SK11422001A3 - Heteroaryl amidines, methylamidines and guanidines as protease inhibitors - Google Patents

Abstract

The present invention is directed to compounds of Formula (I) wherein X is O, S or NR<7> and R<1>-R<7>, Y and Z are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof. Also described are methods for preparing the compounds of Formula (I). The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, plasmin and urokinase. Certain of the compounds exhibit direct, selective inhibition of urokinase, or are intermediates useful for forming compounds having such activity.

Description

Heteroarylamidines, methylamidines and guanidines as protease inhibitors

Technical field

The invention relates to novel heteroaryl compounds which act as inhibitors of enzymes, and in particular to a new class of non-peptide inhibitors of proteolytic enzymes, such as urokinase (µPa).

BACKGROUND OF THE INVENTION

Proteases are enzymes that cleave proteins in one of the specific peptide bonds. Proteases can be divided into four groups according to their mechanism of action: serine, thiol or cysteine, aspartate (acid) proteases and metalloproteases (Cuypers et al., J. Biol. Chem. 257: 7086 (1982)). Proteases are essential for various biological processes, such as digestion, formation and dissolution of blood clots, reproduction and immune responses to foreign cells and organisms. Aberrant proteolysis is associated with multiple disease states in humans and other mammals. Human neutrophil proteases, elastase, and cathepsin G are factors contributing to the development of diseases characterized by tissue destruction. The conditions include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press, Baltimore, (1980)). Other proteases such as plasmin, C-1 esterase, C-3-convertase, urokinase, and tissue plasminogen activators, acrosin and kallikreins have their functions in the normal biological functions of mammals. In many cases, however, it is beneficial to interrupt the function of one or more of these proteolytic enzymes during treatment of a mammal.

Serine proteases include enzymes such as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3-convertase, urokinase and tissue plasminogen activators, acrosin, chymotrypsin, thrombin, factor Xa, and kallikreins.

Human leukocyte elastase is released from polymorphonuclear sites at inflammatory sites and thereby contributes to the development of various conditions. Another neutrophilic human serine protease is cathepsin G. Compounds capable of inhibiting said enzymes are believed to have anti-inflammatory effects useful in the treatment of rheumatism, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in the treatment of pancreatitis. Inhibitors of urokinase plasminogen activator are useful in the treatment of disease states characterized by excessive cell growth, such as benign prostate hypertrophy, prostate cancer, and psoriasis.

Urokinase (urinary type of plasminogen activator or uPA; International Union of Biochemistry Classification Number: EC3.4.21.31) is a proteolytic enzyme that is highly specific for a single peptide bond in plasminogen. It is a multidomain serine protease having a catalytic B chain (amino acids (aa) 144-411) and an amino terminal fragment (ATF, aa 1-143) containing a growth factor-like domain (4-43) and a Kringle domain (aa 47-135) ). It is believed that the Kringle domain of uPA binds heparin but does not bind fibrin, lysine or aminohexanoic acid. The growth factor-like domain has some similarity to the structure of epidermal growth factor (EGF) and is thus referred to as the EGF-like domain. The single chain of pre-uPA is activated by plasmin when cleaved into a two-chain active form that is stabilized by a disulfide bond.

Cleavage of the peptide bond in plasminogen by urokinase (activation of plasminogen) leads to the formation of an effective major protease, plasmin. In many cell types, urokinase acts as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular carrier structures (e.g., extracellular matrix (ECM) and basement membrane (BM). Cells are contained, moving and interacting within the space defined by the ECM and BM The movement of cells in or through the ECM requires local proteolytic degradation or modification of these structures to allow cells to penetrate adjacent structures previously unavailable.

Most important for the ability of urokinase to mediate cell migration and invasiveness is the existence of specific high affinity urokinase receptors (uPARs) that concentrate urokinase on the cell surface, resulting in the formation of locally high concentrations of plasmin between cells and ECM or BM (Blasi, F., and sp Cell Biol 104: 801-804 (1987); Roldan, AL, et al., EMBO J. 9: 467-74 (1990)). The cleavage of pre-uPA to active uPA is accelerated as long as pre-uPA and plasminogen are bound to the receptor. Thus, plasmin activates pre-uPA, which in turn activates more plasmin by cleavage of plasminogen. This positive feedback cycle is apparently limited to proteolysis at cell surface receptors as there is a large excess of protease inhibitors in plasma, including α ₂ antiplasmin, PAI-1 and PAI-2. High concentrations of plasmin between invasive cells and ECM or BM are required to overcome the inhibitory effect of the generally present plasmin inhibitors. Therefore, the predominant role of initiating cell invasiveness has urokinase bound to the cell surface receptor and not the simple free urokinase secreted by the cells.

Plasmin can activate or degrade extracellular proteins such as fibrinogen, fibronectin, and zymogens, including matrix metalloproteinases. Thus, plasminogen activators can regulate extracellular proteolysis, fibrin clot breakdown, tissue remodeling, stem and smooth muscle cell migration, inflammation and metastasis. Urokinase-initiated cell invasiveness is a central factor in several different normal and disease physiological conditions (reviewed in Blasi, F., et al., J. Cell Biol. 104: 801-804 (1987); Dans, K., et al., Adv Cancer Res., 44: 139266 (1985), Littlefield, BA, Ann, NY Acad Sci, 622: 167-175 (1991), Saksela, O., Biochim, Biophys, Acta 823: 35-65 (1985); Testa, JE, and Quigley, JP, Cancer Metast Rev. 9: 353-367 (1990)). Said processes include, but are not limited to, angiogenesis (neovascularization), bone turnover, uterine egg nesting, immune cell infiltration into inflammatory sites, ovulation, spermatogenesis, tissue remodeling in wound healing, restenosis and organ differentiation, fibrosis, local tumor invasion into adjacent areas, metastatic spread of tumor cells from primary and secondary sites, and tissue destruction in arthritis. Therefore, urokinase inhibitors have anti-angiogenic, anti-arthritic, anti-inflammatory, anti-esthenotic, anti-invasive, anti-metastatic, anti-osteoporous, anti-retinopathic (retinopathy-related angiogenesis), contraceptive and tumorostatic effects. Urokinase inhibitors are useful as agents for the treatment of various disease states including, but not limited to, benign prostate hypertrophy, prostate cancer, and psoriasis.

The beneficial effects of urokinase inhibitors have been reported using antiurokinase monoclonal antibodies and certain other known urokinase inhibitors. For example, anti-urokinase monoclonal antibodies have been described to block invasiveness of tumor cells in vitro (Hollas, W., et al., Cancer Res. 51: 3690-3695, (1991); Mcissauer, A., et al., Exp. Cell Res. 192: 453-459 (1991)), tumor metastasis and tumor invasion in vivo (Ossowski, L., J. Cell Biol. 107: 2437-2445 (1988); Ossowski, L., et al., J. Cancer Res. 51: 274-81 (1991)), and angiogenesis in vivo (Jerdan, JA, et al., J. Cell Biol. 115 [3 Pt 2]: 402a (1991)). In addition, amiloride, a known urokinase inhibitor having only moderate activity, is reported to inhibit tumor metastasis in vivo (Kellen, JA, et al., Anticancer Res. 8: 1373-1376 (1988)) and formation of an angiogenesis / capillary information network in vivo. in vitro (Alliegro, MA, et al., J. Cell Biol. 115 [3 Pt 2): 402a (1991)).

Urokinase plays an important role in the healing of vascular wounds and the formation of the arterial neointima after injury, most likely due to cell migration. Urokinase mediates plasmin proteolysis, which in turn promotes wound healing and associated neointima formation (Carmeliet et al., Circ. Res. 81: 829839 (Nov.1997), Lupu et al., Fibrinolysis 10 Supp 2: 33-35 (1996)) . A viral serine proteinase inhibitor SERP-1 was used to reduce plaque formation following primary angioplasty by balloon in rabbits. This effect is attributed to the inhibition of cellular proteinases such as plasmin or urokinase SERP-1 (Lucas et al., Circulation 94: 2890-2900 (1996)).

Thus, there remains a need for non-peptide compounds acting as potent and selective urokinase inhibitors and exhibiting greater bioavailability and fewer side effects than hitherto available urokinase inhibitors. New classes of potent urokinase inhibitors, characterized by high inhibitory capacity and low toxicity, are potentially valuable therapeutic agents for the treatment of various conditions.

SUMMARY OF THE INVENTION

The invention is broadly directed to the use of heteroaryl amidines, methylamidines and guanidine of formula (I) (below) as protease inhibitors, preferably as urokinase inhibitors.

The compounds of the invention have anti-urokinase activity induced by direct, selective inhibition of urokinase, or are intermediates useful in the preparation of compounds having the aforementioned properties. The compounds of the invention inhibit urokinase and are therefore useful as medicaments with anti-angiogenic, anti-arthritic, anti-inflammatory, antirestenotic, anti-invasive, antimetastatic, anti-osteoporous, antiretinopathic (for retinopathy-mediated angiogenesis), contraceptive and tumorostatic effects. Said medicaments are, for example, suitable for the treatment of various disease states including, but not limited to, benign prostatic hypertrophy, prostate cancer, tumor metastasis, and psoriasis.

The invention also provides methods of inhibiting extracellular proteolysis, methods of treating benign prostate hypertrophy, prostate cancer, tumor metastasis, psoriasis, and other conditions, said methods comprising administering a compound of Formula (I).

Several of the heteroaryl compounds described are novel. The invention therefore also includes novel compounds of formula (I).

The invention further encompasses pharmaceutical compositions comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers or diluents and said pharmaceutical compositions further comprising a thrombolytic agent such as tissue plasminogen activator and streptokinase.

The invention further includes processes for the preparation of compounds of formula (I):

Detailed Description of Preferred Embodiments

The invention is broadly directed to a method of inhibiting proteases, in particular serine proteases, characterized by contacting a serine protease with a compound of formula (I):

or a solvate, hydrate or pharmaceutically acceptable salt thereof;

where

X is O, S or NR ⁷ , wherein R ⁷ is hydrogen, alkyl, aralkyl, hydroxy (C 2-4) alkyl, or alkoxy (C 2-4);

Y represents a direct covalent bond, CH 2 or NH;

Z is NR ^S R ^6, hydrogen or alkyl provided that when Y is NH, and Z is hydrogen or alkyl;

R * is hydrogen, amino, hydroxy, halogen, cyano, C 1-4 alkyl or -CHiR, wherein R is hydroxy, amino or C 1-4 alkoxy;

R ² and R ³ each independently represent:

i. hydrogen;

ii. halogen;

iii. hydroxy;

iv. nitro;

in. cyano;

vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocykloamino, diheterocykloamino, monoalkylmonoheterocyclamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, araikylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di (aralkyl) amino, di (aralkenylsulfonyl) amino, di (arylsulfonyl) amino, or di (heteroarylsulfonyl) amino, formylamino, alkanoylamino, alkenoylamino, alkyinoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroaralkanoylamino, H (S) CNH-, or thioacylamino, wherein each aroyal or heteroaroyl-containing group it may be optionally substituted in the aromatic ring and each heterocyclic-containing group may be optionally substituted in the ring moiety;

vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl;

viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl;

ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono- and diarylaminocarbonylamino, or mono- and diaralkylaminocarbonylamino;

x. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy, mono- and diarylaminocarbonyloxy, mono- and diaralkylaminocarbonyloxy;

xi. aminosulfonyl, mono- and dialkylaminosulfonyl, mono- and diarylaminosulfonyl, or mono- and diaralkylaminosulfonyl;

xii. alkoxy, or alkylthio, wherein the alkyl moiety may be optionally substituted;

xiii. aralkoxy, aryloxy, heteroaryloxy, aralkylthio, arylthio, or heteroarylthio, wherein the aryl moiety may be optionally substituted;

xiv. alkylsulfonyl. wherein the alkyl moiety may be optionally substituted;

xv. aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein the aryl portion of each of said groups may be optionally substituted;

xvi. alkenyl or alkynyl;

xvii. optionally substituted aryl;

xviii. optionally substituted alkyl;

xix. optionally substituted aralkyl;

xx. optionally substituted heterocycle; or xxi. optionally substituted cycloalkyl; and

R ^4, R ^s and R ⁶ are each independently hydrogen, Ci.4alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C2-io) alkyl, dialkylamino (C2-io) alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or -CO ₂ R ^W , wherein

R ^w represents alkyl, cycloalkyl, phenyl, benzyl,

O or

wherein R ^d and R ^c are each independently hydrogen, C | -6 alkyl, C ₂ -6alkenyl or phenyl,

R ^r is hydrogen, Cj.fialkyl C _{2nd 6} alkenyl or phenyl,

R ^g is hydrogen, Ci.ôalkyl, Cj./salkenyl or phenyl, and

R ^h represents an aralkyl or C 1-6 alkyl group.

The invention is also directed to novel compounds of formula (I) wherein X, Y and R 1 -R ⁶ are as defined above;

with the proviso that at least one of R ² or R ³ represents a group selected from the group consisting of:

a) an optionally substituted alkyl group, preferably C 1-6 alkyl, even more preferably C 1-3 alkyl;

b) alkoxy, aryloxy, alkylthio or arylthio, wherein each of said groups is optionally substituted;

c) optionally substituted C 6-10 aryl, or optionally substituted aralkyl, with the proviso that R is not a nitrophenyl or aminophenyl group when R ¹ and R ^{2 are} both hydrogen or methyl;

d) optionally substituted heterocycle; and

e) optionally substituted cycloalkyl.

When an alkyl-containing group, a heterocycle-containing group or an aryl-containing group R or R is optionally substituted, optional substituents may include 1-4 non-hydrogen substituents, with the proviso that the resulting compound is stable. Optional alkyl group substituents include groups selected from the group consisting of halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono- or dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or aminocarbonyloxy, mono- or , mono- or diarylaminocarbonyloxy, mono- or diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono- or dialkylaminol, alkylthio and arylthio.

Preferably the optional substituents for the alkyl groups are of chloro, hydroxy, amino, mono (C] .4) alkylamino, di (C | .4 alkyl) amino, formylamino, C ₂ -6acylamino, aminocarbonyl, C _{2nd 8} aminoacyl, C 1. _Ï alkoxy, C-uaryloxy, carboxy, carboxy (C]. ₆₎ alkyl, _{C2. R is} alkoxycarbonyl, nitro, cyano, trifluoromethyl, C 1-6 alkylthio, C 6-6 arylthio, C 1-6 alkylsulfonylamino. C 1-8 -alkylsulfonylamino, C 6-10 arylsulfonylamino, mono- or di (C 1-6) alkylaminocarbonyloxy, mono- or di (C 6-10) arylaminocarbonyloxy, mono- or di (C 7-15) aralkylcarbonyloxy, C 1-8 alkoxycarbonylamino, C 7 -C 18 saralkoxycarbonylamino, cg-Cioaryloxykarbonylamino.

Preferably the optional substituents for the aryl-containing group means a group heterocyklusobsahujúcej the group of chloro, hydroxy, amino, mono (Ci.4) alkylamino, di (Ci. ₄ alkyl) amino, formylamino, C ₂ .6acylamino, aminocarbonyl, C ₂ .gaminoacyl, Whose cycloalkyl, C alkyl, C | .6alkoxy, C-uaryloxy, carboxy, carboxy (Ci.ň) alkyl, _C2 .galkoxykarbonyl, nitro, cyano, trifluoromethyl, Ci.ealkyltio, Cô.naryltio, Ce-uaryl, substituted phenyl, tetrazolyl, thienyl (further optionally substituted with one, two, or three groups including chlorine, hydroxy, C _1-4 alkyl, C 1-4 alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3, 4-propylenedioxy, C ealkylsulfonylamino, C7.1 ₅ aralkylsulfonylamino, C ôarylsulfonylamino, ôalkylsulfonyl C, C-ioarylsulfonyl, mono- or di (Ci.6) alkylaminocarbonyloxy, mono- or di (C6-io) arylaminocarbonyloxy, mono- or di (C7.is) aralkylcarbonyloxy, C 1-6 alkoxycarbonylamino, C 7 -C 15 aralkoxycarbonylamino, C 6 -C 10 aryloxycarbonylamino phenylamino, C ₂ .6tioacylamino, aminocarbonyl, and C ₂ .gaminotioacyl.

Preferably, R * is hydrogen, amino, hydroxy and fluoro.

R ² preferably represents a group of formula (ii):

wherein Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), pyrrolyl, oxazolinyl and benzothienyl.

Preferably R ³ is C 1-6. ₄ alkyl, halo, amino, acylamino, Ci.galkyltio (such as methylthio or ethylthio), C alkoxy (such as methoxy and ethoxy), trifluoromethyl, methylsulfonyl, and benzylthio.

Preferably X is divalent sulfur (S).

Y is preferably a covalent bond or -NH-, most preferably a covalent bond.

Preferably, R ⁴ , R ⁵ and R ⁶ in formula (I) are hydrogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 alkoxy. Suitably, R ⁴ , R ⁵ and R ⁶ are hydrogen, methyl, ethyl, propyl, butyl, hydroxy, methoxy, and ethoxy. In the most preferred embodiments, each of R ⁴ , R ⁵ and R ⁶ is hydrogen.

Also preferably, R ⁴ , R ⁵ and R ⁶ in the formula (I) are prodrug-forming groups such as -CO 2 R ^W , where R ^w in each group is preferably C 1-4 alkyl, C 4-7 cycloalkyl or benzyloxycarbonyl. Preferably R ⁴ , R ⁵ and R ⁶ are hydrogen, methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, cyano, -CO 2 CH 3, -CO 2 CH 2 CH 3 and CO 2 CH 2 CH 2 CH 3. In the most preferred embodiments, each of R ⁴ , R ⁵ and R ^{6 is} hydrogen.

The group -CO ₂ R ^W in substituents R ⁴ , R ⁵ and R ⁶ preferably also represents a group in which R ^w represents one of the groups of the formulas below:

or

R 9 O wherein R ^d -R ^h are as defined above. When R ⁴ , R ⁵ and R ⁶ are -CO 2 R ^w , where R ^w is one of the above groups, the compounds obtained have desirable parameters for drug formulation and bioavailability. Each of R ^d , R ^e and R ^{e is} preferably hydrogen, R ^{f is} preferably methyl, and R ^{h is} preferably benzyl and tert-butyl.

R ^{7 is} preferably hydrogen, C 1-6 alkyl, C 6-10 ar (C 1-4) alkyl, and C 2-6 hydroxyalkyl. Suitably R ⁷ is hydrogen, methyl, ethyl and benzyl.

The term alkyl as used herein, alone or as part of another group, means straight or branched chain radicals of up to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.

The term alkenyl as used herein denotes straight or branched chain radicals having 2 to 20 carbon atoms, unless the number of carbon atoms is limited, such as but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain length is 2 to 10 carbon atoms, even more preferably 2 to 8 carbon atoms, and most preferably 2 to 4 carbon atoms.

The term alkynyl as used herein denotes straight or branched chain radicals of 2 to 20 carbon atoms, unless the number of carbon atoms is limited, containing at least one triple bond in the chain between two carbon atoms, such as but not limited to groups from the group. only thereto, acetylene, 1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain length is 2 to 10 carbon atoms, even more preferably 2 to 8 carbon atoms, and most preferably 2 to 4 carbon atoms.

In all cases in this specification, where an alkenyl or alkynyl moiety is part of a substituent group, an unsaturated linkage, i. the vinylene or ace tylene linkage, preferably not directly attached to the nitrogen, oxygen or sulfur moiety.

The term alkylthio as used herein alone or as part of another group refers to straight or branched chain radicals of 1 to 20 carbon atoms, unless the chain length is limited, attached to, but not limited to, a sulfur atom, methylthio, ethylthio, propylthio, isopropylthio, and the like.

Preferably, the alkylthio chain length is 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms.

The term alkoxy used herein alone or as part of another group refers to straight or branched chain radicals of 1 to 20 carbon atoms, unless the chain length is limited, attached to, but not limited to, oxygen, from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, and the like. Preferably, the length of the alkoxy chain is 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms.

The term cycloalkyl used herein alone or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.

The term halogen or halo used herein alone or as part of another group refers to chlorine, bromine, fluorine or iodine, preferably chlorine.

The term acyl as used herein alone or as part of another group, is - (O) R ^8, wherein ^R is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl. Preferred acyl groups include alkanoyl, aralkanoyl and aroyl groups (-C (O) R ⁵ where R ⁸ represents a C 1-6 alkyl group, a C 6-10 aryl (C 1-4) alkyl or a C 6-10 aryl group).

The term thioacyl is used herein alone or as part of another group is -C (S) R ^B, wherein R ⁸ represents a radical from the group of alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, preferably Cj.ealkyl.

The term thiocarbonyl used herein alone or as part of another group means -C (S) -.

The term monoalkylamine used herein alone or as part of another group refers to an amino group substituted with one C 1 -C 6 alkyl group.

The term dialkylamine used herein alone or as part of another group means an amino group substituted by two alkyl groups each containing 1 to 6 carbon atoms.

The term aryl as used herein alone or as part of another group means monocyclic or bicyclic aromatic groups having 6 to 14 carbon atoms in the ring portion, preferably 6 to 10 carbon atoms in the ring portion such as phenyl, naphthyl or tetrahydronaphthyl.

The term aralkyl or arylalkyl used herein alone or as part of another group means C 1-6 alkyl groups described above containing an aryl substituent, such as a group selected from benzyl, phenylethyl or 2-naphthylmethyl.

The term heterocyclic, heterocyclo, or heterocycle used herein alone or as part of another larger group means a saturated or fully or partially unsaturated 3 to 7-membered monocyclic ring, or a 7 to 10-membered bicyclic ring system containing carbon atoms and one to one four heteroatoms independently selected from the group consisting of O, N and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and includes each bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring and wherein said heterocyclic ring may be substituted on a carbon or nitrogen atom to form a stable compound. Particularly suitable rings contain one oxygen or sulfur atom, one to three nitrogen atoms, or one oxygen or sulfur atom in combination with two nitrogen atoms. Examples of said heterocyclic groups include piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrimidinyl, pyridyl, , pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl , thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, and oxadiazolyl. The term morpholino has the same meaning as morpholinyl.

The term heteroatom as used herein means an oxygen atom (O), a sulfur atom (S), or a nitrogen atom (N). It should be understood, however, that when the heteroatom is nitrogen, it may be in the form of NR ^y R ^z , where R ^y and R ^z independently represent hydrogen or a C 1 -C 8 alkyl group, or together with the nitrogen atom to which they are attached form a saturated or unsaturated 5-, 6-, or 7-membered ring.

The term heteroaryl as used herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 π electrons in cyclic configuration; and containing carbon atoms and 1, 2, or 3 heteroatoms representing oxygen, nitrogen or sulfur (examples of which include thienyl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, quinolyl, quinolyl, quinolyl, quinolyl, quinolyl, quinolyl quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl).

The term prodrug refers to a derivative of a known direct acting drug, wherein said derivative has improved drug delivery parameters and therapeutic value compared to its own drug and is transformed into an active drug by an enzymatic or chemical process. Suitable prodrugs include those compounds wherein R ⁴ , R ⁵ and / or R ⁶ are -CO 2 R ^w , where R ^w is as defined above. See e.g. U.S. Pat. 5,466,81 and Saulnier et al., Bioorg. Med. Chem. 4: 1985-1990 (1994).

The term substituted as used herein means that one or more of the hydrogen atoms of the labeled group is replaced by groups selected from the respective selection provided that the normal valency of any atom is not exceeded and that the substitution results in a stable compound. When the substituent is a keto group (i.e., = 0), the two hydrogens attached to the atom contained in the substituent group are replaced.

The term stable compound or stable formula means that the compound is robust enough to withstand separation from the reaction mixture resulting in a compound of sufficient degree of purity to be processed into an effective drug composition.

A first preferred group of compounds of the invention includes compounds of formula (I) wherein X is sulfur or oxygen; Y represents a covalent bond or -NH-; R ¹ represents hydrogen, amino, hydroxy or halogen; R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, C 1-4 alkyl, amino, cyano, C 1-4 alkoxy or hydroxy, preferably all of these substituents being hydrogen; one of R ² and R ^{3 is} hydrogen, C 1-6 alkyl (optionally substituted with hydroxy, amino, carboxy or aminocarbonyl), C 1-6 alkylthio or C 1-6 alkoxy; and the other of R ² and R ³ is aminoacyl, acylamino, aminosulfonyl, sulfonylamino, aminocarbonylamino, alkoxycarbonylamino, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted benzothienyl, optionally substituted furyl, optionally substituted pyrazolyl or optionally substituted pyridyl.

Specific compounds of the invention include those described in the Examples, such as the following:

4- [4- (4-chloro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-karboxamidén;

4-phenyl-5-methylthiothiophene-2-carboxamidine;

4- [4- (2,4-dichlorophenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4-methyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

methyl 4- [4- (4-phenylphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxylate;

4- [4- (3-methoxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3-hydroxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4-phenyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (4-nitro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4- (3,4-propylenedioxy phenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (4- (naphthalen-2-yl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine;

4-phenyl-5-methylthiothiophene-2-carboxamidine;

4- [4- (4-chloro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4- (4-phenylphenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (4-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (2-naftyltiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (4-chloro-3-methylphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (5-methyl-4-phenyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (4-chloro-3-nitro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (5-phenyl-oxazol-2-yl) -5-methylthiothiophene-2-carboxamide;

-4- [4- (3-fluoro-5-trifluoromethylphenyl) -5-methyl-thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3,5-Bis (trifluoromethyl) phenyl) -5-methyl-thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3-bromo-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3,4-methylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (4-methyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3,5-bis (trifluoromethyl) phenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (2-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4-phenyl-imidazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

Of 4- [4- (2,4-dimethoxyphenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4-benzyltiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (3,4-dichlorophenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3-methyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3,5-dimethoxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (2-methyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (2,5-dimethoxyphenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4,5-diphenylthiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- (2-phenyl) -thiazol-4-yl-5-methylthiothiophene-2-carboxamidine;

4- [4- (2-chloro-3-pyridyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (phenoxymethyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4-cyclohexylthiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

Of 4- [4- (4-chlorophenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (2-hydroxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4- (3-Trifluoromethoxyphenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [4- (2-chloro-4-pyridyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- (5-phenyl-2-pyridyl) -5-methylthiothiophene-2-carboxamidine;

4- [2- (2-chloro-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (3-methoxy-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2,5-dimethoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- (2-aminothiazol-4-yl) -5-methylthiothiophene-2-carboxamidine;

4- [2- (4-chloro-2-methylphenylamino) thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (4-dimethylamino-phenylamino) -thiazole-4-yl] -5-methylthiothiophene-2carboxamidine;

4- [2- (4-methoxy-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (4-hydroxy-3-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [4- (3-hydroxy-4-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2-fluoro-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2,4,5-Trimethylphenyl) aminothiazol-4-yl] -5-methylthiophene-2-carboxamidine;

4- [2- (3-chloro-2-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2-isopropylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (4-benzyloxyphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2-bromophenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2,5-Dichloro-phenyl) -amino-azol-4-yl] -5-methyl-thiothiophene-2-carboxamidine;

4- [2- (2-bromo-4-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2carboxamidine;

4- [2- (2,3-dichlorophenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (3,4,5-trimethoxyphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (2-piperidinylethyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- [2- (4-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine;

4- (4-phenyl-oxazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

4- [2- (diphenylmethyl) aminothiazol-4-yl] -5-mctyltiotiofén-2-carboxamidine; and

4- [2- (3-phenylpropyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine, also as pharmaceutically acceptable salts thereof, such as the hydrochloride, hydrobromide and acetate salts or prodrugs thereof.

A second preferred group of compounds of the invention includes compounds of formula (I) wherein X is sulfur or oxygen; Y represents a covalent bond or -NH-; Z is NR ^S R ^6; R ¹ is hydrogen, amino, hydroxy or halogen;

R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, C 1-4 alkyl, amino, C 1-4 alkoxy or hydroxy, preferably all these substituents being hydrogen; one of R ² or R ³ is hydrogen; ₆ Ci.4alkylovú alkylthio or optionally substituted by OH, _NH2, COOH or aminocarbonyl; and the second of R ² or R ³ represents a group of formula (II):

II where:

Ar is selected from the group consisting of phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imolazolinyl, imidazolinyl, imidazolinyl, imidazolinyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl (preferably phenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, oxazolinyl and benzoticnyl ), wherein any of said groups may optionally contain an exocyclic = O (keto) - or = NR ^V (imino) group, wherein R ^v is alkyl. an aryl, aralkyl, alkylamino, arylimino or aralkylimino group; and

R and R are independently selected from hydrogen, halogen, amino, mono (Ci.4) alkylamino, di (Ci-4) alkylamino, arylamino, mono- and di (C 6 i ₄₎ arylamino, mono- a di (C 6 i ₄₎ ar (C] .6 alkyl) amino, formylamino, C2-6acylamino, aminocarbonyl, C2-8aminoacyl, C2-6tioacylamino, aminocarbonyl, C 2 saminotiacyl, C |. ₆ alkyl, C3.gcykloalkyl, C ôalkoxy, carboxy, carboxy (Ci-6) alkyl, C2-8alkoxykarbonyl, nitro, cyano, trifluoromethyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl , thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-oneary, C 6 ôalkyltio C, _-C6-4 and arylthio, _C-4 and aryl, or C _{6. 14} ar (C | _ ₆₎ alkyl, wherein the above heteroaryl and the aryl portion of the groups consisting of C 6 and ₄ aryloxy, mono- and di (C6_i ₄₎ arylamino, mono- and di (C 6 i ₄₎ ar (C] -6) alkylamino, (C6.] ₄₎ arylthio, (C6-i ₄₎ ar (C]. ₆₎ alkyl and (CO _i-4) aryl may be further substituted with one, two or three radicals from the group halogen , hydroxy, amino, mono (C _1-4 ) alkylamino, di (C _1-4 ) alkylamino, formylamino, C 1-6 alkylamino; ₄ acylamino, C _1-4 aminoacyl, mono- or di (C _1-4 ) alkylaminocarbonyl, thiocarbonylamino, C 1-4 alkylamino; ₄ thioacylamino, (C]. ₄₎ alkoxy, (Co-iojaryloxy, aminocarbonyloxy, mono- or di (Cl. ₄₎ alkylaminocarbonyloxy, mono- or di (C ₆ .i ₀₎ arylaminocarbonyloxy, mono- or di (C 7 is ) aralkylaminocarbonyloxy, C _1-4 alkylsulfonyl, C 6-10 arylsulfonyl, (C 7-15) aralkylsulfonyl, C _1-4 alkylsulfonylamino, C 6-10 arylsulfonylamino, (C 7,1 saralkylsulfonylamino, aminosulfonyl, mono- and dialkylaminosulfonyl, mono- and diarylaminosulfonyl, mono- and diarylamino) C _1-4 alkoxycarbonylamino, C 7-15 aralkoxycarbonylamino, C 6-10 aryloxycarbonylamino, mono- and di (C _1-4 ) alkylaminothiocarbonyl, C 7-6 aralkoxy, carboxy, carboxy (C _1-4 ) alkyl, C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylalkyl, carboxy ₄ ) alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C _1-4 alkylthio and C 6-10 arylthio, or

3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy.

Preferably, R ⁸ and R ⁹ are selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, trifluoromethyl, C 6-10 aryl (further optionally substituted with one or two groups selected from chloro, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), 4-phenylphenyl (bi phenyl), C 1-6 aminoalkyl, carboxy, C 1-6 alkyl , 3,4-methylenedioxy, 3,4-ethylenedioxy,

3,4-propylenedioxy, amino, C 1-6 alkanoylamino, C 6 -aroylamino, C 1-6 hydroxyalkyl, thienyl (further optionally substituted with one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl. More preferably R ² represents a radical from the group of thienyl, oxazolyl, or thiazolyl, optionally substituted with any of the above groups.

Examples of preferred R ⁸ and R ⁹ groups include 4-chlorophenyl, 2,4-dichlorophenyl, methyl, 4-nitrophenyl, 3-nitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3- (2,4-dimethylthien- 5-yl) phenyl, 3-hydroxyphenyl, 5- (carboxymethyl) thien-2-yl, phenyl, 3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, naphthalen-2-yl, 3-phenyl-4- (tetrazole- 5-yl) phenyl, 2,4-dichlorophenyl, 4-phenylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-phenylphenyl, phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl, 4-chloro-3-methylphenyl, 5- methyl-4-phenyl, 4-chloro-3-nitrophenyl, 3-fluoro-5-trifluoromethylphenyl, 3,5-bis (trifluoromethyl), 3-fluoro-5-trifluoromethylphenyl, 3-bromophenol, 3,4-methylenedioxyphenyl, 4 -methylphenyl, 3-methylphenyl, 3,5-bis (trifluoromethyl) phenyl, 2-methoxyphenyl, 6-phenyl-2-pyridyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, benzyl,

3,4-dichlorophenyl, 3-methylphenyl, 3,5-dimethoxyphenyl, 2-methylphenyl, 2,5-dimethoxyphenyl, 2-chloro-3-pyridyl, phenoxymethyl, cyclohexyl, 2-hydroxyphenyl, 3-trifluoromethoxyphenyl, 2-chloro-4- pyridyl, 3-chloro-4-pyridyl, 2-chlorophenylamino,

3-methoxyphenylamino, phenylamino, 2,5-dimethoxyphenylamino, amino, 4-chloro-2-methylphenylamino, 4-dimethylaminophenylamino, 4-methoxyphenylamino, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2-fluorophenylamino, 2,4,5-trimethylphenylamino, 3-chloro-2-methylphenylamino, 2-isopropylphenylamino, 4-benzyloxyphenylamino, 2-bromophenylamino, 2,5-dichlorophenylamino, 2-bromo-4-methylphenylamino, 2,3-dichlorophenylamino, 3, 4,5-trimethoxyphenylamino, 2-piperidinylethylamino, 4-methylphenylamino, 2-thienyl, 2-5,6,7,8-tetrahydronaphthyl, 3- (2-phenoxyacetic acid) phenyl, 2- (2-phenoxyacetic acid) phenyl, diphenylmethylimine.

3-phenylpropylamino, 3-phenylphenyl, phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl, and isopropyl.

A third preferred group of compounds of formula (I) includes compounds wherein:

X is sulfur;

Y represents a covalent bond;

Z is NR ^S R ^6;

R ¹ is hydrogen;

R ³ is methylthio or methyl;

R ⁴ , R ⁵ and R ⁶ all represent hydrogen; and

R ² is a group of formula (II) wherein Ar is a group selected from phenyl, thiazolyl, oxazolyl, benzothienyl, pyridyl, or imidazolyl; and R and R each independently represent hydrogen, a C 6-10 aryl or heterocyclic group, optionally substituted with one, two, or three of the group consisting of chloro, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, amino, carboxy, phenyl , naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy, carboxyethoxy, alkylsulphonylaminophenyl, arylsulphonylaminophenyl, acylsulphonylaminophenyl, aralkylsulphonylaminophenyl, heteroarylsulphonylphenyl, heteroarylsulphonylphenyl, or phenylsulfonyloxyphenyl, where the phenylsulfonyloxyphenyl is a phenyl group; 3,4-mctyléndioxy,

3,4-ethylenedioxy, and 3,4-propylenedioxy.

A fourth preferred group of compounds of formula (I) includes compounds wherein:

X is sulfur;

Y represents a direct covalent bond;

Z is NR ⁵ R ^6;

R ¹ is hydrogen;

R ² represents a radical from alkyl, ar (alkyl), alkylsulfonyl, -SO2 -alkyl, amido, amidino,

where

Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;

R and R each represent a group independently selected from hydrogen, carboxy, phenyl, naphthyl, alkyl, pyridyl, oxazolyl, furyl, cycloalkyl and amino, each of which is optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy, amino, nitro, thiophenyl, benzothiophenyl, fluorenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy, arylsulfonamido, alkylsulfonamido and aryloxy. Each of said 1 to 3 substituent groups may further be optionally substituted with one or more groups selected from the group consisting of alkoxy, haloalkyl, halogen, alkyl, amino, acetyl, hydroxy. dialkylamino, dialkylaminoacyl, monoalkylaminoacyl, -SO 2 -heteroaryl, -SC 2 -aryl, or aryl;

R ³ represents a radical from the group of -SO-alkyl, trifluoromethyl, S (O) -alkyl, hydrogen, alkoxy, alkylthio, alkyl, aralkylthio; and

R ⁴ , R ⁵ , R ⁶ are hydrogen.

Preferred compounds of the above embodiment are compounds wherein Ar is thiazolyl, preferably thiazol-2-yl or thiazol-4-yl, and at least one of R and R is substituted phenyl, most preferably at the 4-thiazol-2-yl position . Also preferred are compounds wherein ^R2 is 4-phenyl-thiazol-2-yl, said phenyl moiety is further optionally substituted, and R ³ is methylthio.

A fifth preferred group of compounds of the invention comprises compounds of formula (III):

III or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein

A is methylthio or methyl;

G 'represents -O-, -S-, -NH-, or a covalent bond;

n is an integer from 1 to 10, preferably from 1 to 6;

m is an integer from 0 to 1; and

R 'and R each represent a group independently selected from hydrogen, alkyl, aryl or aralkyl, or R' and R together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring optionally containing another O, N or S, and when said 3-8 membered heterocyclic ring contains an additional N atom, said nitrogen is N optionally substituted with hydrogen, C | .4alkyl, C6-ioaryl, C6-ioar _{(Ci. 4)} alkyl, acyl , alkoxycarbonyl or benzyloxycarbonyl.

Most preferred compounds of formula (III) include those wherein R 1 and R 2 together with the A atom to which they are attached form a ring group selected from the group consisting of piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl. which is optionally further substituted by 1 to 4 substituent groups.

which is not hydrogen and is selected from the group consisting of halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, mono- or dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or dialkylaminocarbones or diarylaminocarbonyloxy, mono- or diaracylaminocarbonyloxy, alkylsulphonyl, arylsulphonyl, aralkylsulphonyl, alkylsulphonyl amino, arylsulphonylamino, aralkylsulphonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, aralkyl or alkoxycarboxy, carboalkyloxy, carboxy, carboalkoxy, carboxy, carboxy, arylthio, wherein the preferred meanings of these substituents are the same as the preferred meanings given for formula (I) or (II).

Examples of preferred compounds of formula (III) include:

5-Methylthio-4- [4- (3 - ([N- (2-morpholin-4-ylethyl) carbamoyl] methoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2- carboxamidine

5-methylthio-4- (4- [3- (2-morpholin-4-yl-2-oxoethoxy) phenyl] - (1,3-thiazol-2-yl)} thiophene-2-carboxamidine,

5-methylthio-4- (-4- [3- (2- oxo-2-piperazinyletoxy) phenyl] (l, 3-thiazol-2-yl)} thiophene 2-carboxamidine

4- [4- (3 - {[N- (2-aminoethyl) carbamoyl] methoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine,

4- (4- (3- [2- (4-acetylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine,

4- (4- (3- [2- (4-methylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine, the compound described in Example 151,

5-Methylthio-4- [4- (3- (2-oxo-2- [4-benzylpiperazinyl] ethoxy} phenyl) (1,3-thiazol-2-yl)] - thiophene-2-carboxamidine, (D L) -4- (4- {3- [2- (3-Amino-pyrrolidinyl) -2-oxoethoxy] -phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine .

5-Methylthio-4- {4- [3- (2-oxo-2-piperidylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine, (D, L) -ethyl-1 - (2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-2-carboxylate,

5-methylthio-4- {4- [3- (2-oxo-2-pyrrolidinylethoxy) phenyl] - (l, 3-thiazol-2-yl)} thiophene-2-carboxamidine,

5-methylthio-4- [4- (3- {2-oxo-2- [4-benzylpiperidyl] ethoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine, (D, L) -4- (4- {3- [2- (3-methylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine,

4- (4- {3- [2- (4-methylpiperidin!) - 2-oxo-ethoxy] phenyl) (l, 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine,

4- (4- {3- [2- (2-azabicyclo [4.4.0] dec-2-yl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) 5-methylthiothiophen-2 -carboxamidine, (D, L) -ethyl-1- (2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-3-carboxylate,

5-Methylthio-4- {4- [3- (2-oxo-2- (1,2,3,4-tetrahydroquinolyl) ethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2- carboxamidine, ethyl 1- (2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-4-carboxy methacrylate,

4- (4- {3- [2 - ((3R) -3-hydroxypiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine,

D, L-4- (4- (3- [2- (2-etylpiperidyl) -2-oxo-ethoxy] -phenyl} (l, 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine,

4- (4- {3- [2 - ((3S) -3-hydroxypyrrolidinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine,

D, L-4- [4- (3- {2- [3- (liydroxymethyl) piperidyl] -2-oxoethoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine .

4- {4- [3- (2 - {(2R) -2 - [(phenylamino) methyl [pyrrolidinyl} -2-oxoethoxy) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene 2-carboxamidine,

4- [4- (3- (2 - ((3R) -3- (methoxymethyl) pyrrolidinyl) -2-oxoethoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophen-2 carboxamidine,

1- (2- (3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-3-carboxamide, and

2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid;

or a pharmaceutically acceptable salt or prodrug thereof.

A sixth preferred group of compounds of the invention comprises compounds of formula (IV):

R '

or a pharmaceutically acceptable salt or prodrug thereof, wherein

A is methylthio or methyl; and

R 1 represents hydrogen, C 6-14 aryl, C 1-6 alkyl, C 1-6 alkoxy (C 6-14) aryl. amino (C 6-14) aryl, monoalkylamino (C 6-14) aryl, dialkylamino (C 6-14) aryl, heterocycle (C 2-6) alkyl 1 such as morpholinoalkyl. piperazinylalkyl and the like.

C 1-6 alk (C 6-14) aryl, amino (C 1-6) alkyl, mono (C 1-6) alkylamino (C 1-6) alkyl, di (C 1-6) alkylamino (C 1-6) alkyl, hydroxy (C 6-14) aryl, or hydroxy (C 1-6) alkyl, wherein the aryl and heterocyclic rings may further be optionally substituted with 1-4 non-hydrogen substituent groups selected from the group consisting of halogen, hydroxy, amino, mono (C 1-6) alkylamino, di (C 1-6) alkylamino, formylamino, (C 1-6) acylamino, amino (C 1-6) acyl, mono- or di (C 1-6) alkylaminocarbonyl, thiocarbonylamino, (C 1-6 thioacylamino, aminothiocarbonyl, (C 1-6) alkoxy, (C6-io) a ryloxy, aminocarbonyloxy, mono- or di (Ci-6) alkylaminocarbonyloxy, mono- or di (C ₆ _io) arylaminocarbonyloxy, mono- or di (C6-io) ar (Ci.6) alkylaminocarbonyloxy, ( C1-6) alkylsulfonyl, (C6-10) arylsulfonyl, (C6-10) ar (C1-6) alkylsulfonyl, (C1-6alkyisulfonylamino, (C6-10) arylsulfonylamino, (C6-10) ar (C1-6) alkylsulfones lamino, (C 1-6) alkoxycarbony lamino, (C 6-10) ar (C 1-6) alkoxycarbonylamino, (C 6-10) aryloxycarbonylamino, mono- or di (C 1-6) a1 cylaminothiocarbonyl, (C 6-10) ar (C 1-6) alkoxy, carboxy, (C 1-6) carboxyalkyl, (C 1-6) alkoxycarbonyl, (C 1-6) alkoxycarbonyl (C 1-6) alkyl, nitro, cyano, trifluoromethyl (C 1-6) alkylthio, (C 6-10) arylthio.

Examples of preferred compounds of formula (IV) include:

4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- (2 - {[4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(4-chloro-2-methylphenyl) amino] (l, 3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine.

5-methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine,

4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(3-chloro-2-methylphenyl) amino] (l, 3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- (2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-

carboxamidine,

5-Methylthio-4- (2 - {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-

2-carboxamidine,

4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(2-bromo-4-methylphenylamino) (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-

carboxamidine,

5-Methylthio-4- {2 - [(2-morpholin-4-ylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-

carboxamidine,

4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine,

5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine,

4- (2 - {[(4-methylphenyl) methyl] amino} (1H-thiazol-4-yl) -5-methylthiothiophene-4-carboxamidine,

4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine,

4- (2 - {[4-phenoxyphenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine,

5-methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl) thiophene-2-carboxamidine,

5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} - (1,3-thiazol-4-yl)) thiophene-2-carboxamidine,

5-methylthio-4- [2- (3-quinolylamino) (l, 3-thiazol-4-yl)] - thiophene-2-carboxamidine,

5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine,

4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine,

5-methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene-2-carboxamidine,

4- [2- _^(il 3 - [(3-methylpiperidyl) methyl] phenyl} amino) (l, 3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine,

4- (2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxamidine,

4- (2 - ([4- (carbamoylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine,

5-Methyl-4- (2 - ((3,4,5-trimethoxyphenyl) amino) (1,3-thiazol-4-yl)} thiophene-2-carboxamidine,

5-methyl-4- (2 - [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine,

5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine, and

4- (4-isoxazol-5-yl (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine;

as well as their pharmaceutically acceptable salts and their prodrugs.

A seventh preferred group of compounds of the invention includes compounds of formula (I) or pharmaceutically acceptable salts or prodrugs thereof, wherein:

X is sulfur or oxygen, preferably sulfur;

Y represents a covalent bond or -NH-, preferably represents a covalent bond;

Z is NR ⁵ R ^6;

R ¹ represents hydrogen, amino, hydroxy or halogen, preferably hydrogen;

R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, C 1-4 alkyl, amino, C 1-4 alkoxy, or hydroxy, preferably all said substituents are hydrogen;

R ³ is hydrogen, C 1-6 alkylthio, C 1-6 alkyl optionally substituted by OH, NH ₂ , COOH or aminocarbonyl, or C 1-6 alkoxy, preferably methylthio or methyl; and

^R2 is alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino. heteroarylsulfonylamino, di (aralkylsulfonyl) amino, di (aralkenylsulfonyl) amino, di (arylsulfonyl) amino, or di (heteroarylsulfonyl) amino, wherein each aryl or heteroaryl containing group may be optionally substituted on the aromatic ring; or amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocyclylamino, diheterocyclylamino, monoalkylmonoheterocyclylamino, wherein each aryl or heteroaryl containing group may be optionally substituted on an aromatic group may be optionally substituted on an aromatic ring may be optionally substituted ring; or alkanoylamino, alkenoylamino, alkyinoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, each of which may be optionally substituted on an aromatic ring; or alkoxy and alkylthio, wherein each of said groups is optionally substituted, or aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, wherein each of said groups is optionally substituted on an aromatic ring; or alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein each aryl-containing group is optionally substituted on the aromatic ring; or formylamino, H (S) CNH-, or thioacylamino.

Optional substituents are selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, trifluoromethyl. C 6-10 aryl, C 6-10 arylloxy, C 6-10 aryl methoxy (wherein the aryl groups on said aryl-containing substituents are further optionally substituted by one or two of the group consisting of chloro, halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylindioxy or amino), (C 1-6 aminoalkyl, carboxy, alkyl).

3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, mono- or di (C 1-6) alkylamino, mono- or di (C 6-10) arylamino, C 1-6 alkylsulfonylamino, C 6-10 arylsulfonylamino, C1-6acylamino, C1-6alkoxycarbonyl, C1-6alkanoylamino, C6-10aroylamino, C1-6hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl (further optionally substituted by one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl.

According to one aspect of the invention, R ^{2 is} preferably C 1-6 alkylsulfonylamino, C 6-10 (C 1-6) alkylsulfonylamino, C 6-10 (C 2-6) alkenylsulfonylamino, C 6-10 arylsulfonylamino, heteroarylsulfonylamino, di (C 6-10 a (C 1-6)) alkylsulfonyl) amino, di (C 6-10 a (C 2-6) alkenylsulfonyl) amino, di (C ₆ -ioarylsulfonyl) amino, or di (heteroarylsulfonyl) amino, wherein each aryl or heteroaryl containing group may be optionally substituted on the aromatic ring.

Particularly preferred R ² groups according to the invention include C 6-10 arylsulfonylamino, di (C 6-10 arylsulfonyl) amino, C 6-10 ar (C 1-3) alkylsulfonylamino, di (C 6-10 aralkyl (C 1-3) alkylsulfonylamino, thienylsulfonylamino, wherein each of the aforementioned groups). of the groups is optionally substituted on the aromatic ring.

When R ² is substituted by a sulfonyl group, and R ² preferably represents a radical from the group of Biphenylsulfonylamino, bis (biphenylsulfonyl) amino, naphthalene-2-ylsulfonylamino, di (naphthalene-2-ylsulfonyl) amino, 6-bromonaphthalene-2-ylsulfonylamino, di (6-bromonaphthalen-2-ylsulfonyl) amino, naphthalen-1-ylsulfonylamino, di (naphthalen-1-ylsulfonyl) amino, 2-methylphenylsulfonylamino, di (2-methylphenylsulfonyl) amino, 3-methylphenylsulfonylamino, di (3-methylphenylsulfonyl) amino , 4-methylphenylsulfonylamino, di (4-methylphenylsulfonyl) amino, benzylsulfonylamino, 4-methoxyphenylsulfonylamino, di- (4-methoxyphenylsulfonyl) amino, 4-iodophenylsulfonylamino, di- (4-iodophenylsulfonyl) amino, 3,4-dimethoxyphenylsulfonylamino, bis- 3,4-dimethoxyphenylsulfonyl) amino, 2-chlorophenylsulfonyl amino, di- (2-chlorophenylsulfonyl) amino,

3-chlorophenylsulfonylamino, di- (3-chlorophenylsulfonyl) amino, 4-chlorophenylsulfonylamino, di- (4-chlorophenylsulfonyl) amino, phenylsulfonylamino, di (phenylsulfonyl) amino, 4-tert-butylphenylsulfonylamino, di (4- tert -butylphenylsulfonyl) amino , 2-phenyletenylsulfonylamino, and 4- (phenylsulfonyl) thien-2-ylsulfonylamino.

According to another aspect of the invention, R ² preferably represents a group selected from amino, mono (C 1-6 alkylamino, di (C 1-6) alkylamino, mono (C _6-10 ) arylamino, di (C 6-10) arylamino, mono (C 6-10) .6) alkylmono (C _6-10 ) arylamino, monoar (C 1-6) alkylamino, di (C 6-10) ar (C 1-6) alkylamino, mono (C 1-6) alkylmono (C 6-10) ar (C 1-6) alkylamino, monoheteroarylamino, diheteroarylamino, wherein each aryl or heteroaryl group may be optionally substituted in the aromatic ring.

Particularly preferred R ² groups in this embodiment of the invention include mono (C 6-10) arylamino, mono (C 1-6) alkylmono (C 6-10) arylamino, mono (C 6-10) ar (C 1-3) alkylamino, mono (C 1-6) arylamino; 6) alkyl mono (C 6-10) ar (C 1-3) alkylamino, monoheteroarylamino, and mono (C 1-6) alkyl monoheteroarylamino. Examples of suitable heteroarylamino groups include 1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino and quinolin-6-ylamino.

Suitable R ² groups when substituted amino include anilino, naphthalen-2-ylamino, naphthalen-1-ylamino, 4- (biphenyl) thiazol-2-ylamino, 4- (phenyl) thiazol-2-ylamino, 4-phenyls 1-5-Methylthiazol-2-ylamino, 4-hydroxy-4-trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino, pyrimidine-

2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3-fluoro-4-phenyl phenyl amino, 3,4-methylenedioxyphenylamino, butylphenylamino, N-methyl-N- (2-methylphenyl) amino, 3-nitro phenyl amino, 4-methoxyphenylamino,

3-methoxyphenylamino, 2-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino, 3,4-dimethylphenylamino, 3-chlorophenylamino, 4-chlorophenylamino,

4- (3-fluoro-4-methylphenyl) amino, 4- (indan-5-yl) amino, benzylamino, indanylmethylamino, 2,3-dihydrobenzofurylmethyl, 2-phenylimidazol-5-yl, 3-hydroxybenzyl, 3-phenoxyphenylamino, 4-phenoxyphenylamino, 3-benzyloxyphenylamino,

4-benzyloxyphenylamino, quinolin-6-ylamino, quinolin-3-ylamino, 4- (phenylamino) phenylamino, 4- (4-ethylphenyl) phenylamino, 4- (dimethylamino) phenylamino, 4-cyclohexylphenylamino, 4- (9-ethylcarbazole- 3-yl) amino, 4- (tert-butyl) phenylamino, and 4-methylthienylamino.

According to yet another aspect of the invention, R ^{2 is} preferably an acylamino group, such as an alkanoylamino group, an alkonylamino group. aroylamino. aralkanoylamino, aralkenoylamino. heteroaroylamino, heteroaryl alkanoylamino, wherein each of said groups is optionally substituted in the aromatic ring.

Particularly preferred R ² groups according to the above embodiment of the invention include those selected from the group consisting of (C 6-10) arylcarbonylamino, C 6-10 ar (C 1-3) alkylcarbonylamino, C 6-10 aralkyl (C 2-3) alkenylcarbonylamino, C 6-10 aryloxy (C 13). alkylcarbonylamino, C 3-8 cycloalkylcarbonylamino, C 1-6 alkylcarbonylamino, and heteroarylcarbonylamino such as furylcarbonylamino and quinolylcarbonylamino.

Suitably the group R ² as is the case of the acylamino group include, from the group of 3-hydroxyfenylkarbonylamino, 2-fenyletenylkarbonylamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3nitrofenylkarbonylamino, furan-2-ylcarbonyl amino, / t-butylcarbonylamino, 5- (3, 5-dichlorophenoxy) furan-2-ylcarbonylamino, naphthalen-1-ylcarbonylamino, quinolin-2-ylcarbonylamino, 4-ethoxy phenylcarbonylamino, phenoxymethylcarbonylamino, and 3-methylphenylcarbonylamino.

According to another aspect of the invention R ² is preferably C 6-10 aryloxy, C 6-10 ar (C 1-6) alkoxy, C 6-10 aralkylsulfonyl, C 6-10 ar (C 1-6) alkylsulfonyl, or C 6-10 ar (C 2-6) alkenylsulfonyl, wherein each of of said groups is optionally substituted in the aromatic ring. Particularly preferred R ² groups according to the above embodiment include C 6-10 aryloxy and C 6-10 arylsulfonyl.

«J

Suitably R, when it is aryloxy or arylsulfonyl, is a group selected from the group consisting of phenoxy, naphthyloxy, phenylsulfonyl, and naphthylsulfonyl.

Typical compounds of the seventh embodiment of the invention include:

5-methylthio-4- (6-quinolylamino) thiophene-2-carboxamidine,

5-methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxamidine,

5-methylthio-4- (3-quinolylamino) thiophene-2-carboxamidine,

5-methylthio-4- (pyrimidin-2-ylamino) -thiophene-2-carboxamidine.

4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, methyl 4-amino-5-methylthiothiophene-2-carboxylate, methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene- 2-carboxylate,

5-methylthio-4 - [(4-phenyl (1,3-thiazol-2-yl)) amino] thiophene-2-carboxamidine, 5-methylthio-4 - {[4- (4-phenylphenyl)] (1) (3-thiazol-2-yl)] amino} thiophene-2-carboxamidine,

4 - [(5-methyl-4-phenyl-1,3-thiazol-2-yl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- (2-naphthylamino) thiophene-2-carboxamidine,

4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - ((3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxamidine,

4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine,

4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine,

4 - [(3-fluoro-4-phenylphenyl) amino] -5-metyltiotiofcn-2-carboxamidine,

4- (2H-benzo [d] -1,3-dioxolen-5-ylamino) -5-methylthiothiophene-2-carboxamidine,

4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-karboxaniidín,

5-methylthio-4- [benzylamino] thiophen-2-carboxamidine,

4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine,

4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboxamidine,

5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxamidine,

4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamidine,

4 - ((2E) -3-phenylpropyl-2-enoylamino) -5-methylthiothiophene-2-carboxamidine,

4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine,

4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxamidine, methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate,

4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxamidine,

4- (2,2-dimetylpropanoylamino) -5-methylthiothiophene-2-carboxamidine

4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- (naphthylcarbonylamino) -thiophene-2-carboxamidine

5-methylthio-4- (2-quinolylcarbonyl-amino) thiophene-2-carboxamidine,

4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine,

4- [2- (2-hydroxy-5-methoxy-phenyl) acetylamino] -5-methylthiothiophene-2-carboxamidine,

4 - [(4-ethoxyphenyl) carbonyl amino] -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4- (2-phenoxy-acetylamino) -thiophene-2-carboxamidine,

4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine,

5-methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboxamidine,

5-methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboxamidine,

4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4- (methylphenyl amino) -5-methylthiothiophene-2-carboxamidine,

5-methyl-4- (phenylamino) thiophene-2-carboxamidine,

4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboxamide,

4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine,

5-methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxamidine,

4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine,

4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine,

4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamide;

4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - [(2-naphthylsulfonyl) amino] thiophene-2-carboxamidine,

4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - {[(6-bromo (2-naphthyl)) sulfonyl) amino} -5-methylthiothiophene-2-carboxamidine,

4- {bis [(6-bromo (2-naphthyl)) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - [(naphthylsulfonyl) amino] thiophene-2-carboxamidine,

4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine,

4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

4- {bis [(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

4 - {[(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

4- {bis [(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine,

5-methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboxamidine,

5-methylthio-4-phenoxythiophene-2-carboxamidine,

5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxamidine, also as salts thereof such as hydrochloride or trifluoroacetate, and prodrugs thereof.

Methods of use and pharmaceutical compositions

Pharmaceutically acceptable acid addition salts, i.e. salts whose anion does not significantly contribute to toxicity or affect the pharmacological activity of the organic cation, are preferred for use in medicine. Said acid addition salts are prepared by reacting an organic base of formula (I) with an organic or inorganic acid, preferably by bringing both components in solution or by any of the standard methods described in detail in the literature available to a person skilled in the art. Examples of suitable organic acids include carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isothionic acid, succinic acid, cyclamic acid, pivalic acid and the like; suitable inorganic acids include hydrogen halides such as HCl, HBr, H1; sulfuric acid; phosphoric acid and the like. Preferred acids for the preparation of acid addition salts are HCl and acetic acid.

Compounds of the invention represent a new class of potent inhibitors of metalloprotease and acid, thiol and serine protease. Examples of serine proteases inhibited by the compounds of the invention include leukocyte neutrophil protease, a proteolytic enzyme involved in pathogenesis of emphysema; digestive enzymes chymotrypsin and trypsin; pancreatic elastase and catcpsin G, a chymotrypsin-like protease associated with leukocytes; thrombin and factor Xa, proteolytic enzymes involved in the blood coagulation process. The use of the compounds according to the invention is also envisaged for inhibiting thermolysin, metalloprotease and pepsin, acid protease. The compounds of the invention are preferably used to inhibit trypsin-like proteases.

Compounds of the invention that inhibit urokinase plasminogen activator are potentially useful in the treatment of disease states characterized by excessive cell growth. The compounds of the invention are therefore useful as anti-angiogenic, anti-arthritic, anti-inflammatory, antirestenotic, anti-invasive, antimetastatic, antirestenosis, anti-osteoporous, antiretinopathic (for angiogenesis-related retinopathies), contraceptive and tumorostatic agents. These medicaments are useful in the treatment of various disease states including, but not limited to, benign prostatic hypertrophy, prostate cancer, tumor metastasis, restenosis, and psoriasis. The invention also provides methods of inhibiting extracellular proteolysis, methods of treating benign prostatic hypertrophy, prostate cancer, tumor metastasis, restenosis, and psoriasis by administering a compound of Formula (I). In the final application phase, the potency and other biochemical properties of the enzyme inhibiting compounds of the invention are readily determined by standard biochemical methods known in the art. Actual dosages for such administration will depend on the nature and severity of the disease in the patient or animal being treated and will be determined by the attending physician. In general, a dosage range of about 0.01 to 50 mg, preferably 0.1 to about 20 mg per kg per day is contemplated to achieve an effective therapeutic effect.

The final application of the compounds inhibiting chymotrypsin and trypsin is the treatment of pancreatitis. In the final application phase, the potency and other biochemical properties of the enzyme inhibiting compounds of the invention are readily determined by standard biochemical methods known in the art. Of course, the actual doses for their specific end use will depend on the nature and severity of the disease in the patient or animal being treated and will be determined by the attending physician. In order to achieve an effective therapeutic effect, it is contemplated that the dosage range will be about 0.01 to 50 mg, preferably 0.1 to about 20 mg per kg per day.

Compounds of the invention having the ability to inhibit either factor Xa or thrombin can be used for a variety of therapeutic purposes. As factor Xa or thrombin inhibitors, the compounds of the invention inhibit thrombin production. Therefore, the compounds are suitable for the treatment or prevention of conditions characterized by abnormal venous or arterial thromboses with the formation or effects of thrombin. Said conditions include, but are not limited to, deep vein thromboses; disseminated intravascular coagulation resulting from septic shock, viral infection and cancer; myocardial infarction; stroke; coronary artery bypass; formation of fibrin in the eye; hip replacement; and thrombus formation due to thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA).

By effecting both Factor Xa and thrombin on various types of host cells, such as smooth muscle cells, endothelial cells and neutrophils, the compounds of the invention have further utility in the treatment or prevention of adult anxiety respiratory syndrome; inflammatory reactions; wound healing; reperfusion injury; atherosclerosis; and restenosis following balloon-induced angioplasty, atherectomy, and arterial stent delivery. The compounds of the invention may also be useful in the treatment of neoplasia and metastasis, as well as in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

When using the compounds of the invention as thrombin or factor Xa inhibitors, said compounds may be administered in an effective amount in a dosage range of about 0.1 to about 500 mg / kg, preferably in a range of 0.1 to 30 mg / kg body weight on a regimen dosages comprising a daily dose divided into 2-4 doses.

Human leukocyte elastase is released from polymorphonuclear leukocytes at sites of inflammation and thereby contributes to the development of several disease states. The compounds of the invention which are believed to have an anti-inflammatory effect are useful in the treatment of rheumatism, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. The leukocyte elastase inhibitory properties of the compounds of the invention are determined by the methods described below. Cathepsin G is also included in disease states including arthritis, rheumatism and emphysema and, in addition, glomerulonephritis and lung infestation due to pulmonary infection, are readily determined by standard biochemical methods known in the art.

The cathepsin G inhibitory properties of the compounds of the invention are determined as follows. A composition comprising partially purified human cathepsin G is prepared as described by Baugh et al., Biochemistry 15: 836 (1979). The main sources of leukocyte elastase and cathepsin G (with chymotrypsin-like activity) are leukocyte granules. The leukocytes are decomposed and the granules are isolated. Then, the leukocyte granules are extracted with 0.20 M sodium acetate, pH 4, and the extracts are dialyzed overnight at 4 ° C against 0.05 M tris buffer containing 0.05 M NaCl. During dialysis, the protein fraction precipitates and is isolated by centrifugation. This fraction consists predominantly of leukocyte granules with chymotrypsin-like activity. A specific substrate is prepared for each enzyme, N-Suc-Ala-Ala-Pre-Val-p-nitroanilide and Suc-Ala-Ala-PrePhe-p-nitroanilide. The second substrate is not hydrolyzed by leukocyte elastase. Enzyme preparations were performed in 2.00 ml of 0.10 M Hepes buffer pH 7.5 containing 0.50 M NaCl, 10% dimethylsulfoxide and 0.0020 M Suc-AlaAla-Pre-Phe-p-nitroanilide as substrate. . The hydrolysis of p-nitroanilide was monitored at 405 nm and at 25 ° C.

The appropriate dosage range for administration of the compounds of the invention as inhibitors of neutrophil elastase and cathepsin G is dependent on the nature and severity of the disease state, and a suitable dose for the above conditions will be determined by the attending physician in the range of 0.01 to 10 mg / kg body weight per day.

A further use of the compounds of the invention relates to the analysis of the concentration at the active site with commercially available reagents. For example, chymotrypsin is supplied as a standard reagent for the clinical quantification of chymotrypsin activity in pancreatic juice and faeces. These assays are used to diagnose gastrointestinal and pancreatic diseases. Also, pancreatic elastase is commercially available as an agent for quantifying α-antitrypsin in plasma. The plasma concentration of α-antitrypsin increases during severe inflammatory diseases and α-antitrypsin deficiency is associated with the occurrence of pulmonary diseases. The compounds of the invention can be used to increase the accuracy and reproducibility of these assays by standardizing a commercially available elastase reagent by titration. See U.S. Pat. No. 4,499,082.

Protease activity in certain protein extracts that occurs during purification of particular proteins is a frequently occurring problem that can complicate the protein isolation process and lead to compromise solutions. Certain proteases present in these extracts may be inhibited during purification by the compounds of the invention that closely bind to the various proteolytic enzymes.

The pharmaceutical compositions of the invention may be administered to any animal in which the compounds of the invention produce beneficial effects. In the first place, it is human, although the invention is not limited to administering the compounds to humans only.

The pharmaceutical compositions of the invention may be administered by any means that achieve the desired purpose. For example, they can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, buccally, or intraocularly. Alternatively or simultaneously, oral administration may be used. The dose to be administered is dependent on the age, health and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment and the nature of the effect desired.

The pharmaceutical compositions of the invention may be prepared by methods generally known, for example, by means of conventional mixing and granulating methods, dragee-making methods, dissolving or lyophilizing processes. Pharmaceutical preparations for oral administration can be prepared by combining the active compounds with solid additives, optionally grinding the mixture obtained, and processing the mixture of granules, after adding suitable excipients, if desired or necessary, to tablets or dragee cores.

Suitable additives include, in particular, carbohydrates such as lactose or sucrose, mannitol or sorbitol, cellulosic agents and / or calcium phosphates such as calcium phosphate or dibasic calcium phosphate, as well as binders such as starch paste, based on corn starch, wheat starch, rice starch, potato starch , tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrating agents such as the aforementioned starches as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid and salts thereof such as sodium alginate may be added. Adjuvants include, in addition to the aforementioned flow control agents and glidants, for example silica, talc, stearic acid or salts thereof such as magnesium or calcium stearate and / or polyethylene glycol. The dragee cores are provided with a suitable gastric juice-resistant coating, if desired. For this purpose, concentrated carbohydrate solutions may be used, which may optionally contain gum arabic, bismuth, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, solutions and suitable organic solvents or solvent mixtures. Solutions of suitable cellulosic agents such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used to prepare gastric juice-resistant coatings. Dyestuffs or pigments may be added to the tablet or dragee coatings, for example to identify them or to characterize combinations of active compound doses.

Other pharmaceutical preparations suitable for oral administration include two-piece gelatin capsules and soft sealed capsules of gelatin and a plasticizer such as glycerol or sorbitol. The two-part capsule may contain the active compounds in the form of granules which can be mixed with fillers such as lactose, binders such as starches and / or glidants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, they may contain stabilizers.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds in the form of water-soluble compounds, such as water-soluble salts, alkaline solutions and inclusion complexes with cyclodextrin. Particularly preferred salts are the acetate and hydrochloride salts. One or more modified or unmodified cyclodextrins may be used to stabilize and increase the aqueous solubility of the compounds of the invention. Suitable cyclodextrins for the above purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604 and 5,024,998.

In addition, the active compounds may be administered in suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain components that increase the viscosity of the suspension, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. The suspensions may also optionally contain stabilizers.

Methods of preparation

More synthetic methods suitable for preparing the compounds of the invention include the formation of amidine from a carboxylic acid derivative such as an ester or a nitrile. In this process, the ammonium source is used. such as ammonium chloride in an aprotic solvent such as toluene under an inert atmosphere (e.g., nitrogen or argon atmosphere) is added at a temperature of -15 ° C to 5 ° C, preferably at 0 ° C, a Lewis acid such as trimethylaluminium. The appropriate carboxylic acid derivative is added to the mixture and the mixture is heated at reflux for a predetermined period of time, preferably for between 1 and 24 hours, most preferably for 1 to 4 hours. The solution obtained is allowed to cool to room temperature and the amidine product is isolated by known methods.

Description of syntheses

The chemical schemes are listed below after the schemes are described.

Scheme la

Scheme 1a illustrates a general approach to the synthesis of compounds of formula (I) wherein X = O or S, R ³ = alkylthio, aralkylthio, alkyloxy, aralkyloxy or aryloxy, Y = bond and Z = NR ⁵ R ⁶ . As long as R ²² and R ²¹ in compounds (2) and (3) are retained in the final product, they correspond to the substituents R and R of the compound of formula (I). Otherwise, R and R are groups that are converted to R ² and R ³ of formula (I) by further transformation.

The process starts from a heterocycle in which X = O or S is suitably substituted by two leaving groups which are successively replaced with the appropriate nucleophiles (preferably an anion of R ²¹ or R ²² is used as the substituting agent) to form mono- or disubstituted heterocycles. Examples of leaving groups include halogens (chlorine, bromine or iodine), sulfonates (methanesulfonate, toluenesulfonate or trifluoromethanesulfonate) or sulfones (methylsulfonyl). Preferred nucleophilic compositions include anions of thiols or alcohols with an counterion formed by an alkali metal or alkaline earth metal ion such as sodium, lithium, potassium, magnesium or cesium, or in some cases a metal of the transition metal group such as zinc, copper or nickel. In certain cases, when the nucleophile used forms an anion on carbon, a catalytic displacement reaction may be used for the transformation.

Examples of catalysts include palladium-containing compounds, and silver or nickel salts.

Scheme lb

Scheme 1b illustrates an approach allowing the introduction of functional group Y (CNR ⁴ ) Z into compounds of formula (I) wherein X = N, O or S, and R ²² and R ²¹ have the same meaning as in Scheme 1a. Depending on the meaning of the group W in compound (3), several methods can be used to transform W to Y (CNR ⁴ ) Z.

When W in compound (3) represents a cyano group (CN), a primary amide (CONH2) or an ester (CO2R ²³ ), direct conversion to the unsubstituted amidine of formula (5) (ie a compound of formula (I) wherein Y = bond, Z = NR ⁵ R ⁶ and R ⁴ , R ⁵ , R ⁶ = H) by treatment with a Lewis acid-containing reagent complexed with ammonium ions. This complex is prepared by treating ammonia or an ammonium salt, preferably ammonium halide and most preferably ammonium chloride or bromide, with a suitable Lewis acid, preferably trialkylaluminum, and most preferably with trimethyl or triethylaluminum in a Lewis acid inert solvent. For example, when trialkylaluminum and ammonium halide are used as the Lewis acid, the reaction proceeds with the loss of one equivalent of an alkane to form a dialkyl haloaluminium complex with ammonium (see, e.g., Sidler, DR et al., J. Org. Chem., 59: 1231 (1994)). Examples of suitable solvents include unsaturated hydrocarbons such as benzene, toluene, xylenes or mesitylene, preferably toluene, or halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene The amidation reaction is usually carried out at elevated temperatures, preferably at 40 200 ° C, even more preferably at 80-140 ° C and most preferably at the reflux temperature of the solvent at a temperature in the range 80-120 ° C.

When W is a cyano (CN) group, direct conversion to the mono- or disubstituted amidine (5) (R ⁴ , R ⁵ , R ⁶ = H) can also be carried out by treatment with a Lewis acid, preferably trialkylaluminum, complexed with mono- or disubstituted amine H ₂ NR ^:) or HNR'R ⁶ (Garigipati, R.

Tetrahedron Lett. 31: 1969 (1990)). In an alternative method, the same addition of mono- or disubstituted amine can be catalyzed by a copper salt such as CuCl (Rousselet, G., et al., Tetrahedron Lett. 34: 6395 (1993)).

When W in compound (3) is a carboxyl group (CO 2 H), it can be indirectly converted to the unsubstituted amidine (5) by first esterifying it to compound (4) with one of several well known dehydrating agents (e.g. dicyclohexylcarbodiimide) and alcohol (R ^23). OH). Even more preferably, (4) is prepared by converting compound (3) to an acid chloride by treating with one of a number of HCl anhydrides or another acid such as thionyl chloride, POCl 3, PCl 3, PCl 5 or more preferably oxalyl chloride with a catalyst such as Ν, Ν-dimethylformamide. (DMF) or without, and then treatment with an alcohol R ²³ OH. Conversion to unsubstituted amidine (5) (R ⁴ , R ⁵ , R ⁶ = H) can be accomplished by treatment with Lewis acid complexed with ammonium ions.

Amidines (5) can also be prepared indirectly by converting compound (3) (W = CN) to iminoethers (6) by exposure to a strong acid such as hydrogen halide, HBF 4 or other non-nucleophilic acid, preferably HCl gas in the presence of R ²³ OH (R = alkyl, branched alkyl or cycloalkyl, preferably Me or Et) and most preferably with alcohol as solvent. Alternatively, when W = CONH ₂ , conversion to the iminoether can be accomplished by treatment with a trialkyloxonium salt (Meerwein salts). In any case, treatment of the iminoether (6) with ammonia (R ⁵ , R ⁶ = H) or with a mono- or disubstituted amine (HNR ⁵ R ⁶ ) yields the corresponding unsubstituted amidines (5) (ie - classical Pinner synthesis: Pinner, A., Die Iminoaeter und ihre Derivat, Verlag R. Oppenheim, Berlin (1892)).

If in compound (3) W = NH 2, treatment with reagent Z (CNR ⁴ ) L wherein Z = alkyl and L represents a leaving group such as O-alkyl and preferably OMe, a subclass of amidines (135) (Z = alkyl) is prepared which are isomerically with (5) (Formula I wherein Y = NH, Z = H or alkyl). Examples of reagents for said reaction include methyl or ethyl acetimidate hydrochloride. Alternatively, treatment of compound (3) (W = NH 2) with a trialkyl orthoformate ester preferably with trimethyl or triethyl orthoformate followed by amine R ⁴ NH 2 affords the corresponding formidines (135) (Z = H) (formula I where Y = NH , Z = H).

