KR20010098982A - Heteroaryl amidines, methylamidines and guanidines as protease inhibitors - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein X is O, S or NR ⁷ , R ¹ to R ⁷ , Y and Z are as defined in the description, its hydrates, solvates or pharmaceutically acceptable salts thereof Possible salts. The invention also relates to a process for the preparation of compounds of formula (I). The novel compounds of the present invention are potent inhibitors of proteases, particularly trypsin-like serine proteases (e.g., chymotrypsin, trypsin, plasmin and urokinase). Such specific compounds are intermediates useful for direct selective inhibition of urokinase, or for forming compounds having such activity.

Formula I

Description

HETEROARYL AMIDINES, METHYLAMIDINES AND GUANIDINES AS PROTEASE INHIBITORS AS PROTEASE INHIBITORS,

Proteases are enzymes that break down proteins in unity-specific peptide bonds. Proteases can generally be classified into four classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases [Cuypers et al . , J. Biol. Chem. , 257: 7086 (1982)]. Proteases are essential for a variety of biological activities (eg, digestion, formation and dissolution of clots, reproductive and immune responses to foreign cells and organisms). Abnormal proteolytic activity is associated with a number of disease states in humans and other mammals. Human neutrophil protease, elastase, and cathepsin G contribute to disease states caused by tissue damage. These disease states include emphysema, rheumatoid arthritis, corneal ulcers, and nephrosclerosis. [Barret, Enzyme Inhibitors as Drugs , Edited by Sandler, University Park Press, Baltimore, (1980)]. Additional proteases, such as plasmin, C-1 esterase, C-3 convertase, urokinase, histone plasminogen activator, acrosine and calicaine play an important role in the normal biological function of mammals. In many cases, it is beneficial to disrupt the function of one or more proteases during the therapeutic treatment of the mammal.

Examples of serine proteases include elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase and tissue plasminogen activator, acrosine, chymotrypsin, trypsin, Thrombin, factor Xa, and calicaine.

Human leukocyte elastase is released from inflammatory sites by polymorphonuclear leukocytes, and thus contributes to a number of disease states. Cathepsin G is another human neutrophil serine protease. Compounds having the ability to inhibit the activity of these enzymes are expected to have anti-inflammatory effects useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful for treating pancreatitis. Inhibitors of the urokinase plasminogen activator are useful for treating cell and growth disease states (eg, benign prostatic hyperplasia, prostate cancer and psoriasis).

The urokinase (u-type plasminogen activator or uPA; International Union of Biochemistry Classification Number: EC 3.4.21.31) is a protease highly specific for single peptide binding of plasminogen. This is the amino terminal segment (" ATF ", aa 1-143 (SEQ ID NO: 2)) consisting of the catalytic " B " chain (amino acid (aa) 144-411) and the growth factor domain (4-43) and the Kringle domain The uPA kringle domain appears to bind heparin but does not appear to bind to fibrin, lysine or aminohexanoic acid. The growth factor domain is also referred to as the " EGF domain " since it has some similarity to the structure of the epithelial growth factor (EGF). Single-chain pro-uPA is activated by plasmin to decompose the chain into a two-chain active form stabilized by a disulfide bond.

The degradation of peptide bonds in the plasminogen by urokinase ("plasminogen activation") produces plasmin, a potent general protease. Many cell types use urokinase as a key initiator of plasmin-mediated protein degradation or alteration of extracellular support structures (e. G., Extracellular matrix (ECM) and basement membrane (BM)). The cells are present, migrating, and interacting in tissues and organs within the physical structure provided by the ECM and BM. Movement of the cells within the ECM or across the BM causes local proteolysis or modification of these structures, invading the cells into adjacent regions that were not previously used.

The ability of urokinase to mediate cell migration and invasion is important in the presence of specific high affinity urokinase receptors (uPARs) that concentrate urokinase on the cell surface and generate locally high concentrations of plasmin between cells and ECM or BM [ Blasi, F. et al . , Cell Biol. , ≪ / RTI > 104: 801-804 (1987); Roldan, AL et al., EMBO J. , 9: 467-74 (1990)]. Binding interactions are clearly mediated by the EGF-type domain [Rabbani, SA et al . , J. Biol. Chem. , 267: 14151-56 (1992)). When pro-uPA and plasminogen are bound to the receptor, degradation of pro-uPA to active uPA is accelerated. Therefore, plasmin activates pro-uPA, which degrades plasminogen and further activates more plasmin. Because the excess protease inhibitor, including alpha ₂ -plasmin, PAI-1 and PAI-2, is found in plasma, the positive feedback cycle is clearly limited to the receptor-based proteolytic action of the cell surface. High concentration plasmin between invading cells and ECM or BM is needed to overcome the inhibitory effect of the ubiquitous plasmin inhibitor. Therefore, an important role in initiating cell invasion is the urokinase bound to cell surface receptors, not the free urokinase secreted by the cells.

Plasmin can activate or degrade extracellular proteins such as fibrinogen, fibronectin, and proenzyme, as well as matrix metalloproteinases. Thus, plasminogen activators can regulate extracellular proteolytic activity, fibrin clot lysis, tissue remodeling, migration of the developing and smooth muscle cells, inflammation and metastasis. Cell invasion initiated by urokinase has been implicated in a wide range of normal physiological processes and physiological processes of disease states [Blasi, F. et al., J. Cell Biol. , ≪ / RTI > 104: 801-804 (1987); Dano, K. et al . , Adv. Cancer Res. , ≪ / RTI > 44: 139-266 (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). These processes include, but are not limited to, angiogenesis (neovascularization), bone remodeling, intrauterine embryo transfer, immune cell invasion into inflammatory sites, ovulation, coordination, tissue remodeling during wound healing, recurrent stenosis and organ differentiation, , Metastatic spread of tumor cells from the primary site to the secondary site, and tissue damage to arthritis. ≪ RTI ID = 0.0 > Therefore, inhibitors of europinase are useful as anti-angiogenesis, anti-arthritis, anti-inflammatory, anti-recurrent stenosis, anti-invasive, anti-metastasis, anti-osteoporosis, anti- , Contraceptive and tumor arresting activities. Inhibitors of urokinase include agents useful for treating various disease states, including but not limited to benign prostatic hyperplasia, prostate hyperalgesia and psoriasis.

Reported beneficial effects of urokinase inhibitors using anti-urokinase monoclonal antibodies and other known specific anti-urokinase inhibitors. For example, anti-urokinase monoclonal antibodies have been shown to inhibit tumor cell invasion in vitro [Hollas, W. et al . , Cancer Res. , ≪ / RTI > 51: 3690-3695, (1991); Meissauer, A. et al . , Exp. Cell Res. , 192: 453-459 (1991)], tumor metastasis and invasion in vivo [Ossowski, L., J. Cell Biol. , ≪ / RTI > 107: 2437-2445 (1988); Ossowski, L. et al., J. Cancer Res. , 51: 274-81 (1991)] and in vivo generation of neovascularization [Jerdan, JA et al., J. Cell Biol. , 115 [3 Pt 2] : 402a (1991)]. In addition, amylolide (a known eukaryotic inhibitor with only moderate efficacy) has been implicated in tumor metastasis in vivo [Kellen, JA et al . , Anticancer Res. , 8: 1373-1376 (1998)] and in vitro in vivo / capillary network information [Alliegro, MA et al., J. Cell Biol. , 115 [3 Pt 2] : 402a (1991)].

The urokinase plays an important role in the wound healing and the formation of arterial tumor formation, and it seems to affect mainly the cell movement. Eukinase mediates the action of plasmin proteolysis, which further promotes blood vessel wound healing and associated tumorigenesis [Carmeliet et al . , Circ. Res. , ≪ / RTI > 81: 829-839 (November 1997); Lupu et al., Fibrinolysis 10 Supp , 2: 33-35 (1996)]. Viral serine protease inhibitor (SERP-1) was used to reduce plaque formation after primary balloon angioplasty in rabbits. This activity is due to inhibition by SERP-1, a protease of cells (e.g., plasmin or urokinase) [Lucas et al., Circulation , 94: 2890-2900 (1996)].

The need for nonpeptide compounds that are potent and selective eukaryotic inhibitors and have greater bioavailability and fewer side effects than currently available urokinase inhibitors has been steadily emerging. Thus, a new class of potent urokinase inhibitors characterized by excellent inhibitory performance and low toxicity are potential therapeutic agents for a variety of conditions.

The present invention relates to a novel class of nonpeptidic inhibitors of proteolytic enzymes such as urokinase (uPa), and novel heteroaryl compounds which act as enzyme inhibitors.

Summary of the Invention

The present invention relates broadly to the use of heteroarylamidines, methylamidines and guanidines having the formula (I) EMI2.1 wherein R < 1 >

The compounds of the present invention are useful intermediates that exhibit anti-urokinase activity through direct selective activity of urokinase, or to form compounds having such activity. The compounds of the present invention inhibit urokinase, and thus can be used for the treatment and / or prophylaxis of useful anti-angiogenesis, anti-arthritis, anti-inflammation, anti- recurrent stenosis, anti- Retinopathy), contraception and tumor stopping treatment. For example, such therapeutic agents are useful for treating a variety of disease states, including, but not limited to, benign prostatic hyperplasia, prostate cancer, tumor metastasis, and psoriasis.

Also provided are methods of inhibiting extracellular proteolytic activity by administering a compound of formula I, a method of treating benign prostatic hyperplasia, prostate cancer, tumor metastasis, psoriasis and other conditions.

The numerous heteroaryl compounds described herein are novel compounds. The invention therefore also relates to novel compounds of formula (I).

Also provided is a pharmaceutical composition comprising a compound of formula I and at least one pharmaceutically acceptable carrier or diluent, wherein the pharmaceutical composition further comprises a thrombolytic agent such as a tissue plasminogen activator and a streptokinase.

Methods for the synthesis of compounds of formula (I) are also provided.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to a method of inhibiting said protease by contacting said protease, in particular serine protease, with a compound of formula (I), or a solvate, hydrate or pharmaceutically acceptable salt thereof,

Wherein,

X is O, S or NR ⁷ where R ⁷ is hydrogen, alkyl, aralkyl, hydroxy (C _2-4 ) alkyl, or alkoxy (C _2-4 )

Y is a direct covalent bond, CH ₂ or NH,

Z is NR ⁵ R ^6, (in the stage, when Z is hydrogen or alkyl and Y is NH Im) 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 _1-3 alkoxy,

R ² and R ³ are independently

i. Hydrogen,

Ii. halogen,

Iii. Hydroxy,

Iv. Nitro,

V. Cyano,

Vi. Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycloamino, diheterocycloamino, Alkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, alkylsulfonylamino, Amino, di (aralkylsulfonyl) amino, di (aralkylsulfonyl) amino, di (arylsulfonyl) amino, di (heteroarylsulfonyl) amino, formylamino, alkanoylamino, Heteroarylamino, H (S) CNH- or thioacylamino, wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of Or any of the heteroaryl containing groups may optionally be substituted on the aromatic ring and any of said heterocycle containing groups may be optionally cyclic substituted,

Ⅶ. Monoalkylaminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl,

Ⅷ. Aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl,

ix. Monoarylaminocarbonylamino, monoaralkylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, monoaralkylaminocarbonylamino, diaralkylaminocarbonylamino, diarylaminocarbonylamino,

x. Monoalkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy or diaralkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy,

xi. Monoalkylaminosulfonyl, dialkylaminosulfonyl, monoarylaminosulfonyl, diarylaminosulfonyl, monoaralkylaminosulfonyl or diaralkylaminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,

xii. As alkoxy or alkylthio, the alkyl portion of each group may be optionally substituted,

xiii. Aryloxy, heteroaryloxy, aralkylthio, arylthio, or heteroarylthio, wherein the aryl moiety of each group may be optionally substituted,

xiv. As the alkylsulfonyl, the alkyl moiety may be optionally substituted,

xv. Aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl, the aryl portion of each group may be optionally substituted,

x vi. Alkenyl or alkynyl,

xⅶ. Optionally substituted aryl,

xⅷ. Optionally substituted alkyl,

xix. Optionally substituted aralkyl,

xx. An optionally substituted heterocycle, or

xxi. Optionally substituted cycloalkyl,

R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C _2-10 ) alkyl, dialkylamino (C _2-10 ) Amino, alkoxy, hydroxy or -CO ₂ R ^W , wherein R ^W is alkyl, cycloalkyl, phenyl, benzyl, Wherein R ^d and R ^e are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl or phenyl, and R ^f is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, or phenyl , R ^g is hydrogen, C _1-6 alkyl, C _2-6 alkenyl or phenyl, and R ^h is aralkyl or C _1-6 alkyl.

The present invention also relates to novel compounds of formula (I) wherein X, Y and R ¹ -R ⁶ are as defined above, provided that at least one of R ² or R ³ is a group consisting of the following groups (a) to Lt; / RTI >

(a) optionally substituted alkyl groups, preferably C ₁ -C ₆ alkyl, more preferably C ₁ -C ₃ ,

(b) alkoxy, aryloxy, alkylthio or arylthio, any of which is optionally substituted,

(c) optionally substituted C ₆ -C ₁₄ aryl, or optionally substituted aralkyl, except when R ¹ and R ² are both hydrogen or methyl and R ³ is not nitrophenyl or aminophenyl,

(d) optionally substituted heterocycle, and

(e) optionally substituted cycloalkyl.

When an alkyl-containing group, a heterocycle-containing group or an aryl-containing group in R ² or R ³ is optionally substituted, the optional substituent may be 1 to 4 non-hydrogen substituents (provided that the obtained compound is stable). The optional substituent form on the alkyl group may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, Alkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, thioacylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, , Monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxyl, Alkoxycarbonyl, alkoxycarbonyl, aryloxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxy Alkyl carbonyl, nitro, cyano, methyl, alkylthio and arylthio trifluoromethyl.

Preferred optional substituent forms on the alkyl group 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 _2-8 aminoacyl, C _1-6 alkoxy, C _6-14 aryloxy, carboxy, carboxy (C _1-6) alkyl, C _2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C _{1 -6} alkylthio, C _6-14 arylthio, C _1-6 alkylsulfonyl amino, C _7-15 aralkyl kilseol -5-, C _6-10 arylsulfonyl, amino, mono (C _1-6) alkyl, aminocarbonyl (C _1-6 ) alkylaminocarbonyloxy, mono (C _6-10 ) arylaminocarbonyloxy, di (C _6-10 ) arylaminocarbonyloxy, mono (C _7-15 ) Carbonyloxy, di (C _7-15 ) aralkylcarbonyloxy, C _1-6 alkoxycarbonylamino, C _7-15 aralkoxycarbonylamino, and C ₆ -C ₁₀ aryloxycarbonylamino.

Aryl-containing group, and in a preferred form of any substituent on the heterocycle-containing group are chloro, hydroxy, amino, mono (C _1-4) alkylamino, di (C _1-4) alkylamino, formylamino, C _2-6 (C _1-6 ) alkyl, carboxy, carboxy (C _1-6 ) alkyl, carbamoyl, C _1-6 alkoxycarbonyl, C _2-8 aminoacyl, C _3-7 cycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _6-14 aryloxy, , C _2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C _1-6 alkylthio, C _6-14 arylthio, C _6-14 aryl, substituted phenyl, tetrazolyl, thienyl 2 or 3 of hydroxy, C _1-4 alkyl, C _1-4 alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3 , C _1-6 alkylsulfonylamino, C _7-15 arylsulfonylamino, C _1-6 arylsulfonylamino, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl , mono (C _1-6) alkyl-amino-carbonyl-oxy, di (C _1-6) alkyl Diamino-carbonyl-oxy, mono- -C _6-10 arylamino carbonyl-oxy, di -C _6-10 aryl aminocarbonyl-oxy, mono - (C _7-15) aralkyl-carbonyl-oxy, di - (C _7-15 ) Aralkylcarbonyloxy, C _1-6 alkoxycarbonylamino, C ₇ -C ₁₅ aralkoxycarbonylamino, C ₆ -C ₁₀ aryloxycarbonylamino, C _2-6 thioacylamino, aminothiocarbo And C _2-8 aminothioacyl.

Preferred forms of R < ¹ > include hydrogen, amino, hydroxy and fluoro.

A preferred form of R < ² >

Wherein,

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

A preferred form of R ³ is C _1-4 alkyl (optionally substituted), halogen, amino, acylamino, C _1-6 alkylthio such as methylthio or ethylthio, C _1-6 alkoxy, And ethoxy), trifluoromethyl, methylsulfonyl and benzylthio.

A preferred form of X is a divalent sulfur (S).

A preferred form of Y is a covalent bond or -NH-, and a covalent bond is most preferred.

Preferred forms of R ⁴ , R ⁵ and R ⁶ in formula I are hydrogen, hydroxy, cyano, C _1-6 alkyl or C _1-6 alkoxy. Suitable forms of R ⁴ , R ⁵ and R ⁶ include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy and ethoxy. In a most preferred embodiment, R ⁴ , R ⁵ and R ⁶ are each hydrogen.

Preferred forms of R ⁴ , R ⁵ and R ⁶ in formula I include prodrugs such as -CO ₂ R ^W , wherein in each case R ^W is C _1-4 alkyl, C _4-7 cycloalkyl or benzyloxycarbo Nyl. ≪ / RTI > Suitable forms of R ⁴ , R ⁵ and R ⁶ include hydrogen, methyl, ethyl, propyl, n-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 a most preferred embodiment, R ⁴ , R ⁵ and R ⁶ are each hydrogen.

R ⁴ , R ⁵ and R ⁶ are preferably -CO ₂ R ^W groups, and R ^W is (Wherein R &^lt; ^{d >} -R ^{< h} > is as defined above). When R ⁴ , R ⁵ and R ⁶ are -CO ₂ R ^W (wherein R ^W is one of the above formulas), the resulting compound is a prodrug with desirable formulation and bioavailability properties. Preferred forms of each of R ^d , R ^e and R ^g are hydrogen, R ^f is methyl, and preferred forms of R ^h are benzyl and tert-butyl.

Preferred forms of R ⁷ include hydrogen, C _1-6 alkyl, C _6-10 aryl (C _1-4 ) alkyl and C _2-6 hydroxyalkyl. Suitable forms are hydrogen, methyl, ethyl and benzyl.

The term " alkyl " as used herein by itself or as part of another group refers to both straight and branched chain radicals having up to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, Butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.

The term " alkenyl ", as used herein, refers to straight or branched chain radicals having 2-20 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and the like, but are not limited thereto when the length of the chain is not limited thereto. Preferably, the length of the alkenyl chain is 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, and most preferably 2 to 4 carbon atoms.

As used herein, the term " alkynyl " means a straight or branched chain radical having 2-20 carbon atoms wherein there is at least one triple bond between the two carbon atoms in the chain, and acetylene, 1- Propylene, 2-propylene, and the like, but are not limited thereto when the length of the chain is not limited thereto. Preferably, the length of the alkenyl chain is 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, and most preferably 2 to 4 carbon atoms.

In all cases in this specification where alkenyl or alkynyl moieties are present as substituents, it is preferred that the unsaturated bonds, i.e., the vinylene or acetylene linkages, are not bonded directly to the nitrogen, oxygen or sulfur moiety.

The term " alkylthio " as used herein by itself or as part of another group refers to straight or branched chain radicals having 1 to 20 carbon atoms attached to a sulfur atom, such as methylthio, ethylthio, n- Propylthio, isopropylthio and the like, but is not limited thereto when the chain length is not limited thereto. The length of the alkylthio chain is preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms.

The term " alkoxy " as used herein by itself or as part of another group refers to straight or branched chain radicals having 1 to 20 carbon atoms attached to an oxygen atom, including methoxy, ethoxy, n-propyloxy, Foxy, iso-proxy and the like, but is not limited thereto when the chain length is not limited thereto. The length of the alkoxy chain is preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms.

The term " cycloalkyl " as used herein by itself or as part of another group refers to a cycloalkyl group having from 3 to 9 carbon atoms. Typical examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.

The term "halogen" or "halo" as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred.

The term "acyl" as used herein by itself or as part of another group refers to the group -C (O) R ^g wherein R ^g is alkyl, alkenyl, alkynyl, aryl, aralkyl, Heteroaryl, heteroarylalkyl, or heteroarylalkenyl. Preferred acyl groups include alkanoyl, aralkanoyl and aroyl groups [-C (O) R ^g where R ^g is C _1-8 alkyl, C _6-10 aryl (C _1-4 ) alkyl or C _6-10 aryl] to be.

The term "thioacyl" as used herein by itself or as part of another group refers to -C (S) R ^g , wherein R ^g is alkyl, alkenyl, alkynyl, aryl, aralkyl, , Heteroaryl, heteroarylalkyl or heteroarylalkenyl, preferably C _1-8 alkyl.

The term " thiocarbonyl " as used herein by itself or as part of another group refers to the group -C (S) -.

The term " monoalkylamine " as used herein by itself or as part of another group refers to an amino group substituted with one alkyl group having one to six carbon atoms.

The term " dialkylamine " used herein by itself or as part of another group refers to an amino group substituted with two alkyl groups, wherein the number of carbon atoms in each alkyl group is from one to six.

The term " aryl " as used herein by itself or as part of another group refers to a monocyclic or bicyclic ring having 6 to 14 carbon atoms in the ring part, preferably 6 to 10 carbon atoms in the ring part Refers to a cyclic aromatic group, for example, phenyl, naphthyl or tetrahydronaphthyl.

The term "aralkyl" or "arylalkyl" as used herein by itself or as part of another group refers to the aforementioned C _1-6 alkyl group having an aryl substituent, for example, benzyl, phenylethyl or 2 - naphthylmethyl.

The term "heterocyclic", "heterocyclo" or "heterocycle" as used herein by itself or as part of another group refers to a saturated or fully or partially unsaturated 3-7 membered monocyclic ring system, Or 7-10 membered bicyclic ring system consisting of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N and S, said nitrogen and sulfur heteroatoms being optionally substituted with Nitrogen can optionally be quaternized and any ring of heterocyclic rings as defined above includes any bicyclic group fused to the benzene ring and when the resulting compound is stable the heterocyclic ring The ring may be substituted on carbon or nitrogen atoms. A ring comprising one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur in combination with one or two nitrogen atoms is particularly useful. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl Pyrimidinyl, pyridazinyl, oxazolyl, oxazolyl, imidazolyl, imidazolyl, imidazolinyl, pyridyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, Thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl , Benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide Thiomorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

The term "heteroatom" as used herein refers to an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It is to be appreciated that when the heteroatom is nitrogen, it may form an NR ^y R ^z moiety wherein R ^y and R ^z are independently of each other hydrogen or C ₁ to C ₈ alkyl, or saturated with a nitrogen atom to which they are attached Or an unsaturated 5-membered, 6-membered or 7-membered ring.

The term " heteroaryl ", as used herein, refers to an alkyl group having from 5 to 14 ring atoms, 6, 10 or 14 pi electrons shared in the ring arrangement, and 1, 2 or 3 oxygen, (Examples of heteroaryl groups include thienyl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl , Benzoxazolyl, clomenyl, xanthanyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, Isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, , 4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothia Carbonyl, isoxazolyl, furanyl and janil page noksa possess groups).

The term " prodrug " refers to a derivative of a known direct acting agent, which has enhanced delivery and therapeutic effects as compared to the agent, and is converted to the active agent by an enzymatic or chemical process. Useful prodrugs are those wherein R ⁴ , R ⁵ and / or R ⁶ is -CO ₂ R ^w (R ^w is as defined above). U.S. Patent No. 5,466,811 and Saulnier et al . , Bioorg. Med. Chem. Lett. , 4: 1985-1990 (1994).

As used herein, the term " substituted " means that one or more hydrogens of a designated moiety are replaced with a selected one of the above-exemplified groups, provided that they do not exceed the normal atomic valence of the atom and are stable as a result of substitution. When the substituent is keto (i. E. = O), the two hydrogens attached to the atom of the moiety are substituted.

As used herein, " stable compound " or " stable formula " means a compound that is sufficiently strong to survive in the course of separating an effective therapeutic agent to a useful degree of purity from a reaction mixture or formulation.

A first group of preferred compounds within the scope of the present invention includes compounds of formula I wherein X is sulfur or oxygen, Y is a covalent bond or -NH- and R ¹ is hydrogen, amino, hydroxy or halogen R ⁴ , R ⁵ and R ⁶ are independently hydrogen, C _1-4 alkyl, amino, cyano, C _1-4 alkoxy or hydroxy, preferably all are hydrogen and R ² or R ³ One of which is hydrogen, C _1-6 alkyl (optionally substituted by hydroxy, amino, carboxy or aminocarbonyl), C _1-6 alkylthio or C _1-6 alkoxy and the remaining one of R ² or R ³ is amino Optionally substituted benzothienyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, optionally substituted furanyl, Substituted pyrazolyl or optionally substituted pyridyl.

Specific compounds within the scope of the present invention include the following compounds described in the Examples and their pharmaceutically acceptable salts (e.g., hydrochloride, bromate and acetate salts thereof), or prodrugs thereof:

4- [4- (4-chlorophenyl) thiazol-2-yl] -5-methylthiothiophene-

4-phenyl-5-methylthiothiophene-2-carboxymidine,

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

4- (4-methylthiazol-2-yl) -5-methylthiothiophene-

Methyl 4- [4- (4-phenylphenyl) thiazol-2-yl] -5-methylthiothiophene-

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

4- [4- (3-hydroxyphenyl) thiazol-2-yl] -5-methylthiothiophene-

4- (4-phenylthiazol-2-yl) -5-methylthiothiophene-2-carboxidine,

4- [4- (4-nitrophenyl) thiazol-2-yl] -5-methylthiothiophene-

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

4- [4- (3,4-propylene dioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-

4- [4- (4- (naphth-2-yl) thiazol-2-yl] -5- methylthiothiophene-

4-isopropylsulfonyl-5-methylthiothiophene-2-carboxymidine,

4-phenyl-5-methylthiothiophene-2-carboxymidine,

4- [4- (4-chlorophenyl) thiazol-2-yl] -5-methylthiothiophene-

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

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

4- (2-naphthylthiazol-2-yl) -5-methylthiothiophene-2-

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

4- (5-methyl-4-phenylthiazol-2-yl) -5-methylthiothiophene-

4- [4- (4-chloro-3-nitrophenyl) thiazol-2-yl] -5- methylthiothiophene-

4- (5-phenyloxazol-2-yl) -5-methylthiothiophene-2-

5-methylthiophene-2-carboxamide, 4- [4- (3-fluoro-5-trifluoromethylphenyl)

Methyl-thiazol-2-yl] -5-methylthiothiophene-2-carboximidine, 4- [

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

4- [4- (3-bromophenyl) thiazol-2-yl] -5-methylthiothiophene-

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

4- [4- (4-methylphenyl) thiazol-2-yl] -5-methylthiothiophene-

4-f4- (3,5-bis (trifluoromethyl) phenyl) thiazol-2-yl] -5- methylthiothiophene-

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

4- (4-phenylimidazol-2-yl) -5-methylthiothiophene-2-carboxidine,

4- [4- (2,4-dimethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-

4- (4-benzylthiazol-2-yl) -5-methylthiothiophene-2-

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

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

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

4- [4- (2-methylphenyl) thiazol-2-yl] -5-methylthiothiophene-

4- [4- (2,5-dimethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-

4- (4,5-diphenylthiazol-2-yl) -5-methylthiothiophene-2-carboxidine,

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

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

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

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

4- [4- (4-chlorophenyl) thiazol-2-yl] -5-methylthiothiophene-

4- [4- (2-hydroxyphenyl) thiazol-2-yl] -5-methylthiothiophene-

4- [4- (3-Trifluoromethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene-

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

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

4- [2- (2-chlorophenylamino) thiazol-4-yl] -5-methylthiothiophene-

4- [2- (3-methoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene-

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

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

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

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

4- [2- (4-dimethylaminophenylamino) thiazol-4-yl] -5-methylthiothiophene-

4- [2- (4-methoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene-

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

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

4- [2- (2-fluorophenylamino) thiazol-4-yl] -5-methylthiothiophene-

4- [2- (2,4,5-trimethylphenyl) aminothiazol-4-yl] -5-methylthiothiophene-

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

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

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

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

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

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

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

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

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

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

4- (4-phenyloxazol-2-yl) -5-methylthiothiophene-2-

4- [2- (diphenylmethyl) aminothiazol-4-yl] -5-methylthiothiophene-2- carboximidine, and

4- [2- (3-phenylpropyl) aminothiazol-4-yl] -5-methylthiothiophene-2-carboximidine.

And the second group of compounds is preferred comprises a compound of the formula (I), wherein X is sulfur or oxygen within the scope of the invention, Y is a covalent bond or -NH-, Z is NR ⁵ R ⁶ a, R ¹ is hydrogen, amino, hydroxy or halogen, and R ⁴ , R ⁵ and R ⁶ are independently hydrogen, C _1-4 alkyl, amino, C _1-4 alkoxy or hydroxy, , One of R ² or R ³ is hydrogen, C _1-6 alkylthio, C _1-6 alkyl (optionally substituted with OH, NH ₂ , COOH or aminocarbonyl), or C _1-6 alkoxy, and R ² Or the remaining one of R < ³ >

(II)

Wherein,

Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl, Wherein R is selected from the group consisting of pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, (Preferably phenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl , Pyrrolyl, oxazolinyl and benzothienyl), any of which may contain an outward ring O (keto) or = NR ^v (imino) group (R ^v is alkyl, aryl, aral Keto, alkylamino, arylimino or aralkylimino).

R⁸And R⁹Is hydrogen, halogen, amino, mono (C_1-4) Alkylamino, di (C_1-4) Alkylamino, arylamino, mono- (C_6-14) Arylamino, di- (C_6-14) Arylamino, mono- (C_6-14) Arr (C_1-6) Alkylamino, di- (C_6-14) Arr (C_1-6) Alkylamino, formylamino, C_2-6Acylamino, aminocarbonyl, C_2-8Aminoacyl, C_2-6Thioacylamino, aminothiocarbonyl, C_2-8Aminothioacyl, C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkoxy, carboxy, carboxy (C_1-6) Alkyl, C_2-8Wherein the substituents are selected from the group consisting of halogen, cyano, nitro, cyano, trifluoromethyl, thiazolyl, thiazolidinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, (Thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, Oxazolinyl-2-onyl, imidazolin-2-onyl, C_6-14Aryloxy, C_1-6Alkylthio, C_6-14Arylthio, C_6-14Aryl or C_6-14Arr (C_1-6) Alkyl, and C < RTI ID = 0.0 >_6-14Aryloxy, mono-C_6-14Arylamino, di-C_6-14Arylamino, mono-C_6-14Arr (C_1-6) Alkylamino, di-C_6-14Arr (C_1-6) Alkylamino, C_6-14Arylthio, C_6-14 Arr (C_1-6) Alkyl, and C_6-14The above-mentioned heteroaryl and aryl moieties of aryl may optionally be further substituted, preferably halogen, hydroxy, amino, mono (C_1-4) Alkylamino, di (C_1-4) Alkylamino, formylamino, C_1-4Acylamino, C_1-4Aminoacyl, mono- (C_1-4) Alkylaminocarbonyl, di- (C_1-4) Alkylaminocarbonyl, thiocarbonylamino, C_1-4Thioacylamino, aminothiocarbonyl, C_1-4Alkoxy, C_6-10Aryloxy, aminocarbonyloxy, mono- (C_1-4) Alkylaminocarbonyloxy, di- (C_1-4) Alkylaminocarbonyloxy, mono- (C_6-10) Arylaminocarbonyloxy, di- (C_6-10) Arylaminocarbonyloxy, mono- (C_7-15) Aralkylaminocarbonyloxy, di- (C_7-15) Aralkylaminocarbonyloxy, C_1-4Alkylsulfonyl, C_6-10Arylsulfonyl, (C_7-15) Aralkylsulfonyl, C_1-4Alkylsulfonylamino, C_6-10Arylsulfonylamino, (C_7-15) Aralkylsulfonyl, mono-alkylaminosulfonyl, mono-arylaminosulfonyl, di-arylaminosulfonyl, mono-aralkylaminosulfonyl, di-aralkyl Aminosulfonyl, C_1-4Alkoxycarbonylamino, C_7-15Aralkoxycarbonylamino, C_6-10Aryloxycarbonylamino, mono- (C_1-4) Alkylaminothiocarbonyl, di- (C_1-4) Alkylaminothiocarbonyl, C_7-15Aralkoxy, carboxy, carboxy (C_1-4) Alkyl, C_1-4Alkoxycarbonyl, C_1-4Alkoxycarbonylalkyl, carboxy (C_1-4) Alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C_1-4Alkylthio and C_6-102, or 3 of arylthio, or may be optionally further substituted by 3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy .

R ⁸ and R ⁹ in the preferred form is a halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, trifluoromethyl, C _6-10 aryl (chloro, halogen, C _1-6 alkyl, C Optionally further substituted with one or two of _1-6 alkoxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy or amino (Biphenyl), C _1-6 aminoalkyl, carboxy, C _1-6 alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4- (Optionally substituted with one or two of chloro, amino, methyl, methoxy, or hydroxy), optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, C _1-6 alkanoylamino, C _6-14 aroylamino, C _1-6 hydroxyalkyl, And tetrazolyl. More preferably, R < ² > is thienyl, oxazolyl or thiazolyl optionally substituted with any of the foregoing 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, Phenyl, 3- (2,4-dimethylthien-5-yl) phenyl, 3-hydroxyphenyl, 5- (carboxymethyl) Propylenedioxyphenyl, naphth-2-yl, 3-phenyl-4- (tetrazol-5-yl) phenyl, 2,4-dichlorophenyl, 3-methylphenyl, 4-chloro-3-nitrophenyl, 3-chlorophenyl, 3-phenylphenyl, phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl, 5-trifluoromethylphenyl, 3,5-bis (trifluoromethyl), 3-fluoro-5-trifluoromethylphenyl, 3-bromophenol, 3,4- Methylphenyl, 3-methylphenyl, 3,5-bis (trifluoromethyl) phenyl, 2-methoxyphenyl, 6-phenyl-2-pyridyl, 2,4-dimethoxyphenyl, Phenyl, benzyl, 3 , 4-dichlorophenyl, 3-methylphenyl, 3,5-dimethoxyphenyl, 2-methylphenyl, 2,5-dimethoxyphenyl, 2-chloro-3-pyridyl, phenoxymethyl, cyclohexyl, Phenyl, 3-trifluoromethoxyphenyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 2- chlorophenylamino, 3- methoxyphenylamino, 4-methoxyphenylamino, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-methoxyphenylamino, 2-methylphenylamino, 2-isopropylphenylamino, 4-benzyloxyphenylamino, 2-bromophenylamino, 2,5 4-methylphenylamino, 2,3-dichlorophenylamino, 3,4,5-trimethoxyphenylamino, 2-piperidinylethylamino, 4-methylphenylamino, 2- Thienyl, 2-5,6,7,8-tetrahydrono 3-phenylphenyl, phenylthiomethyl, 2-chloro-4, 5-dihydroxyphenyl, 2- (2-phenoxyacetic acid) 5-dimethoxyphenyl and isopropyl.

