4- (2- (4- (3-methoxybenzyl) thiazol-2-ylamino) -2- (2-cyclopropylthiazol-4-yl) ethyl) phenylsulfamic acid;
(S) - {5- [1- (2-ethylthiazol-4-yl) -2- (4-sulfaminophenyl) ethylamino] -2-methyl-2H- [1,2,4] triazol-3-yl methyl ester } carbamic acid;
4 - {(S) -2- [4- (2-methoxyphenyl) thiazol-2-ylamino) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
4 - {(S) -2- [5- (3-methoxyphenyl) oxazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid;
4 - {(S) -2- [4- (2,4-difluorophenyl) thiazol-2-ylamino) -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
(S) -4- {2- [4- (ethoxycarbonyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl-ethyl} phenylsulfamic acid;
(S) -4- {2- [4- (2-ethoxy-2-oxoethyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid;
(S) -4- {2- [4- (4-acetamidophenyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid;
(S) -4- [2- (4-phenylthiazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl] phenylsulfamic acid;
(S) -4- {2- [4- (4- (methoxycarbonyl) phenyl) thiazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid;
4 - {(S) -2- [4- (ethoxycarbonyl) thiazol-2-ylamino] -2- [2- (thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
(S) -4- [2- (4- (methoxycarbonyl) thiazol-5-ylamino] -2- (2-phenylthiazol-4-yl) ethyl] phenylsulfamic acid;
(S) -4- [2- (5-phenyloxazol-2-ylamino)] - 2- (2-phenylthiazol-4-yl) phenylsulfamic acid;
(S) -4- {2- [5- (4-acetamidophenyl) oxazol-2-ylamino] -2- (2-phenylthiazol-4-yl) ethyl} phenylsulfamic acid;
4 - ((S) -2- (5- (2,4-difluorophenyl) oxazol-2-ylamino) -2- (2-phenylthiazol-4-yl) ethyl) phenylsulfamic acid;
4 - {(S) -2- [5- (3-methoxyphenyl) oxazol-2-ylamino] -2 - [(2-thiophen-2-yl) thiazol-4-yl] ethyl} phenylsulfamic acid;
(S) -4- [2- (4,6-dimethylpyrimidin-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl] phenylsulfamic acid and
(S) -4- [2- (4-hydroxy-6-methylpyrimidin-2-ylamino) -2- (2-methylthiazol-4-yl) ethyl] phenylsulfamic acid, or a pharmaceutically acceptable salt thereof. 11. The compound according to any one of claims 1 to 10, where the compounds are salts, including anions selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate and citrate, or cations selected from sodium, lithium, potassium, calcium, magnesium and bismuth. 12. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating a condition selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elastum, Paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis / vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retroletal fibroplasia, Ils disease, Behcet's disease, causing retinitis or x oryoditis of infections, presumptive ocular histoplasmosis, Best’s disease, myopia, congenital fossae in the optic disc, Stargardt’s disease, including inflammation of the periphery of the retina and the ciliary circle of the clinical syndrome, chronic retinal detachment, increased viscosity syndrome, toxoplasmosis, traumatic and post-laser complications associated with poklazarny complications associated with diseases and proliferative vitreoretinopathy; Crohn’s disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Randu-Osler-Weber disease, or hereditary hemorrhagic telangiectasia, solid tumors or “blood tumors” on the head in newborns and acquired immunodeficiency syndrome; skeletal muscle ischemia and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease. 13. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for regulating angiogenesis, vascularization of ischemic tissue, promoting the growth of substitute grafts, promoting tissue repair in the context of directed tissue regeneration (GTR) methods. 14. The compound according to any one of claims 1 to 10, used to treat a condition selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elastum, Paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis / vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retroletal fibroplasia, Ils disease, Behcet's disease, causing retinitis or chorioditis infections, suspected eye histoplasmosis, Best’s disease, myopia, congenital fossa in the optic nerve head, Stargardt’s disease, including inflammation of the periphery of the retina and ciliary circle of the clinical syndrome, chronic retinal detachment, increased viscosity syndrome, toxoplasmosis, traumatic and post-laser complications associated with redness of the disease and prolifera prolifera ; Crohn’s disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Randu-Osler-Weber disease, or hereditary hemorrhagic telangiectasia, solid tumors or “blood tumors” on the head in newborns and acquired immunodeficiency syndrome; skeletal muscle ischemia and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease. 15. The compound according to any one of claims 1 to 10 for use to control angiogenesis, vascularization of ischemic tissue, promote the growth of substitute transplants, promote tissue repair in the context of directed tissue regeneration (GTR) methods.