When W = NH ₂ , compound (3) can also be treated with the reagent Z (CNR ⁴ ) L, where R ⁴ = H and Z = NR ⁵ R ⁶ and L represents a leaving group such as pyrazole, methylpyrazole, SO 3 H, S -alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf), preferably pyrazole, SO 3 H or trifluoromethanesulfonamide (NHTf). Examples of such agents include aminoiminosulfonic acid (Miller, AE and Bischoff, JJ, Synthesis, 777 (1986) and 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, MS, et al., J. Org. Chem. 57: 2497 (1992)) This treatment directly gives guanidines (136) (Formula I wherein Y = NH, Z = NR ^S R ⁶ ) Alternatively, it is also possible to use reagent Z (CNP) L, where Z = NHP and L is a leaving group, such as pyrazole, methylpyrosole, SO 3 H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf) to prepare protected guanidines (P ¹ , P ² = alkoxycarbonyl, aralkoxycarbonyl or alkoxycarbonyl bonded to the polymer likewise, in the description of Scheme 4a), where protecting groups P ¹ and P ^{2 can} then be removed to give unsubstituted compound (136) (R ⁴ , R ⁵ and R ⁶ = H). groups necessary further transformations, in which would not Examples of said protected compositions include N, N'-bis (tert-butoxycarbonyl) -S-methylthiourea (Bergeron, RJ and McManis, JS, J. Org. Chem. 52: 1700 (1987)), N, N'-bis (benzyloxycarbonyl) -1H-pyrazole-1-carboxamidine or N, N'-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (Bernatowicz, MS, et al., Tetrahedron Letters, 34: 3389 (1993)), N, N'-bis (benzyloxycarbonyl) -N-trifluoromethanesulfonyl-guanidine, and N, N'bis (bis (tert-butoxycarbonyl) -N '- trifluoromethanesulfonylguanidine (Feichtinger, K. , et al., J. Org. Chem., 63: 3804 (1998)) Detailed descriptions and examples of these protecting groups and their uses for amidines are further illustrated in Schemes 4a, 4b and 5.

When W in compound (3) is an ester (CO 2 R ²³ ) or a carboxyl group (CO 2 H), indirect conversion to N-substituted or unsubstituted methylamidine (formula (I) wherein Y = CH 2, Z = NR ⁵ R ⁶ ) may be performed wherein the ester or carboxyl is first reduced by one of a number of known reducing agents. When W in compound (3) is an ester group (CO ₂ R), examples of such reducing agents include lithium aluminum hydride (LAH) and lithium borohydride. When W in compound (3) is a carboxyl group (CO ₂ H), examples of reducing agents include LAH and borane complexed with THF, dimethylsulfide, dimethylamine or pyridine. The obtained hydroxymethyl derivative (W = CH ₂ OH) is then converted to a cyanomethyl derivative (w = CH ₂ CN) by first converting it to a leaving group (W = CH ₂ L), wherein the leaving group L represents halogen (chlorine, bromine, or iodine) ) or a sulfonate ester (e.g., methanesulfonate, toluenesulfonate or trifluoromethanesulfonate). Displacement with cyanide can then be accomplished by treatment with a metal cyanide such as LiCN, NaCN, KCN or CuCN in a polar solvent with or without a catalyst such as a crown ether to give a cyanomethyl derivative (see, e.g., Mizuno, Y., et al. Synthesis, 1008 (1980)). More preferably, the conversion of a compound with W = CH ₂ OH to W = CH ₂ CN is carried out by the Mitsunobu reaction (Mitsunobu, O., Synthesis, 1 (1981)) using an azodicarboxylate ester such as diethyl azodicarboxylate or diisopropylazodicarboxylate, Ph ₃ P and a source of cyanide ions such as HCN or more preferably acetone cyanohydrin (Wilk, B. Synthetic Commun. 23: 2481 (1993)). Treatment of the obtained cyanomethyl product (W = CH ₂ CN) under the conditions described for the conversion of compound (3) (W = CN) to compound (5) (either directly or indirectly via compound (6)) affords the corresponding amidinomethyl products.

Scheme lc

Alkyltiotiofény (Compound (3), X = S, R ^{1 =} OH or NH 2, R ^{2 I} SR = ^54, W = CN, CO 2 R ^23, CONH 2), if not commercially available, may be prepared as shown in Scheme Ic. Condensation of carbon disulphide with a malonic acid derivative (R ⁵² CH 2 R ²² ) in the presence of two alkylating agents R ⁵⁴ L and WCH 2 L and a base in a suitable medium affords compound (3) (Dolman, H., European Patent Application No. 0 234 622 A1 (1987)). )). When R 1 → R 1 → CN formed by R 1 is NH 2; when R ²² = R ⁵² = CO ² R ²³ , the resulting R * will be OH; and if R ²² a

R ⁵² = CN, CO 2 R ²³ , formed by R ¹ may be either OH or NH 2 (and R ²² = CN or CO 2 R ²³ ), depending on the reaction conditions and the order of addition of the reagents. Examples of malonic acid derivatives suitable for the transformation include, but are not limited to, malonic acid diesters such as dimethyl malonate or dictyl malonate (R ⁵² , R ²² = CO ² R ²³ , R ²³ = Me or Et), malononitrile (R, R = CN) or methyl or ethyl cyanoacetate (R ⁵² = CO ² R ²³ , R ²² = CN, R ²³ = Me or Et). Cleavable groups include halides such as chloride, bromide or iodide, preferably bromide or iodide, or sulfonates such as toluenesulfonate, benzenesulfonate, methanesulfonate or trifluoromethanesulfonate. Examples of alkylating agents R ⁵⁴ L include primary or secondary alkyl, allyl or aralkyl halides or sulfonates such as methyl iodide, isopropyl bromide, allyl bromide, benzyl chloride or methyl trifluoromethanesulfonate or a 2-haloacetate ester such as tert-butyl 2-bromoacetate. Examples of WCH2L alkylating agents include 2-chloroacetonitrile, methyl 2-bromoacetate, or 2-bromoacetoamide. Suitable media generally include polar aprotic solvents such as Ν, Ν-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO), preferably DMF.

Alternatively, compounds (3) (R ²² = CN) can be prepared from precursors (138) (derived from malononitrile, R ⁵⁴ L and carbon disulphide), WCHSH thioglycolate and a base, in a suitable polar solvent, preferably methanol (Tominaga, Y. et al., J. Heterocyclic Chem. 31: 771 (1994)).

If compound (3) contains an amino group in R ¹ , it can be diazotized followed by removal of nitrogen to give compound (3), R * = H, by treatment with a nitrosating agent in a suitable solvent. Nitrosating agents include nitrosonium tetrafluoroborate, nitrous acid, or more preferably an ester thereof, such as alkyl nitrite and tert-butyl nitrite. Suitable solvents include solvents that are stable to nitrosating agents, DMF, benzene or toluene being preferred.

Scheme ld

The heterocyclic precursors (1) or (2) (X = O, S; W = CC> 2R ²³ , COOH; L = halogen) used in the process of Scheme Ia, can be prepared, if not commercially available, by the methods shown in Scheme Id. Depending on the conditions selected, treatment of compounds such as compounds (139) with elemental halogen (Cl 2, B 12 or I 2, preferably Br 2) or with a N-bromosuccinimide reagent, preferably with N-bromosuccinimide (NBS) affords either Compound (1) or (2). A description of suitable solvents and conditions suitable for the selective preparation of compound (1) or (e) can be found in Karminski-Zamola, G. et al., Heterocycles 38: 759 (1994); Divald, S., et al., J. Org. Chem. 41: 2835 (1976); and Bury, P., et al., Tetrahedron 50: 8793 (1994).

Scheme 2a

Scheme 2a illustrates the synthesis of compounds of formula (12) comprising a subclass of compounds wherein R ² is a group of formula (II) wherein Ar = 2-thiazolyl, Y = bond and Z = NR ⁵ R ⁶ . Using compound (1) as the starting component (L = Br) and using the sequential substitution methods described in Scheme 1a, it is possible to introduce the group R ²¹ to obtain compound (7). A second displacement is then carried out with a metal cyanide such as copper cyanide, sodium cyanide or lithium cyanide, most preferably copper cyanide, at a temperature of 80-200 ° C and preferably at a temperature of 100-140 ° C, in a polar aprotic solvent, preferably DMF; in DMSO, whereby compound (8) is obtained. Following esterification by any of the methods described for the conversion of (3) to (4), conversion to the thioamide is accomplished by treatment with nitrile by any of the methods known in the art (see, e.g., Ren, W., et al., J. Heterocyclic Chem. 23: 1757 (1986) and Paventi, M. and Edward, JT, Can. J. Chem. 65: 282 (1987)). A preferred method includes a process wherein the nitrile is treated with hydrogen sulfide in the presence of a base such as a trialkylamine or a heterocyclic amine, preferably triethylamine or pyridine, in a polar solvent such as acetone, methanol or DMF, preferably methanol. Conversion to thiazole can be accomplished by classical Hantzsch thiazole synthesis followed by amidine preparation as described in Scheme 1b.

Scheme 2b

Scheme 2b illustrates the synthesis of compounds of formula (12) comprising a subclass of compounds in which R ² is a group of formula (II) wherein, in addition to an alternative for Ar = 2-thiazolyl (20) (see (12) Scheme 2a) compounds with group (II) wherein Ar = 2-oxazolyl (16) or 2-imidazolyl (18), (Y = bond and Z = NR ⁵ R ⁶ ). Using compound (9) as a starting material, and selectively hydrolyzing the nitrile with tetrahalophthalic acid, preferably tetrafluoro- or tetrachlorophthalic acid, the method of Gribble, GW et al., Tetrahedron Lett. 29: 6557 (1988) provides compound 7. Conversion to acid chloride can be accomplished using the methods described for converting compound (3) to (4), preferably using oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF. Coupling of the acid chloride to the aminoketone (R ²⁶ COCH (R ²⁷ ) NH 2) can be carried out in the presence of an acid quencher, preferably Ν, Ν-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF). Intermediate (14). Alternatively, the acid chloride can be coupled to a less substituted aminoketone (R ²⁶ COCH ₂ NH ₂ ) followed by optional alkylation with an alkylating agent R ²⁷ L in the presence of a base, preferably NaH or t-BuOK. Transformation of compound (14) to the corresponding 2-oxazolyl- (15), 2-imidazolyl (17), or 2-thiazoles (19) esters can be accomplished by the method described by Suzuki, M., et al., Chem. Pharm. Bull. 34: 31 11 (1986) followed by amidation according to Scheme 1b. In addition, it is possible to carry out the direct conversion of ketoamide (14) to the imidazolyl derivative (18) under the same conditions as described for the conversion of compound (17) to (18), the reaction being carried out over a longer period of time, preferably greater than 2. hours.

Scheme 2c

Scheme 2c shows a general method for the synthesis of oxazoles, imidazoles and thiazoles of the corresponding formulas (27), (29) and (31). The acid of formula (2) (see Scheme 1a) is converted to the ester by methods known in the art (Theodor W. Greene and Peter G. M. Wuts, John Wiley &amp; Sons, Inc. 1991). For example, the methyl ester (21) is prepared by treating the acid in a suitable solvent such as methanol with trimethylsilyldiazomethane. Alternatively, the acid is treated with oxalylchloridoin with a catalytic amount of dimethylformamide (DMF) in a suitable solvent such as dichloromethane to give the acid chloride from which the methyl ester is obtained by treatment with methanol. The ester (21) is treated with a palladium (0) catalyst such as palladium tetrakistriphenylphosphine and an alkylstannane such as hexabutylstannane or tri-n-butylstannium chloride in a suitable solvent such as DMF at elevated temperatures (50 ° C - 120 ° C) to give an arylstannane of formula (22) (Stille, JK, Angew. Chem. Int. Ed. Engl. 25: 508-524 (1986)). The stannane (22) is then treated with acid chloride in the presence of a palladium (0) catalyst to form the ketone (23). Treatment of the ketone with ammonia / ammonium chloride then affords the amine (24). Alternatively, the ketone is reacted with an azide such as sodium azide in a suitable solvent such as DMF and the resulting azidoketone is reduced to the amine (23) by a suitable reducing agent such as catalytic hydrogenation in the presence of palladium on carbon and an acid such as HCl Pharm. Bull. 33: 509-514 (1985)). Ketoamides (25) are prepared by coupling a ketoamine (24) with various suitable functionalized acid chlorides. Alternatively, the amide coupling can be accomplished using a variety of peptide coupling agents, such as dicyclohexylcarbodiimide (Sheehan, JC et al., J. Am. Chem. Soc., 77: 1067 (1955)) or by Castro Reagent (BOP, Castro, B. et al., Synthesis 413 (1976)). According to another approach, amides (25) are prepared directly from ketones (23) by reaction with various amide salts in a suitable solvent. Amide salts are generated by treating amides with various suitable bases, such as sodium hydride (NaH). For example, treatment of acetamide with NaH in DMF at 0 ° C affords sodium acetamide. Ketoamide (25) is cyclized to oxazole (26), imidazole (28) and thiazole (30) using methods similar to those shown in Scheme 2b. Oxazole (26), imidazole (28) and thiazole (30) are treated with trimethylaluminium and ammonium chloride in refluxing toluene to prepare the corresponding amidines (27), (29) and (31).

Scheme 2d

Scheme 2d illustrates the preparation of the compounds of Examples 42-43, wherein R ²¹ and R correspond to the groups R and R in formula (1). Acids (2) can be converted to stannane by treatment with a base such as butyllithium or sec. butyllithium, and then with trimethylstannium chloride. The resulting acid is converted to the ester (22) by methods known in the art (Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, Inc. 1991). For example, the methyl ester can be prepared by treating acid (2) in a suitable solvent, such as methanol with trimethylsilyldiazomethane. The stannane (22) can then be reacted with suitable halides in the presence of catalytic amounts of a palladium catalyst such as palladium tetrakistriphenylphosphine to give esters (32). (Stille, JK, Angew. Chem. Int. Ed. Engl. 25: 508-524 (1986)). The obtained esters are then treated with trimethylaluminium and ammonium chloride in refluxing toluene to give amidines (33). In the case where R ⁴³ L _n (n = 2), it is possible to cross-link to the aryl, heteroaryl or vinyl boronic acid or ester thereof to obtain compounds (34) (Miyaura, N. and Suzuki, A., Chem. Rev. 95: 2457-2483 (1995)). This procedure can usually be carried out in the presence of catalytic amounts of a palladium (0) catalyst such as tetrakistriphenylphosphine palladium and a base such as potassium carbonate in DMF at 90 ° C. Similar cross-couplings can also be achieved using aryl, heteroaryl or vinylstannanes instead of boric acids or boric acid esters. Said esters are then converted to amidines (35) as described above.

Scheme 2e

Scheme 2e depicts a modification of the methods described in Scheme 2b to allow the synthesis of compounds containing a group of formula (II) wherein Ar = 2 thiazolyl, 2-oxazolyl or 2-imidazolyl (Y = bond and Z = NR ⁵ R ⁶ ) but which are positional isomers towards compounds (16), (18) or (20) at the relative positions of R ²⁶ and R ²⁷ . Said step is shown in Scheme 2b by the synthesis of the 2-oxazolyl derivative (39). The acid (13) can be coupled to an amine containing a hydroxy group R ²⁷ CH (NH 2) CH (R ²⁶ ) OH to the amide (36) using several known amide coupling reagents (see Bodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis, Springer-Verlag, New York (1984). Even more preferably, compound (13) is converted to the corresponding acid chloride using any of the methods described for converting compound (3) to (4) followed by treatment with R ²⁷ CH (NH 2) CH (R ²⁶ ) OH in the presence of an acid quencher, preferably N, N-diisopropylethylamine (DIEA) or pyridine, in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to form compound (36). Oxidation of the alcohol (36) to the aldehyde (37) (R ²⁶ = H) or to the ketone (37) (R ²⁶ = alkyl, aryl, aralkyl, heterocycle) can be accomplished by any of several methods commonly known in the art (see, for example, F Carey, FA, Sundberg, RJ Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd edition, Plenum Press, New York (1990)), preferably by moderate Moffatt-type oxidation, such as Swern oxidation (Mancuso, AJ, Huang, SL and Swern, D., J. Org. Chem. 3329 (1976)) or more preferably using a Dess-Martin reagent (Dess, DB and Martin, JC, J. Org. Chem. 48: 4155 (1983)). Conversion to the heterocycle (in this case, oxazole) can be accomplished by a variety of means including phosphorus oxychloride, P2O5, or thionyl chloride (see Moriya, T., et al., J. Med. Chem. 31: 1197 (1988) and references cited therein). in this work). Alternatively, cyclization of compound (37) to the corresponding oxazolinyl derivatives can be accomplished using Burgess reagent or Mitsunobu reaction conditions (Wipf, P. and Miller, CP, Tetrahedron Lett. 3: 907 (1992)). The synthesis ends by amidination to compound (39) as in Scheme 1b.

Scheme 2f

Scheme 2f depicts a general approach for the synthesis of a thiazole of general structural formula (43) (Formula (II), X = S, Ar = thiazolyl). Nitriles of general formula (40) can be treated with hydrogen sulfide (H ₂ S) in a suitable solvent such as methanol or pyridine in the presence of a base such as triethylamine to give thioamides (41) (Ren, W. et al., J. Heterocyclic Chem., 23: 17571763 (1986)). The thioamides (41) can then be treated with various haloketones (42), preferably bromoketones, under suitable reaction conditions such as acetone at reflux or DMF at a heating temperature of 50 ° C to 80 ° C to yield thiazoles (43) ( Hantzsch, AR et al., Ber.20: 3118 (1887)).

Scheme 2g

Scheme 2g depicts one of the methods of synthesizing 2-halo ketones of general structural formula (42) that can be used to prepare the thiazolyl derivatives of Schemes 2a and 2f. The 2-bromoketones (42) can be prepared by treating the ketone (44) with a suitable brominating agent such as Br ₂ or N-bromosuccinimide in a suitable solvent such as chloroform or acetic acid (EP 0393936 A1). Alternatively, ketone (44) is treated with a brominating agent on a polymeric carrier such as poly (4-vinyl) pyridinium bromide resin (Sket, B., et al., Synthetic Communications 19: 2481-2487 (1989)) to yield bromoketones (42). ). In a similar manner, 2-chloroketones are prepared by treating compound (44) with copper (I) chloride in a suitable solvent such as chloroform (Kosower, EM, et al., J. Org. Chem. 28: 630 (1963)).

Scheme 2h

Scheme 2h illustrates another method for preparing 2-halo ketones of general structural formula (42), which is particularly advantageous by using acids (45) or activated carbonyl compounds such as compounds (46) as precursors that are more accessible than ketones (44). The acid (45) is converted to the acid halide (46) (L = Cl, Br, or OCOR ³⁹ ) by treatment with a suitable halogenating agent. For example, the acid chloride is prepared by treating compound (45) with oxalyl chloride and a catalytic amount of DMF in dichloromethane. The acid chloride is converted to the diazoketone by treatment with trimethylsilyldiazomethane (Aoyama, T. et al., Tetrahedron Lett. 21: 44614462 (1980)). The resulting diazoketone is converted to the 2-halo ketone of general structural formula (42) by treatment with a suitable mineral acid. For example, the bromoketone is prepared by treating diazoketone in a suitable solvent such as acetonitrile (CH 3 CN) with a solution of 30% hydrogen bromide in acetic acid (Organic Synthesis Collective Vol. III, 119, John Wiley &amp; Sons, New York, Ed. Horning EC). In an alternative approach, acid (45) is converted to the mixed anhydride (46) by treating a suitable chloroformate such as isobutyl fluoroformate or tert-butyl chloroformate in a suitable solvent such as tetrahydrofuran or dichloromethane in the presence of a base such as N-methylmorpholine. The mixed anhydride (46) is converted to a diazoketone by treatment with trimethylsilyldiazomethane and converting the obtained diazoketone into a haloketone as described above.

Scheme 2i

If amidination is carried out directly after the amide coupling of Scheme 2e, compounds of formula (I) wherein R or R is aminoacyl or aminoiminomethyl may be prepared. Coupling of acid (13) (or the corresponding acid chloride as described above) with an amine R ^S1 R ⁵² NH yields compound (130) that can be converted to the amidine (131). Using either a longer treatment or treatment under more intense conditions (e.g., at higher temperatures) with the Lewis-Ammonia reagent as described in Scheme 1b, the amide group can be converted to the aminoiminomethyl group to give the bisamidine compound (132).

Scheme 3a

The acid (13) can also be converted to the amine (47) from which sulfonamides, ureas and urethanes can be prepared (Formula I) wherein R ² or R ³ = NR ³² SO ² R ³¹ , NHCONR ⁵¹ R ⁵² or NHCOR ³¹ ) . The methodology for introducing these groups to the R ² position of the compound of formula (I) is shown in Scheme 3. Conversion of acid (13) to intermediate acylazide can be accomplished followed by heating said azide in the presence of alcohol under Curtius rearrangement conditions and carbamate ester formation . Subsequent hydrolysis of the carbamate ester affords the amine (47). The intermediate acylazide can be prepared by coupling acid 13 to hydrazine via acid chloride or any other suitable amide coupling method described for Scheme 2e followed by nitrosation of the obtained hydrazide by any nitrosating agent shown in Scheme 1c for the conversion of compound (3) (R ¹ = NH 2). ) to compound 3 (R ^{1 =} H). Even more preferably, the conversion of compound (13) to compound (47) is accomplished by treating acid (13) with diphenylphosphoryl azide in the presence of an alcohol, preferably tert-butanol, and a base, preferably triethylamine or DIEA as shown in Scheme 3a. decomposes to the amine salt (47) by contact with an acid, preferably HCl or trifluoroacetic acid in a suitable solvent such as CH 2 Cl 2. Further treatment with a base such as NaOH or preferably K 2 CO 3 or NaHCO 3 yields the free base (47). Treatment of the amine (47) with a sulfonyl chloride R ³¹ SO ² Cl in the presence of an acid quencher such as pyridine or DIEA followed by optional alkylation of nitrogen with an alkylating agent R ³² L in the presence of a base such as K ₂ CO 3, DIEA or more preferably sodium hydride in solvent , such as THF, MeCN or CH ₂ Cl ₂ , is introduced at the R ² position by a sulfonylamino group (48). If necessary, the transformation can be carried out using less reactive sulfonyl chlorides in the presence of a catalyst, 4-dimethylaminopyridine. Similarly, treatment of the amine (47) with an isocyanate R ^{5 I} NCO or with carbamyl chloride R ^{5 I} R ' ² COCl introduces the aminocarbonylamino group (50) to the R ² position. Similarly, by treatment of the amine (47) with an acid chloride R ^{3 I} COC1 to the position of R ² is introduced carbonylamino (52). Conversion of the esters (48), (50) and (52) to the amidines as described above gives the products (49), (51) and (53). By further conversion of the acylamino group in compound (53) as described for the synthesis of compound (132), iminomethylamino (54) can be introduced at the R ² position.

Scheme 3b

The introduction of an aminosulfonyl group (including monoalkylaminosulfonyl and dialkylaminosulfone groups) at the R ² position of a compound of formula (I) may also be accomplished using a starting amine such as an amine of formula (47). Conversion to the sulfonyl chloride as described by Gengnagel, et al. (US Patent No. 3,947,512 (1976)) and treatment with an amine R ³⁴ NH ₂ followed by optional alkylation of nitrogen with R ³⁵ L (under the sulfonylation alkylation conditions described for Scheme 3a) affords compound (56) which is obtained as described below. converted to amidines (57).

Scheme 3c

In addition to the preparation methods depicted in Scheme 3a, the amine (47) can also be prepared as shown in Scheme 3c. Nitrothienyl ester (122) (DelI'Erba, C. and Spinelli, D., Tetrahedron, 21: 1061 (1965), Dell'Erba, C. et al., J.Chem.Soc, Perkin Trans 2,1779 (1989) 1) containing a suitable leaving group L can be substituted with an anion R ²¹ to give intermediate (123). The amine (47) is then obtained by reduction of the nitro group. Suitable reagents for effecting nitro reduction include hydrogen gas in the presence of a catalyst such as palladium metal or platinum deposited on carbon or barium sulfate in any of a number of suitable solvents such as methanol, ethanol, ethyl acetate, DMF or THF. Even more preferably, tin (II) chloride may be used as the reducing agent in solvents such as DMF or THF, or in the presence of an HCl solvent such as methanol or ethanol. Alternatively, metals such as zinc or iron can be used (Stanetty, P. and Kremslehner, M., Heterocycles 48: 259 (1998)).

Scheme 4a

Scheme 4a illustrates the preparation of compounds of formula (III) and embodiments of Examples 48-48 and 61-77. The amidine group of compounds of formula (60) can be protected with a P ¹ protecting group which can be readily removed from compounds (62) and (64) by methods known in the art (Theodora W. Greene and Peter GM Wuts, John Wiley and Sons, Inc. 1991). For example, the tert-butoxycarbonyl protecting group (BOC) may be removed by treatment with a strongly acidic agent such as hydrogen chloride in a suitable solvent such as dioxane or trifluoroacetic acid in a suitable solvent such as dichloromethane. Benzyloxycarbonyl (Cbz) groups can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in a solvent such as ethanol or tetrahydrofuran.

In some cases, P ¹ may form a solid support such as polystyrene or polyethylene glycol grafted polystyrene, which may be attached to an amidine group by a cleavable linking group such as 4- (benzyloxy) benzyloxycarbonyl (using Wang carbonate resin). Coupling of the amidine to the solid support can be accomplished by treating the solid support containing the linking group with a suitably activated amidine functional group under suitable conditions. For example, the amidine can be coupled to a Wang resin by treating the para-nitrophenyl carbonate resin with an amidine and a suitable base such as DBU in a suitable solvent such as DMF. When D is OH or SH, protected amidines (61) can be alkylated with carboxy-protected haloaliphatic acids (R ³⁶ protecting group) such as bromoacetic acid or bromopropionic acid in the presence of a suitable base, such as cesium carbonate or DIEA, in a suitable solvent, such as DMF with heating, if necessary, to give compounds of general formula (62). When D is ΝΟ ₂ , the nitro group can be reduced prior to alkylation using a suitable reducing agent such as stannous chloride in a suitable solvent such as DMF, or by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran. Other suitable carboxyl protecting groups are well known in the art (Theodora W. Greene and Peter GM Wuts, Protective

Groups in Organic Chemistry, John Wiley &amp; 1991). For example, the tert-butyl ester can be removed by treatment with a strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane or as trifluoroacetic acid in a suitable solvent such as dichloromethane. The benzyl ester can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran, or by alkaline hydrolysis.

If the protecting groups P * and R ³⁶ in compounds (62) are orthogonal (where said property means the ability to preferentially remove one protecting group over another), the R ³⁶ group can preferably be removed to yield acids (63). For example, when P ¹ is BOC and R ³⁶ is OMe, the methyl ester can be removed by treatment with a base such as sodium hydroxide in a suitable solvent such as aqueous tetrahydrofuran, leaving the BOC group intact. If the protecting groups P ¹ and R ³⁶ in compounds (62) are not orthogonal, both protecting groups are removed, and the amidine group can be protected with a suitable protecting group such as BOC or a resin with a suitable functional group. The protected amidine (63) can be treated with various amines under suitable amide coupling conditions in the presence of agents such as 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1,1, 3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides of general structural formula (64). The amidine protecting group can be removed when BOC is used as a protecting group, for example by treatment with an acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane to give amidines (65).

Scheme 4b

Scheme 4b shows a specific example of the method of Scheme 4a. The amidine group of compound (66) can be mono-protected with a tert-butyloxycarbonyl group. The mono-protected phenoxyamidine (67) can be alkylated to phenolic hydroxy groups with a 2-bromoacetic acid ester to give compound (68). In this case, the ester can be removed by treatment with a base, hydrolysis with an aqueous base such as NaOH to give the acid (69). The obtained acid can be treated with various amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to of amides of general structural formula (70). The amines used are unsubstituted or di- or mono-substituted aliphatic or aromatic amines. In some cases, the amines used are cyclic amines such as piperazine and piperidine. The amides (70) are then treated with trifluoroacetic acid to give amidines (71). When the ester (68) is acid labile, it can be treated with trifluoroacetic acid to form the amidine acid (72). The amidine may then be coupled to an insoluble carrier such as polystyrene or polyethylene glycol grafted polystyrene via a cleavable linker group such as a Wang resin containing functional groups such as an activated carbonate group such as pnitrophenyl carbonate or succinimidyl carbonate. Generally, the process can be carried out by treating the activated carbonate resin with an amidine and a suitable base such as DBU in a suitable solvent such as DMF. The carrier-bound acid (73) is then treated with various amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to give amides. The obtained amides are then cleaved from the solid support by treatment with trifluoroacetic acid to prepare compounds of formula (71).

T

Scheme 5

Scheme 5 illustrates a process for the synthesis of amidines containing disubstituted thiazoles including compounds wherein R ² is a group of formula (II) and both R and R are not hydrogen. Ketoamide (74) can be converted to monobromo ketoamide by treatment with bromine in acetic acid. Thiazoles (76) are prepared by reacting a bromoketoamide with a compound of formula (10) under suitable conditions, preferably by heating the mixture in DMF or acetone. The amidines (77) are prepared by heating compound (76) in toluene with trimethylaluminium and ammonium chloride. The amidines (77) are then treated with a strong acid such as HCl to give acids (78). The amidines (78) are protected according to one method with a suitable protecting group such as BOC to give compounds (79). The protected amidines (79) are treated with various amines under conditions suitable for coupling, such as in the presence of HOAt. HATU and DIEA to form various amides. The amidine protecting group can then be removed, for example, when BOC is used as a protecting group by treatment with trifluoroacetic acid in a suitable solvent such as dichloromethane to give amidines (80). According to a second method, the amidines (78) can be captured on a suitable insoluble carrier such as polystyrene or polyethylene glycol graft polystyrene via a cleavable linking group such as Wang resin containing an activated carbonate ester such as p-nitrophenyl carbonate or succinimidyl carbonate to form compound (81). ) bonded to the resin. The resin (81) bound to the resin can be treated with various amines under conditions suitable for coupling such as in the presence of HOAt, HATU and DIEA to form amides. These amides can then be cleaved from the solid support by treatment with trifluoroacetic acid to give amidines (80).

Scheme 6a

Scheme 6a illustrates the preparation of the compounds of Examples 144, 145, 146, 147, 148, 149, 150 and 151. The compounds of the invention in this case correspond to those of formula (I) wherein R ² is a group of formula (II) and wherein Ar represents thiazole and R ³⁷ and R ³⁸ (R ⁸ and R ⁹ in formula (II)) represent a phenyl group which may be optionally substituted. The process starts from 2,5-dibromothiophene (90), which is treated with lithium diisopropylamide and then with R ²¹ L, wherein L is a leaving group, preferably halogen, mesylate, tosylate or methyl sulfate, more preferably iodomethane or methyl sulfate, according to the method of Kano, et al., Heterocycles 20 (10): 2035 (1983), gives compound (91). Compound (91) can be treated with a suitable base, preferably an alkyllithium such as butyllithium, sec-butyllithium or tert-butyllithium, more preferably butyllithium, followed by carbon dioxide gas and converting the obtained carboxylate salt into the free acid using a mineral acid, preferably an acid acid. Conversion to the ester (21) can be accomplished through the preparation of the acid chloride with oxalyl chloride and treatment of the obtained me67.

O of the intermediate acid chloride with an alcohol R in a suitable solvent, preferably dichloromethane, with a suitable base, preferably pyridine. Compound (21) can then be treated with copper (I) cyanide in dimethylformamide at reflux to give compound (9). Compound (9) can be treated with hydrogen sulfide gas in a suitable solvent, preferably methanol containing a suitable base, preferably triethylamine, to give compound (10). Compound (10) may then be treated with a suitable ketone in which L is a leaving group, preferably halogen, mesyl or tosyl, most preferably bromine, in a suitable solvent at reflux temperature, preferably acetone, dimethylformamide, dimethylacetamide, methyl ethyl ketone, or another an aprotic polar solvent, most preferably in acetone, to obtain compound (92). Compound (92) is then treated with a suitable reagent, preferably an aluminum amide reagent to give amidine (93).

Scheme 6b

Scheme 6b illustrates the preparation of the compound of Example 144, which corresponds to a compound wherein R ² is a group of formula (II) and wherein Ar is thiazole and R ⁸ and R ⁹ (R ³⁷ and R ³⁸ in Scheme 6b) are phenyl, which may be optionally substituted. Using 2,5-dibromothiophene (90) as a starting material and treating it with butyllithium gives an anion that is subject to rearrangement (Kano, S., et al., Heterocycles 20: 2035 (1983)). By introducing gaseous carbon dioxide and converting the obtained carboxylate salt to the free acid with a mineral acid, preferably hydrochloric acid, acid (94) is obtained. Conversion to the ester (95) can be accomplished by preparing the acid chloride using oxalyl chloride and treating the intermediate acid chloride with an alcohol R ²³ -OH in a suitable solvent, preferably dichloromethane with a suitable base, preferably pyridine. Compound (95) can then be treated with cuprous cyanide in dimethylformamide at reflux to give compound (96). Compound (96) can be treated with hydrogen sulfide gas in a suitable solvent, preferably methanol containing a suitable base, preferably triethylamine, to give compound (10). Compound (10) may then be treated with a suitable ketone in which L is a leaving group, preferably halo, mesyl or tosyl, most preferably bromine, in a suitable solvent at reflux temperature, preferably acetone, dimethylformamide, dimethylacetamide, methyl ethyl ketone, or another aprotic polar solvent, most preferably in acetone, to obtain compound (98). Compound (98) is then treated with a suitable reagent, preferably an aluminum amide reagent (A1 (CH 3) 3 / NH ₄ Cl) to give amidine (99).

Scheme 7a

Scheme 7a illustrates the preparation of compounds wherein R ² is a group of formula (II) and Ar is thiazol-4-yl. As shown in the scheme, acids (13) can be converted to their acid chlorides by treatment with oxalyl chloride under catalysis with dimethylformamide in dichloromethane, or using thionyl chloride, either neat or in an organic solvent, at room temperature or at elevated temperature. Then, the obtained compounds are homologated to the desired α-halo ketones (100) by sequential treatment with trimethylsilyldiazomethane and hydrogen bromide. Alternatively, diazomethane (generated from Diazald®, Aldrich Chemical Co., Milwaukee, WI) may be used in place of trimethylsilyldiazomethane. Conversion of compound (13) to compound (100) can also be carried out by a method derived from the synthesis of compound (42) from compound (46).

The alpha-halo ketones (100) are then reacted with a suitable thiourea (Scheme 7b) or a thiamide derivative in an organic solvent, preferably acetone or dimethylformamide at 70 ° C to give 2-aminothiazoles or thiazoles (101).

The thiazoles (101) can then be treated with an aluminum amine reagent (AlCH 3) 3 (NH ₄ Cl) prepared at room temperature by reaction of trimethylaluminium with ammonium chloride in an organic solvent, preferably toluene. The ester obtained can then be converted to the amidines (102) at elevated temperature, preferably above 80 ° C.

Scheme 7b

According to Scheme 7b, the amines (110) (or their hydrochloride salts) can be converted to their corresponding mono-substituted thioureas (methane-1-thions) (112) by treatment with thiophosgene to form the corresponding intermediate isothiocyanates (111). A preferred embodiment involves treating the amine with thiophosgene in a biphasic solvent system consisting of a halogenated solvent such as chloroform and an aqueous phase that is saturated sodium bicarbonate. Alternatively, said reaction can be carried out by treating compound (110) with a hindered amine and a thiophosgene such as triethylamine or diisopropylethylamine in an organic solvent such as tetrahydrofuran or dichloromethane. Another alternative to the preparation of isothiocyanates (111) involves the direct treatment of primary amines and carbon disulphide in pyridine with dicyclohexylcarbodiimide (Jochims, Chem. Ber. 101: 1746 (1968)).

Isothiocyanates (11 L) can be converted to thioureas (112) by treatment with a solution of ammonia in alcohol, preferably 2 M ammonia in methanol or ethanol, at room temperature or at elevated temperatures (> 70 ° C). Alternatively, thioureas (112) can be prepared directly from a suitable urea (or from a thioamide of a suitable amide, wherein R ⁸ is an alkyl or aryl group) by treatment with Lawesson's reagent (Lawesson, S.-O., et al., Bull. Soc. Chim. Belg. 87: 223,293 (1978)).

Scheme 8

Scheme 8 illustrates the preparation of compounds of the invention wherein R ² is a group of formula (II) and Ar is a thiazole group and R ³⁷ and R ³⁸ are a phenyl group which may be further substituted by a sulfonylamino or carbonylamino group. The starting thioamide (10) is treated with a 2-haloacetophenone substituted with a nitro group wherein halogen is chlorine, bromine or iodine, preferably bromine, at reflux in a suitable solvent, preferably a solvent comprising acetone, dimethylformamide, dimethylacetamide, methyl ethyl ketone or other polar aprotic solvents. , most preferably in acetone. Reduction of the nitroaryl compound (113) can be accomplished by a suitable reducing agent, preferably tin (II) chloride, titanium (IV) chloride, ferric chloride, lithium metal, sodium metal, catalytic hydrogenation using a platinum or palladium catalyst, and most preferably 20% aqueous titanium chloride solution. The acylation of aniline (114) can be carried out with a suitable acyl compound R ⁴² L, wherein L is halogen, preferably chlorine, in a suitable solvent, preferably in a base-containing dichloromethane, preferably pyridine, N-methylmorpholine or diisopropylethylamine. Alternatively, the acylation of aniline (114) can be performed with an activated carboxylic acid R ⁴² COL, wherein L is a hydroxy group activated by dicyclohexylcarbodiimide, ethyl-3- (diethylamino) -propylcarbodiimide (EDAC), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) or pentafluorophenyl. The sulfonylation of aniline (114) can be carried out with a suitable sulfonyl chloride derivative R ⁴¹ SO ₂ L in a suitable solvent, preferably in a base containing dichloromethane, preferably N-methylmorpholine, diisopropylethylamine or pyridine, most preferably N-methylmorpholine, with a condensation catalyst, preferably DMAP or DMAP. without him. The amidination of compounds (115) and (117) can be carried out using a suitable reaction medium, preferably an aluminum amide composition (A1 (CH ₃ ) ₃ / NH ₄ Cl).

Scheme 9

Scheme 9 illustrates the preparation of compounds of formula (I) wherein one of R ⁵ and R ^{6 is} not hydrogen. The amidines (5) are converted to amidoximes (119) by heating with hydroxylamine in a suitable solvent such as ethanol. Cyanoamidines (120) are prepared by heating the amidines (5) with cyanamide in a suitable solvent such as ethanol (Huffman KR and Schaeffer F., J. Americ.Chem.Soc.28: 1812 (1963). Alternatively, compound (5) with an amine such as methylamine to obtain N-alkylated amidines (121).

Scheme 10

Scheme 10 illustrates an approach for preparing compounds of formula (I) wherein X = S or O, R ² = arylamino, R ³ = alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy, aryloxy, alkylamino, dialkylamino, aralkylamino, diaralkylamino, arylamino or diarylamino, Y = a bond and Z = NR ⁵ R ⁶ .

Aminothiophenol (47) (Formula (I) wherein X = S or O, R ² = NH 2) can be reacted with an aryl boronic acid (R ⁵⁶ B (OR ^S8) 2, R ⁵⁸ = H) or an ester of an aryl boronic acid ( R ^56B (OR ⁵⁸ ) 2, R ⁵⁸ = alkyl), in the presence of a copper-based catalyst, preferably in the presence of copper (II) acetate, and an amine base such as triethylamine or pyridine (Khan, DMT et al., Tetrahedron Lett. 39): 2933 (1998)) to give thienylarylamine (124). The conversion of the ester to the amidine (125) is carried out as described above for Scheme 1b.

Scheme 1 1

Another method for preparing compounds of the invention wherein R ² = arylamino or alkylarylamino and alkylamino and wherein R ³ , Y and Z are as defined for Scheme 10 is depicted in Scheme 11, according to which intermediate (2) (R ²ⁱ = R ³ , L = leaving group) is aminated by methods known in the art. (See, e.g., Ahman, J. and Buchwald, SL, Tetrahedron Lett. 38: 6363 (1997) and Wolfe, JP and Buchwald, SL, Tetrahedron Lett. 38: 6359 (1997). For review, see Frost, C. G and Mendonca, P., J. Chem. Soc., Perkin Trans 1: 2615 (1998) and Wolfe, JP et al., Acc. Chem. Res. 31: 805 (1998)). Compound (2) can be treated with aniline R ⁵⁶ R ⁵⁷ NH (R ⁵⁶ = aryl, R ⁵⁷ = H or alkyl) in the presence of a palladium catalyst, preferably a palladium ligand and a base, to form compound (127). Suitable catalysts include a plurality of Pd (0) or Pd (II) salts such as tetrakis (triphenylphosphino) palladium (0), dichlorobis (acetonitrile) palladium (II) or preferably palladium (II) acetate or tris (dibenzylideneacetone) dipalladium. The most suitable ligands for each individual reaction are often dependent on the type of compound and are described in detail in the above cited papers, but may include 1,1'-bis (diphenylphosphino) ferrocene (DPPF), 1- [2- (diphenylphosphino) ferrocenyl] ethyl methyl ether (PPF) -OMe), or preferably 2,2'-bis (diphenylphosphino)

1,1'-binaphthyl (BINAP). Suitable bases include sodium tert-butoxide or preferably cesium carbonate or potassium phosphate. Suitable solvents include DMF, dioxane, dimethoxyethane or preferably toluene. The conversion of the ester to the amidine (128) is carried out as described in Scheme 1b above.

Scheme 12

The corresponding compounds of formula (I) in which R ² = alkylamino and R ³ , Y and Z are as described in Scheme 10 are prepared as shown in Scheme 12 in a manner that is initiated by reductive alkylation of amine (47) with aldehyde R ⁵⁹ CHO or ketone R ⁵⁹ COR ⁶⁰ in the presence of any of a number of reducing agents including sodium borohydride, sodium cyanoborohydride or, more preferably, sodium or tetralalkylammonium salt of sodium triacetoxyborohydride to prepare compound (129). Suitable solvents depend on the reducing agent used and include an alcohol such as methanol, ethanol or isopropanol, or a solvent such as THF or dichloromethane. The conversion of the ester to the amidine (130) is again carried out as described above for Scheme 1b.

Scheme 13

The scheme depicts an approach for the preparation of compounds of formula (I) wherein R ² is 2-thiazolylamino and R ³ , Y and Z are as described in Scheme 10. In this way, the amine (47) is first converted to thiourea (131) by one of several methods described in Scheme 7b. Further reaction of thiourea with a ketone containing a leaving group R ³⁷ COCH (L) R ³⁸ , preferably a 2-halo ketone as described in Schemes 2f, 2g or 2h affords thiazolylaminothiophenes (132), which are then converted to the corresponding amidines (133) by the methods described above for Scheme 1b.

Scheme la

X = O, S

W = CN, COOH, CONH ₂ , CO ₂ R ^m L = Br

Scheme lb

Z = H, alkyl

Z * NR‘R * Z «KR * R‘

W-COOH (COCI) is put, R ^and OH / (Pt / CH3NjZ R &quot; M &quot;) 7 / W, CH, CONH, CO, R ^and

Al (CH, CHCl 3) toluene (III) CN

W "CN \ HCWR" OH

R * alkyl, aryl, aralkyl X AJ (CHjh / R‘R * NH \ Toluan I & \

Al (CH, h

KK ₄ CI - for Toluane. '&

R * «R ^s « · H

ABOUT

R

Scheme lc

CS, * R ^for CH3 ^and * RH. ♦ WCMjL r “-CH, COjR“, CONH, R “CH. CO, R ^and W * CN, CO, R ^and . CONH, L * CI. Br, 1.01 *. QMS. OH

WCHjSH

138

R ¹² «Ch xs

R ¹ '· = SR *

R '= OH, NH,

W «CH. CONH "CO, R"

Scheme Id diazotization.

R 'HH,

R ^a

X-S R 'H

R ² '= H x = o, SLS Br

L = Br WsCN, COOH

CONH _2i CO _from R ²³

Scheme 2a

R ²¹

Scheme 2b

COOH

COOH (COCl), alkyl COCHjNHj possible ation of a base / ^R! l

M (COCI)

2) R ^F CH (R ⁿ⁾ ₂ HH

COOH

AlfCHih / NK · Cl Toluene

L = Ci. Br, I, OM. * OT.

or 1.awcsson's reagent

Scheme 2c

CHjN. R «/ (R ⁿ «Me) f-Br or (COCl), R ° OH ^ rtOiTíz X *> 0. S W «COOH □ ²¹

L, Cl, Br, I. OTI

NH, / HH * Cl

1) MNj

2) Hi / Pd (CU)

HCl

R "COKHM

Scheme 2d

R ² 'Br 1. bax.D * R ²¹ , Sn (R ') _a w (Ch ₅ ) ₃ SnCl Q 2. ICHjhSiCHH, T or, 1 1 w R ⁿ Ubai J. ₍ ^^ ^x, OR ^and W = COOH X = S, 0 22 (R '= Ma) 2

R l 1, (n = 1-2)

PdtPPhjk

DMF, 120'C

L = Br, I, OTf

R ⁴¹ = aryl, heteroaryl, allyl, vinyl

when n = 2 R ⁴⁴ = aryl, hetero-aryl

RfBOHOH Pd (PPh ₃ ) * DMF, 90 ° CK ₂ CO 3

hl

Scheme 2e

Scheme 2f

HtS / MaOH triethylamine i

Scheme 2g

R “✓

L = halogen

Scheme 2h

R ³⁷ COOH ---------- - R ³⁷ COL

45 ⁴⁶ L = Cl, Br r ³⁸ = h L = Cl, Br, OCOR ³⁹ (R ³⁹ = iBu, tBu) L = Cl, Br

Scheme 2i

x «h. about. with

Scheme 3a

HH

Scheme 3b

HCI / HaKOj / CuSOJHaHSOj 47 —--------- * ·

1) r ^u nh ₂

2) R1 ^, Ubaia (optlonal)

AUCH 3 / NH 4 Cl Toluone </ A

Scheme 3c

x = o, p

L = CI, Br, I, OTs, OMs

Scheme 4a

D «OH. SH. NOi

X S. O M

P ¹ and R ^1.1 remove the protecting (P ') group

HOAT κ

MATU HM OUF V

H

hl

Scheme 4b

BrCHjCOR ¹⁴ CilCO

DMF, 70’C

R ^ -OBu ^1.0 , OMe

. 68

When R ^at OMe

NaOH, THF

When R ^m OBu * 50% TFA / DCM 2% H, O

OBU, DMF

Scheme 5

Scheme 6a

1) LOA, -78 ”C. __________ (j) R ²¹ -t _______________ L = Ct, Br, 1, OWx. OT1, OSO ₂ OM ·

1) baa »-78 ° C _________

2) R ²¹ -L.

L = Cl, Br, I. OM *. OTi, OSOjOMe

W-COOH L-Br

W »COOH L-Br

Scheme 6b

1) Butyllithium, ΤΒ'Ό.

2) corfg)

3) 6N HCl (aq>

1) (COCI) j. CH 3 Cl 2, DMF

2) ^The R-OH. pyridine

CuCN, DMF. reflux

O-Ra

O — R ₂₂

R ^m - Me. IPr

HjS.TEA, MeOH ₂ h no-r _2J

Al (CH 3) NH 4 Cl toluene, reflux

Scheme 7a

acetone or DMF 70 ° C

Scheme 7b liofbsgen _of CHCIy suck d. NaHCO with II c with NH 3 -solvent II H H ₂ NR --- 111 112

110

Scheme 8

Scheme 9

Scheme 10

o 47 x = o, p

R ¹⁷ = H,

R ⁵⁷ ·· H

Scheme 11

L «Cl, Br, I, OSOjCF,

Scheme 12

Scheme 13

AKCHjJj / _NH ^ CI Toluene / δ **

ΗΛ

NH 133

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine

Trimethylaluminium (2.0 M in toluene, 2 mL) was added dropwise over 10 min to a suspension of ammonium chloride (216 mg) in toluene (2 mL), and the reaction mixture was stirred at 0 ° C under N 2. Immediately after reducing the evolution of gas, the mixture was stirred at 25 ° C for 30 minutes and after dissolution of most of the solid, methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - was added in one portion. 5-methylthiothiophene-2-carboxylate (100 mg, Maybridge Chemical Co., Cornwall, UK). This solution was gradually heated to reflux for 1 hour. After heating at reflux for 2.5 h, the reaction mixture was allowed to cool to 25 ° C and poured into a vigorously stirred slurry of silica gel (2 g) in CHCl 3 (20 mL). After 20 minutes, the solids were collected by suction filtration and washed with MeOH (3 x 10 mL). The combined filtrates were evaporated to dryness and the residual yellow solid was subjected to thin layer chromatography to give ΊΊ mg of 4 - [(4-chlorophenyl) (thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine as yellow solid matter. 1 H NMR (DMSO-d ₆ ; 300 MHz) δ 2.80 (s, 3H), 7.55-7.59 (m, 1H), 8.04-8.13 (m, 1H), 8, 31 (s, 1H); 8.69 (s, 1H); 9.2 (br s, 4H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C15H12ClN3S3 365.9 (M + H), found 366.9.

Example 2

5-methylthiothiophene-2-carboxamidine

5- (Methylthio) thiophene-2-carbonitrile (100 mg, Maybridge Chemical Company, Cornwall, UK) was charged to a 2 mL drachm (7.4 mL) dry vial. To this was added a saturated solution of HCl in anhydrous MeOH (4 mL). The vial was then sealed and the mixture was stirred for 24 hours. Then, the vial is cooled in an ice bath, opened and N ₂ is bubbled to remove dissolved HCl.

The solvent is then removed under reduced pressure, and the residue is dried under high vacuum for 24 hours. Methanolic ammonia solution (2 M NH 3 in MeOH) was then added to the vial and the mixture was stirred for 3 days. The methanol is then removed in vacuo and 5-methylthiothiophene-2-carboxamidine is obtained as a yellow solid from the residue obtained by preparative thin layer chromatography. 1 H-NMR (DMSO-d ₆ : 300 MHz) δ 2.64 (s, 3H), 7.22 (d, J = 3.8 Hz), 7.95 (br d, J = 3.33 Hz) 1 H, 9.4 (br s, 4H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C ₆ H ₈ N ₂ S ₂ , 172.3 (M + H), found 173.0.

Example 3

5-Methylthio-4-phenyl-thiophen-2-carboxamidine

Methyl 5-methylthio-4-phenylthiophene-2-carboxylate (100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in a manner similar to Example 1 to give 50 mg of 4-phenyl-5-methylthiothiophene-2-carboxamidine in the form of an off-white solid. 1 H-NMR (DMSO-d 6; 300 MHz) δ 2.65 (s, 3H), 7.39-7.60 (m, 5H), 8.27 (s, 1H), 9.2 (br s , 4H). Mass spectrum (MALDI-TOF, m / z): calcd for C ₂ H | ₂ N ₂ S ₂ 248.4 (M + H), found 249.0.

Example 4

4- [4- (2,4-Dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine

Methyl 4- [4- (2,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in a similar manner by the method described in Example 1 to give 60 mg of 4- (4- (2,4-dichlorophenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine as a yellow solid. 1 H-NMR (DMSO-d ₆ ; 300 MHz) δ 2.77 (s, 3H), 7.6 (dd, J = 2.2 and 8.5 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 8 09 (d, J = 8.5 Hz, 1H), 8.3 (s, 1H), 8.6 (s, 1H) Mass spectrum (MALDI-TOF, m / z): Calcd. 400.0 (M + H), found 400.1.

Example 5

4- (4-Methyl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine

Methyl 4- (4-methyl- (1,3-thiazol-2-yl)) - 5-methyl-thiothiophene-2-carboxylate (100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in a similar manner of Example 1 to give 40 mg of 4- (4-methylthiazol-2-yl) -5-methylthiothiophene-2-carboxamidine as a yellow solid. 1 H-NMR (DMSO-d ₆ ; 300 MHz) δ 2.43 (s, 3H), 2.7 (s, 3H), 7.38 (s, 1H), 8.28 (s, III). Mass spectrum (MALDI-TOF, m / z): Calcd. For C ₁₀ H ₁₁ N ₃ S ₃ 270.0 (M + H), found 270.1.

Example 6

a) methyl 5-methylthio-4- (4- (2-naphthyl) (1,3-thiazol-2-yl) thiophene-2-carboxylate)

Methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (40 mg, Maybridge Chemical Company, Cornwall, UK) was treated with 2-bromo-2'-acetonaphthone (1.1 eq.) In a manner similar to the one described in Example 13, step (a) to give 40 mg of methyl 5-methylthio-4- (4- (2-naphthyl) (1,3-thiazol-2-yl)) thiophene-2-carboxylate. 1 H-NMR (CDCl ₃ / CD ₃ OD; 300 MHz) δ 3.71 (s, 3H), 3.94 (s, 3H), 7.47-7.55 (m, 2H), 7.67 (s, 1H), 7.84-7.99 (m, 3H), 8.08 (dd, J = 1.75 Hz and 8.6 Hz, 1H), 8.3 (s, 1H), 8 1.5 (s, 1H).

b) 5-Methylthio-4- (4- (2-naphthyl) (1,3-thiazol-2-yl)) thiophene-2-carboxamidine

Methyl 5-methylthio-4- (4- (2-naphthyl) (1,3-thiazol-2-yl)) - thiophene-2-carboxylate (40 mg) prepared as described above was treated as described in Example 1 to give 30 mg of 4- [4- (naphth-2-yl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine. 1 H-NMR (DMSO-d ₆ ; 300 MHz) δ 2.83 (s, 3H), 7.52-7.69 (m, 2H), 7.95-8.01 (m, 2H). 8.05 (d, J = 8.6 Hz, 1H), 8.24 (dd, J = 1.69 Hz and 8.6 Hz, 1H),

8.4 (s, 1H), 8.65 (s, 1H), 8.74 (s, 1H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. For C19H15N3S3 382.1 (M + H), found 382.0.

Example 7

5-methylthio-4- [4- (4-phenylphenyl) (l, 3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

a) 5-methylthio-4- [4- (4-phenylphenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate mg (0.109 mmol) methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2 -carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL acetone for synthesis. 4'-Phenyl-2-bromoacetophenone (33 mg, 0.120 mmol; Aldrich Chemical Co., Milwaukee, WI) was then added and the solution was heated at reflux for 2.5 h. The solution was allowed to cool, the solid was filtered off and washed with methanol and dried in vacuo to give 30 mg (65% yield) of methyl 5-methylthio-4- [4- (4-phenylphenyl) (1,3-thiazole-2-). yl)] thiophene-2-carboxylate. 1 H-NMR (DMSO-d ₆ ; 300 MHz) δ 8.28 (s, 1H), 8.24 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7, Δ (d, J = 8.5 Hz, 2H), 7.74-7.77 (m, 2H), 7.48-7.53 (m, 2H), 7.40 (m, 1H), 2 78 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C22H16NO2S3, 423.0 (M + H), found 424.4.

b) 5-methylthio-4-4- (4-phenylphenyl) (1,3-thiazol-2-yl) -thiophene-2-carboxamidine hydrochloride

To a stirred suspension of 0.473 mmol (25 mg) of ammonium chloride (Fisher Scientific Pittsburgh, PA) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 237 μΐ (0.473 mmol) of syringe over 10 minutes at 0 ° C. M trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 0 ° C for 30 minutes, and then 20 mg (0.0473 mmol) of methyl-5-methyl-10-4- [4- (4-phenyl-phenyl) 1] (1,3-thiazol-2-yl)] thiophene-2-carboxylate and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture is then poured into a slurry of 500 mg of silica in 10 ml of chloroform. The silica was then poured into a fritted funnel and washed with 10% methanol / CH 2 Cl 2 solution and concentrated. The crude product was purified on a 1 mm silica plate for preparation using 10% methanol / CH 2 Cl 2 as eluent to give 10 mg (53% yield) of 5-methylthio-4- [4- (4-phenylphenyl) (1 H-NMR). 3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride. Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C21H17N3S3, 408.1 (M + H), found 408.0.

Examples 8 and 9

4- [4- (3-methoxyphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride and 4- [4- (3-hydroxyphenyl)] (1) (3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate mg (0.133 mmol) methyl 4- (aminothioxomethyl) -5-methylthiothiophene The 2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL of acetone for synthesis. 3'-Methoxy-2-bromoacetophenone (0.155 mmol, 36 mg, Aldrich Chemical Co.) was then added and the solution was heated at reflux for 2.5 h. The solution was allowed to cool, the solid was filtered off, washed with methanol and dried in vacuo. Purification of the solid on a 1 mm thick silica plate using 25% ethyl acetate / hexane afforded 31 mg (63% yield) of methyl 4- [4- (3-methoxyphenyl) - (1,3-thiazol-2-yl). 5-Methylthiothiophene-2-carboxylate.

b) 4-4- (3-Methoxyphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride and 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2) yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of 0.821 mmol (44 mg) of ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under a nitrogen atmosphere97 was added 411 μΐ (0.821 mmol) of 2 M trimethylaluminium via syringe over 10 minutes. in toluene (Aldrich Chemical Co.), stirred at 0 ° C for 30 min, and then 31 mg (0.0821 mmol) of methyl 4- [4- (3-methoxyphenyl) (1,3-thiazole- 2-yl) -5-methylthiothiophene-2-carboxylate and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture is then poured into a slurry of 500 mg of silica in 10 ml of chloroform. The silica was then poured into a fritted funnel and washed with 10% methanol / CH 2 Cl 2 and concentrated. The crude product was purified on a 1 mm silica plate for preparation using 10% methanol / Cl 2 Cl as eluent to give 4.2 mg (15% yield) of 4- [4- (3-methoxyphenyl) (1 H-NMR). , 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride and 4.2 mg (15% yield) of 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] 5-methylthiothiophene-2-carboxamidine hydrochloride. 4- [4- (3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride:

1 H-NMR (CD ₃ OD, 300 MHz) δ 8.5 (s, 1H), 7.9 (s, 1H), 7.59-7.65 (m, 2H), 7.33-7, 38 (m, 1H), 6.91-6.95 (m, 1H), 3.87 (s, 1H), 2.8 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H15N3OS3, 361.5 (M + H), found 362.2.

4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride: 1 H-NMR (CD 3 OD, 300 MHz) δ 8.50 (s, 1H), 7.81 (s, 1H), 7.26-7.51 (m, 2H), 7.24 (m, 1H), 6.79 (m, 1H), 2.8 (s, 3H) ). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C15H13N3OS3, 347.5 (M + H), found 348.0.

Example 10

5-Methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine hydrochloride

a) methyl 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) - thiophene-2-carboxylate mg (0.133 mmol) methyl 4- (aminothioxomethyl) -5-methylthiothiophene- 2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL acetone for synthesis. 2-Bromoacetophenone (0.133 mmol, 27 mg, Aldrich Chemical Co.) was then added and the solution was heated at reflux for 2.5 h. The solution was allowed to cool, the solid was filtered off, washed with methanol and dried in vacuo. Purification of the solid on a 1 mm thick silica plate using 25% ethyl acetate / hexane 46 mg (90% yield) mmol) methyl 5-methylthio-4- (4-phenyl- (1,3-thiazol-2)) yl)) - thiophene-2-carboxylate.

b) 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) - thiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.32 mmol (71 mg) of ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under a nitrogen atmosphere was added 2M 662 μΐ (0.821 mmol) of syringe over 10 minutes at 0 ° C. trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 0 ° C for 30 min, and then 46 mg (0.133 mmol) of methyl 5-methylthio-4- (4-phenyl) - (1,3-thiazole) was added to the solution. -2-yl)] thiophene-2-carboxylate and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture is then poured into a slurry of 500 mg of silica in 10 ml of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% MeOH / CH ₂ Cl ₂ and concentrated. The crude product was loaded onto a 2 g silica SPE column using 10% methanol / CH 2 Cl 2 as eluent to give 32.5 mg (75% yield) of 5-methylthio-4- (4-phenyl- (1,3-) - thiazol-2-yl)) thiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ ; 300 MHz) δ 8.70 (s, 1H), 8.25 (s, 1H), 8.07-8.11 (m, 2H), 7.37-7 53 (m, 3H); 2.8 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C15H13N3S3, 331.5 (M + H), found 332.1.

Example 11

5-Methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

a) methyl 5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate mg (0.141 mmol) methyl 4- (aminothioxomethyl) - 5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL of reagent grade acetone. 2-Bromo-4'-nitroacetophenone (0.155 mmol, 38 mg, Aldrich Chemical Co.) was then added and the solution was heated at reflux for 2.5 h. The solution was allowed to cool, the solids were filtered off and washed with methanol and dried in vacuo. Then, the crude product was dissolved in CH 2 Cl 2 and 0.141 mmol of N- (2-mercapto) aminoethyl polystyrene resin (Calbiochem, San Diego, CA; 1.28 mmol / g; 110 mg) was added and stirred overnight. The solution was then filtered, concentrated and dried to give 60 mg (90% yield) of crude methyl-5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene-2. carboxylate.

b) 5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.66 mmol (90 mg) of ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 830 μ1 (1.66 mmol) via syringe over 10 minutes at 0 ° C. 2M trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 0 ° C for 30 minutes, and then 5-methylthio-4- [4- (4-nitrophenyl) (1,3-dimethyl-thio-4- [4- (4-nitrophenyl)] was added to the solution. -thiazol-2-yl)] thiophene-2-carboxylate and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture is then poured into a slurry of 500 mg of silica in 10 ml of chloroform. The silica was then poured into a fritted funnel and washed with 10% methanol / CFHCl and concentrated. The crude product was purified on a 1 mm silica plate for preparation using 10% methanol / CH 2 Cl 2 as eluent to give 12 mg (19% yield) of 5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride. 1 H-NMR (CD 3 OD, 300 MHz) δ 8.58 (s, 1H), 8.32-8.33 (m, 4H), 8.24 (s, 1H), 2.83 (s, 3H) . Mass speck

100 µm (MALDI-TOF, CHCA matrix m / z): calcd. For C 15 H 12 N 4 O 2 S 3, 376.5 (M + H), found 377.3.

Example 12

4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl-4- (4- (2H, 3H-benzo [3,4-e] -1,4-dioxin-6-yl) - (1,3-thiazol-2-yl)) - 5-methylthiothiophene 2-carboxylate mg (0.162 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL of reagent grade acetone. 1- (2H, 3H-Benzo [e] -1,4-dioxin-6-yl) -2-bromo-methan-1-one (0.162 mmol, 42 mg, Maybridge Chemical Co. LTD., Cornwall, UK) was then added. ) and the solution was heated at reflux for 3 hours. The solution was then allowed to cool and stirred for 2 days after which time the reaction solution was concentrated in vacuo. The crude product was dissolved in 50 mL of CH 2 Cl 2 and partitioned between 50 mL of 1 N NaOH (aq). The obtained organic layer was dried over sodium sulfate and concentrated in vacuo to give 60 mg (90% yield) of methyl 4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxylate.

b) 4- (4- (3,4-ethylenedioxyphenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.62 mmol (86 mg) of ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 810 μΐ (1.62 mmol) via syringe over 10 minutes at 0 ° C. 2 M trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 0 ° C for 30 min and then 60 mg (0.162 mmol) of 4- (4- (3,4-ethylenedioxyphenyl) thiazol-2-yl) was added to the solution. Of 5-methylthiothiophene-2-carboxylate and the reaction mixture is heated at reflux for 2.5 h, then the reaction mixture is poured into a slurry of 500 mg of silica in 10 ml of chloroform.

101 into a fritted funnel and washed with 10% methanol / CH 2 Cl 2 and concentrated. The crude product was purified on a 1 mm silica plate for preparation using 10% methanol / CH 2 Cl 2 as eluent to give 47 mg (75% yield) of 4- [4- (3,4-ethylenedioxyphenyl) thiazole-2]. -yl] thiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (CD 3 OD, 300 MHz) δ 8.53 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 2 Hz, 1H), 7.50 (dd, J) = 2.1 Hz and 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 2.8 (s, 3H). Mass spectrum (MALDITOF, CHCA matrix, m / z): Calcd. For C17H15N3O2S3, 389.5 (M + H), found

390.1.

Example 13

4- [4- (4-methoxyphenyl) (1S-thiazol-4-yl) -1H-methylthiothiophene-6-carboxamidine hydrochloride

a) methyl 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate mg (0.122 mmol) methyl 4- (aminothioxomethyl) -5 methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 1.2 mL of reagent grade acetone. 2-Bromo-4'-methoxyacetophenone (0.146 mmol, 28 mg, Aldrich Chemical Co.) was then added and the solution was heated to reflux for 3 hours. The solution was allowed to cool, the solids were filtered off, washed with methanol and dried in vacuo to give 46 mg (90% yield) of methyl 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl) ] -5-methylthiothiophene-2-carboxylate.

b) 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.22 mmol (66 mg) of ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 612 μΐ (1.22 mmol) by syringe over 10 minutes at 0 ° C. 2 M trimethylaluminium in toluene (Aldrich Chemical Co.), stirred for 30 minutes at room temperature

102 ° C and then 46 mg (0.122 mmol) of 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate was added to the solution and the reaction was heated 2.5 h at reflux temperature. The reaction mixture is then poured into a slurry of 500 mg of silica in 10 ml of chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with a 10% methanol / CH 2 Cl 2 solution and concentrated. The crude product was purified on a 1 mm silica plate for preparation using a 10% methanol / CP 2 Cl solution as eluent to give 32 mg (73% yield) of 4- [4- (4-methoxyphenyl) (1, 2). 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (CD ₃ OD, 300 MHz) δ 8.53 (s, 1H), 7.98 (d, J = 7Hz, 2H), 7.75 (s, 1H), 7.01 (d, J = 5Hz, 2H), 3.9 (s, 3H), 2.8 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H15N3OS3, 362.0 (M + H), found

362.2.

Example 14

4- [4- (3,4-Propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (3,4-propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxylate mg (0.170 mmol) methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 5 mL of reagent grade acetone. Then 3 ', 4'-propylenedioxy-2-bromoacetophenone (0.170 mmol, 28 mg, Aldrich Chemical Co.) was added and the solution was heated to reflux for 3 hours. After the solution was allowed to cool, the solids were filtered off and purified on a 1 mm thick silica plate using 20% ethyl acetate / hexane as eluent and dried in vacuo to give 42 mg (59% yield) of methyl-4. - [4- (3,4-propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxylate.

103

b) 4- (4- (3,4-propylenedioxylphenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.01 mmol (54 mg) of ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 510 μΐ (1.22 mmol) via syringe over 10 minutes at 0 ° C. 2 M trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 0 ° C for 30 min, and then methyl-4- [4- (3,4-propylenedioxyphenyl) thiazole-2- (42 mg, 0.101 mmol) was added to the solution. yl) -5-methylthiothiophene-2-carboxylate and the reaction mixture was heated at reflux for 3 h. The reaction mixture is then poured into a slurry of 500 mg of silica in 20 ml of chloroform. The silica was then poured into a glass frit funnel and washed with 10% methanol / CH 2 Cl 2 solution and concentrated to give 20 mg (50% yield) of 4- (4- (3,4-propylenedioxyphenyl) thiazol-2-yl) -5 -methylthiothiophene-2-carboxamidine hydrochloride 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.53 (s, 1H), 7.78 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 2.2 Hz and 8.4 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 4.19-4.28 ( m, 4H), 2.77 (s, 3H), 2.18-2.23 (m, 2H) Mass spectrum (MALDI-TOF, CHCA matrix, m / z): calcd for C18H17N3O2S3, 404.1 ( M + H), found 404.1.

Example 15

5-Methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl)) thiophene-2-carboxamidine acetate

a) 2-bromo-1- (2-thienyl) ethan-1-one

To a solution of 500 mg (3.96 mmol) of 2-acetylthiophene (Aldrich Chemical Co.) in 20 mL of CHCl 3 was added 1 drop of 30% HBr / CH 3 COOH (Aldrich Chemical Co.) and then dropwise over 30 minutes 3.96 mmol ( 633 mg, 204 μΐ) of bromine (Aldrich Chemical Co.). The reaction mixture was then stirred for 1 hour. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on a 1 mm silica preparative plate using pure CH 2 Cl 2 as eluent to give 300 mg (37% yield) of 2-bromo-1- (2-thiophenol).

104 nyl) ethan-1-one. 1 H NMR (CDCl 3, 300 MHz) δ 7.80 (m, 2H), 7.18 (m, 1H), 4.37 (s, 2H).

b) methyl 5-methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl)) thiophene-2-carboxylate mg (0.176 mmol) methyl 4- (aminothioxomethyl) -5-methylthiothiophene The 2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 3 mL of reagent grade acetone. 2-Bromo-1- (2-thienyl) ethan-1-one (0.176 mmol, 36 mg) was then added and the solution was heated to reflux for 3 hours. The solution is then allowed to cool and concentrated. The crude product was dissolved in 20 mL of 1 N HCl (aq.). The organic layer was dried over sodium sulfate to give 115 mg (80% yield) of crude methyl-5-methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl)) - thiophen-2 carboxylate.

105

c) 5-methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl) thiophene-2-carboxamidine acetate)

To a stirred suspension of 2.80 mmol (150 mg) of ammonium chloride (Fisher Scientific) in 5 mL of anhydrous toluene (Aldrich Chemical Co.) under a nitrogen atmosphere was added syringe for 2 minutes at 0 ° C with trimethylaluminum 2 M in toluene ( Aldrich Chemical Co.), stirred at 0 ° C for 25 min and then 115 mg (0.280 mmol) of methyl 5-methylthio-4- (4-2-thienyl) (1,3-thiazole-2-) was added to the solution. yl)] thiophene-2-carboxylate in anhydrous toluene and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture was then poured into a slurry of silica in CH 2 Cl 2. Then the silica was poured into a funnel equipped with a glass frit and washed with a 10% methanol / CH 2 Cl 2 solution and concentrated. The crude product was purified on a 1 mm silica plate for preparation using 10% methanol / CH ₂ Cl _{2 solution} with 1% CH 3 COOH as eluent to give 42 mg (43% yield) of 5-methylthio-4- (4). - (2-thienyl) (1,3-thiazol-2-yl) thiophene-2-carboxamidine acetate 1 H NMR (CD 3 OD, 300 MHz) δ 8.52 (s, 1H), 7.74 (s, 1H) 7.59 (dd, J = 2 Hz and 5 Hz, 1H), 7.42 (dd, J = 2 Hz and 5 Hz, 1H), 7.11 (m, 1H), 2.79 (s, Mass spectrum (MALDI-TOF, CHCA matrix m / z): Calcd. For C 13 H 11 N ₃ S ₄ , 338.0 (M + H), found 337.9.

Example 16

4- [4- (3-bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (3-bromophenyl) (1,3-thiazol-2-yl)] -5-methylthiothiophene-2-carboxylate mg (0.400 mmol) methyl 4- (aminothioxomethyl) -5-methylthiothiophene The 2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 25 mL of reagent grade acetone. 2-Bromo-3'-bromoacetophenone (0.4 mmol, 111 mg) was then added and the solution was heated to reflux for 3 hours. After the solution was allowed to cool, the solids were filtered off and dissolved in 5 ml of hot tetrahydrofuran (THF) (Aldrich Chemical Co.) and purified on a 1 mm silica preparative plate using 20% ethylation.

106 m.p./hexane and drying in vacuo gave 66 mg (40% yield) of methyl 4- [4- (3-bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (3-bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.55 mmol (83 mg) of ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 774 μΐ (1.55 mmol) via syringe over 10 minutes at 0 ° C. solution of 2 mol / L trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 25 ° C for 20 min, and then 66 mg (0.155 mmol) of 4- (4- (3-bromophenyl) (1,3-thiazole-) was added. 2-yl) -5-methylthiothiophene-2-carboxylate and the reaction mixture is heated at reflux for 3 h, then poured into a slurry of 5 g of silica in 25 ml of chloroform, then poured into a funnel equipped with glass. The crude product was purified on a 1 mm silica plate using 10% methanol / CFbCl as eluent to give 63 mg (90% yield) of 4- [4-]. 4- (3-bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 300 MHz) δ 8.49 (s, 1H), 8.21 (m, 1H), 7.96 (m, 2H), 7.50 (m, 1H), 7.5 (m, 1H), 7 34 (m, 1H); 2.8 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix m / z): Calcd. For C 18 H 11 BrNaSa, 411.9 (M + H), found 411.9.

Example 17

4- [4- (4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

(a) Methyl 4- [4- (4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate:

mg (0.202 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD .. Cornwall, U.K.) was dissolved in 10 ml.

107 acetone reagent grade. 2-Bromo-4'-chloro-3'-nitroacetophenone (0.212 mmol, 59 mg) was then added and the solution was heated to reflux for 3 hours. The solution was allowed to cool, the solid was filtered off, dissolved in hot (THF) and purified on a 1 mm silica pad with 20% ethyl acetate / hexane as eluent and dried in vacuo to give 60 mg (70% yield). methyl 4- [4- (4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothifene-2-carboxamidine hydrochloride

To a stirred suspension of 1.40 mmol (75 mg) of ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 700 μΐ (1.40 mmol) via syringe over 10 minutes at 0 ° C. of a 2 mol / L solution of trimethylaluminium in toluene (Aldrich Chemical Co.), stirred for 20 minutes, and then 60 mg (0.140 mmol) of 4- [4- (4-chloro-3-nitrophenyl) (1,3- thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate and the reaction mixture was heated at reflux for 3 h. The reaction mixture is then poured into a slurry of 5 g of silica in 50 ml of chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with a 10% methanol / CH 2 Cl 2 solution and concentrated. The crude product was purified on a 1 mm silica pad using 10% methanol / CH 2 Cl 2 as eluent to give 17 mg (32% yield) of 4- [4- (4-chloro-3-bromophenyl) ( l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (CD 3 OD, 300 MHz) δ 8.538.58 (m, 2H), 8.26 (dd, J = 2.2 Hz and 8.5 Hz, 1H), 8.16 (s, 1H), 7 72 (d, J = 8.5 Hz, 1H); 2.80 (s, 3H).