The third and preferred group of compounds, X is sulfur In the formula I,, Y is a covalent bond, Z is NR ⁵ R ^6, and R ¹ is hydrogen, R ³ is methylthio or methyl, R ^4, R ⁵ and R ⁶ are both hydrogen, R ² is of the formula II [formula, Ar is phenyl, thiazolyl, oxazolyl, benzothienyl, and pyridyl or imidazolyl, R ⁸ and R ⁹ are independently hydrogen or , Or a group selected from 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, Alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl, acylsulfonylaminophenyl, aralkylsulfonylaminophenyl, heteroarylsulfonylaminophenyl (the heteroaryl moiety is optionally substituted with one or more substituents selected from the group consisting of being halo or C _1-6 alkyl-substituted), chlorophenyl, dichlorophenyl, aminophenyl, Optionally substituted by one, two or three of the following: methyl, ethyl, propyl, isopropyl, n-butyl, _Lt; RTI ID = 0.0 > C _6-10 < / RTI > aryl or heterocycle.

A fourth and preferred group of compounds, X is sulfur In the formula I, Y is a direct covalent bond, Z is NR ⁵ R ⁶ and, R ¹ is hydrogen, R ² is alkyl, ar (alkyl), alkylsulfonyl, -SO ₂ -alkyl, amido, amidino, or a group of the formula (Wherein, Ar is phenyl, thiazolyl, oxazolyl, an aromatic or heteroaromatic group already is selected from the group consisting of pyrazolyl and pyridyl, R ⁸ and R ⁹ is hydrogen, carboxy, phenyl, naphthyl, alkyl, Alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, heteroaryl, heteroaryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, A substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, Each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, amino, acetyl, hydroxy , Dialkylamino, Optionally substituted with one or more groups selected from alkyl, alkoxy, dialkylamino, acylamino, 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,

R ⁴ , R ⁵ and R ⁶ are hydrogen.

Preferred compounds of the above embodiments are those wherein Ar is thiazolyl, preferably thiazol-2-yl or thiazol-4-yl, phenyl substituted with at least one of R ⁸ and R ⁹ , most preferably thiazole 2-yl group. Also preferred are compounds wherein R ² is a 4-phenylthiazol-2-yl group (the phenyl is optionally substituted) and R ³ is methylthio.

A fifth group of preferred compounds is a compound of formula III, or a pharmaceutically acceptable salt or prodrug thereof:

Wherein,

A is methylthio or methyl,

G 'is -O-, -S-, -NH- or a covalent bond,

n is an integer of 1-10, preferably 1-6,

m is an integer 0-1,

R 'and R "are independently selected from hydrogen, alkyl, aryl or aralkyl, or R' and R" together with the N atom to which they are attached form a 3-8 membered heterocyclic ring (O, optionally further comprising a box) of the further N atom in the case of the formation, and wherein the 3-8 membered heterocyclic ring further comprises a N atom is hydrogen, C _1-4 alkyl, C _6-10 aryl, C _{6 -O-} aryl (C _1-4 ) alkyl, acyl, alkoxycarbonyl or benzyloxycarbonyl.

The most preferred compounds of formula (III) are those wherein R 'and R " together with the atoms to which they are attached form a ring selected from piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl, Amino, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, mono-alkylaminocarbonyl, di- alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, Mono-arylaminocarbonyloxy, mono-aralkylaminocarbonyloxy, di-alkylaminocarbonyloxy, mono-arylaminocarbonyloxy, di-arylaminocarbonyloxy, mono-aralkylaminocarbonyloxy, di Alkoxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, aryloxycarbonylamino, Alkoxy carbonyl, alkoxy carbonyl, nitro, cyano, trifluoromethyl, alkylthio, and alkylthio, each of which may be optionally substituted with one or more substituents selected from the group consisting of: Each of which is optionally substituted with one to four non-hydrogen substituents selected from arylthio, each of which has the preferred form described above in Formulas I and II.

Examples of preferred compounds of formula (III) include the following compounds, their pharmaceutically acceptable salts or prodrugs:

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- Copy Middin,

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

Methoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-car Copy Middin,

2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5- - carboxamidine,

Phenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophen-2 - carboxamidine,

The compound described in Example 151,

2- (4-benzylpiperazinyl) ethoxy} phenyl) (1,3-thiazol-2-yl)] thiophen- - carboxamidine,

(D, L) -4- (4- {3- [2- (3-aminopyrrolidinyl) -2-oxoethoxy] phenyl} Methyl thiothiophene-2-carboxamidine,

5-methylthio-4- {4- [3- (2-oxo-2-piperidylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-

(D, L) -ethyl 1- (2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol- ) Piperidine-2-carboxylate,

Pyridinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxidine,

2- (4-benzylpiperidyl) ethoxy} phenyl) (1,3-thiazol-2-yl)] thiophen- - carboxamidine,

(D, L) -4- (4- {3- [2- (3-methylpiperidyl) -2-oxoethoxy] phenyl} Methyl thiothiophene-2-carboxamidine,

Phenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophen-2 - carboxamidine,

Phenyl] (1,3-thiazol-2-yl)) - (4- (4- {4- [2- 5-methylthiothiophene-2-carboxymidine,

(D, L) -ethyl 1- (2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol- ) Piperidine-3-carboxylate,

4- (3- (2-oxo-2- (1,2,3,4-tetrahydroquinolyl) ethoxy) phenyl] (1,3-thiazol- )} Thiophene-2-carboxamide,

Methyl-thiazol-4-yl] phenoxy} acetyl) piperidin-4 - carboxylate,

Phenyl) (1, 3-thiazol-2-yl)) - 5-methylpiperazin-1- Thiophene-2-carboxamidine,

D, L-4- (4- {3- [2- (2-ethylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol- Thiophene-2-carboxamidine,

2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methyl Thiophene-2-carboxamidine,

D, L- 4- [4- (3- {2- [3- (hydroxymethyl) piperidyl] -2-oxoethoxy} phenyl) 5-methylthiothiophene-2-carboxymidine,

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

Pyridinyl] -2-oxoethoxy} phenyl] (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxymidine,

Thiazol-4-yl] phenoxy} acetyl) piperidine-3-carboxylic acid ethyl ester was used in place of 1- (2- {3- [2- Carboxamidine, and

2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} -2- Si} acetic acid.

A sixth group of preferred compounds is a compound of formula IV, or a pharmaceutically acceptable salt or prodrug thereof:

Wherein,

A is methylthio or methyl,

R "'is 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, C _6-10 ahreu (C _1-6) alkyl, heterocyclyl (C _2-6) alkyl, C ₁ (for example, the monopole Reno alkyl, piperazinyl alkyl, etc.) _-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) an alkyl, aryl and the heterocyclic ring are halogen, hydroxy, amino, mono (C _1-6) alkylamino (C _1-6 ) alkylamino, formylamino, (C _1-6 ) acylamino, amino (C _1-6 ) acyl, mono- (C _1-6 ) alkylaminocarbonyl, di- _1-6 ) alkylaminocarbonyl, thiocarbonylamino, (C _1-6 ) thioacylamino, aminothiocarbonyl, (C _1-6 ) alkoxy, (C _6-10 ) aryloxy, aminocarbonyloxy , Mono- (C _1-6 ) alkylaminocarbonyloxy, di- (C _1-6) alkyl-amino-carbonyl-oxy, mono - (C _6-10) aryl-amino-carbonyl-oxy, di - (C _6-10) aryl-amino-carbonyl-oxy, mono - (C _6-10) aralkyl (C _{1 -6)} alkylamino-carbonyl-oxy, di - (C _6-10) aralkyl (C _1-6) alkyl, aminocarbonyl-oxy, (C _1-6) alkylsulfonyl, (C _1-6) arylsulfonyl, (C _6-10) aralkyl (C _1-6) alkylsulfonyl, (C _1-6) alkyl-sulfonylamino, C _6-10 aryl-sulfonylamino, (C _6-10) aralkyl (C _1-6) alkylsulfonyl amino, (C _1-6) alkoxycarbonyl, amino, (C _6-10) aralkyl (C _1-6) alkoxycarbonyl, amino, C _6-10 aryloxy carbonyl amino, mono - (C _{1- 6} ) alkylaminothiocarbonyl, di- (C _1-6 ) alkylaminothiocarbonyl, (C _6-10 ) aryl (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, and C _6-10 arylthio selected from Optionally further substituted by 1-4 non-hydrogen substituents There.

Examples of preferred compounds of formula (IV) include the following compounds, their pharmaceutically acceptable salts and their prodrugs:

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

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

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

Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxidine,

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

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

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

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

Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamide, 4- {2- [

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

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

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

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

Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboximidine, 4- {2- [

Amino] (1,3-thiazol-4-yl)} thiophene-2-carboximidine,

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

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

5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-

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

Amino} (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxidine,

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

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

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

(3-thiazol-4-yl)) thiophene-2-carboxamide,

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

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

5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophen-2 - carboxamidine,

Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboximidine, 4- {2 - [(7-bromo-

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

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

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

Methyl} phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxidine ,

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

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

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

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

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

4- (4-isoxazol-5-yl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboximidine.

A preferred group 7 compound is a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, wherein X is sulfur or oxygen, preferably sulfur, Y is a covalent bond or -NH-, and, Z is NR ⁵ and R ^6, R ¹ is hydrogen, amino, hydroxy or halogen, preferably hydrogen, R ^4, R ⁵ and R ⁶ are independently hydrogen, C _1-4 alkyl, amino, C _{1 to 4} alkoxy or hydroxy, preferably all are hydrogen, R ³ is (optionally substituted by OH, NH _2, COOH, or aminocarbonyl) hydrogen, C _1-6 alkylthio, C _1-6 alkyl Or C _1-6 alkoxy, preferably methylthio or methyl,

R ² is selected from the group consisting of alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di (aralkylsulfonyl) amino, di (aralkylsulfonyl) Sulfonyl) amino or di- (heteroarylsulfonyl) amino, any of said aryl or heteroaryl containing groups may be optionally substituted on the aromatic ring,

Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycloamino, diheterocycloamino, As monoalkyl monoheterocycloamino any of said aryl or heteroaryl containing groups may optionally be substituted on the aromatic ring and any of said heterocycle containing groups may optionally be ring-

Alkanoylamino, alkenoylamino, alkinoylamino, aroylamino, aralanoylamino, aralkanoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which may be optionally substituted on the aromatic ring Or,

Alkoxy and alkylthio, any of which is optionally substituted, or an aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkylenylsulfonyl, , ≪ / RTI >

Alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, any of the aryl-containing groups may be optionally substituted on the aromatic ring, or

(S) CNH-, or thioacylamino. ≪ / RTI >

Preferred 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 aryloxy, C _6-10 arylmethoxy, , The aryl group of the aryl containing substituent is selected from the group consisting of chloro, halogen, _C1-6alkyl , _C1-6alkoxy , phenyl, hydroxy, nitro, trifluoromethyl, carboxy, 3,4- Ethylenedioxy, 3,4-propylenedioxy, or amino), C _1-6 aminoalkyl, carboxy, alkyl, 3,4-methylenedioxy, Amino, mono- (C _1-6 ) alkylamino, di- (C _1-6 ) alkylamino, mono-C _6-10 arylamino, di-C _6-10 aryl Amino, C _1-6 alkylsulfonylamino, C _6-10 arylsulfonylamino, C _1-8 acylamino, C _1-8 alkoxycarbonyl, C _1-6 alkanoylamino, C _6-14 aroylamino , C _1-6 hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl ( Optionally substituted with one or two of chloro, amino, methyl, methoxy or hydroxy, and tetrazolyl.

In one aspect of this embodiment, R ² is preferably C _1-6 alkylsulfonylamino, C _6-10 aryl (C _1-6 ) alkylsulfonylamino, C _6-10 aryl (C _2-6 ) nilseol -5-alkenyl, C _6-10 aryl-sulfonylamino, heteroaryl sulfonyl amino, di (C _6-10 ahreu (C _1-6) alkylsulfonyl) amino, di (C _6-10 ahreu (C _{2- 6)} alkenyl nilseol sulfonyl) amino, di (C _6-10 arylsulfonyl) amino, or di- (heteroaryl-sulfonyl) as amino, any of the aryl or heteroaryl containing groups is optionally substituted on an aromatic ring .

Particularly preferred R ² groups in the above embodiments of the present invention include C _6-10 arylsulfonylamino, di- (C _6-10 arylsulfonyl) amino, C _6-10 aryl (C _1-3 ) alkylsulfonylamino , Di- (C _6-10 aryl (C _1-3 ) alkylsulfonyl) amino, thienylsulfonylamino, any of which is optionally substituted on the aromatic ring.

When R ² is a substituted sulfonylamino group, useful forms of R ² include bisphenylsulfonylamino, bis (biphenylsulfonyl) amino, naphth-2-sulfonylamino, di (Naphth-1-ylsulfonyl) amino, naphth-1-ylsulfonylamino, di (naphth- Amino, 2-methylphenylsulfonylamino, di- (2-methylphenylsulfonyl) amino, 3- methylphenylsulfonylamino, (4-methoxyphenylsulfonyl) amino, benzylsulfonylamino, 4-methoxyphenylsulfonylamino, di- (2-chlorophenylsulfonyl) amino, 3,4-dimethoxyphenylsulfonylamino, bis- (3,4-dimethoxyphenylsulfonyl) , 3-chlorophe (4-chlorophenylsulfonyl) amino, phenylsulfonylamino, di- (phenylsulfonyl) amino, di- 4-tert-butylphenylsulfonylamino, di- (4-tert-butylphenylsulfonyl) amino, 2-phenylethenylsulfonylamino and 4- (phenylsulfonyl) have.

In another aspect of the embodiments, R ² is amino, mono (C _1-6) alkylamino, di (C _1-6) alkylamino, mono (C _6-10) alkylamino, di (C _6-10 ) arylamino, mono (C _1-6) alkyl, mono (C _6-10) aryl, amino, mono-aralkyl (C _1-6) alkylamino, di (C _6-10) aralkyl (C _1-6) alkylamino, Mono (C _1-6 ) alkyl mono (C _6-10 ) aryl (C _1-6 ) alkylamino, monoheteroarylamino, diheteroarylamino, or mono (C _1-6 ) _{alkylmonoheteroarylamino} And any of the aryl or heteroaryl containing groups may be optionally substituted on the aromatic ring.

Particularly preferred R < ^{2 >} groups in the above embodiments of the invention include mono ( _C6-10 ) arylamino, mono ( _C1-6 ) alkylmono ( _C6-10 ) arylamino, mono ( _C6-10 ) C _1-3) alkylamino, mono (C _1-6) alkyl, mono (C _6-10) aralkyl (C _1-3) alkylamino, mono-heteroaryl-amino, mono (C _1-6) alkyl, mono-heteroaryl amino . Examples of suitable heteroarylamino groups include 1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino and quinolin-6-ylamino.

When R ² is a substituted amino group, useful forms of R ² include anilino, naphth-2-ylamino, naphth-1-ylamino, 4- (biphenyl) thiazol- (Phenyl) thiazol-2-ylamino, 4-phenyl-5-methylthiazol-2-ylamino, 4-hydroxy-4-trifluoromethylthiazol- Amino, pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3-fluoro- n-butylphenylamino, N-methyl-N- (2-methylphenyl) amino, 3-nitrophenylamino, 4- methoxyphenylamino, 3- methoxyphenylamino, 2- 4- (3-fluoro-4-methylphenyl) amino, 4- (indan-5-yl) Amino, benzylamino, indanylmethylamino, 2,3-dihydrobenzofur 3-phenoxyphenylamino, 4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4-benzyloxyphenylamino, (4-ethylphenyl) phenylamino, 4- (dimethylamino) phenylamino, 4-cyclohexylphenylamino, quinolin- , 4- (9-ethylcarbazol-3-yl) amino, 4- (t-butyl) phenylamino and 4-methylthiophenylamino.

In another aspect of this embodiment, R ² is preferably an acylamino group such as alkanoylamino, alkenoylamino, aroylamino, aralanoylamino, aralkanoylamino, heteroaroylamino, heteroarylalkanoylamino Any of which is optionally substituted on the aromatic ring.

In the embodiment, particularly preferred R ² groups of the present invention, (C _6-10) arylcarbonyl-amino, C _6-10 ahreu (C _1-3) alkyl-carbonyl-amino, C _6-10 ahreu (C _2-3 ) alkenyl-carbonyl-amino, C _6-10 aryloxy (C _1-3) alkyl-carbonyl-amino, C _3-8 cycloalkyl-carbonyl-amino, C _1-6 alkyl-carbonyl-amino, and heteroaryl-carbonyl-amino (e.g. , Furanylcarbonylamino and quinolinylcarbonylamino) ^.

When R ² is an acylamino group, a useful form of R ² is 3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3-nitro Ylcarbonylamino, tert-butylcarbonylamino, 5- (3,5-dichlorophenoxy) furan-2-ylcarbonylamino, naphth-1-ylcarbonylamino , Quinolin-2-ylcarbonylamino, 4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino and 3-methylphenylcarbonylamino.

In another aspect of the embodiments, R ² is a C _6-10 aryloxy, C _6-10 ahreu (C _1-6) alkoxy, C _6-10 arylsulfonyl, C _6-10 ahreu (C _1-6 ) Alkylsulfonyl or C _6-10 aryl (C _2-6 ) alkenylsulfonyl, any of which is optionally substituted on the aromatic ring. Particularly preferred R ² groups in the above embodiments of the present invention include C _6-10 aryloxy and C _6-10 arylsulfonyl.

When R ² is an aryloxy or arylsulfonyl group, useful forms of R ² include phenoxy, naphthyloxy, phenylsulfonyl and naphthylsulfonyl.

Representative compounds within the scope of the seventh embodiment of the invention are the following compounds, their pharmaceutically acceptable salts or prodrugs:

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

Methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboximidine,

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

5-methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboximidine,

4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxidine,

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-

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

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

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

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

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

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

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

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

Methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboximidine,

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

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

Methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxidine,

4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-

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

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

5-methylthio-4- [benzylamino] thiophene-2-carboxymidine,

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

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

Methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-

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

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

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

4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene-

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

4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxidine,

Methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-

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

4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxymidine,

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

5-methylthio-4- (naphthylcarbonylamino) -thiophene-2-carboxymidine,

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

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

4- [2- (2-hydroxy-5-methoxyphenyl) acetylamino] -5-methylthiothiophene-

4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine,

5-methylthio-4- (2-phenoxyacetylamino) -thiophene-2-carboxymidine,

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

Methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboximidine,

Methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboximidine,

Methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboximidine,

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

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

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

4- (methylphenylamino) -5-methylthiothiophene-2-carboxidine,

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

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

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

Methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-

Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-

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

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

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

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

Methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene-

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

Methylthio-4 - [(2-naphthylsulfonyl) -amino] thiophene-2-carboximidine,

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

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

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

Methylthio-4 - [(naphthylsulfonyl) -amino] thiophene-2-carboximidine,

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

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

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

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

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

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

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

Methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboximidine,

5-methylthio-4-phenoxythiophene-2-carboxymidine,

5-methylthio-4- (phenylsulfonyl) thiophene-2-carboximidine.

Uses and Pharmaceutical Compositions

For pharmaceutical applications, pharmaceutically acceptable acid addition salts are preferred where the anion does not contribute significantly to the toxicity or pharmacological activity of the organic cation. The acid addition salts can be obtained by reacting (preferably in solution) an organic base or an inorganic acid with an organic base of formula (I), or by any standard method as described in literature available to those skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like and useful inorganic acids include hydrohalogenic acids such as HCl, HBr, HI, Sulfuric acid, and phosphoric acid. Preferred acids for forming acid addition salts include HCl and acetic acid.

The compounds of the present invention represent a potent inhibitor of a new class of metals, acids, thiols and serine proteases. Examples of serine proteases that are inhibited by compounds within the scope of the present invention include leukocyte neutrophil elastase (a protease associated with the pathogenesis of emphysema); Chymotrypsin and trypsin (digestive enzymes); Pancreatic elastase, and cathepsin G (chymotrypsin-type proteases associated with leukocytes); Thrombin and factor Xa (proteolytic enzyme of blood coagulation pathway). It also relates to the use of the compounds of the present invention in the inhibition of sumolysin, metalloprotease and pepsin (acid protease). The compound of the present invention is preferably used for inhibiting tryptophan protease.

Compounds of the invention that inhibit the urokinase plasminogen activator are potentially useful in treating cellular and growth disease conditions. Thus, the compounds of the present invention that inhibit urokinase may be useful for the treatment and / or prophylaxis of atherosclerotic diseases such as anti-neovascularization, anti-arthritis, anti-inflammation, anti-invasion, anti- Retinopathy), contraceptives, and tumor treatments. For example, such therapeutic agents are useful for treating a variety of disease states including, but not limited to, benign prostatic hyperplasia, prostate cancer, tumor metastasis, recurrent stenosis and psoriasis. Also provided are methods of inhibiting extracellular proteolytic activity by administering a compound of formula I and methods of treating benign prostatic hyperplasia, prostate cancer, tumor metastasis, restenosis and psoriasis. In their end use, the efficacy and other biochemical parameters of the enzyme inhibiting properties of the compounds of this invention are readily ascertained by standard biochemical methods known in the art. The actual dosage range for such use will depend on the nature and severity of the disease state of the patient or animal to be treated as determined by the primary care physician. The general dosage range is expected to be from about 0.01 to about 50 mg, preferably from about 0.1 to about 20 mg, per kilogram of body weight per day for an effective therapeutic effect.

The end use of compounds that inhibit chymotrypsin and trypsin is to treat pancreatitis. In their end use, the efficacy and other biochemical parameters of the enzyme inhibiting properties of the compounds of this invention are readily ascertained by standard biochemical methods known in the art. Of course, the actual dosage range for such use will depend on the nature and severity of the disease state of the patient or animal being treated, as determined by the practitioner. The general dosage range is expected to be from about 0.01 to about 50 mg, preferably from about 0.1 to about 20 mg, per kilogram of body weight per day for an effective therapeutic effect.

Compounds of the invention that exhibit the ability to inhibit Factor Xa or thrombin can be used for a number of therapeutic purposes. The compounds of the present invention inhibit thrombin generation as a factor Xa or a thrombin inhibitor. These compounds are therefore useful for the treatment or prevention of conditions which are manifested by abnormal vein or arterial thrombosis associated with thrombin production or action. These conditions include severe venous thrombosis; Septicemia, viral infections and interstitial coagulopathy which occurs during the course of cancer progression; Myocardial infarction; seizure; Coronary artery bypass; Fibrin formation in the eye; Hip replacement; And thrombosis caused by thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA).

Due to the influence of Factor Xa and thrombin on the host of the cell type (e.g., smooth muscle cells, endothelial cells and neutrophils), the compounds of the present invention are useful in the treatment of adult respiratory distress syndrome; Inflammatory reaction; Wound healing; Reperfusion injury; Atherosclerosis; And in the treatment or prevention of post-traumatic restenosis, such as balloon angioplasty, angioplasty and arterial stent placement. The compounds of the present invention may be useful for the treatment of tumorigenesis, metastasis and neurodegenerative diseases (e. G., Alzheimer ' s disease and Parkinson ' s disease).

When used as a thrombin or Xa factor inhibitor, the compounds of the invention may be administered once a day in an effective amount within the dosage range of from about 0.1 to about 500 mg per kg body weight, preferably 0.1 to 30 mg per kg body weight, or 2 May be administered as a regimen of four divided doses.

Human leukocyte elastase is released from inflammatory sites by polymorphonuclear leukocytes, thus contributing to a number of disease states. The compounds of the present invention are expected to have anti-inflammatory efficacy which is useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases and in the treatment of emphysema. The leukocyte elastase inhibitory properties of the compounds of the present invention are measured by the method described below. Cathepsin G has also been implicated in the disease state of lung invasion caused by arthritis, gout, emphysema, glomerulonephritis, and infection of the lungs. In their end use, the enzyme inhibitory properties of the compounds of formula I are readily ascertained by standard biochemical methods known in the art.

The cathepsin G inhibitory properties of the compounds within the scope of the present invention are determined by the following method. Partially purified human cathepsin G is prepared by the method of Baugh et al., Biochemistry , 15: 836 (1979). Leukocyte granules are the primary source for the production of leukocyte elastase and cathepsin G (chymotrypsin-type active). Leukocytes are dissolved and granules are separated. The leukocyte granules were extracted with 0.20 M sodium acetate (pH 4.0) and the extracts were dialyzed overnight at 4 ° C against 0.05 M Tris buffer (pH 8.0, containing 0.05 M NaCl). The protein fraction is precipitated during the dialysis process and separated by centrifugation. This fraction contains the chymotripine-type activity of most leukocyte granules. Ala-Pro-Val-p-nitroanilide and Suc-Ala-Pro-Phe-p-nitroanilide are prepared for each enzyme. The latter is not hydrolyzed by white blood cell elastase. The enzyme preparation is analyzed in 2.00 mL of 0.10 M Hepes buffer (pH 7.5) containing 0.50 M NaCl, 10% dimethyl sulfoxide and substrate 0.0020 M Suc-Ala-Pro-Phe-p-nitroanilide. The hydrolysis reaction of the p-nitroanilide substrate is monitored at 25 캜, 405 nm.

The useful dosage range for use of the compounds of the present invention as neutrophil elastase inhibitors and cathepsin inhibitors depends on the nature and severity of the disease to be determined by the primary care physician and is in the range of 0.01 to 10 mg per kg of body weight per day, Useful for states.

A further use for the compounds of the present invention is the analysis of commercially available reagent enzymes for active site concentrations. For example, chymotrypsin is provided as a standard reagent for use in clinical quantification of chymotrypsin activity in pancreatic juice and pancreatic waste. These methods diagnose gastrointestinal and pancreatic disorders. Pancreatic elastase is also commercially available as a reagent for the quantification of alpha ₁ -antitrypsin in plasma. Plasma α ₁ - antitrypsin levels are increased during the course of several inflammatory diseases, and α ₁ - antitrypsin deficiency is associated with an increased incidence of lung disease. The accuracy and reproducibility of these assays by appropriate standardization of commercially available elastase supplied as reagents using the compounds of the present invention can be increased. See U.S. Patent No. 4,499,082.

The protease activity of certain protein extracts during the process of purifying a particular protein is a repetitive problem that can complicate the protein separation process and impair the results. Certain proteases present in such extracts can be inhibited during the purification step by compounds of the present invention that bind tightly to various proteases.

The pharmaceutical compositions of the present invention may be administered to any animal that is capable of experiencing the beneficial effects of the compounds of the present invention. Among these animals, the first object is human, but the present invention is not limited thereto.

The pharmaceutical compositions of the present invention may be administered by any means that achieves the desired purpose. For example, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, buccally, or by a guided route. Alternatively, or equivalently, it can be administered by the oral route. The dosage will depend on the age, health and weight of the recipient, the type of concurrent treatment, and in some cases, the frequency of treatment and the nature of the desired effect.

In addition to the pharmacologically active chemicals, the new pharmaceutical preparations may comprise a pharmaceutically acceptable carrier consisting of excipients and auxiliaries which facilitate the processing of the active compounds into preparations which can be used pharmaceutically.

The pharmaceutical preparations of the present invention are prepared in a manner known per se by means of conventional mixing, granulating, sugar-formulating, dissolving, and lyophilizing processes, for example. Thus, the pharmaceutical preparation for oral use can be obtained by adding a suitable adjuvant to obtain a tablet and sugar cores as necessary, and optionally grinding the mixture obtained by mixing the active compound with a solid excipient and processing the mixture of granules.

Suitable excipients are, in particular, fillers such as sugars (e.g. lactose or sucrose), mannitol or sorbitol, cellulose preparations and / or calcium phosphates (e.g. calcium phosphate or calcium hydrogen phosphate) Pastes, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone). If necessary, a disintegrant can be added, for example, the above-mentioned starch and / or carboxymethyl-starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (for example, sodium alginate). In particular, the adjuvant is a flow control agent and a lubricant (e.g., silica, talc, stearic acid or a salt thereof (e.g., magnesium stearate or calcium stearate) and / or polyethylene glycol. Dragee cores are provided with suitable coatings which are resistant to gastric juice, if necessary. For this purpose, concentrated sugar solutions may be used and may optionally comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To prepare gastric-resistant coatings, a solution of a suitable cellulose preparation (e.g., acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate) is used. Dyestuffs or pigments can be added to tablets or dragee coatings, for example for identification or to characterize a combination of administration of active compounds.

Other pharmacological agents that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers (e.g., glycerol or sorbitol). The push-fit capsules may contain the active compound in granular form, which may be mixed with a filler (e.g. lactose), a binder (e.g. starch) and / or a lubricant (e.g. talc or magnesium stearate) . In soft capsules, it is preferred that the active compound is dissolved or suspended in a suitable liquid (e. G., Fatty oil or liquid paraffin). In addition, stabilizers may be added.

Formulations suitable for parenteral administration include aqueous solutions of the active compound in water-soluble form (e. G., Water-soluble salts, alkali solutions and cyclodextrin insertion complexes). Particularly preferred salts are hydrochloride and acetate. One or more modified or unmodified cyclodextrins may be used to stabilize and increase the water solubility of the compounds of the present invention. Cyclodextrins useful for this purpose are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604 and 5,024,998.

In addition, a suspension of the active compound may be administered as a suitable oil infusion suspension. Suitable freeze-dried solvents or carriers include fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides or polyethylene glycol-400 (the compound is dissolved in PEG-400)). Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol and / or dextran. Optionally, the suspension may also contain a stabilizer.

Manufacturing method

Many synthetic methods used to prepare the compounds of the present invention typically involve the formation of amidines from carboxylic acid derivatives (e.g., esters or nitriles). In the above method, ammonia (e.g., ammonium chloride) in an aprotic solvent (e.g., toluene) at a temperature of -15 캜 to 5 캜, preferably 0 캜, in an inert atmosphere (such as an atmosphere of nitrogen or argon gas) To which an Lewis acid (e.g., trimethylaluminum) is added. A suitable carboxylic acid derivative is added to the mixture and refluxed for a predetermined time, preferably 1 hour to 24 hours, most preferably 1 hour to 4 hours. The resulting solution was cooled to room temperature and the amidine product was isolated by a known method.

Synthetic method explanation

The chemical equations are shown after the description of the reaction equations.

Scheme 1a

Scheme 1a illustrates a general preparation method for compounds of formula I wherein X = O or S, R ³ = alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy, Y = and a Z = NR ⁵ R ^6. When R ²¹ and R ²² of compound 2 and compound 3 persist in the final product, they correspond to R ² and R ³ , respectively, of formula (I). Otherwise, R < ²² > and R < ²¹ > represent groups which become R < ² > and R < ³ >

X is O or S and the heterocycle which is suitably substituted with two leaving groups is used as the starting material and these leaving groups are successively substituted by a suitable nucleophile (preferably an anion of the R ²¹ or R ²² group to be substituted is preferred) To produce a monosubstituted heterocycle or a disubstituted heterocycle. Examples of leaving groups include halogen (chlorine, bromine or iodine), sulfonate (methanesulfonate, toluene sulfonate or trifluoromethanesulfonate) or sulfone (methylsulfonyl). Preferred nucleophiles include anions of thiol or alcohol having an alkali or alkaline earth metal (e.g. sodium, lithium, potassium, magnesium or cesium) or optionally a transition metal (e.g. zinc, copper or nickel) have. In certain instances where the nucleophile used has an anion on the carbon, a displacement catalytic reaction may be useful in the reaction. Examples of catalysts include compounds containing palladium, silver or Ni salts.

Scheme 1b

Scheme 1b illustrates a method of providing a compound of formula I with a functional group of Y (CNR ⁴ ) Z wherein X = N, O or S, and R ²² and R ²¹ are as shown in Scheme Ia. Depending on the nature of the W group of compound 3, several methods can be used to transform W to Y (CNR ⁴ ) Z.

When W of the compound 3 is a cyano group (CN), a primary amide (CONH ₂ ) or an ester (CO ₂ R ²³ ), treatment with a reagent comprising a Lewis acid complexed with ammonia gives an unsubstituted amidine 5 with Y = bond, Z = NR ⁵ R ^6, and ^{R 4, R 5, R 6} = H in formula I) can be converted directly. Ammonia or an ammonium salt, preferably an ammonium halide, most preferably ammonium chloride or ammonium bromide, with a suitable Lewis acid, preferably trialkylaluminum, most preferably trimethylaluminum or triethylaluminum, Lt; / RTI > to produce the complex. For example, when trialkylaluminum Lewis acids and ammonium halides are used, one equivalent of alkane is lost during the reaction to produce dialkylhalo complexes of ammonia (e.g., Sidler, DR et al . , J. Org. Chem. , 59: 1231 (1994)). Examples of suitable solvents include unsaturated hydrocarbons (e.g., benzene, toluene, xylene, or mesitylene, preferably toluene) or halogenated hydrocarbons (e.g., dichloroethane, chlorobenzene or dichlorobenzene). The amidine-forming reaction is generally carried out at a high temperature, preferably 40 to 200 DEG C, more preferably 80 to 140 DEG C, most preferably 80 to 120 DEG C, which is the reflux temperature of the solvent.

When W is a cyano group (CN), it is treated with a reagent consisting of a Lewis acid, preferably trialkylaluminum complexed to a mono- or di-substituted amine H ₂ NR ⁵ or HNR ⁵ R ⁶ , to give a monosubstituted amidine or Can be converted directly to a disubstituted amidine 5 (R ⁴ , R ⁵ , R ⁶ = H) [Garigipati, R., Tetrahedron Lett. , ≪ / RTI > 31: 1969 (1990)). Alternatively, the same addition reaction of mono- or di-substituted amines can be catalyzed by a copper salt (e.g., copper (I) chloride) (Rousselet, G. et al . , Tetrahedron Lett. , ≪ / RTI > 34: 6395 (1993)).