108

Example 18

4- [4- (4-chloro-3-methylphenyl) (1,3-thiazol-2-yl) -5-methylthithiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (4-chloro-3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

155 mg (0.627 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate (Maybridge Chemical Co. LTD, Cornwall, U.K.) was dissolved in 10 ml of reagent grade acetone. 2-Bromo-1- (4-chloro-3-methylphenyl) ethan-1-one (0.658 mmol, 163 mg) was then added and the solution was heated to reflux for 3 hours. The solution was allowed to cool, the reaction mixture was concentrated and dissolved in 50 mL of CH 2 Cl 2. The organic layer was then washed with 50 mL of 1M HCl (aq), dried over sodium sulfate, and concentrated. Purification of the crude product on a 1 mm silica pad using 20% ethyl acetate / hexane as eluent gave 168 mg (68% yield) of methyl 1-4- [4- (4-chloro-3-methylphenyl) (1). 3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate.

b) 4- [4- (4-chloro-3-methylphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of ammonium chloride 4.24 mmol (227 mg) in Fisher Scientific in 15 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 2.2 mL (4.24) via syringe over 10 minutes at 0 ° C. mmol) of a 2 mol / L solution of trimethylaluminium in toluene (Aldrich Chemical Co.), stirred for 20 minutes at 25 ° C, and then 168 mg (0.424 mmol) of 4- [4- (4-chloro-3-methylphenyl) was added. (1,3-Thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture was then poured into a slurry of 5 g of silica in chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with 10% methanol / CH 2 Cl 2 and concentrated to give 117 mg (73% yield) of 4- [4- (4-chloro-3-methylphenyl) (1,3-thiazol-2). yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (CD 3 OD,

109

300 MHz) δ 8.53 (s, 1H), 8.03 (dd, J = 1.2 Hz and 2.7 Hz, 1H), 7.9 (s, 1H), 7.85 (dd, J = 2 Hz and 8.5 Hz 1H), 7.38 (dd, J = 8.3 Hz and 17.4 Hz, 1H), 2.8 (s, 3H) 2.45 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H14ClN3S3, 380.0 (M + H), found 380.3.

Example 19

4- (5-methyl-4-phenyl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- (5-methyl-4-phenyl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate mg (0.194 mmol) methyl 4- (aminothioxomethyl) - 5-methylthithiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 5 ml of reagent grade acetone. 2-Bromo-1-phenylpropan-1-one (0.223 mmol, 48 mg) was then added and the solution was refluxed for 5 hours. The solution was allowed to cool, the reaction mixture was concentrated and dissolved in 50 mL of CH 2 Cl 2. The organic layer was then washed with 50 mL of 1 N HCl (aq), dried over sodium sulfate, and concentrated. Purification of the crude product on a 1 mm silica plug using 20% ethyl acetate / hexane as eluent gave 53 mg (76% yield) of methyl 4- (5-methyl-4-phenyl) (1,3-thiazole) -2-yl) -5-methylthiothiophene-2-carboxylate.

b) 4- (5-methyl-4-phenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of 1.47 mmol (78 mg) of ammonium chloride (Fisher Scientific) in 5 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 735 μΐ (1.47 mmol) via syringe over 10 minutes at 0 ° C. of a 2M solution of trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 25 ° C for 20 minutes, and then 53 mg (0.147 mmol) of methyl 4- (5-methyl-4-phenyl) (1) was added to the solution. (3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate and the reaction mixture was

110 is heated at reflux for 2.5 h. The reaction mixture was then poured into a slurry of 5 g of silica in chloroform. The silica was poured onto a sintered glass funnel and washed with 10% MeOH / CH ₂ Cl ₂ and concentrated to give 26 mg (51% yield) of 4- (5-methyl-4-phenyl) (l, 3-thiazole 2-yl) J-5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (CD 3 OD, 300 MHz) δ 8.45 (s, 1H), 7.74-7.77 (m, 2H), 7.44-7.50 (m, 2H), 7.38-7 41 (m, 1H); 2.8 (s, 3H); 2.6 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H15N3S3, 346.0 (M + H), found 345.6.

Example 20

4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine trifluoroacetate

(a) methyl 4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

103 mg (0.416 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 ml of reagent grade acetone. 2-Bromo-4'-methylacetophenone (0.416 mmol, 89 mg) was then added and the solution was heated to reflux for 3 hours. After the solution was allowed to cool, the reaction mixture was concentrated, the crude product was filtered off and washed twice with acetone and purified on a 1 mm silica pad using 20% ethyl acetate / hexane as eluent to give 104 mg (69% yield) methyl 4- [4- (4-methylphenyl) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine trifluoroacetate

To a stirred suspension of 2.87 mmol (154 mg) ammonium chloride (Fisher Scientific) in 10 mL anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 144 μΐ (2.87 mmol) via syringe over 10 minutes at 0 ° C.

111 of a 2M solution of trimethylaluminium in toluene (Aldrich Chemical Co.) was stirred for 20 minutes at 25 ° C, and then 104 mg (0.287 mmol) of 4- [4- (4-methylphenyl) (1,3) was added. -thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate and the reaction mixture was heated at reflux for 3 h. The reaction mixture is then poured into a slurry of 5 g of silica in 50 ml of chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with a 10% methanol / CH 2 Cl 2 solution and concentrated. The crude product was purified on a 1 mm silica plug for preparation using 10% methanol / CH 2 Cl 2 with 1% CH 3 COOH as eluent. The product was then basified with aqueous NaOH, extracted with CHCl3 and concentrated. TFA was added and 4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine trifluoroacetate crystallized from methanol. 1 H NMR (CD 3 OD, 300 MHz) δ 8.62 (s, 1H), 8.12 (s, 1H), 7.98 (d, 1H, J = 8.1 Hz), 7.31 (d, 1H, J = 8.1 Hz), 2.8 (s, 3H) 2.5 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H15N3S3, 346.0 (M + H), found 346.1.

Example 21

4- [4- (2-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) Methyl 4- [4- (2-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

105 mg (0.424 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 ml of reagent grade acetone. 2-Bromo-2'-methoxyacetonone (0.467 mmol, 110 mg) was then added and the solution was heated to reflux for 3 hours. The solution is then allowed to cool and concentrated. The crude product was dissolved in 100 mL of CH 2 Cl 2 and washed once with 50 mL of 1 N NaOH. The resulting organic layer was dried over sodium sulfate, concentrated, and purified on a 1 mm silica plug, eluting with 20% ethyl acetate / hexane.

112 afforded 160 mg (95% yield) of methyl 4- [4- (2-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (2-methoxyphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of ammonium chloride 4.23 mmol (227 mg) in Fisher Scientific in 10 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 2.12 mL (4.23) via syringe over 10 minutes at 0 ° C. mmol) of 2 M trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 25 ° C for 20 min and then 160 mg (0.287 mmol) of methyl 4- [4- (2-methoxyphenyl) (1,3-thiazole) was added to the solution. 2-yl) -5-methylthiothiophene-2-carboxylate in 5 mL of anhydrous toluene and the reaction mixture was heated at reflux for 3 h. The reaction mixture is then poured into a slurry of 5 g of silica in 30 ml of chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with 10% methanol / CH 2 Cl 2 and concentrated. The crude product was purified on a 2 mm silica plug using 10% methanol / CH 2 Cl 2 with 1% NH 4 OH as eluent. The product was then dissolved in 2 mL of 4 N HCl / dioxane and concentrated to give 45 mg (29% yield) of 4- [4- (2-methoxyphenyl) (1,3-thiazol-2-yl)] - 5- methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (DMSO-d 6, 300 MHz) δ 8.68 (s, 1H), 8.36 (dd, J = 1.6 Hz and 7.74 Hz, 1H), 8.21 (s, 1H) 7.36-7.42 (m, 1H), 7.05-7.22 (m, 3H), 3.97 (s, 3H), 2.8 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H15N3OS3, 362.0 (M + H), found 361.7.

Example 22

4- [4- (2,4-Dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (2,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

113 mg (0.424 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 ml of reagent grade acetone. 2-Bromo-2 ', 4'-dimethoxyacetophenone (0.440 mmol, 114 mg) was then added and the solution was heated to reflux for 2.5 hours. After the solution was allowed to cool, the solid crude product was filtered off and washed with methanol and dried to give 91 mg (56% yield) of methyl 4- [4- (2,4-dimethoxyphenyl) (1,3-thiazol-2-yl) ] -5-methylthiothiophene-2-carboxylate.

b) 4- [4- (2,4-dimethoxyphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

To a stirred suspension of ammonium chloride 2.23 mmol (119 mg) in Fisher Scientific in 10 mL of anhydrous toluene (Aldrich Chemical Co.) under nitrogen atmosphere was added 1.1 mL (4.24) via syringe over 10 minutes at 0 ° C. mmol) of a 1 mol / L solution of trimethylaluminium in toluene (Aldrich Chemical Co.), stirred at 25 ° C for 20 min, and then methyl-4- [4 (2,4-dimethoxyphenyl) (81 mg, 0.223 mmol) was added. (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture was then poured into a slurry of silica in chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with a 10% methanol / CFhCl solution and concentrated. The crude product was purified on a 0.5 mm silica plug using 10% methanol / CFhCl to give 32 mg (37% yield) of 4- [4- (2,4-dimethoxyphenyl) (1, 2). 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (CD 3 OD, 300 MHz) δ 8.49 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 6.64 (m, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): calcd for C ₇ H] N3O2S3 _7, 392.1 (M + H), found 392.4.

Example 23

4- [4- (3,4-Dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

114

a) methyl 4- [4- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

176 mg (0.712 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was treated with 2-bromo-3 ', 4'-dichloroacetophenone (0.854) mmol, 330 mg) in a manner similar to that described in Example 22, step (a), to give 270 mg (91% yield) of methyl 1-4- [4- (3,4-dichlorophenyl) (1,3) -thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

270 mg (0.648 mmol) of methyl 4- [4- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate were treated in a manner similar to that described in Example 22, step (b). ) to give 135 mg (52% yield) of 4- [4- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride.

1 H-NMR (CD ₃ OD, 300 MHz) δ 8.54 (s, 1H), 8.22 (d, J = 2 Hz, 1H), 8.02 (s, 1H), 7.94 (dd, J = 2 Hz and 8.4 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 2.79 (s, 3H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. For C15H11Cl2N3S3, 400.0 (M + H), found 400.6.

Example 24

4- [4- (3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

115

106 mg (0.428 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was treated with 2-bromo-3-methylacetophenone (0.428 mmol, 91 mg) similar to by the method described in Example 22, step (a) to give 98 mg (63% yield) of methyl 4- [4- (3-methylphenyl) (1,3-thiazol-2-yl)] - 5- methylthiothiophene-2-carboxylate.

b) 4- [4- (3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride mg (0.271 mmol) 4- [4- (3-methylphenyl) (1) 3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate was treated in a manner analogous to that described in Example 22, step (b) to give 75 mg (80% yield) of 4- [4- (3-methylphenyl) ( 1,3-thiazol-2-yl)] 5-methylthiothiophene-2-carboxamidine hydrochloride.

1 H-NMR (CD ₃ OD, 300 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H), 7.86 (d, J = 14 Hz, 1H), 7.33 (m 1 H, 7.19 (m, 1 H), 2.79 (s, 3 H), 2.42 (s, 3 H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. For C16H15N3S3, 346.0 (M + H), found 346.7.

Example 25

5-Methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

a) methyl 5-methylthio-4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate

Methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (160 mg, 0.647 mmol) (Maybridge Chemical Co. LTD., Cornwall, UK) was reacted with 2-bromo-1- (2-5,6) (7,8-tetrahydronaphthyl) ethan-1-one (0.712 mmol, 180 mg) in a manner similar to that described in Example 22, step (a), to give

116

106 mg (41% yield) of methyl 5-methylthio-4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazo-2-yl)] - 5-methylthiothiophene-2-carboxylate .

b) 5-methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

106 mg (0.264 mmol) of 5-methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)) - thiophene-2-carboxylate were treated in a similar manner as described in Example 22, step (b) to give 88 mg (80% yield) of 5-methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)) -thiophene-2-carboxamidine hydrochloride 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.49 (s, 1H), 7.78 (s, 1H), 7.73 (m, 2H), 7 , 11 (m, 1H), 2.79 (m, 7 H), 1.82-1.86 (m, 4H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): calcd for Ci9H] 9 N ₃ N _3, 386.1 (M + H), found 386.2.

Example 26

4- [4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

100 mg (0.404 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was reacted with 2-bromo-3 ', 5'-dimethoxyacetophenone (0.444 mmol) in a manner similar to that described in Example 22, step (a), to give 44 mg (27% yield) of methyl 4- [4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl) )] - 5-methylthiothiophene-2-carboxylate.

117

b) 4- (4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine hydrochloride mg (0.108 mmol) methyl 4- [4- (3, thiol) 5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate was treated in a manner similar to that described in Example 22, step (b) to give 25 mg (60% yield) of 4- (4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] 5-methylthiothiophene-2-carboxamidine hydrochloride 1 H-NMR (CD 3 OD, 300 MHz) δ 8.52 (s, 1H), 7.91 ( s, 1H), 7.23 (d, J = 2.2 Hz, 1H), 6.50 (t, 1H), 3.85 (s, 6H), 2.89 (s, 3H). (MALDI TOF, CHCA matrix, m / z): calcd. For C17H17N3O2S3: 392.11 (M + H), found 392.4.

Example 27

4- [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 1-4- (4- (2-methylphenyl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

160 mg (0.647 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was treated with 2-bromo-2'-methylacetophenone (0.711 mmol, 152 mg) in a similar manner to that described in Example 22, step (a), to give 124 mg (53% yield) of methyl 4- [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5 -metyltiotiofén-2-carboxy-acrylate.

118

b) 4- [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

124 mg (0.343 mmol) of 4- [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate was treated in a manner similar to that described in Example 22, step (b), and 60 mg (50% yield) of 4- [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride are obtained. 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.50 (s, 1H), 7.65 (m, 2H), 7.22-7.32 (m, 3H), 2.79 (s, 3H), 2.51 (s, 3H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): calcd for C] 6 H ₁₅ N ₃ S3, 346.0 (M + H), found 346.2.

Example 28

4- [4- (2,5-dimethoxyphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (2,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

132 mg (0.534 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornvvali, UK) was treated with 2-bromo-2 ', 5'-dimethoxyacetophenone (0.587 mmol, 152 mg) in a similar manner to that described in Example 22, step (a), and 97 mg (45% yield) of methyl 4- [4- (2,5-dimethoxyphenyl) (1,3-thiazole-2-) was obtained. yl)) - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (2,5-dimethoxyphenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride mg (0.238 mmol) methyl 4- [4- (2, 3-thiophenol-2-yl)] 5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate was treated in a manner similar to that described above

The compound of Example 22, step (b), and 30 mg (32% yield) of 4- [4- (2,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride were obtained. .

1 H-NMR (CD ₃ OD, 300 MHz) δ 8.46 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 3.2 Hz, 1H), 7.05 (d, J = 9Hz, 1H), 6.93 (d, J = 3.2Hz, 1H), 6.90 (d, J = 3.2Hz, 1H), 3.94 (s, 3H) 1.83 (s, 3H), 2.51 (s, 3H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. For C17H17N3O2S3, 392.1 (M + H), found 392.2.

Example 29

4- [4- (4-Chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [4- (4-chloro (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

240 mg (0.970 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was reacted with 2-bromo-1- (4-chloro- (3-chloro-3-carboxylate). -pyridyl) ethan-1-one (1.06 mmol, 250 mg) in a manner similar to that described in Example 22, step (a), to give 286 mg (77% yield) of methyl 4- [4- ( 4-chloro (3-pyridyl)) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (4-Chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

286 mg (0.747 mmol) of methyl 4- [4- (4-chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate was treated in a manner similar to that described above in Example 22, step (b) to give 134 mg (49% yield) of 4- [4- (4-chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2- carboxamidine hydrochloride

120 ridu. Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. For C14H11N4CIS3, 366.9 (M + H), found 366.6.

Example 30

4- (4- (2H-benzo [d] 1,3-dioxolen-5-yl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine hydrochloride

a) 1- (2H-benzo [3,4-d] -1,3-dioxolen-5-yl) -2-bromo-methan-1-one

To a solution of 2.5 g (15.23 mmol) of 3,4-methylenedioxyacetophenone in 200 mL of anhydrous methanol was added 61 mmol (20 g) of poly- (4-vinylpyridinium tribromide), Aldrich Chemical Co., and the reaction mixture was heated for 2 hours. 5 hours at reflux temperature. The solution is then filtered and concentrated. From dichloromethane / hexanes, 1- (2H-benzo [3,4d] 1,3-dioxolen-5-yl) -2-bromo-methan-1-one (1.4 g, 38% yield) was obtained as off-white crystals. ).

1 H-NMR (DMSO-d 6, 300 MHz) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.63 (m, 2H), 7.03 (dd, J = 1, 2 Hz and 7.1 Hz, III), 6.09 (s, 2H), 3.86 (s, 3H), 2.75 (s, 3H).

b) methyl 4- (4- (2H-benzo [d] -1,3-dioxolen-5-yl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

1.4 g (5.66 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was reacted with 1- (2H-benzo [3, 4-d] -1,3-dioxolen-5-yl) -2-bromo-methan-1-one (5.66 mmol, 1.37 g) in a manner similar to that described in Example 22, step (a), to give 1, 55 g (70% yield) methyl 4- (4- (2H-benzo [d] -1,3-dioxolen-5-yl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2 carboxylate.

121

c) 4- (4- (2H-benzo [d] -1,3-dioxolen-5-yl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine hydrochloride

1.55 g (3.95 mmol) of methyl 4- (4- (2H-benzo [d] -1,3-dioxolen-5-yl) (1,3-thiazol-2-yl)) - 5- of methylthiothiophene-2-carboxylate was treated in a manner similar to that described in Example 22, step (b) to give 130 mg (9% yield) of 4- (2H-benzo [d] -1,3-dioxolen-5-yl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (CD 3 OD, 300 MHz) δ 8.51 (s, 1H), 7.73 (s, 1H), 7.58 (m, 2H), 6.89 (d, J = 8 Hz, 1H) 6.00 (s, 2H); 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H13N3O2S3, 376.0 (M + H), found 376.1.

Example 31

4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) 1- (3,4-dimethoxyphenyl) -2-bromoethan-1-one g 1- (3,4-dimethoxyphenyl) ethan-1-one (11.1 mmol) was reacted in a manner similar to that described in Example 15 of step (a) to give 1.2 g (42% yield) of 1- (3,4-dimethoxyphenyl) -2-bromoethan-1-one.

b) methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

105 mg (0.424 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, UK) was reacted with 1- (3,4-dimethoxyphenyl) -2-bromoethane 1-one (0.467 mmol, 120 mg) according to a method similar to that described in Example 22, step (a), to give 148 mg (85% yield) of methyl 4- [4- (3,4-dimethoxyphenyl) (1, 2). 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate.

122

c) 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

148 mg (0.363 mmol) of methyl 4- [4- (3,4-dimethoxyphenyl) - (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate was reacted in a manner similar to that described in Example 22 step (b) to give 70 mg (50% yield) of 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.50 (s, 1H), 7.76 (s, 1H), 7.61 (m, 2H), 7.31 (m, 1H), 7 1.01 (d, J = 8 Hz, 1H), 3.9 (s, 3H) 3.86 (s, 3H), 2.78 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C17H17N3O2S3 392.1 (M + H), found 392.4.

Example 32

4- [4- (2-Chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine

a) methyl 4- [4- (2-chloro (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothifene-2-carboxylate

2-Chloropyridine-3-carbonyl chloride (300 mg, 1.7 mmol) was dissolved in anhydrous CH ₃ CN (4 mL). Trimethylsilyldiazomethane (4 mL, 2 M solution in hexane, 8 mmol) was added dropwise with vigorous magnetic stirring. The resulting yellow solution was stirred at room temperature for 2 hours and then cooled in an ice bath. To the cold solution was added dropwise 30% HBr in acetic acid (2 mL) with vigorous gas evolution. The resulting solution was stirred for one hour, whereupon 2-bromo-1- (2-chloro- (3-pyridyl)) ethan-1-one precipitated. The solid obtained is filtered off and dried under vacuum. The dry solid (142 mg, 0.6 mmol) was dissolved in acetone (10 mL). To this solution was added 5- (methoxycarbonyl) -2- (methylthio) thiophene-3-thiocarboxamide (100 mg, 0.4 mmol, Maybridge Chemical Company, Cornvvall, UK) and the mixture was heated at reflux for 5 h. The solid which precipitated during the process was filtered off, washed with methanol and

123 drying in vacuo afforded 110 mg (71%) of methyl 4- [4- (2-chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate . 1 H NMR (CDCl 3, 300 MHz) δ 2.70 (s, 3H), 3.92 (s, 3H), 7.39 (dd, J = 4.7 and 7.7 Hz, 1H), 8, 11 (s, 1H), 8.22 (s, 1H), 8.38 (dd, J = 1.9 and 4.7 Hz, 1H), 8.62 (dd, J = 1.9 and 7), 7 Hz, 1 H).

b) 4- [4- (2-Chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine

Methyl 1-4- [4- (2-chloro- (3-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (100 mg, 0.26 mmol) prepared work-up in a similar manner to that described in Example 1 to give 50 mg (52%) of 4- [4- (2-chloro (3-pyridyl)) (1,3-thiazol-2-yl)] -5-methylthiothiophene-2-carboxamidine as a solid. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.79 (s, 3H), 7.62 (dd, J = 4.9 and 7.4 Hz, 1H), 8.41 (s, 1H) 8.49 (m, 2H); 8.69 (s, 1H); 9.1 (br s, 2H); 9.4 (br s, 2H).

Mass spectrum (ESI, m / z): Calcd. For C14H11N4S3Cl 367.0 (M + H), found 369.0.

Example 33

4- (4-cyclohexyl- (l, 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine

a) methyl 4- (4-cyclohexyl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

Cyclohexanecarbonyl chloride (300 mg, 2.0 mmol) was treated in a manner similar to that described in Example 32 to give 2-bromo-1-cyclohexylethan-1-one. The dry solid (125 mg) was dissolved in acetone (10 mL). To the obtained solution was added 5- (methoxycarbonyl) -2- (methylthio) thiophene-3-thiocarboxamide (100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) and heated at reflux for 5 hours. Thereafter, the precipitated solid is filtered off and washed with methanol and dried in vacuo to give 100 mg (70%) of methyl 4- (4124 cyclohexyl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate, which was used in the next step without purification.

b) 4- (4-cyclohexyl- (1,3-thiazol-2-yl)) - 5-methyl-thiothiophene-2-carboxamidine

The methyl 4- (4-cyclohexyl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate (100 mg, 0.28 mmol) prepared in the previous step was treated in a manner similar to that described above. in Example 1 to give 60 mg (63%) of 4- (4-cyclohexyl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine as a solid. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 1.21-1.53 (m, 5H), 1.61-1.78 (m, 3H), 2.05 (m, 2H), 2, Δ (s, 3H), 2.74 (m, 1 H), 7.33 (s, 1 H), 8.32 (s, 1 H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C15H19N3S3 338.1 (M + H), found 338.1.

Example 34

4-phenyl-5- (trifluoromethyl) thiophene-2-carboxamidine

Methyl 4-phenyl-5- (trifluoromethyl) thiophene-2-carboxylate (100 mg, 0.37 mmol, Maybridge Chemical Company, Cornwall, UK) was treated in a manner similar to that described in Example 1 to give 80 mg (85%). of 4-phenyl-5- (trifluoromethyl) thiophene-2-carboxamidine as a solid. 1 H NMR (DMSO d6, 300 MHz) δ 7.45-7.52 (m, 5H), 7.79 (d, J = 1.4 Hz, 1H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C12H9F3N2S 271.1 (M + H), found 271.2.

125

Example 35

5-Methylthio-4- (2-phenyl- (1,3-thiazol-4-yl)) thiophene-2-carboxamidine

a) Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxy

5- (Methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (200 mg, 0.86 mmol) prepared as described in Example 95 was charged to a round bottom flask and then anhydrous CH 2 Cl 2 (10 mL) was added. The solution was then cooled in an ice bath under an argon atmosphere. Oxalyl chloride (328 mg, 2.6 mmol) was added followed by anhydrous DMF (500 μΐ). The resulting solution was stirred at 0 ° C for 30 min, then allowed to warm to room temperature while the disappearance of the acid spot was monitored by TLC. After 2 hours the solvent is removed in vacuo and the remaining oxalyl chloride is azeotroped with toluene. The residue is dried under high vacuum to give the acid chloride as a gray solid. This solid was dissolved in anhydrous CH 3 CN (8 mL). While stirring vigorously with a magnetic stirrer, trimethylsilyldiazomethane (4 mL, 8 mmol, 2M solution in hexane) was added dropwise to the reaction mixture, and the resulting yellow solution was stirred at room temperature for 2 hours and then cooled in an ice bath. 30% HBr in acetic acid (2 ml) was added to the solution while vigorous gas evolution was observed, which was stirred for 1 hour during which methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate precipitated. the precipitate was filtered off and dried in vacuo to give 120 mg (45%) of product. ^lH-NMR (CDC1 _3, 300 MHz)? 2.64 (s, 3H), 3.91 (s, 3H), 4.27 (s, 2H), 8.10 (s, 1 H).

b) methyl 1-5-methylthio-4- (2-phenyl- (1,3-thiazol-4-yl)) - thiophene-2-carboxylate

5- (methoxycarbonyl) -2- (methylthio) thiophene-3-thiocarboxamide (100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was dissolved in acetone (20 mL). To this solution was added methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (112 mg) prepared in the previous step, and the reaction mixture was

126 was heated at reflux for 3 hours. The solid was then filtered off and washed with methanol and dried to give 82 mg (65%) of methyl 5-methylthio-4- (2-phenyl- (1,3-thiazol-4-yl)) thiophene-2-carboxylate. 1 H-NMR (CDCl ₃ , 300 MHz) δ 2.67 (s, 3H), 3.91 (s, 3H), 7.44-7.49 (m, 3H), 7.61 (s, 1H ), 8.03-8.06 (m, 2H), 8.28 (s, 1H).

c) 5-methylthio-4- (2-phenyl- (1,3-thiazol-4-yl)) thiophene-2-carboxamidine

The methyl 5-methylthio-4- (2-phenyl- (1,3-thiazol-4-yl)) thiophene-2-carboxylate (80 mg) prepared in the previous step was treated in a manner similar to that described in Example 1 to give 50 mg of 5-methylthio-4- (2-phenyl- (1,3-thiazol-4-yl)) thiophene-2-carboxamidine as a solid. H NMR (DMSO-d _6, 300 MHz) δ 2.75 (s, 3H), 7.51-7.60 (m, 3H), 8.02 (s, 1H), 8.06 (m, 2H) 8.70 (s, 1H), 9.06 (br s, 2H), 9.38 (br s, 2H). Mass spectrum (MALDITOF, m / z): Calcd. For C ₁₅ H 13 N ₃ S ₃ 332.0 (M + H), found 332.1.

Example 36

4- [4- (2-chloro- (4-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine

a) methyl 4- [4- (2-chloro- (4-pyridyl)) (1,3-thiazol-2-yl)] methylthiothiophene-2-carboxylate

2-Chloropyridine-4-carbonyl chloride (300 mg, 1.7 mmol) was dissolved in anhydrous CH ₃ CN (4 mL). Trimethylsilyldiazomethane (4 mL, 8 mmol, 2M in hexane) was added dropwise to the reaction mixture with vigorous stirring with a magnetic stirrer. The resulting yellow solution was stirred at room temperature for 2 hours and then cooled in an ice bath. To the cold solution was added dropwise 30% HBr in acetic acid (2 mL) with vigorous gas evolution. The resulting solution was stirred for one hour to precipitate 2-bromo-1- (2-chloro (4-pyridyl)) ethan-1-one. The solid obtained is filtered off and

127 is dried under vacuum. The dry solid (142 mg, 0.6 mmol) was dissolved in acetone (10 mL). To this solution is added 5- (methoxycarbonyl) -2- (methylthio) thiophene-

3-thiocarboxamide (100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) and the mixture was heated at reflux for 5 h. The solid which precipitated during the process was filtered, washed with methanol, and dried in vacuo to give 100 mg of methyl 4- [4- (2-chloro (4-pyridyl)) (1,3-thiazole-). 2-yl)] - 5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl 3, 300 MHz) δ 2.73 (s, 3H), 3.94 (s, 3H, peaked with H ₂ O peak), 7.92-7.99 (m, 2H), 8.05 (s, 1H), 8.24 (s, 2H), 8.48 (m, 1H).

b) 4- [4- (2-Chloro-4-pyridyl) -1,3-thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine

Methyl 4- [4- (2-chloro (4-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (100 mg, 0.26 mmol) prepared in The previous step was worked up in a manner similar to that described in Example 1 to give 50 mg of 4- [4- (2-chloro- (4-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene -2-carboxamidine in the form of a solid. 1 H NMR (CDCl 3 / CD 3 OD, 300 MHz) δ 2.82 (s, 3H), 7.95 (dd, J = 1.4 and 5.3 Hz, 1H), 8.08 (d, J = 1) 0.1 Hz, 1H), 8.23 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.56 (s, 1H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C14H11N4S3Cl 367.0 (M + H), found 367.1.

Example 37

4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl) -5- (methylsulfonyl) thiophene-2-carboxamidine

4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine (35 mg, 0.1 mmol) prepared according to the method of Example 1 was dissolved in a mixture MeOH and CH 2 Cl 2 (1: 1, 1.6 mL). With vigorous stirring, m-chloroperoxybenzoic acid (100 mg) was added portionwise over 3 hours. The resulting mixture was stirred for an additional 2 hours and then the solvents were removed in vacuo. The obtained residue was dissolved in MeOH (8 mL). To a single-column chromatography column

128 wells were loaded with a strongly acidic anion exchange resin (AG 1 -X8.5 mL, 1.4 meq / mL) and the column was washed with H ₂ O (5 x 5 mL) and MeOH (3 x 5 mL). A methanolic solution of the reaction mixture is then slowly added to the column and the effluent is collected. The column was then washed with MeOH (2 x 5 mL) and the wash was collected again. The combined liquids were evaporated in vacuo and the residue was subjected to preparative thin layer chromatography (silica gel, 10% MeOH in CH 2 Cl 2 with 2% acetic acid). The major spot is isolated from the layer, suspended in CH 2 Cl 2, and filtered. The filtrate was separated and the residue was washed with 10% MeOH in CH 2 Cl 2 with saturated NH 3. The wash solution was combined with the first filtrate and the solvents were removed in vacuo. The obtained solid residue was dissolved in 10% MeOH in CHCl 3 and filtered through a 45 µm filter. The filtrate was collected and evaporated in vacuo to give 20 mg (53%) of an off-white solid. 1 H-NMR (CDCl 3 / CD 3 OD, 300 MHz) δ 3.78 (s, 3H), 7.47 (d,> 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1H), 8.00 (s, 1H), 8.35 (s, 1H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C15H12O2N3S3Cl 398.0 (M + H), found 398.0.

Example 38

Hydrazino [5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) (2-thienyl)] methanimine

a) 5-Methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamide

Liquid ammonia (5 mL) was condensed into a Teflon-lined steel bomb cooled to -78 ° C. Then methyl 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (0.6 g, 1.7 mmol) prepared as described in Example 10 was added in one portion. In step (a), the bomb is sealed and heated in an oil bath at 80 ° C for 48 hours. The bomb was then cooled to -78 ° C, opened, and the ammonia allowed to evaporate at room temperature. The residual solid was collected and dried in vacuo to give 0.5 g (88%) of 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxamide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.75 (s, 3H), 7.38 (m, 1H), 7.40-7.51 (m, 2H), 8.04-8, 18 (m, 2H), 8.19 (s, 1H), 8.20 (s, 1H).

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b) 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carbonitrile

The slurry containing P2O5 (2.7 g, 19 mmol) and hexamethyldisiloxane (6.7 mL) in dichloroethene (13 mL) was heated at 90 ° C with stirring under N ₂ atmosphere. After stirring for 2 h, the clear solution obtained was allowed to cool to 40 ° C. Then 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamide (0.9 g, 2.7 mmol) prepared in the previous step was added to the solution and the mixture was heated at 75 ° C for 5 h. Then the solution was cooled to room temperature and stirred with aqueous NaCl (6 M, 100 mL) for 10 minutes. Upon addition of the aqueous solution, a yellow precipitate precipitated. After 10 minutes, the solid was filtered and dried in vacuo to give (0.5 g, 59%) of 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2- carbonitrile in the form of a yellow solid. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.76 (s, 3H), 7.38 (m, 1H), 7.48 (m, 2H), 8.07 (m, 2H), 8.22 (s, 1 H), 8.51 (s, 1 H).

c) Hydrazino- [5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) - (2-thienyl) methanimine

The 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carbonitrile (100 mg, 0.32 mmol) prepared in the previous step was dissolved in EtOH (10 mL). To this solution was added hydrazine monohydrate (10 eq) and the mixture was heated at reflux for 3 h. The EtOH solution was then concentrated to 1 mL and water (2 mL) was added. This procedure leads to the formation of a white solid. The solid was collected by filtration, washed with a small amount of water, and dried in vacuo to give 50 mg (45%) of hydrazino- [5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) (2). thienyl)] methanimine. 1 H NMR (CD 3 OD / CDCl 3, 300 MHz) δ 2.69 (s, 3H), 7.39 (m, 1H), 7.47 (m, 2H), 7.52 (s, 1H), 98 (m, 2H); 8.10 (s. 1H). Mass spectrum (ESI, m / z): Calcd ₅ H ₁₄ N ₄ S ₃ 347.04 (M + H), found 347.1.

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Example 39 {Imino [5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) (2-thienyl)] methyl} methylamine

5-Methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (20 mg, 0.06 mmol) prepared according to the method of Example 10 step (b) was dissolved in MeOH To this was added a solution of methylamine (0.6 mL, 2M solution in tetrahydrofuran). The resulting solution was heated at reflux for 6 hours, then the solvent was removed in vacuo to give a solid residue. The resulting solid residue was dissolved in a small amount of MeOH. H 2 O was then added dropwise to the methanolic solution until a precipitate formed. The resulting solid was collected, washed with a small amount of water, and dried in vacuo to give 15 mg (72%) of {imino [5-methylthio-4- (4-phenyl-1- (1,3-thiazol-2-yl)]). (2-Thienyl)] methyl} methylamine. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.77 (s, 3H), 3.00 (s, 3H), 7.367.42 (m, 1H), 7.47-7.52 (m 2H, 8.07-8.10 (m, 2H), 8.23 (s, 1H), 8.55 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C16H15N3S3 346.5 (M + H), found 346.2.

Example 40

2- {3- (2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy) acetic acid

a) 2-bromo-1- (3-hydroxyphenyl) ethan-1-one

2-Bromo-1- (3-methoxyphenyl) ethan-1-one (2 g, 8.7 mmol) was added to a round-bottom flask equipped with a magnetic stir bar. A nitrogen atmosphere was then introduced into the flask and CH 2 Cl 2 was introduced. The resulting solution was cooled in a dry ice-acetone bath and BBr 3 (27 mL, 1 M in CH 2 Cl 2) was added dropwise. The solution was then allowed to warm to room temperature overnight. Then the solvent was removed in vacuo and purification of the residue through a low silica gel layer (50 g) gave 1.3 g (69%) of 2-bromo-1- (3-hydroxyphenyl) ethan-1-one as an oil. 1 H-NMR (CDCl 3, 300 MHz) δ 4.47 (s, 2H), 6.21 (s, 1H). 7.14 (m, 1H), 7.35 (m, 1H), 7.52-7.82 (m, 2H).

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b) methyl 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] -5-methylthiothiophene-2-carboxylate

The 2-bromo-1- (3-hydroxyphenyl) ethan-1-one (229 mg, 1.1 mmol) prepared in the above step was treated in a manner similar to that described in Example 13, step (a) to give 225 mg ( 61%) methyl 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate as a solid. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.76 (s, 3H), 3.86 (s, 3H), 6.87 (m, 1H), 7.27 (t, J = 7, 8 Hz, 1H), 7.49 (m, 2H), 8.12 (s, 1H), 8.20 (s, 1H).

c) (tert -Butoxy) -N - ({4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide

4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine (2 g, 5.8 mmol), prepared by treatment with methyl 4- [4- ( 3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate in a manner similar to that described in Example 1, was dissolved in anhydrous DMF (10 mL). To this solution was added di-tert-butyl dicarbonate (1.38 g, 6.3 mmol) and DIEA (2 mL, 11.5 mmol), and the mixture was stirred at room temperature for 18 hours. Then DMF was removed in vacuo and purification of the residue by silica gel column chromatography gave 1.8 g (70%) of (tert-butoxy) -N - ({4- [4- (3-hydroxyphenyl) (1,3- thiazol-2-yl)] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide as an oil. 1 H-NMR (DMSO-d 6, 300 MHz) δ 1.58 (s, 9H), 2.81 (s, 3H), 6.81 (m, 1H), 7.28 (t, J = 8, 0 Hz, 1H), 7,497.52 (m, 2H), 8.09 (s, 1H), 8.71 (s, 1H).

d) tert-Butyl-2- {3- [2- (5 {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} (7-t-butoxy) -N - ({4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide ( The 23 mg (0.05 mmol) prepared in the previous step was dissolved in anhydrous DMF (1 mL). To this solution was added tert-butyl 2-bromoacetate (20 mg, 0.1 mmol), CS 2 CO 3 (33.5 mg, 0.1 mmol), and

132

(5 mg) and heated at 70 ° C for 18 h. Thereafter, the solvent was removed in vacuo and purification of the residue by preparative thin layer silica gel chromatography gave 12 mg (42%) of tert-butyl-2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} - 2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate used in the next step.

e) 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid

7-tert-Butyl-2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] -iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] -phenoxy The acetate (12 mg, 0.02 mmol) prepared in the previous step was dissolved in 1 mL of 50% TFA in CH 2 Cl 2 containing 2% Η ₂ Ο and stirred for 4 hours. The solvent is then removed in vacuo. The residual TFA was removed by azeotropic distillation with toluene to give a yellow-brown solid 8.7 mg (100%) of 2- {3- [2- (5-amidino-2-methylthio-

3-thienyl) -1,3-thiazol-4-yl] -phenoxy} -acetic acid. 1 H-NMR (CD 3 OD / CDCl 3, 300 MHz) δ 2.77 (s, 3H), 4.74 (s, 2H), 6.93 (m, 1H), 7.35 (t, J = 7, 9 Hz, 1H), 7.62 (m, 1H), 7.68 (m, 1H), 7.84 (s, 1H), 8.46 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C 15 N 3 O 3 S 3 406.5 (M + H), found 406.3.

Example 41

2- {2- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid

a) tert-Butyl 1-2- {2- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl] methylthio-3-thienyl) -1,3-thiazole-4 -yl 1 -phenoxy} acetate

4- [4- (2-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine (100 mg, 0.29 mmol) prepared according to the method of Example 196 step (b) was treated with in a manner similar to that described in Example 40, Step (c), to give 100 mg (0.22 mmol, 77%) of (tert-butoxy) -N- [4- [4- (2-hydro-

1 * (1-Phenyl) (1,3-thiazol-2-yl)] - 5-methylthio- (2-thienyl)} iminomethyl) carboxamide. This compound was treated in a similar manner to that described in Example 40 step (d) to give 63 mg (50%) of tert-butyl-2- {2- [2- (5 - {[(/? (butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate. 1 H-NMR (CDCl ₃ , 300 MHz) δ 1.55 (s, 9H), 1.56 (s, 9H), 2.69 (s, 3H), 4.66 (s, 2H), 6, 88 (dd, J = 0.8 and 8.3 Hz, 1H), 7.14 (dt, J = 1.0 and 7.6 Hz, 1H), 7.30 (m, 1H), 8.08 (s, 1H), 8.48 (dd, J = 1.8 and 7.8 Hz, 1H), 8.51 (s, 1H).

b) 2- {2- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid

7-tert-Butyl 2- {2- [2- (5- (tert-butoxy) carbonylamino] -iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (60 mg, 0.12 mmol) prepared in the above step was treated in a manner similar to that described in Example 40 step (e) to give 22 mg (50%) of 2- {2- [2- (5-amidino- 2-methylthio-3-thienyl) -1H-2-thienyl; 3-thiazol-4-yl] phenoxy} acetic acid.

1 H-NMR (DMSO-d 6, 300 MHz) δ 2.80 (s, 3H), 4.90 (s, 2H), 7.17 (m, 2H), 7.36 (m, 1H), 8.41 (d, J = 6.3 Hz, 1 H), 8.60 (s, 1 H), 8.62 (s, 1 H), 9.00 (br s, 2 H), 9.37 (br s, 2 H) . Mass spectrum (ESI, m / z): Calcd. For C 17 H 15 N 3 O 3 S 3 406.5 (M + H), found 406.1.

Example 42

5-Methylthio-4- (6-phenyl- (2-pyridyl)) thiophene-2-carboxamidine

(a) methyl 4- (1,1-dimethyl-1-stannaethyl) -5-methylthiothiophene-2-carboxylate

4-Bromo-5-methylthiothiophene-2-carboxylic acid (EP 0676395 A2) (4.67 g, 18.4 mmol) is dissolved in anhydrous THF (30 mL), charged to a round-bottomed flask and cooled in an atmosphere N 2 to -78 ° C. To this solution is added

Butyllithium (20.3 mL, 40.6 mmol, 2 mol / L in cyclohexane) was added dropwise. The resulting solution was stirred at -78 ° C for 45 minutes and then allowed to warm to -60 ° C. To this solution was added dropwise trimethylstannium chloride (40.6 mL, 40.6 mmol, 1M solution in THF). The solution was stirred at -60 ° C for 30 minutes and then allowed to warm to room temperature. Thereafter, THF was removed in vacuo and the residue was treated with H 2 O and extracted with hexane. The hexane layer was evaporated and the residue was dissolved in Et 2 O. The Et 2 O solution was then washed with 10% HCl, saturated NaCl, and dried over anhydrous MgSO 2. Then Et 2 O was removed in vacuo and the residue taken up in MeOH. The MeOH solution was then treated with trimethylsilyldiazomethane (18.5 mL, 2M in hexane) and stirred at room temperature for 1 hour. The solvent was removed in vacuo to give 2 g (31%) of methyl 4- (1,1-dimethyl-1-stannaethyl) -5-methylthiothiophene-2-carboxylate as an oil. 1 H-NMR (CDCl ₃ , 300 MHz) δ 0.31 (s, 9H), 2.57 (s, 3H), 3.86 (s, 3H), 6.98 (s, 1H).

(b) methyl 4- (6-bromo- (2-pyridyl)) -5-methylthiothifene-2-carboxylate:

Methyl 4- (1,1-dimethyl-1-stannethyl) -5-methylthiothiophene-2-carboxylate (195 mg, 0.56 mmol) prepared in the above step and 2,6-dibromopyridine (398 mg, 1.7 mmol) was added to anhydrous DMF (2 mL). To this mixture was added tetrakistriphenylphosphine palladium (20 mg) and the reaction mixture was heated at 120 ° C for 24 hours. DMF was then removed in vacuo and purification by preparative thin layer chromatography afforded 78 mg (41%) of methyl 4- (6-bromo- (2-pyridyl)) - 5-methylthiothiophene-2-carboxylate as a solid. @ 1 H NMR (CDCl3, 300 MHz) .delta. 2.60 (s, 3H), 3.78 (s, 3H), 7.19 (s, 1H), 7.47 (dd, J = 1, 1 and 7), 7 Hz, 1H), 7.58 (t, J = 7.7, 1H), 7.65 (dd, J = 1.1 and 7.4 Hz, 1H).

c) methyl 5-methylthio-4- (6-phenyl- (2-pyridyl)) thiophene-2-carboxylate

Methyl 4- (6-bromo- (2-pyridyl)) -5-methylthiothiophene-2-carboxylate (78 mg, 0.23 mmol) prepared in the previous step, phenylboronic acid (33 mg) was added to DMF (1 mL). 0.27 mmol) and tetrakistriphenylphosphine palladium (10 mg).

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To this solution was added K 2 CO 3 (75 mg, 0.54 mmol) and H 2 O (0.3 mL) and the mixture was heated with stirring at 90 ° C for 18 hours. Then the solvent was removed in vacuo and the residue was dissolved in EtOAc and extracted with H 2 O, washed with saturated NaCl and dried over anhydrous Na 2 SO 4. Analysis of the aqueous layer by thin layer chromatography reveals the presence of a portion of the hydrolyzed product. Therefore, the aqueous layer was separated by acidification with 10% HCl and extraction with EtOAc. The EtOAc layer was washed with saturated NaCl and dried over anhydrous Na 2 SO 4. This second EtOAc fraction was then evaporated and the residue was dissolved in MeOH and treated with trimethylsilyldiazomethane (1.2 eq). The methanolic solution obtained was combined with the first EtOAc fraction and evaporated. The residue was subjected to preparative thin layer chromatography (10% EtOAc in hexane) to give 40 mg (51%) of methyl 5-methylthio-4- (6-phenyl- (2-pyridyl)) thiophene-2-carboxylate, which is used directly in the next step.

d) 5-methylthio-4- (6-phenyl- (2-pyridyl)) thiophene-2-carboxamidine

The methyl 5-methylthio-4- (6-phenyl- (2-pyridyl)) thiophene-2-carboxylate (40 mg, 0.12 mmol) prepared in the previous step was treated in a manner similar to that described in Example 1 to give 10 mg of 5-methylthio-4- (6-phenyl- (2-pyridyl)) thiophene-2-carboxamidine as a solid. 1 H NMR (CD 3 OD, 300 MHz) δ 2.69 (s, 3H), 7.45-7.60 (m, 3H), 7.62 (s, 1H), 7.79 (dd, J = 0) 9 and 7.8 Hz, 1H), 7.96 (dd, J = 0.9 and 8.0 Hz, 1H), 8.03-8.12 (m, 3H). Mass spectrum (ESI, m / z): Calcd. For C17H15N3S2 326.1 (M + H), found 326.1.

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Example 43

5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxamidine

(a) methyl 5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxylate

Methyl 4- (1,1-dimethyl-1-stannethyl) -5-methylthiothiophene-2-carboxylate (200 mg, 0.57 mmol, prepared according to Example 42 step (a)) and 1-bromo-3 -phenylbenzene (266 mg, 1.14 mmol) was added to anhydrous DMF (2 mL) and tetrakistriphenylphosphine palladium (20 mg) was added and the mixture was heated at 120 ° C for 24 h before DMF was removed in vacuo and purified by purification. The residue was subjected to preparative thin layer chromatography to give 39 mg (20%) of methyl 5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxylate as a solid. 1 H NMR (CD 3 OD, 300 MHz) δ 2.60 (s, 3H), 3.75 (s, 3H), 7.3-7.5 (m, 6H), 7.60-7.66 (m, 4H).

b) 5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxamidine

The methyl 5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxylate (35 mg, 0.1 mmol) prepared in the previous step was treated in a manner similar to that described in Example 1 to give 17 mg of 5-methylthio- 4- (3-phenylphenyl) thiophene-2-carboxamidine as a solid. ¹ H NMR (CD 3 OD, 300 MHz) δ 2.60 (s, 3H), 7.3-7.6 (m, 10H). Mass spectrum (ESI, m / z): Calcd. For C18H16N2S2, 325.4 (M + H), found 325.2.

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Example 44

5-Methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine

a) Methyl 1-5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate

2-Phenylthioacetyl chloride (1.0 g, 5.4 mmol) was treated in a manner similar to that described in Example 32 step (a) to give 2-bromo-1-phenyl-thiomethyletan-1-one. The dry solid (1.3 g, 5 mmol) was dissolved in acetone (25 mL). Then 5- (methoxycarbonyl) -2- (methylthio) thiophene-3-thiocarboxamide (1.32 g, 5.3 mmol, Maybridge Chemical Co.) was added to the solution and the reaction mixture was heated at reflux for 5 hours. A solid precipitates, which is filtered off, washed with acetone and dried to give 1.5 g (71%) of methyl 5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)]. thiophene-2-carboxylate, which was used in the next step without further purification.

b) 5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine

The methyl 5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate (1.5 g, 3.8 mmol) prepared in the previous step was treated in a similar manner as described in Example 1, except that the product was purified by crystallization from methanol to give 0.86 g (60%) of 5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazole-2-). γ I]] thiophene-2-carboxamidine as a solid. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.72 (s, 3H), 4.38 (s, 2H), 7.18-7.39 (m, 5H), 7.57 (s, 1H), 8.46 (s, 1H). Mass spectrum (MALDI-TOF, m / z): calcd for C ₆ Hi ₅ N ₃ S ₄ 378.0 (M + H), found 378.1.

138

Example 45

4- [4- (2-chloro-4,5-dimethoxyphenyl) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2carboxamidine

a) methyl 4- [4- (2-chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

2-chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PC1 ₅ (0.54 g, 2.6 mmol) were placed in a round bottomed flask equipped with a reflux condenser. The mixture was heated in an oil bath at 120 ° C for 70 minutes. After allowing the mixture to cool, the formed phosphorus oxychloride was removed in vacuo to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was then treated in a manner similar to that described in Example 32, step (a) to give 2-bromo-1- (2-chloro-4, 2-chloro-4-carboxylic acid). 5-dimethoxyphenyl) ethan-1-one. The dry solid product (0.65 g, 2.2 mmol) was then dissolved in acetone (25 mL). To this solution was then added 5- (methoxycarbonyl) -2- (methylthio) -thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) and heated at reflux for 5 hours. A solid precipitates, which is filtered off, washed with acetone and dried in vacuo to give 0.53 g (54%) of methyl 4- [4- (2-chloro-4,5-dimethoxyphenyl) (1,3-). thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).

b) 4- [4- (2-chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine

Methyl 4- [4- (2-chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (0.53 g, 1.2 mmol) prepared in a previous step, it was worked up in a manner similar to that described in Example 1 with that. the product was purified by crystallization from methanol to give 0.3 g (60%) of 4- [4- (2

139

-chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine as a solid. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.77 (s, 3H), 3.84 (s, 6H), 7.13 (s, 1H), 7.71 (s, 1H), 8.17 ( s, 1H), 8.69 (s, 1H), 9.16 (br s, 2H), 9.48 (br s, 2H). Mass spectrum (MALDI-TOF, m / z): Calcd. For C17H16N3O2S3Cl, 426.0 (M + H), found 426.6.

Example 46

4- (methylethyl) sulfonyl] -5-methylthiothiophene-2-carboxamidine

Methyl 4 - [(methylethyl) sulfonyl] -5-methylthiothiophene-2-carboxylate (100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in a manner similar to that described in Example 1 to give 50 mg of 4 - [(methylethyl) sulfonyl] -5-methylthiothiophene-2-carboxamidine. ^LH-NMR (DMSO-d, 300 MHz) δ 1.21 (d, J = 6.77 Hz, 6H), 2.66 (s, 3H), 3.55 (m, 1H), 7.85 (s, 1 H). Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. For C 9 H 14 N 2 O 2 S 3, 279.0 (M + H), found 279.3.

Example 47

Methyl 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy Jacetate trifluoroacetate

To a solution of 42 mg (0.094 mmol) of tert-butoxy-N - ({4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide, prepared in a manner similar to that described in Example 40 step (c) in 2 ml of Ν ', Ν'-dimethylformamide (DMF), potassium iodide (0.006 mmol, 1 mg, Aldrich Chemical Co.), cesium carbonate (0.187 mmol, 61 mg, Aldrich Chemical Co.), and methyl bromoacetate (0.187 mmol, 18 μΐ, Aldrich Chemical Co.) and heated at 60 ° C overnight. Thereafter, the reaction solution was concentrated and purified on a 1 mm thick silica pad with 3% methanol / CH 2 Cl 2 to give 11 mg (23%) of methyl 2- {3- [2- (5 - {[(rerc (butoxy) carbonylamino] aminomethyl} -2-methylthio-3-thienyl} -1,3-thiazol-4-yl] phenoxy} acetate which

140 was then treated with 50% trifluoroacetic acid / CFUCb for 1 hour, then concentrated and triturated with diethyl ether and dried to give 7 mg (77% yield) of methyl 2- {3- [2- (5-amidino) 2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate trifluoroacetate The. 1 H-NMR (CD 3 OD, 300 MHz) δ 8.51 (s, 1H), 7.92 (s, 1H), 7.66 (m, 2H), 7.34-7.39 (t, 1H) 6.93 (m, 1H); 4.8 (s, 2H); 3.80 (s, 3H); 2.78 (s, 3H). Mass spectrum (LC-Q ESI, m / z): Calcd. For C ₁₈ H 17 N ₃ O ₃ S ₃ , 419.5 (M + H), found 420.3.

Example 48

5-Methylthio-4- [4- (3 - {[N-benzylcarbamoyl] methoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine trifluoroacetate

100 mg (0.197 mmol) of 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid prepared in the previous step was dissolved in 1 ml of anhydrous DMF and added PyBOP (0.396 mmol, 206 mg), benzylamine (0.396 mmol, 42 mg) and diisopropylethylamine (0.494 mmol, 86 μΐ) and stirred for 18 hours then the solution was concentrated and purified on a 2 g silica SPE column and deprotected with 50% trifluoroacetic acid / dichloromethane to give 60 mg (67% yield) of 5-methylthio-4- [4- (3 - {[N-benzylcarbamoyl]] methoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (CDCH / TFA-d, 300 MHz) δ 8.97 (s, 1H), 7.86 (s, 1H), 7.53 (t, 1H), 7.33 (m, 7H) 7.17 (d, 1H), 4.79 (s, 2H), 4.59 (s, 2H), 2.95 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C24H22N4O2S3 494.6 (M + H), found 495.2.

Example 49

4- {4- [3 - ({N - [(3,4-dimethoxyphenyl) methyl] carbamoyl} methoxy) phenyl] (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxamidine trifluoroacetate

100 mg (0.197 mmol) of 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy {acetic acid}

141 as in Example 48, step (c) was dissolved in 1 mL of anhydrous DMF, and PyBOP (0.396 mmol, 206 mg), 3,4-dimethoxybenzylamine (0.396 mmol, 66 mg), and diisopropylethylamine (0.494 mmol) were added. , 86 μΐ) and the reaction mixture was stirred for 18 hours, then the solution was concentrated and purified on a 2 g silica SPE column and deprotected with 50% trifluoroacetic acid / dichloromethane to give 45 mg (41% yield) of 4- {4- [3]. - ({N - [(3,4-dimethoxyphenyl) methyl] carbamoyl} methoxy) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (CDCl ₃ / TFA-d, 300 MHz) δ 8.48 (s, 1H), 7.78 (s, IH), 7.72 (m, IH), 7.66 (d, IH) ), 7.39 (t, 1H), 7.02 (d, 1H) 4.68 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H), 3.56 (s, 2H) s, 3H), 2.78 (s, 3H). Mass spectrum (LC-Q ESI, m / z): Calcd. For C 26 H 26 N 4 O 4 S 3, 554.6 (M + H), found 555.2.

Example 50

5-methylthio-4- {4- [3 - ({N- [2 (phenylamino) ethyl] carbamoyl} methoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate

100 mg (0.197 mmol) of 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid of the acid prepared in a manner similar to that described in Example 48, step (c), was dissolved in 1 mL of anhydrous DMF, and PyBOP (0.396 mmol, 206 mg), N-phenylethylenediamine (0.396 mmol, 54 mg), and diisopropylethylamine (0.494 mmol, 86) were added. μΐ) and the reaction mixture is stirred for 18 hours, then the solution is concentrated and purified on a 2 g silica SPE column and deprotected with 50% trifluoroacetic acid / dichloromethane to give 65 mg (63% yield) of 5-methylthio-4- {4- [3 - ({N- [2- (phenylamino) ethyl] carbamoyl} methoxy) phenyl] (l, 3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (CDCl ₃ / TFA-d, 300 MHz) δ 8.50 (s, 1H), 7.82 (s, IH), 7.77 (s, IH), 7.66 (d, IH) ), 7.39 (t, 1H), 7.02 (d, 1H) 4.68 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H), 3.56 (s, 2H) s, 3H), 2.78 (s, 3H). Mass spectrum (LC-Q ESI, m / z): Calcd. For C25H25N5O2S3, 523.6 (M + H), found 524.1

142

Example 51

5-Methylthio-4- [4- (3 - {[N- (2-morpholin-4-ylethyl) carbamoyl] methoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine- trifluoroacetate mg (0.164 mmol) 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} of acetic acid prepared in a manner similar to that described in Example 40, step (c), was treated with 2-morpholin-4-ylethylamine (0.328 mmol, 43 μΐ) in a manner similar to that described in Example 48 to give 46 mg (54% yield). 5-Methylthio-4- [4- (3 - {[N- (2-morpholin-4-yl) carbamoyl] methoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2- carboxamidine trifluoroacetate. 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.38 (bs, 2H), 9.08 (bs, 2H), 8.61 (s, 1H), 8.45 (t, 1H), 8 27 (s, 1H); 7.72 (m, 2H); 7.45 (t, 1H); 7.02 (d, J = 8 Hz, 1H); 4.62 (s, 2H); 53-3.64 (m, 5H), 3.243.38 (m, 5H), 2.80 (s, 3H), 1.1 (t, 2H). Mass spectrum (ESI, m / z): Calcd. For C23H27N5O3S3, 517.6 (M + H), found 518.2.

Example 52

5-Methylthio-4- {4- [3- (2-morpholin-4-yl-2-oxoethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate mg (0.144 mmol) 2 - {3- [2- (5 - {[(tert -Butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid, prepared in a manner similar to that described above in Example 48 step (c) was reacted with morpholine (0.288 mmol, 25 μΐ) in a manner similar to that described in Example 48 step (b) to give 50 mg (75% yield) of 5-methylthio-4- {4- [3- (2-morpholin-4-yl-2-oxo-ethoxy) phenyl] (l, 3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (DMSO-d 6 / TFA-d, 300 MHz) δ 9.38 (bs, 1H), 9.08 (bs, 2H), 8.66 (s, 1H), 8.22 (s, 1H), 7.72 (m, 2H), 7.42 (t, 1H), 6.98-7.00 (dd, J = 2.3 Hz and 8.2 Hz, 1H), 4.95 (s) 2H, 3.53-3.67 (m, 8H), 2.82 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 21 H 22 N 4 O 3 S 3 474.6 (M + H), found 475.2.

143

Example 53

5-Methylthio-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate

100 mg (0.198 mmol) of 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino ]iminomethyl} 2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid prepared by a method similar to that described in Example 48, step (c), by treatment with tert-butyl piperazinecarboxylate (0.396 mmol, 74 mg) in a manner similar to that described in Example 48, step (b) to give 40 mg (43% yield). 5-Methylthio-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (DMSO-d 6 / TFA-d, 300 MHz) δ 8.68 (s, 1H), 8.20 (s, 1H), 7.75 (m, 2H) 7.43 (t, 1) H), 7.01 (dd, J = 2.3 Hz and 8.1 Hz, 1H), 5.02 (s, 2H), 3.76 (bs, 4H), 3.17-3.26 ( m, 4H), 2.82 (s, 3H). Mass spectrum (LC-Q ESI, m / z): Calcd. For C21H23N5O2S3 473.6 (M + H), found 474.2.

Example 54

4- [4- (3 - {[N- (2-aminoethyl) carbamoyl] methoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride mg (0.101 mmol) 2 - {3- [2- (5 - {[(tert-butoxy) carbonylamino] imino-methyl} 2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} -acetic acid prepared in a manner similar to that described in Example 48, step (c), was treated with N- (2-aminoethyl) (tert-butoxy) carboxamide (0.202 mmol, 32 mg) in a manner similar to that described in Example 48, step (b) to give 80 mg (80%). % yield) 4- (4- {3 - [(N- {2 - [(tert-butoxy) carbonylamino] ethyl} carbamoyl) methoxy] phenyl} (1,3-thiazol-2-yl)) - 5- methylthiothiophene-2-carboxamidine, from which, by deprotection with 4 N HCl in dioxane, 36 mg (68% yield) of 4- [4- (3 ([N- (2-aminoethyl) carbamoyl] methoxy} phenyl)) is obtained (1,3- thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (CD 3 OD, 300 MHz) δ 8.55 (s, 1H), 7.95 (s, 1H), 7.73 (m, 2H) 7.41 (t, 1H), 7.05 (m, 1H), 4.80 (s, 2H), 3.51 (m, 2H),

144

3.13-3.31 (m, 2H); 2.83 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C19H21N5O2S3 447.5 (M + H), found 448.2.

Example 55

4- (4- {3- [2- (4-acetylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate mg (0.103 mmol) 2- {3- [2- (5 - {[(tert -Butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid prepared in a manner similar to that described above in Example 48, step (c), is reacted with 1-acetylpiperazine (0.154 mmol, 20 mg), 1-hydroxy-7-azabenzotriazole (HOAt)) (0.154 mmol, 21 mg), O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.154 mmol, 58 mg) and diisopropylethylamine (0.258 mmol, 44 μΐ) in DMF to give the crude product, which was purified on a silica pad to prepare a thickness. 1 mm using 3% methanol / dichloromethane gave 28 mg (53% yield) of N - {[4- (4- (3- [2- (4-acetylpiperazinyl) -2-oxoethoxy) phenyl]) (1, 3-thiazol-2-yl) -5-methylthio- (2-thienyl)] iminomethyl} (tert-butoxy) carboxamide. The product was then treated with trifluoroacetic acid: dichloromethane: water (47.5%: 47.5%: 2.5%) for 1 hour, concentrated and purified on a SPE silica column using 15% methanol / dichloromethane as 20 mg (80% yield) of 4- (4- {3- [2- (4-acetylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene were obtained. 2-carboxamidine trifluoroacetate. 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.69 (m, 2H), 7.38 (t, 1H), 6, 99 (dd, J = 2 Hz and 8.1 Hz, 1H), 4.93 (s, 2H), 3.52-3.67 (m, 8H), 2.78 (s, 3H), 2, 12 (s, 3 H). Mass spectrum (ESI, m / z): Calcd. For C23H25N5O3S3 515.6 (M + H), found 516.2.

145

Example 56

4- (4- {3- [2- (4-methylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine trifluoroacetate mg (0.107 mmol) 2- {3- [2- (5 - {[(tert -Butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid prepared in a manner similar to that described above in Example 48, step (c) is reacted with N-methylpiperazine (0.128 mmol, 14 μΐ), 1-hydroxy-7-azabenzotriazole (HOAt) (0.128 mmol, 17 mg), O- (7-azabenzotriazole-1- yl) -1,1,3,3tetramethyluronium hexafluorophosphate) HATU (0.128 mmol, 49 mg) and diisopropylethylamine (0.268 mmol, 56 μΐ) to give the crude product which was partitioned between dichloromethane and 1 N NaOH and washed. The organic layer obtained is similarly washed with 10% citric acid and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to a yellow oil. The resulting oil was purified on a 1 mm silica plug using 5% methanol / dichloromethane to give (tert-butoxy) -N {imino [4- (4- {3- [2- (4- methylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl) -5-methylthio (2-thienyl)] methyl} carboxamide. The product was then treated with trifluoroacetic acid: dichloromethane: water (47.5%: 47.5%: 2.5%) for 1 hour, concentrated and purified on a SPE silica column using 10-15% methanol / dichloromethane as eluent gave 15 mg (33% yield) 4- (4- {3- [2- (4-methylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5 methylthiothiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.52 (s, 1H), 7.91 (s, 1H), 7.69 (m, 2H), 7.38 (t, 1H), 6 .98 (dd, J = 2.0 Hz and 8.1 Hz, 1H), 4.90 (s, 2H), 3.66 (t, 4H), 2.78 (s, 3H), 2.49 -2.57 (m, 4H); 2.35 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C22H25N5O2S3 487.6 (M + H), found 488.2.

146

Example 57

5-methylthio-4- [4- (3- {2-oxo-2- [4-benzylpiperazinyl] ethoxy} phenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine trifluoroacetate.

mg (0.107 mmol) of 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid, prepared by a method similar to that described in Example 48, step (c), treated with N-benzylpiperazine (0.128 mmol, 22 μΐ), 1-hydroxy-7-azabenzotriazole (HOAt) (0.128 mmol, 17 mg), O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.128 mmol, 48 mg) and diisopropylethylamine (0.267 mmol, 50 μΐ) in DMF to give the crude product which was partitioned between dichloromethane and NaOH 1 mol / L and washed. The organic layer obtained is then similarly washed with 10% citric acid and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to a yellow oil. The resulting oil was then purified on a 1 mm thick silica layer using 5% methanol / dichloromethane to give (tert-butoxy) -N- (amino {5-methylthio-4- [4- (3-thiophen-2-yl) thio] - {2-oxo-2- [4-benzylpiperazinyl] ethoxy} phenyl) (1,3-thiazol-2-yl)] (2-thienyl)} methyl) carboxamide. The product obtained is then treated with trifluoroacetic acid: dichloromethane: water (47.5%: 47.5%: 2.5%) for one hour, the mixture is concentrated and purified on a 5 g SPE silica column using 10-15% methanol. dichloromethane as eluent gave 36 mg (60% yield) of 5-methylthio-4- [4- (3- {2-oxo-2- [4-benzylpiperazinyl] ethoxy} phenyl) (1,3-thiazol-2-yl) )] thiophene-2-carboxamidine trifluoroacetate. 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.71 (m, 2H), 7.50 (s, 5H) 7, 39 (t, 1H), 6.99 (dd, J = 2Hz and 8.1Hz, 1H), 4.94 (s, 2H), 4.37 (s, 2H), 3.3 (m, 4H), 2.81 (s, 3H), 2.49-2.57 (m, 4H), 2.35 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C28H29N5O2S3 563.7 (M + H), found 564.3.

147

Example 58 (D, L) -4- (4- {3- [2- (3-Amino-pyrrolidinyl) -2-oxoethoxy] -phenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2- carboxamidine trifluoroacetate mg (0.081 mmol) 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } acetic acid prepared by a method similar to that described in Example 48, step (c), was treated with (D, L) (tert-butoxy) -N-pyrrolidin-3-ylcarboxamide (0.122 mmol, 23 mg), O- ( 7-azabenzotriazol-1-yl) -1,3,3,3-tetramethyluronium hexafluorophosphate) HATU (0.122 mmol, 46 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.122 mmol, 17 mg) and diisopropylethylamine (0.203 mmol) , 35 μΐ) in a manner similar to that described in Example 56 to give 20 mg (53% yield) of (D, L) -4- (4- {3- (2- (3-aminopyrrolidinyl) -2-oxoethoxy) phenyl} (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine trifluoroacetate 1 H-NMR (CD 3 OD, 300 MHz) δ 8.54 (s, 1H), 7.94 (s, 1H) 7.71 (m, 2H), 7.39 (t, 1H), 6.99 (dd, J = 2.0 Hz and 8.1 Hz, 1H), 4.85 (s, 2H), 4 3 Δ (s, 2H), 3.60-4.01 (m, 5H), 2.81 (s, 3H), 2.15-2.71 (m, 2H). Mass spectrum (ESI, m / z): Calcd

C _2I H ₂₃ N ₅ O ₃ S _2, 473.6 (M + H), found 474.3.

Example 59

5-Methylthio-4- {4- [3- (2-oxo-2-piperidylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate mg (0.065 mmol) 2- { 3- [2- (5 - {[(tert-butoxy) carbonylamino ]iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid prepared in a manner similar to that described in Example 40 , step (c) is reacted with piperidine (0.078 mmol, 8 μΐ), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.078 mmol, 30 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.078 mmol, 11 mg) and diisopropylethylamine (0.163 mmol, 56 μΐ) in a manner similar to that described in Example 57 to give 15 mg (41% yield) of 5-methylthio-4- {4 - [3- (2-Oxo-2-piperidyl ethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate.

148 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.54 (s, 1H), 7.92 (s, 1H), 7.69 (m, 2H), 7.357.40 (t, 1H), 6.98 (dd, J = 2 Hz and 8.1 Hz, 1H), 4.95 (s, 2H), 3.52-3.60 (m, 4H), 2.80 (s, 3H), 1.57-1.70 (m, 6H). Mass spectrum (ESI, m / z): Calcd. For C22H24N4O2S3, 472.6 (M + H), found 473.2.

Example 60

2- (3- (2- [5- (imino {[(4-polystyryloxyphenyl) methoxy] carbonylamino} methyl) -2-methylthio-3-thienyl] -1,3-thiazol-4-yl} phenoxy) acetic acid g (1.86 mmol) of p-nitrophenyl carbonate Wang resin (0.93 mmol / g) (Calbiochem-Novabiochem, San Diego, CA) was suspended in 9 mL of anhydrous DMSO: DMF 2: 1 and then added to the suspension. 2 g (4.93 mmol) of 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid is then added, Of 8-diazabicyclo [5.4.0] undec-7-ene, (DBU, 6.69 mmol) and the reaction mixture is shaken vigorously for 5 days, then the resin is washed thoroughly with DMF, MeOH, and diethyl ether and dried in vacuo to give 2 g. resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy] acetic acid.

Example 61 (D, L) -ethyl-1- (2- (3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy acetyl) piperidine- 2-carboxylate trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) (g), prepared in a manner similar to that described in Example 60, was suspended in 1 ml of anhydrous DMF. Then O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M) was added. M, 68 mg), ethyl piperidine-2-carboxylate (0.5 M, 78 μΐ) and diisopropylethylamine (0.233 mmol, 40 μΐ) and shake vigorously for 18 hours, then thoroughly wash the resin with DMF, methanol,

149 with dichloromethane and diethyl ether. After drying, the crude product is separated from the resin by treatment with trifluoroacetic acid: dichloromethane: water (47.5%: 47.5%: 2.5%) for 1 hour. The solution was filtered and concentrated to a yellow oil. Purification on column 2 of SPE silica using a gradient elution with 3% - 10% MeOH / dichloromethane afforded 15 mg (30% yield) of (D, L) -ethyl-1- (2- [3- [2- ( 5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-2-carboxylate trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C25H28N4O4S3, 544.70 (M + H), found 545.2.

Example 62

5-methylthio-4- {4- [3- (2-oxo-2-pyrrolidinylethoxy) phenyl] (l, 3-thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) (g), prepared in a manner similar to that described in Example 60, was suspended in 1 ml of anhydrous DMF. Then O- (7-azabenzotriazol-1-yl) -1,3,3,3-tetramethyluronium hexafluorophosphate) FIATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M, 68 mg) were added. ), pyrrolidine (0.5 mol / l, 42 μΐ) and diisopropylethylamine (0.233 mmol, 40 μΙ) and the reaction mixture is shaken vigorously for 18 hours, then the resin is washed thoroughly with DMF, methanol, dichloromethane and diethyl ether. After drying, the crude product is separated from the resin by treatment with trifluoroacetic acid: dichloromethane: water (47.5%: 47.5%: 2.5%) for 1 hour. Trituration with diethyl ether and drying gave 18 mg (42% yield) of 5-methylthio-4- {4- [3- (2-oxo-2-pyrrolidinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene- 2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C21H22N4O2S3, 458.6 (M + H), found 459.2.

150

Example 63

5-methylthio-4- [4- (3- {2-oxo-2- [4-benzylpiperidyl] ethoxy} phenyl) - (1,3-thiazol-2-yl)] thiophene-2-carboxamidine trifluoroacetate mg ( 0.074 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol / g) , prepared in a manner similar to that described in Example 60, was suspended in 1 mL of anhydrous DMF. Then O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M) was added. M, 68 mg), 4-benzylpiperidine (0.5 mol / l, 88 μΐ) and diisopropylethylamine (0.185 mmol, 32 μΐ) and shaken vigorously for 18 hours, then thoroughly wash the resin with DMF, methanol, dichloromethane and diethyl ether . After drying, the crude product is separated from the resin by treatment with trifluoroacetic acid: dichloromethane: water (47.5%: 47.5%: 2.5%) for 1 hour. Trituration with diethyl ether and drying gave 17 mg (40% yield) of 5-methylthio-4- [4- (3- (2-oxo-2- [4-benzylpiperidyl] ethoxy} phenyl)) - (1,3-thiazole) Mass Spectrum (ESI, m / z): Calcd. For C29H30N4O2S3, 562.7 (M + H), found 563.3.

Example 64 (D, L) -4- (4- {3- (2- (3-methylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2- carboxamidine trifluoroacetate mg (0.074 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0, 93 mmol / g) prepared in a manner similar to that described in Example 60 was treated with (+/-) - 3-methylpiperidine (0.5 M, 59 μΐ) and O- (7-azabenzotriazol-1-yl) - 1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l 68 mg), and diisopropylethylamine (0.185 mmol) , 32 μΐ) in 1 ml of anhydrous DMF in a manner similar to that described in Example 63, yielding 10 mg (28% yield) of (DL) -4- (4- {3- [2- (3-methylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylic

151 boxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C23H26N4O2S3, 486.6 (M + H), found 487.3.

Example 65

4- (4- {3- [2- (4-methylpiperidyl) -2-oxo-ethoxy] -phenyl} (l, 3-thiazol-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate.

mg (0.074 mmol) of resin bound 2- {3- [2- (5-amidino-2-methylthio-

3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol / g), prepared in a manner similar to that described in Example 60, was reacted with

4-methylpiperidine (0.5 mol / l, 59 μΐ) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M, 68 mg), and diisopropylethylamine (0.185 mmol, 32 μΐ) in 1 mL of anhydrous DMF in a manner similar to that described in Example 63, yielding 12 mg (33%). yield) 4- (4- {3- [2- (4-methylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C23H26N4O2S3, 486.6 (M + H), found 487.3.

Example 66

4- (4- {3- [2- (2-azabicyclo [4.4.0] dec-2-yl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene- 2-carboxamidine trifluoroacetate.

mg (0.074 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) g), prepared in a manner similar to that described in Example 60, was reacted with decahydroquinoline (0.5 mol / l, 75 μΐ) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate ) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.185 mmol, 32 μΐ) in 1 ml of anhydrous DMF in a manner similar to that described in Example 63, yielding 16 mg (41% yield) of 4- (4- {3- [2- (2-aza)].

152 Bicyclo [4.4.0] dec-2-yl) -2-oxoethoxy] phenyl} - (1,3-thiazol-2-yl)) - 5-methylthiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C26H30N4O2S3, 526.7 (M + H), found 527.2.

Example 67 (D, L) -ethyl-1- (2- (3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxyacetyl) piperidin-3 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid-carboxylate trifluoroacetate mg (0.074 mmol) 93 mmol / g) prepared in a manner similar to that described in Example 60 was treated with ethyl nipecotate (0.5 mol / l, 75 μΐ) and O- (7-azabenzotriazol-1-yl) -1,1,3 , 3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.185 mmol, 32 μΐ) in 1 ml of anhydrous DMF, in a manner similar to that described in Example 63, to give 18 mg (45% yield) of ethyl 1- (2- {3- [2- (5 amidino-2-methylthio-3-thienyl) -1,3] -thiazol-4-yl] phenoxyacetyl) piperidine-3-karboxyláttrifluóracetátu. Mass spectrum (ESI, m / z): Calcd. For C25H28N4O4S3 545.7 (M + H), found 545.2.

Example 68

5-Methylthio-4- {4- [3- (2-oxo-2- (1,2,3,4-tetrahydroquinolyl) -ethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2 carboxamidine trifluoroacetate.

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93) mmol / g) prepared in a manner similar to that described in Example 60 was reacted with 1,2,3,4-tetrahydroisoquinoline (0.5 mol / L) and O- (7-azabenzotriazol-1-yl) 1,1 , 3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) ) in 1 ml of anhydrous DMF in a manner similar to that described above

153 of the compound described in Example 63, and 20 mg (42% yield) of 5-methylthio-4- {4- [3- (2-oxo-2- (1,2,3,4-tetrahydroquinolyl) ethoxy) phenyl] was obtained. (1,3-Thiazol-2-yl)} thiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C26H24N4O2S3 520.7 (M + H), found 521.2.

Example 69

Ethyl 1- (2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-4-carboxylate trifluoroacetate.

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) g), prepared in a manner similar to that described in Example 60, was treated with ethyl isonipecotate (0.5 mol / l, 77 mg) and O- (7-azabenzotriazol-1-yl) -1,1,3,3- tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 ml of anhydrous DMF in a manner similar to that described in Example 63, to give 21 mg (42% yield) of ethyl 1- (2- {3- [2- (5 amidino-2-methylthio-3-thienyl) -1,3- thiazol-4-yl] phenoxy} acetyl) piperidine-4-carboxylate trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C25H28N4O4S3 545.7 (M + H), found 545.3.

Example 70

4- (4- {3- [2 - ((3R) -3-hydroxypiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) (g), prepared in a manner similar to that described in Example 60, was reacted with R - (+) - 3-hydroxypiperidine (0.5 mol / l, 69 mg) and O- (7-azabenzotriazol-1-yl) - 1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg),

154 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL anhydrous DMF in a manner similar to that described in Example 63, yielding 16 mg (36% yield) 4- (4- {3- [2 ((3R) -3-hydroxypiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) -5-methylthiothiophen-2- carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C22H23N4O3S3 489.7 (M + H), found 489.2.

Example 71

D, L-4- (4- {3- [2- (2-ethylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) g), prepared in a manner similar to that described in Example 60, was reacted with 2-ethylpiperidine (0.5 mol / L) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate ) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 ml of anhydrous DMF in a manner similar to that described in Example 63, yielding 11 mg (23% yield) of D, L-4- (4- {3- [2- (2-ethylpiperidyl) -2-oxoethoxy] phenyl} (1,3- thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C24H27N4O2S3, 501.4 (M + H), found 501.4.

Example 72

4- (4- {3- [2 - ((3S) -3-hydroxypyrrolidinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate.

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) g), prepared in a manner similar to that described in Example 60, was treated with R - (-) - 3-pyrrolidinol (0.5 mol / l, 62 mg) and O- (7-azabenzotriazol-1-yl)

155

-1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL of anhydrous DMF in a manner similar to that described in Example 63 to give 10 mg (23% yield) of 4- (4- {3- [2 ((3S) -3-hydroxy-pyrrolidinyl)] ) -2-oxo-ethoxy] -phenyl} (l, 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C 21 H 22 N 4 O 3 S 3 475.2 (M + H), found 475.2.

Example 73

5-Methylthio-4- (4- {3 - [(N- (5,6,7,8-tetrahydronaphthyl) carbamoyl) methoxy] phenyl} (1,3-thiazol-2-yl)) thiophene-2- carboxamidine trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) g), prepared in a manner similar to that described in Example 60, was reacted with 5,6,7,8-tetrahydro-1-naphthylamine (0.5 mol / l, 73 mg) and O- (7-azabenzotriazole-1). -yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg) , and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL of anhydrous DMF in a manner similar to that described in Example 63 to give 15 mg (30% yield) of 5-methylthio-4- (4- {3 - [(N- ( 5,6,7,8-tetrahydronaphthyl) carbamoyl) methoxy] phenyl} (l, 3-thiazol-2-yl)) thiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C27H26N4O2S3, 535.2 (M + H), found 535.3.

Example 74

D, L-4- [4- (3- {2- [3- (hydroxymethyl) piperidyl] -2-oxoethoxy} phenyl) (1,3-thiazol-2-yl)] -5-methylthiothiophene-2-carboxamidine- trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) g), prepared in a manner similar to that described in Example 60, was reacted

156 with 3-piperidine-methanol (0.5 mol / l, 58 mg) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL anhydrous DMF in a manner similar to that described in Example 40, to give sa 19 mg (40% yield) D, L-4- [4- (3- {2- [3- (hydroxymethyl) -piperidyl] -2-oxoethoxy} phenyl) (1,3-thiazol-2-yl)] 5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C23H25N4O3S2: 503.2 (M + H), found 503.2.

Example 75

4- {4- [3- (2 - {(2R) -2 - [(phenylamino) methyl] pyrrolidinyl} -2-oxoethoxy) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2 carboxamidine trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methyl-thio-3-thienyl) -1H-2-yl] -benzene-1-ol; (3-thiazol-4-yl) phenoxy} acetic acid (0.93 mmol / g), prepared in a manner similar to that described in Example 60, was reacted with (S) - (+) - 2-anilinomethylpyrrolidine (0.5 mol (1.88 mg) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy- 7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL of anhydrous DMF in a manner similar to that described in Example 63, yielding 13 mg (25% yield). 4- {4- [3- (2 - {(2 R) -2 - [(phenylamino) methyl] pyrrolidinyl} -2-oxo-ethoxy) phenyl] (l, 3-thiazol-2-yl)} - 5-methyl- tiotiofén-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C28H28N5O2S3 563.8 (M + H), found 564.2.

Example 76

4- [4- (3- {2 - [(3R) -3- (methoxymethyl) pyrrolidinyl] -2-oxoethoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine -trifIuóroacetát

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy] acetic acid (0.93 mmol) g), preparation

157, in a manner similar to that described in Example 60, was reacted with (S) - (+) - 2-methoxymethylpyrrolidine (0.5 mol / l, 58 mg) and O- (7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL of anhydrous DMF in a manner similar to that described in Example 63 to give 16 mg (35% yield) of 4- [4- (3- {2 - [(3R) -3- (methoxymethyl) -] - pyrrolidinyl] -2-oxo-ethoxy} phenyl) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C23H26N4O3S3: 503.2 (M + H), found 503.3.

Example 77 1- (2- [3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy) acetyl) piperidine-3-carboxamide trifluoroacetate

100 mg (0.093 mmol) of resin-bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (0.93 mmol) (g), prepared in a manner similar to that described in Example 60, was treated with nipecotamide (0.5 mol / 65 mg) and O- (7-azabenzotriazol-1-yl) -1,3,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 mol / l, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 mol / l, 68 mg), and diisopropylethylamine (0.233 mmol, 40 μΐ) in 1 mL of anhydrous DMF in a similar manner of the method described in Example 63 to give 11 mg (23% yield) of 1- (2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl) ] phenoxy} acetyl) piperidine-3-carboxamide trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C23H25N4O3S3 516.2 (M + H), found 516.3.

158

Example 78

5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl] (l, 3-thiazol-2-yl)} thiophene-2-carboxamidine hydrochloride

a) methyl 5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl] - (1,3-thiazol-2-yl)} thiophene-2-carboxylate

435 mg (1.76 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate were dissolved in 10 ml of reagent grade acetone. 2-Bromo-3'-trifluoromethoxy acetophenone, prepared in a manner similar to that described in Example 95, Step (a), (1.76 mmol; 497 mg) was then added and the solution was heated at reflux for 3 hours. The solution was allowed to cool, concentrated to an oil, which was then dissolved in 150 mL of dichloromethane and washed with 50 mL of 10% HCl (aq.) And 50 mL of 2M NaOH (aq.). The obtained organic layer was dried over magnesium sulfate and concentrated to give 877 mg (90% yield) of methyl 5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl] (1,3-thiazol-2-yl) } thiophene-2-carboxylate.

b) 5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine hydrochloride

To a stirred suspension of 19.4 mmol (1.04 g) of ammonium chloride (Fisher Scientific) in 20 ml of anhydrous toluene (Aldrich Chemical Co.) was added, by syringe, for 15 minutes under nitrogen at 0 ° C 9.7 ml (19 ml). (4 mmol) of a 2 mol / L solution of trimethylaluminium in toluene (Aldrich Chemical Co.) and allowed to stir at 0 ° C for 30 min then 837 mg (1.94 mmol) of methyl-5-methylthio-4- { 4- [3- (trifluoromethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxylate and the reaction mixture was heated to reflux for 3 hours. The reaction was then quenched by pouring into a slurry containing 10 g of silica in 50 ml of chloroform. The silica was then poured into a funnel equipped with a glass frit and washed with ethyl acetate, then eluted with 15% methanol.

159 nol / CthCl and the eluate is concentrated. The crude product was purified on a 1 mm layer of silica to prepare a 1 mm layer thickness using 15% methanol / CH 2 Cl 2 and treated with 4 mol / 1 HCl / dioxane to give 37 mg (5% yield) of 5-methylthio-4- {4 - [3- (trifluoromethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.43 (bs, 1.9 H), 9.05 (bs, 1.9 H), 8.67 (s, 1H), 8.43 (s, 1H), 8.10 (m, 2H), 7.65 (t, 1H), 7.40 (m, 1H), 2.8 (s, 3H). Mass spectrum (LCQ-ESI, m / z): Calcd. For C16H12F3N3OS3, 415.5 (M + H), found 416.2.

Example 79

5-Methylthio-4- (5-phenyl- (1,3-oxazol-2-yl)) thiophene-2-carboxamidine hydrochloride

a) methyl 5-methylthio-4- [N- (2-oxo-2-phenylethyl) carbamoyl] thiophene-2-carboxylate

To a stirred suspension of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (300 mg, 1.29 mmol) (prepared as described in Example 95) in 10 mL of CH 2 Cl 2 (under a CaSCU drying tube) was added 135 mL (1 mL). (55 mmol) of oxalyl chloride and then 30 ml of anhydrous DMF. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The resulting yellow solid was dissolved in 10 mL of anhydrous CH 2 Cl 2 and treated with 266 mg (1.55 mmol) of 2-aminoacetophenone. N, N-diisopropylethylamine (DIEA) (756 mL, 4.34 mmol) was then added dropwise over 3 minutes and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to an oil and partitioned between 125 mL of EtOAc and 80 mL of 1 M HCl. The aqueous layer was then extracted with ethyl acetate (2 x 30 mL) and the combined organics were washed with 1 M HCl (60 mL), saturated NaHCO 3 (120 mL) and brine (120 mL) and dried over Na 2 SO 4. Then the solvent was removed in vacuo and recrystallization of the residue from MeOH gave the title compound (314 mg, 70%) as a cream colored powder. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 8.82 (t, 1H, J = 6Hz), 8.43 (s, 1H), 8.02 (d, 2H, J = 7Hz) 7.69 (t, 1H, J = 7Hz), 7.57 (t, 2H, J = 7Hz), 4.72 (d, 2H, J = 6Hz), 3.84 (s,

160

3Η) and 2.57 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calculated for C 16 H ₁₅ NO ₄ S 2 372.0 (M + Na), found 372.1.

b) methyl 5-methylthio-4- (5-phenyl- (1,3-oxazol-2-yl)) - thiophene-2-carboxylate

To a cooled (0 ° C) solution of 80.1 mg (0.229 mmol) of methyl 5-methylthio-4- [N- (2-oxo-2-phenylethyl) carbamoyl] thiophene-2-carboxylate (prepared in the previous step) in 2 ml of anhydrous DMF was added 26.7 ml (0.286 mmol) of phosphorus oxychloride. The reaction mixture was stirred at room temperature for 20 hours and then concentrated in vacuo. The resulting yellow solid residue was recrystallized twice from MeOH to give the title compound as a beige powder (48.8 mg, 64%). 1 H-NMR (300 MHz, DMSO-d 6) δ 8.26 (s, 1H), 7.88 (s, 1H), 7.86 (d, 2H, J = 7 Hz), 7.51 (m 2H, 7.40 (m, 1H), 3.86 (s, 3H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. For C16H13NO3S2 322.0 (M + H), found 331.9.

c) 5-methylthio-4- (5-phenyl-1- (1,3-oxazol-2-yl) thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- (5-phenyl- (1,3-oxazol-2-yl)) thiophene-2-carboxylate (37.0 mg, 0.112 mmol, prepared in the previous step) was treated as in Example 10 step (c) using 59.9 mg (1.12 mmol) ammonium chloride in 0.50 mL toluene and 0.560 mL (1.12 mmol) 2M trimethylaluminium in toluene. The residue obtained is chromatographed on a 5 g column of SPE silica (Waters Sep-Pak) using 10% MeOH-CH 2 Cl 2 as the impurity eluent and then using 20% MeOH-CH 2 Cl as eluent of the product obtained in 39 mg of light yellow glass. Crystallization from MeOH-MeCN gave the title compound (33.4 mg, 85%) as a cream colored solid. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (br s, 2H), 9.13 (br s, 2H), 8.72 (s, 1H), 7.93 (s, 1H) ), 7.84 (d, 2H,> 7 Hz), 7.53 (t, 2H, J = 7 Hz), 7.42 (t, 1H, J = 7 Hz), and 2.80 (s, 3H) . weight

161 spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. For C15H13N3OS2, 316.1 (M + H), found 316.5.

Examples 80 and 81

5-methylthio-4- (4-phenylimidazol-2-yl) thiophene-2-carboxamidine trifluoroacetate and 5-methylthio-4- [N- (2-oxo-2-phenylethyl) carbamoyl] thiophene-2-carboxamidine trifluoroacetate

Methyl 1-5-methylthio-4- [N- (2-oxo-2-phenyl) carbamoyl] thiophene-2-carboxylate (39.4 mg, 0.100 mmol), prepared according to the method of Example 79, step (a) l) was treated as in Example 10, step (b) with 64.2 mg (1.20 mmol) of ammonium chloride in 0.2 mL of toluene and with 0.600 mL (1.20 mmol) of 2 M trimethylaluminium in toluene. The residue obtained is chromatographed on a 5 g column of SPE silica (Waters Sep-Pak) using a gradient of 5-20% MeOH / CFHCl to elute the impurity followed by 20% MeOH-CH2Cl2 to give a yellow resin. Crystallization from MeOH-Et 2 O-MeCN gave 16 mg of a yellow solid which contained two products by 1 H-NMR spectroscopy. A portion of this mixture (11 mg) was purified by reverse phase HPLC (5 m Cg column, 4.6 x 100 mm, gradient 5-100% solvent B over 15 min, solvent A = 0.1% TFA / H2O, solvent B = 0.1% TFA / MeCN (detection at 215 nm) to give 6 mg of 5-methylthio-4- (4-phenylimidazol-2-yl) thiophene-2-carboxamidine trifluoroacetate as a colorless glass. 1 H-NMR (300 MHz, CD 3 OD) δ 8.23 (s, 1H), 7.80 (s, 1H), 7.79 (d, 2H, J = 7 Hz), 7.48 (m, 2H) ), 7.39 (m, 1H), and 2.78 (s, 3H). Mass spectrum (ionization-electrospray): Calcd. For C15H14N4S2 315.1 (M + H), found 315.3. 4 mg of 5-methylthio-4- [N- (2-oxo-2-phenylethyl) carbamoyl] thiophene-2-carboxamidine trifluoroacetate is also isolated as a colorless glass. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.30 (br s, 2H), 8.86 (br s, 2H), 8.68 (t, 1H, J = 5.4 Hz), 8.43 (s, 1H), 8.04 (d, 2H, J = 7Hz), 7.70 (t, 1H, J = 7Hz), 7.58 (t, 2H, J = 7Hz) 4.78 (d, 2H, J = 5.4 Hz), and 2.63 (s, 3H). Mass spectrum (ionization-electrospray): Calcd. For C ₁₅ H ₁₅ N ₃ O ₂ S ₂ 334.1 (M + H), found 334.3.

162

Example 82

4- (4-Phenyl-1,3-thiazol-2-yl) -thiophene-2-carboxamidine hydrochloride

a) 4-bromothiophene-2-carboxylic acid

To a cooled solution (0 ° C) of 10.0 g (47.1 mmol based on 90% purity) of 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company, Milwaukee, WI) in 200 mL tert-butanol was added 100 mL 20% (w / v) NaH ₂ PO ₄ solution and then 60 ml (0.566 mol) of 2-methyl-2-butene. Sodium chlorite (70.8 mmol based on 80% purity) in 60 mL of water was then added with stirring. The biphasic mixture was stirred vigorously for 16 hours at room temperature and then the pH of the aqueous layer was adjusted to 1-2 with 20% HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 120 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 9.8 g of an off-white solid. Recrystallization (three fractions) from a minimum amount of MeCN gave the title compound as a white solid (9.02 g, 93%). 1 H-NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, 1H, J = 1.5 Hz), and 7.55 (d, 1H, J = 1.5 Hz).

b) methyl 1-4-bromothiophene-2-carboxylate

To a cooled solution (-20 ° C) of 6.02 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (prepared in the previous step) in 100 mL of anhydrous MeOH under a nitrogen atmosphere was added dropwise 2.55 mL ( 34.9 mmol) of thionyl chloride at such a rate that the temperature remained below -5 ° C (about 8-10 min). The reaction mixture was stirred at room temperature for 1 hour and then heated at reflux for 8 hours and then cooled and concentrated in vacuo. 6.7 g of a pale amber oil which was passed through a 150 g plug of silica gel using about 600 ml of CH ₂ C1 ₂ (the first 120 ml, containing a minor impurity was removed), and concentrated in vacuo to give a colorless oil the title compound (6.11 g, 95%). ¹ H-NMR (300 MHz, CDCl 3) δ 7.69 (d, 1H, J = 1.5 Hz), 7.45 (d, 1H, J = 1.5 Hz), and 3.90 (s, 3H).

163

c) methyl 4-cyantiophene-2-carboxylate

To a solution of 3.82 g (17.3 mmol) of methyl 4-bromothiophene-2-carboxylate (prepared in the previous step) in 10 mL of anhydrous DMF was added 3.10 g (34.6 mmol) of copper cyanide. The resulting mixture was heated at reflux for 18 hours with stirring, then cooled and poured into 100 mL of 10% (w / v) KCN. The mixture was then extracted with EtOAc (3 x 60 mL) and the combined extracts were washed with 150 mL of water and 150 mL of brine. The dark solution is dried over Na ₂ SO 4, treated with charcoal to decolorize, filtered, and the colorless solution obtained is concentrated in vacuo. The obtained light yellow solid is recrystallized from MeOH to give the title compound as a cream colored solid. 1 H-NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, 1H, J = 1.4 Hz), 7.93 (d, 1H, J = 1.4 Hz), and 3.93 (s , 3H). IR (film): 2235 and 1712 cm ^-1 .

d) methyl 4- (aminothioxomethyl) thiophene-2-carboxylate

A solution of 1.32 g (7.89 mmol) of methyl 4-cyantiophene-2-carboxylate (prepared in the above step) in 200 mL of MeOH reagent grade was degassed for 10 minutes with a nitrogen fed gas dispersion tube. Triethylamine (5.50 mL, 39.5 mmol) was then added and hydrogen sulfide was bubbled into the solution by bubbling with stirring, initially vigorously for 5 minutes and then at a minimum rate (measured by a bubble oil flow meter). The gas was then stopped, the vial was sealed and the contents were stirred at room temperature for 19 hours. The mixture was then concentrated in vacuo to a yellow solid, which was then suspended in 10 mL of EtOH, cooled to -20 ° C and filtered while washing with 5 mL of cold (-20 ° C) EtOH. The resulting solid was dried under suction and then under high vacuum as a beige-brown solid to give the title compound (1.31 g, 82%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.85 (br s, 1H), 9.51 (br s, 1H), 8.50 (d, 1H, J = 1.5 Hz), 8.28 (d, 1H, J = 1.5 Hz), and 3.84 (s, 3H).

164

e) methyl 4- (4-phenyl-1,3-thiazol-2-yl) thiophene-2-carboxylate

To a solution of 150 mg (0.745 mmol) of methyl 4- (aminothioxomethyl) thiophene-2-carboxylate (prepared in the previous step) in 6 mL of acetone was added 148 mg (0.745 mmol) of 2-bromoacetophenone. The reaction mixture is heated at reflux for 2 hours and then concentrated to boiling to about 2 ml. The resulting mixture was cooled (-10 ° C) and filtered with cold acetone (2 x 0.5 mL). A second crop was obtained from the mother liquor and the combined fractions were dried to give the title compound as a beige-brown solid (202 mg, 90%). 1 H-NMR 300 MHz, DMSO-d 6 δ 8.56 (d, 1H, J = 1.5 Hz), 8.25 (d, 1H, J = 1.5 Hz), 8.18 (s, 1H), 8.04 (d, 2H, J = 7Hz), 7.48 (t, 2H, J = 7Hz), 7.38 (t, 1H, J = 7Hz), and 3.89 (t) s, 3H). Mass spectrum (MALDI-TOF, acyano-4-hydroxycinnamic acid matrix) calcd. For C15HHNO2S2: 302.0 (M + H), found 301.8.

f) 4- (4-phenyl-1,3-thiazol-2-yl) thiophene-2-carboxamidine hydrochloride

Methyl 4- (4-phenyl-1,3-thiazol-2-yl) thiophene-2-carboxylate (160 mg, 0.531 mmol, prepared in the previous step) was treated as in Example 10 step (b) with 284 mg ( 5.31 mmol) of ammonium chloride in 2.6 ml of toluene and 2.65 ml (5.30 mmol) of a 2M solution of trimethylaluminium in toluene. The light yellow solid obtained is chromatographed on a column of 10 g of SPE silica (Waters Sep-Pak) by gradient elution with a 5-20% MeOHCH 2 Cl 2 mixture. The resulting light amber colored glass which was triturated with CH2Cl2 and concentrated in vacuo to afford as a beige solid title compound (68 mg, 45%). 'H-NMR (300 MHz, DMSO- d _d) δ 9.51 ( br s, 2H), 9.09 (br s, 2H), 8.71 (d, 1H, J = 1.5Hz), 8.61 (d, 1H, J = 1.5Hz), 8, 21 (s, 1H), 8.05 (d, 2H, J = 7Hz), 7.50 (t, 2H, J = 7Hz), and 7.40 (t, 1H, J = 7Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. For C14H11N3S2: 286.0 (M + H), found 286.3.

Example 83

165

5-Methylthio-4- [4-benzyl- (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

(a) bromo-3-phenylacetone

To a solution of phenylacetyl chloride (132 mL, 1.00 mmol) in anhydrous MeCN (1.0 mL) was added a 2 M solution of trimethylsilyldiazomethane in hexane (1.05 mL, 2.10 mmol). The reaction mixture was stirred at room temperature for 1 hour, then cooled (0 ° C) and a 30% (w / w) solution of HBr in acetic acid (gas evolution) was added dropwise. After 15 minutes the mixture was concentrated in vacuo by flash chromatography on a 2 g silica SPE column (Waters SepPot) using 50% CH ₂ Cl ₂ -hexane to give the title compound as a pale yellow oil (201 mg, 94%). 1 H-NMR (300 MHz, CDCl 3) δ 7.2-7.4 (m, 5H), 3.95 (s, 2H), 3.92 (s, 2H).

b) 5-methylthio-4- [4-benzyl (1,3-thiazol-2-yl)] thiophene-2-carboxylate

Using a method similar to that described in Example 10, using 171 mg (0.690 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 82, step (e)) in 4 ml of acetone and 147 mg. (0.690 mmol) of 1-bromo-3-phenylacetone (prepared in the previous step) gave the title compound (236 mg, 95%) as a pale tan powder. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 7.2-7.4 (m, 5H), 4.11 (s, 2H), 3.84 (s , 3H), and 2.72 (s, 3H). Mass spectrum (MALDITOF, α-cyano-4-hydroxycinnamic acid matrix ₎ calcd. For C 17 H 18 NO ₂ S 3 362.0 (M + H), found 362.3.

c) 5-methylthio-4- [4-benzyl (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- [4-benzyl- (1,3-thiazol-2-yl)] thiophene-2-carboxylate (60 mg, 0.166 mmol, prepared in the previous step) was worked up as follows:

166 of Example 10, step (b) using 88.8 mg (1.66 mmol) ammonium chloride in 0.5 mL toluene and 0.830 mL (5.30 mmol) 2 M trimethylaluminium in toluene, and triturating with MeOH with Et ₂ O gave the title compound as a yellow solid (38.2 mg, 60%). 1 H-NMR (300 MHz, CD ₃ OD) δ 8.43 (s, 1H), 7.167.33 (m, 5H), 4.15 (s, 2H), and 2.75 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. For C16H15N3S3, 346.0 (M + H), found 346.0.

Example 84

5-Methylthio-4- (4-phenyl- (1,3-oxazol-2-yl)) thiophene-2-carboxamidine hydrochloride

a) methyl 4- [N- (2-hydroxy-1-phenylethyl) carbamoyl] -5-methylthiothiophene-2-carboxylate

To a stirred suspension of 1.23 g (5.29 mmol) of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (prepared according to Example 79 step (a)) in 20 mL of anhydrous CH 2 Cl 2 (under a CaSO ₄ drying tube) 1.85 mL (21.2 mmol) of oxalyl chloride was added followed by 30 mL of anhydrous DMF. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The resulting yellow solid was dissolved in 20 mL of anhydrous CH 2 Cl 2, cooled to 0 ° C, 1.85 mL of N, N-diisopropylethylamine (10.6 mmol) and 1.02 g (7.41 mmol) of phenylglycinol were added and the mixture is stirred for 1 hour at room temperature. The mixture was concentrated to an oil and partitioned between 200 mL EtOAc and 200 mL saturated NaHCO ₃ . The organic phase was washed with saturated NaHCO ₃ (200 mL), 10% (w / v) and brine (200 mL) and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and column chromatography of the residue on a 10 g silica SPE column (Waters Sep-Pak) using a gradient elution of 0-20% EtOAc-CH 2 Cl 2 afforded the title compound (1.26 g) as a light yellow solid. , 68%). 1 H-NMR (300 MHz, CDCl 3) δ 8.00 (s, 1H). 7.30-7.42 (m, 5H), 7.08 (d, 1H, J = 7.2 Hz), 5.26 (m, 1H), 3.99 (t, 2H, J = 5, 4 Hz), 3.89 (s, 3H), 2.60 (s, 3H), and 2.33 (t, 1H, J = 6.1

167

Hz). Mass spectrum (electrospray ionization): calculated for C16H17NO4S2 352.1 (M + H), found 352.0.

b) methyl 5-methylthio-4- [N- (2-oxo-1-phenylethyl) carbamoyl] thiophene-2-carboxylate

To a solution of 505 mg (1.44 mmol) of methyl 4- [N- (2-hydroxy-1-phenylethyl) carbamoyl] -5-methylthiothiophene-2-carboxylate (prepared in the previous step) in 20 mL of anhydrous CH 2 Cl 2 is added 856 mg (2.02 mmol) of Dess Martin reagent (Omega Chemical Company, Inc., Levis (Qc) Canada). The reaction mixture was stirred at room temperature in an open flask for 1.5 hours and then concentrated in vacuo to about 10% volume and partitioned between 50 mL EtOAc and 50 mL saturated NaHCO 3 -salts (1: 1). The organic phase was washed with brine (200 mL), dried over Na 2 SO 4 and concentrated in vacuo. It was then re-concentrated from CH 2 Cl 2 and then under high vacuum as a pale yellow foam to give the title compound (495 mg, 98%), which was used in the next step without further purification. 1 H-NMR (300 MHz, CDCl 3) δ 9.64 (s, 1H), 8.04 (s, 1H), 7.59 (d, 1H, J = 5 Hz), 7.36-7.46 (m, 5H), 5.76 (d, 1H, J = 5 Hz), 3.90 (s, 3H), and 2.62 (s, 3H).

c) methyl 1-5-methylthio-4- (4-phenyl- (1,3-oxazol-2-yl)) thiophene-2-carboxylate

To a cooled solution (0 ° C) of 465 mg (1.33 mmol) of methyl 5-methylthio-4- [N- (2-oxo-1-phenylethyl) carbamoyl] thiophene-2-carboxylate (prepared in the previous step) in 6 ml of anhydrous DMF is added 186 ml (2.00 mmol) of phosphorus oxychloride. The reaction mixture was stirred at room temperature for 14 hours, then treated with 10 mL of saturated NaHCO 3 and concentrated to dryness under high vacuum. The residue is partitioned between 80 mL EtOAc and 60 mL water. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (60 mL) and dried over Na 2 SO 4. 406 mg of an amber-colored solid are obtained, from which the major part of the polar impurity is removed as a cream-colored solid by recrystallization from CH2Cl2-Et2O. remaining

The 168 mother liquor was chromatographed on a 10 g column of SPE silica (Waters Sep-Pak) using a gradient elution of 40-100% CFhCl-hexane and the residue was triturated with Et 2 O-hexane (2: 1) to give the title compound as a white solid. beige solid title compound (114 mg, 26%). 1 H-NMR (300 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.93 (s, 1H), 7.83 (m, 2H), 7.43 (m, 2H), 7, 33 (m, 1H), 3.91 (s, 3H), and 2.72 (s, 3H). Mass spectrum (ESI): Calcd. For C ₁₆ H 13 NO ₃ S 2 332.0 (M + H), found 332.2.

d) 5-methylthio-4- (4-phenyl- (1,3-oxazol-2-yl)) thiophene-2-carboxamidine hydrochloride

Methyl 1-5-methylthio-4- (4-phenyl- (1,3-oxazol-2-yl)) thiophene-2-carboxylate (80.3 mg, 0.242 mmol, prepared in the previous step) was treated as in Example Step 10 (b) using 155 mg (2.90 mmol) of ammonium chloride in 1.45 mL of toluene and 1.45 mL (2.90 mmol) of a 2 M solution of trimethylaluminium in toluene. The obtained light yellow solid was chromatographed on a 5 g column of SPE silica (Waters Sep-Pak) using 10% MeOH-CH 2 Cl 2 to give a light yellow resin. Crystallization from 10% MeOHCH 2 Cl 2 (about 1: 3) gave the title compound as a yellow solid (62.2 mg, 82%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.39 (br s, 2H), 8.97 (br s, 2H), 8.78 (s, 1H), 8.60 (s, 1H) ), 7.89 (d, 2H, J = 7Hz), 7.49 (t, 2H, J = 7Hz), 7.38 (t, 1H, J = 7Hz), and 2.80 (s) , 3H). Mass spectrum (ESI): Calcd. For C15H13N3OS2 316.1 (M + H), found 316.2.

Example 85

4- [4- (4-hydroxy-3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

a) 4- (chlorocarbonyl) -2-methoxyphenylacetate

169

To a stirred suspension of 1.00 g (4.76 mmol) of 4-acetoxy-3-methoxybenzoic acid (Pfaltz and Bauer, Inc.) in 4 mL of anhydrous CH 2 Cl 2 (under a CaSCl 2 drying tube) was added 4.15 mL (47, 6 mmol) of oxalyl chloride and then 25 ml of anhydrous DMF. The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo to give the title compound (1.12 g, 103%) as pale yellow crystals. 1 H-NMR (300 MHz, CDCl 3) δ 7.81 (dd, 1H, J = 8.4, 2.1 Hz), 7.66 (d, 1H, 2.1 Hz), 7.19 (d (1H, 8.4 Hz), 3.91 (s, 3H), and 2.35 (s, 3H).

b) 4- (2-bromoacetyl) -2-methoxyphenylacetate

To a solution of 1.09 g (4.6 mmol) of 4- (chlorocarbonyl) -2-methoxyphenyl acetate (prepared in the previous step) in 10.0 mL of anhydrous CH 2 Cl 2 is added 10.0 mL (20.0 mmol) of solution 2. mol / L trimethylsilyldiazomethane in hexane. After stirring at room temperature for 2 hours, the mixture was cooled (0 ° C) and 3.20 mL (16.0 mmol) of 30% HBr in acetic acid (gas evolution) was added dropwise. After 5 min, the mixture was concentrated in vacuo and flash chromatographed on a 10 g silica (Waters Sep-Pak) column with CH 2 Cl 2 to give the title compound (1.28 g, 97%) as a pale yellow crystalline mass. 1 H-NMR (300 MHz, CDCl 3) δ 7.63 (d, 1H, 1.9 Hz), 7.59 (dd, 1H, J = 8.2, 1.9 Hz), 7.16 (d (1H, 8.2 Hz), 4.43 (s, 2H), 3.91 (s, 3H), and 2.35 (s, 3H).

c) 2-methoxy-4- (2- [5- (methoxycarbonyl) -2-methylthio (3-thienyl)] (1,3-thiazol-4-yl)} phenyl acetate

In a manner similar to that described in Example 82, step (e), using 1.00 g (4.04 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Company, Cornwall, UK) at 15 ml of reagent grade acetone and 1.16 g (4.04 mmol) of 4- (2-bromoacetyl) -2-methoxyphenylacetate (prepared in the previous step) gave 1.42 g of the title compound as a yellow solid, which contained by 1 H-NMR spectrum a mixture of about 1: 1 of the title compound and the corresponding compound resulting from a partial loss of acetone. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 8.22 (s, 1H), 8.19 (s,

170

1 H), 8.00 (s, 1H), 7.78 (d, 1H, 1.9 Hz), 7.67 (dd, 1H, J = 8.2, 1.9 Hz), 7.61 ( d, 1H, 1.9 Hz), 7.51 (dd, 1H, J = 8.2, 1.9 Hz), 7.19 (d, 1H, 8.2 Hz), 6.86 (d, 1H, 8.2 Hz), 8.87 (m, 12H), 2.76 (s, 3H), 2.75 (s, 3H), and 2.28 (s, 3H). Mass spectrum (ESI): calcd. For C19H17NO5S3, 436.0 (M + H) and 394.1 (M + H), found 436.1 and 394.2. This mixture is used without further purification in the next step, wherein the amidine formation simultaneously involves the removal of acetone.

d) 4- [4- (4-hydroxy-3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

A portion of the mixture (500 mg, about 1.21 mmol by 1 H-NMR integration) containing 2-methoxy-4- {2- [5- (methoxycarbonyl) -2-methylthio (3-thienyl)] (1,3-thiazol-4) -yl)} phenylacetate (prepared in the previous step) was treated as in Example 10 step (b) using 610 mg (11.4 mmol) of ammonium chloride in 5.7 mL of toluene and 5.70 mL (11.4 mmol) trimethylaluminium 2 mol / L in toluene. The obtained residue was chromatographed on a column of 10 g of SPE silica (Waters Sep-Pak) using a gradient elution of 5-20% MeOH-CH 2 Cl 2 to give a yellow glassy mass which was recrystallized from MeOHCH 2 Cl 2 to give the title compound as a pale yellow solid mass (192 mg, 42%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.35 (br s, 2H), 9.27 (s, 1H), 8.97 (br s, 2H), 8.62 (s, 1H) ), 8.04 (s, 1H), 7.62 (s, 1H), 7.54 (d, 1H, J = 8.2 Hz), 6.88 (d, 1H, J = 8.2 Hz) ), 3.87 (s, 3H), and 2.79 (s, 3H). Mass spectrum (ESI): Calcd. For C16H15N3O2S3 378.0 (M + H), found 378.1.

Example 86

4- [4- (3-hydroxy-4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

(a) 3-acetyloxy-4-methoxybenzoic acid

171

To a suspension of 600 mg (3.57 mmol) of 3-hydroxy-4-methoxybenzoic acid (Aldrich Chemical Company, Milwaukee, WI) in 5 mL of anhydrous CH 2 Cl 2 was added 1.31 mL (7.50 mmol) of N, N, diisopropyl- ethylamine and the mixture is stirred until homogeneous (about 5 minutes). Acetyl chloride (305 mL, 4.28 mmol) was then added dropwise over 2 minutes followed by 2.0 mg ((0.016 mmol) of 4-dimethylaminopyridine) and the reaction mixture was stirred at room temperature for 1 hour. mL of EtOAc and washed with 1 N HCl (3 x 25 mL) The organic phase was extracted with saturated NaHCO 3 (6 x 15 mL) and the combined extracts were saturated with solid NaCl and acidified to pH 2 with concentrated HCl. x 20 mL) and the combined extracts were dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (463 mg, 62%) as a light beige brown powder. 1 H-NMR (300 MHz, CDCl ₃ ) δ 8.00 ( dd, 1H, J = 8.7, 2.0 Hz), 7.79 (d, 1H, 2.0 Hz), 7.00 (d, 1H, 8.7 Hz), 3.91 (s, 3H), and 2.34 (s, 3H).

b) 3- (chlorocarbonyl) -6-methoxyphenyl acetate

Using the method of Example 85, step (a), 400 mg (1.90 mmol) of 3-acetyloxy-4-methoxybenzoic acid (prepared in the previous step) were treated with 663 ml (7.60 mmol) of oxalyl chloride and 25 g of the desired compound. ml of anhydrous DMF with a working time of 2 hours and after work-up, the title compound is obtained in the form of a beige-brown crystalline solid which is used in the next without further purification.

c) 5- (2-Bromoacetyl) -2-methoxyphenyl acetate

Using the method of Example 85, step (b), sample 3 (chlorocarbonyl) -6-methoxyphenylacetate (prepared in the previous step) in 5 mL of anhydrous CH 2 Cl 2 was treated with 2.09 mL (4.18 mmol) of a 2 mol solution. (1) trimethylsilyldiazomethane in hexane and with 456 mL (2.28 mmol) of 30% HBr in acetic acid. Chromatography according to the procedure of Example 85 step (b) followed by recrystallization from CH 2 Cl 2 gave the title compound (366 mg, 67%) as a slightly yellow solid. 'H-NMR (300 MHz, CDCl3) δ

172

7.79 (dd, 1H, J = 8.6, 2.2 Hz), 7.70 (d, 1H, 2.2 Hz), 7.03 (d, IH, 8.6 Hz), 4, 38 (s, 2H), 3.92 (s, 3H), and 2.34 (s, 3H).

d) 2-methoxy-5- {2- [5- (methoxycarbonyl) -2-methylthio (3-thienyl)] (1,3-thiazol-4-yl)} phenylacetate

In a similar manner to that described in Example 82, step (e), using 282 mg (1.14 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Company, Cornwall, UK) in 4 mL of acetone and using 3.27 mg (1.14 mmol) of 5- (2-bromoacetyl) -2-methoxyphenylacetate (prepared in the previous step) gave a yellow solid (374 mg) which, according to 1 H NMR spectrum, contained a mixture of the title compound and the corresponding compounds with a partial loss of acetate of 3: 7. MS (ESI): for C ₁₉ H _I7 NO5S3 and CnH ^ noas calcd 436.0 (M + H) and 394.1 (M + H), found 436.0 and 394.0. This mixture was used in the next step wherein the formation of amidine simultaneously involves removal of the acetate, without purification.

e) 4- [4- (3-hydroxy-4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

A portion of the mixture (320 mg, about 0.788 mmol according to NMR spectroscopy) containing 2-methoxy-5- {2- [5- (methoxycarbonyl) -2-methylthio- (3-thienyl)] (1,3-thiazol-4-yl) The phenylacetate (prepared in the previous step) was treated as in Example 10, step (b), using 415 mg (7.76 mmol) of ammonium chloride in 3.5 ml of toluene and 3.88 ml (7.66 mmol) of the solution. 2 M trimethylaluminium in toluene. Chromatography of the residue on a 10g SPE silica column (Waters Sep Pak) using 10-40% MeOHCH 2 Cl 2 gave a pale yellow solid which was dissolved in 45 mL of DMF and filtered to remove silica gel. Concentration in a high vacuum and recrystallization from MeOH-Et2O gave the title compound as a light brown solid (132 mg, 44%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.49 (br s, 2H), 9.16 (br s, 2H), 8.67 (s, 1H), 7.98 (s, IH) ), 7.5 (overlapped m, 3H), 7.00 (overlapped d.

173

1 H, J = 8.3 Hz), 3.82 (s, 3H), and 2.79 (s, 3H). Mass spectrum (ESI): Calcd. For C16H15N3Cl2S3 378.0 (M + H), found 378.1.

Example 87

5-methylthio-4- (N-phenylcarbamoyl) thiophene-2-carboxamidine hydrochloride

a) 5-methylthio-4- (N-phenylcarbamoyl) thiophene-2-carboxylate

182 mg (0.785 mmol) of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (prepared according to the method of Example 95) in 4 ml of anhydrous CH 2 Cl 2 were treated for 2 hours with 275 ml (3.15 mmol) of oxalyl chloride and 6 ml of anhydrous DMF in a manner similar to that of Example 79, step (a); then the reaction mixture is treated with 206 mL (1.18 mmol) of N, N diisopropylethylamine and 85.9 mL (0.942 mmol) of aniline in 3 mL of anhydrous CH 2 Cl 2 at a working time of 20 minutes. The resulting mixture was then poured into 25 mL of EtOAc and washed with 1N HCl (2 x 25 mL), saturated NaHCO 3 (2 x 25 mL), and brine (25 mL), and dried over Na ₂ SO 4. Removal of the solvent in vacuo gave the title compound (163 mg, 68%) as a light yellow solid. 1 H-NMR (300 MHz, CDCl 3) δ 8.23 (br s, 1H), 8.10 (s, 1H), 7.63 (d, 2H, J = 7 Hz), 7.36 (t, 2H, J = 7Hz), 7.15 (t, 2H, J = 7Hz), 3.90 (s, 3H), and 2.64 (s, 3H).

b) 5-methylthio-4- (N-phenylcarbamoyl) thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- (N-phenylcarbamoyl) thiophene-2-carboxylate (60.0 mg, 0.195 mmol, prepared in the previous step) was treated in a manner similar to that described in Example 10, step (b) using 310 mg (5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of a 2M solution of trimethylaluminium in toluene at a working time of 6 hours. Chromatography of the residue obtained on a 2g silica SPE column (Waters Sep-Pak) using a gradient elution with 5-20% MeOH-CH ₂ Cl ₂ followed by

174 crystallization from MeOH-Et2O gave the title compound (40.3 mg, 71%) as a beige-brown solid. H-NMR (300 MHz, DMSO- d _d) δ 10.24 (s, 1H), 9.34 (br s, 2H), 9.05 (br s, 2H), 8.75 (s, 1 H 7.73 (d, 2H, J = 8Hz), 7.36 (t, 2H, J = 8Hz), 7.11 (m, 1H), and 2.67 (s, 3H). Mass spectrum (ESI): calcd. For C13H13N3OS2 292.1 (M + H), found 292.4.

Examples 88 and 89

5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxamidine hydrochloride and 4- {imino [benzylamino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride

(a) methyl 5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxylate

The title compound was prepared in the same manner as described in Example 87 step (a) using 103 ml (0.942 mmol) of benzylamine and the same amounts of the other reagents as a light yellow solid (167 mg, 66%). 1 H-NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.28-7.38 (m, 5H), 6.58 (br s, 1H), 4.62 (s, 2H, J = 5.7 Hz), 3.87 (s, 3H), and 2.60 (s, 3H).

b) 5-Methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxamidine hydrochloride and 4- {imino [benzylamino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxylate (62.7 mg, 0.195 mmol, prepared in the previous step) was treated in a manner similar to that described in Example 10 step (b) using 310 mg ( 5.80 mmol) of ammonium chloride in 2 ml of toluene and 2.90 ml (5.80 mmol) of a 2 mol / L solution of trimethylaluminium in toluene at a working time of 6 hours.

Chromatography of the residue on a 2g silica SPE column (Waters Sep-Pak) using 5-20% MeOHCH ₂ Cl ₂ gradient elution followed by crystallization from MeOH-Et ₂ O yields as a beige

175 brown solid 5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxamidine hydrochloride (21.1 mg, 35%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 7.93 (s, 1H), 7.28-7.38 (m, 5H), 6.58 (br s, 1H), 4.62 ( s, 2H, J = 5.7 Hz), 3.87 (s, 3H), and 2.60 (s, 3H). Mass spectrum (ESI): Calcd. For C14H15N3OS2 306.1 (M + H), found 306.6.

Isolation and crystallization from MeOH-Et 2 O also yields more polar 4- {imino [benzylamino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride as a beige-brown solid (32.0 mg, 54%). 1 H-NMR (300 MHz, DMSO d6) was consistent with the desired product as its various rotamers. MS (ESI) for C ₄ H] ₆ N4S2 calcd 305.1 (M + H), found 305.8.

Examples 90 and 91

4- [N-benzylcarbamoyl] -5-methylthiothiophene-2-carboxamidine hydrochloride and 4- (imino [methylbenzylamino] methyl) -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiophene-2-carboxylate

The title compound was prepared in the same manner as described in Example 87 step (a) using 122 mL (0.942 mmol) of N-benzylmethylamine and the same amounts of other reagents as a light yellow solid (169 mg, 64%). 1 H-NMR (300 MHz, CDCl 3) δ 7.68 (s, 1H), 7.34 (m, 5H), 4.6 (br m, 2H), 3.86 (s, 3H), 2, 91 (m, 3H), and 2.60 (s, 3H).

b) 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiothiophene-2-carboxamidine hydrochloride and 4- (amino [methyl benzylamino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride

176

Methyl 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiothiophene-2-carboxylate (65.4 mg, 0.195 mmol, prepared in the previous step) was treated in a manner similar to that described in Example 10 step (a) using 310 mg (5.80 mmol) of ammonium chloride in 2 ml of toluene and 2.90 ml (5.80 mmol) of a 2 mol / L solution of trimethylaluminium in toluene at a working time of 6 hours.

Chromatography of the residue on a 2g silica SPE column (Waters Sep-Pak) using 5-20% MeOHCH 2 Cl 2 gradient elution affords 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiothiophene as an amber-colored glassy solid. -2-carboxamidine hydrochloride (34.3 mg, 55%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.32 (br s, 2H), 9.06 (br s, 2H), 8.11 (s, 1H), 7.36 (m, 5H) ), 4.66 (m, 2H), and 2.88 (s, 3H) and 2.66 (s, 3H). Mass spectrum (ESI): Calcd. For C 18 H 11 N 5 OSi 320.1 (M + H), found 320.4.

Isolation and crystallization from MeOH-Et 2 O also yields more polar

4- {imino [methylbenzylamino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride as a beige-brown solid (19.8 mg, 32%). 1 H-NMR (300 MHz, DMSO-d 6) was consistent with the desired product as its various rotamers. Mass spectrum (ESI): Calcd. For C15H18N4S2 319.1 (M + H), found 319.6.

Examples 92 and 93

5-methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxamidine hydrochloride and 4- {imino [(2-phenylethyl) amino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl-5-methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxylate

The title compound was prepared in the same manner as described in Example 87 step (a) using 118 ml (0.942 mmol) of phenethylamine and equal amounts of the other reagents as a light yellow solid

177 masses (165 mg, 63%). 1 H-NMR (300 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.30-7.35 (m, 5H), 6.44 (m, 1H), 3.87 (s, 3H) 3.70 (q, 2H, J = 7Hz), 2.93 (t, 2H, J = 7Hz) and 2.53 (s, 3H).

b) 5-methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxamidine hydrochloride and 4- {imino [(2-phenylethyl) amino] methyl} -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4-methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxylate (65.4 mg, 0.195 mmol, prepared in the previous step) was treated in a manner similar to that described in Example 10, step (a) using 310 mg (5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of a 2 mol / L solution of trimethylaluminium in toluene at a working time of 6 hours.

Chromatography of the residue on a 2g SPE silica column (Waters Sep-Pak) using 5-20% MeOHCH 2 Cl 2 gradient elution followed by crystallization from MeOH-Et 2 O yields 5-methylthio-4- [N-] as a beige-brown solid. (2-phenylethyl) carbamoyl] thiophene-2-carboxamidine hydrochloride (17.4 mg, 28%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 8.89.3 (br m, 4H), 8.48 (m, 1H), 8.35 (s, 1H), 7.26 (m, 5H), 3.44 (m, 2H), 2.82 (t, 3H, J = 7.5 Hz), and 2.61 (s, 3H). Mass spectrum (ESI): Calcd. For C15H17N3OS2 320.1 (M + H), found 320.4.

Isolation and crystallization from MeOH-Et 2 O also yields more polar 4- {imino [(2-phenylethyl) amino] methyl) -5-methylthiothiophene-2-carboxamidine hydrochloride as a beige brown solid (19.1 mg, 31%) . 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.2-7.4 (m, 5H), 3.70 (t, 2H, J = 7.6 Hz) ), 2.96 (t, 2H, J = 7.6 Hz), and 2.71 (s, 3H). Mass spectrum (ESI): Calcd. For C15H18N4S2 319.1 (M + H), found 319.5.

Example 94

178

3-Amino-2-aza-3- [5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) (2-thienyl)] prop-2-enenitrile

To 100 mg (0.302 mmol) of 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (prepared according to the method of Example 10, step (b)) in 3 mL of EtOH 29.6 mg (0.604 mmol) of cyanamide as a solution in 0.3 mL of water are added and the mixture is warmed to temperature and 0.302 mL (0.302 mmol) of aqueous 1 M KOH is added. The solid obtained was dried in vacuo to give the title compound as a light yellow powder (78.4 mg, 73%). 1 H NMR (300 MHz, DMSO-d 6)? ₆ ) _δ 9.31 (br s, 1H), 8.70 (br s, 1H), 8.63 (s, 1H), 8.19 (s, 1H), 8.09 (d, 2H, J) = 7 Hz), 7.49 (t, 2H, J = 7 Hz), 7.39 (t, 1H, J = 7 Hz), and 2.75 (s, 3H). α-cyano-4-hydroxy-cinnamic acid matrix): calcd. for C16H12N4S3 357.0 (M + H), found 357.1.

Example 95

5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid

Methyl 4-cyano-5-methylthiothiophene-2-carboxylate (2.20 g, 10.3 mmol, Maybridge Chemical Company, Cornwall, UK) and tetrafluorophthalic acid (2.45 g, 10.3 mmol) were heated together to give 160 ° C in an 8 ml pressure-sealable tube (Ace Glass Company) with magnetic stir bar. The molten mixture is stirred for 4 days, then cooled, the solid residue is destroyed and extracted with 80 ml of chloroform at reflux. The resulting mixture was cooled, decolourised by the addition of activated carbon (about 0.5 g) and filtered (Celite). The resulting solution was extracted with saturated NaHCO 3 (x 30 mL) and the combined aqueous extracts were acidified to pH 1-2 with concentrated HCl and filtered to give a light brown solid. After dissolution of the solid in a minimum amount of 1M K2CO3 (35-40 ml) and filtration (washing with 10-20 ml of water) to clarify the solution, the solution is slowly acidified to pH 6.5-7.0 with stirring and filtration ( Celite) removed the brown precipitate. The pH adjustment and filtration is repeated and the solution obtained is saturated with solid

179

NaCl and acidified to pH 1-2 with concentrated HCl. The precipitate was filtered off, washed with water (3 x 10 mL) and dried under high vacuum to give a cream colored powder (1.24 g, 52%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 13.14 (br s, 1H), 7.89 (s, 1H), 3.82 (s, 3H) and 2.64 (s, 3H) . Mass spectrum (ESI, negative method): calcd. For C8H8O4S2 232.0 (M '), found 231.7.

Example 96

5-Ethylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine hydrochloride

a) 4- (4-Phenyl- (1,3-thiazol-2-yl)) - 5- (methylsulfonyl) thiophene-2-carboxylate

The title compound was prepared according to the procedure for EXAMPLE 141, step (a) using 600 mg (1.73 mmol) of methyl 5-methylthio-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2 -carboxylate prepared according to Example 10, Step (a) as 642 mg (98%) of a pale yellow powder. 1 H-NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.90 (m, 2H), 7.63 (s, 1H), 7.47 (m, 2H), 7, 39 (m, 1H), 3.98 (s, 3H) and 3.73 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C16H13NO4S3 380.0 (M + H), found 380.2.

b) 4- (4-phenyl) (1,3-thiazol-2-yl) -5- (methylsulfonyl) thiophene-2-carboxamidine hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 141, step (b) using 560 mg (1.48 mmol) of methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- ( methylsulfonyl) thiophene-2-carboxylate prepared in the previous step as 392 mg (66%) of an off-white solid. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.7 (br s, 2H), 9.4 (br s, 2H), 8.58 (s, 1H), 8.43 (s, 1H) ), 8.02 (d, 2H, J = 7Hz), 7.52 (t, 2H, J = 7Hz), 7.43 (t, 1H, J = 7Hz), and 3.90 (s , 3H). Mass spectrum (ESI, m / z): Calcd. For C15H13N3O2S3, 364.0 (M + H), found 364.1.

180

c) 5-ethylthio-4- (4-phenyl (1,3-thiazol-2-yl)) - thiophene-2-carboxamidine hydrochloride

Example 141 step (c) was followed using 23.1 mg (0.0578 mmol) of 4- (4-phenyl) (1,3-thiazol-2-yl) -5- (methylsulfonyl) thiophene. -2-carboxamidine hydrochloride (prepared in the previous step), 64.1 mL (0.867 mmol) of ethanethiol (in two portions over 2 hours), and 40.3 mL (0.231 mmol) of DIEA in 3 mL of methanol to give a yellow preparation resin from which chromatography on a 2g silica SPE column (Waters Sep-Pak) using 0-15% MeOH-CH 2 Cl 2 gradient elution followed by trituration with CH 2 Cl 2 gave the title compound (21.7%) as an off-white solid. mg, 98%). 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (br s, 2H), 9.07 (br s, 2H), 8.68 (s, 1H), 8.28 (s, 1H) ), 8.09 (d, 2H, J = 7Hz), 7.51 (t, 2H, J = 7Hz), 7.40 (t, 1H, J = 7Hz), 3.23 (q, 2H, J = 7Hz) and 1.42 (t, 3H, J = 7Hz). Mass spectrum (Ε): Calcd. For C16H15N3S3 346.1 (M + H), found 346.2.

Example 97

5-Methylthio-4- [4- (phenoxymethyl) (1,3-thiazol-2-yl) thiophene-2-carboxamidine hydrochloride

a) 3-bromo-1-phenoxyacetone

To a solution of 0.050 mmol of phenoxyacetyl chloride in 250 mL of anhydrous MeCN in a low vial of 1 drachma (3.7 mL) (Wheaton Glass) was added 50 mL (0.100 mmol) of a 2M solution of trimethylsilyldiazomethane in hexane and capped with a PTFE cap. . The reaction mixture was stirred on a vortexer for 1 hour, then the mixture was cooled (0 ° C) and 21 mL (0.105 mmol) of 30% HBr in acetic acid (gas evolution) was added dropwise. The mixture is then vortexed for 10 minutes and concentrated in vacuo to a vacuum thickener.

The centrifuge (Speed-Vac, Savant Instruments, Inc.) gave an amber oil which was used directly in the next step.

b) methyl 5-methylthio-4- [4- (phenoxymethyl) (1,3-thiazol-2-yl) thiophene-2-carboxylate

To 3-bromo-1-phenoxyacetone (prepared in the 1 st flask vial) was added 14.8 mg (0.060 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge Chemical Company, Cornwall). (UK) as a 1.48 mL solution of 10 mg / mL in acetone. The vial was then sealed and placed on a flat heated shaker (Innova model 4080, New Brunswick Scientific Co., Inc.) for 4 hours at 55 ° C and 250 rpm. To the obtained suspension was added 50 mg (0.150 mmol) of diethylaminomethylpolystyrene resin (Fluka Chemika-Biochemika, 3.0 mmol / g) as a 0.50 ml suspension of 100 mg / ml in acetone and the mixture was stirred rapidly. Chloroacetyl polystyrene resin (30 mg, 0.150 mmol, Advanced ChemTech Inc., 5.0 mmol / g) was then added followed by NaI (0.750 mg, 0.005 mmol) as a 100 mL solution of 7.5 mg / mL in acetone. The mixture was sealed again and placed on a flat heated shaker and stirred for 22 hours at 55 ° C and 250 rpm. The mixture is then filtered through a 2 ml sintered column (BioRad Biospin minicolone), washed with acetone (2 x 0.5 ml) and MeOH (2 x 0.5 ml) into a 2-mL vial and concentrated in a vacuum centrifuge to concentrate. to give 21.0 mg of the title compound as an off-white solid. 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.82 (s, 1H), 7.13 (m, 2H), 7.07 (m, 2H), 6.96 (m, 1H), 5.22 (s, 2H), 3.85 (s, 3H), and 2.74 (s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid): for C ₁₇ H ₁₅ NO ₃ S ₃ calculated 378.0, found 378.3.

c) 5-methylthio-4- [4- (phenoxymethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxamidine hydrochloride

182

Methyl-5-methylthio-4- [4- (phenoxymethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate (prepared in the previous step) in a 2 drachma canister (7 (4 ml) equipped with a magnetic stirrer was closed under a nitrogen atmosphere with a phenol cap fitted with a PTFE whisper opening. A 1 mol / L solution of freshly prepared reagent from trimethylaluminium and ammonium chloride in toluene was then added by the method of Example 10 step (b) (0.750 mL, 0.750 mmol) via syringe so that one needle passing through the whisper was used to evacuate the gases. the second needle passing through the whisper is used to inject the reagent. The vial was then placed under nitrogen atmosphere on an aluminum heating block (Fisher Scientific Dry Bath Incubator equipped with a custom made nitrogen distribution cover). The gas distribution is purged with nitrogen and the reaction mixture with a large magnetic stirring motor located upside down on the top of the gas distributor. The reaction mixture was then heated at 100 ° C for 4 hours and then cooled to room temperature over about 2 hours. The reaction in the vial is then carefully quenched by the addition of 0.5 g of silica gel in 2 ml of CH 2 Cl 2, the vial is sealed and the contents are shaken until homogeneous. The resulting slurry was then filtered through a 4 ml fritted column (isolation microcolumn) into a 2-vial vial, washing with CH 2 Cl 2 (2 x 1 mL), CH ₂ Cl ₂ -MeOH (1: 1, 1 x 1 mL) and MeOH (2 x 1 mL). ) and the filtrate is concentrated in a vacuum centrifuge to concentrate to a yellow solid. Filtration through t

A 500 mg SPE silica column (Supelco LC-Si) using 10% MeOHCH 2 Cl 2 gave the title compound (14.8 mg) as a yellow solid. ¹ HNMR (300 MHz, DMSO-d ₆ ) δ 9.45 (d, 2H, J = 8.2 Hz), 9.11 (d, 2H, J = 8.2 Hz), 8.97 (br s 2 H, 8.65 (s, 1 H). 7.90 (s, 1H), 7.0-7.5 (m, 5H), 5.25 (s, 2H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. For C17H15NO3S3 362.0 (M + H), found 361.7.

Examples 98 - 126

Examples 98-104 were prepared according to the procedure of Example 97 steps (b) and (c) using the reactant specified in the table. The compounds of Examples 105-126 were prepared according to the procedure of Example 97 steps (a), (b) and (c) using 0.05 mmol of the reactant.

183

Mass Spectrum (ESI) Example reactant compound formula Calculated (M + H) found 98 1-bromopinacolone 4- [4- (tert-butyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride c ₁₃ h ₁₇ n ₃ s 3 312.1 312.2 99 4-fluorophenacyl bromide 4- [4- (4-fluorophenyl) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2karboxamidínhydrochlorid c ₁₅ h ₁₂ fn ₃ S ₃ 350.2 350.2 100 4-Cyanophenacyl bromide 4- [4- (4-amidinophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride C ₆ Hi ₅ N ₅ S 3 374.1 374.2 101 3-fluorophenacyl bromide 4- (4- (3-fluorophenyl) (1,3-thiazol-2-yl)] - 5 methylthiothiophene-2-carboxamidine hydrochloride c ₁₅ h ₁₂ fn ₃ S ₃ 350.0 350.2 102 4- (diethylamino) phenacyl bromide 4- {4- [4- (diethylamino) phenyl] (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxamidine hydrochloride C ₁₉ H ₂₂ N ₄ S 3 403.1 403.2 103 '3-chlorophenacylbromide 4- (4- (3-chlorophenyl) (1,3-thiazol-2-yl)] - 5 methylthiothiophene-2-carboxamidine hydrochloride C ₅ H ₁₂ C1n ₃ of ₃ 366.0 366.1

184

Mass Spectrum (ESI) Example reactant compound formula Calculated (M + H) found 104 3,4difluórfenacylbromid 4- [4- (3,4-difluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride C 11 H 11 F 2 N ₃ S ₃ 368.0 368.2 105 2,6difluórbenzoylchlorid 4- [4- (2,6-difluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride CuHnFr N3S3 368.0 368.2 106 4-ethoxybenzoyl chloride 4- [4- (4-ethoxyphenyl) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene2-carboxamidine hydrochloride c ₁₇ h _I7 n ₃ o S3 376.1 376.2 107 3-chlorophenoxyacetyl chloride 4- {4 - [(4-chlorophenoxy) methyl] (l, 3-thiazol-2-yl)} - 5-methylthiothiophene2-carboxamidine hydrochloride C ₆ H ₁₄ ClN 3 -OS 3 396.0 396.1 108 cyclopentanecarbonyl 4- (4-Cyclopentyl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine hydrochloride C ₄ Hi ₇ N3S 3 324.1 324.2 109 1-naphthoyl chloride 5-methylthio-4- (4naftyl (l, 3-thiazol-2-yl)) thiophene-2-carboxamidine hydrochloride C ₁₉ H ₁₅ N ₃ S 3 382.1 382.2

185

Mass Spectrum (ESI) Example reactant compound formula Calculated (M + H) found 110 3,5dichlórbenzoylchlorid 4- (4- (3,5- dichlorophenyl) (l, 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride C ₁₅ HhCl ₂ n ₃ s ₃ 400.0 400.1 111 2,5difluórbenzoylchlorid 4- (4- (2,5-difluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride CisHnFzn ₃ s ₃ 368.0 368.2 112 9-fluorenone-4-carbonyl chloride 5-Methylthio-4- [4- (9-oxofluoren-4-yl) (1,3-thiazol-2-yl) -thiophene-2-carboxamidine hydrochloride c ₂₂ h ₁₅ n ₃ axes ₃ 434.1 434.2 113 3-methoxyphenylacetyl chloride 4- (4- (3- methoxyphenyl) methyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride C1 ₇ H ₁₇ N ₃ O N ₃ 376.1 376.2 114 4-metylvaleroylchlorid 4- (4- (3-methylbutyl) (1,3-thiazol-2-yl)] -5-methylthiothiophene-2-carboxamidine hydrochloride Ci ₄ H ₉ N ₃ S 3 326.1 326.2 115 3- (2-chlorophenyl) -5metylizoxazol-4-carbonyl chloride 4- {4- [3- (2-chlorophenyl) 5-methylisoxazol-4-yl] (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride C | ₉ H ₁₅ C1n ₄ axes ₃ 447.0 447.1

186

Mass spec- trum 1 ESI) Example reactant compound formula Calculated (M + H) found 116 4amyloxybenzoylchlorid 5-Methylthio 4- [4- (4-pentyl-oxyphenyl) (1,3-thiazol-2-yl)] -thiophene-2-carboxamidine hydrochloride C 20 H 23 N ₃ O ₃ 418.1 418.2 117 1- (4-Chlorophenyl) -1-cyclopentanecarbonyl chloride 4- {4 - [(4-chlorophenyl) cyclopentyl] (l, 3-thiazol-2-yl)} - 5-methylthiothiophene2-carboxamidine hydrochloride C20H20CI- N3S3 434.1 434.3 118 4- (trifluoromethoxy) benzoyl chloride 5-methylthio-4- {4- [4- (trifluoromethoxy) phenyl] (l, 3-thiazol-2-yl) thiophene-2karboxamidínhydrochlorid C | ₆ H ₁₂ F ₃ N 3-axis ₃ 416.0 416.1 119 3-chloro-benzo [b] thiophene-2-carbonyl 4- [4- (3-chlorobenzo [b] thiophen-2-yl) (1,3-thiazol-2-yl)] -5-methylthiothiophene-2-carboxamidine hydrochloride c ₁₇ h ₁₂ ci- N3S4 422.0 422.1 120 3- (2-chloro-6-fluorophenyl) -5metylizoxazol-4-carbonyl chloride 4- {4- [3- (6-chloro-2-fluoro-phenyl) -5-methylisoxazol-4-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride C19H14NC1 F-N4OS3 456.0 465.1

187

Mass Spectrum (ESI) Example reactant compound formula Calculated (M + H) found 121 3-cyanobenzoyl chloride 4- [4- (3-amidinophenyl) (1,3-thiazol-2-yl)] - 5methylthiothiophene-2-carboxamidine hydrochloride C16H15N5S 3 374.1 374.7 122 4-methoxyphenylacetyl chloride 4- {4 - [(4-methoxyphenyl) methyl] (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride Ci ₇ H ₁₇ N ₃ O ₃ 376.1 376.2 123 3- (t-butyl) -1-benzylpyrazol-5-carbonyl chloride 4- {4- [3- (t-butyl) pyrazol-5-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride _I9 C _{for 16} hours with 3? ₅ 378.1 378.2 124 3- (4-chlorophenyl) -2,2dimetylpropanoylchlorid 5-Methylthio-4- [4- (1-methylvinyl) (1,3-thiazol-2-yl)} thiophene-2-carboxamidine hydrochloride C | _I3 H ₂ N ₃ S 3 296.0 296.2 125 N- (lnaftalénsulfonyl) 1-phenylalanyl chloride 5-Methylthio-4- (4- {1 [(naphthylsulfonyl) amino] -2-phenylethyl} (1,3-thiazol-2-yl)) thiophene-2-carboxamidine hydrochloride C ₂₇ H24N4-O2S4 565.1 565.1 126 2-bromo-5metoxybenzoylchlorid 4- [4- (2-bromo-5-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride CiôHuBr-N ₃ OS ₃ 440.0 440.2

188

Example 127

a) 1- [3,5-bis (trifluoromethyl) phenyl-2-bromo-methan-1-one

A stirred suspension of 1 g (3.9 mmol) of 3,5-bis (trifluoromethyl) acetophenone (Lancaster, Windham, NH, USA) in dry methanol (20 mL) and containing 1 g (15 mmol, 2.6 eq.) Of poly - (4-vinyl-pyridinium tribromide) (Aldrich, Mihvaukee, WI, USA) is protected from moisture with dry nitrogen and heated at reflux for 70 minutes. The polymer is then filtered from the cooled solution, washed twice with methanol and twice with dichloromethane. Removal of the solvents in vacuo gave 1- [3,5-bis (trifluoromethyl) phenyl] -2-bromoethan-1-one (1.2 g, 92%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.43 (m, 2H), 8.12 (m, 1H), 4.46 (s, 3H).

b) methyl {4- {4- [3,5-bis (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 101 mg (0.3 mmol) of 1- [3,5-bis ( trifluoromethyl) phenyl] -2-bromoethan-1-one prepared in a manner similar to that described in Example 8, step (a), and obtained as a solid of 4- {4- [3,5-bis (trifluoromethyl) phenyl] (1). 3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate (7 mg, 5%).

1 H-NMR (DMSO-d 6, 300 MHz) δ 8.75 (s, 1H), 8.73 (m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3 87 (s, 3H); 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C19H11NO2S3F6 484.0 (M + H), found 484.0.

c) 4- {4- [3,5-bis (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine

189

Methyl 1-4- [4-3,5-bis (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (7 mg, 14.5 mmol) was treated in a manner similar to that described in Example 10, step (b), and was obtained as a yellow solid 4 {4- [3,5-bis (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxamidine (6 mg, 89%). 1 H-NMR (DMSO-d ₆ , 300 MHz) 8.78 (s, 1H), 8.74 (s, 2H), 8.62 (s, 1H), 8.15 (s, 1H), 2 82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C17HHN3S3F6: 468.0 (M + H), found 468.0.

Example 128

a) 2-Bromo-1- [3-fluoro-5- (trifluoromethyl) phenyl] ethan-1-one

A stirred suspension of 1 g (4.5 mmol) of 3-fluoro-5- (trifluoromethyl) acetophenone (Lancaster, Windham, NH, USA) was treated in a manner similar to that described in Example 127 step (a) to give a 2-bromo mixture. 1- [3-fluoro-5- (trifluoromethyl) phenyl] ethan-1-one and its 1: 1 dibromo derivative (1.6 g, 100%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.25-7.52 (m, 6H), 6.54 (s, 1H), 4.42 (s, 2H).

b) methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 86 mg (0.3 mmol) of 2-bromo-1- [3- fluoro-5- (trifluoromethyl) phenyl] ethan-1-one by a method similar to that described in Example 8, step (a), and was obtained as a solid of 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] ( 1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (41 mg, 31%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.59 (s, 1H), 8.29 (m, 1H), 8.27 (s, 1H), 8.25 and 8.21 (m (1H, conformers ratio 1: 1), 7.73 and 7.70 (m, 1H, conformers ratio 1: 1). Mass spectrum (MALDI TOF, CHCA matrix, m / z): Calcd. calcd 434.0 (M + H), found 434.0.

190

c) 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine

Treat methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (40 mg, 0.92 mmol). in a manner similar to that described in Example 10, Step (b), to give 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl) as a yellow solid } -5-methylthiothiophene-2-carboxamidine (31 mg, 81%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.36 (br s, 2H), 9.01 (br s, 2H), 8.68 (s, 1H), 8.63 (s, 1H) ), 8.30 (m, 1H), 8.25 and 8.22 (m, 1H, 1: 1 conformer ratio), 7.75 and 7.73 (m, 1H, 1: 1 conformer ratio), 2 82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H11N3S3F4 418.5 (M + H), found 418.0.

Example 129

a) 2-Bromo-1- [3-fluoro-5- (trifluoromethyl) phenyl] propan-1-one

A stirred suspension of 1 g (4.5 mmol) of 1- [3-fluoro-5- (trifluoromethyl) phenyl] propan-1-one (Lancaster, Windham, NH, USA) was treated in a manner similar to that described in Example 127, step (a). a) to give 2-bromo-1- [3-fluoro-5- (trifluoromethyl) phenyl] propan-1-one (1.33 g, 99%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.07 (m, 1H), 7.92 and 7.89 (m, 1H, conformers ratio 1: 1), 7.57 and 7.55 (m 1H, conformer ratio 1: 1), 5.20 (q, 1H, J = 6.6 Hz), 1.93 (d, 3H, J = 6.6 Hz).

b) methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxylate

191

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 90 mg (0.3 mmol) of 2-bromo-1- [ 3-fluoro-5- (trifluoromethyl) phenyl] propan-1-one in a manner similar to that described in Example 8, step (a), to give methyl 4- {4- [3-fluoro-5- ( trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (31.9 mg, 24%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.17 (s, 1H), 7.98 (m, 1H), 7.95 and 7.92 (m, 1H, conformers ratio 1: 1), 7.77 and 7.74 (m, 1H, conformer ratio 1: 1), 3.87 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C18H13NO2S3F4: 448.0 (M + H), found 448.0.

c) 4- {4- [3-Fluoro-5- (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine

Methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (30 mg, 0.067 mmol) ) was treated in a manner similar to that described in Example 10, Step (b), to give 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] -5-methyl- (1,3) as a yellow solid. -thiazol-2-yl)} 5-methylthiothiophene-2-carboxamidine (32 mg, quantitative yield). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.42 (br s, 2H), 9.03 (br s, 2H), 8.60 (s, 1H), 7.98 (m, 1H) 7.95 and 7.92 (m, 1H, conformer ratio 1: 1), 7.79 and 7.76 (m, 1H, conformer ratio 1: 1), 2.78 (s, 3H), 2, 71 (s, 3 H). Mass spectrum (MALDITOF, CHCA matrix, m / z): Calcd. For C17H13N3S3F4: 432.0 (M + H), found 432.6.