When W of the compound 3 is a carboxyl group (CO ₂ H), an initial esterification reaction with an alcohol (R ²³ OH) by any one of a number of known dehydrating agents (for example, dicyclohexylcarbodiimide) Can be converted indirectly to unsubstituted amidine 5. More preferably, HCl and another acid (such as thionyl chloride, POCl ₃ , PCl ₃ , PCl ₃ , and N-dimethylformamide (DMF)) are reacted under conditions that do not contain the added catalyst ₅ , or, more preferably, oxalyl chloride) to form the acid chloride, followed by treatment with alcohol R < ²³ > OH to prepare compound 4. [ Can be converted to unsubstituted amidine 5 (R ⁴ , R ⁵ , R ⁶ = H) by treatment with a Lewis acid complexed with ammonia.

It is also possible to use strong acids (e.g., hydrogen halide, HBF _4, or the like) in the presence of an alcohol R ²³ OH (R ²³ = alkyl, branched chain alkyl or cycloalkyl, preferably Me or Et) (W = CN) may be converted to iminoether 6 by indirectly exposing the compound 3 (W = CN) to an amide 5 or other non-nucleophilic acid, preferably in gas phase HCl. Alternatively, when W = CONH ₂ , conversion to the iminoether can be effected by treatment with a trialkyloxonium salt (Mirwain salt). In any case, treatment of the iminoether ^{6 with} ammonia (R ⁵ _, R ⁶ = H), monosubstituted amine or disubstituted amine (HNR ⁵ R ⁶ ) gives the corresponding unsubstituted amidine or substituted amidine 5 (Ie, classic Pinner synthesis method: Pinner, A., Die Imino aether und ihre Derivate , Verlag R. Oppenheim, Berlin (1982)).

When W = NH ₂ in compound 3, treatment with reagent Z (CNR ⁴ ) L where Z = alkyl and L is a leaving group (e.g. O-alkyl, preferably OMe) Lt; / RTI > = H or alkyl) is obtained. Examples of reagents for this reaction include methyl or ethyl acetimidate hydrochloride. Alternatively, treating the compound 3 (W = NH ₂ ) with a trialkylorthoformate ester, preferably trimethyl- or triethylorthoformate, followed by treatment of the amine R ⁴ NH ₂ gives the corresponding porphyrin = H) (Y = NH, Z = H).

When W = NH ₂ , R ₄ = H and Z = NR ⁵ R ⁶ and L is a leaving group (eg, pyrazole, methylpyrazole, SO ₃ H, S-alkyl, S- Compound 3 is reacted with reagent Z (CNR ⁴ ) L, which is lonomethylsulfonate (OTf) or trifluoromethanesulfonamide (NHTf), preferably pyrazole, SO ₃ H or trifluoromethanesulfonamide (NHTf) Can be processed. Examples of these reagents include aminoiminosulfonic acids [Miller, AE and Bischoff, JJ, Synthesis , 777 (1986)] and 1H-pyrazole-1-carboxymidine hydrochloride [Bernatowicz, MS et al . , J. Org. Chem. , 57: 2497 (1992). The treatment directly provides guanidine 136 (Y = NH, Z = NR ⁵ R ⁶ ). Alternatively, the reagent Z (CNP ¹⁾ L (where, Z = NHP and ^2, L is a leaving group (for example, pyrazole, methylpyrazole, SO ₃ H, S- alkyl, S- aryl, trifluoromethane (P ¹ , P ² = alkoxycarbonyl, araloxycarbonyl, or similar to that shown in Scheme 4a below), using a suitable base (e.g., sulfonate (OTf) or trifluoromethanesulfonamide Alkoxycarbonyl bonded to the polymer), then the protecting groups P ¹ and P ² are removed to provide the unsubstituted compound 136 (R ⁴ , R ⁵ and R ⁶ = H). If the unprotected guanidine is unstable, the protected guanidine is advantageous when further modification is required after introduction of the guanidine functionality. Examples of these protecting reagents 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 -carbamidin or N, N'- bis (tert- butoxycarbonyl) Pyrazole-1-carboxidines [Bernatowicz, MS et al., Tetrahedron Letters , 34, 3389 (1993)], N, N'-bis (benzyloxycarbonyl) -N "-trifluoromethanesulfonylguanidine, and Such as N, N'-bis (tert-butoxycarbonyl) -N "-trifluoromethanesulfonylguanidine [Feichtinger, K. et al. , J. Org. Chem. , 63: 3804 Reagents 4a, 4b and 5 further illustrate details of the protecting groups and their amidine protecting uses.

When W is an ester (CO ₂ R ²³ ) or a carboxyl group (CO ₂ H) in compound ³ , the reaction of the compound of formula I with N-substituted or unsubstituted methylamidine (Y = CH ₂ , Z = NR ⁵ R ⁶ ) Indirect conversion can be carried out by an initial reduction reaction of the ester or carboxyl group with any of a number of known reducing agents. When W in the compound 3 is an ester (CO ₂ R ²³ ), examples of the reducing agent include a reducing agent such as lithium aluminum hydride (LAH) and lithium borohydride. When W in the compound 3 is a carboxyl group (CO ₂ H), examples of the reducing agent include LAH and borane complexed with THF, dimethylsulfide, dimethylamine or pyridine. The resulting hydroxymethyl derivative (W = CH ₂ OH) is prepared by reacting the leaving group L with a leaving group such as a halogen (chlorine, bromine or iodine) or a sulfonate ester (e.g. methanesulfonate, toluene sulfonate or trifluoromethanesulfonate) Is converted to a cyanomethyl derivative (W = CH ₂ CN) by the initial formation of a group (W = CH ₂ L). Subsequently, L is treated with a cyanide (for example, LiCN, NaCN, KCN or CuCN) in a polar solvent (such as DMF) using a catalyst such as a crown ether or without using a catalyst Cyanomethyl derivatives (see, for example, Mizuno, Y. et al., Synthesis , 1008, (1980)]. More preferably, an azodicarboxylate ester (e.g. diethyl azodicarboxylate or diisopropyl azodicarboxylate), Ph ₃ P and a source of cyanide (e.g. HCN, more preferably acetone W = CH ₂ OH can be converted to W = CH ₂ CN by a Mitsunobu reaction [Mitsunobu, O., Synthesis , 1 (1981)] using a method (Wilk, B., Synthetic Commun. , ≪ / RTI > 23: 2481 (1993)). Treatment of the cyanomethyl intermediate (W = CH ₂ CN) prepared under the conditions described for the conversion of compound 3 (W = CN) to compound 5 (direct or indirect conversion via compound 6) gave the corresponding amidinomethyl The product is obtained.

Scheme 1c

When not commercially available, alkylthiothiophene (compound 3, X = S, R ¹ = OH or NH ₂ , R ²¹ = SR ⁵⁴ , W = CN, CO ₂ R ²³ , CONH ₂ ) Can be synthesized. Compound 3 is obtained by condensing carbon disulfide and 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 [Dolman, H., Application 0 234 622 A1 (1987)]. When R ²² = R ⁵² = CN, R ¹ becomes NH ₂ , and when R ²² = R ⁵² = CO ₂ R ²³ , R ¹ becomes OH and R ²² = R ⁵² = CN, CO ₂ R ²³ , R ¹ may be 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 this modification include malonate diesters such as dimethyl malonate or diethyl malonate (R ⁵² , R ²² = CO ₂ R ²³ , R ²³ = Me or Et), malononitrile R ⁵² , R ²² = CN) or methyl or ethyl cyanoacetate (R ⁵² = CO ₂ R ²³ , R ²² = CN, R ²³ = Me or Et). Include sulfonates such as chloride, bromide or iodide, preferably halides such as bromide or iodide, or sulfonates such as toluene sulfonate, benzene sulfonate, methane sulfonate or trifluoromethane sulfonate. Examples of R ⁵⁴ L include primary or secondary alkyl, allyl or aralkyl halides or sulfonates (e.g., methyl iodide, isopropyl bromide, allyl bromide, benzyl chloride or methyltrifluoromethanesulfonate) Or 2-haloacetate esters such as tert-butyl 2-bromoacetate. Examples of alkylating agents WCH ₂ L include 2-chloroacetonitrile, methyl 2-bromoacetate or 2-bromoacetamide Suitable media are generally polar aprotic solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidinone Dimethylsulfoxide (DMSO), preferably DMF.

Alternatively, compound 3 (R ²² = CN) can be synthesized from precursor 138 (derived from malononitrile, R ⁵⁴ L and carbon disulfide), thioglycolate WCHSH and base in a suitable polar solvent, preferably methanol [Tominaga, Y. et al. , J. Heterocyclic Chem. , ≪ / RTI > 31: 771 (1994)).

When compound 3 contains an amino group in R ¹ , this compound can be treated with a nitrosating agent in a suitable solvent to diazotize, followed by loss of nitrogen to give compound 3 (R ¹ = H). Nitrogen extinguishing agents include nitrosonium tetrafluoroborate, nitrous acid, and more preferably alkyl nitrite esters (e.g., tert-butyl nitrite). Suitable solvents are DMF, benzene or toluene, which are stable solvents for nitrosating agents.

Scheme 1d

If not commercially available, the heterocyclic precursor 1 or 2 (X = O, S; W = CO ₂ R ²³ , COOH, L = halogen) used in Scheme 1a can be synthesized by the method shown in Scheme 1d. Depending on the conditions used, the reaction is carried out with a halogen element (Cl ₂ , Br ₂ or I ₂ , preferably Br ₂ ) or an N-halosuccinimide reagent, preferably N-bromosuccinimide (NBS) When the compound is treated, Compound 1 or 2 is directly obtained. A description of solvents or conditions suitable for selectively preparing Compound 1 or 2 can be found in Karminski-Zamola, G et al., Heterocycles , 38: 759 (1994); Divald, S. et al . , J. Org. Chem. , ≪ / RTI > 41: 2835 (1976); And Bury, P. et al., Tetrahedron , 50: 8793 (1994)).

Scheme 2a

Scheme 2a is R ² that shows the synthesis of formula II (Ar = 2- thio thiazolyl, Y = bond and Z = NR ⁵ R ⁶⁾ of compound 12 represents a compound of the subclass. Compound 7 can be obtained by first introducing R ²¹ using the compound 1 (L = Br) as a starting material and using a series of substitution methods discussed in Scheme Ia. Subsequently, a solution of the cyanide metal (e.g., copper (I) cyanide, sodium cyanide or lithium cyanide in a polar aprotic solvent, preferably DMF or DMSO, at a temperature of 80-200 ° C, preferably 100-140 ° C, Copper cyanide (I)) to obtain Compound 8. [ The esterification reaction may be carried out by any method described for converting compound 3 into compound 4, followed by any method known in the art [see, for example, Ren, W., et al. , J. Heterocyclic Chem. , 23: 1757 (1986) and Paventi, M. and Edward, JT, Can. J. Chem. , 65: 282 (1987)) to convert the nitrile to the thioamide. The preferred process is to treat the nitrile with hydrogen sulphide in the presence of a base (trialkylamine or heterocyclic amine, preferably triethylamine or pyridine) in a polar solvent such as acetone, methanol or DMF, preferably methanol . The conversion to the thiazole can be carried out by the amidine-forming reaction described in Scheme 1b, followed by the classic Hantzsch thiazole synthesis method.

Scheme 2b

Scheme 2b shows that in addition to the alternative route to Ar = 2-thiazolyl (20) (see compound 12 in Scheme 2a), Ar = 2-oxazolyl (16) or 2- imidazolyl (18) Z = NR < ⁵ > R < ⁶ >), wherein R < ² > represents a subclass of a compound of formula II. Gribble, GW et al . , Tetrahedron Lett. , 29: 6557 (1998)], compound 9 was used as starting material to selectively hydrolyze nitrile with tetrahalophthalic acid, preferably tetrafluorophthalic acid or tetrachlorophthalic acid, to obtain compound 7 have. Conversion to the oxalyl chloride chloride in dichloromethane, preferably in the presence of a catalytic amount of DMF, can be carried out using methods discussed for the conversion of compound 3 to compound 4. The acid chloride is reacted with an amino ketone (R) in the presence of an acid scavenger, preferably N, N-diisopropylethylamine (DIEA) or pyridine, in a suitable solvent (e.g. DMF, dichloromethane or tetrahydrofuran by coupling the _{^{26 COCH (R 27) NH 2}} ) it can be obtained usually in intermediate 14. Alternatively, with an alkylating agent R ²⁷ L in the presence of a less-substituted aminoketone of the acid chloride was coupled to _{^{(R 26 COCH 2 NH 2)}} , a base, preferably NaH or t-BuOK can be any Alkylation . Suzuki, M. et al. , Chem. Pharm. Bull. Imidazolyl (17) or 2-thiazolyl (19) ester in the manner of Scheme 1b, 34: 311 (1986) Can be carried out. It is also possible to convert keto amide 14 directly to imidazolyl derivative 18 under the same conditions as convert compound 17 to compound 18 when performed for a long period of time, preferably for 2 hours or more.

Scheme 2c

Scheme 2c describes the general synthetic route for oxazoles, imidazoles and thiazoles of structures 27, 29 and 31, respectively. The acid 2 (see Scheme 1a) is converted to an ester by methods known in the art [Theodora W. Green and Peter GM Wuts, John Wiley and Sons, Inc., 1991]. For example, the acid is treated with trimethylsilyldiazomethane in a suitable solvent (e.g., methanol) to form the methyl ester 21. Alternatively, the acid is treated with oxalyl chloride and a catalytic amount of dimethylformamide (DMF) in a suitable solvent (e.g., dichloromethane) to form the acid chloride, followed by treatment with methanol to obtain the methyl ester. (E.g., palladium tetrakistriphenylphosphine) and alkyltin (e.g., hexa-n-butyl 2-tin or chloride tri-naphthalene) catalysts in a suitable solvent (e.g., DMF) n-butyltin) to give the aryl tin of general structure 22 (Stille, JK, Angew. Chem. Int. Ed. Engl. , 25: 508-524 (1986)). Thereafter, tin 22 is treated with an acid chloride in the presence of a palladium (0) catalyst to obtain ketone 23. The ketone is treated with ammonia / ammonium chloride to give amine 24. Alternatively, the azidoketone obtained by reacting an azide (e.g., sodium azide) with a ketone in a suitable solvent (e.g., DMF) may be treated with a catalytic hydrogenation reaction in the presence of Pd / C and an acid Is reduced to the amine 23 using a suitable reducing agent [ Chem. Pharm. Bull. , 33: 509-514 (1985). The keto amines (24) are coupled with a variety of suitably functionalized acid chlorides to form keto amides 25. Alternatively, the amide coupling can be carried out using any of a number of peptide coupling reagents (e.g., 1,3-dicyclohexylcarbodiimide) [Sheehan, JC et al . , J. Am. Chem. Soc. , 77: 1067 (1955)] or Castro reagent [BOP, Castro, B. et al., Synthesis , 413 (1976)]. In another method, the amide 25 is prepared directly from the ketone 23 by reaction with various amide salts in a suitable solvent (e.g., DMF). The amide salt is prepared by treating the amide with a suitable base (e.g., sodium hydride (NaH)). For example, acetamide is treated with NaH in DMF at 0 < 0 > C to give sodium acetamide. Using a method analogous to that shown in Scheme 2b, the keto amide 25 is cyclized to oxazole 26, imidazole 28 and thiazole 30. Oxazole 26, imidazole 28 and thiazole 30 are treated with trimethylaluminum and ammonium chloride in refluxing toluene to give amidines 27, 29 and 31, respectively.

Scheme 2d

Scheme 2d describes a process for preparing a compound of Example 42-43 R ²¹ and R ⁴³ corresponds to R ^3, and R ² of formula I. A base (e.g., n-butyl lithium or sec-butyl lithium) and trimethyltin chloride are successively treated to convert the acid 2 to a tin compound. The acid prepared by the method known in the art [Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Chemistry , John Wiley and Sons, Inc., 1991] can then be converted to ester 22. For example, a methyl ester can be prepared by treating an acid 2 with trimethylsilyl diazomethane in a suitable solvent (e.g., methanol). The tin compound 22 can be reacted with a suitable halide in the presence of a catalytic amount of a palladium catalyst (e.g., palladium tetrakistriphenylphosphine) to provide ester 32 (Stille, JK, Angew. Chem. Int. Ed. Engl. , 25: 508-524 (1986)). These esters are then treated with trimethylaluminum and ammonium chloride in refluxing toluene to afford amidine 33. When R ⁴³ L _n (n = 2), it can be cross-coupled to an aryl, heteroaryl or vinyl boronic acid or ester to provide compound 34 (Miyaura, N. and Suzuki, A., Chem. Rev. , ≪ / RTI > 95: 2457-2483 (1995)). This can be performed predominantly in the presence of a catalytic amount of a palladium (0) catalyst (e.g., tetrakistriphenylphosphine palladium) and a base (potassium carbonate) in DMF at 90 < 0 > C. Similar cross-coupling reactions can also be achieved using aryl, heteroaryl and vinyl tin instead of boronic acid or ester. These esters are converted to amidine (35) in the manner described above.

Scheme 2e

Scheme 2e is Ar = 2-thiazolyl, 2-oxazolyl or 2-imidazolyl (Y = bond and Z = NR ⁵ R ⁶⁾ or, the substituents R ²⁶ and compounds on the relative positions of the R ²⁷ 16, 18 or 20 Lt; RTI ID = 0.0 > (II) < / RTI > This is shown in Scheme 2b for the synthesis of the 2-oxazolyl derivative 39. Thus, the acid 13 can be coupled to the hydroxy-containing amine R ²⁷ CH (NH ₂ ) CH (R ²⁶ ) OH by any of a number of amide coupling agents known in the art [see Bodanszky , M. and Bodanszky, A., The Practice of Peptide Synthesis , Springer-Verlag, New York (1984)]. More preferably, any of the methods mentioned for converting compound 3 to compound 4 can be used to convert compound 13 to the corresponding acid chloride, followed by reaction with a suitable base such as, for example, DMF, dichloromethane or tetrahydrofuran THF)) acid scavenger, preferably N, N- diisopropylethylamine (DIEA) or pyridine in the presence of _{^{R 27 CH (NH 2) CH}} (R 26) can be processed as a OH to obtain the compound 36 have. Oxidation of alcohol 36 with aldehyde 37 (R ²⁶ = H) or ketone 37 (R ²⁶ = alkyl, aryl, aralkyl, heterocycle) can be carried out by any of the many conventional methods known in the art, Preferably a mild Moffatt type oxidation reaction (see, for example, US Pat. No. 5,301,502, Carey, FA, Sundberg, RJ, Advanced Organic Chemistry, Part B: Reactions and Synthesis , 3rd edition, Plenum Press, New York , Swern oxidation) [Moncuso, AJ, Huang, SL and Swern, D., J. Org. Chem. , 3329 (1976)], more preferably the Dess-Martin reagent [Dess, DB and Martin, JC, J. Org. Chem. , ≪ / RTI > 48: 4155 (1983). The conversion to a heterocycle, in this case oxazole, is achieved with any of a number of reagents including phosphorus oxychloride, P ₂ O ₅ or thionyl chloride [Moriya, T., et al . , J. Med. Chem. , ≪ / RTI > 31: 1197 (1998) and references therein). Alternatively, termination of compound 37 with a Burgess reagent or using Mitsunobu conditions gives the corresponding oxazolidinyl derivatives [Wipf, P. and Miller, CP, Tetrahedron Lett. , ≪ / RTI > 3: 907 (1992)). The final amidination reaction to compound 39 as in Scheme 1b completes the synthesis.

Scheme 2f

Scheme 2f shows a general approach to thiazole synthesis of structure 43 (II, X = S, Ar = thiazolyl). The nitrile of structure 40 is treated with hydrogen sulfide (H ₂ S) in the presence of a base (e.g. triethylamine) in a suitable solvent such as methanol or pyridine to give the thioamide 41 [Ren, W et al ., J. Heterocyclic Chem . , 23: 1757-1763 (1986)). Thiazole 43 is then prepared by treating thioamide 41 with various haloketones 42, preferably bromo ketone, under suitable reaction conditions such as refluxing acetone or DMF heated to 50-80 < 0 > C [Hantzsch, Ber. , 20: 3118 (1887)].

Reaction formula 2g

Scheme 2g depicts one synthetic route to the 2-haloketone of structure 42 used in the synthesis of thiazolyl derivatives as in schemes 2a and 2f. Bromo ketone 42 (L = Br) is prepared by treating ketone 44 with a suitable brominating agent (e.g., Br ₂ or N-bromosuccinimide) in a suitable solvent such as chloroform or acetic acid (see EP 0393936 A1). Alternatively, the ketone 44 can be treated with a brominating agent (e.g., a poly (4-vinyl) pyridinium bromide resin [Sket, B. et al., Synthetic Communications , 19: 2481-2487 Ketone 42. In a similar manner, compound 44 is treated with copper (II) chloride in a suitable solvent such as chloroform to give 2-chloroketone (Kosower, EM et al. , J. Org. Chem. , 28: 630 (1963).

Scheme 2h

Scheme 2h illustrates another synthetic route to a 2-haloketone of structure 42 that is particularly useful in that it utilizes an acid 45 or an activated carbonyl compound (e.g., 46 compound) as a more readily available precursor than ketone 44 . Treatment with an appropriate halogenating agent converts the acid 45 to the acid chloride 46 (L = Cl, Br or OCOR ³⁹ ). For example, compound 45 is treated with oxalyl chloride and a catalytic amount of DMF in dichloromethane to produce the acid chloride. Trimethylsilyldiazomethane is used to convert the acid chloride to the diazo ketone (Aoyama, T. et al . , Tetrahedron Lett. , 21: 4461-4462 (1980)]. The diazo ketone thus prepared is converted to the 2-haloketone of structure 42 by treatment with an appropriate mineral acid. For example, a suitable solvent (such as acetonitrile (CH ₃ CN)) to prepare a bromo ketone by treating the diazo ketone in 30% hydrogen bromide (HBr) solution of acetic acid [Organic Synthesis Collective, Vol III, 119 , John Wiley and Sons, New York, Ed. Horning EC]. In an alternative process, the appropriate chloroformate in a suitable solvent (e.g., tetrahydrofuran or dichloromethane) in the presence of a base (e.g., N-methylmorpholine) (e.g., isobutyl chloroformate or tert- butyl chloroformate ) To convert the acid 45 into the mixed acid anhydride 46. The diazo ketone obtained by converting the mixed acid anhydride 46 into a diazo ketone by treatment with trimethylsilyl diazomethane is converted into a halo ketone by the above-described method.

Scheme 2i

When the amidation reaction immediately follows amide coupling as described in Scheme 2e, compounds of formula I wherein R < ^{2 >} or R < ³ > are aminoacyl or aminoiminomethyl can be derived. Thus, the coupling reaction of the acid 13 (or the corresponding acid chloride as described above) with the amine R < ⁵¹ > R < ⁵² > NH may provide compound 130, When the Lewis acid-ammonia reagent as described in Scheme 1b is subjected to a longer or more intense addition treatment (e. G., High temperature), 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 an amine 47 (R ² or R ³ = NR ³² SO ₂ R ³¹ , NHCONR ⁵¹ R ⁵² or NHCOR ³¹ ) in which sulfonamide, urea and urethane can be formed. Scheme 3a illustrates a method for introducing these three groups into R < ² > of formula (I). The carbamate ester of the alcohol can be prepared by converting the acid 13 to an intermediate acyl azide and then heating the azide in the presence of alcohol under the Curtius conditions. Subsequently, the carbamate ester is hydrolyzed to obtain the amine 47. Compound 3 (R ¹ = NH ₂ ) is reacted with compound 3 (R (NH ₂ )) in Scheme 1c, either by coupling acid 13 to the hydrazine via an acid chloride or by any of the amide coupling methods discussed in Scheme 2e, ¹ = H), the hydrazide thus prepared is nitrosated to synthesize the intermediate acyl azide. More preferably, the process for converting compound 13 to compound 47 is carried out in the presence of an alcohol, preferably tert-butanol, and a base, preferably triethylamine or DIEA, as shown in Scheme 3a, with diphenylphosphoryl azide Treatment of dorosic acid 13 affords tert-butyl carbamate which is readily cleaved by the salt of amine 47 upon exposure to 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, preferably K ₂ CO ₃ or NaHCO ₃ gives the free base 47. Treatment of amine 47 with sulfonyl chloride R ³¹ SO ₂ Cl in the presence of an acid scavenger (such as pyridine or DIEA) followed by treatment of the amine 47 with a base such as K ₂ (eg, THF, MeCN or CH ₂ Cl ₂ ) CO _3, as DIEA or more preferably, to obtain the sulfonyl amine functional group 48 to the R ² to carry out any alkylation on the nitrogen with an alkylating agent R ³² L in the presence of sodium hydride). If desired, such modifications may be catalyzed by the presence of 4-dimethylaminopyridine to the less reactive sulfonyl chloride. Similar treatment of the amine 47 with isocyanate R ⁵¹ NCO or carbamyl chloride R ⁵¹ R ⁵² COCl gives the aminocarbonylamine functionality (50) to R ² . Similar treatment of amine 47 with the acid chloride R < ³¹ > COCl gives the carbonyl amine functionality 52 to R < ^{2 &} gt ;. Conversion of the esters of compounds 48, 50 and 52 to amidine as described above gives the products 49, 51 and 53. Further conversion of the acylamino group of compound 53 as discussed in the synthesis of compound 132 provides an approach to the iminomethylamino group (54) for R < ² >.

Scheme 3b

The introduction of an aminosulfonyl group (including monoalkylaminosulfonyl and dialkylaminosulfonyl groups) to R ² of formula I can also be carried out using an amine such as compound 47 as a starting material. Methods such as geng Nagel (under the sulfonylation and alkylation conditions described in Scheme 3a) [U.S. Patent No. 3,947,512 No. (1976)] and then was converted to the chloride, sulfonyl amine treatment with R ³⁴ NH ₂ by a, R ³⁵ L To give compound 56, which is further converted to amidine 57 as described above.

Scheme 3c

In addition to the synthetic method outlined in Scheme 3a, amine 47 can also be prepared as shown in Scheme 3c. Nitrotienyl esters 122 having suitable leaving groups L (Dell'Erba, C. and Spinelli, D., Tetrahedron , 21: 1061 (1965), Dell'Erba, C et al. , J. Chem. Soc., Perkin Trans 2 , 1779 (1989)] can be substituted with an R ²¹ anion to provide intermediate 123. Subsequently, amine 47 is derived from the reduction reaction of the nitro group. Suitable reagents which result in the reduction of the nitro functionality are in the presence of a catalyst such as palladium or platinum metal deposited on carbon or barium sulphate in any solvent (e.g., methanol, ethanol, ethyl acetate, DMF or THF) Hydrogen gas. More preferably, the tin (II) chloride can be used as a reducing agent in a solvent such as DMF or THF, or in the presence of HCl in a solvent such as methanol or ethanol. Alternatively, metals such as zinc or iron [Stanetty, P. and Kremslehner, M., Heterocycles , 48: 259 (1998)] can also be used.

Scheme 4a

Scheme 4a shows the preparation of compounds of formula III, Examples 48-59 and Examples 61-77. The amidinyl moiety of the compound of structure 60 can be protected with a protecting group P < ¹ >, which protecting group can be protected using a method known to those skilled in the art [Theodora W. Greene and Peter GM Wuts, John Wiley and Sons, 62 and 64, respectively. For example, the tert-butoxycarbonyl (BOC) protecting group can be removed by exposure to a strongly acidic medium (e.g., hydrochloric acid) in a suitable solvent (e.g. dioxane) or by treatment with trifluoroacetic acid in a suitable solvent such as methylene chloride Can be removed. The benzyloxycarbonyl (Cbz) protecting group can be removed by catalytic hydrogenation using Pd / C as a catalyst in a solvent such as ethanol or tetrahydrofuran.

In some cases, P ¹ is a polystyrene or polyethylene glycol-grafted polystyrene that can be bonded to the amidine moiety through a detachable linking group (e.g., 4- (benzyloxy) benzyloxy-carbonyl (using a carbonate Wang resin) Can be the same solid support. A solid having a linking group containing a suitably activated functional group under suitable conditions can be treated with amidine to bind the amidine to the solid support. For example, amidine can be coupled to Wang resin by treating para-nitrophenyl carbonate with amidine and a suitable base (e.g., DBU) in a suitable solvent (e.g., DMF). When D is OH or SH, the carboxy-protected (protecting group is R ³⁶ ) haloaliphatic acid (in the presence of a suitable base such as cesium carbonate or DIEA) in a suitable solvent (E.g., bromoacetic acid or bromopropionic acid) can be alkylated to give the compound of structure 62. Alternatively, When D is NO ₂ , a suitable reducing agent (e.g., tin (II) chloride) is used in an appropriate solvent (e.g., DMF) prior to the alkylation reaction, or Pd / C is added to the catalyst in a solvent such as ethanol or tetrahydrofuran The nitro group can be reduced by a catalytic hydrogenation reaction. Other useful carboxy protecting groups are known in the art [Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Chemistry , John Wiley and Sons, Inc., 1991]. For example, the tert-butyl ester can be removed by exposure to a strong acidic medium such as hydrochloric acid in a suitable solvent such as dioxane, or trifluoroacetic acid in a suitable solvent such as methylene chloride. The benzyl ester can be removed by catalytic hydrogenation using Pd / C as a catalyst in a solvent such as ethanol or tetrahydrofuran or by base hydrolysis.

When the protecting groups P ¹ and R ³⁶ of the compound 62 are orthogonal (defined as the ability to remove a preferred protecting group from both protecting groups), R ³⁶ can be preferentially removed to give an acid 63. For example, if 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 that does not damage the BOC group (e.g., aqueous tetrahydrofuran). If the protecting groups P < ¹ > and R < ³⁶ > of the compound 62 are not orthogonal, both protecting groups are removed and the amidine can be protected with a suitable protecting group such as BOC or a suitably functionalized resin. Under suitable amide coupling conditions, for example, 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium The protected amidine 63 in the presence of hexafluorophosphate (HATU) and DIEA can be treated with various amines to produce amides of structure 64. Amidine 65 can then be obtained, for example, by treatment with an acid such as trifluoroacetic acid in an appropriate solvent such as methylene chloride (where a BOC protecting group is used) to remove the amidine protecting group.

Scheme 4b

Scheme 4b depicts a specific example using the method described in Scheme 4a. The amidine portion of compound 66 may be mono-protected with a tert-butyloxycarbonyl group. The single protected phenoxyamidine 67 can be alkylated on the hydroxy group in the phenol with an ester of 2-bromoacetic acid to give 68. [ When the ester can be removed with a base. Acid 69 can be obtained by hydrolysis with an aqueous base (e.g., NaOH). 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and The acid can be treated with various amines in the presence of DIEA to produce amides of structure 70. Amines are unsubstituted, mono- or di-substituted aliphatic or aromatic amines. In some cases, the amine is a cyclic amine such as piperazine and piperidine. The amine 70 is then treated with trifluoroacetic acid to afford amidine 71. When ester 68 is unstable in acid, it can be treated with triacetic acid to give amidino-acid 72. This amidine can be loaded onto an insoluble support such as polystyrene or polyethylene glycol grafted polystyrene via a detachable linking group (e.g., Wang) acting as an active carbonate (e.g., p-nitrophenyl carbonate or succinimidyl carbonate). Typically, this can be done by treating the active carbonate resin with amidine and a suitable base (e.g., DBU) in a suitable solvent such as DMF. The acid 73 bound to the support is reacted with 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexa Amides can be prepared by treatment with various amines in the presence of fluorophosphate (HATU) and DIEA. The amide is then separated from the solid support by treatment with trifluoroacetic acid to give the compound of structure 71.

Scheme 5

Scheme 5 depicts the synthetic route to disubstituted thiazole-containing amidine, wherein R ² is a compound of formula II and R ⁸ and R ⁹ are both non-hydrogen substituents. The ketoamide 74 can be converted to mono-bromo ketoamide by treatment with bromine in acetic acid. Thiazole 76 is prepared by reacting compound 10 with bromoketoamide by heating the mixture under suitable conditions, preferably in DMF or acetone. Compound 76 in toluene is heated with trimethylaluminum and ammonium chloride to produce amidine 77. Treatment of the amidine 77 with a strong acid (e. G. HCl) gives the acid 78. Amidine 78 is coupled via a first pathway protected with a suitable protecting group such as BOC to give compound 79. Under suitable coupling conditions, the protected amidines 79, for example in the presence of HOAt, HATU and DIEA, are treated with various amines to produce various amides. Subsequently, the amidine protecting group is removed by treatment with trifluoroacetic acid in a suitable solvent such as methylene chloride (when the BOC protecting group is used) to obtain amidine 80. [ In the second path, the amidine 78 is linked to an amphiphilic polymer such as polystyrene or polyethylene glycol-grafted polystyrene via a removable linking group (e.g., Wang resin) that acts as an active carbonate ester (e.g., p-nitrophenyl carbonate or succinimidyl carbonate) To obtain a skeleton 81 which is loaded on the support and bonded to the resin. Under suitable coupling conditions, for example, the acid 81 bonded to the resin in the presence of HOAT, HATU and DIEA can be treated with various amines to form an amide. Thereafter, the amide is separated from the solid support by treatment with trifluoroacetic acid to obtain amidine 80.

Scheme 6a

Scheme 6a depicts the preparation of compounds of Examples 144, 145, 146, 147, 148, 149, 150 and 151. The compounds of the present invention correspond to compounds of formula I wherein R ² is a formula II, Ar is a thiazole, and R ³⁷ and R ³⁸ (R ⁸ and R ^{9 in} formula II) are further substituted phenyl groups. After treatment with lithium diisopropylamide according to the method of Kano et al., Heterocycles, 20 (10): 2035 (1983), starting from 2,5-dibromothiophene 90, Is treated with R < ²¹ > L, preferably halogen, mesylate, tosylate or methylsulfate, more preferably iodomethane or methylsulfate, to obtain compound 91. Compound 91 is treated with an appropriate base, preferably alkyllithium such as n-butyllithium, sec-butyllithium, or t-butyllithium, more preferably n-butyllithium and then treated with carbon dioxide gas The carboxylate salt is converted to the free acid by mineral acid, preferably hydrochloric acid. Oxalyl chloride can be used to convert the intermediate acid chloride to the ester 21 by treatment with an alcohol R < ²³ > in a suitable solvent, preferably dichloromethane, containing a suitable base, preferably pyridine. Compound 21 can be treated with copper (I) cyanide in refluxing dimethylformamide 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. Preferably at reflux in an appropriate solvent, preferably acetone, dimethylformamide, dimethylacetamide, methyl ethyl ketone or other polar protic solvent, most preferably acetone, while L is a leaving group, preferably a halogen, mesyl or tosyl, Compound 10 can be treated with a suitable ketone such as bromo to give compound 92. Compound 92 is treated with a suitable reagent, preferably an aluminum amide reagent, to afford amidine 93.