Example 130

a) 1- [3,5-bis (trifluoromethyl) phenyl] -2-bromopropan-1-one

A stirred suspension of 1 g (3.7 mmol) of 1- [3,5-bis (trifluoromethyl) phenyl] -propan-1-one (Lancaster, Windham, NJ, USA) was treated in a similar manner

192 of the method described in Example 127, Step (a) to prepare 2-bromo-1- [3-fluoro-5- (trifluoromethyl) phenyl] propan-1-one (1.1 g, 86%). H-NMR (DMSO-d _À, 300 MHz) δ 8.46 (m, 2H), 8.09 (m, 1), 5.26 (q, 1 H, J = 6.6 Hz), 1. 96 (d, 3H, J = 6.5Hz). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C11H15OBrF6 349.0 (M + H), found 348.9.

b) methyl 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 105 mg of 1- [3,5-bis (trifluoromethyl) phenyl] 2-bromopropan-1-one by a method similar to that described in Example 8, step (a) and after purification by preparative thin layer chromatography, methyl 4- {4- [3,5-bis (trifluoromethyl) was obtained as a solid. phenyl] -5-methyl- (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate (16.2 mg, 11%). 1 H NMR (DMSO-d ₆ , 300 MHz) δ 8.41 (m, 2H), 8.18 (m, 2H), 3.86 (s, 3H), 2.75 (s, 3H), 2 71 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C19H13NO2S3F6, 498.0 (M + H), found 497.6.

c) 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine

Methyl 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (15 mg, 0.031 mmol) was treated in a manner similar to that described in Example 10, Step (b), to give 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl- (1,3-thiazole) as a yellow solid. -2-yl) -5-methylthiothiophene-2-carboxamidine (13 mg, 88%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.39 (br s, 2H), 8.94 (br s, 2H), 8.58 (s, 1H), 8.40 (m, 2H) 8.19 (m, 1H); 2.79 (s, 3H); 2.73 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C18H13N3S3F6: 482.0 (M + H). found 482.5.

193

Example 131

a) 2-bromo-1,2-diphenylethan-1-one

A stirred suspension of 0.2 g (1 mmol) of deoxybenzoin was treated in a manner similar to that described in Example 127, step (a) to prepare 2-bromo-1,2-diphenyletan-1-one (270 mg, 98%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.10-8.06 (m, 2H), 7.95-7.31 (m, 8H), 7.21 (s, 1H).

b) methyl 4- (4,5-diphenyl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 92 mg (0.3 mmol) of 2-bromo-1,2-carboxylate. -diphenylethan-1-one by a method similar to that described in Example 8, step (a) and after purification by preparative thin layer chromatography, methyl 4- (4,5-diphenyl (1,3-thiazol-2)) was obtained as a solid. 5-methylthiothiophene-2-carboxylate (9 mg, 7%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.94 (br s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 08 (s, 1H), 7.93 and 7.20 (AB quartet, 2H, J = 8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J = 8.2 Hz), 2 77 (s, 3H), 1.33 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C22H17NO2S3 424.0 (M + H), found 424.3.

c) 4- (4,5-diphenyl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2 carboxamidine

Methyl 1-4- (4,5-diphenyl-1- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (9 mg, 0.021 mmol) was treated in a manner similar to that described in of Example 10, step (b), to give 4- (4,5-diphenyl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine (3 mg, 35%) as a brown oil. . Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C21H17N3S3, 408.1 (M + H), found 408.0.

194

Example 132

a) methyl 4- (4-benzo [b] thiophen-2-yl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate was treated with 77 mg (0.3 mmol) of 3-bromoacetylbenzo [b] thiophene (Maybridge, Cornwall, UK) by a method similar to that described in Example 8, step (a) and after purification by preparative thin layer chromatography, methyl 4- (4-benzo [b] thiophen-2-yl- (1,3-thiazol-2) was obtained as a solid. 5-methylthiothiophene-2-carboxylate (28 mg, 23%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.63 (d, 1H, J = 7.4 Hz), 8.30 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.53-7.46 (m, 2H), 3.87 (s, 3H), 2.78 (s, 3H).

b) 4- (4-Benzo [b] thiophen-2-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine

Methyl 4- (4-benzo [b] thiophen-2-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate (28 mg, 0.69 mmol) was treated in a similar manner according to the method described in Example 10 step (b) and as a brown solid, 4- (4-benzo [b] thiophen-2-yl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene- 2-carboxamidine (17 mg, 64%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.22 (br s, 4H), 8.68 (s, 1H), 8.66 (d, 1H, J = 7.6 Hz), 8, 30 (s, 1H); 8.25 (s, 1H); 8.10 (d, 1H, J = 7.3 Hz); 7.55-7.45 (m, 2H); 2.81 (s) , 3H). Mass spectrum (MALDI-TOF, GA matrix, m / z): Calcd. For C17H13N3S4: 388.0 (M + H), found 388.2.

Example 133

195

a) methyl 4- (4-benzo [d] benzo [3,4-b] furan-3-yl (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 86 mg (0.3 mmol) of 2- (bromoacetyl) -dibenzofuran (Aldrich, Milwaukee, WI, USA) in a manner similar to that described in Example 8, step (a) and purified by preparative thin layer chromatography to give methyl 4- (4,5-diphenyl- (1,3-) - as a solid. thiazol-2-yl) -5-methylthiothiophene-2-carboxylate (45 mg, 36%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.83-7.44 (m, 7H), 8.29 (s, 1H), 8.27 (s, 1H), 3.88 (s 3H), 2.80 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C ₂ H 15 NO ₃ S ₃ 438.0 (M + H), found 438.5.

b) 4-4-Benzo [d] benzo [3,4-b] furan-3-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine

Methyl 4- (4-benzo [d] benzo [3,4-b] furan-3-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate (45 mg, 0 11 mmol) was treated in a manner similar to that described in Example 10, Step (b) to give 4-4-benzo [d] benzo [3,4-b] furan-3-yl- as a yellow solid. (1,3-thiazol-2-yl) -5-methylthio-thio-phen-2-carboxamidine (16.8 mg, 36%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.72-9.10 (m, 3H), 8.84-7.31 (m, 9H), 2.84 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C21H15N3OS3: 422.0 (M + H), found 421.9.

Example 134

a) methyl 4- (4- (4-nitrophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate

A solution of 1 g (4 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) is treated with 987 mg (4 mmol)

196

2-Bromo-4'-nitroacetophenone in a manner similar to that described in Example 8, Step (a), as a brown solid gives methyl 4- (4- (4-nitrophenyl) (1,3-thiazole-2-) yl) -5-methylthiothiophene-2-carboxylate (1.7 g, quantitative yield). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.57 (s, 1H), 8.34 (s, 4H), 8.25 (s, 1H), 3.94 (s, 3H), 3 81 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H12N2O4S3: 393.0 (M + H), found 392.8.

b) methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

Methyl 4- (4- (4-nitrophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (800 mg, 2 mmol) was dissolved in 150 mL of tetrahydrofuran and subjected to workup after 1 hour with 20% titanium tetrachloride solution (Fisher Scientific, Pittsburgh, PA, USA). The mixture was poured into 2M sodium hydroxide solution (100 mL) and extracted with dichloromethane (4 x 50 mL). The combined organics were washed with saturated brine and dried over anhydrous sodium sulfate. The solid was filtered off and the solvent was removed in vacuo. The product obtained was purified by chromatography on silica gel (30 g), eluting with dichloromethane: methanol 98/2 (v / v) to give methyl-4- (4- (4-aminophenyl) as a solid. (1, 3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate (500 mg, 69%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.17 (s, 1H), 7.77 (s, 1H), 7.74 and 6.62 (AB quartet, 2H, J = 8.6) Hz), 5.35 (s, 2H), 3.86 (s, 3H), 2.74 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H14N2O2S3 363.0 (M + H), found 362.4.

c) methyl 4- (4- {4 - [(methylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate

Methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (200 mg, 0.55 mmol) was dissolved in dry dichloromethane ( 20 ml). Then N-methylmorpholine (150 μΐ, 1.38 mmol) and dimethylaminopyridine (6.1 mg, 0.055 mmol) were added, the mixture was cooled in an ice bath and then added dropwise.

197 methanesulfonyl chloride (43 μΐ, 0.55 mmol). The mixture was then stirred at room temperature for 8 days. The mixture was then partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (20 mL). The aqueous layer was extracted with dichloromethane (3 x 20 mL) and the combined organics were washed with saturated sodium bicarbonate (20 mL), brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo. Silica gel column chromatography (100 g) using dichloromethane: methanol 99/1 (v / v) as the eluent afforded methyl 4- (4- {4 - [(methylsulfonyl) amino] phenyl as a solid. (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate (155 mg, 64%). 1 H-NMR (DMSO-d ₆ , 300 MHz), δ 9.92 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.40 and 6.90 ( AB quartet, 2H, J = 8.7 Hz), 3.87 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix m / z): Calcd. For C17H16N2O4S4: 441.0 (M + H), found 441.2.

d) 4- (4- {4 - [(methylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine

Methyl 4- (4- {4 - [(methylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (81 mg, 0.184 mmol) was treated in a similar manner. by the method described in Example 10, step (b), to give a light brown solid of 4- (4- {4 - [(methylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5- methylthiothiophene-2-carboxamidine (24.9 mg, 32%). H-NMR (DMSO-d _b, 300 MHz) δ 10.0 (br s, 1H), 9.3 (br s, 2H), 8.98 (s, 1H), 8.65 (s, 1 H 8.21 (s, 1H), 7.98 and 7.5 (AB quartet, 2H, J = 8.6 Hz), 3.05 (s, 3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H16N4O2S4: 425.0 (M + H), found 425.1.

Example 135

198

a) methyl 4- (4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate

Methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (100 mg, 0.28 mmol) was dissolved in dry dichloromethane (10 ml). Then N-methylmorpholine (46 μΐ, 0.42 mmol) and dimethylaminopyridine (3.4 mg, 0.028 mmol) were added, the mixture was cooled in an ice bath and benzenesulfonyl chloride (35 μΐ, 0.28 mmol) was added dropwise. . The resulting mixture was stirred at room temperature for 24 hours. The mixture was then worked up as described in Example 134, step (c). Trituration with dichloromethane and methanol gave 4- (4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (44 mg) , 31%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 10.46 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.19 (AB) quartet 2H, J = 8.7 Hz), 7.81 (m, 2H), 7.64-7.54 (m, 3H), 3.85 (s, 3H), 2.74 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C 22 H 18 N 2 O 4 S 4 504.2 (M + H), found 504.1.

b) 4- (4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine

Methyl 4- (4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (30 mg, 0.060 mmol) was treated in a similar manner as described in Example 10, step (b) and as a yellow solid, 4- (4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methyl was thus prepared. Thiothiophene-2-carboxamidine (12.6 mg, 43%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.13 (br s, 3H), 8.60 (s, 1H), 8.08 (s, 1H), 7.93 and 7.20 (AB) quartet, 2H, J = 8.7 Hz), 7.827.79 (m, 2H), 7.65-7.53 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H) . Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C21H18N4O2S4: 487.0 (M + H), found 487.7.

Example 136

199

a) Methyl 4- (4- {4 [(trifluoromethylsulfonyl) amino] phenyl) (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate

Methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (200 mg, 0.55 mmol) was dissolved in dry pyridine (20 mL) . The mixture was cooled in an ice bath and trifluoromethanesulfonic anhydride was added. The mixture was then stirred at room temperature for 1.5 hours. Further work-up was carried out as described in Example 134, step (c). Silica gel column chromatography (30 g) using hexanes: ethyl acetate 7: 3 (v / v) followed by preparative thin layer chromatography using dichloromethane: methanol 99: 1 (v / v) as a The solid obtained was methyl 4- (4- {4 - [(trifluoromethylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate (160 mg, 59%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.48 and 7.87 (s, conformer ratio 3/2, 1H), 8.23 (s, 1H), 8.21 (s, 1H) 8.29 and 7.84 (AB quartet, 2H, conformer ratio 2/3, J = 8.7 Hz), 8.10 and 7.37 (AB quartet, 2H, J = 8.7 Hz), 3 87 and 3.86 (s, conformer ratio 2/3, 3H), 2.77 and 2.76 (s, conformer ratio 2/3, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C17H13N2O4S4F4: 495.0 (M + H), found 495.6.

b) 4- (4- {4 - [(trifluoromethylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

Methyl 1-4- (4- {4 - [(trifluoromethylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (30 mg, 0.061 mmol) was treated as follows in a similar manner to that described in Example 10, step (b), as a light brown solid to give 4- (4- {4 - [(trifluoromethylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine (21.6 mg, 74%). H-NMR (DMSO-d _6, 300 MHz) δ 9.39 (br s, 2H), 8.97 (br s, 2H), 8.64 (s, 1H), 8.24 (s, 1H). 8.12 and 7.39 (AB quartet, 2H, J = 8.7 Hz), 4.78 (br s, 1H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): C] ₄ 6Hi3N4O2S F3 calcd 479.0 (M + H), found 479.5.

200

Example 137

a) methyl 4- (4- {4 - [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate

Methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (33 mg, 0.09 mmol) was dissolved in dry dichloromethane (5 mL) . Then N-methylmorpholine (10 μΐ, 0.09 mmol) and p-toluenesulfonyl chloride (17 mg, 0.09 mmol) were added and the mixture was stirred at room temperature for 5 days. Further work-up is carried out as in Example 134, step (c). Trituration with dichloromethane and methanol gave methyl 4- (4- {4 - [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (20 mg, 43 %) in the form of a brown solid. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 10.39 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.18 ( AB quartet, 2H, J = 8.7 Hz), 7.68 and 7.5 (AB quartet, 2H, J = 8.2 Hz), 3.85 (s, 3H), 2.74 (s, 3H) 2.27 (s, 3H). Mass spectrum (MALDITOF, CHCA matrix, m / z): Calcd. For C23H20N2O4S4: 517.2 (M + H), found 517.0.

b) 4- (4- {4 - [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine

Methyl 4- (4- {4 - [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (15 mg, 0.029 mmol) was treated in a similar manner as described in Example 10, step (b), to give 4- (4- {4 - [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5 as a light brown solid. -methylthiothiophene-2-carboxamidine (17.9 mg, 81%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.94 (br s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08 (s, 1H), 7.93 and 7.20 (AB quartet, 2H, J = 8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J = 8.2 Hz), 2, 77 (s, 3H); 2.33 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): 02S C22H2oN _{4 4} Calc'd 501.1 (M + H), found 501.1.

201

Example 138

a) Methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxylate

To a stirred solution of 764 mg (2 mmol) of methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (2.5 mL) was added 30% hydrogen peroxide (0.45 mL, 4 mmol). The solution was stirred at room temperature for 45 hours. After two hours, dichloromethane (10 mL) was added. After 4 hours and 24 hours, additional hydrogen peroxide (2 x 0.45 ml) was added. The mixture was then quenched with 10% sodium sulfite in brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Silica gel column chromatography (45 g) using dichloromethane: methanol 99: 1 (v / v) gave methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2) as a solid. -yl)] - 5- (methylsulfinyl) thiophene-2-carboxylate (720 mg, 90%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.37 (s, 1H), 8.30 (s, 1H), 8.05 and 7.52 (AB quartet, 2H, J = 8.6) Hz), 3.91 (s, 3H), 3.16 (s, 3H). Mass spectrum (MALDI-TOF, GA matrix, m / z): Calcd. For C16H12NO3S3Cl, 398.0 (M + H), found 397.8.

b) 4- (4- (4-chlorophenyl) (1,3-thiazol-2-yl)) - 5- (methylsulfinyl) thiophene-2-carboxamidine

Methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfinyl) thiophene-2-carboxylate (100 mg, 0.25 mmol) was treated in a manner similar to that described above in Example 10, step (b), and purified by preparative thin layer chromatography using dichloromethane: methanol: acetic acid 9: 1: 0.5 (v / v / v) as eluent to give a solid 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfinyl) thiophene-2-carboxamidine (18.2

202 mg, 19%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.33 (s, 1H), 8.22 (s, 1H), 8.05 and 7.57 (AB quartet, 2H, J = 8.6 Hz) 1.12 (s, 3H). Mass spectrum (MALDITOF, CHCA matrix m / z): Calcd. For C18H18N5OS3Cl: 382.0 (M + H), found

382.1.

Example 139

a) Methyl 4-cyano-5- (methylsulfonyl) thiophene-2-carboxylate

The stirred solution obtained by dissolving (4.5 g, 21 mmol) of methyl 4-cyano-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) in dichloromethane (250 mL) was treated with m-chloroperbenzoic acid (250 mL) at room temperature. 15.3 g, 90 mmol) at a working time of 2.25 h. The mixture was filtered and the solid was washed with dichloromethane (2 x 50 mL). The filtrate was washed with sodium bicarbonate (2 x 100 mL), sodium thiosulfate (100 mL), sodium bicarbonate (100 mL), water (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave methyl 4-cyano-5- (methylsulfonyl) thiophene-2-carboxylate as a solid (4.91 g, 95%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.44 (s, 1Η), 3.91 (s, 3H), 3.58 (s, 3Η).

b) methyl 4-cyano-5-methoxythiophene-2-carboxylate

Methyl 4-cyano-5- (methylsulfonyl) thiophene-2-carboxylate (2 g, 8 mmol) was refluxed with 0.5 M sodium methoxide in methanol (16 mL) for 15 min. After cooling, the crystallized solid was collected on a Buchner funnel and washed with methanol (50 mL) to give methyl 4-cyano-5-methoxythiophene-2-carboxylate (1.145 g, 73%) as a solid. Δ H-NMR (DMSO-d 6, 300 MHz) δ 8.87 (s, 1H), 4.19 (s, 3H), 3.82 (s, 3H).

c) methyl 4- (aminothioxomethyl) -5-methoxythiophene-2-carboxylate

203

Methyl 4-cyano-5-methoxythiophene-2-carboxylate (1 g, 5 mmol) was dissolved in dry methanol (150 mL) and triethylamine (3.5 mL, 25.4 mmol) was added. After degassing the solution with argon for 10 minutes, hydrogen sulfide was bubbled through the solution for 5 hours. The solution was then stirred for 18 hours at room temperature, then degassed by bubbling argon (6 h), concentrated to 20 mL, and acetone (20 mL) was added. The dark solid was collected on a Buchner funnel and washed with acetone. Recrystallization of the resulting solid from hot acetone gave methyl 4- (aminothioxomethyl) -5-methoxythiophene-2-carboxylate (683 mg, 59%) as a brown oil. Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C8H9NO3S2 232.0 (M + H), found 232.4.

d) Methyl 5-methoxy-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate

A solution of 400 mg (1.73 mmol) of methyl 4- (aminothioxomethyl) -5-methoxythiophene-2-carboxylate was treated with 345 mg (1.73 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, WI, USA) in a similar manner by the method described in Example 8, Step (a), as a solid to give methyl 5-methoxy-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxylate (56 mg). , 10%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.22 (s, 1H), 8.14 (s, 1H), 8.05 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H); 4.26 (s, 3H); 3.85 (s, 3H).

e) 5-Methoxy-4- (4-phenyl- (1,3-thiazol-2-yl)) -thiophene-2-carboxamidine

Methyl 5-methoxy-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (55 mg, 0.16 mmol) was treated in a manner similar to that described in Example 10, step (b)) to give 5-methoxy-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (36 mg, 69%) as a yellow solid. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.34 (br s, 2H), 8.94 (br s, 2H), 8.70 (s, 1H), 8.20 (s, 1H) ), 8.07 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 4.32 (s, 3H). Mass spectrum (MALDITOF, CHCA matrix, m / z): Calcd. For C15H13N3OS2 316.5 (M + H), found

316.1.

204

Example 140

(a) methyl 4-cyano-5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate

To a stirred solution of methyl 4-cyano-5- (methylsulfonyl) thiophene-2-carboxylate (2.5 g, 10 mmol) (Example 139, step (a)) in dry methanol (15 mL) was added p-methoxybenzyl mercaptan. (3.8 mL, 28 mmol) and triethylamine (1.4 mL, 10 mmol). The solution was then heated to reflux for 15 minutes and then cooled. The resulting solid was then collected on a Buchner funnel and washed with methanol (2 x 25 mL) to give methyl 4-cyano 5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate (2.84 g, 89) as a solid. %).

b) methyl 4- (aminothioxomethyl) -5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate

Methyl 4-cyano-5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate (2.5 g, 7.8 mmol) was treated as in Example 139 step (c) to give a solid. methyl 4- (aminothioxomethyl) -5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate (1.32 g, 48%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.64 (s, 1H), 9.28 (s, 1H), 8.08 (s, 1H), 7.35 and 6.92 (AB quartet) H, J = 8.7 Hz), 4.27 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H).

c) methyl 5- (methoxyphenylthio) -4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate

A solution of 1.2 g (3.4 mmol) of methyl 4- (aminothioxomethyl) -5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate is treated with 676 mg (3.4 mmol) of 2-bromoacetophenone ( Aldrich, Milwaukee, WI, USA) using a method similar to that described in Example 8, step (a), to give methyl-5 as a solid.

205

- (methoxyphenylthio) -4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (755 mg, 49%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.26 (s, 1H), 8.22 (s, 1H), 8.04 (m, 2H), 7.48 (m, 2H), 7 38 (m, 1H), 7.33 and 6.89 (AB quartet, 2H, J = 8.7 Hz), 4.40 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3 H).

d) 5- (methoxyphenylthio) -4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine

Methyl 1-5- (methoxyphenylthio) -4- (4-phenyl 1- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (100 mg, 0.22 mmol) was treated in a manner similar to that described in of Example 10, step (b), as an orange solid to give 5-methoxy-4- (4-phenyl- (1,3-thiazol-2-yl)) -thiophene-2-carboxamidine (94 mg, 91 %). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.49 (br s, 2H), 9.15 (br s, 2H), 8.70 (s, 1H), 8.26 (s, 1H) 8.07 (m, 2H), 7.49 (m, 2H), 7.40 (m, 1H), 7.35 and 6.90 (AB quartet, 2H, J = 8.7 Hz), 4 41 (s, 2H); 3.73 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C 22 H 19 N 3 OS 3 438.5 (M + H), found 438.1.

Example 141

a) methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxylate

A stirred solution of 1 g (2.6 mmol) of methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) in dry dichloromethane (50 mL) was treated with m-chloroperbenzoic acid (1.94 g, 11.3 mmol) and stirred at room temperature for 1.5 hours. The solution was filtered and the solid washed with dichloromethane. The filtrate was washed with sodium bicarbonate solution (2 x 20 mL), sodium thiosulfate solution (20 mL), sodium bicarbonate solution (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxylate (826) as a light brown solid. mg, 77%). weight

206% (MALDI-TOF, CHCA matrix, m / z) calcd for C16H12NO4S3Cl 414.0 (M + H), found 414.8.

b) 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxamidine

Methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxylate (200 mg, 0.4 mmol) was treated in a manner similar to that described above in Example 10, step (b), and a yellow solid gave 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxamidine (85); mg, 53%)

c) 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (phenylethyl) thiophene-2-carboxamidine

A stirred solution of 80 mg (0.2 mmol) of 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene-2-carboxamidine-benzyl mercaptan (115 μΐ, 0.980 mmol) ) was treated as in Example 140 step (a) and worked up on a silica gel (20 g) column using dichloromethane: methanol: acetic acid 9: 1: 0.5 (v / v / v) 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (phenylmethylthio) thiophene-2-carboxamidine (75 mg, 85%) was obtained as a pale orange solid. 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.44 (br s, 2H), 9.03 (br s, 2H), 8.67 (s, 1H), 8.33 (s, 1H) , 8.08 and 7.56 (AB quartet, 2H, J = 8.7 Hz), 7.547.17 (m, 5H), 4.45 (s, 2H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C21H18N3S3Cl: 442.0 (M + H), found 442.7.

Example 142

a) 1- [5- (tert-Butyl) -2-methyl- (3-furyl)] - 2-bromo-methan-1-one

207

A solution obtained by dissolving 1 g (5 mmol) of 5- (tert-butyl) -2-methylfuran-3-carbonyl chloride (Maybridge, Cornwall, UK) in dry acetonitrile (4 mL) and 6.25 mL (12.5 mmol) of 2. M trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, WI) was stirred at room temperature for 1.75 h and then cooled in an ice bath for 5 minutes. Then 30% hydrogen bromide in acetic acid (2 mL, 10 mmol) was added dropwise over 10 minutes. The resulting reaction mixture was then stirred for an additional 10 minutes in an ice bath. Evaporation of the solvents gave 1- [5- (tert-butyl) -2-methyl- (3-furyl)] - 2-bromo-methan-1-one as a brown oil (1 g, 77%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 6.50 (s, 1H), 4.57 (s, 2H), 2.52 (s, 1H), 1.24 (s, 9H). Mass spectrum (LCA, m / z): CiiH | 5 O ₂ Br Calculated 259.1 and 261.1 (M + H), found 259.1 and 261.1.

b) methyl 4- {4- [5- (tert-butyl) -2-methyl- (3-furyl)] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate

A solution of 955 mg (3.86 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 1 g (3.86 mmol) of 1- [5 - (/ tert-Butyl) -2-methyl- (3-furyl)] - 2-bromo-methan-1-one (1 g) by a method similar to that described in Example 8, Step (a), as a red-brown solid to give methyl -4- {4- [5- (tert-butyl) -2-methyl- (3-furyl)] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (999 mg, 64 %). H-NMR (DMSO-d _6, 300 MHz) δ 8.14 (s, III), 7.74 (s, IH), 6.46 (s, IH), 3.86 (s, 3H), 2, 74 (s, 3H), 2.66 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C19H21NO3S3, 408.1 (M + H), found 408.0.

c) 4- {4- [5- (tert-Butyl) -2-methyl- (3-furyl)] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine

Methyl 4- {4- [5- (tert-butyl) -2-methyl- (3-furyl)] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (940 mg, 2.3 mmol) was treated in a manner similar to that described in Example 10 step (b) to give 4- {4- [5- (tert-butyl) -2-methyl- (3-furyl)] as a yellow solid. (1,3-Thiazol-2-yl)} - 5-methylthiothio

208 phen-2-carboxamidine (930 mg, quantitative yield). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.42 (br s, 2H), 9.03 (br s, 2H), 8.59 (s, 1H), 7.77 (s, 1H) 6.47 (s, 1H), 2.78 (s, 3H), 2.68 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDITOF, CHCA matrix, m / z): Calcd. For C18H21N3OS3: 392.1 (M + H), found

392.1.

Example 143

a) 1- [3- (tert-Butyl) -1-benzylpyrazol-5-yl] -2-bromo-methan-1-one

To a solution of 3- (tert-butyl) -1-benzylpyrazole-5-carbonyl chloride (g, 3.6 mmol) (Maybridge, Cornwall, UK) in dry acetonitrile (4 mL) was added 4.5 mL (9 mmol). of a 2 mol / L solution of trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, WI, USA). After stirring for 1 h 20 minutes at room temperature, the mixture was cooled in an ice bath for 5 minutes. A 30% solution of hydrogen bromide in acetic acid (2 mL, 10 mmol) was then added dropwise over 15 minutes. The reaction mixture was then stirred for an additional 15 minutes in an ice bath. Filtration of the precipitated solid and evaporation of the solvent gave 1- [3- (tert-butyl) -1-benzylpyrazol-5-yl] -2-bromo-methan-1-one (1.47 g, quantitative) as an orange solid. yield). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 7.33-7.06 (m, 5H), 7.08 (s, 1H), 5.64 (s, 2H), 4.57 (s 2H, 1.28 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C16H13NiOBr 335.1 and 337.1 (M + H), found 335.6 and 337.6.

b) methyl 4- {4- [3- (tert-butyl) -1-benzylpyrazol-5-yl] (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxylate

A solution of 823 mg (3.3 mmol of methyl 4 (aminotioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was treated with 1.36 g (3.3 mmol) of 1- [3- (Zerc -butyl) -1-benzylpyrazol-5-yl] -2-bromoethane-1-one by a method similar to that described in Example 8, step (a), and is obtained in the form of

209 crystalline solid methyl 4- {4- [3- (tert-butyl) -1-benzylpyrazol-5-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (1) , 25 g, 79%). H-NMR (DMSO-d _6, 300 MHz) δ 8.11 (s, IH), 8.05 (s, IH), 7.28 to 6.99 (m, 5 H), 6.70 (s, H 1.88 (s, 2H), 3.86 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C24H25N3O2S3, 484.1 (M + H), found 483.9.

c) 4- {4- [3- (tert-Butyl) -1-benzylpyrazol-5-yl] (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine

Methyl 4- {4- [3- (tert-butyl) -1-benzylpyrazol-5-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (1.2 mg (2.6 mmol) was treated in a manner similar to that described in Example 10, Step (b) to give 4- {4- [3- (tert-butyl) -1-benzylpyrazole-5-yl] solid as a yellow solid. yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxamidine (1.21 g, quantitative yield). H-NMR (DMSO-d _6, 300 MHz) δ 9.43 (br s, IH), 9.07 (br s, IH), 8.60 (s, 1H), 8.04 (s, 1 H, ), 7.37-6.97 (m, 5H), 6.70 (s, 1H), 5.92 (s, 2H), 2.73 (s, 3H), 1.30 (s, 9H) . Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C23H25N5S3 468.1 (M + H), found 468.1.

Example 144

a) 4-bromo-5-methylthiophene-2-carboxylic acid

A stirred solution of 1 g (3.9 mmol) of 2-methyl-3,5-dibromothiophene (prepared according to the method of Kano, S. et al., Heterocycles 20 (10): 2035,1983) in dry tetrahydrofuran (10 mL) was added to the reaction mixture. The reaction mixture was cooled to -78 ° C and a 2M solution of butyllithium in cyclohexane (1.93 mL, 3.87 mmol) was added over 3 minutes. The reaction mixture was stirred at -78 ° C for 3 minutes and then added to tetrahydrofuran (100 mL) containing suspended solid ice. The resulting mixture was allowed to warm to room temperature with stirring. Then carefully add 6 mol / l hydrochloric acid (50 ml)

210 ml). Water (50 ml) was then added and the layers were separated. The aqueous layer was extracted with diethyl ether (4 x 30 mL). The combined organics were washed with water, brine and dried over sodium sulfate. Then the solvent was removed in vacuo to give a 85:15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid as a light brown solid (780 mg, 90%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 13.33 (br s, 1H), 7.62 (s, 1H), 7.56 and 7.34 (AB quartet, 0.35H, J = 3.9 Hz), 2.41 (s, 3H). Gas Chromatography / Mass Spectrometry (m / z): Calcd for C 6 H 5 CHSBr 220.9 and 222.9 (M + H), found 221.3 and 223.3. 206.9 and 208.9 (M + H) calcd.

b) Methyl 4-bromo-5-methylthiophene-2-carboxylate

A solution of 780 mg (3.5 mmol) of a 85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid dissolved in methanol (50 mL) was treated with 9 mL (18 mL). mmol) of a 2 mol / L solution of trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, WI, USA). Evaporation of the solvents gave a brown oil mixture containing 8/2 of methyl 4-bromo-5-methylthiophene-2-carboxylate and methyl 5-bromothiophene-2-carboxylate (858 mg, quantitative yield). Gas Chromatography / Mass Spectrometry (m / z): Calcd. For C7H2O2SBr: 234.9 and 236.9 (M + H), found 235.3 and 237.3. For C 6 H 40 O 2 Br calculated 220.9 and 222.9 (M + H), found 221.3 and 223.3.

c) methyl 4-cyano-5-methylthiophene-2-carboxylate

A solution prepared by dissolving a mixture of 8/2 823 mg (3.5 mmol) of methyl 4-bromo-5-methylthiophene-2-carboxylate and methyl 5-bromothiophene-2-carboxylate in dry dimethylformamide (5 mL) was heated. at reflux temperature with copper (I) cyanide (345 mg, 3.9 mmol) for 7 h. The cooled solution was poured into aqueous 0.1 M sodium cyanide (200 mL) and extracted with diethyl ether (5 x 30 mL). The organics were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed in vacuo.

211 kuu. The resulting brown solid was purified by silica gel column chromatography using hexanes: ethyl acetate 9/1 (v / v) to give methyl-4-cyano-5-methylthiophene-2- as a yellow solid. of carboxylate and methyl 5-methylthiophene-2-carboxylate in a ratio of 95/5 (369 mg, 68%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 8.06 (s, 1H), 8.05 and 7.90 (2H, 0.1 H, J = 4.0 Hz, minor component), 3, 87 (s, 3H, minor component), 3.84 (s, 3H) 2.68 (s, 3H).

d) methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate

A stirred solution of methyl 4-cyano-5-methylthiophene-2-carboxylate (804 mg, 4.4 mmol) was treated in a manner similar to that described in Example 139, step (c), after fractional crystallization of unreacted starting nitriletanol as a brown solid. The mixture was concentrated to give methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate and methyl 4-cyano-5-methylthiophene-2-carboxylate (457 mg, 48%) in a 2: 3 ratio. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.93 (br s, 1H, minor component), 9.34 (br s, 1H, minor component), 8.06 (s, 1H, major component) ), 7.77 (s, 1H, minor component), 3.84 (s, 3H, minor component), 3.81 (s, 3H, major component), 2.68 (s, 3H, major component), 2.61 (s, 2H, major component). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C8H9NO2S2: 216.0 (M + H), found 216.4.

e) methyl 1-5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate

A solution of 200 mg (0.93 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate was treated with 185 mg (0.93 mmol) of 2-bromoacetophenone in a manner similar to that described in Example 8 step (a) and after Purification by thin layer chromatography using hexanes: ethyl acetate 7/3 (v / v) as eluent gave methyl 5-methyl-4- (4-phenyl- (1,3-thiazole) as a solid. 2-yl) thiophene-2-carboxylate and methyl 4-cyano-5-methylthiophene-2-carboxylate (96 mg, 36%).

212

f) 5-methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxamidine

Methyl 4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (64 mg, 0.23 mmol) was treated in a manner similar to that described in Example 10 step (b) and after preparative HPLC (Dynamax C18 column, 300Å pore size, 10 µm particle size, 40% to 100% acetonitrile in 0.1% aqueous trifluoroacetic acid over 30 minutes) gave 5-methyl as an off-white solid -4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (0.6 mg, 0.9%). 1 H-NMR (CD ₃ OD, 300 MHz) δ 8.44 (s, 1H), 8.02 (m, 2H), 7.92 (s, 1H), 7.45 (m, 2H), 7 36 (m, 1H); 2.96 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C15H13N3S2: 300.1 (M + H), found 300.6.

g) 5- (4-phenyl-1,3-thiazol-2-yl) -thiophene-2-carboxamide

5- (4-Phenyl-1,3-thiazol-2-yl) -thiophene-2-carboxamide (2 mg) was isolated from the mixture purified by the HPLC method of the previous step as an off-white solid. 1 H-NMR (methanol-d ₄ , 300 MHz) δ 7.99 (m, 2H), 7.97 (s, 1H), 7.95 and 7.78 (AB quartet, 2H, J = 4.2) Hz), 7.48-7.35 (m, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C14H11N3S2 286.0 (M + H), found

286.2.

Example 145

a) Methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate

A solution of 257 mg (0.48 mmol, based on a mixture containing 60% nitrile) of methyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate was treated with 124 mg (0.48 mmol) of 2-bromo- (3). (4'-dimethoxy) acetophenone (Example 31, step (a)) in a manner similar to that described in Example 8, step (a) and in the form

213 solids gave methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate (95 mg, 53%). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calcd. For C18H17NO4S2, 376.1 (M + H), found 376.3.

b) 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxamide

Methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate (95 mg, 0.25 mmol) was treated in a manner similar to that described in Example 10, step (b), and a yellow solid gave 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxamide (8). mg, 9%). 1 H-NMR (methanol-d ₄ , 300 MHz) δ 8.42 (s, 1H), 7.81 (s, 1H), 7.61 (m, 2H), 7.03 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 2.95 (s, 3H). Mass spectrum (MALDITOF, CHCA matrix, m / z): for C17H17N3O2S2 360.1 (M + H), found 360.2.

Example 146

a) 4-Bromo-5-methylthiophene-2-carboxylic acid

A solution of 27.65 g (108 mmol) of 2-methyl-3,5-dibromothiophene (prepared as described in Kano, S. et al., Heterocycles 20 (10): 2035, 1983) prepared by dissolving the above component in dry tetrahydrofuran ( 280 mL), cooled to -78 ° C and 2 M butyllithium in cyclohexane (54 mL, 108 mmol) was added over 10 min. The reaction mixture was stirred for 20 minutes at -78 ° C and then dry carbon dioxide was introduced into the solution for 1.5 hours while warming to room temperature. 5M hydrochloric acid (100 ml) was then added carefully. The layers were separated and the aqueous layer was extracted with diethyl ether (4 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents in vacuo gave off as an off-white

214 solids gave 4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 13.34 (br s, 1H), 7.61 (s, 1H), 2.41 (s, 3H).

b) isopropyl 4-bromo-5-methylthiophene-2-carboxylate

A solution of 5 g (22.6 mmol) of 4-bromo-5-methylthiophene-2-carboxylic acid in dry dichloromethane (200 mL) was treated with oxalyl chloride (2 mL, 22.6 mmol) and dimethylformamide (100 μΐ) with stirring in an ice bath for 30 minutes and then 2.5 hours at room temperature. Then the solvent was removed in vacuo and the residue was passed through a silica gel column using hexanes: ethyl acetate 7/3 (v / v), ethyl acetate and dichloromethane as eluent. The solvent was then removed in vacuo and the resulting oil was dissolved in dry dichloromethane (100 mL). The resulting solution was treated with dry pyridine (9 mL, 113 mmol) and dry isopropanol (40 mL, 522 mmol) for 88 hours. Then, the solvent was removed in vacuo and the residue was partitioned between sodium bicarbonate (150 mL) and dichloromethane (75 mL). The aqueous layer was extracted with dichloromethane (2 x 20 mL) and the combined organic layers were washed with sodium bicarbonate (30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. The residue was purified by column chromatography using hexanes: ethyl acetate 9/1 (v / v) to give isopropyl 4-bromo-5-methylthiophene-2-carboxylate as a pale yellow oil (1.91 g, 32%). ¹ H-NMR (DMSO-d 6, 300 MHz) δ 7.66 (s, 1H), 5.07 (septet, 1H, J = 6.2 Hz), 2.42 (s, 3H), 1.29 (d, 6H, J = 6.2Hz). Mass spectrum (ESI, m / z): Found: 264.8.

c) isopropyl 4-cyano-5-methylthiophene-2-carboxylate

A stirred solution of 1.9 g (7.3 mmol) of isopropyl 4-bromo-5-methylthiophene-2-carboxylate, prepared by dissolving in dry dimethylformamide (30 mL), was heated to reflux with copper (I) cyanide (785 mg, 8, 8 mmol) 16 hours. The cooled solution was then poured into 0.1 M aqueous sodium cyanide solution (300 mL) and extracted with diethyl ether (4 x 40 mL). Organic fractions shall be

215 were washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Silica gel column chromatography using hexanes: ethyl acetate 9/1 (v / v) afforded isopropyl 4-cyano-5-methylthiophene-2-carboxylate (960 mg, 63%) as a yellow crystalline mass. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.01 (s, 1H), 5.09 (septet, 1H, J = 6.2 Hz), 2.67 (s, 3H), 1, 29 (d, 6H, J = 6.2Hz).

d) isopropyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate

A stirred solution of 960 mg (4.59 mmol) of isopropyl 4-cyano-5-methylthiophene-2-carboxylate was treated in a manner similar to that described in Example 139, step (c), and crystallized from diethyl ether to give a solid. isopropyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate (623 mg, 56%). 1 H NMR (DMSO-d 6, 300 MHz) δ 9.93 (br s, 1H), 9.34 (br s, 1H), 7.54 (s, 1H), 5.07 (septet, 1H, J = 6.2 Hz), 2.60 (s, 3H), 1.29 (d, 6H, J = 6.2 Hz). Mass spectrum (MALDI-TOF, GA matrix, m / z): Calcd. For C10H13NO2S2: 244.0 (M + H), found 243.8.

e) Isopropyl 5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl) thiophene-2-carboxylate

A solution of 375 mg (1.54 mmol) of isopropyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate was treated with 307 mg (1.54 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, WI, USA) in a manner similar to that described in Example 8, step (a) and is crystallized from methanol to give isopropyl-5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl)) as light brown needles. ) Thiophene-2-carboxylate (347 mg, 66%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 8.23 (s, 1H), 8.09 (s, 1H), 8.05 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet, 1H, J = 6.2 Hz), 2.86 (s, 3H), 1.33 (d, 6H, J = 6.2 Hz). Mass spectrum (ESI, m / z): Calcd. For C18H17NO2S2, 344.1 (M + H). found 344.1.

f) 5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine

216

Isopropyl 5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (340 mg, 0.99 mmol) was treated in a manner similar to that described in Example 10, step (b) and 5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (360 mg, quantitative yield) was obtained as a yellow solid. The product obtained was dissolved in dry methanol (20 ml) and treated with 1M HCl (g) in diethyl ether. Evaporation of the solvents in vacuo and recrystallization from methanol gave the hydrochloride salt of 5-methyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (252 mg, m.p. 76%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.45 (br s, 2H), 9.10 (br s, 2H), 8.56 (s, 1H), 8.27 (s, 1H) 8.06 (m, 2H); 7.50 (m, 2H); 7.40 (m, 1H); 2.93 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 18 H 11 N 5 OS: 300.1 (M + H), found

300.2.

Example 147

a) 2-methyl-5 - [(methylethyl) oxycarbonyl] thiophene-3-carboxylic acid

A stirred mixture of tetrafluorophthalic acid isopropyl 2-methyl-3-cyantiophene-5-carboxylate (570 mg, 2.39 mmol) was heated in a glass pressure bottle at 160 ° C for 66 h. The cooled residue was triturated with hot chloroform (30 mL), treated with standard and filtered through celite. The celite was then washed with hot chloroform (30 mL). The cooled chloroform extracts were filtered and extracted with saturated sodium bicarbonate (4 x 10 mL). The basic extracts were washed with chloroform, filtered through celite and acidified to pH 1 with concentrated hydrochloric acid. The solid was filtered and washed with water (3 x 10 mL) to give 2-methyl-5 - [(methylethyl) oxycarbonyl] thiophene-3-carboxylic acid (288 mg, 53%) as a light brown solid. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 13.03 (br s, 1H), 7.85 (s, 1H), 5.08 (septet, 1H, J = 6.2 Hz), 2 71 (s, 3H), 1.29 (d, 6H, J = 6.2Hz). Mass spectrum (ESI, m / z): Calcd. For C 10 H 12 O 4 S 229.1 (M + H), found 228.8.

217

b) isopropyl 1-4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate

A stirred solution of 300 mg (1.3 mmol) of 2-methyl-5 - [(methyl-ethyl) oxycarbonyl] thiophene-3-carboxylic acid in dry dichloromethane (10 mL) was treated with oxalyl chloride (174 μΐ, 2 mmol) and dimethylformamide. (50 μΐ). The resulting mixture was stirred at room temperature for 1.25 hours, then the solvent was removed in vacuo and the residue was passed through a pad of silica gel (1 inch) in a 60 mL glass frit Buchner funnel using dichloromethane as the eluent (150 mL). The material was treated in a manner similar to that described in Example 142, Step (a) to give isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (266 mg, 67%) as a solid.

T

c) isopropyl 4- (2-amino- (1,3-thiazol-4-yl)) -5-methylthiophene-2-carboxylate

A solution of 260 mg (0.85 mmol) of isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate was treated with 65 mg (0.85 mmol) of thiourea in a manner similar to that described in Example 8, step (a). ) to give 4- (2-amino- (1,3-thiazol-4-yl)) - 5-methylthiophene-2-carboxylate (257 mg, quantitative yield) as a white solid. 1 H-NMR (DMSO-d 6, 300 MHz) δ 7.90 (s, 1H), 6.93 (s, 1H), 5.09 (septet, 1H, J = 6.2 Hz), 2.61 (s, 3H), 1.29 (d, 6H, J = 6.2 Hz). Mass spectrum (ESI, m / z): Calcd. For C12H14N2O2S2: 283.1 (M + H), found 283.1.

d) 4- (2-Amino- (1,3-thiazol-4-yl)) - 5-methylthiophene-2-carboxamidine

Isopropyl 4- (2-amino- (1,3-thiazol-4-yl)) - 5-methylthiophene-2-carboxylate (240 mg, 0.85 mmol) was treated in a manner similar to that described in Example 10 step (b). ) to give 4- (2-amino- (1,3-thiazol-4-yl) -5-methylthiophene-2-carboxamidine (20 mg, 10%) as a solid. 1 H NMR (DMSO-)? δ d, 300 MHz): δ 9.30 (br s, 2H), 8.99 (bs, 2H), 8.28 (s, 1H), 6.78 (s, 1H), 2.71 (s, 3H) NMR spectrum (ESI, m / z): Calcd. For C9H10N4S2: 238.8 (M + H), found

239.2.

Example 148

a) 4-bromo-5-ethylthiophene-2-carboxylic acid

A stirred solution of 10 g (35 mmol) of 4,5-dibromothiophene-2-carboxylic acid (Lancaster, Windham, NH, USA) in dry THF (100 mL) was cooled to "78 ° C." Then, 35 ml (70 mmol) of 2.0 M butyllithium in cyclohexane (Aldrich, Milwaukee, WI, USA) was added dropwise over 15 minutes and the reaction mixture was stirred at -78 ° C for 15 minutes. The reaction was quenched with ethyl iodide (2.8 mL, 35 mmol) and allowed to warm to room temperature. The mixture was then carefully poured into 6 mol / L hydrochloric acid (100 mL) and extracted with diethyl ether (4 x 50 mL). The organic layers were washed with water (2 x 50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. Removal of the solvents in vacuo gave 2-ethyl-3-bromo-thiophene-5-carboxylate (7 g, 85%) as a dark solid. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 13.25 (br s, 1H), 7.62 (s, 1H), 2.80 (q, 2H, J = 7.5 Hz), 1 23 (t, 3H, J = 7.5Hz).

b) isopropyl 4-bromo-5-ethylthiophene-2-carboxylate

A solution of 7 g (30 mmol) of 4-bromo-5-ethylthiophene-2-carboxylic acid in dry dichloromethane (200 mL) was treated with oxalyl chloride (3.2 mL, 36 mmol) and dimethylformamide (0.5 mL) at the time of treatment. 18,5 h. Then the solvent was removed in vacuo and the residual brown oil was passed through a pad of silica gel (5.08 cm (2)) in a 350 mL glass frit Biichner funnel using 700 mL of hexanes: ethyl acetate 9/1 (v / v). as eluent. The eluate was concentrated in vacuo and the oil was dissolved in dry dichloromethane (200 mL). The resulting solution was treated with pyridine (12 mL, 150 mmol) and dry isopropanol (60 mL, 750 mmol) for 4 h at room temperature.

219

The solvent was then removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and water (200 mL). The aqueous layers were then extracted with dichloromethane (2 x 30 mL). The combined organic layers were then extracted with sodium bicarbonate (2 x 30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo. Purification by silica gel column chromatography (250 g) eluting with hexanes: ethyl acetate 95/5 (v / v) as an yellow oil gave isopropyl 2-ethyl-3-bromo-thiophene-5-carboxylate (m.p. 4 g, 48%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 7.66 (s, 1H), 5.89 (septet, 1H, J = 6.2 Hz), 2.80 (q, 2H, J = 7) 5 Hz), 1.29 (d, 6H, J = 6.0 Hz), 1.24 (t, 3H, J = 7.5 Hz).

c) isopropyl 4-cyano-5-ethylthiophene-2-carboxylate

A stirred solution of 4 g (14.4 mmol) of isopropyl 4-bromo-5-ethylthiophene-2-carboxylate in dry dimethylformamide (50 mL) was heated to reflux with copper cyanide (1.94 g, 22 mmol) for 8 hours. The cooled mixture was then poured into 0.1 M copper cyanide solution (500 mL) and extracted with diethyl ether (4 x 50 mL). The organic layers were washed twice with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo. Silica gel column chromatography (400 g) eluting with hexanes: ethyl acetate 9/1 (v / v) gave isopropyl 2-ethyl-3-cyano-thiophene-5-carboxylate as a pale yellow oil ( 1.7 g, 53%). 1 H NMR (DMSO-d 6, 300 MHz) δ 8.03 (s, 1H), 5.10 (septet, 1H, J = 6.2 Hz), 3.04 (q, 2H, J = 7.5 Hz) 1.31 (t, 3H, J = 7.5 Hz), 1.30 (d, 6H, J = 6.2 Hz). Mass spectrum (ESI m / z): Calcd. For C11H13NO2S 224.1 (M + H), found 224.0.

d) isopropyl 4- (aminothioxomethyl) -5-ethylthiophene-2-carboxylate

A stirred solution of 1.7 g (7.6 mmol) of isopropyl 4-cyano-5-ethylthiophene-2-carboxylate was treated as described in Example 139, step (c) to give isopropyl-5- as a yellow solid. ethyl 4- (aminothioxomethyl) -5-ethylthiophene-2-carboxylate (1.45 g, 74%). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.93 (br s,

220

1Η), 9.39 (br s, 1H), 8.04 (s, 1H), 5.08 (septet, 1H, J = 6.2 Hz), 3.08 (q, 2H, J = 7, 5 Hz), 1.29 (d, 6H, J = 6.2 Hz), 1.24 (t, 3H, J = 7.5 Hz).

(e) isopropyl-5-ethyl-4- (4-phenyl- (1,3-thiazol-2-yl)) - thiophene-2-carboxylate:

A solution of 450 mg (1.75 mmol) of isopropyl 5-ethyl-4- (aminothioxomethyl) -5-ethylthiophene-2-carboxylate was treated with 348 mg (1.75 mmol) of 2-bromoacetophenone (Aldrich, Milaukee, WI, USA) in a manner analogous to that described in Example 8, Step (a), as an off-white solid affording isopropyl-5-ethyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene- 2-carboxylate (303 mg, 49%). 1 H-NMR (DMSO-d ⁶ , 300 MHz) δ 8.22 (s, 1H), 8.07 (s, 1H), 8.03 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet, 1H, J = 6.2 Hz), 3.34 (q, 2H, J = 7.4 Hz), 1.39 (t, 3H, J = 7.4 Hz), 1.33 (d, 6H, J = 6.2 Hz). Mass spectrum (ESI, m / z): Calcd. For C19H19NO2S2 358.1 (M + H), found 358.1.

f) 5-ethyl-4- (4-phenyl- (1,3-thiazol-2-yl) thiophene-2-carboxamidine)

Isopropyl 5-ethyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxylate (250 mg, 0.70 mmol) was treated in a manner similar to that described in Example 10, step (b)) to give 5-ethyl-4- (4-phenyl- (1,3-thiazol-2-yl)) thiophene-2-carboxamidine (148 mg, 67%) as a yellow solid. 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.44 (br s, 2H), 9.07 (br s, 2H), 8.54 (s, 1H), 8.26 (s, 1H) 8.05 (m, 2H), 7.50 (m, 2H), 8.70 (s, 1H), 7.40 (m, 1H), 3.44 (q, 2H, J = 7.4 Hz), 1.42 (t, 3H, J = 7.4 Hz). Mass spectrum (ESI, m / z): Calcd. For C16H15N3S2 314.1 (M + H), found 314.2.

Example 149

a) Isopropyl 1-4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate

221

A solution of 1.97 g (8.1 mmol) of isopropyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate was reacted with 1.74 g (8.1 mmol) of 3'-hydroxy-2-bromoacetophenone (Example). 40, step (a)) in a manner similar to that described in Example 8, step (a) and after silica gel column chromatography using hexane: ethyl acetate 7/3 (v / v) as eluent, crystallization from acetonitrile and recrystallization from hexanes afforded isopropyl 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate (1.4 g, 48%) as a brown solid ). 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 9.57 (br s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.46 (m, 2H) 7.26 (m, 1H), 6.78 (m, 1H), 5.12 (septet, 1H, J = 6.2 Hz), 2.85 (s, 3H), 1.33 (d, 6H, J = 6.2Hz). Mass spectrum (ESI, m / z): Calcd. For C 18 H 17 NO 3 S 2 360.1 (M + H), found 360.1.

b) 4- (4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)) - 5-methylthiophene-2-carboxamide

Isopropyl 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate (1.4 g, 3.89 mmol) was treated in a manner similar to that described in of Example 10, step (b), as a brown solid to give 4- (4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxamide (360 mg, 31%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.62 (br s, 1H), 9.45 (br s, 1H), 9.09 (br s, 1H), 8.53 ( s, 1H), 8.16 (s, 1H), 7.47 (m, 2H), 7.27 (m, 1H), 6.80 (m, 1H), 2.93 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C15H13N3OS2: 316.1 (M + H), found 316.2.

Example 150

a) (tert -Butoxy) -N - ({4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methyl- (2-thienyl)} aminomethyl) carboxamide

A stirred solution of 320 mg (1 mmol) of 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxamide in dry dimethylformamide (50 mL) was treated with

222 was treated with 262 mg (1.2 mmol) of di- tert -butyl dicarbonate (Acros, Pittsburgh, PA, USA) and with diisopropylethylamine (261 μΐ, 1.5 mmol) at room temperature and a working time of 64 hours. The resulting mixture was poured into sodium bicarbonate solution (200 mL) and extracted with dichloromethane (6 x 30 mL). The organic extracts were washed twice with brine (50 mL) and dried over anhydrous sodium sulfate. Then the solvent was removed in vacuo and chromatography on a silica gel column (100 g) using dichloromethane: methanol 95/5 (v / v) gave (tert-butoxy) -N - ({4- [ 4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methyl- (2-thienyl)} iminomethyl) carboxamide (247 mg, 59%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.56 (s, 1H), 9.12 (br s, 2H), 8.47 (s, 1H), 8.09 (s, 1H), 7.46 (m, 2H), 7.26 (m, 1H), 6.78 (m, 1H), 2.83 (s, 3H), 1.45 (s, 9H). Mass spectrum (ESI, m / z): Calcd. For C20H21N3O3S2 416.1 (M + H), found 415.7.

b) Methyl-2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} - acetate

A stirred solution of 247 mg (0.595 mmol) of (tert-butoxy) -N - ({4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methyl- (2-thienyl) Iminomethyl) carboxamide in dry dimethylformamide (4 mL) was treated with cesium carbonate (291 mg, 0.89 mmol) and methyl bromoacetate (136 mg, 0.89 mmol) at 60 ° C for 3 hours. The mixture was poured into water (50 mL) and extracted with dichloromethane (9x10 mL). The organic extracts were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Then the solvent was removed in vacuo and chromatography on a silica gel column (50 g) using dichloromethane: methanol 98/2 (v / v) afforded methyl 2- {3- [2- (5- { [(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (178 mg, 61%). Mass spectrum (ESI, m / z): Calcd. For C23H25N3O5S2 488.1 (M + H), 388.1 ((M-BOC) + H), found 487.8, 388.2.

223

c) Methyl 1-2- (3- [2- (5-amidino-2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy Jacetate

Methyl 2- (3- (2- (5 - {[(tert-butoxy) carbonylamino] -iminomethyl} -yl] phenoxy} acetate (15 mg, 0.031 mmol) was treated with dichloromethane: trifluoroacetic acid 1/1) (v / v) with 2.5% water at a working time of 1.5 hours at room temperature Removal of the solvents in vacuo afforded methyl 2- (3- [2- (5-amidino-) - as a brown solid). 2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (8.1 mg, 52%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.38 (br s, 2H), 8.94 (br s, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m, 2H), 7.41 (m, 1H) 6.96 (m, 1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H) Mass Spectrum (ESI, m / z): for C] gHi7N3O3S ₂ Calc'd 388.1 (M + H), found 388.3.

Example 151

a) 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid

A stirred solution of 50 mg (0.11 mmol) of methyl 2- (3- [2- (5 - ([(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazole- 4-yl] phenoxy} acetate in tetrahydrofuran (10 ml) was treated with 2M aqueous sodium hydroxide solution (2 ml) at room temperature and for 1 hour 10 minutes, then the solvent was removed in vacuo. 2.54 cm (1) in a 60 mL Buchner funnel with a glass sinter) using dichloromethane: methanol 8/2 (v / v) as eluent to give 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} -acetic acid (44 mg, 88%). * HNMR ( DMSO-d ₆ , 300 MHz) δ 9.38 (br s, 2H), 8.94 (br s, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m, 2H), 7.41 (m, 1H), 6.96 (m, 1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H) Mass spectrum (ESI, m / z): Calcd. For C22H23N3O5S2, 474.1 (M + H), 374.1 ((M-BOC) + H), found 374.2, 473.7.

224

b) 2- {3- [2- (5-amidino-2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid

Methyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (4 mg, 0.0084 mmol) was treated with dichloromethane: trifluoroacetic acid 1/1 (v / v) with 2.5% water at room temperature for 2 h 35 min. Removal of the solvents in vacuo gave 2- {3- [2- (5-amidino-2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid as a solid (2). (9 mg, 71%). Mass spectrum (ESI, m / z): calcd for CnHi5N3O3S ₂ 373.1 (M + H), found 374.2.

c) tert-Butyl-4- (2- {3- [2- (5 - {[(tert-butoxy) (carbonylamino) iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperazinecarboxylate

Stir solution 40 mg (0.084 mmol) 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] -iminomethyl} -2-methyl-3-thienyl) -1,3-thiazole-4 -yl] phenoxy} acetic acid in dry dimethylformamide (5 mL) is treated with hydroxybenzotriazole (23 mg, 0.17 mmol), with 32 mg (0.17 mmol) of N-tert-butoxycarbonylpiperazine (Lancaster, Windham, NH, USA) 65 mg (0.17 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, Ν ', Ν'-tetramethyluronium hexafluorophosphate (HATU) at room temperature for 20 hours. The mixture was then partitioned between dichloromethane (50 mL) and brine (50 mL). The aqueous layers were extracted twice with dichloromethane (50 mL) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo. Purification by preparative thin layer chromatography using dichloromethane: methanol 95/5 (v / v) afforded tert-butyl-4- (2- {3- [2- (5 - {[( Tert -Butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperazinecarboxylate (25 mg, 46%). 1 H-NMR (DMSO-d 6, 300 MHz) δ 9.13 (br s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.63 (m, 2H), 7.39 (m, 1H), 6.95 (m, 1H), 4.93 (s, 2H), 3.47-3.34 (m, 8H), 2.82 (s, 311), 1 45 (s, 9H). 1.42 (s, 9H). Mass spectrum (ESI, m / z): for C 31 H 39 N ₅ O ₆ S ₂

225 calcd. 642.3 (M + H), 542.3 ((M-BOC) + H), 442.3 ((M-2 BOC) + H), found 642.0, 542.2, 442.3 .

d) 5-methyl-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxamidine

Tert-Butyl-4- (2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -], 3-thiazol-4-yl] phenoxy Acetyl) piperazinecarboxylate (25 mg, 0.039 mmol) was treated with a mixture of dichloromethane: trifluoroacetic acid 1/1 (v / v) with 2.5% water at a working time of 2 h. Removal of the solvents in vacuo gave 5-methyl-4- [4- (3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2 as an off-white solid. -carboxamidine (27.4 mg, quantitative yield) 1 H-NMR (methanol-d ₄ , 300 MHz) δ 8.41 (s, 1H), 7.94 (s, 1H), 7.67 (m, 2H), 7.39 (m, 1H), 7.00 (m, 1H), 4.96 (s, 2H), 3.88 (m, 4H), 3.25 (m, 4H), 2, 95 (s, 3H) Mass spectrum (ESI, m / z): Calcd. For C21H23N5O2S2: 442.1 (M + H), found 442.4.

Example 152

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate

To a stirred mixture of 2-methylthio- (5-carbomethoxy) -thiophene-3-carboxylic acid (2.0 g, 8.61 mmol) in 28 mL of CH 2 Cl 2 containing 0.8 mL of DMF was added slowly at 0 ° C under nitrogen. syringe oxalyl chloride (1.9 eq., 16.3 mmol). After one hour, the reaction mixture was allowed to warm to room temperature and then stirred for an additional 1 hour. Then the reaction mixture is filtered through a 20 cm layer of silica gel moistened with 50% ethyl acetate: hexane in a 30 ml glass bottom funnel and eluted until the same product is detected by UV irradiation. The solvent was then concentrated in vacuo, azeotroped with toluene (x1) and dried in vacuo to give the acid chloride (1.52) as a pale yellow solid. The acid chloride obtained is then dissolved in 20 ml of CH 3 CN, cooled to 0 ° C and stirred at room temperature

Treat dropwise with TMSCHN 3 (2.1 eq., 6.3 mL, 2M in hexanes) via syringe. The reaction mixture was then allowed to warm to room temperature (0.5 h), cooled again to 5 ° C and immediately treated with 30% HBr in acetic acid (0.66 mL) which was added dropwise via addition funnel. After 15 min at 0 ° C, the reaction mixture was diluted with 20 mL of ether, filtered and washed thoroughly with ether (3 x 20 mL). The yellow solids were dried under vacuum to give methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (1.0 g, 37% yield) as a yellow powder. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.66 (s, 3H), 3.84 (s, 3H), 5.03 (s, 2H), 8.29 (s, 1H).

Example 153

Isopropyl 1- 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate

To a stirred slurry of 2-methyl- (5-carboisopropoxy) -thiophene-3-carboxylic acid (0.40 g, 1.75 mmol) in 15 mL of CH 2 Cl 2 containing 0.8 mL of DMF was slowly added at 0 ° C under nitrogen. syringe oxalyl chloride (1.9 eq., 3.32 mmol). After one hour, the reaction mixture was allowed to warm to room temperature and then stirred for an additional 1 hour. The solvent was then concentrated in vacuo, azeotroped with toluene (x1) and dried in vacuo to give the acid chloride (0.397 g, 1.60 mmol) as a pale yellow solid. The acid chloride obtained is then dissolved in 7 mL of CH 3 CN, cooled to 0 ° C and treated dropwise with syringe with TMSCHN 3 (2.1 eq, 1.68 mL, 2M in hexanes). The reaction mixture was then allowed to warm to room temperature (0.5 h), cooled again to 5 ° C and immediately treated with 30% HBr in acetic acid (0.5 mL), which was added dropwise via addition funnel. After 15 minutes at 0 ° C, the reaction mixture is filtered through a 10 cm layer of silica gel moistened with 50% ethyl acetate-hexanes in a glass bottom funnel and eluted with the same system until UV detection disappears. The solvent was then concentrated in vacuo to give isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (0.329 g, 61% yield) as an oil which solidified to a tan tan product on standing. 'H-NMR (DMSO-d,

227

300 MHz) δ 1.31 (d, 6H, J = 6.3 Hz), 2.71 (s, 3H), 4.60 (s, 2H), 5.09 (m, 1H), 8.08 (s, 1 H).

Example 154

(a) methyl 5-methylthio-4- [2- (phenylamino) - (1,3-thiazol-4-yl)] - thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60.5 mg, 0.19 mmol) was slurried in 4 mL of acetone with phenylthiourea (1 eq, 30 mg) and heated at 70 ° C. After 3 hours the reaction was allowed to cool to room temperature, filtered and dried in vacuo to give 62.5 mg (69% yield) of methyl 5-methylthio-4- [2- (phenylamino) - (1,3- thiazol-4-yl)] - thiophene-2-carboxylate hydrobromide. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.65 (s, 3H), 3.83 (s, 3H), 6.95-6.99 (m, 1H), 7.28-7, 35 (m, 4H), 7.67 (d, 1H, J = 1.4, 7.7 Hz), 8.06 (s, 1H), 10.54 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C16H14N2O2S3 362.49 (M + H), found 363.7.

b) 5-methylthio-4- [2- (phenylamino) (1,3-thiazol-4-yl) -thiophene-2-carboxamidine hydrochloride

A flame-dried flask containing 57.8 mg (8 eq., 1.08 mmol) of NH 4 Cl under N 2 was charged with 1.3 mL of toluene. To the resulting stirred slurry was added AlMe 3 (8 eq, 2M / hexanes, 0.54 mL) dropwise over 3 minutes and the mixture was allowed to stir for an additional 5 minutes. Then methyl 5-methylthio-4- [2 (phenylamino) - (1,3-thiazol-4-yl)] - thiophene-2-carboxylate hydrobromide (1 eq, 60 mg, 0.135 mmol) was added rapidly in one portion. and the resulting mixture was placed in an oil bath at 120 ° C. After 2 hours 10 minutes at this temperature, the eluent was no longer detectable by TLC (silica gel 60 F 254, Merck KGaA, Darmstadt, Germany, CH 2 Cl 2 -MeOH-AcOH 9: 1: 0.5). indicating the end of the reaction. Then the reaction mixture is left to you

The mixture was cooled to room temperature and a stirred slurry of 1.3 g SiO ₂ in 20 mL CHCl 3 was added by pipette. The residue in the flask was washed with 4 mL of MeOH, sonicated briefly and added to the slurry of SiO 2. The slurry was then stirred for 10 minutes and then filtered through a 15 ml sintered glass funnel containing 20 g of SiO ₂ in 50% CHCl 3 / MeOH. The yellow fraction was collected. TLC showed essentially pure product. Then the solvent was removed in vacuo and the residue was triturated with 10% MeOH-CH ₂ Cl ₂ . The solids were removed by filtration. Removal of the solvent in vacuo gave 30.1 mg (66% yield) of 5-methylthio-4- [2- (phenylamino) - (1,3-thiazol-4-yl)] thiophene-2- as a red-brown powder. carboxamidine. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.73 (s, 3H), (m, 1H), 7.15 (s, 1H), 7.30-7.35 (m, 1H) 7.78 (d, 1H, J = 8.7 Hz), 8.49 (s, 1H), 8.87 (bs, 2H), 9.31 (bs, 2H), 10.38 (s, IH). Mass spectrum (ESI) m / z: Calcd. For C15H14N4S3, 346.50 (M + H), found 347.2.

Example 155

(a) methyl 4- {2 - [(2-chlorophenyl) anilino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (50 mg) was reacted with 2-chlorophenylthiourea (26.7 mg) as described in Example 154, step (a) to yield 58 mg (75 mg). %) methyl 4- {2 - [(2-chlorophenyl) amino] - (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide. H-NMR (DMSO-d _6, 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H), 7.04 (m, IH), 7.32-7.38 (m, 2H ), 7.47 (dd, 1H, J = 1.4, 8.7 Hz), 8.12 (s, 1H), 8.56 (dd, IH, J = 1.4, 8.3 Hz) , 9.75 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 16 H 13 ClN 2 O 2 S 3 396.94 (M + H), found 397.1.

b) 4- {2 - [(2-chlorophenyl) amino] (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

229

Methyl 4- {2 - [(2-chlorophenyl) amino] - (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (40 mg, 0.08 mmol) was treated as described in Example 154 step (b) to yield 24 mg (71.8%) of 4- {2 - [(2-chlorophenyl) amino] (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.71 (s, 3H), 7.04 (td, 1H, J = 1,4, 7.8 Hz), 7.21 (s, 1H 7.35 (t, 1H, J = 8.5 Hz), 8.42 (s, 1H), 8.57 (dd, 1H, J = 1.3, 8.3 Hz), 8.80 (bs, 2H), 9.26 (bs, 2H), 9.79 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C15H14N4S3Cl: 380.94 (M + H), found 381.1.

Example 156

(a) methyl 4- (2-amino- (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide)

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was reacted with thiourea (12 mg) as described in Example 154 step (a) to yield 54 mg (70 mg). % yield) methyl 4- (2-amino- (1,3-thiazol-4-yl)) -5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.69 (s, 3H), 3.83 (s, 3H), 7.00 (s, 1H), 8.05 (s, 1H). Mass Spectrum (ESI) m / z: Calcd. For C 10 H 10 O 2 S 3 N 2 286.41 (M + H), found

287.1.

b) 4- (2-amino- (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- (2-amino- (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate hydrobromide (110 mg, 0.29 mmol) was treated as described in Example 154, step (b). The amidine (74 mg) obtained is stirred in 3 ml of dry methanol under N 2 and treated with about 1 ml of ether saturated with dry HCl gas. Dry ether (1.5 ml) was then added, left at room temperature for 2 hours, and then 40 mg (45% yield) of 4- (2-amino- (1,3-thiazol-4-yl)) was obtained by filtration. 5-methyl-

230 Thiophiene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.69 (s, 3H), 6.90 (s, 1H), 8.44 (s, 1H), 9.20, 9.42 (s (4H, NH). Mass spectrum (ESI) m / z: Calcd. For C 9 H 10 N 4 S 3 270.4 (M + H), found 271.2.

Example 157

a) methyl 4- {2 - ((2,5-dimethoxy-phenyl) -amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (49.4 mg, 0.15 mmol) was treated with 2,5-dimethoxyphenylthiourea (37.2 mg) as described in Example 154, step (a). a) in a yield of 65.5 mg (87%) of methyl-4 {2 - ((2,5-dimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2- 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.66 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H) 6.49 (dd, 1H, J = 3.0, 8.8 Hz), 6.92 (d, 1H, J = 8.9 Hz), 7.26 (s, 1H), 8.17 (s, 1H), 8.37 (d, 1H, J = 3.1 Hz), 9.70 (s, 1H) Mass Spectrum (ESI) m / z: Calcd. for C18H18N2O4S3: 422.54 (M + H). ), found

423.1.

b) 4- (2 - ((2,5-dimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine

Methyl 4- (2 - [(2,5-dimethoxyphenyl) amino] - (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxylate hydrobromide (45.5 mg, 0.09 mmol) work up as described in Example 154 step (b) followed by preparative thin layer chromatography (500 mm silica gel plate, JTBaker, Phillipsburg, NJ, 10% methanol-CH 2 Cl 2, saturated with NH ₃ ) afforded 9.9 mg (27%). yield) 4- {2 - [(2,5-dimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine. 1 H-NMR (DMSO-d ₆ , 300 MHz) ) δ 2.60 (s, 3H), 3.73 (s, 3H), 3.81 (s, 3H), 6.48 (dd, 1H, J = 3.1, 8.8 Hz), 6 92 (d, 1H, J = 7.9Hz), 7.05 (s, 1H), 7.5 (bs,

231

2Η), 8.04 (s, 1H), 8.34 (d, 1H, J = 1.0 Hz), 9.6 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C17H18N4O2S3 406.55 (M + H), found 407.1.

Example 158

a) methyl 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (53.3 mg, 0.17 mmol) was reacted with 2-methoxyphenylthiourea (34.5 mg) as described in Example 154, step (a). ) with a yield of 61 mg (76%) of methyl 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.67 (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 6.53 (d, 1H, J = 6.8 Hz), 7.13-7.24 (m, 2H), 7.29 (s, 3H), 7.59 (m, 1H), 8.16 (s, 3H), 10.32 (s, 1 H). Mass spectrum (ESI) m / z: Calcd. For C 17 H 16 N 2 O 3 S 3 392.52 (M + H), found 393.2.

b) 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(3-methoxyphenyl) amino] - (1-3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (54.6 mg, 0.11 mmol) was treated as described above. as described in Example 154 step (b) to yield 25.2 mg (56%) of 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride . 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.71 (s, 3H), 3.77 (s, 3H), 6.54 (m, 1H), 7.15 (s, 3H), 7 19-7.28 (m, 2H); 7.47 (m, 1H); 8.46 (s, 1H); 8.86 (bs, 2H);

9.28 (bs, 2H); 10.36 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 16 H 16 N 4 OS 3 376.52 (M + H), found 377.2.

Example 159

232

a) methyl 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (41.3 mg, 0.13 mmol) was reacted with 5-methoxyphenylthiourea (26.8 mg) as described in Example 154, step (a). ) in 25 mg (41%) of methyl 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxylate hydrobromide. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.64, 2.68 (s, 3H rotamer), 3.72, 3.73 (s, 3H rotamer), 3.83 (s, 3H), 6.91 (dd, 2H, J = 6.7, 8.8 Hz), 7.21 (s, 1H), 7.59 (d, 1H, J = 9.0 Hz), 7.67 (d 1 H, J = 9.0 Hz), 8.05, 8.13 (s, 1H rotamer), 10.16, 10.34 (bs, 1H, rotamer). Mass spectrum (ESI) m / z: Calcd. For C 17 H 16 N 2 O 2 S 3 392.52 (M + H), found 393.1.

b) 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(4-methoxyphenyl) amino] - (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (22 mg, 0.046 mmol) was treated as described in Example 154 Step (b) yielding 11.5 mg (61%) of 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.72 (s, 3H), 3.73 (s, 3H), 6.91 (d, 2H, J = 9.0 Hz), 7, 08 (s, 1H), 7.69 (d, 2H, J = 9.1 Hz), 8.44 (s, 1H), 8.83 (bs, 2H), 9.28 (bs, 2H), 10.15 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 16 H 16 N 4 OS 3 376.52 (M + H), found 377.1.

Example 160

a) 4- (2 - ([4- (dimethylamino) phenyl) amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide

233

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was reacted with 4-N, N-dimethylaminophenylthiourea (31.5 mg) as described in Example 154, step (a), with a yield of 53.2 mg (75%) of methyl 4- (2 - {[4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2 -karboxyláthydrobromid. 1 H-NMR (DMSO-d ⁶ , 300 MHz) δ 2.69 (s, 3H), 3.15 (s, 6H), 3.83 (s, 3H), 7.36 (s, 1H), 7.55 (bs, 2H), 7.88 (d, 2H, J = 8.3 Hz), 8.16 (s, 1H), 10.56 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C 18 H 18 N 3 O 2 S 5 405.56 (M + H), found 406.1.

b) 4- (2 - ([4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride)

Methyl 4- (2 - {[4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate hydrobromide (50 mg, 0.10 mmol) was treated as follows as described in Example 154 step (b) to yield 9.4 mg (22%) of 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J = 9.2 Hz), 7.00 (s, 1H), 7.56 (d, 2H, J = 9.1 Hz), 8.31 (s, 1H), 8.68 (bs, 3H), 9.92 (bs, 1H).

Example 161

a) methyl 4- {2- [4-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was reacted with 2-methyl-4-chlorophenylthiourea (32.1 mg) as described in Example 154 step (a) with a yield of 62.2 mg (79%) of methyl 4- {2 - [(4-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2 -karboxyláthydrobromidu. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.28, 2.29 (s, 3H rotamer), 2.62, 2.66 (s, 3H rotamer), 3.82 (s, 3H) 7.21-7.29 (m, 3H), 8.04, 8.11 (s,

234

1Η rotamer), 8.17 (d, 1H, J = 8.8 Hz), 8.30 (d, 1H, J = 8.4 Hz), 9.44 (s, 1H), 9.59 (s , 1H). MS (ESI) m / z: Calcd. For C17H15ClN2O2S3 410.96 (M + H), found 411.1.

b) 4- {2 - [(4-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(4-chloro-2-methylphenyl) amino] - (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (55 mg, 0.17 mmol) worked up as in Example 154, step (b), yielding 16 mg (22%) of 4- {2 - [(4-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5 methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.30 (s, 3H), 2.70 (s, 3H), 7.15 (s, 1H), 7.23-7.29 (m, 2H), 8.34 (d, 1H, J = 8.6Hz), 8.44 (s, 1H), 8.86 (bs, 2H),

9.29 (bs, 2H); 9.47 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 16 H 15 ClN 4 S 3 394.97 (M + H), found 395.1.

Example 162

a) methyl 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was reacted with diphenylmethanethiourea (38 mg) as described in Example 154, step (a), to yield 145 mg. (100%) methyl 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide after removal of the solvent in vacuo. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.50 (s, 3H), 2.80 (s, 3H), 6.13, 6.18 (d, 1H rotamer, J = 7.9 Hz 7.23-7.41 (m, 11H), 8.00, 8.02 (s, 1H rotamer), 8.73, 8.86 (d, 1H, rotamer, J = 8.0 Hz) . Mass spectrum (ESI) m / z: Calcd. For C23H20N2O2S3: 452.62, found: 453.0.

235

b) 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine

Methyl 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (96.3 mg, 0.18 mmol) was treated as described in Example 154 step (b) with a yield of 16 mg (20%) of 4- {2 [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz), 2.59 (s, 3H), 6.23 (d, 1H, J = 7.9 Hz), 6.84 (s, 1H), 7.22 -7.40 (m, 10H), 8.09 (bs, 3H), 8.12 (s, 1H), 8.68 (d, 1H, J = 8.4 Hz). Mass spectrum (ESI) m / z: Calcd. For C 22 H 20 N 4 S 3 436.62 (M + H), found 437.1.

Example 163

a) methyl 5-methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (131 mg, 0.42 mmol) was reacted with propylphenylthiourea (82.3 mg) in DMF as described in Example 154, step (a), the reaction mixture was then filtered through a 5 cm pad of silica gel in a 15 mL glass frit funnel using 10% methanol-CHCl 3. Concentration of the solvent in vacuo afforded 203 mg (100% yield) of methyl 5-methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide . 1 H NMR (DMSO-d ₆ , 300 MHz) δ 1.89 (m, 2H), 2.62 (s, 3H), 2.63-2.71 (m, 2H), 3.27-3, 39 (m, 2H), 3.82 (s, 3H), 6.97 (s, 1H), 7.15-7.31 (m, 5H), 8.06 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C19H20N2O2S3: 404.57 (M + H), found 405.1.

236

b) 5-methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)] thiophene-2-carboxamidine hydrochloride

Methyl 1-5-methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thio-phenyl-2-carboxylate hydrobromide (112 mg, 0.23 mmol) was treated as in Example 154 step (b) to yield 16 mg (16%) of 5-methylthio-4- {2 - [(3-phenylpropyl) amino] - (1,3-thiazol-4-yl)} thiophene-2 -carboxamidine hydrochloride, which was further purified by preparative thin layer chromatography using 20% methanol-CH 2 Cl 2 saturated with ammonia as eluent. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.89 (m, 2H), 2.54 (s, 1H), 2.66 (t, 2H, J = 7.3 Hz), 3, 31 (m, 2H), 6.69 (bs, 3H), 6.76 (s, 1H), 7.15-7.31 (m, 5H), 7.69 (m, 1H), 7.84 (s, 1 H). Mass spectrum (ESI) m / z: Calcd. For C18H20N4S3 388.58 (M + H), found 389.2.

Example 164

a) methyl 5-methylthio-4- {2 - ((2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl) thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.21 mmol) was reacted with 2,4,5-trimethylphenylthiourea as described in Example 154 step (a) to yield 42, 3 mg (41%) of methyl 5-methylthio-4 {2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.16 (s, 3H), 2.18 (s, 3H), 2.19 (s, 3H), 2.64 (s, 3H), 3 82 (s, 3H), 6.97 (s, 1H), 7.18 (s, 1H), 7.86 (s, 1H), 8.12 (s, 1H),

9.29 (s, 1 H). Mass spectrum (ESI) m / z: Calcd. For C19H20N2O2S3: 404.57 (M + H), found 405.1.

b) 5-methylthio-4- {2- (2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl) -thiophene-2-carboxamidine hydrochloride

237

Methyl 5-methylthio-4- {2 - ((2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl) thiophene-2-carboxylate hydrobromide (37.3 mg, 0.07 mmol) ) was treated as in Example 154 step (b) to yield 28.3 mg (95%) of 5-methylthio-4- {2 [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4). 1-H-NMR (DMSO-d ₆ , 300 MHz) δ 2.16 (s, 3H), 2.19 (s, 3H), 2.20 (s, 3H) 2.68 (s, 3H), 6.97 (s, 1H), 7.03 (s, 1H), 7.84 (s, 1H), 8.41 (s, 1H), 8.84 (s, 1H); bs, 2H), 9.26 (bs, 3H) Mass Spectrum (ESI) m / z: Calcd. for C18H20N4S3: 388.58 (M + H), found 389.2.

Example 165

a) methyl 4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-fluorophenylthiourea as described in Example 154 step (a) to yield 55.6 mg (70%). %) methyl 4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.68 (s, 3H), 3.83 (s, 3H), 6.96-7.04 (m, 1H), 7.14-7, 29 (m, 3H), 7.35 (s, 1H), 8.06, 8.14 (s, 1H rotamer), 8.61 (td, 1H rotamer, J = 1.5 8.5 Hz), 10.14, 10.30 (s, 1H rotamer). Mass spectrum (ESI) m / z: Calcd. For C ₁₆ H ₁₃ FN ₂ O ₂ S 3 380.48 (M + H), found 381.1.

b) 4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxylate hydrobromide (55.6 mg, 0.13 mmol) was treated as described above. as described in Example 154, step (b), with a yield of 12.4 mg (24%) of 4- (2 - ((2-fluorophenyl) amino) (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride. H-NMR (DMSO-d _d. 300 MHz): δ 2.72 (s, 3H);

238

3.16 (s, 3H), 6.97-7.08 (m, 1H), 7.18-7.36 (m, 4H), 8.49 (s, 1H), 8.70 (td, 1H, 1.4, 8.4 Hz), 8.92 (bs, 2H), 9.32 (bs, 2H), 10.18 (d, 1H, J = 1.6 Hz). Mass spectrum (ESI) m / z: Calcd. For C 15 H 13 FN 4 S 3 364.49 (M + H), found 365.1.

Example 166

a) methyl 4- {2 - [(3-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-methyl-3-chlorophenylthiourea (39 mg) as described in Example 154, step (a). ) with a yield of 61.8 mg (66%) of methyl 4- {2 - ((3-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Mass spectrum (ESI) m / z: Calcd. For C17H15ClN2O2S3, 410.96 (M + H), found 411.1.

b) 4- {2 - [(3-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - ((3-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (61.8 mg, 0.12 mmol) was treated as described in Example 154 step (b) to yield 46.7 mg (90%) of 4- {2 - [(3-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} 5-methylthiothiophene-2-carboxamidine hydrochloride. H NMR (DMSO-d _b, 300 MHz) δ 2.34 (s, 3H), 2.69 (s, 3H), 7.15 (s, 1 H), 7 18-7.26 (m, 2H), 8.12 (d, 1H, J = 7.9Hz), 8.41 (s, 1H), 8.84 (bs, 2H), 9.27 ( bs, 2H), 9.61 (s, 1H) Mass Spectrum (ESI) m / z: Calcd. for C16H15ClN4S3: 394.97 (M + H), found 395.1.

Example 167

239

a) methyl 4- (2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-isopropylphenylthiourea (40 mg) as described in Example 154, step (a), to yield. 33.1 mg (36% methyl 4- (2 - {[2- (methylethyl) phenyl] amino) (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.17 (d, 6H, J = 6.7 Hz), 2.60, 2.65 (s, 3H rotamer), 3.27 (s, 1H), 3.82 (s, 3H), 7.13 (s, 1H), 7.14-7.25 (m, 2H), 7.34-7.37 (m, 1H), 7.78 (m, 1H), 7.99, 8.08 (s, 1H rotamer), 9.52, 9.61 (bs, 1H rotamer). Mass spectrum (ESI) m / z: for C 19 H 20 N 2 O 2 S 3 404.57 (M + H), found 405.1.

b) 4- (2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- (2 - {(2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl)) -5-methylthiothiophene-2-carboxylate hydrobromide (33.1 mg, 0, 06 mmol) was treated as in Example 154, step (b), yielding 22.4 mg (88%) of 4- (2 - {[2 (methylethyl) phenyl] amino} (1,3-thiazol-4-). yl) -5-methylthiothiophene-2-carboxamidine hydrochloride 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.19 (d, 6H, J = 6.8 Hz), 2.70 (s, 3H) 3.32 (m, 1H); 7.04 (s, 1H); 7.14-7.25 (m, 2H); 7.35 (dd, 1H, J = 1.4, 7.5 Hz) 7.86 (dd, 1H, J = 1.4, 7.9 Hz), 8.37 (s, 1H) Mass spectrum (ESI) m / z: Calcd. For C18H20N4S3: 388.58 (M + H). ), found 389.2.

Example 168

a) methyl 5-methylthio-4- (2 - {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate

240

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (336.3 mg, 1.08 mmol) was reacted with 4-benzyloxyphenylthiourea (279 mg) as described in Example 154, step (a) with yield 450 mg (76%) of methyl 4- (2 - {[4-phenylmethoxyphenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylatehydrobromide. Mass spectrum (ESI) m / z: for C 23 H 20 N 2 O 3 S 3 468.61 (M + H), found 469.2.

b) 5-methylthio-4- (2 - {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine hydrochloride

Methyl 1-4- (2 - {[4-phenylmethoxyphenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate hydrobromide (100 mg, 0.18 mmol) was treated as described in of Example 154, step (b), with a yield of 23.9 mg (27%) of 5-methylthio-4- (2 - {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl) ) thiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.73 (s, 3H), 5.08 (s, 2H), 7.00 (d, 2H, J = 8.2 Hz), 7, 09 (s, 1H), 7.31-7.47 (m, 5H), 7.70 (d, 2H, J = 8.0 Hz), 8.47 (s, 1H), 8.88 (bs) 2H, 9.30 (bs, 2H), 10.20 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 20 N 4 OS 3 452.62 (M + H), found 453.1.

Example 169

a) methyl 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-bromophenylthiourea (44 mg) as described in Example 154, step (a), to yield. 63.1 mg (64%) of methyl 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.65 (s, 3H), 3.82 (s, 3H), 7.00 (m, 1H), 7.33 (s, 1H), 7 , 40 (m, 1H), 7.64 (dd, 1H, J = 1.4, 7.9 Hz), 8.04, 8.11 (s, 1H rotamer), 8.27, 8.37 (dd, IH), 9.60. 9.80 (bs, 1H rotamer, J = 1.5, 8.2 Hz). materials

241% (ESI) m / z: Calcd. For C16H11Br2Cl2S5: 441.39 (M + H), found 441.1.

b) 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (63.1 mg, 0.12 mmol) was treated as described in Example 154, step (b), yielding 47.9 mg (86%) of 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.70 (s, 3H), 7.01 (m IH), 7.20 (s, IH), 7.40 (m, IH), 7, 65 (dd, 1H, J = 1.5, 8.0), 8.38 (dd, 1H, J = 1.5, 8.3 Hz), 8.44 (s, 1H), 8.89 ( bs, 2H), 9.30 (bs, 2H), 9.62 (s, 1H). MS (ESI) m / z: ₄ to Ci5Hi3BrN S3 calculated 425.39 (M + H), found 425.1.

Example 170

a) methyl 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2,6-dichlorophenylthiourea (42 mg) as described in Example 154, step (a), with a yield of 63.1 mg (65%) of methyl 4- {2 [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.59 (s, 3H), 3.8 (s, 3H), 7.15 (s, 1H), 7.36 (m, 1H), 7.61 (m, 2H), 7.97 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C16H12Cl2N2O2S3 431.38 (M + H), found 431.0.

b) 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

242

Methyl 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (43 mg, 0.08 mmol) was treated as follows: as described in Example 154, step (b), with a yield of 14.5 mg (40%) of 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5- methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.69 (s, 3H), 7.15 (s, 1H), 7.18-7.26 (m, 2H), 8.13 (d, 1H, J = 7.5Hz), 8.41 (s, 1H), 8.84 (bs, 2H), 9.27 (bs, 2H), 9.61 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C15H12Cl2N4S3: 415.39 (M + H), found 415.1.

Example 171

a) methyl 4- {2 - [(2-bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was treated with 2-bromo-4-methylphenylthiourea (47 mg) as described in Example 154, step (a), with a yield of 62 mg (61%) of methyl 4 {2 - [(2-bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.28 (s, 3H), 3.82 (s, 311), 7.21 (m, 1H), 7.27 (s, 1H), 7 48 (m, 1H), 8.14, 8.17 (s, 1H rotamer), 9.52, 9.72 (bs, 1H rotamer). Mass Spectrum (ESI) m / z: for

C 17 H 18 BrN 2 O 2 S 3 calculated 455.42 (M + H), found 455.0.

b) 4- {2 - [(2-bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(2-bromo-4-methylphenylamino) (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (62 mg, 0.11 mmol) was treated with according to the procedure described in Example 154, step (b), in a yield of 26 mg (50%) of 4- {2 - [(2-bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5- methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.28 (s, 3H), 2.70 (s, 3H), 7.14 (s, 1H), 7.21 (dd, 1H, J) = 1.6, 8.5 Hz), 7.49 (d, 1H, J = 1.5 Hz), 8.16 (d, 1H, 8.3 Hz),

243

8.41 (s, 1H), 8.85 (bs, 2H), 9.28 (bs, 2H), 9.53 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 18 H 18 Br 2 S 5 439.42 (M + H), found 439.1.

Example 172

a) Methyl 5-methylthio-4- {2 - [(2-morpholin-4-ylethyl) amino] - (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (100 mg, 0.32 mmol) was reacted with 1-ethylmorpholinothiourea (61.2 mg) as described in Example 154, step (a) with a yield of 120.8 mg (79%) of methyl 5-methylthio-4- {2 - [(2-morpholin-4-ylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide . 1 H-NMR (CD 3 OD, 300 MHz) δ 2.64 (s, 3H), 3.43-3.52 (m, 5H), 3.83-3.86 (m, 10H), 6.95 ( s, 1H), 8.04 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C16H21N3O3S3 399.55 (M + H), found 400.1.

b) 5-meetylthio-4- {2 - [(2-morpholin-4-ylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrochloride

Methyl-5-methylthio-4- {2 - [(2-morpholin-4-yl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide (62 mg, 0.12 mmol) was treated as in Example 154, step (b), yielding 26 mg (52%) of 5-methylthio-4- {2 - [(2-morpholin-4-ylethyl) amino] (1,3-thiazole- 4-yl)} thiophene-2-carboxylate hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.69 (s, 3H), 3.16-3.95 (m, 15H), 6.96 (s, 1H), 8.01 (bs, 1H), 8.49 (s, 1H), 8.84 (bs, 2H), 9.28 (bs, 2H), 10.49 (bs, 1H). Mass Spec (ESI) m / z: Calcd. For C ₁₅ H ₂₁ N ₅ OS ₃ 383.56 (M + H), found 384.2.

Example 173

244

a) methyl 4- {2 - ((2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2,3-dichlorophenylthiourea (42 mg) as described in Example 154, step (a) with yield 60.5 mg (62%) of methyl 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H), 7.27 (dd, 1H, J = 1.5, 6.5 Hz) ), 7.36 (d, 1H, J = 8.2 Hz), 7.43 (s, 1H), 8.14 (s, 1H), 8.62 (dd, 1H, J = 1.5, 8.4 Hz), 9.95 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C16H12Cl2N2O2S3 431.38 (M + H), found 431.1.

b) 4- {2- [2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (60.5 mg, 0.11 mmol) was worked up. according to the procedure described in Example 154, step (b), yielding 15 mg (30%) of 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene 2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.71 (s, 3H), 7.27-7.28-7.41 (m, 2H), 8.45 (s, 1H), 8 63 (dd, 1H, J = 1.5, 8.4 Hz), 8.84 (bs, 2H), 9.29 (bs, 2H), 9.99 (s, 1H). Mass Spectrum (ESI) m / z: Calcd. For C15H12Cl2N4S3: 415.34 (M + H), found 415.1.

Example 174

a) Methyl 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide

245

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was treated with 2,3,4-trimethoxyphenylthiourea (46 mg) as described in Example 154, step (a). ) with a yield of 61.8 mg (63%) of methyl-5-methylthio-4- {2 - ((3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2- 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.67 (s, 3H), 3.81 (s, 6H), 3.82 (s, 3H), 7.11 (s, 2H) 7.25 (s, 1H), 8.19 (s, 1H), 10.25 (s, 1H) Mass Spectrum (ESI) m / z: calcd for C18H20N4O3S3 436.56 (M + H), found 437.1.

b) 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) aminol] (1,3-thiazol-4-yl) thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- {2 - [(3, {2 - ((3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)] thiophene-2-carboxylate hydrobromide (61) (8 mg, 0.11 mmol) was treated as in Example 154, step (b) to yield 14 mg (27%) of 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] ( 1,3-thiazol-4-yl)} thiophene-2-carboxamidine hydrochloride 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.70 (s, 3H), 3.61 (s, 3H), 3 80 (s, 6H), 7.08 (s, 2H), 7.14 (s, 1H), 8.44 (s, 1H), 8.84 (bs, 2H), 9.26 (bs, 2H), 10.29 (s, 1H) Mass spectrum (ESI) m / z: calcd. For C18H20N4O3S3 436.56 (M + H), found 437.1.

Example 175

a) Methyl 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (100 mg, 0.32 mmol) was treated with N-methylpiperidylthiourea (60.6 mg) as described in Example 154, step (a) with yield 90 mg (59%) of methyl 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 1.41 (m, 2H), 1.70-1.79 (m, 6H),

246

2.65 (s, 3H), 2.95 (m, 2H), 3.52 (m, 2H), 3.73 (m, 2H), 3.82 (s, 3H), 7.08 (s 1H, 7.96 (t, 1H, J = 5.3 Hz), 8.09 (s, 1H), 9.40 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C17H23N3O2S3: 397.6 (M + H), found 398.1.

b) 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide (72 mg, 0.15 mmol) was treated as in Example 154, step (b), with a yield of 26.8 mg (43%) of 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2- karboxamidínydrochloridu. 1 HNMR (DMSO-d 6, 300 MHz) δ 1.40 (m, 2H), 1.72-1.79 (m, 6H), 2.69 (s, 3H), 2.96 (m, 2H) 3.51 (m, 2H), 3.76 (m, 2H), 6.97 (s, 1H), 8.08 (t, 1H, J = 5.5 Hz), 8.60 (s, 1H), 8.95 (bs, 1H), 9.35 (bs, 2H), 10.25 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C ₁₆ H ₂₃ N 5 S ₃ : 381.1 (M + H), found 382.2.

Example 176

a) methyl 1-4- (2 - ([(4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) -5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (111 mg, 0.35 mmol) was reacted with 4-methylphenylmethylthiourea by the method of Example 154, step (a) in a yield of 125 mg (81%). methyl 4- (2 - ([(4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) -5-methylthiothiophene-2-carboxylate hydrobromide Mass Spectrum (ESI) m / z: for C 18 H 18 N 2 O 2 S 2 calcd 358.5 (M + H), found 359.1.

b) 4- (2 - ([(4-methylphenyl) methyl] amino | (1,3-thiazol-4-yl)) -5-methylthiothiophene-2-carboxamidine hydrochloride

247

Methyl 4- (2 - {[(4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate hydrobromide (118 mg, 0.26 mmol) was treated as described above. as described in Example 154, step (b), yielding 58.2 mg (54%) of 4- (2 - ([(4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) -5-methyl 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.27 (s, 3H), 2.66 (s, 3H), 4.49 (d, 2H, J = 5.7 Hz), 6.88 (s, 1H), 7.13 (d, 2H, J = 7.8 Hz), 7.27 (d, 2H, J = 8.0 Hz), 8.20 (t, 1H, J = 5.8 Hz), 8.42 (s, 1H), 8.90 (bs, 2H), 9.27 (bs, 2H) Mass Spectrum (ESI) m / z: C17H18N4S3 calculated 374.55 (M + H), found 375.2.

Example 177

a) amino {[4- (4-chlorophenoxy) phenyl] amino} methan-1-thione

Unless otherwise stated, all thioureas, isothiocyanates, thioamides and amines are obtained from Maybridge Chemical Co. Ltd. (Cornwall, UK), Transworld Chemical Co. (Rockville, MD), or Aldrich Chemical Co., (Milwaukee, WI). i). 4-Amino-4'-chlorodiphenyl ether (TCI America, Portland OR, 520 mg, 2.03 mmol) was slurried in 10 mL of ether and treated with about 1 mL of ether saturated with HCl gas. After 5 minutes, the solvent was removed in vacuo. Thereafter, to the biphasic solution, amine-HCl salts in 20 mL of CHCl 3 saturated NaHCO 3 (1: 1 v / v) at room temperature were added dropwise via addition funnel thiophosgene (1.2 eq, 2.4 mmol) in 5 mL CHCl3. The reaction mixture was then stirred vigorously for 1 hour (TLC, 50% ethyl acetate-hexanes indicated complete conversion showing a spot with higher Rf), then the layers were separated, the aqueous layer was extracted with CHCl 3 (1 x 20 mL) and the combined organic layers were washed with brine. solution (1 x 20 mL) and dried (Na 2 SO 4). Concentration in vacuo afforded crude 4- (4-chlorophenoxy) -phenylisothiocyanate (414 mg). 1.0 M NH ₃ in 5 mL methanol (Aldrich Chemical Co., Mil

248 Waukee, WI)). The tube is then sealed and immersed in an 80 ° C oil bath. After 2 hours, cool the reaction mixture to 0 ° C in an ice bath. Precipitated fractions were filtered and dried in vacuo to give amino {[4- (4-chlorophenoxy) phenyl] amino} methan-1-thione (328 mg, 79%). ¹ H-NMR (DMSOd 6, 300 MHz) δ 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 13 H 11 ClN 2 OS 278.8 (M + H), found 279.4.

b) methyl 1-4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (309 mg, 1.0 mmol) was treated with amino {[4- (4-chlorophenoxy) phenyl] amino} methan-1-thione ( 297 mg) as described in Example 154, step (a), with a yield of 410 mg (72%) of methyl 4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazole-4- yl)) - 5methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m / z: Calcd. For C 22 H 17 ClN 2 O 3 S 3 489.1 (M + H), found 489.1.

c) 4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate hydrobromide (300 mg, 0.52 mmol) worked up as in Example 154, step (b), yielding 129.9 mg (49%) of 4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.72 (s, 3H), 6.97 (m, 2H), 7.07 (m, 2H), 7.15 (s, 1H), 7.40 (m, 2H), 7.85 (m, 2H), 8.46 (s, 1H), 8.82 (bs, 2H), 9.27 (bs, 2H), 10.43 (bss) , 1H). Mass spectrum (ESI) m / z: Calcd. For C 21 H 17 ClN 4 OS 3 473.1 (M + H), found 473.2, 475.1.

Example 178

249

(a) methyl-5-methylthio-4- [2 - ({4- [5- (trifluoromethyl) (2-pyridyl)] phenyl} amino) (1,3-thiazol-4-yl)] thiophene- 2-carboxylate

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (70 mg, 0.23 mmol) was treated with 4- [5- (trifluoromethyl) pyrid-2-yloxy] thiobenzamide (50 mg) by a method of as described in Example 154, step (a), with a yield of 115 mg (98%) of methyl 5-methylthio-4- [2 - ({4- [5- (trifluoromethyl) (2-pyridyloxy)] phenyl} amino) (1). , 3-thiazol-4-yl)] thiophene-2-carboxylate. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.70 (s, 3H), 3.85 (s, 3H), 7.38 (m, 3H), 8.10 (m, 1H), 8 18 (s, 1 H), 8.28 (dd, 1 H, J = 2.7, 8.8 Hz), 8.32 (s, 1 H), 8.60 (m, 1 H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 15 F 3 N 2 O 3 S 3 508.56 (M + H), found 509.2.

b) 5-methylthio-4- [2 - ({4- [5- (trifluoromethyl) (2-pyridyloxy)] phenyl} amino) (1,3-thiazol-4-yl) thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- [2 - ({4- [5- (trifluoromethyl) (2-pyridyl)] phenyl} amino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate (95 mg, 0.18 mmol) was treated as in Example 154, step (b) to yield 30.3 mg (32%) of 5-methylthio-4- [2 - ({4- [5- (trifluoromethyl)] (2-pyridyloxy)] phenyl} amino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.75 (s, 3H), 7.34 (d, 1H, J = 8.7 Hz), 7.41 (m, 2H), 8.01 (s, 1H), 8.10-8.14 (m, 2H), 8.29 (dd, 1H, J = 2.5, 8.4 Hz), 8.60 (m, 1H), 8, 63 (s, 1H), 8.91 (bs, 2H), 9.31 (bs, 2H). Mass spectrum (ESI) m / z: Calcd. For C 21 H 15 F 3 N 4 OS 3

492.6 (M + H), found 493.1.

Example 179

(a) methyl 4- (2 - {[4-phenoxyphenyl] amino] (1,3-thiazol-4-yl) -5-methylthiothiophene-

-2-carboxylate hydrobromide

250

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (200 mg, 0.64 mmol) was treated with 4-phenoxyphenylthiourea (158 mg) as described in Example 154 step (a) to yield 300 mg. (88%) methyl 4- (2 - {[4-phenoxyphenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide Mass Spectrum (ESI) m / c: for C 22 H 18 N 2 O 3 S 3 calcd 454.6 (M + H), found 455.2.

b) 4- (2 - {[4-phenoxyphenyl) amino) (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- (2 - {[4-phenoxyphenyl] amino) (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate hydrobromide (230 mg, 0.42 mmol) was treated as described in Example 154 , step (b) and purification by preparative thin layer chromatography (20% methanol-ClHCl-saturated NH 3, silica gel plate 500 mm, JTBaker, Phillipsburg, NJ) gave 86 mg (47% yield) of the product. A 46 mg portion of the product was dissolved in 1 mL of methanol, treated with three drops of ether saturated with HCl gas and concentrated in vacuo with toluene (2x5 mL) to give 42.3 mg (21% yield) of 4- (2- { [4-Phenoxyphenyl] amino} - (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.71 (s, 3H) ), 6.97-7.11 (m, 4H), 7.15 (s, 1H), 7.36 (m, 2H), 7.72, 7.85 (d, 2H rotamer), J = 8 7 Hz), 8.36, 8.55 (s, 1H rotamer), 9.00 (bs, 2H), 9.35 (bs, 2H), 10.49 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 21 H 18 N 4 OS 3 438.6 (M + H), found 439.2.

Example 180

a) amino {[4- (phenylamino) phenyl] amino) methan-1-thione

4-Aminodiphenylamine (500 mg, 2.71 mmol) was treated as described in Example 177, step (a) and recrystallized from toluene to give 350 mg.

251 (53% yield) amino ([4- (phenylamino) phenyl] amino} methan-1-thione) 1 H-NMR (DMSO-d 6, 300 MHz) δ 6.80 (m, 1H), 7.01- 7.24 (m, 8H), 8.15 (s, 1H), 9.45 (s, 1H) Mass Spectrum (ESI) m / z: calcd for C 13 H 13 N 3 S 243.33 (M + H), found 244 '2.

b) methyl 5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was treated with amino {[4- (phenylamino) phenyl] amino} methan-1-thione (70, 8 mg) as described in Example 154, step (a), to give 71 mg (47% yield) of methyl 5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3) thiazol-4-yl)) thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H), 6.73 (m, 1H), 6.96-7.24 (m, 9H), 7.63 (d, 1H, J = 8.6 Hz), 8.12 (s, 1H), 10.13 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 19 N 3 O 2 S 3 453.60 (M + H), found 454.2.

c) 5-Methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide (71 mg, 0.13 mmol) was treated as in Example 154, step (b), yielding 23.3 mg (38%) of 5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4). yl)) thiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.72 (s, 3H), 6.74 (t, 1H, J = 7.3 Hz), 6.98 (d, 1H, J = 7) 6 Hz), 7.08 (m, 2H), 7.18 (m, 2H), 7.66 (d, 2H, J = 8.9 Hz), 7.99 (s, 1H), 45 (s, 1H), 9.03 (bs, 4H), 10.17 (s, 1H). MS (ESI) m / z for C ₂ H ₁₉ N ₅ S3 calculated 437.59 (M + H), found 438.2.

Example 181

252

a) amino - {[4-benzylphenyl] amino} methane-1-thione (500 mg, 2.73 mmol) was treated as in Example 177 step (a) to yield 410 mg (62%) of amino {[4- benzylphenyl] amino} methane-l-thione. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 3.89 (s, 2H), 7.14-7.28 (m, 9H), 9.59 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 14 H 14 N 2 O 3 242.1 (M + H), found 243.2.

b) methyl-5-methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was treated with amino {[4-benzylphenyl] amino} methane-1-thione (70.5 mg) according to the procedure described in Example 154, step (a) in a yield of 70.1 (47%) methyl-5-methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H), 3.87 (s, 2H), 7.14-7.30 (m 8H), 7.66 (d, 2H, J = 8.5 Hz), 8.12 (s, 1H), 10.23 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 19 N 3 O 2 S 3

453.6 (M + H), found 454.2.

c) 5-methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine hydrochloride

Methyl 1-5-methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide (82.2 mg, 0.15 mmol) was treated as in Example 154 step (b) to yield 5-methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene (33.4 mg, 47%). 2-carboxamidine hydrochloride. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.72 (s, 3H), 3.89 (s, 2H), 7.12 (s, 1H), 7,167.29 (m, 7H), 7, 69 (d, 2H, J = 8.6 Hz), 8.43 (s, 1H), 9.02 (bs, 4H), 10.28 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 20 N 4 S 3 436.6 (M + H), found 437.2.

Example 182

253

a) ({4 - [(Aminothioxomethyl) amino] phenyl} sulfonyl) piperidine

4-Aminophenylsulfonylpiperidine (500 mg, 2.08 mol) was treated as described in Example 177, step (a) to yield 382 mg (61%) of ({4 - [(aminothioxomethyl) amino] phenyl} sulfonyl) piperidine. 1 H-NMR (DMSO-d 6, 300 MHz) δ 1.34 (m, 2H), 1.53 (m, 4H), 2.85 (m, 4H), 7.62 (m, 2H), 7 78 (m, 2H); 10.10 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C 12 H 17 N 3 O 2 S 2 299.4 (M + H), found 300.2.

b) methyl 1-5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino] (1,3-thiazol-4-yl) thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was treated with ({4 - [(aminothioxomethyl) amino] phenyl} sulfonyl) piperidine (87.1 mg). ) as described in Example 154, Step (a), with a yield of 105 mg (63%) of methyl 1-5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} (1,3-thiazol-4yl) )) thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.33 (m, 2H), 1.52 (m, 4H), 2.69 (s, 3H), 2.84 (m, 4H), 3.82 (s, 3H), 7.43 (s, 1H), 7.66 (m, 2H), 7.98 (m, 2H), 8.16 (s, 1H), 10.85 (s) , 1H). Mass spectrum (ESI) m / z: Calcd. For C21H23N3O4S4: 509.69 (M + H), found 510.2.

c) 5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} (1,3-thiazo-4-yl) thiophene-2-carboxamidine hydrochloride

Methyl 1-5-methylthio-4- (2 - {[4- (piperidinylsulfonyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide (105 mg, 0.17) mmol) was treated as in Example 154, step (b) to give 30.3 mg (34%) of 5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} (1,3-thiazole) 4-yl)) thiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 1.36 (m, 2H), 1.54 (m, 4H), 2.76 (s, 3H), 2.86 (m, 4H), 7 30 (s, 1H); 7.68 (d, 2H, J = 8.8 Hz); 8.03 (d, 2H, J = 8.8 Hz); 8.51 (s, 1H); 84 (bs, 2H), 9.28 (bs, 2H), 10.94 (s,

254

1Η). Mass spectrum (ESI) m / z: Calcd. For C 20 H 23 N 5 O 2 S 5 493.69 (M + H), found 494.2.

Example 183

a) amino (3-quinolylamino) methane-1-thione

3-Aminoquinoline (500 mg, 3.46 mmol) was treated as in Example 177, step (a) to yield 285 mg (41%) of amino (3-quinolylamino) methan-1-thione. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 7.57 (m, 1H), 7.67 (m, 1H), 7.94 (m, 2H), 8.41 (d, 1H, J = 2.4 Hz), 8.85 (d, 1H, J = 2.5 Hz), 10.03 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 10 H 9 N 3 S 203.3 (M + H), found 204.1.

b) methyl 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was treated with amino (3-quinolylamino) methan-1-thione (59.1 mg) as described in of Example 154, step (a), with a yield of 107.5 mg (78%) of methyl 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2- carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.75 (s, 3H), 3.84 (s, 3H), 7.52 (s, 1H), 7.92-8.05 (m 2 H, 8.22 (s, 1 H), 9.22 (m, 2 H). Mass spectrum (ESI) m / z: Calcd. For C19H15N3O2S3 413.54 (M + H), found 414.1.

c) 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl) -thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate hydrobromide (107.5 mg, 0.21 mmol) was treated as described in

255 of Example 154, step (b), with a yield of 4.5 mg (4.9%) of 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2 -karboxamidínhydrochloridu. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 2.80 (s, 3H), 7.29 (s, 1H), 7.59 (m, 2H), 7.93 (m, 2H), 8.54 (s, 1H), 8.89 (bs, 2H), 8.91 (m, 1H), 9.16 (m, 1H), 9.29 (bs, 2H), 10.97 (s) , 1H). Mass spectrum (ESI) m / z: Calcd. For C18H15N5S3: 397.5 (M + H), found 398.1.

Example 184

a) methyl 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl) thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was treated with 2-napthylthiourea (42.4 mg) as described in Example 154, step (a), with yield 82.5 mg (80%) of methyl 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate hydrobromide. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3H), 7.31 (s, 1H), 7.507.67 (m, 4H), 7.93 (m, 1H), 8.15 (s, 1H), 8.31-8.35 (m, 1H), 8.46 (d, 1H, J = 7.6), 10.22 (s, 1H) ). Mass Spectrum (ESI) m / z: Calcd. For C20H18N2O2S3 412.6 (M + H), found 413.1.

c) 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate hydrobromide (42.7 mg, 0.086 mmol) was treated as described in Example 154 step (b) to yield 5.8 mg (16%) of 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine hydrochloride. ¹ H-NMR (DMSO-d 6, 300 MHz) δ 2.72 (s, 3H), 7.12-7.27 (m, 3H), 7.50-7.68 (m, 3H), 7, 94 (m, 1H), 8.32-8.35 (m, m, 1H), 8.51 (s, 1H), 8.97 (bs, 2H), 9.34 (bs, 2H),

256

10.26 (s, 1 H). Mass spectrum (ESI) m / z: Calcd. For C 19 H 16 N 4 S 3

396.6 (M + H), found 397.2.

Example 185

(a) methyl 4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was treated with 2,3-methylenedioxyphenylthiourea (41.2 mg) as described in Example 154, step (a), with a yield of 51 mg (50%) of methyl 4- [2- (2H-benzo [3,4-d] -1,3-dioxolan-5-ylamino) (1,3-thiazol-4-) yl)] - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO d 6, 300 MHz) δ 2.66 (s, 3H), 3.83 (s, 3H), 5.98 (s, 2H), 6.84-6.89 (m, 1H 6.96, 7.04 (dd, 1H rotamer, J = 2.2, 8.5 Hz), 7.25 (s, 1H), 7.46, 7.60 (d, 1H rotamer, J) = 2.1 Hz), 8.05, 8.13 (s, 1H rotamer), 10.19, 10.34 (s, 1H, rotamer). Mass spectrum (ESI) m / z: Calcd. For C 17 H 14 N 2 O 4 S 3 406.5 (M + H), found 407.1.

b) 4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) - (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxylate hydrobromide (51) mg (0.10 mmol) was treated as in Example 154, step (b) to yield 16.6 mg (39%) of 4- [2- (2H-benzo [3,4-d] -1,3-dioxolane). -5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.71 (s, 3H), 5.98 (s, 2H), 6.87 (d, 1H, J = 8.2 Hz), 7, 09-7.13 (m, 2H), 7.67 (d, 1H, J = 2.4Hz), 8.50 (s, 1H), 8.95 (bs, 2H), 9.33 (bs) 2H, 10.30 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C16H14N4O2S3: 390.51 (M + H), found 391.2.

257

Example 186

a) amino [(7-bromofluoren-2-yl) amino] methane-1-thione

2-Amino-7-bromofluorene (500 mg, 1.90 mmol) was treated as described in Example 177, step (a) to yield 128 mg (21%) of amino [(7-bromofluoren-2-yl) amino] methane-l-thione. 1 H-NMR (DMSO-d 6, 300 MHz) δ 3.35 (s, 2H), 7.35 (d, 1H, J = 8.3 Hz), 7.54 (d, 1H, J = 8, 0 Hz), 7.66 (s, 1H), 7.77-7.87 (m, 3H), 9.80 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For CuHuBrNiS 319.2 (M + H), found 320.1, 321.1.

b) methyl 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was treated with amino [(7-bromofluoren-2-yl) amino] methanes-1-thione (92). , 8 mg) as described in Example 154, Step (a), with a yield of 141 mg (82%) of methyl 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-) yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.70 (s, 3H), 3.83 (s, 3H), 3.93 (s, 2H), 7.33 (s, 1H), 7 51 (dd, 1H, J = 1.9, 8.0 Hz), 7.65 (dd, 1H, J = 2.0, 8.4 Hz), 7.74 (ad, 2H, J = 8) 3 Hz), 7.83 (ad, 1H, J = 8.4 Hz), 8.18 (s, 1H), 8.23 (d, 1H, J = 1.4 Hz), 10.47 ( s, 1H).

c) 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (100 mg, 0.15 mmol) was treated with according to the procedure described in Example 154, step (b), yielding 3.3 mg (4%) of 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5- methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.76 (s, 3H), 3.95 (s, 2H),

258

7.18 (s, 1H), 7.54 (dd, 1H, J = 1.8, 10.0 Hz), 7.67-7.76 (m, 3H), 7.85 (d, 1H, J = 8.2 Hz), 8.23 (s, 1H), 8.50 (s, 1H), 10.53 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 17 BrN ₄ S ₃ 513.5 (M + H), found 513.1, 515.1.

Example 187

a) methyl 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was treated with 4-cyclohexylphenylthiourea (49.2 mg) as described in Example 154, step (a). ) with a yield of 45 mg (41%) of methyl 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 1.23-1.39 (m, 5H), 1.71-1.79 (m, 5H), 2.68 (s, 3H), 3, 83 (s, 3H), 7.16 (d, 2H, J = 8.6 Hz), 7.26 (s, 1H), 7.65 (d, 2H, J = 8.7 Hz), 14 (s, 1 H), 10.19 (s, 1 H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 24 N 2 O 2 S 444.64 (M + H), found 445.2.

b) 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate hydrobromide (31.1 mg, 0.059 mmol) was treated as described in Example 154, step (b), yielding 12.8 mg (47%) of 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.33-1.40 (m, 5H), 1.68-1.79 (m, 5H), 2.44 (m, 1H), 2 73 (s, 3H), 7.12 (s, 1H), 7.18 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 8 47 (s, 1H), 8.85 (bs, 2H), 9.32 (bs, 2H), 10.28 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C21H24N4S3: 428.64 (M + H), found 429.2.

259

Example 188

a) amino-4- [4- (phenyldiazenyl) phenyl] amino} methan-1-thione

The 4-phenylazophenyl isothiocyanate (314 mg, 1.30 mmol) was treated as described in Example 177, step (a), part (ii) to yield 295 mg (88%) of amino {[4- (phenyldiazenyl) phenyl] amino} methane-l-thione. 1 H-NMR (DMSO-d 6, 300 MHz) δ 6.84 (m, 1H), 7.57 (m, 2H), 7.73 (m, 2H), 7.85-7.89 (m, 4H), 10.04 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 13 H 12 N 4 S 256.3 (M + H), found 257.2.

b) methyl 1-5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino) (1,3-thiazol-4-yl) thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was treated with amino {[4- (phenyldiazenyl) phenyl] amino} methan-1-thione (53, 8 mg) as described in Example 154, step (a), yielding 80.6 mg (70%) of methyl 5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3- thiazol-4-yl)) thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d 6, 300 MHz) δ 2.72 (s, 3H), 3.84 (s, 3H), 7.46 (s, 1H), 7.49-7.61 (m, 3H), 7.84 (m, 2H), 7.91-8.02 (m, 4H), 8.20 (s, 1H), 10.83 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 22 H 18 N 4 O 2 S 3 466.6 (M + H), found 467.1.

c) 5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine hydrochloride

Methyl 5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate hydrobromide (47.7 mg, 0.087 mmol) was worked up. according to the procedure described in Example 154, step (b), yielding 32.8 mg (77%) of 5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazole- 4-yl)) thiophene-2-carboxylic

260 boxamidine hydrochloride. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.78 (s, 3H), 7.26 (s, 1H), 7.49-7.63 (m, 3H), 7.66-7 74 (m, 3H), 7.84-8.08 (m, 3H), 8.60 (s, 1H), 11.02 (bs, 1H). Mass spectrum (ESI) m / z: Calcd. For C 21 H 18 N 6 S 3

450.6 (M + H), found 451.1.

Example 189

a) {3 - [(aminothioxomethyl) amino] phenyl} methan-1-ol

The 3-aminobenzyl alcohol (550 mg, 4.46 mmol) was treated as described in Example 177, step (a) to yield 618 mg (76%) of {3 - [(aminothioxomethyl) amino] phenyl} methan-1-ol. 1 H-NMR (DMSO-d 6, 300 MHz) δ 4.47 (d, 2H, J = 5.6 Hz), 5.19 (t, 1H, J = 5.7 Hz), 7.06 (d 1H, J = 6.2 Hz), 7.18-7.30 (m, 3H), 9.73 (s, 1H).

b) Methyl 5-methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (1.01 g, 3.26 mmol) was reacted with {3 - [(aminothioxomethyl) amino] phenyl} methan-1-ol as described in Example 154, step (a), yielding 1.42 g (92%) of methyl-5-methylthio-4- (2 - {[3 (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) -thiophene-2-carboxylate hydrobromide. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3H), 4.49 (s, 2H), 6.92 (m, 1H), 7, 23-7.31 (m, 2H), 7.60 (m, 1H), 7.81 (bs, 1H), 8.17 (s, 1H), 10.29 (bs, 1H).

c) 5-methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine hydrochloride

261

Methyl 5-methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene-2-carboxylate hydrobromide (700 mg, 1.47 mmol) work up as in Example 154, step (b), using 1: 9: 1 methanol-CH 2 CH-DMF as eluent, to give 195 mg (32% yield) of 5-methylthio-4- (2 - ([3]). - (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl) thiophene-2-carboxamidine hydrochloride 1 H-NMR (DMSO-d 6, 300 MHz) 82.71 (s, 3H), 4, 50 (s, 2H), 6.93 (d, 1H, J = 7.6Hz), 7.15 (s, 1H), 7.21-7.27 (m, 1H), 7.38 (bs) 1 H, 7.65 (d, 1 H, J = 8.1 Hz), 7.80 (s, 1 H), 8.53 (s, 1 H), 8.94 (bs, 2 H), 9.32 (bs, 2H), 10.37 (s, 1H) Mass Spectrum (ESI) m / z: calcd for C 16 H 16 N 4 OS 3 376.5 (M + H), found 377.2.

Example 190

a) (tert -Butoxy) -N - [(4- {2 - [(3-hydroxymethylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthio- (2-thienyl) iminomethyl] amide

5-Methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene-2-carboxamidine (103 mg, 0.27 mmol) was slurried with THF (4 mL) and treated with 0.5 mL 0.5 N NaOH. Then t-butyl dicarbonate (0.40 mmol) was added in one portion and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between CH 2 Cl 2 and water. The organic layer was separated, washed with brine (1 x 20 mL) and dried (Na 2 SO 4). Removal of the solvent in vacuo followed by purification by preparative thin layer chromatography (500 mm silica gel, JT Baker, Phillipsburg, NJ, 1% methanol-CH ₂ Cl ₂ ) gave 45 mg (35% yield) ((tert-butoxy) - N - [(4- {2 - [(3-hydroxymethylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthio- (2-thienyl) iminomethyl] carboxamide 1 H-NMR ( DMSO-d ₆ , 300 MHz) δ 1.44 (s, 9H), 2.66 (s, 3H), 4.49 (d, 2H, J = 5.7 Hz), 5.15 (t, 1H J = 5.5 Hz), 6.92 (d, 1H, J = 7.5 Hz), 6.96 (s, 1H), 7.26 (m, 1H), 7.66-7.75 (m, 2H), 8.38 (s, 1H), 8.98 (bs, 2H), 10.24 (s, 1H).

262

b) (tert -Butoxy) -N- (imino- {4- [2 - ({3 - {(3-methylpiperidyl) methyl] phenyl} amino) (1,3-thiazol-4-yl)] - 5 methylthio- (2-thienyl) methyl) carboxamide

To a stirred solution of ((tert -butoxy) -N - [(4- {2 - [(3-hydroxymethylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthio- (2-thienyl) (Iminomethyl) carboxamide (45 mg, 0.094 mmol) under N2 was added triethylamine (2 eq, 26.3 μΐ) followed by methanesulfonyl chloride (Aldrich Chemical Co., Milwaukee, WI, 0.13 mmol, 10.2 μΐ). The reaction mixture was stirred for 1 hour and then partitioned between CFUCU-water and the organic layer was washed with brine (20 mL), filtered through a 5 cm layer of silica gel in a sintered glass funnel and dried (Na 2 SO 4). 3-methylpiperidine (0.18 mmol, 21.4 μΐ) was added to 25.3 mg (0.045 mmol) of mesylate in 0.5 mL of DMF, and the crude mesylate (44 mg) was used immediately without further purification. The resulting reaction mixture was heated in an oil bath at 65 ° C for 4 hours, then the reaction mixture was concentrated in vacuo and purified by preparative thin layer chromatography (250 mm silica gel, 10% methanol-CH 2 Cl 2). 2, JT Baker, Phillipsburg, NJ) to give 8.2 mg (32% yield) of (tert -butoxy) -N- (imino {4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl) (amino) (1,3-thiazol-4-yl)] - 5-methylthio- (2-thienyl)} methyl) carboxamide. MS (ESI) m / z: Calcd for C27H35N5O2S3 557.8 (M + H), found 557.9, 458.2 (C (O) OC _{(CH3) 3).}

c) 4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride (tert-butoxy) - N- (imino {4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthio- (2-thienyl)} methyl ) carboxamide (8.2 mg, 0.014 mmol) was stirred at 0 ° C for 30 min with 2 mL of a solution containing 10% HCl (3 mol / L) -ethyl acetate, then the solvent was removed in vacuo to give 8 mg (100 mg). % yield) 4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H-NMR (DMSO-d 6, 300 MHz) δ 0.83 (d, 3H, J = 5.6 Hz), 1.54-2.48 (m, 5H), 2.52-2.63 ( m, 4H), 2.66 (s, 3H), 4.23 (d, 2H, J = 4.8Hz), 7.15-7.23 (m, 2H), 7.41 (t, 1H, J) = 7.8 Hz), 7.867.92 (m, 2H), 8.63 (s, 1H), 9.01 (bs, 2H), 9.42 (bs, 2H), 10.63 (s, 1H) ). Mass Spectrum63 (ESI) m / z calcd. For C22H27N5S3 457.7 (M + H), found

458.2.

Example 191

a) methyl 5-methylthio-4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was treated with 3-hydroxyphenylthiourea (32.6 mg) as described in Example 154, step (a), with a yield of 80.2 mg (92%) of methyl 5-methylthio-4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - thiophene-2-carboxylate hydrobromide. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3H), 6.38 (d, 1H, J = 7.6 Hz), 7, 06-7.12 (m, 2H), 7.20-7.29 (m, 2H), 8.14 (s, 1H), 10.17 (s, 1H).

b) 4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 1-5-methylthio-4- [2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide (460 mg, 1.0 mmol) was worked up. according to the procedure described in Example 154, step (b), yielding 215 mg (54%) of 4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2- carboxamidine. Mass spectrum (ESI) m / z: Calcd. For C15H14N4OS3 362.5 (M + H), found 363.2.

c) (tert -Butoxy) -N - [(4- {2 - [(4-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthio (2-thienyl) iminomethyl ] carboxamide

264

To a stirred solution of 4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine hydrochloride (215 mg, 0.48 mmol) in 4 mL of CH 2 Cl 2 -DMF (3: 1, v / v) was added diisopropylethylamine (1.2 eq). Di-tert-butyl dicarbonate (1.2 eq, 127 mg, Aldrich Chemicals, Milwaukee, WI) in 1 mL CH 2 Cl 2 was then added dropwise via addition funnel. The reaction mixture was stirred overnight, partitioned between CH 2 Cl 2 -H 2 O and the layers were separated. The organic layer was dried (Na 2 SO 4) and concentrated in vacuo. Purification of the residue by flash chromatography (1% methanol-CH 2 Cl 2) afforded 60 mg (27% yield) of (tert -butoxy) -N - [(4- {2 - [(4-hydroxyphenyl) amino] (1,3-thiazole-). 4-yl)} - 5-methylthio (2-thienyl)) iminomethyl] carboxamide. NMR (DMSO-d 6, 300 MHz) δ 1.44 (s, 9H), 2.72 (s, 3H), 6.38 (m, 1H), 6.96 (s, 1H), 7.06- 7.12 (m, 2H), 7.28 (m, 1H), 8.35 (s, 1H), 9.00 (bs, 2H), 9.28 (s, 1H), 10.11 (s) , 1H). Mass spectrum (ESI) m / z: Calcd. For C 20 H 22 N 4 O ₃ S 3 462.6 (M + H), found 462.7, 363.2 [-C (O) OC (CH ₃ ) ₃ ].

d) (tert -Butoxy) -N - {[4- (2 - {[3- (carbamoylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthio- (2 thienyl)] imino-methyl) carboxamide

To a stirred solution of (tert -butoxy) -N - [(4- {2 - [(4-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthio- (2-thienyl) iminomethyl] carboxamide (65 mg, 0.14 mmol) in 1.5 mL DMF was sequentially added CS 2 CO 3 (1.5 eq, 60.1 mg, Aldrich Chemicals, Milwaukee, WI), bromoacetamide (1.2 eq, 20, 4 mg, Aldrich Chemicals, Milwaukee, WI), and a catalytic amount of KI. The reaction mixture was heated to 58 ° C in an oil bath, stirred for 48 hours, and then an additional 0.6 equivalents of bromoacetamide was added. The reaction mixture was stirred for an additional 24 hours and then the reaction mixture was filtered and concentrated in vacuo. Purification of the residue by preparative thin layer chromatography (50% ethyl acetate-hexanes) gave 9 mg (12% yield) of (tert -butoxy) -N - ([4- (2 - {[3- (carbamoylmethoxy) phenyl] amino)) (l, 3-thiazol-4-yl)) - 5-methylthio (2-thienyl)] iminomethyl} carboxamide. Mass spectrum (ESI) m / z: Calcd. For C 22 H 25 N 5 O 4 S 3 519.7 (M + H), found 519.7, 420.7 [-C (O) OC (CH ₃ ) ₃ ].

265

e) 4- (2 - {[4- (carbamoylmethoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine trifluoroacetate

To a stirred suspension of (tert-butoxy) [4- (2 - {[3- (carbamoylmethoxy) phenyl] amino) (1,3-thiazol-4-yl)) - 5-methylthio- (2-thienyl)] iminomethyl} of carboxamide (about 4 mg, 0.007 mmol) in CH 2 Cl 2-DMF (4 mL, 3: 1 v / v) at 0 ° C was added 1 mL of trifluoroacetic acid. The homogeneous solution was then further stirred for 40 minutes at the above temperature, warmed to room temperature for 30 minutes and concentrated in vacuo to give 4 mg (100% yield) of 4- (2 - {[4- (carbamoylmethoxy) phenyl] amino (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine trifluoroacetate. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.75 (s, 3H), 4.21 (d, 2H, J = 5.7 Hz), 6.64 (dd, 1H, J = 2, 4.28 (Hz), 6.97 (dd, 1H, J = 1.1, 8.2 Hz), 7.16 (s, 1H), 7.22 (m, 1H), 7.60- 7.63 (m, 1H), 7.69-7.72 (m, 1H), 7.88 (t, 1H, J = 2.1 Hz), 8.42 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C17H17N5O2S3, 419.6 (M + H), found 420.1.

Example 192

a) Isopropyl 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - thiophene-2-carboxylate hydrobromide

Isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (84 mg, 0.27 mmol) was treated with 3,4,5-trimethoxyphenylthiourea (66.5 mg) as described in Example 154, step (a) with a yield of 68 mg (48%) of isopropyl 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide. Mass spectrum (ESI) m / z: Calcd. For C 21 H 24 N 2 O 5 S 2 448.56 (M + H), found 449.0.

266

b) 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl) thiophene-2-carboxamidine hydrochloride

Isopropyl-5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide (59 mg, 0.11 mmol) work up as described in Example 154, step (b), yielding 24.4 mg (50%) of 5-methyl-4- {2 [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazole-4- yl)} thiophene-2-carboxamidine hydrochloride. H NMR (DMSO-d _b, 300 MHz) δ 2.81 (s, 3H), 3.61 (s, 3H), 3.77 (s, 6H), 7.04 (s, 2H), 7 10.09 (s, 1H); 8.40 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 18 H 20 N 4 O 3 S 2 404.5 (M + H), found 405.2.

Example 193

a) Isopropyl 5-methyl-4- {2 - [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide

Isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (91 mg, 0.29 mmol) was treated with 4-phenoxyphenylthiourea (72.6 mg) as described in Example 154, step (a) with yield 115 mg (75%) of isopropyl-5-methyl-4- {2 - [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate hydrobromide. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 1.28 (d, 6H, J = 6.2 Hz), 2.70 (s, 3H), 6.06 (quintet, 1H, J = 6, 2 Hz), 6.92-7.09 (m, 5H), 7.15 (s, 1H), 7.30-7.37 (m, 2H), 7.56-7.70 (m, 2H) 7.98 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 24 H 22 N 2 O 3 S 2 450.6 (M + H), found 451.2, 409.2 [-CH (CH ₃ ) 2].

b) 5-methyl-4- {2- [4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine hydrochloride

Isopropyl-5-methyl-4- {2 - [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl) thiophene-2-carboxylate hydrobromide (95.5 mg, 0.17 mmol) was treated as described above. in Example 154, step (b), with a yield of 23.8 mg (32%) of 5-methyl-4- {2 - [(4)

267

-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine hydrochloride. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.76 (s, 3H), 6.95-7.12 (m, 6H), 7.34-7.39 (m, 2H), 7.72 -7.78 (m, 2H), 8.33 (s, 1H), 8.98 (bs, 3H), 10.29 (bs, 1H). Mass Spectrum (ESI) m / z: Calcd. For C21H18N4O2S3 406.5 (M + H), found

407.2.

Example 194

a) Isopropyl 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2-carboxylate hydrobromide

Isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (64 mg, 0.21 mmol) was treated with phenylthiourea (32.1 mg) as described in Example 154, step (a), to yield 80 mg (87%) of isopropyl-5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2-carboxylate hydrobromide. Mass spectrum (ESI) m / z: Calcd. For C 18 H 18 N 2 O 2 S 358.5 (M + H), found 359.2.

b) 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2-carboxamidine hydrochloride

Isopropyl 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2-carboxylate hydrobromide (74 mg, 0.16 mmol) was treated as described in Example step (a). b) phenylthiourea (24.3 mg) in a yield of 15 mg (28%) of 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine hydrochloride, which is further purified by recrystallization from methanol-water. H NMR (DMSO-d _b, 300 MHz) δ 2.79 (s, 3H), 6.96 (t, 1 H, J = 7.2 Hz), 7.09 (s, 1H), 7.33 (t, 2H, J = 7.5Hz), 7.71 (d, 2H, J = 7.7Hz), 8.39 (s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H), 10.37 (s, 1 H). Mass spectrum (ESI) m / z: Calcd. For C 15 H 14 N 4 S 3 314.4 (M + H), found 315.2.

268

Example 195

a) methyl 4- (4-isoxazol-5-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate

Methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (872 mg, 2.51 mmol) was treated with 2-bromo-1-isoxazol-5-yletan-1-one (737 mg, prepared from isoxazole) Of -5-carbonyl chloride [Maybridge Chemicals, Cornwall, UK] as described in Example 177, step (a), according to the procedure of Example 154, step (a), yielding 704 mg (83%) of methyl 4- (4-isoxazole- 5-yl- (l, 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.75 (s, 3H), 3.85 (s, 3H), 6.93 (d, 1H, J = 1.8 Hz), 8.22 ( s, 1H), 8.38 (s, 1H), 8.70 (d, 1H, J = 1.8 Hz).

b) 4- (4-isoxazol-5-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- (4-isoxazol-5-yl- (1,3-thiazol-2-yl)) -5-methylthiothiophene-2-carboxylate (350 mg, 1.03 mmol) was treated as described in Example 154, step (b) to yield 290 mg (78%) of 4- (4-isoxazol-5-yl- (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine hydrochloride, which was further purified by recrystallization from methanol-isopropanol-water (3: 1: 0.2 v / v / v). 1 H NMR (DMSO-d 6, 300 MHz) δ 2.79 (s, 3H), 6.93 (d, 1H, J = 1.9 Hz), 8.45 (s, 1H), 8.74 ( m, 2H), 9.23 (bs, 2H), 9.53 (bs, 2H). Mass spectrum (MALDI-TOF, CHCA matrix) m / z: Calcd. For C 12 H 10 N 4 OS 3 322.4 (M + H), found 323.3.

Example 196

269

a) methyl 4- [4- (2-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate

Methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (808 mg, 3.26 mmol) was treated with 2- (2-bromoacetyl) hydroxybenzene (925 mg, prepared from 2 (chlorocarbonyl) phenylacetate [Aldrich Chemicals , Milwaukee, WI] as described in Example 177, step (a), as described in Example 154, step (a), with a yield of 433 mg (37%) of methyl 4- [4- (2-hydroxyphenyl) (1,3) -thiazol-2-yl)] 5-methylthiothiophene-2-carboxylate. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.77 (s, 3H), 3.86 (s, 3H), 6.91-7.00 (m, 2H), 7.23 (m, 1H) 8.14-8.19 (m, 2H), 8.24 (s, 1H). Mass spectrum (ESI) m / z: Calcd. For C 16 H 13 NO 3 S 3 363.48 (M + H), found 364.2.

b) 4- [4- (2-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride

Methyl 4- [4- (2-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (400 mg, 1.1 mmol) was treated as described in Example 154, step (b) with a yield of 173 mg (41%) of 4- [4- (2-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamidine hydrochloride. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.81 (s, 3H), 6.92-7.02 (m, 2H), 7.22 (m, 1H), 8.20 (dd, 1H) J = 1.7 (7.8 Hz), 8.27 (s, 1H), 8.65 (s, 1H), 9.00 (bs, 2H), 9.41 (bs, 2H), 10 58 (s, 1 H). Mass Spectrum (ESI) m / z: Calcd. For C15H13N3OS3 347.48 (M + H), found

348.2.

Example 197

5-Methylthio-4- (6-quinolylamino) thiophene-2-carboxamidine hydrochloride

(a) methyl 1-5-methylthio-4- (6-quinolylamino) thiophene-2-carboxylate

270

In a oven-dried glass vial equipped with a stir bar was charged a mixture of 65.2 mg (0.244 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 241, step (a)), 5.2 mg. (9.5 mol%) palladium acetate, 22.2 mg (14.6 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 125 mg (0.384 mmol) of cesium carbonate and 50.3 mg (0.349 mmol) of 6-aminoquinoline. The vial was then placed in the inlet bag, washed with dry argon, and anhydrous toluene (488 μΐ) was added. The vial was then sealed with a Teflon-insert screw cap and heated at 100 ° C for 48 hours. Ethyl acetate (2 x 2 mL) was added to the cooled suspension, the mixture was filtered (celite) then washed with ethyl acetate (2 x 2 mL), and the solvent was removed in vacuo. Purification of the residue on a 10g silica SPE column using 5-12% ethyl acetate CH 2 Cl 2 gradient elution gave 53.3 mg (66%) of the title compound as a pale yellow resin. 1 H-NMR (CDCl 3, 400 MHz) δ 8.77 (dd, 1H, J = 4.2, 1.6 Hz), 8.04 (d, 1H, J = 9.4 Hz), 8.02 (d, 1H, J = 8.4Hz), 7.90 (s, 1H), 7.41 (dd, 1H, J = 9.0, 2.6Hz), 7.36 (dd, 1H, J = 8.3, 4.2 Hz), 7.27 (d, 1H, J = 2.6 Hz), 3.92 (s, 3H) and 2.45 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C16H15N2O2S2, 331.1 (M + H), found 331.2.

b) 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxamidine hydrochloride

To a suspension of ammonium chloride (85.6 mg, 1.60 mmol) in anhydrous toluene (0.76 mL) was added dropwise trimethylaluminum (2.0 mol / L in toluene, 0.76 mL) under argon at 0 ° C. , 1.52 mmol). The resulting mixture was stirred at 25 ° C for 30 minutes and then 50.2 mg (0.152 mmol) of methyl 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxylate (prepared in the previous step) was added. This mixture was slowly warmed to 100 ° C and stirred for 4 hours. Add cooled to a vigorously stirred slurry of silica gel (3 g) in chloroform (15 mL). The suspension was then filtered (celite), washed with 25% MeOH-CH ₂ Cl ₂ (2x5 mL), 50% MeOH-CH ₂ Cl ₂ (2x5 mL) and 75% MeOH-CH ₂ Cl ₂ (2x5 mL). The combined washings were concentrated and purification of the residue on a 5g SPE silica column eluting with a 10-15% MeOH-CH 2 Cl 2 gradient afforded 42.2 mg (79%) of the title compound as a yellow solid. H-NMR

271 (DMSO-d 6, 400 MHz) δ 9 ', 39 (br s, 2H), 9.12 (br s, 2H), 8.63 (dd, 1H, J = 4.2, 1.6 Hz) 8.44 (s, 1H), 8.16 (m, 2H), 7.89 (d, 1H, J = 8.5 Hz), 7.54 (dd, 1H, J = 9.1, 2) 6 Hz), 7.39 (dd, 1H, J = 8.3, 4.2 Hz), 7.20 (d, 1H, J = 2.5 Hz) and 2.55 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C15H14N4S2 315.1 (M + H), found 315.2.

Example 198

5-Methylthio-4 - [(3-phenylphenyl) aminothiophene-2-carboxamidine hydrochloride

(a) methyl 5-methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxylate

Using the same procedure as described in Example 197, step (a), using 62.2 mg (0.233 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 241, step (a)) ), 4.7 mg (9.0 mol%) of palladium acetate, 20.0 mg (13.8 mol%) of racemic BINAP, 140 mg (0.430 mmol) of cesium carbonate, 48.2 mg (0.285 mmol) 3 -aminobiphenyl and 466 μΐ toluene, and chromatography as described above using 20-40% CH 2 Cl 2 gave 52.3 mg (63%) of the title compound as a yellow resin. 1 H NMR (CDCl ₃ , 400 MHz) δ 7.81 (s, 1H), 7.61 (m, 2H), 7.46 (m, 2H), 7.38 (m, 2H), 7.21 (m, 2H), 7.03 (m, 1H), 6.22 (s, 1H), 3.90 (s, 3H), 2.43 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C19H17NO2S2, 356.1 (M + H), found 356.2.

b) 5-methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxamidine hydrochloride

In the same manner as described in Example 197, step (b) using 46.4 mg (0.131 mmol) of methyl 5-methylthio-4 - [(3-phenylphenyl) amino] thio-phen-2-carboxylate (prepared in the previous step). ), 0.76 ml trimethylaluminium (2.0 mol / L in toluene, 1.57 mmol), 87.7 mg ammonium chloride (1.64 mmol)

272 and 0.79 ml of toluene, and purification on a 5g silica SPE column using 5-10% MeOH-CHaCl gave 46.8 mg (95%) of the title compound as a yellow foam. 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 9.04 (br s, 4H), 8.10 (s, 1H), 8.06 (s, 1H), 7.62 (m, 2H) 7.46 (m, 2H); 7.35 (m, 2H); 7.19 (t, 1H, J = 1.9 Hz); 7.12 (d, 1H, J = 8.2 Hz) 6.95 (dd, 1H, J = 7.8, 1.9 Hz), 2.53 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C18H17N3S2 340.1 (M + H), found

340.2.

Example 199

5-methylthio-4- (3-quinolylamino) thiophene-2-carboxamidine hydrochloride

(a) methyl 5-methylthio-4- (3-quinolylamino) thiophene-2-carboxylate

In the same manner as described in Example 197, step (a), using 104 mg (0.389 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to Example 241, step (a)), 7.1 mg (8.1 mol%) of palladium acetate, 29.3 mg (12.1 mol%) of racemic BINAP, 192 mg (0.589 mmol) of cesium carbonate, 70.5 mg (0.489 mmol) of 3-aminoquinoline and 778 μΐ toluene, and chromatography described above using 3-8% ethyl acetate-CH ₂ Cl ₂ gave 34.4 mg (27%) of the title compound as a yellow resin. 1 H-NMR (CDCl 3, 400 MHz) δ 8.73 (d, 1H, J = 2.5 Hz), 8.04 (d, 1H, J = 8.2 Hz), 7.85 (d, 1H) J = 4.0 Hz), 7.71 (d, 1H, J = 7.9 Hz), 7.62 (m, 1H), 7.56 (m, 2H), 6.34 (s, 1H) ), 3.93 (s, 3H) and 2.46 (s, 3H). Mass spectrum (ESI, m / z): for C 16 H 14 N 2 O 2 S 2 331.1 (M + H), found 331.3.

b) 5-methylthio-4- (3-quinolylamino) thiophene-2-carboxamidine hydrochloride

In the same manner as described in Example 197, step (b), using 32.3 mg (0.0977 mmol) of methyl 5-methylthio-4- (3-quinolylamino) thiophene-2-carboxylate (prepared in the previous step). 0.586 ml trimethylaluminium

273 (2.0 M in toluene, 1.17 mmol), 65.8 mg ammonium chloride (1.26 mmol) and 0.59 mL toluene, and purified on a 5g SPE silica column using a 5-12 Concentration from MeOH-MeCN (1: 1) yielded 17.3 mg (51%) of the title compound as a tan tan solid. 1 H NMR (DMSO-d 6, 400 MHz) δ 9.09 (br s, 4H), 8.79 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7, 89 (m, 1H), 7.79 (m, 1H), 7.56 (s, 1H), 7.50 (m, 2H) and 2.55 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C15H14N4S2 315.1 (M + H), found 315.4.

Example 200

5-Methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboxamidine hydrochloride

(a) methyl 5-methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboxylate

In the same manner as described in Example 197, step (a), using 50.9 mg (0.191 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to Example 241, step (a)), 2, 7 mg (6.3 mol%) of palladium acetate, 11.3 mg (9.5 mol%) of racemic BINAP, 101 mg (0.310 mmol) of cesium carbonate, 25.9 mg (0.270 mmol) of 2-aminopyridine and 381 μΐ dioxane, and chromatography as described above using 5-10% ethyl acetate-hexane gave 16.7 mg (31%) of the title compound as a crystalline solid. 1 H NMR (CDCl 3, 400 MHz) δ 8.72 (s, 1H), 8.49 (d, 1H, J = 4.8 Hz), 6.80 (t, 1H, J = 4.8 Hz), 3.92 (s, 3H), 2.42 (s, 3H) and 1.28 (br s, 2H). Mass spectrum (ESI, m / z): Calcd. For C11H11N3O2S2, 282.0 (M + H), found 282.3.

b) 5-methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboxamidine hydrochloride

In the same manner as described in Example 197, step (b), using 15.2 mg (0.0540 mmol) of methyl 5-methylthio-4- (pyrimidin-2-ylamino) thiophene

274

2-carboxylate (prepared in the previous step), 0.324 ml trimethylaluminium (2.0 mol / L in toluene, 0.648 mmol), 36.4 mg ammonium chloride (0.680 mmol) and 0.32 ml toluene, and purified on a 2g oxide column Silica SPE using 5-15% MeOH-CH 2 Cl 2 gave, after concentration from MeOH-MeCN (1:10), 11.4 mg (70%) of the title compound as a pale yellow crystalline mass. 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 9.24 (br s, 2H), 8.85 (br s, 2H), 8.45 (d, 1H, J = 4.8 Hz), 8.25 (s, 1H), 6.87 (t, 1H, J = 4.8 Hz) and 2.53 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C10H11N5S2 266.1 (M + H), found

266.2.

Example 201

4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxylate

In the same manner as described in Example 197, step (a), using 122 mg (0.457 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to Example 241, step (a)), 9.9 mg (9.7 mol%) palladium acetate, 42.3 mg (14.9 mol%) racemic BINAP, 206 mg (0.632 mmol) cesium carbonate, 102 mg (0.582 mmol) 4-cyclohexylaniline and 913 μΐ toluene, and the chromatography described above with a mixture of 20-40% CH ₂ Cl ₂ hexane as a light green gum afforded 73.8 mg (45%) of the title compound. * NMR (CDCl3, 400 MHz) δ 7.74 (s, 1H), 7.15 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 8.4 Hz), 6.12 (s, 1H), 3.88 (s, 3H), 2.48 (m, 1H), 2.39 (s, 3H), 1.87 (m, 4H), 1.76 (br d, 1H, J = 12.5 Hz), 1.41 (m, 4H) and 1.28 (m, 1H). Mass spectrum (ESI, m / z): 3 NO _{2 2} Cj9H S2 calcd 362.1 (M + H), found 362.4.

b) 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

275

In the same manner as described in Example 197, step (b), using 70.2 mg (0.194 mmol) of methyl 4 - [(4-cyclohexylphenyl) amino) -5-methylthiothiophene-2-carboxylate (prepared in the previous step). 0.970 mL of trimethylaluminium (2.0 mol / L in toluene, 1.94 mmol), 109 mg of ammonium chloride (2.04 mmol) and 0.97 mL of toluene, and purified on a 10g silica SPE column using 4 - 8% MeOH-CH 2 Cl 2 gave 57.7 mg (78%) of the title compound as a yellow foam. 1 H-NMR (DMSO-d 6, 400 MHz) δ 8.45 (br s, 4H), 7.97 (s, 1H), 7.86 (s, 1H), 7.08 (d, 2H, J) = 8.5 Hz), 6.92 (d, 2H, J = 8.5 Hz), 2.48 (s, 3H), 1.65-1.85 (m, 5H) and 1.35 (m , 5H). Mass spectrum (ESI, m / z): Calcd. For C18H23N3S2 346.1 (M + H), found 346.4.

Example 202

Methyl 4-amino-5-methylthiothiophene-2-carboxylate

In a pressure tube (Ace Glass, Vineland, NJ) containing 1.0 g (4.30 mmol) of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (prepared according to the method of Example 95), 1.01 mL (1 , 1 eq, 4.73 mmol) of diphenylphosphoryl azide, and 1.57 mL (2.1 eq, 9.03 mmol) of Ν, Ν-diisopropylethylamine are added with 7 mL of tert-butanol. The resulting mixture was sealed and heated at 80 ° C in an oil bath for 6 hours. The dark-colored reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude oil was dissolved in 3 mL CH 2 Cl 2 and then treated with CH ₂ Cl ₂ -trifluoroacetic acid 1: 1 followed by 0.5 mL H ₂ O. After 6 hours, the mixture was concentrated in vacuo, dissolved in 50 mL of CH 2 Cl 2, washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ) and passed through a pad of silica gel using 50% ethyl acetate-hexanes as eluent. The solvent was concentrated in vacuo and the crude product was purified by preparative thin layer chromatography (20% ethyl acetate-hexanes, 2000 µm, silica gel) to yield 210 mg (24%) of methyl 4-amino-5-methylthiothiophene-2-carboxylate as oil paint honey. 1 H-NMR (DMSO-d ₆ , 300 MHz) δ 2.28 (s, 3H), 3.77 (s, 3H), 5.36 (bs, 2H), 7.24 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C7H9NO2S2 204.02 (M + H), found 204.0.