Scheme 6b

Figure 6 shows the preparation of the compound of Example 144, corresponding to a compound wherein R ² is a formula II, Ar is a thiazole, and R ⁸ and R ⁹ (R ³⁷ and R ³⁸ in Scheme 6b) are optionally substituted phenyl Respectively. Treatment with n-butyllithium using 2,5-dibromothiophene 90 as a starting material produces an anion which is displaced (Kano, S. et al., Heterocycles , 20: 2035 (1983)). The carboxylate salt obtained by quenching with carbon dioxide gas is converted to the free acid using mineral acid, preferably hydrochloric acid, to obtain acid 94. [ The acid chloride is prepared using oxalyl chloride and the intermediate acid chloride is converted to ester 95 by treatment with the alcohol R ²³ -OH in a suitable solvent, preferably dichloromethane, containing a suitable base, preferably pyridine. Compound 95 is treated with copper cyanide (I) in refluxing dimethylformamide to obtain compound 96. Compound 96 can be treated with hydrogen sulfide gas in a suitable solvent, preferably methanol, containing a suitable base, preferably triethylamine, to obtain compound 97. Preferably at reflux in an appropriate solvent, preferably acetone, dimethylformamide, dimethylacetamide, methyl ethyl ketone or other polar protic solvent, most preferably acetone, while L is a leaving group, preferably a halogen, mesyl or tosyl, Compound 97 can be treated with an appropriate ketone such as bromo to give compound 98. Compound 98 is treated with a suitable reagent, preferably an aluminum amide reagent (Al (CH ₃ ) ₃ / NH ₄ Cl) to afford amidine 99.

Scheme 7a

Scheme 7a illustrates a process for preparing a compound wherein R < ² > is Formula II and Ar is Thiazol-4-yl. As shown, the acid 13 can be converted to an acid chloride by treatment with oxalyl chloride containing a dimethylformamide catalyst in methylene chloride, or with thionyl chloride in pure thionyl chloride or an organic solvent at ambient or elevated temperature. This is followed by treatment with trimethylsilyldiazomethane and hydrobromic acid in succession to give the desired alpha-halo ketone 100. An alternative is to use diazomethane (produced from Diazald (registered trademark) product of Aldrich Chemical Co., Wisconsin, USA) instead of trimethylsilyldiazomethane. Compound 13 can also be converted to compound 100 using methods derived from the compound 46 to derive the compound 42.

Subsequently, alpha-haloketone 100 is reacted with an appropriate thiourea (Scheme 7b) or thioamide derivative in an organic solvent, preferably acetone or dimethylformamide, at 70 ° C to obtain 2-aminothiazole or thiazole 101.

Thiazole 101 can be treated with an aluminum amine reagent (Al (CH ₃ ) ₃ / NH ₄ Cl) formed at room temperature by reacting trimethylaluminum with ammonium chloride in an organic solvent, preferably toluene. The ester can then be converted to amidine 102 at elevated temperature, preferably above 80 < 0 > C.

Scheme 7b

As shown in Scheme 7b, the intermediate isothiocyanate 111 can be treated with thiophosgene to convert amine 110 (or the hydrochloride thereof) to their respective monosubstituted thiourea (methane-1-thione) have. Preferred conditions include treating the amine with a thiophosgene in a two phase solvent system consisting of an aqueous layer of a halogenated solvent (e.g., chloroform) and saturated sodium bicarbonate. Alternatively, the reaction can be accomplished by treatment of compound 110 with an interfering amine (e. G., Triethylamine or diisopropylethylamine) and thiophosgene in an organic solvent (e. G., Tetrahydrofuran or methylene chloride). Another alternative to isothiocyanate 111 is the direct treatment of the primary amine and carbon disulfide in pyridine with dicyclohexylcarbodiimide [Jochims, Chem. Ber. , ≪ / RTI > 101: 1746 (1968)].

The isothiocyanate 111 can be converted to the thiourea 112 by treatment with a solution of ammonia in an ammonia-alcohol solution, preferably methanol or ethanol, at room or elevated temperature (> 70 ° C). Alternatively, a suitable urea (or a thioamide from a suitable amide wherein R < ⁸ > = alkyl or aryl) is reacted with a Lewesson reagent (Lawesson, SO et al . , Bull. Soc. Chim. Belg. , 87: 223, 293 To produce thiourea 112 directly.

Scheme 8

Scheme 8 illustrates a process for preparing compounds of the present invention wherein R ² is a formula II, Ar is a thiazole, and R ³⁷ and R ³⁸ are phenyl, which is further substituted by a sulfonylamino or carbonylamino group. Using the thioamide 10 as starting material, treatment with a halogenochloro, bromo or iodo, preferably bromo, nitro substituted 2-halo-acetophenone in a suitable solvent, preferably acetone, dimethylformamide, dimethylacetate Amide, methyl ethyl ketone or other polar protic solvent, most preferably acetone. A catalytic hydrogenation reaction on a suitable reducing agent, preferably tin (II) chloride, titanium (II) chloride, iron (III) chloride, lithium metal, sodium metal, platinum or palladium catalyst, most preferably 20% The reduction reaction of the nitroaryl compound 113 can be carried out. Aniline 114 with an appropriate acyl compound R ⁴² L in the presence of a base, preferably pyridine, N-methylmorpholine or diisopropylethylamine, preferably dichloromethane, with halogen, preferably chloro, It can be mislead. Alternatively, dicyclohexylcarbodiimide, ethyl 3- (diethylamino) propyl carbodiimide (EDAC), O- (7-azabenzotriazol-1-yl) -N, N, N'N '-Tetramethyluronium hexafluorophosphate (HATU) or an active carboxylic acid compound R ⁴² COL wherein L is hydroxy, activated with pentafluorophenyl, can be used to acylate aniline 114. Preferably N-methylmorpholine, diisopropylethylamine or pyridine, most preferably N-methylmorpholine in the presence or absence of a condensation catalyst, preferably dimethylaminopyridine (DMAP) Aniline 114 can be sulfonylated using a suitable sulfonyl compound R ⁴¹ SO ₂ L in a suitable solvent, preferably dichloromethane. Compounds 115 and 117 may be amidinylated using a suitable reagent, preferably an aluminum amide reagent (Al (CH ₃ ) ₃ / NH ₄ Cl).

Scheme 9

Scheme 9 depicts the preparation of compounds of formula I wherein one of R < ⁵ > and R < ⁶ > is a non-hydrogen substituent. Is heated with hydroxylamine in a suitable solvent such as ethanol to convert amidine 5 to amide oxime 119. Amidine 5 is heated with a cyanamide in a suitable solvent such as ethanol to produce cyanoamidine 120. [Huffman, KR and Schaeffer, F., J. Amer. Chem. Soc. , 28: 1812 (1963)]. Alternatively, compound 5 can be heated with an amine such as methylamine to give the N-alkylated amidine 121.

Scheme 10

Scheme 10 illustrates a process 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, ralkil amino, showing the arylamino or diarylamino, Y = bond and Z = NR ⁵ R ⁶ approach to compounds of formula I.

Copper catalysts, preferably copper (II) acetate, and amine bases such as triethylamine or pyridine [Chan, DM et al . , Tetrahedron Lett. R ⁵⁸ B (OR ⁵⁸ ) ₂ , R ⁵⁸ = H) in the presence of an aminothiophene (X = S or O; R ² = NH ₂ ) Or an arylboronic ester (R ⁵⁶ B (OR ⁵⁸ ) ₂ , R ⁵⁸ = alkyl) can be reacted to give thienyl arylamine 124. The ester is converted to amidine 125 by the method described above in Scheme 1b.

Scheme 11

R < ² > = arylamino or alkylarylamino, and R < ³ >, Y and Z are as described in Scheme 10, are shown in Scheme 11 and used in the art To intermediate 2 (R ²¹ = R ³ , L = leaving group). [Eg, 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. , ≪ / RTI > 31: 805 (1998). Compound 127 can thus be obtained by treating compound 2 with aniline R ⁵⁶ R ⁵⁷ NH (R ⁵⁶ = aryl, R ⁵⁷ = H or alkyl) in the presence of a palladium catalyst (suitable palladium ligand) and base. Suitable catalysts include any of a number of Pd (0) or Pd (II) salts such as tetrakis (triphenylphosphino) palladium (0), dichlorobis (acetonitrile) palladium (II) Palladium (II) or tris (dibenzylideneacetone) dipalladium). The ligands most suitable for a given reaction are often compound dependent and are described in detail in the aforementioned references, but are not limited to, 1,1'-bis (diphenylphosphino) ferrocene (DPPF), 1- [2- (diphenylphosphino) Ferrocenyl] ethyl methyl ether (PPF-OMe), preferably 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP). Suitable bases include sodium t-butoxide, preferably cesium carbonate or potassium phosphate. Useful solvents include DMF, dioxane, dimethoxyethane, preferably toluene. The ester is converted to amidine 128 by the method described above in Scheme 1b.

Scheme 12

As shown in Scheme 12, the corresponding compounds of formula I wherein R < ² > = alkylamino and R < ³ >, Y and Z are as described in Scheme 10 can be prepared from sodium borohydride, cyanoborohydride, Is subjected to an initial reductive alkylation reaction with an aldehyde R ⁵⁹ CHO or ketone R ⁵⁹ COR ⁶⁰ in the presence of any reducing agent among a number of suitable reducing agents including sodium or tetraalkylammonium salts of triacetoxyborohydride to give compound 129 . Depending on the reducing agent used, suitable solvents include alcohols (e.g., methanol, ethanol or isopropanol) or solvents such as THF or dichloromethane. The ester is converted to amidine 130 by the method described above in Scheme 1b.

Scheme 13

Scheme 13 depicts an approach to compounds of Formula I wherein R ² is 2-thiazolylamino and R ³ , Y and Z are as described in Scheme 10. In this method, the amine 47 can be converted to thiourea 131 using various methods outlined in Scheme 7b. The thiourea aminothiophene 132 was prepared by further reacting the leaving group-substituted ketone R ³⁷ COCH (L) R ³⁸ , preferably 2-haloketone as described in Scheme 2f, 2g or 2h, with thiourea Which can then be converted to the corresponding amidine 133 by the method described above in Scheme 1b.

Example 1

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

Trimethylaluminum (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) with stirring under N ₂ at 0 ° C. When the gas evolution was relieved, the mixture was stirred at 25 < 0 > C for 30 minutes and when most of the solids were dissolved, methyl 4- [4- (4- chlorophenyl) (1,3- ] -5-methylthiothiophene-2-carboxylate (100 mg, product of Maybridge Chemical Co., Cornwall, UK) was added all at once. This solution was heated to reflux in stages over 1 hour. After refluxing for 2.5 hours, the reaction mixture was cooled to 25 ° C and poured into a vigorously stirred silica gel (2 g) slurry in CHCl ₃ (20 mL). After 20 min, the solid was collected by suction filtration and washed with MeOH (3 x 10 mL). The collected filtrate was evaporated to dryness, and the residual yellow solid was treated by refinement thin layer chromatography to obtain 4 - [(4-chlorophenyl) thiazol-2-yl] -5- methylthiothiophene- 77 mg of 2-carboxymidine was obtained. ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 2.80 (s, 3H), 7.55-7.59 (m, lH), 8.04-8.13 (m, 1H), 8.31 (s, 1H), 8.69 (s, 1H), 9.2 (broad s, 4H). Mass spectrum (MALDI-TOF, m / z ): C 15 H 12 theoretical value for _{ClN 3 S 3: 365.9 (M} + H), Found; 366.9.

Example 2

5-methylthiothiophene-2-carboxidine

5- (Methylthio) thiophene-2-carbonitrile (100 mg, product of Maybridge Chemical Company, Cornwall, UK) was placed in an anhydrous two-dose vial. To this was added saturated HCl solution in anhydrous MeOH (4 mL). The vial was capped tightly and the mixture was stirred for 24 hours. The vial was cooled in an ice bath, the stopper was opened, and N ₂ was bubbled through the solution to remove dissolved HCl. The solvent was removed in vacuo and the resulting residue was dried under high vacuum for 24 hours. A methanolic ammonia solution (2M NH _{3 in} MeOH) was added to the vial and the mixture was stirred for 3 days. The methanol was removed in vacuo and the resulting residue was treated by thin layer chromatography to give 5- (methylthio) thiophene-2-carboxymidine in the form of a yellow solid. ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ2.64 (s, 3H), 7.22 (d, J = 3.8 Hz, 1H), 7.95 (broad d, J = 3.33 Hz, 1H), 9.4 (broad s, 4H). Mass spectrum (MALDI-TOF, m / z ): C 6 H 8 N 2 Calcd for _{S 2, 172.3 (M + H} ), Found; 173.0.

Example 3

5-methylthio-4-phenylthiophene-2-carboxidine

Methylthio-4-phenylthiophene-2-carboxylate (100 mg, product of Maybridge Chemical Company, Cornwall, UK) was treated in a manner similar to Example 1 to give 4-phenyl-5- 50 mg of methylthiothiophene-2-carboxymidine was obtained. ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 2.65 (s, 3H), 7.39-7.60 (m, 5H), 8.27 (s, 1H), 9.2 (broad s, Mass spectrum (MALDI-TOF, m / z ): C 12 H 12 N 2 Calcd for _{S 2, 248.4 (M + H} ), Found; 249.0.

Example 4

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

Carboxylate (100 mg, commercially available from Maybridge Chemical Co., Cornwall, Conn.) Was added to a solution of methyl 4- [4- (2,4-dichlorophenyl) Company) was treated in a manner similar to Example 1 to give 4- [4- (2,4-dichlorophenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxidine 60 mg. ^{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, 1 H), 8.3 (s, 1 H), 8.6 (s, 1 H). Mass spectrum (MALDI-TOF, m / z): Theoretical value for C ₁₅ H ₁₁ N ₃ S ₃ Cl ₂ 400.0 (M + H), found 400.1.

Example 5

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

Methylthiothiophene-2-carboxylate (lOOmg, product of Maybridge Chemical Company, Cornwall, UK) was added to a solution of Example 1 To obtain 40 mg of 4- (4-methylthiazol-2-yl) -5-methylthiothiophene-2-carboxymidine as a yellow solid. ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 2.43 (s, 3H), 2.7 (s, 3H), 7.38 (s, 1H), 8.28 (s, 1H). Mass spectrum (MALDI-TOF, m / z ): C 10 H 11 N 3 theoretical value for _{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- -5-methylthiothiophene-2-carboxylate (40 mg, from Maybridge Chemical Company, Cornwall, UK) was prepared in analogy to example 13 step (a) from 2-bromo-2'-acetonaph (1.1 eq.) 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), 747-7.55 (m, 2H), 7.67 (s, 1H), 7.84-7.99 ( m, 3H), 8.08 (dd, J = 1.75 Hz and 8.6 Hz, IH), 8.3 (s, IH), 8.5 (s, IH).

b) 5-Methylthio-4- (4- (2-naphthyl) (1,3-thiazol-2-yl)) thiophene-2-carboximidine: Thiophene-2-carboxylate (40 mg) was treated in a similar manner to Example 1 to give 4- [2- (4-fluorophenyl) 30 mg of 4- (naphth-2-yl) thiazol-2-yl] -5-methylthiothiophene-2-carboximidine was obtained. ^{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, IH), 8.4 (s, IH), 8.65 (s, IH), 8.74 (s, IH). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 19} H 15 N 3 S 3 Calcd, 382.1 (M + H) for, Found; 382.0.

Example 7

5-methylthio-4- [4- (4-phenylphenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxidine hydrochloride

a) Methyl 5-methylthio-4- [4- (4-phenylphenyl) (1,3-thiazol- -5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD, Cornwall, UK) was dissolved in 2 mL of reagent grade acetone. 4-phenyl-2-bromoacetophenone (33 mg; 0.120 mmol, from Aldrich Chemical Co., Milwaukee, Wis.) Was added and the solution refluxed for 2.5 h. The solution was cooled and the solid filtered off, washed with methanol and dried in vacuo to give methyl 5-methylthio-4- [4- (4-phenylphenyl) (1,3-thiazol- 2-carboxylate (65% yield). ^{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), 7.8 (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) C 22 H} 16 NO 2 Calcd for _{S 3: 423.0 (M + H} ), Found; 424.4.

b) 5-Methylthio-4- [4- (4-phenylphenyl) (1,3-thiazol-2- yl)] thiophene-

(Aldrich Chemical Co.) was added to a stirred suspension of 0.473 mmol (25 mg) of ammonium chloride (Fisher Scientific product, Pittsburgh, Pa.) In 2 mL of anhydrous toluene (from Aldrich Chemical Co.) 237 μl (0.0473 mmol) of 2M trimethylaluminum in tetrahydrofuran (1 ml) was added with a syringe for 10 minutes, and the mixture was stirred at 0 ° C for 30 minutes. To this solution was added methyl 5-methylthio-4- [4- Thiazol-2-yl)] thiophene-2-carboxylate (20 mg, 0.0473 mmol) was added thereto, and the mixture was refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 10 mL of chloroform. The silica was poured onto a sintered glass funnel, washed with 10% methanol / CH ₂ Cl ₂ solution, and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 5-methylthio-4- [4- (4-phenylphenyl) (1,3- Yl) thiophene-2-carboxamide hydrochloride (10 mg, 53% yield). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 21 H} 17 theoretical value for the _{N 3 S 3: 408. 1 (} M + H), Found; 408.0.

Examples 8 and 9

Thiazole-2-carboxamide hydrochloride and 4- [4- (3-hydroxyphenyl) (1,3-thiazol- Phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride

a) Methyl 4- [4- (3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 2-carboxylate: Methyl 4- (aminothioxomethyl ) -5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL of reagent grade acetone. 3'-methoxy-2-bromoacetophenone (0.155 mmol; 36 mg, from Aldrich Chemical Co.) was added and the solution was refluxed for 2.5 hours. The solution was cooled and the solid filtered, washed with methanol and dried under vacuum. The solid was purified on a 1 mm silica plate (eluent: 25% ethyl acetate / hexane) to give methyl 4- [4- (3-methoxyphenyl) (1,3- thiazol- Thiophene-2-carboxylate (63% yield).

b) 4- [4- (3-Methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2- carboxydin hydrochloride: 2 mL of anhydrous toluene (manufactured by Aldrich Chemical Co.) left under nitrogen atmosphere at 0 ° C (0.821 mmol) of 2 M trimethylaluminum in toluene (manufactured by Aldrich Chemical Co.) was added to the stirred suspension of 0.821 mmol (44 mg) of ammonium chloride (product of Fisher Scientific) in 10 minutes by syringe, , And then 31 mg of methyl 4- [4- (3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (0.0821 mmol) was added thereto and refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 10 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 4- [4- (3-methoxyphenyl) (1,3- thiazol- 5-methylthiothiophene-2-carboxydin hydrochloride 4.4 mg (15% yield) and 4- [4- (3-hydroxyphenyl) Thiophene-2-carboxydin hydrochloride (4.2 mg, 15% yield). 4- [4- (3-methoxyphenyl) (1, 3-thiazol-2-yl)] - 5-methylthio-thiophene-2-carboxamide pyrimidine _{^{hydrochloride: 1 H-NMR (CD 3}} OD; 300 1H), 3.87 (s, 1H), 7.59-7.65 (m, 2H), 7.33-7.38 , 2.8 (s, 3H) mass spectrum (MALDI-TOF, CHCA matrix, m / z); C ₁₆ H ₁₅ N ₃ OS ₃ : 361.5 (M + H), 362.2. 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthio-thiophene-2-carboxamide pyrimidine _{^{hydrochloride: 1 H-NMR (CD 3}} OD; 300 2H), 7.24 (m, 1H), 6.79 (m, 1H), 2.8 (s, 3H) mass spectrum (MALDI -TOF, CHCA _{matrix, m / z) C 15 H} 13 N 3 theoretical value for the _{OS 3: 347.5 (m + H} ), Found; 348.0.

Example 10

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

a) Methyl 5-methylthio-4- (4- (phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxylate: Methyl 4- (aminothioxomethyl) 33 mg (0.133 mmol) of thiothiophene-2-carboxylate (product of Maybridge Chemical Co. LTD, Cornwall, UK) was dissolved in 2 mL of reagent grade acetone. 2-Bromoacetophenone (0.133 mmol; 27 mg The solution was cooled and the solid was filtered off, washed with methanol and dried under vacuum. The solid was purified on a 1 mm silica plate (eluent: 25% ethyl < RTI ID = 0.0 > Acetate / hexane mixture) to give 46 mg (90% yield) of methyl 5-methylthio-4- (4-phenyl (1,3- thiazol-2-yl)) thiophene- .

b) 5-Methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxydin hydrochloride: To a solution of anhydrous toluene (1.32 mmol) of 2 M trimethylaluminum in toluene (from Aldrich Chemical Co.) was added to the stirred suspension of 1.32 mmol (71 mg) of ammonium chloride (Fisher Scientific product) in 2 mL of acetonitrile , And the mixture was stirred at 0 ° C for 30 minutes. Then, 46 mg of methyl 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- 0.133 mmol) was added thereto and refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 10 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 2 g silica SPE column (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 5-methylthio-4- (4-phenyl (1,3-thiazol- -2-carboxamide hydrochloride (75% yield). ^{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) C 15 H} 13 N 3 S Calcd for ₃ 331.5 (M + H), Found; 332.1.

Example 11

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

a) Methyl 5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene- 2-carboxylate: Methyl 4- (aminothioxomethyl) 38 mg (0.114 mmol) of 5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 2 mL of reagent grade acetone. 2-Bromo-4'-nitroacetophenone (0.155 mmol; 38 mg, from Aldrich Chemical Co.) was added and the solution was refluxed for 2.5 hours. The solution was cooled and the solid was filtered off, washed with methanol and dried under vacuum. The crude product was dissolved in CH ₂ Cl ₂ and 0.141 mmol of N- (2-mercapto) aminoethyl polystyrene resin (1.28 mmol / g: 110 mg, Calbiochem product, San Diego, CA) was added and stirred overnight . The solution was filtered, concentrated and dried to give crude methyl 5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene- 60% yield (90% yield) of the compound.

b) 5-Methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene-2-carboximidine hydrochloride: To a stirred suspension of 1.66 mmol (90 mg) of ammonium chloride (Fisher Scientific product) in 2 mL of toluene (Aldrich Chemical Co.) was added 830 μL (1.66 mmol) of 2M trimethylaluminum in toluene (from Aldrich Chemical Co.) After stirring for 10 minutes at 0 ° C, the solution was added with 5-methylthio-4- [4- (4-nitrophenyl) (1,3-thiazol-2-yl)] thiophene -2-carboxylate (60 mg, 0.166 mmol) was added thereto, and the mixture was refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 10 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 5-methylthio-4- [4- (4- nitrophenyl) (1,3- Yl) thiophene-2-carboxamide hydrochloride (12 mg, 19% yield). ¹ H-NMR (CD ₃ OD, 300 MHz)? 8.58 (s, 1H), 8.32-8.33 (m, 4H), 8.24 (s, 1H), 2.83 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 15 H} 12 N 4 O 2 Calcd for _{S 3: 376.5 (M + H} ), Found; 377.3.

Example 12

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

a) Preparation of methyl 4- (4- (2H, 3H-benzo [3,4-e] 1,4- dioxin-6-yl) Carboxylate: 40 mg (0.62 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (commercially available from Maybridge Chemical Co. LTD, mmol) was dissolved in 2 mL of reagent grade acetone. (0.162 mmol; 42 mg; product of Maybridge Chemical Co. LTD., Cornwall, UK) was added to a solution of 1- (2H, 3H- benzo [e] 1,4- dioxin- ) Was added, and the solution was refluxed for 3 hours. The solution was cooled, stirred for 2 days, and then 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.). An organic layer was obtained, dried over sodium sulfate, and concentrated to give 60 mg (0.25 mmol) of methyl 4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 90% yield).

b) 4- [4- (3,4-Ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxydin hydrochloride: Anhydrous toluene (1.62 mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) was added to a stirred suspension of 1.62 mmol (86 mg) of ammonium chloride (Fisher Scientific product) in 2 mL of acetonitrile After the addition, the mixture was stirred for 30 minutes at 0 ° C, and then a solution of methyl 4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5- methylthiothiophene- Carboxylate (60 mg, 0.162 mmol) was added thereto, and the mixture was refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 10 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 4- [4- (3,4-ethylenedioxyphenyl) thiazol- Thiophene-2-carboxidine hydrochloride (75% yield). ¹ H-NMR (CD ₃ OD, 300 MHz)? 8.53 (s, IH), 7.73 (s, IH), 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 (MALDI-TOF, CHCA _{matrix, m / z) C 17 H} 15 N 3 O 2 Calcd for _{S 3: 389.5 (M + H} ), Found; 390.1.

Example 13

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

a) Methyl 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] methylthiothiophene- 30 mg (0.122 mmol) of 5-methylthiothiophene-2-carboxylate (manufactured by 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; from Aldrich Chemical Co.) was added and the solution was refluxed for 3 hours. The solution was cooled and the solid filtered and washed with methanol and dried under vacuum to give methyl 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5- Carboxylate (46 mg, 90% yield).

b) 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxydin hydrochloride: To a stirred suspension of 1.22 mmol (66 mg) of ammonium chloride (Fisher Scientific product) in 2 mL of anhydrous toluene (Aldrich Chemical Co.) was added 612 μL (1.22 mmol) of 2 M trimethylaluminum in toluene (from Aldrich Chemical Co.) And the mixture was stirred at 0 ° C for 30 minutes. Then, to the solution was added 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5- Thiophene-2-carboxylate (46 mg, 0.122 mmol) was added thereto, and the mixture was refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 10 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 4- [4- (4-methoxyphenyl) (1,3- thiazol- To obtain 32 mg (73% yield) of 5-methylthiothiophene-2-carboxidine hydrochloride. _{^{1 H-NMR (CD 3 OD}} , 300 MHz) δ 8.53 (s, 1H), 7.98 (d, J = 7 Hz, 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) Theoretical value for C ₁₆ H ₁₅ N ₃ OS ₃ : 362.0 (M + H), found 362.2.

Example 14

4- [4- (3,4-propylene dioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxidine hydrochloride

a) Methyl 4- [4- (3,4-propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2- carboxylate: Methyl 4- (aminothioxomethyl) -5 -Methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD, Cornwall, UK) was dissolved in 5 mL of reagent grade acetone. 3 ', 4'-propylenedioxy-2-bromoacetophenone (0.170 mmol; 28 mg; manufactured by Maybridge Chemical Co. LTD, Cornwall, UK) was added and the solution refluxed for 3 hours. The solution was cooled and the solid was filtered off and purified on a 1 mm silica tablet plate (eluent: 20% ethyl acetate / hexane) and dried in vacuo to give methyl 4- [4- (3,4-propylene dioxyphenyl) 2-yl] -5-methylthiothiophene-2-carboxylate (yield: 59%).

b) 4- [4- (3,4-Propylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene-2-carboxydin hydrochloride: Anhydrous toluene 510 μl (1.01 mmol) of 2 M trimethylaluminum in toluene (Aldrich Chemical Co.) was added to a stirred suspension of 1.01 mmol (54 mg) of ammonium chloride (Fisher Scientific product) in 2 mL of acetonitrile After the addition, the mixture was stirred for 30 minutes at 0 ° C, and then a solution of methyl 4- [4- (3,4-propylene dioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- Carboxylate (42 mg, 0.101 mmol) was added, and the mixture was refluxed for 3 hours. The reaction mixture was quenched by pouring onto a 500 mg silica slurry in 20 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated to give 4- [4- (3,4-propylene dioxyphenyl) thiazol-2-yl] -5- 2-carboxydin hydrochloride (50% yield). _{^{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 , 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) C 18 H} 17 N 3 O 2 Calcd for _{S 3: 404.1 (M + H} ), Found; 404.1

Example 15

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

a) 2-Bromo-1- (2-thienyl) ethan-1-one: To a solution of 500 mg (3.96 mmol) of 2- acetylthiophene (from Aldrich Chemical Co.) dissolved in 20 mL of CHCl ₃ was added 30% A drop of HBr / CH ₃ COOH (from Aldrich Chemical Co.) and 3.96 mmol (633 mg; 204 μl) of bromine (from Aldrich Chemical Co.) were added dropwise over 30 minutes. The reaction was stirred for 1 hour. The solution was concentrated to an oil phase and dried under vacuum. The crude product was purified on a 1 mm silica purification plate (eluent: knit CH ₂ Cl ₂ ) to give 300 mg (37% yield) of 2-bromo-1- (2-thienyl) 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- 44 mg (0.176 mmol) of 5-methylthiothiophene-2-carboxylate (manufactured by 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 added and the solution refluxed for 3 h. The solution was cooled and concentrated. The crude product was dissolved in 20 mL of CH ₂ Cl ₂ and washed with 20 mL 1N HCl (aq.). An organic layer was obtained and dried over sodium sulfate to give crude methyl 5-methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl)) thiophene-2-carboxylate 115 mg (80% yield).

c) 5-Methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl)) thiophene-2-carboxymidine acetate: To a stirred suspension of 2.80 mmol (150 mg) of ammonium chloride (Fisher Scientific product) in 5 mL of toluene (Aldrich Chemical Co.) was added 1.5 mL (2.8 mmol) of 2 M trimethylaluminum in toluene (from Aldrich Chemical Co.) After stirring for 15 minutes, the mixture was stirred at 0 ° C for 25 minutes. Then, to the solution was added 115 mg of methyl 5-methylthio-4- (4- (2-thienyl) (1,3-thiazol-2-yl)) thiophene-2-carboxylate in 5 mL of anhydrous toluene (0.280 mmol) and refluxed for 1.5 hours. The reaction mixture was quenched by pouring onto a silica slurry in CH ₂ Cl ₂ . The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 1 mm silica tablet plate (eluent: 10% methanol / CH ₂ Cl ₂ containing 1% CH ₃ COOH) to give 5-methylthio-4- (4- (2-thienyl) , 3-thiazol-2-yl)) thiophene-2-carboxymidine acetate (43% yield). _{^{1 H-NMR (CD 3 OD}} ; 300 MHz) δ8.52 (s, 1H). 1H), 7.79 (s, 1H), 7.59 (dd, J = 2 Hz and 5 Hz, 1H), 7.42 (dd, J = 2 Hz and 5 Hz, . Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 13 H} 11 N 3 S 4 Calcd for: 338.0 (M + H), Found; 337.9.

Example 16

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

a) Methyl 4- [4- (3-bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate: Methyl 4- (aminothioxomethyl ) -5-methylthiothiophene-2-carboxylate (manufactured by 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 added and the solution was refluxed for 3 hours. The solution was cooled and the solid was filtered and dissolved in 5 mL of hot tetrahydrofuran (THF) (Aldrich Chemical Co.) and purified on a 1 mm silica plate (eluent: 20% ethyl acetate / hexanes) And dried to obtain 66 mg (40% yield) of methyl 4- [4- (3-bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- .

b) 4- [4- (4- (3-Bromophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxymidine hydrochloride: To a stirred suspension of 1.55 mmol (83 mg) of ammonium chloride (Fisher Scientific product) in 10 mL of anhydrous toluene (from Aldrich Chemical Co.) left under a nitrogen atmosphere was added 774 μL (1.55 mmol) of 2 M trimethylaluminum in toluene ) Was added with a syringe for 10 minutes and then stirred for 20 minutes at 25 DEG C. Then, to the solution was added 4- [4- (3-bromophenyl) (1,3-thiazol- The reaction mixture was poured onto a 5 g slurry of silica in 25 mL of chloroform to quench the silica. The silica was poured onto a sintered glass funnel, 10% was concentrated and washed with methanol / CH ₂ Cl ₂ solution of the crude product was a 1 mm silica plate: purified on (eluent 10% methanol _{/ CH 2 Cl 2) 4- [} 4- (3- bromo Phenyl) (1,3-thiazol-2-yl)] - 5-methylthio-thiophene-2-carboxamide hydrochloride, pyrimidine 63 mg (yield 90% _{^{yield) 1 HNMR (CD 3 OD;}} 300 MHz) δ 1H), 8.21 (m, 1H), 7.96 (m, 2H), 7.50 (m, spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 15 H} 12 theoretical value for _{BrN 3 S 3: 411.9 (M} + H), Found; 411.9.

Example 17

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

a) Methyl 4- [4- (4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD, Cornwall, UK) (50 mg, 0.202 mmol) was dissolved in 10 mL of reagent grade acetone. 2-Bromo-4'-chloro-3'-nitroacetophenone (0.212 mmol; 59 mg) was added and the solution refluxed for 3 h. The solution was cooled and the solid was filtered off and dissolved in hot tetrahydrofuran (THF) and purified on a 1 mm silica plate (eluent: 20% ethyl acetate / hexanes) and dried under vacuum to give methyl 4- [4- ( (70% yield) of 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-methylthiothiophene-2-carboxymidine hydrochloride: Was added to a stirred suspension of 1.40 mmol (75 mg) of ammonium chloride (Fisher Scientific product) in 10 mL of anhydrous toluene (from Aldrich Chemical Co.), left under a nitrogen atmosphere, to a solution of 700 μL of 2 M trimethylaluminum in toluene ) Was added by a syringe for 10 minutes and then stirred for 20 minutes. Thereafter, 60 mg (0.140 mmol) of 4- [4- (4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- mmol) was added and the mixture was refluxed for 3 hours. The reaction mixture was quenched by pouring onto a 5 g silica slurry in 50 mL of chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂ ) to give 4- [4- (4-chloro-3- nitrophenyl) (1,3- ] -5-methylthiothiophene-2-carboxidine hydrochloride (32% yield). _{^{1 H-NMR (CD 3 OD}} ; 300 MHz) δ 8.53-8.58 (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, 1 H), 2.80 (s, 3 H).