276

Example 203

Methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate

To a stirred biphasic mixture of C 2 H-NaHCl 3 (1: 1, v / v) of 5 ml containing 98 mg (0.48 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was added 43 μΐ (1.2 eq, 0.57 mmol) of thiophosgene (Aldrich Chemical, Milwaukee, WI). The reaction mixture was stirred vigorously overnight, diluted with CH 2 Cl 2 (50 mL), and the layers were separated. The organic layer was washed with NaHCO ₃ (1x15 mL), brine (1 x 15 mL), and dried (Na 2 SO 4). Concentration in vacuo afforded the crude isothiocyanate which was dissolved in 5 mL of 2 M NH ₃ in MeOH and stirred overnight. then the reaction mixture is concentrated to 1/2 volume and filtered. The filtered solids were washed with acetone and dried, yielding methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate in 79.8% yield (64.3%) as a tan tan solid. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.51 (s, 3H), 3.81 (s, 3H), 7.41 (bs, 2H), 8.03 (s, 1H) and 9, 27 (bs, 1 H). Mass spectrum (ESI, m / z): Calcd. For C8H10N2O2S3 263.00 (M + H), found 263.2.

Example 204

5-Methylthio-4 - [(4-phenyl- (1,3-thiazol-2-yl)) amino] thiophene-2-carboxamidine

(a) methyl 5-methylthio-4 - [(4-phenyl- (1,3-thiazol-2-yl) amino] thiophene-2-carboxylate)

To a 25 mL round bottom flask containing 40 mg (0.15 mmol) of methyl 4 - [(aminotioxomethyl) amino] -5-methylthiothiophene-2-carboxylate and 30.3 mg (1 eq, 0.15 mmol) of bromoacetophenone are added 2 ml of acetone and the resulting mixture is heated at reflux for 18 hours. Then the reaction mixture was cooled to room temperature and filtered to give 50 mg (92%) of methyl 5-methylthio-4 - [(4277).

I

phenyl- (1,3-thiazol-2-yl) amino] thiophene-2-carboxylate, which was used without further purification. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.49 (s, 3H), 3.84 (s, 3H), 7.09 (s, 1H), 7.26-7.48 (m, 3H), 7.85 (m, 2H), 8.63 (s, 1H), 10.06 (bs, 1H). Mass spectrum (ESI, m / z): Calcd. For C16HUN2O2S3, 363.03 (M + H), found 363.4.

b) 5-methylthio-4 - [(4-phenyl- (1,3-thiazol-2-yl) amino] thiophene-2-carboxamidine)

In a similar manner to that described in Example 154, step (b), 47 mg (0.13 mmol) of methyl 5-methylthio-4 - [(4-phenyl- (1,3-thiazol-2-yl)) amino] thiophene-2 carboxylate was reacted with 0.5 ml (8 eq., 1.04 mmol) reagent AlMe3 / _NH4Cl, and purified by preparative thin layer chromatography (20% MeOHCHCh-saturated with NH 3, 500 pm silica gel plate) afforded 19 mg of ( 42%) 5-methylthio-4 - [(4-phenyl- (1,3-thiazol-2-yl)) amino] thiophene-2-carboxamidine as a yellow solid. 1 H NMR (DMSO-d ₆ , 300 MHz) δ 2.43 (s, 3H), 7.27-7.42 (m, 4H), 7.90 (d, 2H, J = 7.1 Hz) 8.41 (s, 1 H). Mass spectrum (ESI, m / z): Calcd. For C15H14N4S3 347.05 (M + H), found 347.1.

Example 205

5-Methylthio-4 - ([4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxamidine

a) methyl 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxylate

In a manner similar to that described in Example 204, Step (a), 53 mg (0.2 mmol) of methyl 4 - [(aminotioxomethyl) amino] -5-methylthiothiophene-2-carboxylate was reacted with 55.6 mg (0.2 mmol) of 4-phenyl-bromoacetophenone for 3 hours to give 57 mg (65%) of methyl-5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino } thiophene-2-carboxylate. 1 H NMR (DMSO-d 6, 300 MHz) δ 2.51 (s, 3H), 3.86 (s, 3H), 6.93 (s, 1H rotamer), 7.10 (s, 1H rotamer), 7.27 (s,

278

1H rotamer), 7.37-7.50 (m, 3H rotamer), 7.72-7.76 (m, 4H rotamer), 8.4 (d, 2H, 8.4 Hz), 8.66 ( s, 1H rotamer), 10.10 (bs, 1H). Mass spectrum (ESI, m / z): Calcd. For C22H18N2O2S3: 439.06 (M + H), found 439.2.

b) 5-methylthio-4 - {[4- (4-phenylphenyl (1,3-thiazol-2-yl)] amino} thiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b), 57 mg (0.12 mmol) of methyl 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxylate was treated with 6.7 equivalents (0.87 mmol) of AlMe3 / NH4Cl and purified by preparative thin layer chromatography (20% MeOH-CHCl3-saturated NH3, 500 µm silica gel plate) to give 20.7 mg (40.7%) 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxamidine. 1 H NMR (DMSO-d 6, 400 MHz) δ 2.51 (s, 3H), 6.93 (s, 1H), 7.10 (s, 1H), 7.27 (s, IH), 7, 35-7.50 (m, 4H), 7.72-7.76 (m, 4H), 7.94-7.96 (m, 2H), 8.66 (s, 1H), 10.11 ( bs, 1H). Mass spectrum CMS, m / z): Calcd. For C21H18N4S3: 423.08 (M + H), found 423.2.

Example 206

4 - [(5-methyl-4-phenyl (l, 3-thiazol-2-yl)) amino] -5-methyl-2-tiotiofén carboxamidine

a) methyl 4 - [(5-methyl-4-phenyl- (1,3-thiazol-2-yl) amino] -5-methylthiothiophene-2-carboxylate

In a manner similar to that described in Example 204, Step (a), 51 mg (0.19 mmol) of methyl 4 - [(aminotioxomethyl) amino] -5-methylthiothiophene-2-carboxylate was reacted with 41.4 mg (0.38 mmol). mmol) of 2-bromopropiophenone (Aldrich Chemical Co., Milwaukee, WI) for 4 hours in 2 mL of DMF. Concentration of the reaction mixture in vacuo afforded 73 mg (100%) of methyl 4 - [(5-methyl-4-phenyl- (1,3-thiazole)).

279

2-yl)) amino] -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): Calcd. For C17H16N2O2S3 377.05 (M + H), found 377.2.

b) 4 - [(5-methyl-4-phenyl- (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene-2-carboxamidine

In a manner similar to that described in Example 204, Step (b), 73 mg (0.19 mmol) of methyl 4 - [(5-methyl-4-phenyl- (1,3-thiazol-2-yl)) amino] - 5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (1.5 mmol) of AlMe3 / NH4Cl and purified by preparative thin layer chromatography (20% MeoH-CHCl3-saturated NH3, S1O2 plate 500 pm) to give 17.9 mg ( 26%) 4 [(5-methyl-4-phenyl- (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene-2-carboxamidine. 1 H NMR (DMSO-d ₆ , 300 MHz): δ 2.40 (s, 3H), 2.51 (s, 3H rotamer), 2.73 (s, 3H rotamer), 7.29-7.44 (m, 2H rotamer), 7.64-7.73 (m, 3H rotamer), 7.95 (s, 1H rotamer), 8.06 (s, 1H rotamer). Mass spectrum (ESI, m / z): Calcd. For C16H16N4S3, 361.06 (M + H), found 361.2.

Example 207

4 - {[4-hydroxy-4- (trifluoromethyl) (l, 3-thiazoline-2-yl)] amino} -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5-methylthiothiophene-2-carboxylate

In a manner similar to that described in Example 204, Step (a), 56 mg (0.21 mmol) of methyl 4 - [(aminotioxomethyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 40 mg (0.21 mmol) of the compound. bromotrifluoroacetone (Aldrich Chemical Co., Milwaukee, WI) to give 40.3 mg (54%) of methyl 4 - {[4-hydroxy-4 (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} 5-methylthiothiophene-2-carboxylate.

280

Mass spectrum (ESI, m / z): Calcd. For CHHHF3N2O3S3 373.00 (M + H), found 373.0.

b) 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} 5-methylthiothiophene-2-carboxamidine

In a manner similar to that described in Example 204, Step (b), 40 mg (0.11 mmol) of methyl 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} Of 5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (0.89 mmol) of AlMe3 / NH4Cl and purified by preparative thin layer chromatography (20% MeoH-CHCl3-saturated NH3, S1O2 plate 500 µm) to give 11 mg (28%). %) 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5-methylthiothiophene-2-carboxamidine as a 1: 1 mixture of tautomeric cyclized aminal and open imine: first 1 H NMR (DMSO-d 6, 300 MHz) δ 2.73 (s, 3H tautomer), 2.89 (s, 3H tautomer), 3.36 (d, 2H, J = 6.5 Hz), 3, 62 (d, 2H, J = 7.2 Hz), 7.95 (s, 1H), 8.36 (bs, 2H), 9.79 (bs, 1H). Mass spectrum (ESI, m / z): Calcd. For C10H11F3N4OS3 357.01 (M + H), found 357.2.

Example 208

5-methylthio-4- (2-naphthylamino) thiophene-2-carboxamidine

a) 5-methylthio-4- (2-naphthylamino) -thiophene-2-carboxylate

In a oven-dried round bottom flask equipped with a Teflon-coated stir bar and rubber whisper, 190 mg (0.93 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 320 mg (2 eq., 1.86) were charged. mmol) of 2-naphthalene-boric acid (Lancaster Synthesis, Windham, NH), and 168 mg (1 eq, 0.93 mmol) of Cu (OAc) 2 (Aldrich Chemical Co., Milwaukee, WI). The flask was purged with argon and then charged with 4 mL of CH 2 Cl 2 followed by 259 μΙ (2 eq., 1.86 mmol) of NEt 3. The resulting mixture was stirred vigorously for 48 hours and then filtered

281 was triturated through a low layer of SiO 2 using 50% ethyl acetate-hexanes as eluent. Concentration of the solvent in vacuo and purification of the residue by preparative thin layer chromatography (25% ethyl acetate-hexanes, S1O2 plate 1000 µm) afforded 170 mg (55%) of methyl-5-methylthio-4- (2-naphthylamino) -thiophene-2- carboxylate and 54 mg (28%) of methyl 4-amino-5-methylthiothiophene-2-carboxylate starting material. 1 H NMR (CDCl ₃ , 400 MHz) δ 2.43 (s, 3H), 3.92 (s, 3H), 6.29 (s, 1H), 7.21 (dd, 1H, J = 2), 35, 8.7 Hz), 7.33-7.37 (m, 2H), 7.45 (m, 1H), 7.71 (d, 1H, J = 8.2 Hz), 7.78 ( m, 2H), 7.88 (s, 1 H). Mass spectrum (ESI, m / z): Calcd. For C17H15NO2S2, 330.06 (M + H), found 330.1.

b) 5-methylthio-4- (2-naphthylamino) thiophene-2-carboxamidine hydrochloride

In a similar manner to that described in Example 154, step (b), 730 mg (2.21 mmol) of methyl 5-methylthio-4- (2-naphthylamino) -thiophene-2-carboxylate was treated with 8 equivalents (17.7 mmol). of AlMe ₃ / NH 4 Cl and purification by preparative thin layer chromatography (20% MeOH-CH 3 saturated NH 3, 1000 µm silica gel plate) gave 5-methylthio-4- (2-naphthylamino) -thiophene-2-carboxamidine which was dissolved in 4 mL dry MeOH, cooled to 0 ° C and carefully treated with 1.6 mL (1.5 equivalents, 3.31 mmol) of HCl (2 mol / L) in ether. The reaction mixture was left overnight at 5 ° C and then concentrated in vacuo with toluene (3 x 10 mL) and then with hexanes (2 x 10 mL). The yellow solid was then dried in vacuo to give 415 mg (53.6%) of 5-methylthio-4- (2-naphthylamino) -thiophene-2-carboxamidine hydrochloride. 1 H NMR (DMSO-d 6, 400 MHz) δ 2.53 (s, 3H), 7.20 (d, 1H, J = 2.2 Hz), 7.24-7.31 (m, 2H), 7.38 (m, 1H), 7.69 (d, 1H, 8.1 Hz), 7.75-7.79 (m, 2H), 8.13 (s, 1H), 8.24 (s 1 H, 9.06 (bs, 2H), 9.33 (bs, 2H). Mass spectrum (ESI, m / z): Calcd. For C16H15N3S2 314.08 (M + H), found 314.5.

Example 209

4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine

282

a) 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

66.6 mg (0.32 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 100 mg (2 eq., 0.64 mmol) of 4-chlorophenylboronic acid in a yield of 11.8 mg (11.7 mg). %) methyl 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate and 21 mg (31.5%) of unreacted feedstock. 1 H NMR (CDCl 3, 400 MHz) δ 2.41 (s, 3H), 3.89 (s, 3H), 6.09 (bs, 1H), 6.94 (d, 2H, J = 8, 6 Hz), 7.25 (d, 2H, J = 8.6 Hz), 7.70 (s, 1H).

b) 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

In a manner similar to that described in Example 154, Step (b), 11.8 mg (0.037 mmol) of methyl 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (2.96) mmol) of AlMe3 / NH4Cl reagent in a yield of 13 mg (100%) of 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine. H NMR (DMSO-d _b, 400 MHz) δ 2.41 (s, 3H), 6.91-6.95 (m, 2H), 7.10-7.13 (m, 2H), 7, 64 (s, 1H), 7.93 (s, 1H), 8.67 (bs, 2H), 9.11 (bs, 2H). Mass spectrum (ESI, m / z): Calcd. For C ₁₂ H 12 ClN ₃ S ₂ : 298.02 (M + H), found 298.1.

Example 210

4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

a) 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

55.7 mg (0.27 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate

283 reaction with 73.4 mg (2 eq, 0.54 mmol) of 3-methylphenylboronic acid in a yield

29.2 mg (36.8%) of methyl 4 - [(3-methyl) amino] -5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl ₃ , 400 MHz) δ 2.35 (s, 3H), 2.40 (s, 3H), 3.89 (s, 3H), 6.11 (bs, 1H), 6.80 -6.86 (m, 3H), 7.20 (m, 1H), 7.77 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C14H15NO2S2 294.06 (M + H), found 294.1.

b) 4- (3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b) was used

29.2 mg (0.098 mmol) of methyl 4 - [(3-methyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (0.78 mmol) of AlMe3 / NH4Cl and purified by preparative thin layer chromatography (20 mL). % MeOH-CH (saturated NH 3, 500 µm silica gel plate) gave 27 mg (100%) of 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine. ¹ H NMR (CDCl 3, 400 MHz) δ 2.24 (s, 3H), 2.50 (s, 3H), 6.65 (d, 1H, J = 7.3 Hz), 6.74-6, 76 (m, 2H), 7.10 (m, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 9.07 (bs, 3H). Mass spectrum (ESI, m / z): Calcd. For C 13 H 15 N 3 S 2 278.08 (M + H), found 278.2.

Example 211

4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

73.2 mg (0.35 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 109 mg (2 eq., 0.70 mmol) of 3-methoxyphenylboronic acid in a yield.

25.2 mg (23%) of methyl 4 - [(3-methoxyphenyl) amino] 5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl 3, 400 MHz) δ 2.40 (s, 3H), 3.81 (s, 3H), 3.89 (s, 3H), 6.12 (s, 1H), 6.43- 6.63 (m, 2H); 7.20 (m, 1H); 7.78 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C14H15NO3S2, 310.06 (M + H), found 310.1.

284

b) 4- (3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

In a similar manner to that described in Example 154, step (b) was used

25.2 mg (0.081 mmol) of methyl 4 - [(3-methyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (0.64 mmol) of AlMej / NH 2 Cl reagent to yield 27 mg (100%). 14 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine. ¹ H NMR (DMSO, 400 MHz) δ 2.49 (s, 3H), 3.71 (s, 3H), 6.41 (dd, 1H, tJ = 2.1, 8.0 Hz), 6.49 (s) m, 1H), 6.50-6.54 (m, 1H), 7.12 (m, 1H), 7.97 (s, 1H), 8.01 (s, 1H), 8.88 (bs) 2 H, 9.23 (bs, 2H). Mass spectrum (ESI, m / z): Calcd. For C13H15N3OS2 294.07 (M + H), found 294.1.

Example 212

4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 118 mg (2 eq., 0.72 mmol) of 3-isopropylphenylboronic acid in a yield of 22.6 mg (19%). 5%) methyl 4 - [(3-methylethylphenyl) amino] -5-methylthiothiophene-2-carboxylate. ¹ H NMR (CDCl 3, 400 MHz) δ 1.27 (d, 6H, J = 6.9 Hz), 2.40 (s, 3H), 2.89 (m, 1H), 3.88 (s, 3H), 6.15 (s, 1H), 6.86-6.89 (m, 3H), 7.24 (m, 1H), 7.77 (s, 1H).

b) 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine

In a manner similar to that described in Example 154, Step (b), 22.6 mg (0.07 mmol) of methyl 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate was reacted with 8 equivalents (0.56 mmol) of AlMe ₃ / NH 4 Cl

285 solvents in a yield of 18.9 mg (78.8%) of 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine. 1 H NMR (DMSO-d 6, 400 MHz) δ 1.18 (d, 6H, J = 9.2 Hz), 2.51 (s, 3H), 2.81 (m, 1H), 6.71- 6.77 (m, 2H), 6.85 (s, 1H), 7.14 (m, 1H), 7.98 (s, 1H), 8.32 (s, 1H), 8.88 (bs) 2 H, 9.23 (bs, 2H). Mass spectrum (ESI, m / z): CISH] ₉ N3S2 calcd 306.11 (M + H), found 306.2.

Example 213

5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxamidine

(a) methyl 5-methylthio-4- (3-nitrophenyl) amino] thiophene-2-carboxylate

In a similar manner to that described in Example 154, step (b) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 120 mg (2 eq., 0.72 mmol) of 3-nitrophenylboronic acid in a yield.

14.5 mg (12.4%) of methyl 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxylate. 1 H NMR (CDCl ₃ , 400 MHz) δ 2.45 (s, 3H), 3.93 (s, 3H), 6.21 (s, 1H), 7.41-7.47 (m, 2H) 7.73-7.78 (m, 3H).

b) 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b) was used

14.5 mg (0.04 mmol) of methyl 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxylate was treated with 8 equivalents (0.35 mmol) of AlMe 3 / NH ₄ Cl reagent to yield 4.3 mg (34.8%) of 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxamidine. Mass Spectrum (ESI, m / z):

For C12H12N4O2S2 calculated 309.05 (M + H), found 309.2.

Example 214

286

4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 118 mg (2 eq., 0.72 mmol) of 4-isopropylphenylboronic acid in a yield of 14.5 mg (12.5 mg). %) methyl 4 - [(4-methylethylphenyl) amino] -5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl 3, 400 MHz) δ 1.26 (d, 6H, J = 6.2 Hz), 2.39 (s, 3H), 2.89 (m, 1H), 3.89 (s, 3H), 6.98-7.01 (m, 2H), 7.17-7.19 (m, 2H), 7.73 (s, 1H).

b) 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b) was used

14.5 mg (0.045 mmol) of methyl 4 - ([4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate was allowed to react with 8 equiv (0.36 mmol) AlMe3 / _NH4Cl reagent to give 11, 4 mg (74%) of 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d ₆ , 400 MHz) δ 1.17 (d, 6H, J = 9.2 Hz), 2.51 (s, 3H), 2.81 (m, 1H), 6.92 (d, 2H, J = 11.4 Hz), 7.10 (d, 2H, J = U, 2 Hz), 7.88 (s, 1H), 7.96 (s, 1H), 8.89 (bs, 2H), 9.22 (bs, 2H), MS (ESI, m / z) Calcd for C15H19N3S2 306.1 (M + H), found 306.2.

Example 215

4 - ((3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxamide

a) methyl 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxylate

287

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 108 mg (2 eq, 0.72 mmol) of 3,4-dimethylphenylboronic acid in a yield of 135.9 mg. (32.4%) methyl 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl 3, 400 MHz) δ 2.24 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.88 (s, 3H), 6.11 ( bs, 1H), 6.80-6.84 (m, 2H), 7.07 (d, 1H, J = 7.9 Hz), 7.71 (s, 1H).

b) 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b) was used

35.6 mg (0.116 mmol) of methyl 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (0.93 mmol) of AlMe 3 / NH ₄ Cl reagent to yield 26.1 mg (68.5%) of 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine. 1 H NMR (DMSO-d 6, 400 MHz) δ 2.13 (s, 3H), 2.16 (s, 3H), 2.51 (s, 3H), 6.69-6.78 (m, 2H) ), 6.99 (d, 1H, J = 10.8 Hz), 7.76 (s, 1H), 7.91 (s, 1H), 8.82 (bs, 2H), 9.17 (bs) , 2H). Mass spectrum (ESI, m / z): Calcd. For C14H17N3S2 292.09 (M + H), found 292.2.

Example 216

5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine

a) methyl 5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 142.5 mg (2 eq., 0.72 mmol) of 4-phenylphenylboronic acid in a yield of 24.5. mg (19.1%) of methyl 4 - [(4-phenylphenyl) amino] 5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl 3, 400 MHz) δ 2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H),

288

7.08-7.14 (m, 2H); 7.33 (m, 1H); 7.43-7.46 (m, 2H); 7.54-7.60 (m, 4H); 82 (s, 1 H).

b) 5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b) was used

24.5 mg (0.07 mmol) of methyl 4 - [(4-phenylphenyl) amino] -5-methylthiothiophene-2 carboxylate was treated with 8 equivalents (0.56 mmol) of AlMe ₃ / NH ₄ Cl reagent in a yield. 16.9 mg (64.1%) of 5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.51 (s, 3H), 7.03 (d, 2H, J = 8.6 Hz), 7.26-7.61 (m, 7H) 8.04 (s, 1H); 8.15 (s, 1H); 8.88 (bs, 2H); 9.25 (bs, 2H). Mass spectrum (ESI, m / z): Calcd. For C18H17N3S2, 340.09 (M + H), found 340.2.

Example 217

4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 155.5 mg (2 eq., 0.72 mmol) of 3-fluoro-4-phenylphenylboronic acid in a yield. 50.6 mg (41.6%) of methyl 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl ₃ , 400 MHz) δ 2.44 (s, 3H), 3.91 (s, 3H), 6.19 (s, 1H), 6.78-6.86 (m, 2H) 7.32-7.39 (m, 2H), 7.73-7.47 (m, 2H), 7.55 (d, 1H, J = 6.9 Hz), 7.82 (s, 1H ).

b) 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

289

In a similar manner to that described in Example 154, step (b) was used

50.6 mg (0.13 mmol) of methyl 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (1.08 mmol) of AlMej / NH 4 Cl reagent with a yield of 39 mg (76.1%) of 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxamidine. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.51 (s, 3H), 6.756.87 (m, 2H), 7.30-7.50 (m, 6H), 8.06 (s, 1H), 8.37 (s, 1H), 8.90 (bs, 2H), 9.27 (bs, 2H). Mass spectrum (ESI, m / z): Calcd. For C 18 H 16 FN 3 S 2 358.08 (M + H), found 358.2.

Example 218

4- (2H-benzo [d] -l, 3-dioxolen-5-ylamino) -5-metyltlziotiofén-2-carboxamidine

a) methyl 4- (2H-benzo [d] -1,3-dioxoien-5-ylamino) -5-methylthiothifene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was reacted with 119.4 mg (2 eq., 0.72 mmol) of 3,4-methylenedioxyphenylboronic acid in a yield of 24.4 mg. (20.9%) methyl 4- (2H-benzo [d] -1,3-dioxolen-5-ylamino) -5-methylthiothiophene-2-carboxylate.

1 H NMR (CDCl ₃ , 400 MHz) δ 2.39 (s, 3H), 3.87 (s, 3H), 5.96 (s, 2H), 6.00 (bs, 1H), 6.52 (dd, 1H, J = 2.3, 8.3 Hz), 6.63 (d, 1H, J = 2.2 Hz), 6.76 (d, 1H, J = 8.3 Hz), 7 59 (s, 1 H).

b) 4- (2H-benzo [d] -1,3-dioxolen-5-ylamino) -5-methylthiothiophene-2-carboxamidine

In a similar manner to that described in Example 154, step (b) was used

24.4 mg (0.075 mmol) of methyl 4- (2H-benzo [d] -1,3-dioxolen-5-ylamino) -5-methyl

290 of thiothiophene-2-carboxylate was treated with 8 equivalents (0.6 mmol) of the AlMej / NH-tCl reagent to yield 7.7 mg (29.7%) of 4- (2H-benzo [d] -1,3-). dioxolen-5-ylamino) -5-methylthiothiophene-2 carboxamidine. 1 H NMR (DMSO-d 6, 400 MHz) δ 2.51 (s, 3H), 5.95 (s, 2H), 6.46 (dd, 1H, J = 3.0, 11.2 Hz), 6.65 (d, 1H, J = 2.8Hz), 6.79 (d, 1H, J = 11.0Hz), 7.80 (s, 1H), 7.87 (s, 1H), 91 (bs, 2H); 9.24 (bs, 2H). Mass spectrum (ESI, m / z): C ₃ N _{3 3} Hi O2S2 calculated 308.05 (M + H), found 308.2.

Example 219

4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 208, step (a) was used

74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was treated with 128 mg (2 eq., 0.72 mmol) of 4-butylphenylboronic acid in a yield of 22.2 mg (18%). Methyl 3 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxylate. 1 H NMR (CDCl ₃ , 400 MHz) δ 0.97 (t, 2H, J = 7.4 Hz), 1.38 (m, 2H), 1.59 (m, 2H, peaked with water), 2, 39 (s, 3H), 2.58 (t, 2H, J = 7.6Hz), 3.90 (s, 3H), 6.12 (bs, 1H), 6.97 (d, 2H, J = 8.2 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.73 (s, 1H).

b) 4- (4-butylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

In a manner similar to that described in Example 154, step (b), 22.2 mg (0.06 mmol) of methyl 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents (0 , 52 mmol) of the AIMC3 / NH4Cl reagent in a yield of 18.9 mg (88%) of 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxamidine. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 0.89 (t, 2H, J = 9.7 Hz), 1.23-1.33 (m, 2H), 1.51 (m, 2H), 2.47 -2.50 (m, 2H overlapped with DMSO-d6), 2.51 (s, 3H), 6.90 (d.

291

2Η, J = 11.3 Hz), 7.05 (d, 2H, J = 11.2 Hz), 7.86 (s, 1H), 7.94 (s, 1H), 8.78 (bs, 2H), 9.21 (bs, 2H). Mass spectrum (ESI, m / z): Calcd. For C16H21N3S2, 320.13 (M + H), found 320.2.

Example 220

5-methylthio-4- [benzylamino] thiophene-2-carboxamidine

(a) methyl 5-methylthio-4- [benzylamino] thiophene-2-carboxylate

Weigh 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate and 30.7 mg (0.29 mmol) of benzaldehyde into a suitable size vial (for 2 lanes) equipped with a stir bar and whisper. 1 ml of a mixture of CH 2 Cl 2-DMF (2: 1 v / v) and 135 mg (2.2 eq., 0.63 mmol) of NaHB (OAc) ₃ was then added to the vial. The reaction mixture was then purged with Ar and stirred for 48 hours. Then, 2 mL of CH 3 OH was added and the reaction stirred for an additional 15 minutes and then diluted with 20 mL of CH 2 Cl 2. The organic layer was then washed with water (2 x 20 mL), dried (Na 2 SO 4) and concentrated in vacuo in an oven-dried flask of suitable size (2 drams) to yield crude methyl-5-methylthio-4- [benzylamino] thiophene. -2-carboxylate together with unreacted imine. The crude reaction mixture was then converted to the amidine without further purification. Mass spectrum (ESI, m / z): Calcd. For C11H15NO2S2 294.06 (M + H), found 292.2 (imine),

294.2.

b) 5-methylthio-4- [benzylamino] thiophene-2-carboxamidine

To a vial of suitable size (2-dram, 7.4 mL)) equipped with a stir bar with methyl 5-methylthio-4- [benzylamino] thiophene-2-carboxylate (estimated amount 0.29 mmol) was added 2 mL of toluene and then 8 equivalents (2.32 mmol) of AlMes / NHaCl reagent. The resulting yellow mixture was heated at 110 ° C for 3 hours, then cooled to room temperature and then a slurry prepared

292 with 1 g SiO ₂ and 10 ml CHCl 3. The mixture was stirred for 15 minutes and then the slurry was placed in a 15 ml glass filter funnel containing a layer of silica gel and eluted with a solvent mixture of 50% CHCl 3 -CH 3 OH. Removal of the solvent in vacuo gave the crude product which was purified by preparative thin layer chromatography (SiO ₂ 500 µm, 20% CH ₃ OH-CHCl 3 -substituted NH ₃ ) to give 14.8 mg (18.3% relative to methyl-4- amino-5-methylene-2-carboxylate tyltiotiofén) 5-methylthio-4- [benzylamino] thiophene-2-carboxamidine trifluoroacetate. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.49 (s, 3H), 4.35 (d, 2H, J = 6.7 Hz), 5.91 (t, 1H, J = 6, 8 Hz), 7.20-7.38 (m, 6H). Mass spectrum (ESI, m / z): Calcd. For C13H15N3S2 278.08 (M + H), found 278.3.

Example 221

4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine

a) methyl 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxylate

In a manner similar to that described in Example 220, Step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.3 mg (0.29 mmol) of 5-indanecarboxaldehyde was reacted , and 135 mg (2.2 eq., 0.63 mmol) of NaHB (OAc) 3 to yield methyl 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): Calcd. For C17H19NO2S2: 334.09 (M + H), found 332.3 (imine), 333.4.

b) 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine

Using the method described in Example 220, Step (b), 22.0 mg (27.3% of methyl 4-amino-5-methylthiothiophene-2-carboxylate) of 4- (indan-5-ylamino) -5-methylthiothiophene was obtained. 2-carboxamidine trifluoroacetate. 1 H NMR (DMSO-d 6, 400 MHz) δ 1.94-2.01 (m, 2H), 2.49 (s, 3H), 2.77-2.82 (m, 4H), 4.29 (d, 2H, J = 5.6 Hz), 5.78 (t, 1H, J = 8.1 Hz), 7.08 (d, 1H, J = 7.8 Hz), 7.14 (d) 1H, J = 7.5 Hz), 7.20 (s, 1H), 7.23 (s, 1H).

293

1Η). Mass spectrum (ESI, m / z): Calcd. For C16H18N3S2, 318.11 (M + H), found 318.3.

Example 222

4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxamidine

a) methyl 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxylate

In a manner similar to that described in Example 220, Step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.9 mg (0.29 mmol) of 2.3 were reacted -dihydrobenzo [b] furan-5-carboxaldehyde, and 135 mg (2.2 eq., 0.63 mmol) of NaHB (OAc) 3 to yield methyl 4- (2,3-dihydrobenzo [b] furan-5-). ylamino) -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): Calcd. For C16H17NO3S2 336.07 (M + H), found 334.3 (imine).

335.3.

b) 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxamidine

In a manner similar to that described in Example 220, Step (b), 21.8 mg (23.5% of methyl 4-amino-5-methylthiothiophene-2-carboxylate) of 4- (2,3-dihydrobenzo [b] furan-5) was obtained. ylamino) -5-methylthiothiophene-2-carboxamidine trifluoroacetate. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.49 (s, 3H), 3.13 (t, 2H, J = 8.7 Hz), 4.24 (d, 2H, J = 6, 6 Hz), 4.48 (t, 2H, J = 8.7 Hz), 5.69 (t, 1H, J = 6.7 Hz), 6.68 (d, 1H, J = 12.4 Hz) 7.06 (d, 1H, J = 7.4 Hz), 7.21 (s, 1H), 7.26 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C15H17N3OS2 320.09 (M + H), found 320.3.

Example 223

294

5-methylthio-4 - [(2- phenyl-imidazol-4-yl) amino) thiophene-2-carboxamidine

(a) methyl 5-methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboxylate

In a manner similar to that described in Example 220, Step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.9 mg (0.29 mmol) of 4-formyl are reacted. -2-phenylimidazole and 135 mg (2.2 eq., 0.63 mmol) of NaHB (OAc) 3 to yield methyl 5-4 - [(phenylimidazol-4-yl) amino] thiophene-2-carboxylate. Mass spectrum (ESI, m / z): Calcd. For C17H17NO3S2 360.08 (M + H), found 360.0.

b) 5-methylthio-4 - [(2-phenylimidazol-4-yl) amino) thiophene-2-carboxamidine

In a similar manner to that described in Example 220, step (b), 30.9 mg (30% of methyl 4-amino-5-methylthiothiophene-2-carboxylate) of 5-methylthio-4 - [(2-phenylimidazole-4-) was obtained. yl) amino) -thiophene-2-carboxamidine trifluoroacetate. ^l H NMR (DMSO-d _6, 400 MHz) δ 2.49 (s, 3H), 4.30-4.38 (m, 3H), 7.09 (bs, 1H), 7.32 (m, 1H) 7.40-7.44 (m, 3H), 7.90-7.95 (m, 3H), 8.43 (bs, 3H). Mass spectrum (ESI, m / z): Calcd. For C16H17N5S2, 344.10 (M + H), found 344.2.

Example 224

5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxamidine

(a) methyl 5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxylate

In a manner similar to that described in Example 220, Step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate (0.29 mmol) was reacted with 45.5 mg (0.29 mmol). 2-quinolinecarboxaldehyde, and 135 mg (2.2 eq., 0.63 mmol) of NaHB (OAc) 3 in yield of methyl-5-methylthio-4 - [(2295)

(quinolylmethyl) amino] thiophene-2-carboxylate. Mass spectrum (ESI, m / z): Calcd. For C17H16N2O2S2 345.07 (M + H), found 343.3.

b) 5-methylthio-4 - [(2-quinolinylmethyl) amino] thiophene-2-carboxamidine

In a manner similar to that described in Example 220, Step (b), 2.5 mg (2.6% of methyl 4-amino-5-methylthiothiophene-2-carboxylate) of 5-methylthio-4 - [(2-quinols) ) amino] thiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI, m / z): Calcd. For C16H16N4S2, 329.09 (M + H), found 329.3.

Example 225

4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxylate

In a manner similar to that described in Example 220, Step (a), 61.6 mg (0.30 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.5 mg (0.30 mmol) was reacted 3. -acetoxybenzaldehyde, and 135 mg (2.2 eq., 0.63 mmol) of NaHB (OAc) 3 in yield of methyl 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): for C 14 H 16 NO 3 S 2 352.07 (M + H), found 350.2 (imine), 352.1.

b) methyl 1-4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxylate

In a similar manner to that described in Example 220, step (b), 7.9 mg (8.9% of methyl 4-amino-5-methylthiothiophene-2-carboxylate) methyl 4 - {[(3-hydroxyphenyl) methyl] was obtained. ] amino} -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): for CH 3 H 15 N 3 OS 2 294.07 (M + H), found 294.3.

296

Example 226

5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamidine

a) methyl 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxylate

To a stirred solution of 114 mg (0.55 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate in 4 mL of CH 2 Cl 2 at 0 ° C was added via syringe 142 µΐ (1.5 eq, 0.82 mmol). Of Ν, Ν-diisopropylethylamine and then 71.3 μΐ (1.1 eq., 0.61 mmol) of benzoyl chloride. The reaction mixture was allowed to warm to room temperature and then stirred for an additional 4 hours. The reaction mixture was then partitioned in 40 mL of CH 2 Cl 2: saturated NaHCO 3 1: 1 (v / v), the organic layer was separated, washed with 20 mL of brine, dried (Na 2 SO 4) and concentrated in vacuo to give 113 mg. (66.8%) methyl 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxylate which was used without further purification. 1 H NMR (DMSO-d 6, 400 MHz) δ 2.55 (s, 3H), 3.83 (s, 3H), 7.47-7.56 (m, 2H), 7.64 (m, 1H) 7.88 (s, 1H), 7.93-7.99 (m, 2H), 10.12 (s, 1H). Mass spectrum (Ε, m / z): Calcd. For C14H13NO3S2 308.04 (M + H), found 308.2.

b) 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamidine

In a manner similar to that described in Example 154, step (b), 100 mg (0.32 mmol) of methyl 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate was treated with 8 equivalents ( 2.58 mmol) of AlMe3 / NH4Cl in a yield of 95.4 mg (100%) of 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamidine. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.59 (s, 3H), 7.30-7.64 (m, 3H), 7.98-8.00 (m, 2H), 8, 23 (s, 1H), 9.19 (bs, 2H), 9.41 (bs, 2H), 10.35 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C13H14N3OS2 292.06 (M + H), found 292.2.

297

Examples 227-240

To each 2-drachma vial (7.4 mL) equipped with a stir bar and a Teflon whisper was added 0.3-0.6 mmol of the appropriate acid chloride (1 eq) followed by 1 equivalent of methyl-4-amino-5- of methylthiothiophene-2-carboxylate as a 1 M solution in CH 2 Cl 2. Then additional ml of CH 2 Cl 2 was added followed by 1.5 equivalents of Ν, Ν-diisopropylamine. An argon atmosphere was then introduced into each vial and stirred for 3 hours. Then 4 ml of saturated NaHCO 3 are added and the contents are stirred for an additional 5 minutes. The aqueous layer was removed by pipette and Na ₂ SO ₄ was added to each vial by pipette. The vials were then left overnight and then treated on 5g silica gel (SPE) columns using 0.5% MeOH-CH 2 Cl 2 as eluent. Then, the obtained amides are concentrated in vacuo in pre-weighed 2 drachma vials (7.4 mL) equipped with a stir bar and a Teflon whisper for subsequent amidation reaction. An argon atmosphere was introduced into the vials, charged with 2 mL of toluene and then 8 equivalents of AlMe 3 / NH ₄ Cl reagent as a 1 M solution in toluene. The reaction mixtures are then heated in a heating block at 110 ° C for hours. Then they are cooled to room temperature and the contents of each vial are pipetted into a slurry prepared from 1.5 g of silica gel in 15 ml of CH 2 Cl 2. The individual slurries were vigorously stirred for 15 minutes then filtered through a 15 mL glass filter funnel containing a 20 cm tall silica gel layer using 50% CHCl 3 -MeOH. Combine the yellow fractions and concentrate in vacuo. The solids were triturated with 10% MeOHCHCl 3 and filtered. Concentration in vacuo gave the crude amidines, which were purified by preparative thin layer chromatography (20% MeOH CHCl 3 - saturated NH 3, 500 µm SiO ₂ ) to give the corresponding amidines as their corresponding free bases.

298

example acid chloride Amidine product yield ³ 227 cinnamoyl 4 - ((2E) -3-phenyl-prop-2-enoylamino) -5metyltiotiofén-2-carboxamidine 15.3% 228 4-chlorobenzoyl chloride 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 44,6% 229 cyklohexoylchlorid 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxamidine 17.8% 230 3-nitro-4-methylbenzoyl chloride methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate 8.8% 231 2-furoyl-Chioride 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxamidine 13.3% 232 2,2-dimethyl-propanoyl chloride 4- (2,2-Dimethylpropanoylamino) -5-methylthiothiophene-2-carboxamidine 8.5% 233 5- (3,5-dichlorophenoxy) furan-2-carbonyl chloride 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonyl-amino} -5-methylthiothiophene-2carboxamidine 22.9% 234 1-naphthoyl chloride 5-methylthio-4- (naphthylcarbonylamino) thiophene-2-carboxamidine 3.1% 235 2-chinolylchlorid 5-methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboxamidine 6.8% 236 3-methoxybenzoyl chloride 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 6.8% 237 2- (2,5-dimethoxyphenyl) acetyl chloride 4- [2- (2-hydroxy-5-methoxyphenyl) acetylamino] -5-methylthiothiophene-2-carboxamidine 18.3% 238 4-ethoxybenzoyl chloride 4 - [(4-ethoxyphenyl) carbonylamino] -5metyltiotiofén-2-carboxamidine 34% 239 2-phenoxyacetyl chloride 5-methylthio-4- (2-phenoxy-acetylamino) -thiophene-2-carboxamidine 10% 240 3-methylbenzoyl chloride 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 21.1%

The yield is based on the starting methyl 4-amino-5-methylthiothiophene-2-carboxylate.

Example 227

4 - ((2 E) -3-Phenylprop-2-enoylamino) -5-methylthiothiophene-2-carboxamide

299

a) methyl 4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene-2-carboxylate

Yield: 100%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.49 (s, 3H), 3.83 (s, 3H), 7.12 (d, 1H, J = 15.7 Hz), 7.41 -7.66 (m, 6H), 8.24 (s, 1H), 9.92 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C16H15NO3S2, 334.06 (M + H), 334.1.

b) 4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 2.54 (s, 3H), 7.13 ( d, 1H, J = 15.7 Hz), 7.41-7.51 (m, 3H), 7.59-7.66 (m, 2H), 8.40 (s, 1H), 8.81 (bs, 3H), 10.02 (bs, 1H). Mass spectrum (ESI, m / z): Calcd. For C15H15N3OS2 318.07 (M + H), 318.2.

Example 228

4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate

Yield: 53%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.55 (s, 3H), 3.83 (s, 3H), 7.62 (d, 2H, J = 8.5 Hz), 7.87 (s, 1H), 7.97 (d, 2H, J = 8.5 Hz), 10.21 (s, 1H).

b) 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 2.59 (s, 3H), 7.63-7.66 (m 2H, 7.988.01 (m, 2H), 8.99 (bs, 2H), 9.33 (bs, 2H), 10.39 (s, 1H). Mass spectrum (ESI, m / z): C13H | 2C1N3OS ₂ calculated 326.02 (M + H), found 326.2.

300

Example 229

4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxamidine

(a) methyl 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxylate

Yield: 69.9%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 1.22-1.81 (m, 11H), 2.51 (s, 3H), 3.82 (s, 3H), 7.97 (s, 1H), 9.55 (s, 1H). Mass spectrum (ΕΞΙ, m / z): Calcd. For C14H19NO3S2 314.09 (M + H), found 314.2.

b) 4- (Cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.59 (s, 3H), 7.63-7.66 (m, 2H), 7 98-8.01 (m, 2H), 8.99 (bs, 2H), 9.33 (bs, 2H), 10.39 (s, 1H). Mass spectrum (ΕΞΙ, m / z): Calcd. For < ₃ ? ₃ ? ₂ ? -3θ? ₂ 298.10 (M + H), found 298.2.

Example 230

Methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate

a) methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate

Yield: 80%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.56 (s, 3H), 2.61 (s, 3H), 3.82 (s, 3H), 7.70 (d, 1H, J = 8.1 Hz), 7.86 (s, 1H), 8.19 (dd, 1H, J = 1.7, 8.0 Hz), 8.56 (d, 1H, J = 1.7 Hz) 10.41 (s, 1 H). MS (ΕΞΙ, m / z): Ci5H ₁₄ N ₂ C ^ 2 calculated 367.42 (M + H) 367.2.

b) methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate

301 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.47 (s, 3H), 2.61 (s, 3H), 7.12 (bs, 3H), 7.69-7.73 (m 2H), 8.20 (dd, 1H, J = 1.6, 7.9 Hz), 8.57 (d, 1H, J = 1.6 Hz). Mass spectrum (ESI, m / z): Calcd. For C14H14N4O3S2 351.06 (M + H), found 351.2.

Example 231

4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxamidine

a) 4- (2-Furylcarbonylamino) -5-methylthiothiophene-2-carboxylate

Yield: 100%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.54 (s, 3H), 3.83 (s, 3H), 6.71 (dd, 1H, J = 1.8, 3.4 Hz) 7.33 (d, 1H, J = 3.5Hz), 7.87 (s, 1H), 7.95 (m, 1H), 9.93 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C12H11NO4S2: 298.02 (M + H), found 298.3.

b) 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.51 (s, 3H), 6.71 (dd, 1H, J = 1) Δ, 3.5 Hz), 7.18 (bs, 3H), 7.32 (d, 1H, J = 3.4 Hz), 7.79 (s, 1H), 7.96 (m, 1H). Mass spectrum (ESI, m / z): Calcd. For C11H11N3O2S2: 282.04 (M + H), found 282.2.

Example 232

4- (2,2-dimetylpropanoylamino) -5-methylthiothiophene-2-carboxamidine

a) Methyl 4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxylate

302

Yield: 93.4%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 1.23 (s, 9H), 2.51 (s, 3H), 3.81 (s, 3H), 7.74 (s, 1H), 9 .04 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C 12 H 17 NO 3 S 2 288.07 (M + H), found 288.1.

b) 4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 1.24 (s, 9H), 2.55 (s, 3H), 8 1.05 (s, 1H), 9.0 (bs, 3H), 9.1 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C11H17N3OS2 272.09 (M + H), found 272.2.

Example 233

4 - {[5- (3,5-Dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2-carboxylate

Yield: 96.9%. Mass spectrum (ESI, m / z): Calcd. For C ₁₈ H ₁₃ Cl ₂ NO ₅ S ₂ 457.97 (M + H), found 457.9.

b) 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 2.53 ( s, 3H), 6.12-6.17 (m, 1H), 6.79 (d, 1H, J = 1.8 Hz), 7.40-7.43 (m, 2H), 7.70 (m, 1H), 8.13 (s, 1H), 8.92 (bs, 2H), 9.21 (bs, 1H), 10.06 (s, 1H). Mass spectrum (ESI, m / z): m.p.

C17H14Cl2N3O3S2 calculated 441.99 (M + H), found 442.2.

303

Example 234

5-methylthio-4- (naphthylcarbonylamino) thiophene-2-carboxamidine

a) methyl 5-methylthio-4- (naphthylcarbonylamino) thiophene-2-carboxylate

Yield: 80.8%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 7.59-7.67 (m, 3H), 7.80 (d, 1H, J = 6.8 Hz), 8.02-8.34 ( m, 4H), 10.38 (s, 1H).

b) 5-methylthio-4- (naphthylcarbonylamino) thiophene-2-carboxamidine 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.50 (s, 3H), 7.60 (m, 3H), 7.76 (d, 1H, J = 6.7 Hz), 7.94 (s, 1H), 8.03 (d, 1H, J = 6.8 Hz), 8.09 (d, IH, 8.3 Hz) ), 8.30 (d, 1H, J = 8.8 Hz). Mass spectrum (ESI, m / z): Calcd. For C17H15N3OS2 342.07 (M + H), found 342.2.

Example 235

5-methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboxamidine

(a) methyl 5-methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboxylate

Yield: 80.9%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.59 (s, 3H), 3.86 (s, 3H), 8.03-8.06 (m, 3H), 8.24-8, 29 (m, 3H), 9.58 (s, 1H), 10.63 (s, 1H).

b) 5-methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 2.53 (s, 3H), 7.21 (bs, 3H), 7, 74 (s, 1H), 7.96-7.98 (m, 2H), 8.19-8.22 (m, 4H), 9.77 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C16H14N4OS2: 343.45 (M + H), found 343.1.

304

Example 236

4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate

Yield: 90.3%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.55 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 7.19 (m, 1H), 7 39-7.59 (m, 3H), 7.85 (s, 1H), 10.09 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C15H15NO4S2 338.05 (M + H), found 338.3.

b) 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 2.58 (s, 3H), 3.84 (s, 3H), 7.19 (dd, 1H, J = 2.1, 8.1 Hz), 7.45-7.57 (m, 3H), 8.15 (s, 1H), 9.11 (bs, 4H) , 10.32 (bs, 1H). Mass spectrum (ESI, m / z): Calcd. For C ₁₄ H ₁₅ N ₃ O ₂ S ₂ 322.07 (M + H), found 322.2.

Example 237

4- [2- (2,5-Dimethoxyphenyl) acetylamino] -5-methylthiothiophene-2-carboxamidine

(a) methyl 1-4- (2- (2,5-dimethoxyphenyl) acetylamino] -5-methylthiothiophene-2-carboxylate 1 H NMR (DMSO-d 6, 400 MHz) δ 2.47 (s, 3H), 3, 67 (s, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.80 (s, 3H), 6.81 (dd, 1H, J = 3.0, 8, 8 Hz), 6.87 (d, 1H, J = 3.0 Hz), 6.93 (d, 1H, J = 8.9 Hz), 8.04 (s, 1H), 9.62 (s (1H);

305

b) 4- [2- (2,5-dimethoxyphenyl) acetylamino] methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz), δ 2.38 (s, 3H), 3.66 (s, 2H), 3.70 (s, 3H), 3.76 (s, 3H), 6.81 (dd, 1H, J = 3.3, 8.0 Hz), 6.88-6.94 (m 2 H, 7.91 (s, 1H), 9.42 (bs, 1H).

Example 238

4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine

a) 4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate 1 H NMR (DMSO-d ₆ , 400 MHz) δ 1.36 (t, 3H, J = 7.0 Hz), 2 54 (s, 3H), 3.83 (s, 3H), 4.13 (q, 2H, J = 7.0 Hz), 7.05 (d, 2H, J = 8.8 Hz), 7 87 (s, 1H), 7.93 (d, 2H, J = 8.8 Hz), 9.93 (s, 1H). Mass spectrum (ESI, m / z): calcd C 16 H 17 NO 4 S 2 calculated 352.07 (M + H), found 352.2.

b) 4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d ₆ , 400 MHz) δ 1.36 (t, 3H, J = 7.0 Hz), 2 55 (s, 3H), 4.13 (q, 2H, J = 7.0 Hz), 7.04-7.08 (m, 2H), 7.94-7.97 (m, 2H), 8.09 (s, 1H), 8.73 (bs, 3H), 10.01 (bs, 1H). Mass spectrum (ESI, m / z): Calcd. For C15H11N3O2S2 336.08 (M + H), found 336.2.

Example 239

5-methylthio-4- (2-phenoxy-acetylamino) -thiophene-2-carboxamidine

306

(a) methyl 5-methylthio-4- (2-phenoxyacetylamino) thiophene-2-carboxylate

Yield: 79%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.48 (s, 3H), 3.82 (s, 3H), 4.78 (s, 2H), 6.97-7.02 (m, 2H), 7.31-7.35 (m, 2H), 8.05 (s, 1H), 9.80 (s, 1H).

(b) 5-methylthio-4- (2-phenoxyacetylamino) thiophene-2-carboxamidine 1 H NMR (DMSO-d 6, 400 MHz) δ 2.52 (s, 3H), 4.81 (s, 2H), 6, 97-7.04 (m, 3H), 7.31-7.35 (m, 2H), 8.26 (s, 1H), 8.84 (bs, 4H). Mass spectrum (ESI, m / z): Calcd. For C14H15N3O2S2 322.43 (M + H), found 322.2.

Example 240

4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate

Yield: 79%. 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.40 (s, 3H), 2.55 (s, 3H), 3.83 (s, 3H), 4.78 (s, 2H), 7 42-7.43 (m, 2H); 7.47-7.77 (m, 2H); 7.86 (s, 1H); 10.06 (s, 1H). Mass spectrum (ESI, m / z): Calcd. For C 18 H 15 NO 3 S 2 322.06 (M + H), found 322.2.

b) 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine 1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.40 (s, 3H), 2.55 (s, 3H) 7.43-7.44 (m, 2H), 7.75-7.78 (m, 2H), 8.05 (s, 1H), 8.52 (bs, 3H), 10.12 (bs) , 1H). Mass spectrum (ESI, m / z): Calcd. For C14H15N3OS2 306.07 (M + H), found 306.2.

307

Example 241

(a) methyl 4-bromo-5-methylthiothiophene-2-carboxylate

To a stirred solution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol) prepared by the method of Kleemann, et al., EP 0676395 A2, in dry methanol (750 mL) was added dropwise thionyl chloride (7 mL, 96 mL). mmol). The reaction mixture was stirred at room temperature for 10 minutes and then the solution was heated to reflux for 7.5 hours with stirring. The solution was then cooled and the solvent removed in vacuo. The resulting solid was dissolved in dichloromethane (1500 mL), washed with saturated sodium bicarbonate solution (2 x 300 mL), water (300 mL), saturated brine (300 mL), and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo. The resulting solid was then recrystallized twice from hexane / ethyl acetate to give methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). 1 H NMR (CDCl 3, 400 MHz), δ 7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).

b) methyl 1-5-methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboxylate

In a 1 drachma (3.7 mL) vial dried in an oven, was added a dry mixture containing 60 mg (0.225 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylic acid prepared in the previous step, 3.0 mg (6). palladium (II) acetate (Aldrich Chemical Co., Milwaukee, WI), 12.6 mg (9 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (Strem, Newburyport , MA), 110 mg (0.34 mmol, 1.5 eq.) Of cesium carbonate (Aldrich Chemical Co., Milwaukee, WI), and 54 mg (0.29 mmol, 1.3 eq.) Of 3-benzyloxyaniline ( Aldrich Chemical Co., Milwaukee, WI). The vial was then purged in the "glove box" with dry argon, dry toluene (450 μΐ, 0.5 mol / L) was added and the system was heated at 100 ° C for 36 hours. Ethyl acetate (4 mL) was added to the cooled suspension, passed through a 1 inch (2.54 cm) pad of celite, washed with ethyl acetate (2 x 4 mL), and the solvent was removed in vacuo. Purification by preparative thin layer chromatography (dichloromethane)

308 mole: hexanes (1: 1) gave 13 mg (15%) of the title compound as a pale yellow solid. 1 H-NMR CDCl ₃ , 400 MHz) δ 7.77 (s, 1H), 7.47-6.59 (m, 9H), 6.11 (s, 1H), 5.07 (s, 2H) 3.89 (s, 3H); 2.47 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 20 H 19 NO 3 S 2, 386.1 (M + H), found 386.3.

c) 5-methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine

To a suspension of ammonium chloride (216 mg) in toluene (2 mL) was added dropwise over 10 min trimethylaluminum (2.0 mol / L in toluene, 2 mL) under an atmosphere of dry nitrogen at 0 ° C. The mixture was stirred at 25 ° C for 30 minutes, when most of the solids had dissolved and then withdrawn by syringe and added to 13 mg (0.03 mmol) of methyl-5-methylthio-4 - {[3- (phenylmethoxy)]. phenyl] amino} thiophene-2-carboxylate. Then the reaction mixture was gradually heated to reflux and stirred for 2 hours and 10 minutes. Pour the cooled mixture into a vigorously stirred slurry of silica gel (2 g) in chloroform (20 mL). Methanol (50 mL) was added to the resulting suspension and passed through a 1 inch (2.54 cm) silica gel filter funnel, washed with methanol (50 mL), and the solvent was removed in vacuo. The crude product is purified on a 5 g silica gel column of SPE, where it is first washed with dichloromethane and then eluted with 10% methanol in dichloromethane. The product is then further purified by preparative high performance liquid chromatography (HPLC) using a Dynamax C18 column, 60 Å pore size, 10 μΜ particle size, 40-100% methanol in 0.1% trifluoroacetic acid to yield 5.4 mg of the title compound (45 mg). %) as a yellow solid. 1 H NMR (CD 3 OD, 400 MHz) δ 7.84 (s, 1H), 7.44-6.60 (m, 9H), 5.08 (s, 2H), 2.48 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C19H19N3OS2, 370.1 (M + H), found 370.2.

Example 242

309

(a) methyl 5-methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboxylate

A stirred suspension containing 80 mg (0.299 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 72 mg (0.389 mmol, 1.3 eq) of 3-phenoxyaniline (Aldrich, Milwaukee, WI) was treated as described in Example 241, degree v (b). Further purification of the product by preparative thin layer chromatography using 10% ethyl acetate in hexane gave 36 mg of the title compound (32%) as a yellow oil. 1 H-NMR (CDCl 3, 400 MHz) δ 7.76 (s, 1H), 7.406.65 (m, 9H), 6.26 (s, 1H), 3.89 (s, 3H), 2.40 (s, 3 H). Mass spectrum (ESI, m / z): Calcd. For C19H17NO3S2, 372.1 (M + H), found 372.2.

b) 5-methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboxamidine

Methyl 5-methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboxylate (36 mg, 0.097 mmol) was treated as in Example 241, step (c), without purification by HPLC. to give 30 mg of the title compound (86%) as an orange glass. 1 H-NMR (CDCl 3, 400 MHz) δ 9.28 (s, 2H), 8.11 (s, 2H), 7.99 (s, 1H), 7.34-6.50 (m, 9H) 6.29 (s, 1H); 2.35 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C18H17N3OS2 356.1 (M + H), found 356.2.

Example 243

a) 5-Methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboxamidine

A stirred suspension of 80 mg (0.299 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 72 mg (0.389 mmol, 1.3 eq) of 4-phenoxyaniline (Aldrich, Milwaukee, WI) was treated as described in Example 241, step (b). Further purification of the product by preparative thin layer chromatography using 10% ethyl acetate in hexane gave 53 mg of the title compound (48%) as a yellow oil. 1 H-NMR (CDCl ₃ , 400 MHz) δ 7.70 (s, 1H), 7.34-7.00 (m, 9H),

310

6.11 (s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C19H17NO3S2, 372.1 (M + H), found 372.1.

b) 5-methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboxamidine

Methyl 5-methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboxylate (53 mg, 0.14 mmol) was treated as described in Example 241, step (c), without purification by the method. HPLC to yield 58 mg of the title compound (quantitative yield) as an orange glass. 1 H-NMR (CDCl 3, 400 MHz) δ 8.89 (s, 2H), 8.59 (s, 2H), 8.00 (s, 1H), 7.25-6.87 (m, 9H) 6.20 (s, 1H); 2.27 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C18H17N3OS2 356.1 (M + H), found 356.2.

Example 244

a) methyl 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate

A stirred suspension of 103 mg (0.386 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 57 mg (0.46 mmol, 1.2 eq) of 2-methoxyaniline (Aldrich, Milwaukee, WI) was treated in a similar manner by the method described in Example 241, Step (b) to yield 78 mg of the title compound (65%) as a yellow oil. 1 H-NMR (CDCl 3, 400 MHz) δ 7.82 (s, 1H), 7.12-6.52 (m, 4H), 6.52 (s, 1H), 3.92 (s, 3H) 3.87 (s, 3H); 2.40 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C14H15NO3S2, 310.1 (M + H), found 310.2.

b) 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine

Methyl 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate (78 mg, 0.25 mmol) was treated as described in Example 241, step (c) but without purification by HPLC to yield 75 mg. title compound (quant

311) in the form of an orange glassy mass. 1 H-NMR (CD 3 OD, 400 MHz), δ 7.91 (s, 1H), 7.15-6.93 (m, 4H), 3.93 (s, 3H), 2.48 (s, 3H) ). Mass spectrum (ESI, m / z): Calcd. For C13H15N3OS2 294.1 (M + H), found 294.2.

Example 245

a) methyl 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate

A dry mixture containing 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate, 51 mg (14.9 mol%) of tris was added to a 1 drachma vial (3.7 mL) dried in an oven. (dibenzylideneacetone) dipalladium (Lancaster, Pelham, NH), 52 mg (22.3 mol%) of racemic 2,2'-bis (diphenylphosphino) -Ι, Γ-binaphthyl (Strem, Newburyport, MA), 183 mg (0 , 56 mmol, 1.5 eq) of cesium carbonate (Aldrich Chemical Co., Milwaukee, WI), and 71 µΐ (0.49 mmol, 1.3 eq) of 2-methylaniline (Aldrich Chemical Co., Milwaukee, WI) ). The vial is then purged in the glove cap with dry argon, dry toluene (750 μΐ, 0.5 mol / l) is added and the system is heated at 100 ° C for 40 hours. Ethyl acetate (4 mL) was added to the cooled suspension, passed through a 1 inch (2.54 cm) pad of celite, washed with ethyl acetate (2 x 4 mL), and the solvent was removed in vacuo. Purification by preparative thin layer chromatography (dichloromethane: hexanes, 1: 1) afforded 67 mg of the title compound (61%) as a yellow oil. 1 H-NMR CDCl ₃ , 400 MHz) δ 7.64 (s, 1H), 7.23-6.94 (m, 4H), 5.91 (br s, 1H), 3.88 (s, 3H) 2.41 (s, 3H), 2.31 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 14 H 15 NO 2 S 2 294.1 (M + H), found 294.2.

b) 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

Methyl 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate (67 mg, 0.23 mmol) was treated as described in Example 241, step (c) but without purification by HPLC to yield 20 mg. of the title compound (30%) as a yellow glass. H 1 H-NMR (CD 3 OD, 400 MHz) δ 7.56 (s, 1H), 7.24-6.99 (m,

312

4Η), 2.49 (s, 3H), 2.29 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 13 H 15 N 3 S 2 278.1 (M + H), found 278.2.

Example 246

a) methyl 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate

A stirred suspension of 80 mg (0.299 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 41 µL (0.389 mol, 1.3 eq.) Of 3-chloroaniline (Aldrich, Milwaukee, WI) was treated in a manner similar to that described. in Example 241, step (b), yielding 47 mg of the title compound (50%) as a yellow oil. 1 H-NMR (CDCl 3, 400 MHz) δ 7.75 (s, 1H), 7.23-6.89 (m, 4H), 6.10 (s, 1H), 3.89 (s, 3H) 2.42 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 13 H 12 NO 2 S 2 Cl 314.0 (M + H), found 314.1.

b) 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine

Methyl 1-4 - ((3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate (47 mg, 0.15 mmol) was treated as described in Example 241, step (c) to yield 33 mg of the title compound. Compounds (75%) as a light yellow solid. * HNMR (DMSO-d 6, 400 MHz) δ 9.22 (s, 2H), 8.81 (s, 2H), 8.22 (s, 1H) 7.99 (s, 1H), 7.24-6.82 (m, 4H), 2.53 (s, 3H) Mass Spectrum (ESI, m / z): Calcd. For C12H12N3S2Cl: 298.0 (M) + H), found 298.3.

Example 247

(a) methyl 4- (methylphenylamino) -5-methylthiothiophene-2-carboxylate

313

A stirred suspension of 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 72 μΐ (0.487 mmol, 1.3 eq) of N-methylaniline (Aldrich Chemical Co., Milwaukee, WI) was treated as described above. in a similar manner to that described in Example 245, step (a), to give 23 mg of the title compound (21%) as a yellow oil. 1 H-NMR (CDCl ₃ , 400 MHz) δ 7.61 (s, 1H), 7.26-6.68 (m, 5H), 3.89 (s, 3H), 3.25 (s, 3H), 2.50 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 14 H 15 NO 2 S 2 294.1 (M + H), found 294.3.

b) 4- (methylphenylamino) -5-methylthiothiophene-2-carboxamidine

Methyl 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate (23 mg, 0.078 mmol) was treated as in Example 241, step (c) but without purification by HPLC, yield 5, 6 mg of the title compound (26%) as a yellow glass. 1 H-NMR (CD ₃ OD, 400 MHz) δ 7.83 (s, 1H), 7.246.71 (m, 4H), 3.27 (s, 3H), 2.57 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C 13 H 15 N 3 S 2 278.1 (M + H), found 278.3.

Example 248

a) Methyl 1-5-methyl-4- (phenylamino) thiophene-2-carboxylate

A stirred suspension of 400 mg (1.7 mmol) of methyl 5-methyl-4-bromo-thiophene-2-carboxylate and 192 μΐ (2.1 mmol, 1.25 eq) of aniline (Aldrich, Milwaukee, WI) is treated. in a manner similar to that described in Example 241, Step (b), yielding 66 mg of the title compound as a brown glass (16%). 1 H-NMR (DMSO-d 6, 400 MHz) δ 7.70 (s, 1H), 7.56 (s, 1H), 7.17 (m, 2H), 6.72 (m, 3H), 3 79 (s, 3H), 2.31 (s, 3H). Mass spectrum (MALDI, gentisic acid matrix, m / z): Calcd. For C 13 H 13 NO 2 S 248.1 (M + H), found 247.5.

314

b) 5-methyl-4- (phenylamino) thiophene-2-carboxamidine

Methyl 4- (methylphenylamino) -5-methylthiothiophene-2-carboxylate (66 mg, 0.27 mmol) was treated as in Example 241, step (c) but without purification by HPLC to yield 57 mg of the title compound (91). %) in the form of a brown glassy mass. 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 9.17 (s, 2H), 8.85 (s, 2H), 7.98 (s, 1H), 7.85 (s, 1H), 7.21-6.73 (m, 5H); 2.39 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C12H13N3S 232.1 (M + H), found 232.2.

Example 249

a) methyl 4 - ([4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboxylate

A stirred suspension of 100 mg (0.267 mmol) of methyl 5-methyl-4-bromo-thiophene-2-carboxylate and 66 mg (0.35 mmol, 1.3 eq.) Of 4-amino-N, N-dimethylaniline (Fluka, Miewaukee, WI) was treated in a manner similar to that described in Example 241, step (b), but using an ethyl acetate / hexane purification step by preparative thin layer chromatography to yield 86 mg of the title compound (quantitative yield) as an orange glassy mass. . 1 H NMR (CDCl 3, 400 MHz) δ 7.53 (s, 1H), 7.16 and 6.62 (AB quartet, 4H, J = 8.9 Hz), 5.99 (s, 1H), 3, 86 (s, 3H), 2.94 (s, 6H), 2.39 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C15H18N2O2S2, 323.1 (M + H), found 323.3.

b) 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboxamidine

Methyl 4- (methylphenylamino) -5-methylthiothiophene-2-carboxylate (86 mg, 0.267 mmol) was treated as in Example 241, step (c), but without purification by HPLC. The product obtained was purified by passing through a 2 mm thick basic alumina layer using 10% methanol in dichloromethane (15 mL) to yield 62 mg of the title compound (76%) as a brown glass.

315 vité mass. 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 8.95 (s, 4H), 7.75 (s, 1H), 7.56 (s, 1H), 6.97 and 6.72 (AB) quartet, 4H, J = 8.9 Hz), 2.83 (s, 6H), 2.44 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C14H18N4S2 307.1 (M + H), found 307.3.

Example 250

4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4 - [(4-ethylphenyl) aminol-5-methylthiothiophene-2-carboxylate

An oven-dried vial was charged with a mixture containing 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared in Example 241, step (a)), 5.8 mg (6.9 mol%). palladium (II) acetate, 21.7 mg (9.3 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 171.5 mg (0.526 mmol) of cesium carbonate and 59 mg (0.487 mmol) of 4-ethylaniline. (Aldrich Chemical Co., Milwaukee, WI). The vial was then purged in the sleeve with dry argon, and anhydrous toluene (749 μΐ) was added. The vial was capped with a Teflon insert screw plug and heated at 100 ° C for 48 hours. The cooled suspension was filtered (Celite), washed with ethyl acetate (2x2 mL) and the solvent was removed in vacuo. The residue was purified by preparative thin-layer silica chromatography (1 mm thick) using 40% dichloromethane-hexanes to yield 14 mg (12%) of methyl 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2- carboxylate in the form of a pale yellow resin, which is used directly in the next step.

b) 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

To a suspension of ammonium chloride (19 mg, 0.363 mmol) in anhydrous toluene (1 mL) was added dropwise at 0 ° C trimethylaluminum (2.0 mol / L in toluene, 0.182 mL, 0.363 mmol) under argon. The mixture was stirred at room temperature for 30 minutes

316 [deg.] C. and then 14 mg (0.036 mmol) of methyl 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxylate (prepared in the previous step) was added. The reaction mixture was then slowly warmed to 100 ° C and stirred for 4 hours. The cooled mixture was poured into a vigorously stirred slurry of silica gel (1.3 g) in chloroform (20 mL). The resulting suspension was filtered (silica) and washed with 50% MeOH-CH 2 Cl 2 (2 x 50). The eluates are concentrated and the residue is purified on a preparative 0.5 mm silica layer using 10% MeOHCH 2 Cl 2 in a yield of 8 mg (67%) of 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine- hydrochloride as a yellow oil. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.84 (s, 1H), 7.14 (d, 2H, 8 Hz), 7.01 (d, 2H, 8 Hz), 2.55 (q, 2H, 65.5 Hz), 2.48 (s, 3H), 1.23 (t, 3H, 15.2 Hz). Mass spectrum (ESI, m / z): Calcd. For C14H17N3S2: 292.1 (M + H), found 292.5.

Example 251

5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine hydrochloride The

a) Methyl 1-5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxylate

Using the procedure of Example 250, step (a), using 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared in Example 241, step (a)), 5.5 mg (6.5%) palladium (II) acetate, 23.6 mg (10.1 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 194 mg (0.595 mmol) of cesium carbonate and 3 mg (0.488 mmol) of 4-benzyloxyaniline and 749 μΐ of toluene and chromatography as above using 40% CH ₂ Cl ₂ -hexane gave 7 mg (5%) of methyl-5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxylate as a yellow resin, which was used directly in the next step.

317

b) 5-methylthio-4 - [{4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine hydrochloride

Using the procedure described in Example 250, step (b), using 7 mg (0.018 mmol) of methyl 5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxylate (prepared in the previous step), 0.091 ml trimethylaluminium (2.0 mol / L in toluene, 0.182 mmol), 10 mg ammonium chloride (0.182 mmol) and 1 ml toluene, and purified on a 0.5 mm silica pad to prepare with 10% MeOH-CH ₂ Cl ₂ as 3 mg (41%) of 5-methylthio-4 - {[4 (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine hydrochloride was obtained as a yellow oil. 1 H-NMR (CD ₃ OD, 400 MHz) δ 7.72 (s, 1H), 7.45 (d, 2H, 7Hz), 7.39 (t, 2H, 9 Hz), 7.37 (d 1 H, 12 Hz), 7.06 (d, 2H, 12 Hz), 6.97 (d, 2H, 12 Hz), 5.08 (s, 2H), 2.46 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C19H19N3OS2, 370.1 (M + H), found 370.3.

Example 252

5-Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxamidine hydrochloride

a) 5-Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxylate

Using the procedure of Example 250, step (a), using 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to Example 241, step (a)), 5.5 mg (6.5%) palladium (II) acetate, 21.6 mg (9.3 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 173.7 mg (0.533 mmol) of cesium carbonate and 92.3 mg (0.500 mmol) of N-phenyl-1,4-phenylenediamine and 749 μΐ of toluene and chromatography as above using 40% CH 2 Cl 2 -hexane gave 58 mg of methyl-5-methylthio-4 - {[4] (phenylamino) phenyl] amino} thiophene-2-carboxylate as a brown solid. 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 7.85 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.14 (t, 2H, 16) Hz), 6.99 (d, 2H, 16 Hz), 6.90 (q, 4H, 44 Hz), 6.70 (t, 2H, 4 Hz), 3.77 (s, 3H), 2, 43 (s, 3 H).

318

b) 5-methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxamidine hydrochloride

Using the procedure described in Example 250, step (b), using 58 mg (0.156 mmol) of methyl 5-methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxylate (prepared in the previous step), 0.783 ml of trimethylaluminium (2.0 mol / L in toluene, 1.56 mmol), 84 mg of ammonium chloride (1.56 mmol) and 10 ml of toluene, and purification on a silica pad using 50% MeOHCH2Cl2 as eluent gave 50 mg (75%) 5-methylthio-4 - ([4- (phenylamino) phenyl] amino} thiophene-2-carboxamidine hydrochloride as a brown solid 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 7 91 (d, 2H, 12 Hz), 7.78 (s, 1H), 7.20 (t, 3H, 12 Hz), 7.04-6.94 (m, 5H), 6.71 (m , IH), 2.47 (s, 3H). Mass spectrum (ESI, m / z): C ₈ Hi _{8 N4} S2 calcd 355.1 (m + H), found 355.4.

Example 253

4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

a) methyl 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate

In a oven-dried glass vial equipped with a stir bar was charged a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 241, step (a)), 7.1 mg (7). palladium (II) acetate, 29.4 mg (10.5 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 69 1 mg (0.561 mmol) of p-anisidine. The vial was then transferred to a glove cap and purged with argon and anhydrous toluene (0.9 mL) was added. The vial was then sealed with a Teflon-lined screw plug and heated at 100 ° C for 48 hours. Ethyl acetate (4 mL) was added to the cooled suspension, the mixture was filtered (Celite), washed with ethyl acetate (2 x 2 mL), and the solvent was removed in vacuo. Why

319 of the residue by preparative thin layer chromatography on silica gel (40% CH 2 Cl 2 in hexane) gave 83 mg (60%) of the title compound as a yellow oil. 1 H-NMR (CDCl 3, 400 MHz) δ 2.39 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 6.03 (s, 1H), 6.89 (m, 2H), 7.03 (m, 2H), 7.58 (s, 1H).

b) 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine hydrochloride

To a suspension of ammonium chloride (216 mg, 4 mmol) in anhydrous toluene (1 mL) under argon was added dropwise trimethylaluminum (2.0 M in toluene, 2 mL, 4 mmol) dropwise at room temperature. The mixture was stirred at 25 ° C for 30 minutes and then 80 mg (0.259 mmol) of methyl 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate (prepared in the previous step) in anhydrous toluene (1) was added. ml). The reaction mixture was then slowly warmed to 100 ° C and stirred for 2.5 h. The cooled mixture was poured into a vigorously stirred slurry of silica gel (3 g) in chloroform (20 mL). Then, the suspension was filtered while washing with MeOH (4x5 mL) and 50% MeOH-CH 2 Cl 2 (4x5 mL). The combined eluates were concentrated and the residue was purified on a 2g SPE silica column to give 50 mg (59%) of the title compound as a solid orange solid using 5% MeOH-CH 2 Cl 2. 1 H-NMR (DMSO-d 6, 400 MHz) δ 2.44 (s, 3H), 3.69 (s, 3H), 6.84 (m, 2H), 6.98 (m, 2H), 7 73 (s, 1H), 7.84 (s, 1H), 9.01 (br s, 2H), 9.24 (br s, 2H). Mass spectrum (ESI, m / z): Calcd. For C13H15N3OS2 294.1 (M + H), found 294.2.

Example 254

4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

a) methyl 4 - [(3-fluoro-4-methylphenyl) aminol-5-methylthiothiophene-2-carboxylate

320

In a oven-dried glass vial equipped with a stir bar, a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 241, step (a)), 41 mg (10 mol%) .) palisium tris (dibenzylideneacetone), 42 mg (15 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, cesium carbonate 205 mg (0.629 mmol) and 70 mg (0.56 mmol) 3-fluoro-4-methylaniline. The vial was then transferred to a glove cap and purged with argon and anhydrous toluene (0.9 mL) was added. The vial was then sealed with a Teflon-lined screw plug and heated at 100 ° C for 48 hours. Ethyl acetate (4 mL) was added to the cooled suspension, the mixture was filtered (Celite), washed with ethyl acetate (2 x 2 mL), and the solvent was removed in vacuo. Purification of the residue by preparative thin layer chromatography on silica gel (10% Et 2 O in hexane) afforded 103 mg (70%) of the title compound as a yellow oil. 1 H-NMR (CDCl ₃ , 400 MHz) δ 2.22 (d, 3H, J = 1.6 Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 ( s, 1H), 6.68 (m, 1H), 6.71 (s, 1H), 7.08 (m, 1H), 7.72 (s, 1H).

b) 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine

Using the method described in Example 253, step (b), using 103 mg (0.349 mmol) of methyl 1-4 - ((3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate (prepared in the previous step), 2 ml of trimethylaluminium (2.0 mol / l in toluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 ml of toluene, and purified on a 2g silica SPE column using 5% MeOH-CH2Cl2 as eluent. to give 45 mg (44%) of the title compound as a yellow foam 1 H-NMR (DMSO-d 6, 400 MHz) δ 2.13 (s, 3H), 2.50 (s, 3H), 6.70 (m (2H), 7.10 (m, 1H), 7.98 (s, 1H), 8.09 (s, 1H), 9.16 (br s, 4H) Mass spectrum (ESI, m / z) for C13H14FN3S2 calculated 296.1 (M + H), found 296.2.

Example 255

4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine

321

a) methyl 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxylate;

In the same manner as described in Example 254, step (a) using 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 241, step (a)), 41 mg ( 10 mol% tris (dibenzylideneacetone) palladium, 42 mg (15 mol%) racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 205 mg (0.629 mmol) cesium carbonate and 74.8 mg ( 0.56 mmol) of 5-aminoindan in 900 μΐ of toluene, and chromatography of the above using 40% (CH 2 Cl 2 -hexane) gave 100 mg (73%) of the title compound as a yellow resin. 1 H-NMR (CDCl 3, 400 MHz) δ 2.05-2.12 (m, 2H), 2.85-2.90 (m, 4H), 3.86 (s, 3H), 6.09 ( s, 1H), 6.82 (d, 1H, J = 8.0 Hz), 6.93 (s, 1H), 7.14 (d, 1H, J = 8.0 Hz), 7.70 (s, 1H).

b) 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine

Using the procedure described in Example 253, step (b), using 100 mg (0.33 mmol) of methyl 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxylate (prepared in the preceding step), 2 ml of trimethylaluminium ( 2.0 mol / L in toluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL of toluene, and purified on a 2g silica SPE column using 5% MeOH-CH 2 Cl as eluent to give 65% yield. mg (65%) of the title compound as a yellow foam. 1 H-NMR (DMSO-d ₆ , 400 MHz) δ 1.99 (m, 2H), 2.48 (s, 3H), 2.78 (m, 4H), 6.77 (dd, 1H, J) = 8.0, 1.78 Hz), 6.86 (s, 1H), 7.08 (d, 1H, J = 8.1 Hz), 7.80 (s, 1H), 7.94 (s 1 H, 9.13 (br s, 4H). Mass spectrum (ESI, m / z): Calcd. For C15H17N3S2: 304.1 (M + H), found 304.3.

Example 256

4 - [(9-ethylcarbazole-3-yl) amino] -5-methylthiothiophene-2-carboxamidine

322

a) Methyl 4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxylate

In the same manner as described in Example 254, step (a) using 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to the method of Example 241, step (a)), 41 mg ( 10 mol% of tris (dibenzylideneacetone) palladium, 42 mg (15 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 118 mg (0.56) mmol) of 3-amino-9-ethylcarbazole in 900 µL of toluene, and the above chromatography using 40% CH ₂ Cl ₂ -hexane gave 80 mg (47%) of the title compound as a yellow resin. 1 H-NMR (CDCl 3, 400 MHz) δ 1.46 (t, 3H, J = 7.2 Hz), 2.44 (s, 3H), 3.85 (s, 3H), 4.39 (q 2H, J = 7.2 Hz), 6.25 (s, 1H), 7.24 (m, 1H), 7.28 (s, 1H), 7.40 (m, 2H), 7.49 (m, 1H), 7.61 (s, 1H), 7.83 (d, 1H, J = 2.1 Hz), 8.06 (d, 1H, J = 7.8 Hz).

b) 4- (9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxamidine

Using the procedure described in Example 253, step (b), using 80 mg (0.21 mmol) of methyl 4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxylate (prepared in the previous step). 2 ml of trimethylaluminium (2.0 mol / l in toluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 ml of toluene, and purified on a 2g silica SPE column using 5% MeOHCH2Cl2 as eluent 56 mg (70%) of the title compound as a yellow foam. 1 H-NMR (DMSO-d 6, 400 MHz) δ 1.31 (t, 3H, J = 7.0 Hz), 2.50 (s, 3H), 4.42 (q, 2H, J = 7, 0 Hz), 7.14 (m, 1H), 7.27 (dd, 1H, J = 8.7, 2.1 Hz), 7.43 (m, 1H), 7.56 (m, 2H) 7.82 (d, 1H, J = 2.0 Hz), 7.87 (s, 1H), 7.92 (s, 1H), 8.10 (d, 1H, J = 7.7 Hz) , 9.11 (br s, 4H). Mass spectrum (ESI, m / z): Calcd. For C20H20N4S2 381.1 (M + H), found 381.3.

Examples 257 and 258

5-Methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamide n-trifluoroacetate

323

4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine trifluoroacetate

a) methyl 5-methylthio-4 - [(phenylsulfonyl) amino] thiophene-2-carboxylate and methyl 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxylate

A mixture of 50 mg (0.24 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate (prepared according to Example 202), 68 mg (0.27 mmol) was added to a round-bottom dried oven equipped with a stir bar. Of 4-biphenylsulfonyl chloride and 50 mg (0.49 mmol) of 4-dimethylaminopyridine. The flask was purged with dry argon and anhydrous acetonitrile (3 mL) was added. The reaction mixture was then heated at reflux for 3 hours, and then the solvent was removed in vacuo. The crude reaction mixture was extracted with ethyl acetate (2 x 25 mL) of 1M HCl (50 mL). The organic layer was separated, dried (Na 2 SO 4), filtered and concentrated in vacuo to give a foam which, after work-up with silica chromatography using 30% ethyl ether-hexane, gave 143 mg of methyl 5-methylthio-4 - [( phenylsulfonyl) amino] thiophene-2-carboxylate and methyl 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxylate. The resulting mixture was used in the next step without further purification. Mass spectrum (ESI, m / z): Calcd. For C19H17NO4S3 420.0 (M + H), found 419.7.

b) 5-methylthio-4 - {[(phenylphenyl) sulfonyl] amino} thiophene-2-carboxamidine trifluoroacetate and 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine trifluoroacetate

To a suspension of ammonium chloride (155 mg, 2.89 mmol) in anhydrous toluene (2.0 mL) at 0 ° C under argon was added dropwise trimethylaluminum (2.0 mol / L in toluene, 1.36 mL, 2 mL). , 72 mmol). The mixture was stirred at 25 ° C for 30 minutes and then 143 mg of a mixture of methyl 5-methylthio-4 - [(phenylsulfonyl) aminothiophene-2-carboxylate and methyl 1-4- {bis [(4-phenylphenyl) sulfonyl] amino was added. 5-methylthiothiophene-2-carboxylate (prepared in the previous step) in anhydrous toluene (2.0 mL). The reaction mixture was then slowly warmed to 100 ° C and stirred for 4 hours

324 ny. The cooled mixture was poured into a vigorously stirred slurry of silica gel (2 g) in chloroform (15 mL). Then the suspension was filtered (Celite) washing with mixtures of 25% MeOH-CH ₂ Cl ₂ (2 x 5 mL), 50% MeOH-CH ₂ Cl ₂ (2 x 5 mL) and 75% MeOH-CH ₂ Cl ₂ (2 x 5 mL). The combined eluates were concentrated and the residue obtained was purified on a 10g SPE silica gel column eluting with a gradient of 10-15% MeOH-CH ₂ Cl ₂ saturated with ammonia to give 66 mg of a mixture of the title compounds as a yellow solid. Reversed phase preparative HPLC chromatography using a Rainin SD-1 Dynamax system and a 2-inch C18 Dynamax 60A reverse phase column and gradient elution of 30% MeOH / 0.1% TFA in water to 100% MeOH using a flow rate 50 ml / min gave 15 mg of 5-methylthio-4 - ([(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamidine trifluoroacetate; mass spectrum (ESI, m / z): calcd. For C18H17N3O2S3: 404.0 ( M + H), found 404.1 and 11 mg of 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine trifluoroacetate, mass spectrum (ESI, m / z): for C 30 H 25 N 3 O 4 S 4 Calcd. 619.8 (M + H), found 620.2.

Examples 259-282

The methods described in Examples 257 and 258 were used to prepare the following compounds:

325

Mass spec. ESI, m / z example reactant compound formula Off. M + H Find. M + H 259 1-naphthalenesulfonyl chloride 5-methylthio-4 - [(2-naphthylsulfonyl) amino] thiophene-2-carboxamidine CjôHisNaOz s ₃ 378.0 378.1 260 1-naphthalenesulfonyl chloride 4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine C26H21N3O4 s ₄ 568.0 568.1 261 7brómnaftalénsulfonylchlorid 4 - {[(6-bromo- (2-naphthyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine CjôHuBr - N3O2S3 455.9 * 262 7brómnaftalénsulfonylchlorid 4- {bis [(6-bromo- (2-naphthyl) sulfonyl] amino}) - 5-methylthiothiophene-2- carboxamidine C2ôHi9Br2 - N3O4S4 723.9 * 263 2-naphthalenesulfonyl chloride 5-methylthio-4- [naphthylsulfonyl) amino] thiophene-2carboxamidine CiôH] 5N3O2 S3 378.0 378.1 264 2-naphthalenesulfonyl chloride 4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine C26H21N3O4 S4 568.7 568.3 265 o-toluenesulfonyl 4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C13H15N3O2 S3 342.4 342.1 266 o-toluenesulfonyl 4- {bis [(2-methylphenyl) sulfonyl) amino} -5-methylthiothiophene-2carboxamidine C20H21N3O4 s ₄ 496.6 496.1 267 m-toluenesulfonyl chloride 4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C13HMN3O2 S3 342.0 342.1 268 m-toluenesulfonyl chloride 4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methyl-tiotiofén-2carboxamidine C20H21N3O4 s ₄ 496.6 496.0 269 p-toluenesulfonyl chloride 4 - {[(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C ₁₃ H | ₅ a3O ₂ S 3 342.0 342.1

326

Mass spec. ESI, m / z example reactant compound formula Off. M + H Find. M + H 270 p-toluenesulfonyl chloride 4- {bis [(4-methylphenyl) sulfonyl] amino} thiophene-2carboxamidine C 20 H 21 N 3 O ₄ with ₄ 496.6 496.1 271 a-toluenesulfonyl chloride 5-methylthio-4 - {[benzenesulfonyl] amino} thiophene-2carboxamidine C ₁₃ H ₁₅ N ₃ O 2 s ₃ 342.0 342.1 272 4-methoxybenzenesulfonyl chloride 4 - {[(4-methoxyphenyl) sulfonyl) amino} -5metyltiotiofén-2carboxamidine C ₁ 3 H ₁₅ N ₃ O ₃ S ₃ 358.0 358.1 273 4-methoxybenzenesulfonyl chloride 4- {bis [(4-methoxyphenyl) sulfonyl] amino} -5metyltiotiofén-2carboxamidine C20H21N3O6 with ₄ 528.0 528.0 274 4-iodobenzene sulfonyl chloride 4 - {[(4-iodophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C12H12N3O2 S3 453.9 454.0 275 3,4-Dimethoxy-benzenesulfonyl chloride 4 ^- {[(3,4-dimethoxyphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C14H17N3O4 S3 388.0 388.1 276 3,4-Dimethoxy-benzenesulfonyl chloride 4- {bis [(3,4-dimethoxyphenyl) sulfonyl] amino} -5-tiotiofén-2-carboxamidine C22H25N3O8 S4 588.0 588.1 277 2-chlorobenzenesulfonyl chloride 4 - {[(2-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C12H12 Cl- N3O2S3 361.9 362.1

327

Mass spec. ESI, m / z example reactant compound formula Off. M + H Find. M + H 278 3-chlorobenzenesulfonyl chloride 4 - {[(3-chlorophenyl) sulfonyl) amino} -5-methylthiothiophene-2-carboxamidine c ₁₂ h ₁₂ ciN ₃ O ₂ S 3 361.9 362.1 279 3-chlorobenzenesulfonyl chloride 4- {bis [(3-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine C ₁₅ H ₁₅ Cl ₂ - N 3 O 4 S 4 535.9 537.9 280 4-chlorobenzenesulfonyl chloride [(^ -ChlórfenyOsulfonyHaminol-S-methylthiothiophene-2-carboxamidine C ₂ H) ₂ C1n ₃ of _{3 2} of 361.9 362.1 281 4-chlorobenzenesulfonyl chloride 4- {bis [(4-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine CigHi5Cl ₂ N ₃ O ₄ S 535.9 * 282 benzenesulfonyl 5-methylthio-4 - [(phenylsulfonyl] amino] -5tiofén-2-carboxamidine C ₁₂ H 13 N ₃ O ₂ S3 328.0 328.1 283 benzenesulfonyl 4- [bis (phenylsulfonyl) amino] -5-methylthiophene-2-carboxamidine C 18 H 17 N ₃ O ₄ s ₄ 468.0 467.9 284 4 / t-butylbenzenesulfonyl chloride 4- ({[4- (tert-butyl) phenyl] sulfonyl} amino) -5-methylthiothiophene-2-carboxamidine C ₁₆ H ₂₁ N ₃ O ₂ S3 384.0 384.2 285 4-tert-butylbenzenesulfonyl chloride 4- (bis {[4 - (/ t-butyl) phenyl) sulfonyl] amino} -5-methyl-2 carboxamidine tiotiofén C ₂ 6H33N ₃ O ₄ s ₄ 580.1 580.2 286 trans-P-styrenesulfonyl 4 - {[((lE) -2-phenylvinyl) sulphonyl] amino) -5-methylthiothiophene-2carboxamidine C1 ₄ H1 ₅ N3O ₂ s ₃ 354.0 * 287 4-benzene-sulfonyltiofén-2-sulfonyl chloride 5-methylthio-4 - ({[4- (phenylsulfonyl) (2-thienyl)] sulfonyl} amino) thiophene2-carboxamidine C 16 H 15 N ₃ O ₄ s ₅ 473.9 474.1

* inconclusive mass spectrometry results

328

Example 288

5-methylthio-4-phenoxythiophene-2-carboxamidine trifluoroacetate

(a) methyl 5-methylthio-4-phenoxythiophene-2-carboxylate

A mixture of 100 mg (0.37 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to Example 241), 20 mg of Cu (0) (Brewster) was added to a round-bottom flask, dried in an oven equipped with a stir bar. , RQ and Groening T., Organic Syntheses, Vol. II, Note 1, pp. 445-446) and 42 mg (0.46 mmol) of phenol. The flask was purged with dry argon and anhydrous tetrahydrofuran (5 mL) was added. The reaction mixture was then heated at reflux for 48 hours and then the solvent was removed in vacuo. The resulting residue was purified on a 10g SPE silica column eluting with a gradient of 50-100% CH 2 Cl 2 -hexane to yield 48 mg of methyl 5-methylthio-4-phenoxythiophene-2-carboxylate (37%). 1 H-NMR (CDCl 3, 400 MHz) δ 7.39 (s, 1H), 7.32 (m, 2H), 7.09 (m, 2H), 6.97 (d, 1H, J = 8, 4 Hz), 3.86 (s, 3H) and 2.49 (s, 3H).

b) 5-methylthio-4-phenoxythiophene-2-carboxamidine trifluoroacetate

Use the method described in Example 257, step (b), using 48.0 mg (0.17 mmol) of methyl 5-methylthio-4-phenoxythiophene-2-carboxylate (prepared in the previous step), 78 mg of ammonium chloride (1, 2). 5 mmol), 0.68 ml trimethylaluminium (2.0 mol / L in toluene, 1.3 mmol) and 3 ml anhydrous toluene and using the above reverse phase chromatography separation using the Rainin SD-1 Dynamax system and column 2 in. with reverse phase C18 Dynamax 60A and gradient elution with 30% MeOH / 0.1% TFA in water to 100% MeOH at a flow rate of 50 mL / min. 1 H-NMR (CD ₃ OD, 400 MHz) δ 7.66 (s, 1H), 7.39 (t, 2H, J = 7.5 Hz), 7.17 (t, 2H, J = 7, 4 Hz), 7.02 (d, 1H, J = 7.7 Hz) and 2.58 (s, 3H). Mass spectrum (ESI, m / z): Calcd. For C12H12N2OS2 265.0 (M + H), found 262.2.

329

Example 289

5-Methylthio-4- (phenylsulfonyl) thiophene-2-carboxamidine trifluoroacetate

a) 4-bromo-5-methylthiothiophene-2-carboxylic acid

To 1.0 g (3.7 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (prepared according to Example 241, step (a)) dissolved in 25 mL of MeOH was added 450 mg of NaOH dissolved in 10 mL of H ₂ O. the reaction was stirred for 5 hours at room temperature and the solvent removed in vacuo. The residue was extracted with ethyl acetate (ex 50 mL) and 1 N HCl. The organic layer was separated, dried (Na ₂ SO 4), filtered and concentrated in vacuo to give 833 mg (89%) of 4-bromo-5-methylthiothiophene-2-carboxylic acid as a white solid.

b) 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxylic acid

100 mg (0.39 mmol) of 4-bromo-5-methylthiothiophene-2-carboxylic acid (prepared in the previous step) was charged to a round-bottom flask dried in a drying oven equipped with a stir bar. The flask was purged with dry argon and anhydrous tetrahydrofuran (3 mL) was added. The solution was then cooled to -78 ° C, then 511 µL of tert-butyllithium (0.87 mmol, 1.7 mol in tetrahydrofuran) was added. The resulting mixture was stirred for 45 minutes and then 77 mg of benzenesulfonyl fluoride (0.39 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was then stirred for 12 hours and then carefully quenched with H ₂ O. The solvent was removed in vacuo and the residue was extracted with ethyl acetate (2 x 50 mL) and HCl (1 mol / L). The organic layer was separated, dried (Na ₂ SO 4), filtered and concentrated in vacuo to give 130 mg of a solid. The solid product obtained is used in the next step without further purification.

c) methyl 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxylate

330

To a solution of 25 mg of the mixture obtained in the preceding step in 3 ml of MeOH was added dropwise 397 μΐ of trimethylsilyldiazomethane (0.79 mmol, 2 mol / L in hexanes) and the reaction mixture was stirred for 1 hour. The solvent is then removed in vacuo. The resulting residue was purified on a 10g SPE silica column eluting with 50-100% ethyl acetate-hexane to give 13.8 mg of methyl 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxylate. Mass spectrum (ESI, m / z): Calcd. For C13H12O4S3 329.0 (M + H), found 329.0.

d) 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxamidine trifluoroacetate

Using the procedure described in Example 257, step (b), using 20 mg of ammonium chloride (0.376) using 13.8 mg (0.044 mmol) of methyl 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxylate (prepared in the previous step). mmol), 0.176 mL of trimethylaluminium (solution (2.0 mol / L) in toluene, 0.353 mmol) and 3 mL of anhydrous toluene and chromatography performed as described above using the Rainin SD-1 Dynamax system and a 2-in column. reversed phase C18 Dynamax 60A and gradient elution with 30% MeOH / 0.1% TFA in water to 100% MeOH at a flow rate of 50 ml / min yielded 2.3 mg of 5-methylthio-4- (phenylsulfonyl) thiophene- 2-carboxamidine trifluoroacetate. 1 H-NMR (CD 3 OD, 400 MHz) δ 8.42 (s, 1H), 8.04 (m, 2H), 7.70 (m, 2H), 7.62 (m, 1H) and 2.70 (s, 3 H). Mass spectrum (ESI, m / z): Calcd. For C12H12N2O2S3 313.0 (M + H), found 313.2.

Example 290

Preparation of tablets

Tablets containing the following active compound, containing 25.0, 50.0, and 100.0 mg, are prepared as follows:

a. 4- (4-methyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine;

b. 4- [4- (4-phenylphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine.

331

Tablets containing the active compound containing 25 to 100 mg content in mg active compound 25.0 50.0 100.0 microcrystalline cellulose 37.25 100.0 200.0 food corn starch 37.25 4.25 8.5 magnesium stearate 0.50 0.75 1.5

All the active compound, cellulose and a portion of the corn starch are mixed and granulated to form a paste with a corn starch content of 10%. The granulate obtained is then sieved, dried and mixed with the rest of the corn starch and magnesium stearate. The resulting granulate is then compressed into tablets containing 25.0, 50.0, and 100.0 mg of active ingredient per tablet.

Example 291

Solution for intravenous administration

A dosage form comprising the above active compounds for intravenous administration is prepared as follows:

active compound 0.5-10.0 mg sodium citrate citric acid sodium chloride water for inj. (USP) 5-50 mg 1-15 mg 1-8 mg qs 1 ml

Using the above amounts, the active compound is dissolved in a preformed solution of sodium chloride, citric acid, and sodium citrate in water for injection (USP, p. 1636, United States Pharmacopeia / National Formulary 1995, issued by the United States Pharmacopeial Convention, Inc., Rockville, Maryland (1994).

332

Example 292

In vitro inhibition of purified enzymes

Reagents: all buffer salts were obtained from Sigma

Chemical Company (St. Louis, MO), and were of the highest achievable purity.

Enzyme substrates,

N-benzoyl-Phe-Val-Arg-p-nitroanilide (Sigma B7632)

N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride (Sigma B2291),

N-p-tosyl-Gly-Pre-Lys-p-nitroanilide (Sigma T6140)

N-succinyl-Ala-Ala-Pre-Phe-p-nitroanilide (Sigma S7388) and

N-CBZ-Val-Gly-Arg-p-nitroanilide (Sigma C7271) was obtained from the company. N-succinyl-Ala-Ala-Pre-Arg-p-nitroanilide (BACHEM L-1720) and N-succinyl-Ala-Ala-Pre-Val-p-nitroanilide (BACHEM L-1770) were obtained from BACHEM (King of Prussia) , PA).

Human α-thrombin, human factor Xa, and human plasmin were obtained from Enzyme Research Laboratories (South Bend, Indiana). Bovine α-chymo-trypsin (Sigma C4129), bovine trypsin (Sigma T8642) and human kidney cell urokinase (Sigma U5004) were obtained from Sigma. Human leukocyte elastase was obtained from Elastin Products (Pacific, MO).

Assay K i: All assays are based on the ability of the test compound to inhibit enzyme-catalyzed hydrolysis of the peptide p-nitroanilide substrate. In a typical K i assay, a substrate in DMSO is used that is diluted into assay buffer containing 50 mM HEPES, 200 mM NaCl, pH 7.5. The final concentrations of each substrate are as shown below. In general, substrate concentrations are lower than those determined to determine the K _m value. Test compounds are formulated as solutions at 1.0 mg / ml in DMSO. Dilution is done in DMSO to prepare 8 final concentrations including 200 fold

333 concentration range. Enzyme solutions are prepared in buffers for the assay at the concentrations given below.

In a typical K value, 280 μΐ of substrate solution, 10 μΐ of test compound solution are pipetted into each well of a 96-well plate and the plate is equilibrated at 37 ° C in a Molecular Devices plate reader for> 15 minutes. The reaction is initiated by the addition of a 10 μΐ portion of enzyme and the increase in absorbance at 205 nm is recorded for 15 minutes. Results corresponding to at least a 10% increase in total substrate hydrolysis are used for evaluation. The ratio of the rate (rate of change of absorbance versus time) of the sample without the test compound to the rate of the sample containing the test compound is plotted as a function of the concentration of the test compound. The results are evaluated by the linear regression method and the steepness of the curve is calculated. The inverse of the slope corresponds to the experimentally determined value of K).

Thrombin: Thrombin activity is evaluated by its ability to hydrolyze the substrate, N-succinyl-Ala-Ala-ro-Arg-p-nitroanilide. prepare substrate solutions at 32 μΜ (32 μΜ <<K _m = 180 μΜ) in assay buffer. The final DMSO concentration is 4.3%. Purified human α-thrombin is diluted in assay buffer to a concentration of 15 nM. The final concentration in the reaction is: [thrombin] = 0.5 nM, [substrate N-succinyl-Ala-Ala-Pre-Arg-p-nitroanilide] = 32 μΜ.

Factor X [FXa]: FXa activity is evaluated by its ability to hydrolyze the substrate, N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride. Prepare substrate solutions of 51 μΜ (51 K K _m = 1.3 mM) in assay buffer. The final DMSO concentration is 4.3%. Purified activated human factor X is diluted in assay buffer to a concentration of 300 nM. The final concentration in the reaction is: [FXa] = 10 nM, [N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride] = 51 μΜ.

Plasmin: The activity of plasmin is determined by its ability to hydrolyze the substrate, Nβ-Tosyl-Gly-Pre-Lys-p-nitroanilide. Prepare solutions of the substrate at 37 μ 37 (37 μΜ «K _m = 243 μΜ) in the assay buffer. final

334 DMSO concentration is 4.3%. Purified activated human plasmin is diluted in assay buffer to a concentration of 240 nM. The final concentration in the reaction is: [plasmin] = 8 nM, [N-β-Tosyl-Gly-Pre-Lys-β-nitroanilide] = 37 μΜ.

Chymotrypsin: The activity of chymotrypsin is determined by its ability to hydrolyze N-succinyl-Ala-Ala-Pre-Phe-p-nitroanilide. Prepare substrate solutions of 14 μΜ (14 μΜ << K _m = 62 μΜ) in assay buffer. The final DMSO concentration is 4.3%. Purified bovine chymotrypsin is diluted in assay buffer to a concentration of 81 nM. The final concentration in the reaction is: [chymotrypsin] = 2.7 nM, [N-succinyl-Ala-Ala-Pre-Phe-p-nitroanilide] = 14 μΜ.

Trypsin: trypsin activity is determined by its ability to hydrolyze N-benzoyl-Phe-Val-Arg-p-nitroanilide. Prepare substrate solutions of 13 μΜ (13 μΜ << K _m = 291 μΜ) in assay buffer. The final DMSO concentration is 4.3%. Purified bovine trypsin is diluted in assay buffer to a concentration of 120 nM. The final concentration in the reaction is: [trypsin] = 4 nM, [N-benzoyl-Phe-Val-Arg-p-nitroanilide] = 13 μΜ.

Elastase: elastase activities are determined by its ability to hydrolyze N-succinyl-Ala-Ala-Pre-Val-p-nitroanilide. Prepare substrate solutions of 19 μΜ (19 μΜ Μ K _m = 89 μΜ) in the assay buffer. The final DMSO concentration is 4.3%. Purified human leukocyte elastase is diluted in assay buffer to a concentration of 750 nM. The final concentration in the reaction is: [elastase] = 25 nM, [N-succinyl-Ala-Ala-Pre-Val-p-nitroanilide] = 19 μΜ.

Urokinase: urokinase activity is assessed by its ability to hydrolyze N-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solutions of 100 μΜ (100 μΜ K K _m = 1,2 mM μΜ) are prepared in assay buffer. The final DMSO concentration is 4.3%. Purified human kidney urokinase is diluted in assay buffer to a concentration of 1.2 μΜ. The final concentration in the reaction is: [urokinase] = 40 nM, [N-CBZ-Val-Gly-Arg-p-nitroanilide] = 100 mM.

The results of the activity determination examples are shown in the table below.

335

Protease Inhibition

protease K, (micromol) Example # trypsin 0,858 8 trypsin 0,474 52 factor Xa 2.73 94 factor Xa 3.00 119 chymotrypsin 4.90 11 tPA 9.49 1 plasmin 7.31 12 C1S 0,940 283

In addition, the following compounds had K i values in the micromolar concentration range of 0.016 to 3.5 for uPA:

Example # 28, 40, 53, 79, 84, 89, 131, 138, 139, 140, 143, 145, 172, 187, 200, 204, 206, 208, 213, 220, 222, 223, 227, 233, 235, 239, 260, 281 and 288.

These results indicate that the compounds of the invention are protease inhibitors, including urokinase.

It will be apparent to those skilled in the art from the foregoing description of the invention that there are equivalent conditions, formulations and other parameters that do not affect the scope of the invention or any embodiment thereof in any way. All cited patents and publications are incorporated by reference in their entirety.

Claims (76)

PATENT CLAIMS 1. A compound of formula (I): or a solvate, hydrate or pharmaceutically acceptable salt thereof; where X is O, S or NR ⁷ wherein R ⁷ is hydrogen, alkyl, aralkyl, hydroxy (C ₂ .4) alkyl, or alkoxy (C ₂ .4) alkyl; Y is a covalent bond, CH ₂ or NH; Z is NR ^S R ^6, hydrogen or alkyl provided that when Y is NH and Z is hydrogen or alkyl; R ¹ is hydrogen, amino, hydroxy, halogen, cyano, C 1-4 alkyl or -CH ₂ R, wherein R is hydroxy, amino or C 1-4 alkoxy; R ² and R ³ each independently represent: i. hydrogen; ii. halogen; iii. hydroxy; iv. nitro; in. cyano; 337 vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocykloamino, diheterocykloamino, monoalkylmonoheterocykloamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonyiamino, arylsulfonylamino, heteroarylsulfonylamino, di (aralkyl) amino, di (aralkenylsulfonyl) amino, di (arylsulfonyl) amino, or di (heteroarylsulfonyl) amino, formylamino, alkanoylamino, alkenoylamino, alkyinoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroaralkanoylamino, H (S) CNH-, or thioacylamino, wherein each aryl- or heteroaryl- the containing group may be optionally substituted in the aromatic ring and each heterocyclic group containing group may be optionally substituted in the ring moiety; vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl; viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl; ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono- and diarylaminocarbonylamino, or mono- and diaralkylaminocarbonylamino; x. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy, mono- and diarylaminocarbonyloxy, mono- and diaralkylaminocarbonyloxy; xi. aminosulfonyl, mono- and dialkylaminosulfonyl, mono- and diarylaminosulfonyl, or mono- and diaralkylaminosulfonyl; xii. alkoxy, or alkylthio, wherein the alkyl moiety may be optionally substituted; 338 xiii. aralkoxy, aryloxy, heteroaryloxy, aralkylthio, arylthio, or heteroarylthio, wherein the aryl portion of each group may be optionally substituted; xiv. alkylsulfonyl, wherein the alkyl moiety may be optionally substituted; xv. aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein the aryl portion of each of said groups may be optionally substituted; xvi. alkenyl or alkynyl; xvii. optionally substituted aryl; xviii. optionally substituted alkyl; xix. optionally substituted aralkyl; xx. optionally substituted heterocycle; or xxi. optionally substituted cycloalkyl; and R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, C 1-6. ₄ alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C2-io) alkyl, dialkylamino (C2-io) alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or -CC> 2 R ^W wherein R ^w represents alkyl, cycloalkyl, phenyl, benzyl, or R * R® 339 wherein R ^d and R ^c each independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl or phenyl, R ^f is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or phenyl, R ⁸ represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl or phenyl and R ^h represents an aralkyl or C 1-6 alkyl group; with the proviso that at least one of R ² or R ³ represents a group selected from the group consisting of: a) an optionally substituted alkyl group, preferably C 1-6 alkyl, even more preferably C 1-6 alkyl; b) alkoxy, aryloxy, alkylthio or arylthio, wherein each of said groups is optionally substituted; c) optionally substituted C 6-18 aryl or optionally substituted aralkyl, provided that R ^{3 is} not a nitrophenyl or aminophenyl group when R ¹ and R ^{2 are} both hydrogen or methyl; d) optionally substituted heterocycle; and e) optionally substituted cycloalkyl. A compound according to claim 1, wherein R ² or R ³ is alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl, and the alkyl portion of said alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl group is optionally substituted with 1-4 groups selected from the group consisting of: halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyl 340 monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminokarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio . The compound of claim 1, wherein R ³ is an optionally substituted alkyl or alkylthio group. The compound of claim 2 wherein said 1 to 4 substituent groups are selected from the group consisting of chloro, hydroxy, amino, mono (C _1-4 ) alkylamino, di (C 1-4) alkylamino, formylamino, C 2-6 acylamino, aminocarbonyl, C 2 C 8-6 aminoacyl, C 2-6 thioacylamino, aminothiocarbonyl, C 2-8 aminothioacyl, C 1-8 alkoxy, C 1-8 aryloxy, carboxy, carboxy (C 1-6) alkyl, C 2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C 1. ₆ alkylthio, C ₆ arylthio -i _4, Ciearalkylsulfo-phenylamino, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, mono (C6-io) arylaminocarbonyloxy, di (co. io) arylaminocarbonyloxy, mono-aralkylcarbonyloxy, diaralkylcarbonyloxy, C 1-6 alkoxycarbonylamino, C 6 -C 6 aralkoxycarbonylamino, and C 6 -C 10 aaryloxycarbonylamino. The compound of claim 1, wherein at least one of R ² and R ³ is aryl, aralkoxy, arylthio, aralkyl, aryloxy, aralkylthio, aralkylsulfonyl, arylsulfonyl, heterocycle or heterocycloalkyl optionally substituted with 1 to 4 halo, hydroxy, thiol groups a group, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoal 341 kylaminokarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminokarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino. Aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, , alkylthio, and arylthio. The compound of claim 5, wherein said 1-4 substituent groups are selected from the group consisting of chloro, hydroxy, amino, mono (C 1-4) alkylamino, di (C 1-4) alkylamino, formylamino, C 2-6 acylamino, aminocarbonyl, C 2-6 aminoacyl, C 3-7 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 aryloxy, carboxy, carboxy (C 1-6) alkyl, C 2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C 1-6 alkylthio, C 6-6 arylthio, C 6-6 naryl, tetrazolyl, thienyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, C 1-6 alkyisulfonylamino, C 1-6 alkylsulfonylamino, C 1-6 arylsulfonylamino, mono- or diaralkylcarbonyloxy, C 1-6 alkoxycarbonylamino, C 7 -C 6 arisarboxy , C 6 -C 10 aryloxycarbonylamino, C 2-6 thioacylamino, aminothiocarbonyl, and C 2-8 aminothioacyl. The compound of claim 1 wherein X is sulfur or oxygen; Y represents a covalent bond or -NH-; R ¹ represents hydrogen, amino, hydroxy or halogen; one of R ² and R ³ is hydrogen, C 1-6 alkylthio, C 1-6 alkyl or C 1-6 alkoxy and the other of R ² and R ³ is aminoacyl, acylamino, aminosulfonyl, sulfonylamino, aminocarbonylamino, alkoxycarbonyla 342 8th 8th 9th 9th mino, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted benzothienyl, optionally substituted furanyl, optionally substituted pyrazolyl or optionally substituted pyridyl. A compound according to claim 7 wherein R ⁴ , R ⁵ and R ⁶ are hydrogen. The compound of claim 1 wherein X is sulfur or oxygen; Y represents a covalent bond or -NH-; Z is NR ⁵ R ^6; R * is hydrogen, amino, hydroxy or halogen; one of R ² or R ³ represents hydrogen, C 1-6 alkylthio, C 1-6 alkyl or C 1-6 alkoxy; and the other of R ² and R ³ represents a group of formula (II): II where: Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, tetrazolyl, pyrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, imiazazolyl, triazolyl, benzothiazolyl, benzothienyl, benzothienyl, benzothiol 1,3-oxazolidin-2-one, imidazolin-2-one; R ⁸ and R ⁹ each independently represent a group selected from hydrogen. halo. amino. mono (C _1-4 ) alkylamino. arylamino. mo No 343 (C ₆ .i4) arylamino, di (C 6 i ₄₎ arylamino, mono (C 6 i ₄₎ r (Ci.6) alkylamino, di (C6-i4) ar (C] -6) alkylamino, di (C] .6 alkyl) amino, formylamino, C ₂ .6acylamino, aminocarbonyl, C ₂ -8aminoacyl, C ₂ -6tioacylamino, aminocarbonyl, C ₂ .8aminotioacyl, Ci.ealkyl, C 3-6 cycloalkyl, Ci.ealkoxy, carboxy, carboxy ( C | -6) alkyl, C2-8alkoxykarbonyl, nitro, cyano, trifluoromethyl, tetrazolyl, thienyl, C-uaryloxy, C ealkyltio, Cô.uaryltio, and _4-C 6 aryl and C6-i4ar (Ci-6) alkyl, wherein the aryl portions of each of said groups are optionally substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, amino, mono (C 1-4) alkylamino, di (C 1-4) alkylamino, formylamino, C 1-4 acylamino, C 1-4 alkyl. ₄ aminoacyl, mono (Ci. ₄₎ alkylaminocarbonyl, di (Ci. ₄₎ alkylaminocarbonyl, thiocarbonylamino, C. ₄ thioacylamino, (C _1-4 ) alkoxy, (C 6-10) arylaminocarbonyloxy, mono (C _1-4 ) alkylaminocarbonyloxy, di (C _1-4 ) alkylaminocarbonyloxy, mono (C 6-10) arylaminocarbonyloxy, di (C 6-10) arylaminocarbonyloxy mono (4-i ₂₎ aralkylaminokarbonyloxy, di ₍₄ .t ₂₎ aralkylaminokarbonyloxy, C ₄ alkylsulfonyl, C-ioarylsulfonyl, (C7-i2) aralkyl, Ci. ₄ alkylsulfonylamino, C-ioarylsulfonylamino, (C7.] ₂ ) aralkylsulfonylamino, C ₄ alkoxycarbonylamino, aralkoxycarbonylamino C7.i _2, -C ioaryloxykarbonylamino, mono (Ci. ₄₎ alkylaminothiocarbonyl, di (C |. ₄₎ alkylaminothiocarbonyl, C7 and ₂ aralkoxy, carboxy, carboxy (Ci. ₄₎ alkyl, , C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, C _1-4 alkylthio, C 6-10 arylthio, 3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy; R ⁴ , R ⁵ , R ⁶ independently represent hydrogen, C 1-6. Alkyl, amino, C _1-4 alkyl. ₄ alkoxy and hydroxy. The compound of claim 9 wherein X is sulfur; Y represents a covalent bond; Z is NR ⁵ R ^6; 344 R ¹ is hydrogen; R ² is a group of formula (II) wherein Ar is phenyl, thiazolyl, oxazolyl, pyridyl, or imidazolyl; R ⁸ and R ⁹ each independently represent a group selected from hydrogen and a C 6-10 aryl group optionally substituted with one to three groups independently selected from the group consisting of chloro, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, aminophenyl, carboxyphenyl, nitrophenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, and 3,4-propylenedioxy. R ³ is methylthio or methyl; R ⁴ , R ⁵ and R ⁶ all represent hydrogen. The compound of claim 1, wherein X is sulfur; Y represents a direct covalent bond; Z is NR ⁵ R ^6; R ¹ is hydrogen; R ² represents a radical from alkyl, ar (alkyl), alkylsulfonyl, -SO-alkyl, amido. amidino, or 345 II where Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl; R ⁸ and R ⁹ each independently represent a group selected from hydrogen, carboxy, phenyl, naphthyl, alkyl, pyridyl, oxazolyl, furyl, cycloalkyl and amino, each of which is optionally substituted with 1 to 3 groups independently selected from the group consisting of: halogen, alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy, amino, nitro, thiophenyl, benzothiophenyl, fluorenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy, arylsulfonamido, alkylsulfonamido and aryloxy, wherein each of said 1 to 3 substituent groups may further be optionally substituted with one or more groups independently selected from alkoxy, haloalkyl, halogen, alkyl, amino, acetyl, hydroxy, dialkylamino, dialkylaminoacyl, monoalkylaminoacyl, -SO ₂ -heteroaryl, -SO 2 -aryl, or aryl; R ³ is -SO ₂ -alkyl, trifluoromethyl, S (O) -alkyl, hydrogen, alkoxy, alkylthio, alkyl, aralkylthio; and R ⁴ , R ⁵ , R ⁶ are hydrogen. The compound of claim 11, wherein Ar is a thiazolyl group and at least one of R ¹⁷ and R ¹⁸ is a phenyl group. 346 A compound according to claim 11 or 12, wherein said thiazolyl group is thiazol-2-yl. The compound of claim 13, wherein R ² is a 4-phenylthiazol-2-yl group wherein said phenyl group is optionally further substituted. A compound according to claim 11 or 12, wherein said thiazolyl group is thiazol-4-yl. The compound of claim 15, wherein R ² is a 2-aminothiazol-4-yl group. The compound of claim 11, wherein said oxazolyl group is oxazol-2-yl. The compound of claim 11, wherein said oxazolyl group is oxazol-4-yl. A compound according to claim 11, wherein R ^{3 is} methylthio. 20. Compound of formula (I) 347, or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein X is sulfur; Y represents a covalent bond; Z is NR ⁵ R ^6; R ¹ is hydrogen; R ² is a group of formula (II) II where Ar is phenyl, thiazolyl or oxazo; and R is each independently selected from hydrogen and C 6-10 aryl, optionally substituted with 1 to 3 groups independently selected from chloro, hydroxy, C 1-4 alkyl, C 1-4. 4alkoxy, phenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, and 3,4-propylenedioxy; R ³ is methylthio; and R ⁴ , R ⁵ . R ⁶ are hydrogen. 348 I A compound of formula (I), or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein X is sulfur; Y represents a covalent bond; R ¹ is hydrogen; R ² is a group of formula (II) wherein Ar represents a thiazolyl group; R ⁸ and R ⁹ each independently represent a group selected from the group consisting of hydrogen and C 6-10 aryl substituted by a sulfonamide group; R ³ is methylthio; and R ⁴ , R ⁵ , R ⁶ are hydrogen. 349 The compound of claim 21, wherein said sulfonamide group is a group selected from the group consisting of C 6-10 aryl sulfonamide, alkylsulfonamide, alkoxysulfonamide, and heteroarylsulfonamide. The compound of claim 22, wherein said sulfonamide group is selected from the group consisting of 4-methylphenylsulfonamide, methylsulfonamide, phenylsulfonamide, trifluoromethylsulfonamide, 4-fluorophenylsulfonamide, 4-chlorophenylsulfonamide, 3-chlorophenylsulfonamide, 4-chlorophenylsulfonamide, 4-fluorophenylsulfonamide, 4-fluorophenylsulfonamide, thiophene) sulfonamide, 2- (5-chlorothiophene) sulfonamide, butylsulfonamide, and isopropylsulfonamide. 24. Compound of formula (I) NR * or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein X is sulfur; Y represents a covalent bond; Z is NR ^S R ^6; R ¹ is hydrogen; R ² is a group of formula (II) 350 ΛΪ where Ar represents a thiazolyl group; R and R each independently represent a group selected from hydrogen and C 6-10 aryl, optionally substituted with a group independently selected from -CH ₂ C (O) -alkoxy, -OCH ₂ C (O) -amino, -OCH ₂ C (O ) -NH-alkyl, and -OCH ₂ C (O) N (alkyl) _2; R ³ is methylthio; and R ⁴ , R ⁵ , R ⁶ are hydrogen. 25. Compound of formula (III): NH 3 or a salt thereof. where A is methylthio or methyl; 351 G 'represents -O-, -S-, -NH-, or a covalent bond; n is an integer from 1 to 10; m is an integer from 0 to 1; and R 'and R' are each independently selected from hydrogen, alkyl, aryl or aralkyl, or R 'and R together with the nitrogen atom to which they are attached form a 3 to 8 membered heterocyclic ring optionally containing another O atom , N, or S. The compound of claim 25, wherein said 3-8 membered heterocyclic ring contains another N atom, and the other nitrogen atom is optionally substituted with hydrogen, C 1-6. ₄ alkyl, C-ioaryl, C6-ioar (C [. ₄₎ alkyl, alkoxy, alkoxycarbonyl, or benzyloxycarbonyl. The compound of claim 25, wherein said 3-8 membered heterocyclic ring is a ring selected from the group consisting of piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl, optionally further substituted with from 1 to 4 substituent groups selected from the group consisting of halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminokarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, and alkylthio and arylthio. 352 The compound of claim 11, wherein Ar represents a thiazolyl group; and one of R ⁸ and R ⁹ is hydrogen, and the other of R ⁸ and R ⁹ is amino, wherein said amino group is optionally substituted with halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminokarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio. 29. Compound of formula (IV): Where? A is methylthio or methyl; and 353 R "is hydrogen, C6-i4aryl, C alkyl, alkoxy, (C6-i4) aryl, amino (C ₆ .i4) aryl, monoalkylamino (C6-i4) aryl, di (C6-i4) aryl, C6-ioar (C _1-6 ) alkyl, C 1-6 alk (C _1-6 ) aryl, amino (C 1-6) alkyl, mono (C _1-6 ) alkylamino (C 1-6) alkyl, dialkylamino (C 1-6) alkyl, hydroxy (C 6-14) aryl, hydroxy (C 1-6) alkyl, wherein each of said groups is optionally substituted with 1-4 non-hydrogen substituent groups selected from the group consisting of halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, mono- or dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di (C 1-6) alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or diaralkylaminocarbonyloxy, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono- or dialkylaminothiocarbonyl, aralkox γ, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio, and arylthio. The compound of claim 29 which is a compound selected from the group consisting of: 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- (2 - {[4- (dimethylamino) phenyl] amino} (l, 3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(4-chloro-2-methylphenyl) amino] (l, 3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 354 5-methylthio-4- {2 - ((3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine, 5-methylthio-4- (2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine, 4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(3-chloro-2-methylphenyl) amino] (l, 3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- (2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2 - ([4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine, 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(2,6-dichlorophenyl) amino] (l, 3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(2-bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- {2 - [(2-morpholin-4-ylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine, 4- (2 - ((2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine, 5-methylthio-4- (2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine. 355 4- (2 - {[(4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine, 4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine, 4- (2 - {[4-phenoxyphenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine, 5-methylthio-4- (2 - {[4-benzylphenyl] amino} (l, 3-thiazol-4-yl) thiophene-2-carboxamidine, 5-methylthio-4- (2 - {[4- (piperidinylsulfonyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine, 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine, 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine, 4- [2- (2H-benzo [3,4-d] -l, 3-dioxolan-5-ylamino) (l, 3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxamidine, 5-methylthio 4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene-2-carboxamidine, 356 4- (2 - ((3 - ((3-methylpiperidyl) methyl) phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxamidine, 4- (2 - [(3-hydroxyphenyl) amino] (l, 3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamidine, 4- (2 - {(4- (carbamoylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamidine, 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxamidine, 5-methyl-4- {2 - [(4-phenoxyphenyl) amino] ( _1,3' -thiazol-4-yl)} thiophene-2-carboxamidine, 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamidine, 4- (4-isoxazol-5-yl (l, 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxamidine; The compound of claim 1 which is a compound selected from the group consisting of: Of 4- [4- (4-chlorophenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine; 4-phenyl-1-5-methylthiothiophene-2-carboxamidine; 4- (4- (2,4-dichlorophenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-methyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [4- (3-methoxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4- (3-hydroxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-phenyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- (4- (4-nitro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 357 4- [4- (3,4-Propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (4- (Naphthalen-2-yl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine, and 4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine; or a hydrate, solvate or pharmaceutically acceptable salt thereof. 32. The compound of claim 11 which is a compound selected from the group consisting of: 4-phenyl-5-methylthiothiophene-2-carboxamidine; Of 4- [4- (4-chlorophenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (4-fenylfenyi) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3-hydroxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-phenyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [4- (4-nitro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2carboxamidine; 4- [4- (4-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4- (3,4-propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine; 4- (4-methyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [4- (2,4-Dichloro-phenyl) -thiazol-2-yl] -5-methyl-thiothiophene-2-carboxamidine 4- (2-naftyltiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 358 4- [4- (4-chloro-3-methyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (5-methyl-4-phenyl-thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [4- (4-chloro-3-nitro-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (5-phenyl-oxazol-2-yl) -5-methylthiothiophene-2-carboxamidine; -4- [4- (3-fluoro-5-trifluoromethylphenyl) -5-methyl-thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3,5-bis (trifluoromethyl) phenyl) -5-methyl-thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3-bromo-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3,4-methylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (4-methyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3,5-bis (trifluoromethyl) phenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (2-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-phenyl-imidazol-2-yl) -5-methylthiothiophene-2-carboxamidine; Of 4- [4- (2,4-dimethoxyphenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-benzyltiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [4- (3,4-dichlorophenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3-methyl-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (3,5-dimethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 359 4- [4- (2-methylphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4- (2,5-dimethoxyphenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4,5-diphenylthiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- (2-phenyl) -thiazol-4-yl-5-methylthiothiophene-2-carboxamidine; 4- [4- (2-chloro-3-pyridyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (phenoxymethyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-cyklohexyltiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; Of 4- [4- (4-chlorophenyl) -thiazole-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (2-hydroxy-phenyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4- (3-Trifluoromethoxyphenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [4- (2-chloro-4-pyridyl) -thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (5-phenyl-2-pyridyl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (2-chloro-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- [2- (3-methoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- (2- (phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- (2- (2,5-dimethoxyphenylamino) thiazol-4-yl) -5-methylthiothiophene-2-carboxamidine; 4- (2-aminothiazol-4-yl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (4-chloro-2-methyl-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- [2- (4-dimethylamino-phenylamino) -thiazole-4-yl] -5-methylthiothiophene-2carboxamidine; 360 4- [2- (4-methoxy-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- [4- (4-hydroxy-3-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4- (3-hydroxy-4-methoxyphenyl) thiazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (2-fluoro-phenylamino) -thiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- (2- (2,4,5-Trimethylphenyl) aminothiazol-4-yl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (3-chloro-2-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- [2- (2-isopropylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- [2- (4-benzyloxyphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- [2- (2-bromophenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- (2- (2,5-dichlorophenyl) aminothiazol-4-yl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (2-bromo-4-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2carboxamidine; 4- [2- (2,3-dichlorophenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- (2- (3,4,5-tri methoxyphenyl) aminothiazol-4-yl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (2-piperidinylethyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 361 4- [2- (4-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; 4- (4-phenyl-oxazol-2-yl) -5-methylthiothiophene-2-carboxamidine; 4- [2- (diphenylmethyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine; and 4- [2- (3-phenylpropyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboxamidine, or a solvate, hydrate or pharmaceutically acceptable salt thereof, 33. A method of treating a disease selected from the group consisting of benign prostatic hypertrophy, prostate cancer, tumor metastasis, restenosis and psoriasis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I): or a solvate, hydrate or pharmaceutically acceptable salt thereof; where X is O, S or NR ⁷ ; R ⁷ is hydrogen, alkyl, aralkyl, hydroxy (C _3-4 ) alkyl, alkoxy (C _3-4 ) alkyl; Y is a covalent bond, CH ₂ or NH; Z is NR ⁵ R ^6; R ¹ is hydrogen, amino. hydroxy, halogen, cyano, C _1-4 alkyl, -CH ₂ R, wherein R represents a hydroxyamino or a C 1-3 alkoxy group; 362 2 3 R and R each independently represent a group selected from the group consisting of: i. hydrogen; ii. halogen; iii. hydroxy; iv. nitro; in. cyano; vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, alkarylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, formylamino, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino; vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, arylaminocarbonyl, or aminoacyl; viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl; ix. aminocarbonylamino, monoalkylaminocarbonylamino, dialkylaminocarbonylamino, monoarylaminocarbonylamino, diarylaminocarbonylamino, monoaralkylaminocarbonylamino or diaralkylaminocarbonylamino; x. aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy; xi. aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, monoarylaminosulfonyl, diarylaminosulfonyl, or monoaralkylaminosulfonyl, or diaralkylaminosulfonyl; 363 xii. alkoxy, or alkylthio, wherein the alkyl portion of said alkoxy or alkylthio group may be optionally substituted; xiii. aralkoxy, aryloxy, aralkylthio or arylthio, wherein the aryl portion of said aralkoxy, aryloxy, aralkythio or arylthio group may be optionally substituted; xiv. alkylsulfonyl, wherein the alkyl moiety may be optionally substituted; xv. aralkylsulfonyl or arylsulfonyl, wherein the aryl portion of each of said groups may be optionally substituted; xvi. alkenyl or alkynyl; xvii. optionally substituted aryl; xviii. optionally substituted alkyl; xix. optionally substituted aralkyl; xx. optionally substituted heterocycle; or xxi. optionally substituted cycloalkyl; and R ^4, R ^s and R ⁶ are each independently hydrogen, C | .4alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C2-io) alkyl, dialkylamino (C2.io) alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy . 34. The method of claim 33, wherein said effective amount is between about 0.01 to about 50 milligrams per kilogram per day. 364 35. The method of claim 33, wherein said effective amount is between about 0.1 to about 20 milligrams per kilogram per day. 36. A pharmaceutical composition comprising a compound according to claim 1 or claim 11, or a pharmaceutically acceptable ester, salt or ether thereof, and a pharmaceutically acceptable carrier. 37. The pharmaceutical composition of claim 36, wherein the content of said compound in the composition is between 0.01 to 100 mg. 38. A method of inhibiting a protease selected from the group consisting of leukocyte neutrophil elastase, chymotrypsin, trypsin, pancreatic elastase, cathepsin G, thrombin, urokinase, factor Xa, plasmin, thermolysin, C1 esterase, C-3 convertase, arosine, thrombin, kallikines characterized in that it comprises contacting said protease with a compound according to claim 1 or claim 11. 39. The method of claim 38, wherein said protease is trypsin, chymotrypsin, plasmin, or urokinase. 40. A method of treating adult respiratory distress syndrome, wound healing, rheumatism, rheumatoid arthritis, reperfusion injury, atherosclerosis, restenosis, neoplasia, metastasis, emphysema, Alzheimer's disease, pancreatitis, benign prostate hypertrophy or psoriasis, cancer, wherein the patient to be treated is administered an effective amount of a compound of claim 1 or claim 11. 365 41. The pharmaceutical composition of claim 36, which is suitable for parenteral, oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular administration. A process for the preparation of a compound of formula (I) or a solvate, hydrate or pharmaceutically acceptable salt thereof. where X is O, S or NR ^7; R ⁷ is hydrogen, alkyl, aralkyl, hydroxy (C 2-4) alkyl, or alkoxy (C 2-4) alkyl; Y represents a direct covalent bond, CH 2 or NH; R ¹ is hydrogen, amino, hydroxy, halogen, cyano, C 1-4 alkyl, and -CH 2 R, wherein R is hydroxyamino or C 1-4. ₃ alkoxy; R ² and R ³ each independently represent a group consisting of: i. hydrogen; ii. halogen; 366 iii. hydroxy; iv. nitro; in. cyano; vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, alkarylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, formylamino, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino; vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, arylaminocarbonyl, or aminoacyl; viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl; ix. aminocarbonylamino, monoalkylaminocarbonylamino, dialkylaminocarbonylamino, monoarylaminocarbonylamino, diarylaminocarbonylamino, monoaralkylaminocarbonylamino or diaralkylaminocarbonylamino; x. aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, or diaralkylaminocarbonyloxy; xi. aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, monoarylaminosulfonyl, diarylaminosulfonyl, or monoaralkylaminosulfonyl, or diaralkylaminosulfonyl; xii. alkoxy or alkylthio, wherein the alkyl portion of said alkoxy or alkylthio group may be optionally substituted; 367 xiii. aralkoxy, aryloxy, aralkylthio or arylthio, wherein the aryl part of said aralkoxy-, aryloxy-, aralkylthio- or arylthio group may be optionally substituted; xiv. alkylsulfonyl, wherein the alkyl moiety may be optionally substituted; xv. aralkylsulfonyl or arylsulfonyl, wherein the aryl portion of each of said groups may be optionally substituted; xvi. alkenyl or alkynyl; xvii. optionally substituted aryl; xviii. optionally substituted alkyl; xix. optionally substituted aralkyl; xx. optionally substituted heterocycle; or xxi. optionally substituted cycloalkyl; and R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, C 1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C 2-10) alkyl, dialkylamino (C 2-10) alkyl, carboxyalkyl, cyano, amino, alkoxy, hydroxy or hydrazino ; characterized in that said method comprises: (a) preparing a mixture by adding Lewis acid to a suspension of anhydrous ammonium chloride in an aprotic solvent under an inert atmosphere at a temperature of about 0 ° C; b) stirring the mixture at room temperature to room temperature and further mixing until substantially all of the solids have dissolved. c) adding a compound of formula (V) to said mixture 368 ii *? wherein R-R, R, X and Y are as defined above; and t> R is alkyl and aryl; d) heating said mixture at reflux for a predetermined time, followed by cooling said mixture to room temperature. 43. The process of claim 42, wherein said Lewis acid is trimethylaluminum or triethylaluminum. 44. The process of claim 42 wherein said aprotic solvent is selected from the group consisting of toluene, benzene, xylene or mesitylene. 45. A pharmaceutical composition suitable for oral administration according to claim 41, wherein the content of said compound in the composition is in the range of 25 mg to 100 mg. A pharmaceutical composition suitable for parenteral administration according to claim 41, wherein the content of said compound in the composition is in the range of 0.5 mg to 10 mg. 369 The compound of claim 1, wherein X is sulfur. The compound of claim 1, wherein Y is a covalent bond. The compound of claim 1, wherein R ¹ is hydrogen. The compound of claim 1, wherein each of R ⁴ , R ^5, and R ⁶ is hydrogen. A compound according to claim 1, wherein R ³ is methylthio or methyl. The compound of claim 1, wherein the aryl portion of R ² is optionally substituted with 1 to 4 groups selected from the group consisting of halogen, C 1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, trifluoromethyl, C 6-10 aryl, C 6-10 aryloxy, C 6-10 aryllmethoxy , C1-6 aminoalkyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3.4- propylenedioxy, amino, mono (C1-6) alkylamino, di (C1-6) alkylamino, mono (C6-10) arylamino, di (C6-10) arylamino, C1-6alkyisulfonylamino, C6-10arylsulfonylamino, C1.gacylamino C 1-6 alkoxycarbonyl, C 1-6 alkanoylamino, C 6-14 aroylamino, C 1-6 hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl and tetrazole. The compound of claim 52, wherein each of the groups consisting of C 6-10 aryl, C 6-10 arylloxy, C 6-10 aryl methoxy is further substituted with one or two groups including chloro, halogen, C 1-6. C ₆ alkyl; ₆ alkoxy, phenyl, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3.4- propylenedioxy or amino. 370 The compound of claim 52, wherein said optional substituent group, which is thienyl, is further substituted by one or two of chloro, amino, methyl, methoxy or hydroxy. The compound of claim 1, wherein R ² is C 1-6 alkylsulfonylamino, C 6-10 aralkyl (C 1-6) alkylsulfonylamino, C 6-10 aralkyl (C 2-6) alkenylsulfonylamino, C 6-10 arylsulfonylamino, heteroarylsulfonylamino, di ( C ₆ -ioar (C 1-6) alkylsulfonyl) amino, di (C ₆ -ioar (C 2-6) alkenylsulfonyl) amino, di (C 6-10 arylsulfonyl) amino or di (heteroarylsulfonyl) amino, wherein each of said aryl or heteroaryl is optionally substituted on the aromatic ring. The compound of claim 55, wherein R is C 6-10 arylsulfonylamino, di (C 6-10 arylsulfonyl) amino, C _6-10 ar (C _1-3 ) alkylsulfonylamino, di (C 6-10 aralkyl (C _1-3 ) alkylsulfonyl) amino or thienylsulfonylamino, wherein each of said aryl or thienyl-containing groups is optionally further substituted. A compound according to claim 1 wherein R ² is biphenylsulfonylamino, bis (biphenylsulfonyl) amino, naphthalen-2-ylsulfonylamino, di (naphthalenylsulfonyl) amino, 6-bromonaphthalen-2-ylsulfonylamino, di (6-bromonaphthalen-2-ylsulfonyl) amino, naphthalen-1-ylsulfonylamino, di (naphthalen-1-ylsulfonyl) amino, 2-methylphenylsulfonylamino, di (2-methylphenylsulfonyl) amino, 3-methylphenylsulfonylamino, di (3-methylphenylsulfonyl) amino, 4-methylphenylsulfonylamino, di (4) -methylphenylsulfonyl) amino, benzylsulfonylamino, 4-methoxyphenylsulfonylamino, di (4-methoxyphenylsulfonyl) amino, 4-iodophenylsulfonylamino, di (4-iodophenylsulfonyl) amino, 3,4-dimethoxyphenylsulfonylamino, bis (3,4-dimethoxyphenylsulfonyl) amino, 2 chlorophenyl 371 sulfonylamino, di (2-chlorophenylsulfonyl) amino, 3-chlorophenylsulfonylamino, di (3-chlorophenylsulfonyl) amino, 4-chlorophenylsulfonylamino, di (4-chlorophenylsulfonyl) amino, phenylsulfonylamino, di (phenylsulfonyl) amino, 4-tert-butylphenylsulfonyl (4-tert-butylphenylsulfonyl) amino, 2-phenyletenylsulfonylamino or 4- (phenylsulfonyl) thien-2-ylsulfonylamino. 58. The compound of claim 1, wherein R ² represents a radical from the group consisting of amino, mono (C ôJalkylamino, di (Ci-6) alkylamino, mono- _(C6-IO) arylamino, di (C6-io) arylamino, mono ( C 1-6 alkylmono (C 6-10) arylamino, mono (C 1-6) alkylamino, di (C 6-10) ar (C 1-6) alkylamino, mono (C 1-6) alkylmono (C 6-10) ar (C 1-6) alkylamino, monoheteroaryl amino, diheteroarylamino, mono (C 1-6) alkylmonoheteroarylamino, wherein each of the aryl or heteroaryl containing groups is optionally substituted in the aromatic ring. A compound according to claim 58, wherein R ² is mono (C 6-10) arylamino, mono (C 1-6) alkylmono (C 6-10) arylamino, mono (C 6-10) ar (C 1-3) alkylamino , mono (C 1-6) alkylmono (C 6-10) ar (C 1-3) alkylamino, monoheteroarylamino or mono (C 1-6) alkylmonoheteroarylamino. The compound of claim 59, wherein R ² is 1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino and quinolin-6-ylamino. A compound according to claim 58, wherein R ² is anilino, naphthalen-2-ylamino, naphthalen-1-ylamino, 4- (biphenyl) thiazol-2-ylamino, 4- (phenyl) thiazol-2-ylamino, 4. phenyl-5-methylthiazol-2-ylamino, 4-hydroxy-4-trifluoromethylthiazol-2-ylamino. 3-Phenylphenylamino, pyrimidine 372 din-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3-fluoro-4-phenylphenylamino, 3,4-methylenedioxyphenylamino, butylphenylamino, N-methyl-N- (2-methylphenyl) amino, 3-nitrophenylamino, 4-methoxyphenylamino, 3-methoxyphenylamino, 2-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino, 3,4-dimethylphenylamino, 3-chlorophenylamino, 4-chlorophenylamino, 4- (3-fluoro-4-methylphenyl) amino 4- (indan-5-yl) amino, benzylamino, indanylmethylamino, 2,3-dihydrobenzofuranylmethylamino, 2-phenylimidazol-5-ylamino, 3-hydroxybenzylamino, 3-phenoxyphenylamino, 4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4-benzyloxyphenylamino, quinolin-6-ylamino, quinolin-3-ylamino, 4- (phenylamino) phenylamino, 4- (4-ethylphenyl) phenylamino, 4- (dimethylamino) phenylamino, 4-cyclohexylphenylamino, 4- (9-ethylcarbazol-3-yl) amino, 4- (tert-butyl) phenylamino and 4-methylthiophenylamino. • y _# The compound of claim 1, wherein R is an alkanoylamino, alkenoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, or heteroarylalkanoylamino group, each of which is optionally substituted on the aromatic ring. 63. A compound according to claim 62 wherein R is (C 6-10 arylcarbonylamino), C 6-10 aralkyl (C 1-3) alkylcarbonylamino, C 6-10 aralkyl (C 2-3) alkenylcarbonylamino, (C 6-3) alkylcarbonylamino , C 3-8 cycloalkylcarbonylamino, C 1-6 alkylcarbonylamino and heteroarylcarbonylamino. 64. The compound of claim 63, wherein R ² represents a radical from the group of a furanylkarbonylamino chinolinylkarbonylamino. 373 65. The compound of claim 63, wherein R ² represents a radical from the group of 3-hydroxyfenylkarbonylamino, 2-fenyIetenylkarbonylamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3-nitrofenylkarbonylamino, furan-2-ylcarbonylamino, / t-butylcarbonylamino, 5- (3- 5-dichlorophenoxy) furan-2-ylcarbonylamino, naphthalen-1-ylcarbonylamino, quinolin-2-ylcarbonylamino, 4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino and 3-methylphenylcarbonylamino. A compound according to claim 1, wherein R ² is a group selected from the group consisting of C 6-10 aryloxy, C 6-10 ar (C 1-6) alkoxy, C 6-10 arylsulfonyl, C 6-10 ar (C 1-6) alkylsulfonyl and C 6-10 ar (C 2-6) 6) alkenylsulfonyl, wherein each of said groups is optionally substituted in the aromatic ring. A compound according to claim 66, wherein R ² is a group selected from the group consisting of C 6-10 aryloxy and C 6-10 arylsulfonyl. A compound according to claim 67, wherein R ² is a phenoxy, naphthyloxy, phenylsulfonyl or naphthylsulfonyl group. 69. The compound of claim 1 which is a compound selected from the group consisting of: 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxamidine, 5-methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxamidine, 5-methylthio-4- (3-quinolylamino) thiophene-2-carboxamidine, 5-methylthio-4- (pyrimidin-2-ylamino) -thiophene-2-carboxamidine, 4 - [(4-Cyclohexyl-phenyl) amino] -5-methylthiothiophene-2-carboxamidine, 374 methyl 4-amino-5-methylthiothiophene-2-carboxylate, methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate, 5-methylthio-4 - [(4-phenyl (1,3- thiazol-2-yl) amino] thiophene-2-carboxamidine, 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxamidine, 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2-naphthylamino) thiophene-2-carboxamidine, 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxamidine, 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine, 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- [benzylamino] thiophene-2-carboxamidine, 375 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboxamidine, 5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxamidine, 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamidine, 4 - ((2E) -3-phenyl-prop-2-enoylamino) -5-methylthiothiophene-2-carboxamidine, 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxamidine, methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate, 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxamidine, 4- (2,2-dimetylpropanoylamino) -5-methylthiothiophene-2-carboxamidine 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (naphthylcarbonylamino) -thiophene-2-carboxamidine, 5-methylthio-4- (2-quinolylcarbonyl-amino) thiophene-2-carboxamidine, 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 4- [2- (2-hydroxy-5-methoxy-phenyl) acetylamino] -5-methylthiothiophene-2-carboxamidine, 4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2-phenoxyacetylamino) -thiophene-2-carboxamidine, 376 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine, 5-methylthio-4 - [(3-phenoxy phenyl) amino] thiophene-2-carboxamidine, 5-methylthio-4- [(4-phenoxyphenyl) amino] thiophene-2-carboxamidine, 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2- carboxamidine, 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4- (methylphenylamino) -5-methylthiothiophene-2-carboxamidine, 5-methyl-4- (phenylamino) thiophene-2-carboxamidine, 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxamidine, 5-methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxamidine, 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4- (indan-5-ylamino) 5-methylthiothiophene-2-carboxamidine, 4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamidine, 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(2-naphthylsulfonyl) amino] thiophene-2-carboxamidine, 4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine, 377 4 - {[(6-bromo (2-naphthyl)) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- {bis [(6-bromo (2-naphthyl)) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(naphthylsulfonyl) amino] thiophene-2-carboxamidine, 4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- (bis [(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - {[(4-methylphenyl) sulfonyl] amino} -5methylthiothiophene-2 carboxamidine, 4- {bis [(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboxamidine, 5-methylthio-4-phenoxythiophene-2-carboxamidine, 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxamidine, or a salt, solvate, hydrate or prodrug thereof. 70. Compound of formula (I): NR, or a solvate, hydrate or pharmaceutically acceptable salt thereof. where: 378 X is oxygen or sulfur; Y represents a covalent bond or -NH-. Z is NR ⁵ R ^6; R ¹ represents hydrogen, amino, hydroxy or halogen; ^R2 is alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di (aralkyl) amino, di (aralkenylsulfonyl) amino, di (arylsulfonyl) amino, or di (heteroarylsulfonyl) amino, wherein any of the aryl or heteroaryl containing groups can be substituted for the an aromatic ring; or amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocyclylamino, diheterocyclylamino, monoalkylmonoheterocyclylamino, wherein each aryl or heterocycle containing group is optionally substituted on an aromatic; or alkanoylamino, alkenoylamino, alkyinoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, each of which may be optionally substituted on an aromatic ring; or alkoxy, alkylthio, aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, each of said groups being optionally substituted; or alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein each aryl-containing group is optionally substituted on the aromatic ring; or formylamino, H (S) CNH-, or thioacylamino; • J R is hydrogen, C 1-6 alkyl, C 1-6 alkyl optionally substituted with OH, NH 2, COOH, aminocarbonyl or C 1-4 alkoxy. 379 71. A pharmaceutical composition comprising a compound of claim 70, or a pharmaceutically acceptable ester, salt or ether thereof, and a pharmaceutically acceptable carrier. 72. The pharmaceutical composition of claim 71 wherein the content of said compound in the composition is in the range of 0.01 to 100 mg. 73. A method of inhibiting a protease selected from the group consisting of leukocyte neutrophil elastase, chymotrypsin, trypsin, pancreatic elastase, cathepsin G, thrombin, urokinase, factor Xa, plasmin, thermolysin, Cl esterase, C-3 convertase, acrosin, thrombin, kallikine, kallikine characterized in that it comprises contacting said protease with a compound according to claim 70. 74. The method of claim 73, wherein said protease is trypsin, chymotrypsin, plasmin, or urokinase. 75. A method of treating adult respiratory distress syndrome, wound healing, rheumatism, rheumatoid arthritis, reperfusion injury, atherosclerosis, restenosis, neoplasia, metastasis, Alzheimer's disease, pancreatitis, benign prostatic hypertrophy, or prostate cancer, psoriasis, psoriasis, wherein the patient in need of treatment is administered an effective amount of a compound of claim 70. 76. The compound of claim 70 which is selected from the group consisting of: 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxamidine, 380 5-methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxamidine, 5-methylthio-4- (3-quinolylamino) thiophene-2-carboxamidine, 5-methylthio-4- (pyrimidin-2-ylamino) -thiophene-2-carboxamidine, 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, methyl 4-amino-5-methylthiothiophene-2-carboxylate, methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2- carboxylate 5-methylthio-4 - [(4-phenyl (1,3-thiazol-2-yl)) amino] thiophene-2-carboxamidine, 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxamidine, 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino) -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2-naphthylamino) thiophene-2-carboxamidine, 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxamidine, 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine, 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 381 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- [benzylamino] thiophene-2-carboxamidine, 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboxamidine, 5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxamidine, 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamidine, 4 - ((2E) -3-phenyl-prop-2-enoylamino) -5-methylthiothiophene-2-carboxamidine, 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxamidine, methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate, 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxamidine, 4- (2,2-dimetylpropanoylamino) -5-methylthiothiophene-2-carboxamidine 4 - {[5- (3,5-Dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2- carboxamidine, 5-methylthio-4- (naphthylcarbonylamino) -thiophene-2-carboxamidine, 5-methylthio-4- (2-quinolylcarbonyl-amino) thiophene-2-carboxamidine, 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 382 4- [2- (2-hydroxy-5-methoxy-phenyl) acetylamino] -5-methylthiothiophene-2-carboxamidine, 4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4- (2-phenoxyacetylamino) -thiophene-2-carboxamidine, 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine, 5-methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboxamidine, 5-methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboxamidine, 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4- (methylphenylamino) -5-methylthiothiophene-2-carboxamidine, 5-methyl-4- (phenylamino) thiophene-2-carboxamidine, 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxamidine, 5-methylthio-4 - {[4- (phenylamino) phenyl] amino) -thiophene-2-carboxamidine, 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxamidine, 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxamidine, 4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamidine, 383 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(2-naphthylsulfonyl) amino] thiophene-2-carboxamidine, 4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[(6-bromo (2-naphthyl)) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- {bis [(6-bromo (2-naphthyl)) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - [(naphthylsulfonyl) amino] thiophene-2-carboxamidine, 4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxamidine, 4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- {bis [(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4 - {[(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 4- {bis [(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxamidine, 5-methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboxamidine, 5-methylthio-4-phenoxythiophene-2-carboxamidine, 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxamidine, or a salt or prodrug thereof.