Example l8

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

a) Methyl 4- [4- (4-chloro-3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Oxomethyl) -5-methylthiothiophene-2-carboxylate (available from Maybridge Chemical Co. LTD, Cornwall, UK) was dissolved in 10 mL of reagent grade acetone. 2-Bromo-l- (4-chloro-3-methylphenyl) ethan-l-one (0.658 mmol; 163 mg) was added and the solution refluxed for 3 h. The solution was cooled and the reaction mixture was concentrated and dissolved in 50 mL of CH ₂ Cl ₂ . The organic layer was washed with 50 mL of 1 N HCl (aq.), Dried over sodium sulfate and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 20% ethyl acetate / hexane) to give methyl 4- [4- (4-chloro-3- methylphenyl) (1,3- thiazol- To obtain 168 mg (68% yield) of 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (4-Chloro-3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxydin hydrochloride: 2.2 mL (4.24 mmol) of 2 M trimethylaluminum in toluene (from Aldrich Chemical Co.) was added to a stirred suspension of 4.24 mmol (227 mg) of ammonium chloride (Fisher Scientific product) in 15 mL of anhydrous toluene (from Aldrich Chemical Co.) Was added with a syringe for 10 minutes, and then stirred at 25 DEG C for 20 minutes. Thereafter, 168 mg (0.424 g) of methyl 4- [4- (4-chloro-3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- mmol) was added thereto and refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 5 g silica slurry in chloroform. The silica was poured onto a sintered glass funnel and washed with a 10% methanol / CH ₂ Cl ₂ solution and concentrated to give 4- [4- (4-chloro-3-methylphenyl) -5-methylthiothiophene-2-carboxidine hydrochloride (73% yield). ¹ H-NMR (CD ₃ OD, 300 N HZ) 隆 8.53 (s, 1H), 8.03 (dd, J = 1.2 Hz and 2.7 Hz, 1H), 7.9 And 8.5 Hz, IH), 7.38 (dd, J = 8.3 Hz and 17.4 Hz, IH), 2.8 (s, 3H), 2.45 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z) Theoretical value for C ₁₆ H ₁₄ ClN ₃ S ₃ : 380.0 (M + H), experimental value 380.3.

Example 19

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

a) Methyl 4- (5-methyl-4-phenyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene- 48 mg (0.194 mmol) of 5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-l-phenylpropan-l-one (0.223 mmol; 48 mg) was added and the solution was refluxed for 5 hours. The solution was cooled and the reaction mixture was concentrated and dissolved in 50 mL of CH ₂ Cl ₂ . The organic layer was washed with 50 mL of 1 N HCl (aq.), Dried over sodium sulfate and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 20% ethyl acetate / hexane) to give methyl 4- (5-methyl-4-phenyl (1,3-thiazol- Thiophene-2-carboxylate (76% yield).

b) 4- (5-Methyl-4-phenyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboximidine hydrochloride: To a solution of anhydrous toluene (1.47 mmol) of 2 M trimethylaluminum in toluene (from Aldrich Chemical Co.) was added to a stirred suspension of 1.47 mmol (78 mg) of ammonium chloride (Fisher Scientific product) in 5 mL of water (Aldrich Chemical Co.) Minute, followed by stirring at 25 DEG C for 20 minutes. Then, 53 mg (0.147 mmol) of methyl 4- (5-methyl-4-phenyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene- And refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a 5 g silica slurry in chloroform. The silica was poured onto a sintered glass funnel and washed with 10% methanol / CH ₂ Cl ₂ solution and then concentrated to give 4- (5-methyl-4-phenyl (1,3-thiazol- 26 mg (51% yield) of thiothiophene-2-carboxydin hydrochloride was obtained. _{^{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 , ≪ / RTI > 3H), 2.6 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 16 H} 15 N 3 S 3 Calcd for: 346.0 (M + H), Found; 345.6.

Example 20

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

a) Methyl 4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 103 mg (0.416 mmol) of 5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-4'-methylacetophenone (0.416 mmol; 89 mg) was added and the solution refluxed for 3 h. The solution was cooled and the crude product was filtered and washed twice with acetone and purified on a 1 mm silica plate (eluent: 20% ethyl acetate / hexane) to give methyl 4- [4- (4- methylphenyl) , 3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate 104 mg (69% yield).

b) 4- [4- (4-Methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxyridine trifluoroacetate: To a stirred suspension of 2.87 mmol (154 mg) of ammonium chloride (Fisher Scientific product) in 10 mL of anhydrous toluene (from Aldrich Chemical Co.) was added 144 μL (2.87 mmol) of 2 M trimethylaluminum in toluene (from Aldrich Chemical Co.) The mixture was stirred for 10 minutes at 25 DEG C for 20 minutes. Thereafter, 104 mg (0.287 mmol) of 4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- And refluxed for 3 hours. The reaction mixture was quenched by pouring onto a 5 g silica slurry in 50 mL of chloroform. The silica was poured onto a sintered glass funnel, washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. Subsequently, the crude product was purified by silica plate 1 mm was purified on (eluent 1% CH ₃ COOH 10% methanol / CH ₂ Cl ₂ containing a). That was then, the base product with an aqueous NaOH screen, and extracted with CHCl ₃ and concentrated. TFA was added and the product was crystallized from methanol to give 4- [4- (4-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 2- carboxymidine trifluoroacetate (20 mg; 30% yield). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.62 (s, 1H), 8.12 (s, 1H), 7.98 , 2.8 (s, 3 H) 2.5 (s, 3 H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 16 H} 15 N 3 S 3 Calcd for: 346.0 (M + H), Found; 346.1.

Example 21

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

a) Methyl 4- [4- (2-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate: Methyl 4- (aminothioxomethyl ) -5-methylthiothiophene-2-carboxylate (available from Maybridge Chemical Co. LTD, Cornwall, UK) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2'-methoxyacetophenone (0.467 mmol; 110 mg) was added and the solution refluxed for 3 hours. The solution was cooled and the solution was 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 organic layer was dried over sodium sulfate, concentrated, and then purified on a 1 mm silica plate (eluent: 20% ethyl acetate / hexane) to give methyl 4- [4- (2-methoxyphenyl) -Thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (yield 95%).

b) 4- [4- (2-Methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxydin hydrochloride: To a stirred suspension of 4.23 mmol (227 mg) of ammonium chloride (Fisher Scientific product) in 10 mL of anhydrous toluene (from Aldrich Chemical Co.) was added 2.12 mL (4.23 mmol) of 2 M trimethylaluminum in toluene And the mixture was stirred at 25 ° C for 20 minutes. Then, a solution of 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate 160 mg (0.287 mmol) was added and refluxed for 3 hours. The reaction mixture was quenched by pouring onto a 5 g silica slurry in 30 mL of chloroform. The silica was poured onto a sintered glass funnel, washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. The crude product was then purified on a 2 mm silica purification plate (eluent: 10% methanol / CH ₂ Cl ₂ containing 1% NH ₄ OH). The product was then dissolved in 2 mL of 4N HCl / dioxane and concentrated to give 4- [4- (4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5- -2-carboxamide hydrochloride (45 mg, 29% yield). ^{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) Theoretical value for C ₁₆ H ₁₅ N ₃ OS ₃ : 362.0 (M + H), found 361.7.

Example 22

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

a) Methyl 4- [4- (2,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Oxomethyl) -5-methylthiothiophene-2-carboxylate (manufactured by Maybridge Chemical Co. LTD., Cornwall, UK) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-4 ' -dimethoxyacetophenone (0.440 mmol; 114 mg) was added and the solution refluxed for 2.5 hours. The solution was cooled and the crude product was recovered as a solid, washed with methanol and dried to give methyl 4- [4- (2,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - To obtain 91 mg (56% yield) of 5-methylthiothiophene-2-carboxylate.

b) 4- [4- (2,4-Dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxydin hydrochloride: To a stirred suspension of 2.23 mmol (119 mg) of ammonium chloride (Fisher Scientific product) in 10 mL of anhydrous toluene (from Aldrich Chemical Co.) was added 1.1 mL (2.23 mmol) of 2 M trimethylaluminum in toluene over 10 min Then, the mixture was stirred at 25 占 폚 for 20 minutes. Thereafter, 81 mg (0.223 g) of methyl 4- [4- (2,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- mmol) was added thereto and refluxed for 2.5 hours. The reaction mixture was quenched by pouring onto a silica slurry in chloroform. The silica was poured onto a sintered glass funnel, washed with 10% methanol / CH ₂ Cl ₂ solution and concentrated. Subsequently, the crude product was first purified 0.5 mm silica plate (eluent: 10% methanol / CH ₂ Cl ₂₎ to give on, 4- [4- (2,4-dimethoxyphenyl) (1, 3-thiazol -2 Yl) -5-methylthiothiophene-2-carboxydin hydrochloride (37% yield). _{^{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) C 17 H} 17 N 3 O 2 Calcd for _{S 3: 392.1 (M + H} ), Found; 392 4.

Example 23

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

a) Methyl 4- [4- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 176 mg (0.712 mmol) of methyl 5-methylthiothiophene-2-carboxylate (commercially available from Maybridge Chemical Co. LTD, Cornwall, UK) was reacted with 2- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5 (5-fluorophenyl) -Methylthiothiophene-2-carboxylate (91% yield).

b) 4- [4- (3,4-Dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 270 mg (0.648 mmol) of (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 135 mg (52% yield) of 4- [4- (3,4-dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- ). ¹ H-NMR (CD ₃ OD, 300 MHz)? 8.54 (s, 1H), 8.22 (d, J = 2 Hz, 1H), 8.02 , ≪ / RTI > 1H), 7.58 (d, J = 8.5 Hz, 1H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 15 H} 11 Cl 2 N 3 theoretical value for _{S 3: 400.0 (M + H} ), Found; 400.6.

Example 24

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

a) Methyl 4- [4- (3-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 106 mg (0.428 mmol) of 5-methylthiothiophene-2-carboxylate (commercially available from Maybridge Chemical Co. LTD, Cornwall, UK) was reacted with 2-bromo-3 -Methylacetophenone (0.428 mmol, 91 mg) to give methyl 4- [4- (3-methylphenyl) (1,3-thiazol- 98% yield (63% yield) of the compound.

b) 4- [4- (3-Methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- (98 mg, 0.271 mmol) was treated in a manner similar to that of Example 22, step (b) to give 4- (3-thiazol-2-yl) (80% yield) of [4- (3-methylphenyl) (1,3-thiazol-2-yl)] - 5- methylthiothiophene-2-carboxidine hydrochloride. _{^{1 H-NMR (CD 3 OD}} ; 300 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H), 7.86 (d, J = l4 Hz, 2H), 7.33 (m, 1H), 7.19 (m, 1H), 2.79 (s, 3H), 2.42 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 16 H} 15 N 3 theoretical value for _{S 3: 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-

a) Methyl 5-methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl) thiophene- Carboxylate (160 mg, 0.647 mmol) (obtained from Maybridge Chemical Co. LTD, Cornwall, UK) was added to a solution of the title compound of step (a) of Example 22 1- (2-5,6,7,8-tetrahydronaphthyl) ethan-1-one (0.712 mmol; 180 mg) to give methyl 5-methylthio-4 (41% yield) of (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)) thiophene-2-carboxylate .

b) 5-Methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)) thiophene- : Methyl 5-methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3-thiazol-2-yl)) thiophene- (0.264 mmol) was treated in a similar manner to step (b) of Example 22 to give 5-methylthio-4- (4- (2-5,6,7,8-tetrahydronaphthyl) (1,3 -Thiazol-2-yl)) thiophene-2-carboxidine hydrochloride 88 mg (80% yield). ¹ H-NMR (CD ₃ OD, 300 MHz)? 8.49 (s, 1H), 7.78 (m, 2H) 1.86 (m, 4H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 19 H} 19 N 3 theoretical value for _{S 3: 386.1 (M + H} ), Found; 386.2

Example 26

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

a) Methyl 4- [4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Carboxylate 100 mg (0.404 mmol) (from Maybridge Chemical Co. LTD, Cornwall, UK) was treated in a manner similar to step (a) of Example 22 to give 2- Bromo-3 ', 5'-dimethoxyacetophenone (0.444 mmol) to give methyl 4- [4- (3,5-dimethoxyphenyl) -Methylthiothiophene-2-carboxylate (27% yield).

b) 4- [4- (3,5-Dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxydin hydrochloride: Methyl 4- [4- 44 mg (0.108 mmol) of (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Was treated in a similar manner to 25 mg of (4- (4- (3,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 60% yield). _{^{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) mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 17 H} 17 N 3 O 2 Calcd for _{S 3: 392.11 (M + H} ), Found; 392.4.

Example 27

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

a) Methyl 4- [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 160 mg (0.647 mmol) of 5-methylthiothiophene-2-carboxylate (available from Maybridge Chemical Co. LTD, Cornwall, UK) was reacted with 2-bromo- -Methylacetophenone (0.711 mmol, 152 mg) to give methyl 4- [4- (2-methylphenyl) (1,3-thiazol- To give 124 mg (53% yield) of the compound.

b) 4- [4- (2-Methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Carboxylate (124 mg, 0.343 mmol) was treated in a manner similar to that of Example 22, step (b) to give 4-tert-butyl- (50% yield) of [4- (2-methylphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride. _{^{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) C 16 H} 15 N 3 S 3 Calcd for: 346.0 (M + H), Found; 346.2.

Example 28

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

a) Methyl 4- [4- (2,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Oxothiophene-2-carboxylate 132 mg (0.534 mmol) (from Maybridge Chemical Co. LTD, Cornwall, UK) was prepared in a manner similar to step (a) of Example 22 using 2- Bromo-2 ', 5'-dimethoxyacetophenone (0.587 mmol, 152 mg) to obtain methyl 4- [4- (2,5- dimethoxyphenyl) ] -5-methylthiothiophene-2-carboxylate (yield 45%).

b) 4- [4- (2,5-Dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- (B) of Example 22 was reacted with 97 mg (0.238 mmol) of (2,5-dimethoxyphenyl) (1,3-thiazol- Was treated in a similar manner to Example 1 to obtain 30 mg of (4- (4- (2,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 32% yield). _{^{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 = 9 Hz, 1H) , 3.93 (s, 3H), 3.83 (s, 3H), 2.51 (s, 3H), 6.93 (d, J = 3.2 Hz, Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 17 H} 17 N 3 O 2 Calcd for _{S 3: 392.1 (M + H} ), Found; 392.1.

Example 29

(3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride

a) Methyl 4- [4- (4- (chloro (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 240 mg (0.970 mmol) of (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (available from Maybridge Chemical Co. LTD, Cornwall, UK) was prepared by a similar method to step (a) Was reacted with methyl 4- [4- (4-chloro (3-pyridyl)) ethan-1-one (1.06 mmol, ) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (yield 77%).

b) 4- [4- (4-Chloro (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 286 mg (0.747 mmol) of 4- (4-chloro (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carbaldehyde Pyridine hydrochloride 134 mg (49% yield). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z) C 14 H} 11 N 4 Calcd for _{ClS 3: 366.9 (M + H} ), Found; 366.6.

Example 30

Yl) - 5-methylthiothiophene-2-carboxymidine hydrochloride (prepared according to the method described in Example 1)

a) 1- (2H-benzo [3,4-d] 1,3-dioxolen-5-yl) -2-bromoanthan- 61 mmol (20 g) of poly (4-vinylpyridinium tribromide) (manufactured by Aldrich Chemical Co.) was added to a solution of 2.5 g (15.23 mmol) of phenone and refluxed for 2.5 hours. The solution was filtered and concentrated. (1.4 g, 38% yield) from 1- (2H-benzo [3,4-d] ). ^{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, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 2.75 (s, 3H).

b) Preparation of methyl 4- (4- (2H-benzo [d] 1,3-dioxolen-5-yl) rate: methyl 4- (4-amino-thioxo-methyl) -5-methylthio-thiophene-2-carboxylate 1.4 g (5.66 mmol) (. Maybridge Chemical Co. LTD of England product Cornwall material) the steps of example 22 ( benzo [3,4-d] 1,3-dioxolen-5-yl) -2-bromoanthan-1-one (5.66 mmol, 1.37 g) in a similar manner to a) A solution of methyl 4- (4- (2H-benzo [d] 1,3-dioxolen-5-yl) 1.55 g (70% yield) was obtained.

c) Preparation of 4- (4- (2H-benzo [d] 1,3-dioxolen-5-yl) Methylthiothiophene-2-carboxamide hydrochloride: Methyl 4- (4- (2H- benzo [d] 1,3-dioxolen-5-yl) Carboxylate 1.55 g (3.95 mmol) was treated in a similar manner to step (b) of Example 22 to give 4- (4- (2H-benzo [d] 1,3- dioxolen- 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine hydrochloride 130 mg (9% yield). _{^{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 (MALDl-TOF, CHCA _{matrix, m / z) C 16 H} 13 N 3 O 2 Calcd for _{S 3: 376.0 (M + H} ), Found; 376.1.

Example 31

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

a) 1- (3,4-Dimethoxyphenyl) -2-bromoanthan-1-one: 2 g (11.1 mmol) of 1- (3,4- dimethoxyphenyl) ethan- Was treated in a similar manner to step (a) to give 1.2 g (42% yield) of 1- (3,4-dimethoxyphenyl) -2-bromoanthan-1-one.

b) Methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- -5-methylthiothiophene-2-carboxylate (105 mg, 0.424 mmol) (commercially available from Maybridge Chemical Co. LTD, Cornwall, UK) was reacted with 1- (0.467 mmol, 120 mg) was reacted with methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thia 2-yl)] - 5-methylthiothiophene-2-carboxylate (85% yield).

c) 4- [4- (3,4-Dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Carboxylate (148 mg, 0.363 mmol) was reacted with the compound obtained in step (b) and step (b) of Example 22 to obtain the titled compound The reaction was carried out in a similar manner to obtain 70 mg (50%) of 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- % Yield). _{^{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), 7.01 (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) C 17 H} 17 N 3 O 2 Calcd for _{S 3: 392.1 (M + H} ), Found; 392.4.

Example 32

(3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine

a) Methyl 4- [4- (2-chloro (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- pyridine-3-carbonyl (300 mg, 1.7 mmol) was dissolved in anhydrous CH ₃ CN (4 mL). While stirring with magnetic stirrer, trimethylsilyldiazomethane (4 mL, 2M solution in hexane, 8 mmol) was added dropwise to the reaction mixture. The resulting yellow solution was stirred at room temperature for 2 hours, and the mixture was cooled in an ice bath. 30% HBr in acetic acid (2 mL) was added dropwise to the cooling solution, at which time the gas was vigorously released. The solution was stirred for 1 hour, during which 2-bromo-1- (2-chloro (3-pyridyl)) ethan-1-one precipitated. The solid was filtered off and dried in vacuo. 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, from Maybridge Chemical Company, Cornwall, UK) And the mixture was heated to reflux. At this time, the precipitated solid was filtered, washed with methanol and dried under vacuum to give methyl 4- [4- (2-chloro (3-pyridyl)) (1,3-thiazol- 110 mg (71%) of 5-methylthiothiophene-2-carboxylate was obtained. _{^{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, IH), 8.62 (dd, J = 1.9 and 7.7 Hz, IH).

b) 4- [4- (2-Chloro (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboximidine: -5-methylthiothiophene-2-carboxylate (100 mg, 0.26 mmol) was added to a solution of methyl 4- [4- (2-chloro (3- pyridyl) (3-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene was obtained in the same manner as in Example 1, 50 mg (52%) of 2-carboxymidine was obtained. ^{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, 1 H), 9.1 (broad s, 2H), 9.4 (broad s, 2H). Mass spectrum (ESI, m / z): C 14 H 11 N 4 theoretical value for _{S 3 Cl: 367.0 (M +} H), Found; 369.0.

Example 33

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

a) Methyl 4- (cyclohexyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2- carboxylate: Cyclohexanecarbonyl chloride (300 mg, 2.0 mmol) 2-bromo-1-cyclohexylethan-1-one was obtained by treatment in a similar manner to Example 32. 2-Bromo- This dry solid (125 mg) was dissolved in acetone (10 mL). To this solution was added 5- (methoxycarbonyl) -2- (methylthio) -thiophene-3-thiocarboxamide (100 mg, 0.4 mmol, product of Maybridge Chemical Company, Cornwall, UK) And the mixture was heated to reflux. At this time, the precipitated solid was filtered, washed with methanol and dried under vacuum to obtain methyl 4- (4-cyclohexyl (1,3-thiazol-2-yl) Carboxylate (100 mg, 70%) which was used in the next step without further purification.

b) 4- (4-Cyclohexyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboximidine: Methyl 4- (4-cyclohexyl Carboxylate (100 mg, 0.28 mmol) was treated in a similar manner to Example 1 to give 4- (4-tert-butoxycarbonylamino) (63%) of cyclohexyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine. ^{1 H-NMR (DMSO-d} 6; 300MHz) δ 1.21-1.53 (m, 5H), 1.61-1.78 (m, 3H), 2.05 (m, 2H), 2.7 (s, 3H), 2.74 (m, 1H ), 7.33 (s, 1 H), 8.32 (s, 1 H). Mass spectrum (MALDl-TOF, / mz) : C 15 H 19 N 3 S 3 Calcd, 338.1 (M + H), Found; 338.1 for.

Example 34

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

Carboxylate (100 mg, 0.37 mmol, product of Maybridge Chemical Company, Cornwall, UK) was treated in a similar manner to Example 1 to give the title compound as a solid To obtain 80 mg (85%) of 4-phenyl-5- (trifluoromethyl) thiophene-2-carboxidine. ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 7.45-7.52 (m, 5H), 7.79 (d, J = 1.4 Hz, 1H). Mass spectrum (MALDI-TOF, m / z): Theoretical value for C ₁₂ H ₉ F ₃ N ₂ S, 271.1 (M + H), found 271.2.

Example 35

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

a) Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate The 5- (methoxycarbonyl) -2-methylthiothiophene- Carboxylic acid (200 mg, 0.86 mmol) was taken in a round bottom flask and anhydrous CH ₂ Cl ₂ (10 mL) was poured. The solution was cooled in an ice bath under an argon atmosphere. To this mixture was added oxalyl chloride (328 mg, 2.6 mmol) followed by anhydrous DMF (500 μL). The resulting solution was stirred at 4 < 0 > C for 30 minutes and then monitored for acid disappearance by TLC while warming to room temperature. After 2 h, the solvent was removed in vacuo and the residual oxalyl chloride was removed by azeotropic distillation with toluene. The resulting residue was dried under high vacuum to give an acid chloride in the form of a gray solid. This solid was dissolved in anhydrous CH ₃ CN (8 mL). Trimethylsilyldiazomethane (4 mL, 8 mmol, 2M solution in hexane) was added dropwise to the reaction mixture while stirring well with magnetic stirrer. The resulting yellow solution was stirred at room temperature for 2 hours and then the mixture was cooled in an ice bath. 30% HBr in acetic acid (2 mL) was added dropwise to the cooling solution, at which time the gas evolved vigorously. The solution was stirred for 1 hour, during which methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate precipitated. The solid was collected by filtration and dried under vacuum to give the title compound 120 mg (45%). _{^{1 H-NMR (CDCl 3;}} 300 MHz) δ 2.64 (s, 3H), 3.91 (s, 3H), 4.27 (s, 2H), 8.10 (s, 1H).

b) Methyl 5-methylthio-4- (2-phenyl (1,3-thiazol-4-yl)) thiophene-2-carboxylate 5- (Methoxycarbonyl) -2- ) -Thiophene-3-thiocarboxamide (100 mg, 0.4 mmol, product of Maybridge Chemical Company, Cornwall, UK) was dissolved in acetone (20 ml). To this solution, methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (112 mg) prepared in the previous step was added and the mixture was heated to reflux for 3 hours. The precipitated solid was filtered, washed with acetone and dried under vacuum to give methyl 5-methylthio-4- (2-phenyl (1,3-thiazol-4-yl)) thiophene- 82 mg (65%) was obtained. _{^{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, 1 H).

c) 5-Methylthio-4- (2-phenyl (1,3-thiazol-4-yl)) thiophene-2-carboximidine: Carboxylate (80 mg) was treated in a similar manner to Example 1 to give 5-methylthio-4- (2- (2-methyl-thiazol- Phenyl (1,3-thiazol-4-yl)) thiophene-2-carboxidine. ^{1 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 (broad s, 2H), 9.38 (broad s, 2H). Mass spectrum (MALDI-TOF, m / z ): C 15 H 13 N 3 theoretical value for _{S 3, 332.0 (M + H} ), Found; 332.1

Example 36

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

a) Methyl 4- [4- (2-chloro (4-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 2-carboxylate: pyridine-4-carbonyl (300 mg, 1.7 mmol) was dissolved in anhydrous CH ₃ CN (4 mL). While stirring with a magnetic stirrer, trimethylsilyldiazomethane (4 mL, 8 mmol, 2M solution in hexane) was added dropwise to the reaction mixture. The resulting yellow solution was stirred at room temperature for 2 hours, and the mixture was cooled in an ice bath. 30% HBr in acetic acid (2 mL) was added dropwise to the cooling solution, at which time the gas was vigorously released. The solution was stirred for 1 hour, during which 2-bromo-1- (2-chloro (4-pyridyl)) ethan-1-one precipitated. The solid was 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, from Maybridge Chemical Company, Cornwall, UK) And the mixture was heated to reflux. At this time, the precipitated solid was filtered, washed with methanol and then dried under vacuum to give methyl 4- [4- (2-chloro (4-pyridyl)) (1,3-thiazol- 100 mg of 5-methylthiothiophene-2-carboxylate was obtained. _{^{1 H-NMR (CD 3 OD}} ; 300 MHz) δ 2.73 (s, 3H), 3.94 (s, 3H, overlapping H ₂ O peak), 7.92-7.99 (m, 2H) , 8.05 (s, 1H), 8.24 (s, 2 H), 8.48 (m, 1 H).

b) 4- [4- (2-Chloro (4-pyridyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboximidine: Carboxylate (100 mg, 0. 26 mmol) was added to a solution of methyl 4- [4- (2-chloro (4-pyridyl) ) Was prepared in a similar manner to Example 1 to yield 4- [4- (2-chloro (4-pyridyl)) (1,3-thiazol-2-yl)] - 5-methylthiothiophene -2-carboxamidine (50 mg). ¹ H-NMR (CDCl ₃ / CD ₃ OD, 300 MHz)? 2.82 (s, 3H), 7.95 (dd, J = 1.4 and 5.3 Hz, 1H), 8.08 (s, 1 H), 8.42 (d, J = 5.3 Hz, 1 H), 8.56 (s, 1 H). Mass spectrum (MALDI-TOF, m / z ): C 14 H 11 N 4 theoretical value for _{S 3 Cl, 367.0 (M +} H), Found; 367.1.

Example 37

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

2-yl)] - 5-methylthiothiophene-2-carboxidine (35 mg, 0.1 mmol, ) Was dissolved in a mixture of MeOH and CH ₂ Cl ₂ (1: 1, 6 mL). To this solution, while stirring, m-chloroperoxybenzoic acid (100 mg) fractions were added over 3 hours. The mixture was stirred for another 2 hours and the solvent was removed in vacuo. The resulting residue was dissolved in MeOH (8 mL). The strong anion exchange resin (AG 1-X8, 5 ml, 1.4 meq / mL) was charged to a disposable chromatography column and washed with H ₂ O (5 x 5 mL) and MeOH (3 x 5 mL). The methanol-based solution obtained in the reaction was gradually introduced into this column and the column effluent was collected. The column was washed with MeOH (2 x 5 mL) and the washings were also collected. The collected effluent was evaporated in vacuo and the residue was treated with purified thin layer chromatography (silica gel, 10% MeOH in CH ₂ Cl ₂ containing 20% acetic acid). The main band was separated, suspended in CH ₂ Cl ₂ , and filtered. The filtrate was collected and the residue was washed with 10% MeOH in CH ₂ Cl ₂ saturated with NH ₃ . The washings were combined with the crude filtrate and the solvent was removed under vacuum. After dissolving the obtained solid in a 10% MeOH in CHCl _3, and filtered through a 0.45 ㎛ 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, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1H), 8.00 (s , ≪ / RTI > 1H), 8.35 (s, 1H). Mass spectrum (MALDI-TOF, m / z ): C 15 H 12 O 2 N 3 theoretical value for _{S 3 Cl, 398.0 (M +} H), Found; 398.0.

Example 38

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

A solution of 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- Lt; / RTI > Methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxylate prepared in step a) of Example 10 (0.6 g, 1.7 mmol ) Was injected at once and the Bombs were sealed and heated in an oil bath at 80 占 폚 for 48 hours. The Bombes were cooled to -78 [deg.] C and then opened to evaporate the ammonia at room temperature. The residual solid was collected and dried under vacuum to obtain 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), < / RTI > 8.20 (s, 1H).

b) 5- methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carbonitrile: P ₂ in N ₂ with stirring under an atmosphere, dichloroethane (13 mL) The slurry of O ₅ (2.7 g, 19 mmol) and hexamethyldisiloxane (6.7 mL) was heated to 90 < 0 > C. After heating for 2 hours, the resulting clear solution was cooled to 40 < 0 > C. To the solution was added 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxamide (0.9 g, 2.7 mmol) , And the mixture was heated at 75 DEG C for 5 hours. The solution was cooled to room temperature and stirred with aqueous NaCl (6 M, 100 mL) for 10 min. Upon addition of the aqueous solution a yellow solid precipitated. After 10 min, the solid was filtered off and dried in vacuo to give 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carbonitrile (0.5 g, 59%). ^{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, 1H), 8.51 (s, 1 H).

c) hydrazino [5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl) (100 mg, 0.32 mmol) was dissolved in EtOH (10 mL). To this solution was added hydrazine monohydrate (10 equivalents) and the mixture was heated under reflux for 3 hours. The EtOH solution was concentrated to 1 mL and water (2 mL) was added. This gave a white solid. The solid was collected by filtration, washed with a small amount of water and dried under vacuum to give hydrazino [5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl) ] Methaneimine (45 mg). _{^{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), 7.98 (m, 2H) , 8.10 (s, 1 H). Mass spectrum (ESI, m / z): C 15 H 14 N 4 theoretical value for _{S 3, 347.04 (M + H} ), Found; 347.1.

Example 39

{Imino [5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)

4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboximidine (20 mg, 0.06 mmol) prepared in step (b) ) Was dissolved in MeOH and methylamine (0.6 mL, 2M solution in tetrahydrofuran) was added to this solution. The solution was refluxed for 6 hours and the solvent was removed in vacuo to give a solid. This solid was dissolved in a small amount of MeOH. H ₂ O was added dropwise to the methanolic solution until a precipitate formed. The solid was separated and washed with a small amount of water and dried under vacuum to give {imino [5-methylthio-4- (4-phenyl (1,3-thiazol- ] Methyl} methylamine (15 mg, 72%). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 2.77 (s, 3H), 3.00 (s, 3H), 7.36-7.42 (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): C 16 H 15 N 3 S 3 Calcd, 346.5 (M + H) for, Found; 346.2.

Example 40

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

2-Bromo-1- (3-methoxyphenyl) ethan-1-one (2 g, 8.7 mmol) was added to a solution of 2-bromo-1- (3-hydroxyphenyl) ethan- Was taken in a round bottom flask equipped with a stirring bar. The flask was placed under an N ₂ atmosphere 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 resulting solution was allowed to warm to room temperature overnight. The solvent was removed in vacuo and the residue was purified by passing through a pad of silica gel (50 g) to give 1.3 g (69%) of 2-bromo-1- (3-hydroxyphenyl) ethan- . ¹ H-NMR (CDCl ₃ ; 300 MHz)? 4.47 (s, 2H), 6.21 (s, 1H), 7.14 (m, 1H), 7.35 (m, 1H), 7.52-7.82 (m, 2H).

b) Methyl 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate: (229 mg, 1.1 mmol) was treated in a similar manner to step (a) of Example 13 to give methyl 4- [4- (3-hydroxyphenyl) ethan- Hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (225 mg, 61%). ^{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, 2 H), 8.12 (s, 1 H), 8.20 (s, 1 H).

c) Synthesis of (tert-butoxy) -N - ({4- [4- (3-hydroxyphenyl) imino-methyl) carboxamide: methyl 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthio conduct thiophene-2-carboxylate example (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboximidine (prepared by treating 2 g , 5.8 mmol) was dissolved in anhydrous DMF (10 mL). To this solution di-tert-butyl dicarbonate (1.38 g, 6.3 mmol) and DIEA (2 mL, 11.5 mmol) were added and the mixture was stirred at room temperature for 18 hours. The DMF was removed in vacuo and the residue was purified by silica gel column chromatography to give (tert-butoxy) -N - ({4- [4- (3- hydroxyphenyl) Yl)] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide (1.8 g, 70%). ^{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), 7.49-7.52 (m, 2 H), 8.09 (s, 1 H), 8.71 (s, 1 H).

d) Preparation of tert-butyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazole Yl)] phenoxy} acetate: To a solution of (tert-butoxy) -N - ({4- [4- (3-hydroxyphenyl) )] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide (23 mg, 0.05 mmol) 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 KI (5 mg) and the mixture was heated at 70 ° C for 18 hours. The solvent was removed under vacuum and the residue was purified by silica gel thin layer chromatography to give tert-butyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2 -Methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (12 mg, 42%) which was used in the next step.

e) 2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid: tert- Butyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol- ] Phenoxy} acetate (12 mg, 0.02 mmol) was dissolved in 1 mL of 50% TFA in CH ₂ Cl ₂ containing 2% H ₂ O and stirred for 4 hours. The solvent was removed in vacuo. Residual TFA was azeotropically removed with toluene to give 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol- ) Acetic acid (8.7 mg, 100%). _{^{1 H-NMR (CD 3 OD}} / CDCl 3, 30O 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, IH), 7.68 (m, IH), 7.84 (s, IH), 8.46 (s, IH). Mass spectrum (ESI, m / z): C 17 H 15 N 3 O 3 Calcd for _{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) Preparation of tert-butyl 2- {2- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazole Yl] phenoxy} acetate: 4- [4- (2-Hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methyl (100 mg, 0.29 mmol) was treated in a similar manner to step (c) of Example 40 to give (tert-butoxy) -N - ({4- [4- (3-thiazol-2-yl)] - 5-methylthio (2-thienyl)} iminomethyl) carboxamide (100 mg, 0.22 mmol, 77%). This compound was treated in a similar manner to step (d) of Example 40 to give tert-butyl 2- {2- [2- (5 - {[(tert-butoxy) carbonylamino] Methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (63 mg, 50%). _{^{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 J = 1.8 and 7.8 Hz, 1H), 8.51 (s, 1H), 7.14 (dt, J = 1H).

b) 2- {2- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid: tert- Butyl 2- {2- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazol- ] Phenoxy} acetate (60 mg, 0.12 mmol) was treated in a manner similar to that of Example 40, step (e) to give 2- {2- [2- (5-amidino-2-methylthio-3- ) -1,3-thiazol-4-yl] phenoxy} acetic acid (22 mg, 50%). ^{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 , 8.60 (s, 1H), 8.62 (s, 1H), 9.00 (broad s, 2H), 9.37 (broad s, 2H). Mass spectrum (ESI, m / z): C 17 H 15 N 3 O 3 Calcd for _{S 3, 406.5 (M + H} ), Found; 406.1.

Example 42

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

a) Methyl 4- (1,1-dimethyl-1-stearylethyl) -5-methylthiothiophene-2-carboxylate: 4-Bromo-5-methylthiothiophene- EP 0676395 A2) (4.67 g, 18.4 mmol) was dissolved in anhydrous THF (30 mL) and taken in a round bottom flask and cooled to -78 ° C under N ₂ atmosphere. To this solution n-butyllithium (20.3 mL, 40.6 mmol, 2M in cyclohexane) was added dropwise. The resulting solution was stirred at -78 < 0 > C for 45 minutes and then warmed to -60 < 0 > C. To this solution was added trimethyltin chloride (40.6 mL, 40.6 mmol, 1M in THF) dropwise. The solution was stirred at -60 占 폚 for 30 minutes and then warmed to room temperature. After removing the THF under vacuum, 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 washed with 10% HCl and saturated NaCl and dried over anhydrous MgSO ₄ . Et ₂ O was removed in vacuo and the residue taken up in MeOH. The MeOH solution was 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-stanolethyl) -5-methylthiothiophene-2-carboxylate in oil. ¹ H-NMR (CDCl ₃ , 300 MHz)? 0.31 (s, 9H), 2.57 (s, 3H), 3.86 (s, 3H), 6.98

b) Methyl 4- (6-bromo (2-pyridyl)) - 5-methylthiothiophene-2-carboxylate: Methyl 4- (1,1-dimethyl- Ethyl) -5-methylthiothiophene-2-carboxylate (195 mg, 0.56 mmol) and 2,6-dibromopyridine (398 mg, 1.7 mmol) were taken in anhydrous DMF (2 mL). To this mixture was added tetrakisphenylphosphine-palladium (20 mg) and the mixture was heated at 120 ° C for 24 hours. The DMF was removed in vacuo and the residue was purified by purified silica gel thin layer chromatography to give methyl 4- (6-bromo (2-pyridyl)) - 5-methylthiothiophene-2-carboxylate 78 mg (41%). _{^{1 H-NMR (CDCl 3;}} 300 MHz) δ 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- -5-methylthiothiophene-2-carboxylate (78 mg, 0.23 mmol), phenylboronic acid (33 mg, 0.27 mmol) and tetrakistriphenylphosphine- palladium (10 mg) . 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 stirred and then heated at 90 ° C. for 18 hours. The solvent was removed under vacuum, 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. The aqueous layer was treated by thin layer chromatography to confirm the presence of a substantial hydrolyzed product. Thus, the aqueous layer was separated, acidified with 10% HCl and extracted with EtOAc. Washing the EtOAc layer with saturated NaCl and dried over anhydrous Na ₂ SO _4. This second EtOAc fraction was evaporated and the residue was dissolved in MeOH and then treated with trimethylsilyldiazomethane (1.2 eq.). The methanolic solution and the first EtOAc fraction were combined and evaporated. The residue was purified by thin layer chromatography (10% EtOAc in hexanes) to afford 40 mg (51%) of methyl 5-methylthio-4- (6- phenyl (2- pyridyl) ), Which was used directly in the next step.

methylthio-4- (6-phenyl (2-pyridyl)) thiophene-2-carboximidine: Carboxylate (40 mg, 0.12 mmol) was treated in a similar manner to Example 1 to give 5-methylthio-4- (6-phenyl (2-pyridyl) 10 mg of ophen-2-carboxamidine was obtained. ¹ H-NMR (CD ₃ OD, 300 MHz)? 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, 1 H), 8.03 - 8.12 (m, 3H). Mass spectrum (ESI, m / z): C 17 H 15 N 3 theoretical value for _{S 2, 326.1 (M + H} ), Found; 326.1.

Example 43

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

a) Methyl 5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxylate: Methyl 4- (1,1-dimethyl- 1-stanolethyl) -5-methylthiothiophen- -Carboxylate (200 mg, 0.57 mmol, prepared in step a) of Example 42 and 1-bromo-3-phenylbenzene (266 mg, 1.14 mmol) were taken in anhydrous DMF (2 mL). To this mixture was added tetrakistriphenylphosphine-palladium (20 mg) and the mixture was heated at 120 占 폚 for 24 hours. The DMF was removed in vacuo and the residue was purified by preparative silica gel thin layer chromatography to give 39 mg (20%) of methyl 5-methylthio-4- (3-phenylphenyl) thiophene- . ¹ H-NMR (CD ₃ OD, 300 MHz)? 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-carboximidine: Methyl 5-methylthio-4- (3- phenylphenyl) thiophene- (35 mg, 0.1 mmol) was treated in a similar manner to Example 1 to obtain 17 mg of 5-methylthio-4- (3-phenylphenyl) thiophene-2-carboxymidine as a solid. ¹ H-NMR (CD ₃ OD, 300 MHz)? 2.60 (s, 3H), 7.3-7.6 (m, 10H). Mass spectrum (ESI, m / z): C 18 H 16 N 2 Calcd for _{S 2, 325.4 (M + H} ), Found; 325.2.

Example 44

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

a) Methyl 5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate: 5.4 mmol) was treated in a similar manner to step (a) of Example 32 to give 2-bromo-1-phenylthiomethylethane-1-one. The dry solid (1.3 g, 5.3 mmol) was dissolved in acetone (25 ml). To this solution was added 5- (methoxycarbonyl) -2- (methylthio) -thiophene-3-thiocarboxamide (1.32 g, 5.3 mmol, product of Maybridge Chemical Co., Cornwall, UK) Lt; / RTI > for one hour. The precipitated solid was filtered, washed with acetone and dried under vacuum to obtain methyl 5-methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene- Carboxylate (1.5 g, 71%). This was used in the next step without further purification.

b) 5-Methylthio-4- [4- (phenylthiomethyl) (1,3-thiazol-2-yl)] thiophene-2-carboximidine: Thiophene-2-carboxylate (1.5 g, 3.8 mmol) was treated in a similar manner to Example 1 to give the product Was crystallized from methanol to obtain 0.86 g (60%) of 5-methylthio-4- [4- (phenylthiomethyl) (1,3- thiazol- ≪ / RTI > ^{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, H ). Mass spectrum (MALDI-TOF, m / z ): C 16 H 15 N 3 S 4 theoretical value for, 378.0 (M + H), Found; 378.1.

Example 45

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

a) Methyl 4- [4- (2-chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl ₅ (0.54 g, 2.6 mmol) were placed in a round bottom flask equipped with a reflux condenser. The mixture was heated in an oil bath to 120 < 0 > C for 70 minutes. The mixture was cooled and phosphorus oxychloride formed was removed in vacuo to give 0.52 g (96%) of 2-chloro-4, 5-dimethoxybenzoyl chloride as a solid. Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated in a similar manner to step (a) of Example 32 to give 2-bromo- Dimethoxyphenyl) ethan-1-one. The dry solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution was added 5- (methoxycarbonyl) -2- (methylthio) -thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) and the mixture was refluxed for 5 hours. At this time, the precipitated solid was filtered, washed with acetone and dried under vacuum to give methyl 4- [4- (2-chloro-4, 5-dimethoxyphenyl) )] - 5-methylthiothiophene-2-carboxylate (0.53 g, 54%). ^{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, 1 H), 8.13 (s, 1 H), 8.17 (s, 1 H).

b) 4- [4- (2-Chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- The obtained methyl 4- [4- (2-chloro-4,5-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- g, 1.2 mmol) was treated in a similar manner to Example 1, and the product was crystallized from methanol to give 4- [4- (2-chloro-4, 5-dimethoxyphenyl) -2-yl)] - 5-methylthiothiophene-2-carboxidine (0.3 g, 60%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 2.77 (s, 3H), 3.84 (s, 6H), 7.13 (s, (s, 1 H), 9.16 (broad s, 2H), 9.48 (broad s, 2H). Mass spectrum (MALDI-TOF, m / z ): C 17 H 16 N 3 O 2 Calcd for _{S 3 Cl, 426.0 (M +} H), Found; 426.6.

Example 46

4 - [(methylethyl) sulfonyl] -5-methylthiothiophene-2-carboxidine

5-methylthiothiophene-2-carboxylate (100 mg, product of Maybridge Chemical Company, Cornwall, UK) was treated in a manner similar to Example 1 to give 4- [ (Methylethyl) sulfonyl] -5-methylthiothiophene-2-carboxidine (50 mg). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 1.21 (d, J = 6.77 Hz, 6H), 2.66 (s, 3H), 3.55 (m, 1H), 7.85 Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 9} H 14 N 2 O 2 Calcd for _{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} acetate Trifluoroacetate

(Tert-butoxy) -N - ({4- [4- (3-hydroxyphenyl) -N ' To a solution of 42 mg (0.094 mmol) potassium iodide (0.006 mmol, 1 eq.) In THF (10 mL) was added a solution of 2- (2-thienyl) 1 mg, commercially available from Aldrich Chemical Co.), cesium carbonate (0.187 mmol, 61 mg, from Aldrich Chemical Co.), and methyl bromoacetate (0.187 mmol, 18 μl, from Aldrich Chemical Co.) Lt; / RTI > The reaction solution was concentrated and purified on a 1 mm silica purification plate (eluent: 3% methanol / CH ₂ Cl ₂ ) to obtain methyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] Yl) phenoxy} acetate (23% yield), which was then chromatographed on silica gel using 50% trifluoro < RTI ID = 0.0 > After treatment with a solution of rosic acid / CH ₂ Cl ₂ for 1 h, it was concentrated, triturated with diethyl ether and dried to give methyl 2- {3- [2- (5-amidino-2-methylthio-3-thienyl ) -1,3-thiazol-4-yl] phenoxy} acetate trifluoroacetate (77% yield). _{^{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) Theoretical values for C ₁₈ H ₁₇ N ₃ O ₃ S ₃ . 419.5 (M + H), 420.3.

Example 48

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

A mixture of 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thienyl) -1,3-thiazole (0.396 mmol, 42 mg) and diisopropylethylamine (0.494 mmol) were dissolved in 1 mL of anhydrous DMF and PyBOP (0.396 mmol, 206 mg) mmol) was added and stirred for 18 hours, then the solution was concentrated, purified on a 2 g silica SPE column and deprotected with 50% trifluoroacetic acid / methylene chloride to give 5-methylthio-4- [ Thiophene-2-carboxymidine trifluoroacetate (67 mg, yield: 67%) was obtained as colorless crystals from 4- (3 - {[N-benzylcarbamoyl] methoxy} ). _{^{1 H-NMR (CDCl 3 /}} 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 C ₂₄ H ₂₂ N ₄ O ₂ S ₃ : 494.6 (M + H), 495.2.

Example 49

Methyl) carbamoyl} methoxy) phenyl) (1,3-thiazol-2-yl)} - 5-methyl Thiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, Yl) phenoxy} acetic acid (100 mg, 0.197 mmol) was dissolved in anhydrous DMF (1 mL), PyBOP (0.396 mmol, 206 mg), 3,4- dimethoxybenzylamine (0.396 mmol, 66 mg) and diisopropylethylamine (0.494 mmol; 86 l) were added and stirred for 18 hours, then the solution was concentrated and purified on a 2 g silica SPE column. Phenyl)] (1,3 < / RTI >< RTI ID = 0.0 > -Thiazol-2-yl)} - 5-methylthiothiophene-2-carboxymidine trifluoroacetate (41% yield). _{^{1 H-NMR (CDCl 3 /}} TFA-d: 300 MHz) δ 8.48 (s, 1H), 7.78 (s, 1H), 7.72 (m, 1H), 7.66 (d, 1H), 7.39 (t, 1H) , 7.02 (d, 1H), 4.68 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H), 3.56 (s, 3H). 2.78 (s, 3 H). Mass Spectrum (LC-Q ESI, m / z) C 26 H 26 N 4 O 4 Calcd for _{S 3: 554.6 (M + H} ), Found; 555.2

Example 50

Methoxy) phenyl] (1,3-thiazol-2-yl)} thiophene (hereinafter referred to as " -2-carboxamidine trifluoroacetate

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, (0.396 mmol, 206 mg) and N-phenylethylenediamine (0.396 mmol) were dissolved in 1 mL of anhydrous DMF, , 54 mg) and diisopropylethylamine (0.494 mmol; 86 l) were added and stirred for 18 hours, then the solution was concentrated and purified on a 2 g silica SPE column. Phenyl)] (1 < / RTI >< RTI ID = 0.0 > , 3-thiazol-2-yl)} thiophene-2-carboxymidine trifluoroacetate (63% yield). _{^{1 H-NMR (CDCl 3 /}} TFA-d; 300 MHz) δ 8.50 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.66 (d, 1H), 7.39 (t, 1H) , 7.02 (d, 1 H), 4.68 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H). 3.56 (s, 3 H). 2.78 (s, 3 H). Mass Spectrum (LC-Q ESI, m / z) C 25 H 25 N 5 O 2 Calcd for _{S 3: 523.6 (M + H} ), Found; 524.1

Example 51

Methoxy} phenyl) (1, 3-thiazol-2-yl)] - Thiophene-2-carboxydimidine trifluoroacetate

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 40, 3-thiazol-4-yl] phenoxy} acetic acid 83 mg (0.164 mmol) was reacted with 2-morpholin-4-ylethylamine (0.328 mmol, To give 5-methylthio-4- [4- (3 - {[N- (2-morpholin-4- ylethyl) carbamoyl] methoxy} phenyl) )] Thiophene-2-carboxymidine trifluoroacetate (54 mg, 54% yield). ^{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), 3.53-3.64 (m, 5H), 3.24-3.38 2.80 (s, 3 H), 1.1 (t, 2 H). Mass spectrum (ESI. M / z) Theoretical value for C ₂₃ H ₂₇ N ₅ O ₃ S ₃ : 517.6 (M + H), found 518.2.

Example 52

5-methylthio-4- {4- [3- (2-morpholin-4-yl-2-oxyethoxy) phenyl] (1,3-thiazol- Gt; trifluoroacetate < / RTI >

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, step (c) Yl) phenoxy} acetic acid (73 mg, 0.144 mmol) was reacted with morpholine (0.288 mmol; 25 μl) to give 5-methylthio-4- {4- [ 50 mg (75%) of 3- (2-morpholin-4-yl-2-oxoethoxy) phenyl] Yield). ^{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, IH), 6.98-7.00 (dd, J = 2.3 Hz and 8.2 Hz, IH), 4.95 (s, 2H), 3.53-3.67 (m, 8H), 2.82 (s, Mass spectrum (ESI, m / z) C 21 H 22 N 4 O 3 S 3 Calcd for: 474.6 (M + H), Found; 475.2.

Example 53

5-methylthio-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene- Fluoroacetate

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, (100 mg, 0.198 mmol) was reacted with tert-butylpiperazinecarboxylate (0.396 mmol; 74%) in a manner similar to that of Example 48, step (b) mg) to give 5-methylthio-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol- -Carboxamidine trifluoroacetate (43% yield). ^{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, 1H), 7.01 (dd, J = 2.3 Hz and 8.1 Hz, IH), 5.02 (s, 2H), 3.76 (bs, 4H), 3.17-3.26 (m, 4H). 2.82 (s, 3 H). Mass Spectrum (LC-Q ESI, m / z) C 21 H 23 N 5 O 2 Calcd for _{S 3: 473.6 (M + H} ), Found; 474.2.

Example 54

Methoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2- Carboxamidine hydrochloride

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, step (c) Yl) phenoxy} acetic acid 51 mg (0.101 mmol) was reacted with N- (2-aminoethyl) (tert-butoxy) ) Carboxamide (0.202 mmol; 32 mg) to give 4- (4- {3 - [(N- {2 - [(tert- butoxy) carbonylamino] ethyl} carbamoyl) methoxy] phenyl } (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxinidine (80% yield). This was then deprotected with 4N HCl in dioxane to give 4- [4- (3- {[N- (2-aminoethyl) carbamoyl] methoxy} phenyl) (1,3- Yl] -5-methylthiothiophene-2-carboxidine hydrochloride (68% yield). ¹ H-NMR (CD ₃ OD, 300 MHz)? 8.55 (s, 1H), 7.95 (s, 1H), 7.73 (m, 2H), 7.41 s, 2H), 3.51 (m, 2H), 3.13-3.31 (m, 2H), 2.83 (s, 3H). Mass spectrum (ESI, m / z) C 19 H 21 N 5 O 2 Calcd for _{S 3: 447.5 (M + H} ), Found; 448.2.

Example 55

2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5- -Carboxamidine trifluoroacetate < RTI ID = 0.0 >

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, step (c) (0.154 mmol, 20 mg), 1-hydroxy-7-azabenzotriazole HOAt (0.154 mmol, 21 mg), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.154 mmol , 58 mg) and diisopropylethylamine (0.258 mmol, 44)) to give the crude product which was then purified on a 1 mm silica plate (eluent: 3% methanol / methylene chloride) Phenyl} (1, 3-thiazol-2-yl)) - 5-methylthio (2 (4-acetylpiperazinyl) -Thienyl)] iminomethyl} (tert-butoxy) carboxamide (yield: 53%). This was then reacted with a solution of trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour, concentrated and then purified on a silica SPE column (eluent: 15% methanol / methylene chloride) 2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5- -Carboxamidine trifluoroacetate (80% yield). ¹ H-NMR (CD ₃ OD, 300 MHz)? 8.48 (s, IH), 7.91 (s, IH), 7.69 (m, 2H), 7.38 8.1 Hz, 1H), 4.93 (s, 2H), 3.52-3.67 (m, 8H), 2.78 (s, 3H), 2.12 (s, 3H). Mass spectrum (ESI, m / z) C 23 H 25 N 5 O 3 S 3 Calcd for: 515.6 (M + H), Found; 516.2.

Example 56

Phenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophen-2 -Carboxamidine trifluoroacetate < RTI ID = 0.0 >

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, step (c) 4-yl] phenoxy} acetic acid (54 mg, 0.107 mmol) was added to a solution of N-methylpiperazine (0.128 mmol, 14 μl), 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 , 49 mg) and diisopropylethylamine (0.268 mmol, 56 [mu] l) to give the crude product which was then partitioned between methylene chloride and 1N NaOH and washed. An organic layer was obtained, which was similarly washed with 10% citric acid and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to give a yellow oil. The oil was then purified on a 1 mm silica plate (eluent: 5% methanol / methylene chloride) to give (tert-butoxy) -N- {imino [4- (4- {3- [2- -Methylpiperazinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl) -5-methylthio (2-thienyl)] methyl} carboxamide, This was reacted with a solution of trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour, concentrated and then purified on a silica SPE column (eluent: 10-15% methanol / methylene chloride) Phenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophen-2 -Carboxamidine trifluoroacetate (33% yield). _{^{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) C 22 H 25 N 5 O 2 Calcd for _{S 3: 487.6 (M + H} ), Found; 488.2

Example 57

2- (4-benzylpiperazinyl) ethoxy} phenyl) (1,3-thiazol-2-yl)] thiophen- -Carboxamidine trifluoroacetate < RTI ID = 0.0 >

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, step (c) Benzylpiperazine (0.128 mmol, 22 [mu] l), 1-hydroxy-7-azabenzo [ 17.0 mg of triazole (HOAt) (0.128 mmol, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU mmol, 48 mg) and diisopropylethylamine (0.267 mmol, 50 [mu] l) to give the crude product which was then partitioned between methylene chloride and 1N NaOH and washed. An organic layer was obtained, which was similarly washed with 10% citric acid and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to give a yellow oil. The oil was then purified on a 1 mm silica gel purification plate (eluent: 5% methanol / methylene chloride) to give (tert-butoxy) -N- (imino { (3-thiazol-2-yl)] (2-thienyl)} methyl) carboxamide was obtained in the same manner as in [ This was reacted with a solution of trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour, concentrated and then purified on a 5 g silica SPE column (eluent: 10-15% methanol / methylene chloride) To obtain 5- methylthio-4- [4- (3- {2-oxo-2- [4-benzylpiperazinyl] ethoxy} phenyl) -2-carboxymidine trifluoroacetate (60% yield). _{^{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 2H), 4.37 (s, 2H), 3.3 (m, 4H), 2.81 (s, 3H), 2.49-2.57 (m, 4H), 2.35 (s, 3 H). Mass (ESI, m / z) C 28 H 29 N 5 O 2 Calcd for _{S 3: 563.7 (M + H} ), Found; 564.3.

Example 58

(D, L) -4- (4- {3- [2- (3-aminopyrrolidinyl) -2-oxoethoxy] phenyl} Methylthiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 48, step (c) Thiazol-4-yl] phenoxy} acetic acid was prepared from (D, L) (tert-butoxy) -N- (0.122 mmol, 23 mg), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (D, L) -4- (4- {4- [2- (4-Fluoro-benzyloxy) 3- [2- (3-aminopyrrolidinyl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene- (20% yield). _{^{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), 4.37 (s, 2H), 3.60-4.01 (m, 5H), 2.81 (s, 3H), 2.15-2. Mass spectrum (ESI, m / z) C 21 H 23 N 5 O 2 Calcd for _{S 3: 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- Fluoroacetate

2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methylthio-3-thiazolecarboxamide prepared by a method similar to that of Example 40, (0.078 mmol, 8 占)), O- (7-aza-benzyloxy) -1,3-thiazol-4-yl] phenoxy} acetic acid was obtained in a similar manner to Example 57, (0.078 mmol, 30 mg), 1-hydroxy-7-azabenzotriazole (HOAt) ( 4- (3- (2-oxo-2-piperidylethoxy) phenyl] propionamide was obtained by reacting 5-methylthio-4- {4- [3- (1, 3-thiazol-2-yl)} thiophene-2-carboxymidine trifluoroacetate (41% yield). _{^{1 H-NMR (CD 3 OD}} ; 300 MHz) δ 8.54 (s, 1H), 7.92 (s, 1H), 7.69 (m, 2H), 7.35-7.40 (t, 1H), 6.98 (dd, J = 2 2H), 3.52-3.60 (m, 4H), 2.80 (s, 3H), 1.57 - 1.70 (m, 6H). Mass spectrum (ESI, m / z) Theoretical values for C ₂₂ H ₂₄ N ₄ O ₂ S ₃ . 472.6 (M + H), 473.2.

Example 60

2- (3- {2- [5- (Imino {[(4-polystyryloxyphenyl) methoxy] carbonylamino} methyl) -2-methylthio-3-thienyl] -1,3-thia 4-yl} phenoxy) acetic acid

2 g (1.86 mmol) of p-nitrophenyl carbonate Wang resin (0.93 mmol / g) (Calbiochem-Novabiochem, San Diego, Calif., USA) was suspended in 9 mL of a 2: 1 mixture of dry DMSO: DMF. 2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (2 g, 4.93 mmol) After addition, 1 mL of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 6.69 mmol) was added and vigorously shaken for 5 days. The resin was thoroughly washed with DMF, MeOH and diethyl ether Washed and dried under vacuum to obtain a resin bound 2- {3- [2- (5-amidino-2-methylthio-3-thienyl) -1,3-thiazol-4- yl] phenoxy} 2 g was obtained.

Example 61

(D, L) -ethyl 1- (2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol- ) Piperidine-2-carboxylate < / RTI > trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was suspended in 1 mL of anhydrous DMF. HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzo (5-fluorobenzyloxy) (0.5 M, 78 [mu] l) and diisopropylethylamine (0.233 mmol, 40 [mu] l) were added and the mixture was stirred vigorously for 18 hours After shaking, the resin was thoroughly washed with DMF, methanol, methylene chloride and diethyl ether. After drying, the crude product was removed from the resin by reaction with a solution of trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour. The solution was filtered and concentrated to a yellow oil. After purification on a 2 g silica SPE column (eluent: 3% to 10% gradient MeOH / methylene chloride), (D, L) -ethyl 1- (2- {3- [2- (5-Amidino- -Methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperidine-2-carboxylate trifluoroacetate in 30% yield. Mass spectrum (ESI, m / z) C 25 H 28 N 4 O 4 S 3 Calcd for: 544.70 (M + H), Found; 545.2.

Example 62

Phenylthiazol-2-yl)} thiophene-2-carboxamidine tri (methoxycarbonyl) Fluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was suspended in 1 mL of anhydrous DMF. HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzo (5-fluorobenzyloxy) After addition of triazole (HOAt) (0.5 M; 68 mg), pyrrolidine (0.5 M, 42 μl) and diisopropylethylamine (0.233 mmol, 40 μl) and vigorously shaking for 18 hours, , Methanol, methylene chloride and diethyl ether. After drying, the crude product was removed from the resin by reaction with a solution of trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour. After being triturated with diethyl ether and dried, a mixture of 5-methylthio-4- {4- [3- (2-oxo-2-pyrrolidinylethoxy) phenyl] (1,3- } Thiophene-2-carboxyridine trifluoroacetate (42% yield). Mass spectrum (ESI, m / z) C 21 H 22 N 4 O 2 Calcd for _{S 3: 458.6 (M + H} ), Found; 459.2.

Example 63

2- (4-benzylpiperidyl) ethoxy} phenyl) (1,3-thiazol-2-yl)] thiophen- -Carboxamidine trifluoroacetate < RTI ID = 0.0 >

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was suspended in 1 mL of anhydrous DMF. HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzo (5-fluorobenzyloxy) After addition of triazole (HOAt) (0.5 M; 68 mg), 4-benzylpiperidine (0.5 M, 88 μl) and diisopropylethylamine (0.185 mmol, 32 μl) and vigorously shaking for 18 hours, The resin was thoroughly washed with DMF, methanol, methylene chloride and diethyl ether. After drying, the crude product was removed from the resin by reaction with a solution of trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour. After the reaction mixture was triturated with diethyl ether and dried, 5-methylthio-4- [4- (3- {2-oxo-2- [4- benzylpiperidylethoxy} phenyl) -2-yl)] thiophene-2-carboxymidine trifluoroacetate (40% yield). Mass spectrum (ESI, m / z) C 29 H 30 N 4 O 2 Calcd for _{S 3: 562.7 (M + H} ), Found; 563.3.

Example 64

(D, L) -4- (4- {3- [2- (3-methylpiperidyl) -2-oxoethoxy] phenyl} Methylthiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (80 mg, 0.074 mmol) was reacted with (+/-) -3-methylpiperidine (0.5 M, 59 [mu] l), O- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.185 mmol, 32 μL) to give 4- (4- {3- [2- (3- methylpiperidyl) -2-oxoethoxy ] Phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2- carboxymidine trifluoroacetate in 28% yield. Mass spectrum (ESI, m / z) C 23 H 26 N 4 O 2 Calcd for _{S 3: 486.6 (M + H} ), Found; 487.3.

Example 65

Phenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophen-2 -Carboxamidine trifluoroacetate < RTI ID = 0.0 >

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was treated in a similar manner to Example 63 with 4-methylpiperidine (0.5 M, 59 쨉 L), O- (7-azabenzotriazole -1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1 -hydroxy-7-azabenzotriazole (HOAt) (0.5 M; (4-methylpiperidyl) -2-oxoethoxy] phenyl} (1, 2-dihydroxyphenyl) 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxymidine trifluoroacetate (33% yield). Mass spectrum (ESI, m / z) C 23 H 26 N 4 O 2 Calcd for _{S 3: 486.6 (M + H} ), Found; 487.3.

Example 66

4-yl) -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was treated in a similar manner to Example 63 with decahydroquinoline (0.5 M, 75)), O- (7-azabenzotriazole- HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) (0.185 mmol, 32 [mu] l) to give 4- (4- {3- [2- (2- azabicyclo [4.4.0] dec- 2- yl) -2-oxoethoxy] Phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxymidine trifluoroacetate in 41% yield. Mass spectrum (ESI, m / z) Theoretical values for C ₂₆ H ₃₀ N ₄ O ₂ S ₃ . 526.7 (M + H), 527.2.

Example 67

(D, L) -ethyl 1- (2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol- ) Piperidine-3-carboxylate < / RTI > Trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (80 mg, 0.074 mmol) in acetic acid (0.93 mmol / g) was treated in a similar manner to Example 63 with ethylnipecotate (0.5 M, 78 ㎕), O- (7-azabenzotriazole- -Yl) -1,1,3,3-tetramethyluronium hexafluorophosphate HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) ) And diisopropylethylamine (0.185 mmol, 32 μl) to obtain ethyl 1- (2- {3- [2- (5-amidino-2-methylthio- Thiazol-4-yl] phenoxy} acetyl) piperidine-3-carboxylate trifluoroacetate (45% yield). Mass spectrum (ESI, m / z) C 25 H 28 N 4 O 4 S 3 Calcd for: 545.7 (M + H), Found; 545.2.

Example 68

4- (3- (2-oxo-2- (1,2,3,4-tetrahydroquinolyl) ethoxy) phenyl] (1,3-thiazol- } Thiophene-2-carboxydinidine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was treated in a similar manner to Example 63 with 1,2,3,4-tetrahydroisoquinoline (0.5 M), O- (7-aza 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) 4- {3- [2-oxo-2- (1, 2, 3, 4, 4-dihydroxyphenyl) (Tetrahydroquinolyl) ethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxydinidine trifluoroacetate was obtained in 42% yield. Mass spectrum (ESI, m / z) C 26 H 24 N 4 O 2 Calcd for _{S 3: 520.7 (M + H} ), Found; 521.2.

Example 69

Methyl-thiazol-4-yl] phenoxy} acetyl) piperidin-4 -Carboxylate < / RTI > trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (0.5 M, 77 mg), O- (7-azabenzotriazole-1, 2-diazabicyclo < RTI ID = 0.0 & -Yl) -1,1,3,3-tetramethyluronium hexafluorophosphate HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) ) And diisopropylethylamine (0.233 mmol, 40 μl) to obtain ethyl 1- (2- {3- [2- (5-amidino-2-methylthio- Thiazol-4-yl] phenoxy} acetyl) piperidine-4-carboxylate trifluoroacetate (42% yield). Mass spectrum (ESI, m / z) C 25 H 28 N 4 O 4 S 3 Calcd for: 545.7 (M + H), Found; 545.3.

Example 70

Phenyl) (1, 3-thiazol-2-yl)) - 5-methylpiperazin-1- Thiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (+) - 3-hydroxypiperidine (0.5 M, 69 mg), O- (3-hydroxypiperidine) in 1 mL of anhydrous DMF was treated in the same manner as in Example 63 with 100 mg (0.093 mmol) (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (4- (3- {2 - ((3R) -3-hydroxypiperidyl) thiomorpholine by reacting 4- (4- -2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxymidine trifluoroacetate in 36% yield. Mass spectrum (ESl, m / z) C 22 H 23 N 4 O 3 S 3 Calcd for: 489.7 (M + H), Found; 489.2.

Example 71

D, L-4- (4- {3- [2- (2-ethylpiperidyl) -2-oxoethoxy] phenyl} (1,3-thiazol- Thiophene-2-carboxydimidine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was treated in a similar manner to Example 63 with 2-ethylpiperidine (0.5M), O- (7-azabenzotriazole- HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) And 4- (4- {3- [2- (2-ethylpiperidyl) -2-oxoethoxy] phenyl} (1 , 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxymidine trifluoroacetate (23% yield). Mass spectrum (ESI, m / z) Calcd for C ₂₄ H ₂₇ N ₄ O ₂ S ₃ : 501.4 (M + H), experimental value 501.4.

Example 72

2-oxoethoxy] phenyl} (1,3-thiazol-2-yl)) - 5-methyl Thiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (-) - 3-pyrrolidinol (0.5 M, 62 mg), O- (7-methylpyrrolidinone) in 1 mL of anhydrous DMF was treated in the same manner as in Example 63 with 100 mg (0.093 mmol) -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1 -hydroxy-7-azabenzotriazole (4- (3- {2 - ((3S) -3-hydroxypyrrolidinyl) -2 (2-hydroxypyrrolidinyl) (3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxymidine trifluoroacetate was obtained in a yield of 23%. Mass spectrum (ESI, m / z) C 21 H 22 N 4 O 3 S 3 Calcd for: 475.2 (M + H), Found; 475.2.

Example 73

4- (4- {3 - [(N- (5,6,7,8-tetrahydronaphthyl) carbamoyl) methoxy] phenyl} (1,3- Yl)) thiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy 1-naphthylamine (0.5 M, 73 mg) in 1 mL of anhydrous DMF was treated in the same manner as in Example 63 with 100 mg (0.093 mmol) of acetic acid (0.93 mmol / (HATU, 0.5 M, 190 mg), 1-hydroxy-7- (4-fluorobenzyloxy) -1,3,3-tetramethyluronium hexafluorophosphate 4- (4- {3 - [(N- (5,6-dihydro-5H-pyrrolo [ Thiophene-2-carboxymidine trifluoroacetate (15 mg, 30%) was obtained in the same manner as in Example 1, Yield). Mass spectrum (ESI, m / z) Theoretical value for C ₂₇ H ₂₆ N ₄ O ₂ S ₃ : 535.2 (M + H), experimental value 535.3.

Example 74

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

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy } Acetic acid (0.93 mmol / g) was treated in a similar manner to Example 63 with 3-piperidinemethanol (0.5 M, 58 mg), O- (7-azabenzotriazole -1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1 -hydroxy-7-azabenzotriazole (HOAt) (0.5 M; (4- (3- {2- [3- (hydroxymethyl) piperidyl] -2-oxo < / RTI > Ethoxy} phenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxyridine trifluoroacetate in 40% yield. Mass spectrum (ESI, m / z) C 23 H 25 N 4 O 3 S 3 Calcd for: 503.2 (M + H), Found; 503.2.

Example 75

Pyrrolidinyl} -2-oxoethoxy) phenyl] (1,3-thiazol-2-yl) -5-methylthiothiophene-2-carboxydinidine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (S) - (+) - 2-anilinomethylpyrrolidine (0.5 M, 88 mg) in 1 mL of anhydrous DMF was treated in the same manner as in Example 63 with 100 mg (0.093 mmol) (HATU, 0.5 M, 190 mg), 1-hydroxy-7- (4-fluorobenzyloxy) -1,3,3-tetramethyluronium hexafluorophosphate 2 - [(2 - {[(2R) -2 - [(4-methylpiperidin- Phenylamino) methyl] pyrrolidinyl} -2-oxoethoxy) phenyl] (1,3-thiazol-2-yl)} - 5- methylthiothiophene- 2- carboxymidine trifluoroacetate 13 mg (25% yield). Mass spectrum (ESI, m / z) C 28 H 28 N 5 O 2 Calcd for _{S 3: 563.8 (M + H} ), Found; 564.2.

Example 76

Pyrrolidinyl] -2-oxoethoxy} phenyl) (1,3-thiazol-2-yl)] - (4- 5-methylthiothiophene-2-carboxyridine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (S) - (+) - 2-methoxymethylpyrrolidine (0.5 M, 58 mg) in 1 mL of anhydrous DMF was treated in the same manner as in Example 63 with 100 mg (0.093 mmol) (HATU, 0.5 M, 190 mg), 1-hydroxy-7- (4-fluorobenzyloxy) -1,3,3-tetramethyluronium hexafluorophosphate (4- (3- {2 - [(3R) -3- (2-methylpiperazin-1-yl) (3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxamide trifluoroacetate 16 mg (35 % Yield). Mass spectrum (ESI, m / z) C 23 H 26 N 4 O 3 S 3 Calcd for: 503.2 (M + H), Found; 503.3.

Example 77

Thiazol-4-yl] phenoxy} acetyl) piperidine-3-carboxylic acid ethyl ester was used in place of 1- (2- {3- [2- Carboxymidine trifluoroacetate

2- {3- [2- (5-Amidino-2-methylthio-3-thienyl) -1,3-thiazol-4-yl] phenoxy (0.5 M, 68 mg), O- (7-azabenzotriazole-1 (1 H) -quinolinone) in 1 mL of anhydrous DMF was treated in the same manner as in Example 63 with 100 mg (0.093 mmol) -Yl) -1,1,3,3-tetramethyluronium hexafluorophosphate HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) ) And diisopropylethylamine (0.233 mmol, 40 [mu] l) to give 1- (2- {3- [2- (5-amidino-2-methylthio-3-thienyl) Yl] phenoxy} acetyl) piperidine-3-carboxymidine trifluoroacetate (23% yield). Mass spectrum (ESI, m / z) C 23 H 25 N 4 O 3 S 3 Calcd for: 516.2 (M + H), Found; 516.3.

Example 78

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

a) Methyl 5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl] (1,3-thiazol- Aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (435 mg, 1.76 mmol) was dissolved in 10 mL of reagent grade acetone. 2-Bromo-3'-trifluoromethoxyacetophenone (1.76 mmol, 497 mg) prepared by a method similar to the step (a) of Example 95 was added and the solution was refluxed for 3 hours. The solution was cooled and concentrated to an oil, dissolved in 150 mL of methylene chloride, and then washed with 50 mL of 10% HCl (aq.) And 50 mL of 2N NaOH (aq.). An organic layer was obtained which was dried over magnesium sulfate and concentrated to give methyl-5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl] (1,3- )} Thiophene-2-carboxylate (90% yield).

b) 5-Methylthio-4- {4- [3- (trifluoromethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene- To a stirred suspension of 19.4 mmol (1.04 g) of ammonium chloride (Fisher Scientific Pittsburgh, Pa., USA) in 20 mL of anhydrous toluene (from Aldrich Chemical Co.) left under an atmosphere was added 2 M 9.7 mL (19.4 mmol) of trimethyl aluminum was added for 15 minutes with a syringe, and the mixture was stirred at 0 ° C for 30 minutes. To this solution was added methyl-5-methylthio-4- {4- [3- (trifluoromethoxy) phenyl ] (1,3-thiazol-2-yl)} thiophene-2-carboxylate (837 mg, 1.94 mmol) was added thereto and refluxed for 3 hours. The reaction mixture was quenched by pouring onto a 10 g silica slurry in 50 mL of chloroform. The silica was poured onto a sintered glass funnel, washed with 15% methanol / CH ₂ Cl ₂ solution, and concentrated. The crude product was purified on a 1 mm silica plate (eluent: 15% methanol / CH ₂ Cl ₂ solution) and treated with 4 N HCl / dioxane to give 5-methylthio-4- {4- [3- (3-thiazol-2-yl)} thiophene-2-carboxymidine hydrochloride (yield: 5%). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 9.43 (bs, 1.9H), 9.05 (bs, 1.9H), 8.67 (s, 1H), 8.43 (s, 1H), 8.10 (m, 2H) , 7.65 (t, 1 H), 7.40 (m, 1 H), 2.8 (s, 3 H). Mass spectrum (LCQ-ESI, m / z) Calcd for C ₁₆ H ₁₂ F ₃ N ₃ OS ₃ : 415.5 (M + H), found 416.2.

Example 79

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

carboxylate: anhydrous CH ₂ Cl ₂ (under a drying tube for CaSO ₄ ), 10 g of methyl 10-methylthio-4- [N- (2-oxo-2-phenylethyl) carbamoyl] thiophene- To a stirred suspension of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (prepared in Example 95) in 300 mL (1.29 mmol) 30 mL of anhydrous DMF was added. After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo. The resulting yellow solid was dissolved in 10 mL of anhydrous CH ₂ Cl ₂ , cooled (0 캜), and then 266 mg (1.55 mmol) of 2-aminoacetophenone was added. N, N-Diisopropylethylamine (DIEA) (756 mL, 4.34 mmol) was 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 EtOAc and 80 mL 1 M HCl. The aqueous layer was extracted with ethyl acetate (2 x 30 mL) and the combined organic phases washed with 1 M HCl (60 mL), saturated NaHCO ₃ (120 mL) and brine (120 mL), dried over Na ₂ SO ₄ . After removal of the solvent in vacuo, the residue was recrystallized from MeOH to give the title compound as a cream-colored powder (314 mg, 70%). ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.82 (t, 1H, J = 6 Hz), 8.43 (s, 1H), 8.02 (d, 2H, J = 7 Hz), 7.69 (t, 1H J = 7 Hz), 7.57 (t, 2H, J = 7 Hz), 4.72 (d, 2H, J = 6 Hz), 3.84 (s, 3H) and 2.57 Mass spectrum (MALDI-TOF, cyano-4-hydroxycinnamic acid matrix) Theoretical value for C ₁₆ H ₁₅ NO ₄ S ₂ : 372.0 (M + Na). Experimental value: 372.1.

b) Methyl 5-methylthio-4- (5-phenyl (1,3-oxazol-2-yl)) thiophene- To a cooled (0 ° C) solution of 80.1 mg (0.229 mmol) of N- (2-oxo-2-phenylethyl) carbamoyl] thiophene- (0.286 mmol). After stirring at room temperature for 20 minutes, the mixture was concentrated in vacuo. The resulting yellow solid was recrystallized twice from MeOH to give the title compound (48.8 mg, 64%) as a beige powder. ^{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 , ≪ / RTI > 1H), 3.86 (s, 3H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, cyano-4-hydroxycinnamic acid matrix) Theoretical value for C ₁₆ H ₁₃ NO ₃ S ₂ : 332.0 (M + H). Experiment 331.9.

c) 5-Methylthio-4- (5-phenyl (1,3-oxazol-2-yl)) thiophene- Yl)) thiophene-2-carboxylate (37.0 mg, 0.112 mmol, prepared in the previous step) was added to a solution of 59.9 mg (1.12 mmol) of ammonium chloride in 0.50 mL of toluene and 2 M Was treated according to step (b) of Example 10 using 0.560 mL (1.12 mmol) of trimethylaluminum. The resulting residue was purified by chromatography on a 5 g silica SPE column (Waters Sep-Pak) (eluent: eluting impurities with 10% MeOH-CH ₂ Cl ₂ followed by 20% MeOH-CH ₂ Cl ₂ ) To obtain 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 (broad s, 2H), 9.13 (broad s, 2H), 8.72 (s, 1H), 7.93 (s, 1H), 7.84 (d, 2H, J = 7Hz), 7.53 (t, 2H, J = 7 Hz), 7.42 (t, 1H, J = 7 Hz), and 2.80 (s, 3H). Mass spectrum (MALDI-TOF, cyano-4-hydroxycinnamic acid matrix) C ₁₅ H ₁₃ N ₃ theoretical value for the _{OS 2: 316.1 (M + H} ). Experimental value: 316.5.

Examples 80 and 81

4- (4-phenylimidazol-2-yl) thiophene-2-carboxydin trifluoroacetate and 5-methylthio-4- [N- Ethyl) carbamoyl] thiophene-2-carboxymidine trifluoroacetate

Carboxylate (39.4 mg, 0.100 mmol, prepared as described in step a) of Example 79, using methyl 5-methylthio-4- [N- (2- oxo-2- phenylethyl) carbamoyl] thiophene- ) Was treated according to the procedure for step (b) of Example 10 using 64.2 mg (1.20 mmol) of ammonium chloride in 0.2 mL of toluene and 0.600 mL (1.20 mmol) of 2 M trimethylaluminum in toluene. The resulting residue was purified by chromatography on a 5 g silica SPE column (Waters Sep-Pak) (eluent: 5-20% gradient eluting with MeOH-CH ₂ Cl ₂ followed by elution with 20% MeOH-CH ₂ Cl ₂ ) To obtain a yellow resin. Crystallization from MeOH-Et ₂ O-MeCN gave 16 mg of a yellow solid consisting of two products, as evidenced by ¹ H-NMR spectrum. A portion of the mixture (11 mg) was purified by reverse phase HPLC (5 m C ₈ column, 4.6 x 100 mm, 5-100% gradient solvent B for 15 min, solvent A = 0.1% TFA / H ₂ O, / MeCN, detected at 215 nm) afforded 6 mg of 5-methylthio-4- (4-phenylimidazol-2-yl) thiophene-2- carboxymidine 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 (electrospray ionization) C ₁₅ H ₁₄ N ₄ S Calcd for _{2: 315.1 (M + H)} . Experimental value: 315.3. Further, 4 mg of 5-methylthio-4- [N- (2-oxo-2-phenylethyl) carbamoyl] -thiophene-2-carboxymidine trifluoroacetate was isolated as a colorless glass. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.30 (broad s, 2H), 8.86 (broad s, 2H), 8.68 (t, 1H, J = 5.4 Hz), 8.43 (s, 1H), 8.04 2H, J = 7 Hz), 7.70 (t, 1H, J = 7 Hz), 7.58 (t, 2H, J = 7 Hz) s, 3H). Mass spectrum (electrospray _{ionization) C 15 H 15 N 3 O} 2 S Calcd for _{2: 334.1 (M + H)} . Experimental value: 334.3.

Example 82

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

a) 4-Bromothiophene-2-carboxylic acid: A solution of 0.0 g (47.1 mmol) of 4-bromothiophene-2-carbaldehyde (from Aldrich Chemical Company, Milwaukee, Wis.) in 200 mL of t- , was added a cooled 90% (0 ℃) 20% (w / v in the solution), NaH ₂ PO ₄ was added to 100 mL, 2- methyl-2-butene 60 mL (0.566 mol) having a purity basis). Sodium chlorite (70.8 mmol, 80% purity) in 60 mL water was added with stirring. The biphasic mixture was vigorously stirred at room temperature for 16 hours 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 organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield 9.8 g of an off-white solid. Recrystallization from minimum MeCN (3 fractions) gave the title compound as a white solid (9.02 g, 93%). ¹ H-NMR (300 MHz, CDCl ₃ )? 7.79 (d, 1H, J = 1.5 Hz) and 7.55 (d, 1H, J = 1.5 Hz).

b) Methyl 4-bromothiophene-2-carboxylate: To a solution of 6.02 g (29.1 mmol) 4-bromothiophene-2-carboxylic acid (prepared in the previous step) 20 [deg.] C) was added dropwise 2.55 mL (34.9 mmol) of thionyl chloride at a rate to keep the temperature below -5 [deg.] C (about 8-10 min). After stirring at room temperature for 1 hour, the mixture was refluxed for 8 hours, cooled and concentrated in vacuo. 6.7 g of the resulting pale amber oil was passed through a pad of 150 g silica gel containing approximately 600 mL of CH ₂ Cl ₂ (the first 120 mL containing small amounts of impurities was discarded) and concentrated in vacuo to give a colorless oil To give the title compound (6.11 g, 95%). ¹ H-NMR (300 MHz, CDCl ₃ )? 7.69 (d, 1H, J = 1.5 Hz), 7.45 (d, 1H, J = 1.5 Hz) and 3.90 (s, 3H).

c) Methyl 4-cyanothiophene-2-carboxylate: To a solution of 3.82 g (17.3 mmol) methyl 4-bromothiophene-2-carboxylate (prepared in the previous step) in 10 mL anhydrous DMF was added copper cyanide (I) 3.10 g (34.6 mmol). The mixture was heated to reflux with stirring for 18 hours, cooled and poured into 100 mL of 10% (w / v) KCN. The mixture was extracted with EtOAc (3 x 60 mL) and the combined extracts were washed with 150 mL each of water and brine. After drying the solution of dark color over Na ₂ SO _4, treated with decolorizing carbon for, the filtrate obtained by the colorless solution concentrated in vacuo. The resulting light yellow solid was recrystallized from MeOH to give the title compound (1.67 g, 58%) as a cream colored solid. ¹ H-NMR (300 MHz, CDCl ₃ )? 8.09 (d, IH, 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: Reagent grade 1.32 g (7.89 mmol) methyl 4-cyanothiophene-2-carboxylate (prepared in the previous step) The solution was degassed with nitrogen for 10 minutes through a frit gas dispersion tube. Triethylamine (5.50 mL, 39.5 mmol) was added and hydrogen sulfide gas was bubbled through the solution for 5 min at a vigorous rate and then bubbled through the minimum rate (measured through outlet oil bubbler) with stirring for 5 h. Gas injection was stopped, the mixture was capped and stirred at room temperature for 19 hours. The mixture was concentrated in vacuo to a yellow solid, suspended in 10 mL EtOH, cooled to -20 C, filtered and washed with cold (-20 C) 5 mL EtOH. The obtained solid was suction-dried, and then vacuum-dried to obtain the title compound (1.31 g, 82%) as a beige solid. ¹ H-NMR (300 MHz, DMSO-d ₆ )? 9.85 (broad s, 1H), 9.51 1.5 Hz), and 3.84 (s, 3H).

e) Methyl 4- (4-phenyl-1,3-thiazol-2-yl) thiophene-2-carboxylate: To a solution of methyl 4- (aminothioxomethyl) Bromoacetophenone 148 mg (0.745 mmol) was added to a solution of the compound of formula (I) (150 mg, 0.745 mmol). After refluxing for 2 hours, the mixture was boiled and concentrated to a volume of about 2 mL. The resulting mixture was cooled (-10 <0> C), filtered and washed with cold acetone (2 x 0.5 mL). A second fraction was obtained from the mother liquor and the combined fractions were dried to give the title compound as a beige solid (202 mg, 90%). ¹ H-NMR (300 MHz, DMSO-d ₆ )? 8.56 (d, 1H, J = 1.5 Hz), 8.25 J = 7 Hz), 7.48 (t, 2H, J = 7 Hz), 7.38 (t, 1H, J = 7 Hz), and 3.89 (s, 3H). Mass spectrum (MALDI TOF, cyano-4-hydroxycinnamic acid matrix) Theoretical value for C ₁₅ H ₁₁ NO ₂ S ₂ : 302.0 (M + H). Experimental value: 301.8.

f) 4- (4-Phenyl-1,3-thiazol-2-yl) thiophene-2-carboxidine hydrochloride: (160 mg, 0.531 mmol, prepared in the previous step) was treated with 284 mg (5.31 mmol) of ammonium chloride in 2.6 mL of toluene and 2.65 mL (5.30 mmol) of 2M trimethylaluminum in toluene Was treated according to the procedure of step (b) of Example 10. The resulting pale yellow solid 10 g silica SPE column and treated with (Waters Sep-Pak) (5-20 % gradient MeOH-CH ₂ Cl ₂₎ chromatography on. The resulting pale amber glass was triturated with CH ₂ Cl ₂ -MeCN and concentrated in vacuo to give the title compound as a beige solid (68 mg, 45%). ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.51 (broad s, 2H), 9.09 (broad s, 2H), 8.71 (d, 1H, J = 1.5 Hz), 8.61 (d, 1H, J = 1H, J = 7 Hz), 8.21 (s, 1H), 8.05 (d, 2H, J = 7 Hz), 7.50 (t, 2H, J = 7 Hz), and 7.40 (t, Mass spectrum (MALDI-TOF, cyano-4-hydroxycinnamic acid matrix) C ₁₄ H ₁₁ N ₃ theoretical value for the _{S 2: 286.0 (M + H} ). Experimental value: 286.3.

Example 83

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

a) Bromo-3-phenylacetone: To a solution of 132 mL (1.00 mmol) of phenylacetyl chloride in 1.0 mL of anhydrous MeCN was added 1.05 mL (2.10 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane. After stirring at room temperature for 1 hour, the mixture was cooled (0 &lt; 0 &gt; C) and 300 mL (1.50 mmol) of 30 wt% HBr in acetic acid was added dropwise (gas evolution). After stirring for 15 min, the mixture was concentrated in vacuo and chromatographed rapidly on a 2 g silica SPE column (Waters Sep-Pak) containing 50% CH ₂ Cl ₂ -hexane to give the title compound as a light 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) Methyl 5-methylthio-4- [4-benzyl (1,3-thiazol-2-yl)] thiophene-2-carboxylate: In a manner similar to that of Example 10, methyl 4 171 mg (0.690 mmol) and 1-bromo-3-phenylacetone (prepared in step (e) of Example 82) were added to a solution of (2-methylthiophene- (147 mg, 0.690 mmol), the title compound (236 mg, 95%) was obtained as a pale brown 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 (MALDI-TOF, cyano-4-hydroxycinnamic acid _{matrix) C 17 H 15 NO 2 S} 3 Calcd for: 362.0 (M + H). Experimental value: 362 3.

c) 5-Methylthio-4- [4-benzyl (1,3-thiazol-2-yl)] thiophene- Thiophene-2-carboxylate (60 mg, 0.166 mmol, prepared in the previous step) was added to a solution of 88.8 mg (1.66 mmol) ammonium chloride in 0.5 mL toluene and 2 M Was treated according to the procedure of step (b) of Example 10 using 0.830 mL (5.30 mmol) of trimethylaluminum. After grinding in MeOH with Et ₂ O, to give the title compound as a yellow solid state (38.2 mg, 60%). ¹ H-NMR (300 MHz, CD ₃ OD)? 8.43 (s, 1H), 7.16-7.33 (m, 5H), 4.15 (s, 2H), and 2.75 (s, 3H). Mass spectrum (MALDI-TOF, cyano-4-hydroxycinnamic acid _{matrix) C 16 H 15 N 3 S} 3 Calcd for: 346.0 (M + H). Experimental value: 346.0.

Example 84

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

a) Methyl 4- [N- (2-hydroxy-1-phenylethyl) carbamoyl] -5-methylthiothiophene-2-carboxylate: Anhydrous CH ₂ Cl ₂ (under CaSO ₄ drying tube) To a stirred suspension of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (prepared in step a) of Example 79 (1.23 g, 5.29 mmol) in 20 mL of oxalyl chloride 1.85 mL (21.2 mmol) and anhydrous DMF (30 mL). After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo. The resulting yellow solid was dissolved in 20 mL of anhydrous CH ₂ Cl ₂ , cooled (0 ° C.), and 1.85 mL (10.6 mmol) of N, N-diisopropylethylamine and 1.02 g (7.41 mmol) of phenylglycinol After the addition, the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to an oil and was 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) citric acid and brine (200 mL) and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by chromatography on a 10 g silica SPE column (Waters Sep-Pak) (eluent: 0-20% gradient EtOAc-CH ₂ Cl ₂ ) to afford the title compound as a light yellow solid (1.26 g, 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 Hz). Mass spectrum (electrospray ionization) Theoretical values for C ₁₆ H ₁₇ NO ₄ S ₂ . 352.1 (M + H). Found: 352.0.

b) Methyl 5-methylthio -4- [N- (2- oxo-1-phenylethyl) carbamoyl] thiophene-2-carboxylate: anhydrous CH ₂ Cl ₂ 20 mL methyl 4- [N- in To a solution of 505 mg (1.44 mmol) of (2-hydroxy-1-phenylethyl) carbamoyl] -5-methylthiothiophene- (Product of Omega Chemical Company, Inc., of Qc) was added 856 mg (2.02 mmol). After stirring for 1.5 hours in an open flask at room temperature, the mixture was concentrated to about 10% by volume in a vacuum, 50 mL EtOAc and 50 mL saturated NaHCO ₃ - brine: was partitioned between (1: 1). After which the organic phase was washed with brine (200 mL), dried over Na ₂ SO _4, and concentrated in vacuo. Concentrated again from CH ₂ Cl ₂ and concentrated under high vacuum to give the title compound (495 mg, 98%) as a pale yellow foam 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 , 2H, J = 5 Hz), 3.90 (s, 3H), and 2.62 (s, 3H).

c) Methyl 5-methylthio-4- (4-phenyl (1,3-oxazol-2-yl)) thiophene- To a cooled (0 ° C) solution of 465 mg (1.33 mmol) of N- (2-oxo-1-phenylethyl) carbamoyl] thiophene- (2.00 mmol). After stirring at room temperature for 14 h, the mixture was treated with 10 mL of saturated NaHCO ₃ and dried concentrated under high vacuum. The resulting residue was partitioned between 80 mL EtOAc and 60 mL water. The aqueous layer was extracted with EtOAc (2 x 10 mL), washed the combined organic phases with brine (60 mL), dried over Na ₂ SO _4. The resulting amber solid (406 mg) was recrystallized from CH ₂ Cl ₂ -Et ₂ O to remove most of the impurities in the creamy solid state. The remaining mother liquor was treated by chromatography on a 10 g silica SPE column (Waters Sep-Pak) (eluent: 40 to 100% gradient CH ₂ Cl ₂ -hexane) and the residue was partitioned between Et ₂ O- ) To obtain the title compound (114 mg, 26%) as an open flame solid. ^{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) C 16 H 13 NO} 3 Calcd for _{S 2: 332.0 (M + H} ) : Found 332.2.

d) Methyl 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 added to a solution of 155 mg (2.90 mmol) of ammonium chloride in 1.45 mL of toluene and 2 M Was treated according to the procedure of step (b) of Example 10 using 1.45 mL (2.90 mmol) of trimethylaluminum. The resulting pale yellow solid was treated by chromatography on a 5 g silica SPE column (Waters Sep-Pak) (eluent: 10% MeOH-CH ₂ Cl ₂ ) to yield a pale yellow resin. Crystallization from MeOH-Et ₂ O (ca. 1: 3) gave the title compound (62.2 mg, 82%) as a yellow solid. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.39 (broad s, 2H), 8.97 (broad s, 2H), 8.78 (s, 1H), 8.60 (s, 1H), 7.89 (d, 2H, J = 7 Hz), 7.49 (t, 2H, J = 7 Hz), 7.38 (t, 1H, J = 7 Hz), and 2.80 (s, 3H). Mass spectrum _{(ESI) C 15 H 13 N} 3 theoretical value for the _{OS 2: 316.1 (M + H} ). Experimental value: 316.2.

Example 85

Methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride

a) 4- (Chlorocarbonyl) -2-methoxyphenylacetate: To a solution of 4-acetoxy-3-methoxybenzoic acid (Pfaltz and Bauer, Inc.) in 4 mL anhydrous CH ₂ Cl ₂ (under CaSO ₄ drying tube). To a stirred suspension of 1.00 g (4.76 mmol) 4.15 mL (47.6 mmol) oxalyl chloride and 25 mL anhydrous DMF were added. After stirring at room temperature for 4 hours, the mixture was 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.l9 (d, 1H, 8.4 Hz), 3.91 ( s, 3H), and 2.35 (s, 3H).

b) 4- (2-Bromoacetyl) -2-methoxyphenylacetate: 1.09 g of 4- (chlorocarbonyl) -2-methoxyphenylacetate (prepared in the previous step) in 10 mL of anhydrous CH ₂ Cl ₂ (4.6 mmol) 10.0 mL (20.0 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane was added. After stirring at room temperature for 2 hours, the mixture was cooled (0 C) and 3.20 mL (16.0 mmol) of 30 wt% HBr in acetic acid was added dropwise (gas evolution). After stirring for 5 min, the mixture was concentrated in vacuo and treated rapidly by chromatography (eluent: CH ₂ Cl ₂ ) on a 10 g silica SPE column (Waters Sep-Pak) to give the title compound as a pale yellow crystalline solid , 97%). ^{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)} phenylacetate: (Aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (commercially available from Maybridge Chemical Co, Cornwall, UK) in 15 mL of reagent grade acetone using a procedure similar to step (e) . Using 1.00 g (4.04 mmol) of 4- (2-bromoacetyl) -2-methoxyphenylacetate (prepared in the previous step) and 1.16 g (4.04 mmol) of the title compound as a yellow solid, 1.42 g , Which is composed of approximately 1: 1 mixture of the corresponding compound in which the title compound and the acetate are partially eliminated by ¹ H-NMR spectrum. ¹ H-NMR (300 MHz, DMSO-d ₆ )? 8.27 (s, IH), 8.22 (s, IH), 8.19 1H, J = 8.2, 1.9 Hz), 7.61 (d, 1H, J = 8.2 Hz), 7.67 (dd, 2H), 2.76 (s, 3H), 2.75 (s, 3H), 2.28 (s, 3H). 436.0 (M + H) and 394.1 (M + H): Mass spectrum _{(ESI) C 19 H 17 NO} 5 S 3 and C ₁₇ H ₁₅ NO ₃ S ₃ Calcd for. Experimental values: 436.1 and 394.2. This mixture was used without further purification in the next step in parallel with amidine formation and acetate removal.

d) 4- [4- (4-Hydroxy-3-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 2- carboxydin hydrochloride: (3-thienyl)] - (1,3-thiazol-4-yl)} phenylacetate (prepared in the previous step) (500 mg, about 1.21 mmol, based on ¹ H-NMR integration) was treated with 610 mg (11.4 mmol) of ammonium chloride in 5.7 mL of toluene and 5.70 mL (11.4 mmol) of 2M trimethylaluminum in toluene (B) of Example 10. &lt; / RTI &gt; The resulting residue was treated by chromatography on a 10 g silica SPE column (Waters Sep-Pak) (eluent: 5-20% gradient MeOH-CH ₂ Cl ₂ ) to give a yellow glass, which was dissolved in MeOH-CH ₂ Cl ₂ to obtain the title compound (192 mg, 42%) as a pale yellow solid. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.35 (broad s, 2H), 9.27 (s, 1H), 8.97 (broad 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 _{) C 16 H 15 N 3 O} 2 S 3 Calcd .378.0 (M + H for). Experimental value: 378.1.

Example 86

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

a) 3-Acetyloxy-4-methoxybenzoic acid: To a suspension of 600 mg (3.57 mmol) of 3-hydroxy-4-methoxybenzoic acid (from Aldrich Chemical Company) in 5 mL of anhydrous CH ₂ Cl ₂ was added N, N -Diisopropylethylamine (1.31 mL, 7.50 mmol) was added and the mixture was stirred until homogeneous (about 5 minutes). After acetyl chloride (305 mL, 4.28 mmol) was added dropwise over 2 minutes, 2.0 mg (0.016 mmol) of 4-dimethylaminopyridine was added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into 50 mL of EtOAc and washed with 1 M 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 using concentrated HCl. The resulting suspension was extracted with EtOAc (3 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 an off-white solid. ¹ H-NMR (300 MHz, CDCl ₃ )? 8.00 (dd, 1H, J = 8.7, 2.0 Hz), 7.79 (d, 1H, 2.0 Hz), 7.00 3H), and 2.34 (s, 3H).

b) 3- (Chlorocarbonyl) -6-methoxyphenylacetate: Using the procedure of Example 85 step (a), 400 mg (from Preparation) of 3-acetyloxy-4-methoxybenzoic acid (1.90 mmol) was treated with oxalyl chloride (663 mL, 7.60 mmol) and anhydrous DMF (25 mL) for 2 h and extracted to give the title compound as a beige crystalline solid which was used in the next step without further purification.

c) 5- (2- bromoacetyl) -2-methoxyphenyl acetate: Using the procedure of Example 85 step (B) in anhydrous CH ₂ Cl ₂ 5 mL 3- (chloro-carbonyl of) -6 -Methoxyphenylacetate (prepared in the previous step) A total sample was treated with 2.09 mL (4.18 mmol) of a 2M solution of trimethylsilyldiazomethane in hexane and 456 mL (2.28 mmol) of 30 wt% HBr in acetic acid. The crude product was purified by chromatography in the same manner as in step (b) of Example 85, and then recrystallized from CH ₂ Cl ₂ -hexane to obtain the title compound (366 mg, 67%) as a pale yellow solid. ^{1 H-NMR (300 MHz,} CDCl 3) δ 7.79 (dd, 1H, J = 8.6, 2.2 Hz), 7.70 (d, 1H, 2.2 Hz), 7.03 (d, 1H, 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: (Aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (commercially available from Maybridge Chemical Co., Cornwall, UK) in 4 mL of acetone, using a procedure similar to step (e) (374 mg) was obtained using 282 mg (1.14 mmol) of the title compound and 3.27 mg (1.14 mmol) of 5- (2-bromoacetyl) -2-methoxyphenylacetate (prepared in the previous step) It consists of a 3: 7 mixture of the title compound and the corresponding compound, partially disappearing of the acetate, by ¹ H-NMR spectrum. 436.0 (M + H) and 394.1 (M + H): Mass spectrum _{(ESI) C 19 H 17 NO} 5 S 3 and C ₁₇ H ₁₅ NO ₃ S ₃ Calcd for. Experimental values: 436.0 and 394.0. This mixture was used without further purification in the next step in parallel with amidine formation and acetate removal.

e) 4- [4- (3-Hydroxy-4-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- 2- carboxydin hydrochloride: (3-thienyl)] - (1,3-thiazol-4-yl)} phenylacetate (prepared in the previous step) (320 mg, about 0.788 mmol, based on ¹ H-NMR integration) was treated with 415 mg (7.76 mmol) of ammonium chloride in 3.5 mL of toluene and 3.88 mL (7.66 mmol) of 2 M trimethylaluminum in toluene (B) of Example 10. &lt; / RTI &gt; The resulting residue was treated by chromatography on a 10 g silica SPE column (Waters Sep-Pak) (eluent: 10-40% gradient MeOH-CH ₂ Cl ₂ ) to give a light yellow solid which was dissolved in 45 mL of DMF , And the silica gel was removed by filtration. And concentrated under high vacuum, MeOH-Et ₂ O to give a light brown recrystallized from title compound in solid form (132 mg, 44%). ¹ H-NMR (300 MHz, DMSO-d ₆ )? 9.49 (broad s, 2H), 9.16 (broad s, 2H), 8.67 3H), 7.00 (unidentified d, IH, J = 8.3 Hz), 3.82 (s, 3H), and 2.79 (s, 3H). Mass spectrum _{(ESI) C 16 H 15 N} 3 O 2 S 3 of the theoretical value: 378.0 (M + H). Experimental value: 378.1.

Example 87

5-methylthio-4- (N-phenylcarbamoyl) thiophene-2-carboxymidine hydrochloride

a) Methyl 5-methylthio -4- (N- phenylcarbamoyl) thiophene-2-carboxylate: 4 mL of anhydrous CHCl ₂ of 5- (methoxycarbonyl) -2-methylthio thiophene -3 -Carboxylic acid (prepared in Example 95) (182 mg, 0.785 mmol) was treated with 275 mL (3.15 mmol) of oxalyl chloride and 6 mL of anhydrous DMF in a similar manner to step (a) of Example 79 for 2 hours , Treated with 206 mL (1.18 mmol) of N, N-diisopropylethylamine in 3 mL of anhydrous CH ₂ Cl ₂ and 85.9 mL (0.942 mmol) of aniline for 20 minutes. The mixture was poured into 25 mL of EtOAc and washed with 1 M HCl (2 x 25 mL), saturated NaHCO ₃ (2 x 25 mL) and brine (25 mL), then dried over Na ₂ SO ₄ . After removal of the solvent in vacuo, the pure title compound (163 mg, 68%) was obtained as a light yellow solid. ^{1 H-NMR (300 MHz,} CDCl 3) δ 8.23 (broad s, 1H), 8.10 (s, 1H), 7.63 (d, 2H, J = 7 Hz), 7.36 (t, 2H, J = 7 Hz) , 7.15 (t, 2H, J = 7 Hz), 3.90 (s, 3H), and 2.64 (s, 3H).

b) Methyl 5-methylthio-4- (N-phenylcarbamoyl) thiophene-2-carboxylate (60.0 mg, 0.195 mmol, prepared in the previous step) was reacted with 310 mg (5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2M trimethylaluminum in toluene in step was treated for 6 hours in a manner similar to that of b). The residue obtained 2 g chromatography on a silica SPE column (Waters Sep-Pak) (eluent: MeOH-CH ₂ Cl ₂ for 5-20% gradient) and then treated with, crystallized from MeOH-Et ₂ O beige To give the title compound (40.3 mg, 71%) as a solid. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 10.24 (s, 1H), 9.34 (broad s, 2H), 9.05 (broad s, 2H), 8.75 (s, 1H), 7.73 (d, 2H, J = 8 Hz), 7.36 (t, 2H, J = 8 Hz), 7.11 (m, 1H), and 2.67 (s, 3H). Mass spectrum (ESI) Calcd for C ₁₃ H ₁₃ N ₃ OS ₂ : 292.1 (M + H). Experimental value: 292.4.

Examples 88 and 89

5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxydin hydrochloride and 4- {imino [benzylamino] methyl} -5-methylthiothiophene-

a) Methyl 5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxylate: Using all other reagents in the same amount as 10 mL (0.942 mmol) benzylamine, (167 mg, 66%) was obtained in the form of pale yellow solid by the same procedure as in (a). ^{1 H-NMR (300 MHz,} CDCl 3) δ 7.93 (s, 1H), 7.28-7.38 (m, 5H), 6.58 (broad s, 1H), 4.62 (s, 2H, J = 5.7 Hz), 3.87 ( s, 3H), and 2.60 (s, 3H).

b) Preparation of 5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxydin hydrochloride and 4- {imino [benzylamino] methyl} -5-methylthiothiophene- pyrimidine hydrochloride: methyl 5-methylthio -4- [N- benzyl-carbamoyl] thiophene-ammonium chloride in a 2-carboxylate (62.7 mg, 0.195 mmol, prepared in the previous step), 2 mL toluene, 310 mg (5.80 mmol) and 2.90 mL (5.80 mmol) of 2 M trimethylaluminum in toluene in a manner similar to that of Example 10, step (b).

The residue obtained 2 g chromatography on a silica SPE column (Waters Sep-Pak) (eluent: MeOH-CH ₂ Cl ₂ for 5-20% gradient) and then treated with, crystallized from MeOH-Et ₂ O beige To obtain 5-methylthio-4- [N-benzylcarbamoyl] thiophene-2-carboxidine hydrochloride (21.1 mg, 35%) in a solid state. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 7.93 (s, 1H), 7.28-7.38 (m, 5H), 6.58 (broad s, 1H), 4.62 (s, 2H, J = 5.7Hz), 3.87 (s, 3H), and 2.60 (s, 3H). Mass spectrum (ESI) Calculated for C ₁₄ H ₁₅ N ₃ OS ₂ : 306.1 (M + H). Experimental value: 306.6.

Further separation and crystallization from MeOH-Et ₂ O gave 4- {imino [benzylamino] methyl} -5-methylthiothiophene-2-carboxydin hydrochloride (32.0 mg, 54%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) broad mixture of rotomers consistent with the desired product. Mass spectrum _{(ESI) C 14 H 16 N} 4 S Calcd for _{2: 305.1 (M + H)} . Experimental value: 305.8.

Examples 90 and 91

Methyl-N-benzylcarbamoyl] -5-methylthiothiophene-2-carboxidine hydrochloride and 4- {imino [methylbenzylamino] methyl} -5-methylthiothiophene- -Carboxamide hydrochloride

a) Methyl 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiothiophene-2-carboxylate: All other reagents equivalent to 122 mL (0.942 mmol) of N-benzylmethylamine were used And the title compound (169 mg, 64%) was obtained as a pale yellow solid by the same procedure as in the step (a) of Example 87. ^{1 H-NMR (300 MHz,} CDCl 3) δ 7.68 (s, 1H), 7.34 (m, 5H), 4.6 (broad m, 2H), 3.86 (s, 3H), 2.91 (m, 3H), and 2.60 (s, 3 H).

b) Synthesis of 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiothiophene-2-carboxydin hydrochloride and 4- {imino [benzylamino] methyl} -5-methylthiothiophene- 2 -carboxylate (65.4 mg, 0.195 mmol, prepared in the previous step) was added to a solution of 4- [N-methyl-N-benzylcarbamoyl] -5-methylthiothiophene- A solution of 310 mg (5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2M trimethylaluminum in toluene was used for 6 hours in a manner similar to that of Example 10, step (a).

The resulting residue was treated by chromatography on a 2 g silica SPE column (Waters Sep-Pak) (eluent: 5-20% gradient MeOH-CH ₂ Cl ₂ ) to give 4- [N- -Benzylcarbamoyl] -5-methylthiothiophene-2-carboxidine hydrochloride (34.3 mg, 55%). ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.32 (broad s, 2H), 9.06 (broad s, 2H), 8.11 (s, 1H), 7.36 (m, 5H), 4.66 (m, 2H) , 2.88 (s, 3H) and 2.66 (s, 3H). Mass spectrum (ESI) C ₁₅ H ₁₇ N ₃ OS ₂ : 320.1 (M + H). Experimental value: 320.4.

Separated and crystallized from MeOH-Et ₂ O to give 4- {imino [methylbenzylamino] methyl} -5-methylthiothiophene-2-carbamidine hydrochloride (19.8 mg, 32%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) broad mixture of rotomers consistent with the desired product. Mass spectrum (ESI) Calcd for _{C 15 H 18 N 4 S 2} . 319.2 (M + H). Experimental value: 319.6.

Examples 92 and 93

(2-phenylethyl) amino] methyl} -5-methyl &lt; / RTI &gt; Thiothiophene-2-carboxymidine hydrochloride

a) Methyl 5-methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxylate: Phenylethylamine l 18 mL (0.942 mmol) , The title compound (165 mg, 63%) was obtained as a pale yellow solid by the same procedure as in the step (a) of Example 87. ^{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 = 7 Hz), 2.93 (t, 2H, J = 7 Hz), and 2.53 (s, 3H).

b) A mixture of 5-methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxidine hydrochloride and 4- {imino [ -Methylthiothiophene-2-carboxymidine hydrochloride: To a solution of methyl 5-methylthio-4- [N- (2- phenylethyl) carbamoyl] thiophene- Was prepared in a manner similar to that of Example 10, step (a), by using 310 mg (5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2 M trimethylaluminum in toluene Lt; / RTI &gt;

The residue obtained 2 g chromatography on a silica SPE column (Waters Sep-Pak) (eluent: MeOH-CH ₂ Cl ₂ for 5-20% gradient) and then treated with, crystallized from MeOH-Et ₂ O beige Methylthio-4- [N- (2-phenylethyl) carbamoyl] thiophene-2-carboxidine hydrochloride (17.4 mg, 28%) as a solid. ¹ H-NMR (300 MHz, DMSO-d ₆ )? 8.8-9.3 (broad m, 4H), 8.48 (m, 1H), 8.35 ), 2.82 (t, 3H, J = 7.5 Hz), and 2.61 (s, 3H). Mass spectrum (ESI) C ₁₅ H ₁₇ N ₃ OS ₂ : 320.1 (M + H). Experimental value: 320.4.

Further separation and crystallization from MeOH-Et ₂ O gave 4- {imino [(2-phenylethyl) amino] methyl} -5-methylthiothiophene-2-carboxaldehyde (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) C 15 H 18 N} 4 S Calcd for _{2: 319.1 (M + H)} . Experimental value: 319.5.

Example 94

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

100 mg (0.302 mmol) of 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- ) Was added 29.6 mg (0.604 mmol) of cyanamide as a solution in 0.3 mL of water. The mixture was heated to reflux and 0.302 mL (0.302 mmol) of 1 M aqueous KOH was added. After 3 hours, the mixture was cooled (0 C), filtered and washed with ice-cold EtOH. The obtained solid was dried in vacuo to give the title compound (78.4 mg, 73%) as a pale yellow powder. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.31 (broad s, 1H), 8.70 (broad 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). Mass spectrum (MALDI-TOF, cyano-4-hydroxycinnamic acid _{matrix) C 16 H 12 N 4 S} 3 Calcd for: 357.0 (M + H). Experimental value: 357.1.

Example 95

5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid

Methylthiothiophene-2-carboxylate (2.20 g, 10.3 mmol, commercially obtained from Maybridge Chemical Company, Cornwall, UK) was added to an 8 mL sealable pressure tube (Ace Glass Company) Product) and tetrafluorophthalic acid (2.45 g, 10.3 mmol) were heated to 160 &lt; 0 &gt; C. The molten mixture was stirred for 4 days, and after cooling, the obtained residue was pulverized and extracted by refluxing with 80 mL of chloroform. The mixture was cooled, decolorizing carbon (about 0.5 g) was added, and the mixture was filtered (Celite). The resulting solution was extracted with saturated NaHCO ₃ (4 x 30 mL), the aqueous extracts were combined, acidified to pH 1-2 with concentrated HCl, and filtered to give a pale brown solid. The solids were dissolved in a minimum amount of 1 MK ₂ CO ₃ (35-40 mL), then the solution was purified by filtration (washing with 10-20 mL of water), then slowly acidified to pH 6.5-7 with stirring and filtered Celite) to remove the brown precipitate. The pH adjustment and filtration were repeated, the resulting solution was saturated with solid NaCl and acidified to pH 1-2 with concentrated HCl. The precipitate was filtered, washed with water (3 x 10 mL) and dried over P ₂ O ₅ under high vacuum to give the title compound (1.24 g, 52%) as a cream colored powder. ^{1 H-NMR (300 MHz;} DMSO-d 6) δ 13.14 (broad s, 1H), 7.89 (s, 1H), 3.82 (s, 3H) and 2.64 (s, 3H). Mass spectrum (ESI, negative mode) Theoretical value for C ₈ H ₈ O ₄ S ₂ : 232.0 (M-). Experimental value: 231.7

Example 96

5-Ethylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxidine hydrochloride

a) Methyl 4- (4-phenyl (1,3-thiazol-2-yl)) - 5- (methylsulfonyl) thiophene-2-carboxylate: 600 mg (1.73 mmol) of methyl 5-methylthio-4- (4-phenyl (1,3-thiazol-2-yl) thiophene- ¹ H-NMR (300 MHz, CDCl ₃ )? 7.93 (s, IH), 7.90 (m, 2H), 7.63 (s, 1H ), 7.47 (m, 2H), 7.39 (m, IH), 3.98 (s, 3H) and 3.73 (s, 3H). Mass spectrum (ESI, m / z): C ₁₆ H ₁₃ NO ₄ S ₃ Theoretical value 380.0 (M + H), Experiment 380.2.

b) 4- (4-Phenyl) (1,3-thiazol-2-yl)) - 5- (methylsulfonyl) thiophene-2- carboxymidine hydrochloride: Methyl 4- [ 560 mg (1.48 mmol) of 5- (4-chlorophenyl) (1,3-thiazol-2-yl) b), 392 mg (66%) of the title compound was obtained as an off-white solid. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.7 (broad s, 2H), 9.4 (broad s, 2H), 8.58 (s, 1H), 8.43 (s, 1H), 8.02 (d, 2H, J = 7 Hz), 7.52 (t, 2H, J = 7 Hz), 7.43 (t, 1H, J = 7 Hz), and 3.90 (s, 3H). Mass spectrum (ESI, m / z): C 15 H 13 N 3 O 2 Calcd for _{S 3 364.0 (M + H)} , Found; 364.1.

c) 5-Ethylthio-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- -2,5-dihydro-2-pyrrolidin-2-yl)) - 5- (methylsulfonyl) thiophene-2-carboxydin hydrochloride (prepared in the previous step), 64.1 mL (0.867 mmol) 2 fractions) and DIEA (40.3 mL, 0.231 mmol) in 3 mL of methanol was treated according to step (c) of Example 141 to give a yellow resin which was purified on a 2 g silica SPE column (Waters Sep-Pak) The residue was treated with chromatography (eluent: 0-15% gradient MeOH-CH ₂ Cl ₂ ) and triturated with CH ₂ Cl ₂ to give the title compound (21.7 mg, 98%) as an off-white solid. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.45 (broad s, 2H), 9.07 (broad s, 2H), 8.68 (s, 1H), 8.28 (s, 1H), 8.09 (d, 2H, J = 7 Hz), 7.51 (t, 2H, J = 7 Hz), 7.40 (t, 1H, J = 7 Hz), 3.23 7 Hz). Mass spectrum _{(ESI) C 16 H 15 N} 3 S 3 Calcd for: 346.1 (M + H). Experimental value: 346.2.

Example 97

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

a) 3-Bromo-1-phenoxyacetone: To a solution of phenoxyacetyl chloride 6.c (0.050 mmol) in 250 mL of anhydrous MeCN in a short vial of 1-Dir (from Wheaton Glass) was added trimethylsilyldiazo 50 mL (0.100 mmol) of a 2 M solution of methane was added and the vial was closed with a PTFE lined stopper. After stirring for 1 h at room temperature in a vortex shaker, the mixture was cooled (0 ° C) and 21 mL (0.105 mmol) of 30 wt% HBr in acetic acid was added dropwise (gas evolution). After shaking for 10 minutes, the mixture was concentrated in vacuo on a vacuum centrifuge concentrator (Speed-Vac, Savant Instruments, Inc.) to give 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: 3-Bromo- (Prepared in 1 dumb vial in the previous step) was added to a solution of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (available from Cornwall, UK) in the form of 1.48 mL of a 10 mg / 14.8 mg (0.060 mmol) was added. The vial was capped tightly and placed on a heated platform puff (Innova Model 4080, manufactured by New Brunswick Scientific Co., Inc.) and shaken at 55 ° C and 250 rpm for 4 hours. To the resulting mixture was added 50 mg (0.150 mmol) of diethylaminomethyl-polystyrene resin (Fluka Chemika-Biochemika, 3.0 mmol / g) in the form of 0.50 mL of a 10O mg / mL suspension in acetone and the mixture was briefly shaken. NaI (0.750 mg, 0.005 mmol) was then added to 100 mL of a 7.5 mg / mL solution in acetone, followed by the addition of chloroacetylpolystyrene resin (30 mg, 0.150 mmol, product of Advanced ChemTech Inc., 5.0 mmol / Respectively. The mixture was tightly capped again, placed on a heated platform puff, and shaken at 55 [deg.] C, 250 rpm for 22 hours. The mixture was filtered through a 2 mL fritted column (BioRad Biospin mini column) and washed with 2 drops of vial with acetone (2 x 0.5 mL) and MeOH (2 x 0.5 mL). Concentration on a vacuum centrifugal concentrator afforded 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 (MALDl-TOF, cyano- 4- hydroxycinnamic acid matrix) C ₁₇ H ₁₅ NO ₃ S ₃ : 378.0 (M + H). Experimental value. 378.3

c) 5-Methylthio-4- [4- (phenoxymethyl) (1,3-thiazol-2-yl)] thiophene-2-carboximidine hydrochloride: To a solution of 2 Methylthio-4- [4- (phenoxymethyl) (1,3-thiazol-2-yl)] thiophene-2-carboxylate (prepared in the previous step) The backing was closed with a top open phenol stopper with silicon barrier. According to step b) of Example 10, a 1 M solution of the reagent (0.750 mL, 0.750 mmol) freshly prepared from trimethylaluminum and ammonium chloride in toluene was purged once with a needle to allow gas to pass through and then pierced a second time Injected with a syringe. The vial was placed in an aluminum heating block under nitrogen (a Fisher Scient 1fic dry bath thermostat equipped with a custom nitrogen manifold cover). The manifold was purged with nitrogen and the reactants were stirred by a large magnetic stirrer motor located on top of the manifold. The reaction was heated to 100 &lt; 0 &gt; C for 4 hours and cooled at room temperature for about 2 hours. The vial contents were poured into 0.5 g of silica gel in 2 mL of CH ₂ Cl ₂ and carefully quenched, and the stopper was closed and shaken until homogeneous. The slurry was filtered through a 4 mL fritted column (Isolab microcolumn) into a 2-dive vial and washed with CH ₂ Cl ₂ (2 x 1 mL), CH ₂ Cl ₂ -MeOH (1: 1, 1 x 1 mL) 2 x 1 mL) and the filtrate was concentrated to a yellow solid on a vacuum centrifugal concentrator. Filtration through a 50O mg silica SPE column (Supelco LC-Si) (eluent: 10% MeOH-CH ₂ Cl ₂ ) gave the title compound (14.8 mg) as a yellow solid. ^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.45 (d, 2H, J = 8.2 Hz), 9.11 (d, 2H, J = 8.2 Hz), 8.97 (broad s, 2H), 8.65 (s, 1H), 7.90 (s, 1 H), 7.0-7.5 (m, 5H), 5.25 (s, 2H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, Gen tooth acid _{matrix) C 17 H 15 NO 3 S} 3 Calcd for: 362.0 (M + H). Experimental value: 361.7.

Examples 98 to 126

Examples 98 to 104 were carried out according to the procedures of steps (b) and (c) of Example 97 using 0.050 mmol of the reagent listed in the following table. Examples 105 to 126 were carried out using 0.05 mmol of reagent according to the procedures of steps (a), (b) and (c) of Example 97.

Mass spectrum (ESI) Example reagent compound The Theoretical (M + H) Experimental value 98 1-bromopinacolone 4- [4- (tert-Butyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C13H17N3S3 312.1 312.2 99 4-fluorophenacyl bromide 4- [4- (4-fluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C15H12FN3S3 350.0 350.2 100 4-cyanophenacyl bromide 4- [4- (4-amidinophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C16H15N5S3 374.1 374.2 101 3-fluorophenacyl bromide 4- [4- (3-fluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxymidine hydrochloride C15H12FN3S3 350.0 350.2 102 4- (diethylamino) phenacyl bromide 4- {4- [4- (diethylamino) phenyl] (1,3-thiazol-2-yl)} - 5- methylthiothiophene-2-carboxidine hydrochloride C19H22N4S3 403.1 403.2 103 3-chlorophenacyl bromide 4- [4- (3-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C15H12ClN3S3 366.0 366.1

104 3,4-difluorophenacyl bromide 4- [4- (3,4-difluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C15H11F2N3S3 368.0 368.2 105 2,6-difluorobenzoyl chloride 4- [4- (2,6-difluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C15H11F2N3S3 368.0 368.2 106 4-ethoxy-benzoyl chloride 4- [4- (4-ethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C17H17N3OS3 376.1 376.2 107 4-chlorophenoxyacetyl chloride 4- {4 - [(4-chlorophenoxy) methyl] (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxidine hydrochloride C16H14ClN3OS3 396.0 396.1 108 Cyclopentanecarbonyl chloride 4- (4-Cyclopentyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine hydrochloride C14H17N3S3 324.1 324.2 109 1-naphthoyl chloride 5-methylthio-4- (4-naphthyl (1,3-thiazol-2-yl)) thiophene-2-carboxidine hydrochloride C19H15N3S3 382.1 382.2 110 3,5-dichlorobenzoyl chloride 4- [4- (3,5-Dichlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C15H11Cl2N3S3 400.0 400.1 111 2,5-difluorobenzoyl chloride 4- [4- (2,5-difluorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C15H11F2N3S3 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-carboxidine hydrochloride C22H15N3OS3 434.1 434.2

113 3-methoxyphenylacetyl chloride 4- {4 - [(3-methoxyphenyl) methyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride C17H17N3OS3 376.1 376.2 114 4-methylvaleroyl chloride 4- [4- (3-Methylbutyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C14H19N3S3 326.1 326.2 115 3- (2-Chlorophenyl) -5-methylisoxazole-4-carbonyl chloride 4-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carbaldehyde Pyridine hydrochloride C19H15ClN4OS3 447.0 447.1 116 4-n-amyloxybenzoyl chloride 5-methylthio-4- [4- (4-pentyloxyphenyl) (1,3-thiazol-2-yl)] thiophene-2-carboxidine hydrochloride C20H23N3OS3 418.1 418.2 117 1- (4-Chlorophenyl) -1-cyclopentanecarbonyl chloride Cyclopentyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride C20H20ClN3S3 434.1 434.3 118 4- (trifluoromethoxy) benzoyl chloride 5-methylthio-4- {4- [4- (trifluoromethoxy) phenyl] (1,3-thiazol-2-yl)} thiophene-2-carboxidine hydrochloride C16H12F3N3OS3 416.O 416.1 119 3-chlorobenzo [b] thiophene-2-carbonyl chloride Thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C17H12ClN3S4 422.0 422.1 120 3- (2-Chloro-6-fluorophenyl) -5-methylisoxazole-4-carbonyl chloride 5-methylisoxazol-4-yl] (1,3-thiazol-2-yl)} - 5-methylthioti 2-carboxamidine hydrochloride C19H14ClFN4OS3 465.0 465.1 121 3-cyanobenzoyl chloride 4- [4- (3-amidinophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C16H15N5S3 374.1 374.7

122 Methoxyphenylacetyl chloride 4- {4 - [(4-methoxyphenyl) methyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride C17H17N3OS3 376.1 376.2 123 3- (t-butyl) -1-benzylpyrazole-5-carbonyl chloride 5-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride C16H19N5S3 378.1 378.2 124 3- (4-chlorophenyl) -2,2-dimethylpropanoyl chloride 5-methylthio-4- [4- (1-methylvinyl) (1,3-thiazol-2-yl)] thiophene-2-carboxymidine hydrochloride C12H13N3S3 296.0 296.2 125 (1-naphthalenesulfonyl) -1-phenylalanyl chloride 4- (4- {1 - [(naphthylsulfonyl) amino] -2-phenylethyl} (1,3-thiazol-2-yl)) thiophene-2-carboxidine hydrochloride C27H24N4O2S4 565.1 565.1 126 2-Bromo-5-methoxybenzoyl chloride 4- [4- (2-Bromo-5-methoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxidine hydrochloride C16H14BrN3OS3 440.0 440.2

Example 127

a) 1- [3,5-Bis (trifluoromethyl) phenyl] -2-bromoanthan-1-one To a solution of 3,5-bis (trifluoromethyl) acetophenone ( A stirred suspension of 1 g (3. 5 mmol) of poly (4-vinylpyridinium tribromide) (Aldrich, Milwaukee, Wisconsin, USA) (1 g, 3.9 mmol) , And the mixture was heated under reflux for 70 minutes. The polymer was filtered from the cold solution, washed with methanol and washed twice with dichloromethane. The solvent was removed in vacuo to give 1- [3,5-bis (trifluoromethyl) phenyl] -2-bromoanthan-1-one (1.2 g, 92%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 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- A solution of 75 mg (0.3 mmol) of 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (commercially available from Maybridge, Conwell, UK) was added to a solution of 1- [3,5- Methyl] phenyl] -2-bromoanthan-1-one was reacted with 101 mg (0.3 mmol) of the title compound in the same manner as in the step (a) of Example 8 to obtain methyl 4- {4- [ (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, 3 H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Theoretical value for C ₁₈ H ₁₁ NO ₂ S ₃ F ₆ , 484.0 (M + H), found 484.0.

c) 4- {4- [3,5-Bis (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene- Carboxylate (7 mg, 14.5 mmol) was added to a solution of 4- [3,5- bis (trifluoromethyl) phenyl] (1,3-thiazol- Was treated in a similar manner to Example 10, step (b) to give 4- {4- [3,5-bis (trifluoromethyl) phenyl] (1,3-thiazol- } -5-methylthiothiophene-2-carboxidine (6 mg, 89%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz) 8.78 (s, 1 H), 8.74 (s, 2H), 8.62 (s, Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 17} H 11 N 3 theoretical value for _{S 3 F 6, 468.0 (M} + H), Found; 468.0.

Example 128

a) 2-Bromo-l- [3-fluoro-5- (trifluoromethyl) phenyl] ethan- l- one: 3-Fluoro-5- (trifluoromethyl) acetophenone (Lancaster, Windham A mixture of 2-bromo-1- [3-fluoro-5- (trifluoromethyl) pyridin-2-ylmethyl] Phenyl] ethan-1-one and a 1: 1 mixture of the dibrominated product (1.6 g, 100%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.25-7.52 (m, 6H), 6.54 (s, 1H), 4.42 (s, 2H).

b) Synthesis of methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene- : A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, Fluoro-5- (trifluoromethyl) phenyl] ethan-1-one was reacted with 86 mg (0.3 mmol) of the title compound in a similar manner to the step (a) of Example 8 to obtain methyl 4- {4- [3- (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, 1: container formers of the first non- ), 7.73 and 7.70 (m, 1H, Conformer in 1: 1 ratio). Mass spectrum (MALDI-TOF, CHCA matrix, m / z). Theoretical value for C ₁₇ H ₁₁ NO ₂ S ₃ F ₄ , 434.0 (M + H), experimental value 434.0.

c) 4- {4- [3-Fluoro- 5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene- Methyl 4- (3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene- mg, 0.92 mmol) was treated in a similar manner to step (b) of Example 10 to give 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] Thiazol-2-yl)} - 5-methylthiothiophene-2-carboxidine (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, Conformer of 1: 1 ratio), 7.75 and 7.73 (m, 1H, Conformer of 1: 1 ratio), 2.82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 16} H 11 N 3 S 3 F 4 to the theoretical value, 418.5 (M + H), Found; 418.0

Example l29

a) 1- [3-Fluoro-5- (trifluoromethyl) phenyl] propane 1-one (Lancaster, Windham, NH, USA) was treated in a similar manner to step (a) of Example 127 to give 2-bromo-1- [ 5- (trifluoromethyl) phenyl] propan-1-one (1.33 g, 99%). ¹ H NMR (DMSO-d ₆ ; 300 MHz) 8 8.07 (m, 1H), 7.92 and 7.89 (m, 1H, Conformer of 1: 1 ratio), 7.57 and 7.55 , 5.20 (q, IH, J = 6.6 Hz), 1.93 (d, 3H, J = 6.6 Hz).

b) Preparation of methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene- : A solution of 75 mg (0.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (available from Maybridge, Conwell, UK) was added to a solution of 2- (A) of Example 8 was reacted with 90 mg (0.3 mmol) of 4-fluoro-5- (trifluoromethyl) phenyl] propan- Yl)} - 5-methylthiothiophene-2-carboxylate (31.9 mg, 24%) was obtained as colorless crystals from 4- (trifluoromethyl) ). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 8.17 (s, 1H), 7.98 (m, 1H), 7.95 and 7.92 (m, 1H, 1: container formers of 1 ratio), 7.77 and 7.74 (m , 1H, Conformer of 1: 1 ratio), 3.87 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 18} H 13 NO 2 S 3 F 4 to the theoretical value, 448.0 (M + H), Found; 448.0.

c) Preparation of 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] -5-methyl (1,3- thiazol- Carboxylate: To a solution of methyl 4- {4- [3-fluoro-5- (trifluoromethyl) phenyl] -5-methyl (1,3- thiazol- Carboxylate (30 mg, 0.067 mmol) was treated in a similar manner to Example 10, step (b) to give 4- {4- [3-fluoro-5- (trifluoromethyl) ) Phenyl] -5-methyl (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxidine (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 of 1: 1 ratio), 7.79 and 7.76 (m, 1H, Conformer of 1: 1 ratio), 2.78 (s, 3H), 2.71 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z). _{C 17 H 13 N 3 S 3} F 4 to the theoretical value, 432.0 (M + H), Found; 432.6.

Example 130

a) 1- [3,5-Bis (trifluoromethyl) phenyl] -2-bromopropan- 1- A stirred suspension of 1 g (3.7 mmol) of 2-bromo-l- (3-fluoro-5- ( Trifluoromethyl) phenyl] propan-1-one (1.1 g, 86%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.46 (m, 2H), 8.09 (m, 1), 5.26 ). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): theoretical value for C ₁₁ H ₇ OBrF ₆ , 349.0 (M + H), experimental value 348.9.

b) Synthesis of methyl 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl (1,3-thiazol-2-yl)} - 5-methylthiothiophene- carboxylate: methyl 4- (4-amino-thioxo-methyl) -5-methylthio-thiophene-2-carboxylate (United Kingdom Maybridge of Cornwall product material) 1, a solution of 75 ㎎ (0.3 mmol) [3,5- bis (Trifluoromethyl) phenyl] -2-bromopropane-1-one with 105 mg in the same manner as in the step (a) of Example 8 and purifying by purified thin layer chromatography, 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 (N1ALDI-TOF, CHCA _{matrix, m / z): C 19} H 13 NO 2 Calcd for _{S 3 F 6, 498.0 (M} + H), Found; 497.6.

c) Synthesis of 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl (1,3-thiazol-2-yl)} - 5-methylthiothiophene- pyrimidine: methyl 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5-methyl (1,3-thiazol-2-yl)} - 5-methylthio-thiophene-2- (15 mg, 0.031 mmol) was treated in a similar manner to step (b) of Example 10 to give 4- {4- [3,5-bis (trifluoromethyl) phenyl] -5- Methyl (thiazol-2-yl)} - 5-methylthiothiophene-2-carboxidine (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, 3 H), 2.73 (s, 3 H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 18} H 13 N 3 theoretical value for _{S 3 F 6, 482.0 (M} + H), Found; 482.5.

Example l31

a) A stirred suspension of 2-bromo-1,2-diphenylethan-1-one: deoxybenzoin 0.2 g (1 mmol) was treated in a similar manner to step 127 a) of Example 127 to give 2- Diphenylethan-1-one (270 mg, 98%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 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: Methyl 4- (aminothioxomethyl) -Methylthiothiophene-2-carboxylate (product of Maybridge, Cornwall, UK) in 5 mL of DMF was added to a solution of 2-bromo-1,2-diphenylethan-1-one (92 mg, 0.3 mmol ) In a similar manner to the step (a) of Example 8, and after purification by purification thin-layer chromatography, methyl 4- (4,5-diphenyl (1,3-thiazol- Yl)) - 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, 0.3H), 8.08 (s, 1H), 7.93 and 7.20 ( 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): C 22} H 17 NO 2 Calcd for _{S 3, 424.0 (M + H} ), Found; 424.3.

c) 4- (4,5-diphenyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene- , 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (9 mg, 0.021 mmol) was treated in a similar manner to step (b) To obtain 4- (4,5-diphenyl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboximidine (3 mg, 35%). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 21} H 17 N 3 S 3 Calcd, 408.1 (M + H) for, Found; 408.0.

Example 132

a) Preparation of methyl 4- (4-benzo [b] thiophen-2-yl (1,3-thiazol- A solution of 75 mg (0.3 mmol) of 3-bromoacetylbenzo [b] thiophene (available from Maybridge, Cornwall, UK) ) Was reacted with the compound of Example 8 in a similar manner to step (a) of Example 8, and after purification by purification thin layer chromatography, methyl 4- (4-benzo [b] thiophen- -Thiazol-2-yl)) - 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- Carboxylate (28 mg, 0.69 mmol) was added to a solution of the compound of Example 10 (step &lt; RTI ID = 0.0 &gt; b) to give 4- (4-benzo [b] thiophen-2-yl (1,3-thiazol-2-yl)) - 5-methylthiothiophene- Carboxymidine (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, 1 H), 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): C 17} H 13 N 3 S 4 theoretical value for, 388.0 (M + H), Found; 388.2.

Example l33

a) Synthesis of methyl 4- (4-benzo [d] benzo [3,4-b] furan-3-yl (1,3-thiazol- rate: methyl 4- (4-amino-thioxo-methyl) -5-methylthio-thiophene-2-carboxylate a solution of (UK Maybridge of Cornwall product material) 75 ㎎ (0.3 mmol) 2- ( bromoacetyl) - D Was reacted with 86 mg (0.3 mmol) of benzofuran (Aldrich, Milwaukee, WI) in a similar manner to step (a) of Example 8, and after purification by purification thin layer chromatography, methyl 4- (4,5-diphenyl (1,3-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). Theoretical value for C ₂₂ H ₁₅ NO ₃ S ₃ , 438.0 (M + H), experimental value 438.5.

b) 4-4-Benzo [d] benzo [3,4-b] furan-3-yl (1,3- thiazol- Methyl 4- (4-benzo [d] benzo [3,4-b] furan-3-yl (1,3-thiazol- 45 mg, 0.11 mmol) was treated in a similar manner to step (b) of Example 10 to give 4- (4-benzo [d] benzo [3,4- b] 3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine (16.8 mg, 36%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 9.72-9.10 (m, 3H), 8.84-7.31 (m, 9H), 2.84 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 21} H 15 N 3 theoretical value for the _{OS 3, 422.0 (M + H} ), Found; 421.9.

Example 134

a) Methyl 4- (4- (4-nitrophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene- (4 mmol) of 2-bromo-4'-nitroacetophenone and 987 mg (4 mmol) of 2-bromothiophene-2-carboxylate 8 (step a) to obtain methyl 4- (4- (4-nitrophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophen- -Carboxylate (1.7 g, quantitative yield). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.57 (s, 1H), 8.34 (s, 4H), 8.25 (s, 1H), 3.94 (s, 3H), 3.81 Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 16} H 12 N 2 O 4 S Calcd for ₃ 393.0 (M + H), Found; 392.8.

b) Methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl) 2-carboxylate (800 mg, 2 mmol) was dissolved in 150 mL of tetrahydrofuran, and 20% titanium chloride (Fisher Scientific, Pittsburgh, Pa.) For 1 hour. The mixture was poured into 2 M sodium hydroxide solution (100 mL) and extracted with dichloromethane (4 x 50 mL). The organic layers were combined, washed with saturated brine solution and dried over anhydrous sodium sulfate. The solids were filtered and the solvent was dried in vacuo. This material was treated with silica gel (30 g) with column chromatography (eluent: dichloromethane: methanol 98/2 (v: v)) to obtain solid 4- (4- (4- 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). C ₁₆ H ₁₄ N ₂ O ₂ Calcd for _{S 3: 363.0 (M + H} ), Found; 362.4

c) Methyl 4- (4- {4- [(methylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl) -5-methylthiothiophene- Carboxylate (200 mg, 0.55 mmol) was dissolved in anhydrous dichloromethane (20 mL, 20 mmol), and the mixture was stirred at room temperature for 3 hours. ). To this was added N-methylmorpholine (150 L, 1.38 mmol) and dimethylaminopyridine (6.1 mg, 0.055 mmol) and the mixture was cooled in an ice bath followed by methanesulfonyl chloride (43 L, 0.55 mmol) . The mixture was then stirred at room temperature for 8 days. The mixture was 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 organic layers were washed with saturated sodium bicarbonate (20 mL), brine (2 x 20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. Was treated with silica gel (100 g) with column chromatography (eluent: dichloromethane: methanol 99: 1 (v: v)) to obtain methyl 4- (4- {4- [(methylsulfonyl) amino] phenyl } (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): C 17 H} 16 N 2 O 4 S 4 Calcd for: 4441.0 (M + H), Found; 441.2.

d) Preparation of 4- (4- {4- [(methylsulfonyl) amino] phenyl} (1,3-thiazol- (81 mg, 0.184 mmol) was added to a solution of (4- {4 - [(methylsulfonyl) amino] phenyl} (1,3-thiazol- (4- {4- [(methylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine (24.9 mg, 32%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 10.0 (br s, 1 H), 9.3 (br s, , 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): C 16} H 16 N 4 O 2 Calcd for _{S 4: 425.0 (M + H} ), Found; 425.1.

Example 135

a) Methyl 4- (4- {4- [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl) -5-methylthiothiophene- Carboxylate (100 mg, 0.28 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to -78 &lt; 0 & To this was added N-methylmorpholine (46 L, 0.42 mmol) and dimethylaminopyridine (3.4 mg, 0.028 mmol) and the mixture was cooled in an ice bath followed by benzenesulfonyl chloride (35 [ The mixture was stirred at room temperature for 24 hours, and the operation was carried out in the same manner as in step (c) of Example 134. Trituration with dichloromethane and methanol afforded crystals of methyl 4- ( (44 mg, 31%) was obtained as white crystals from 4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol- ^{. 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):. 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- (30 mg, 0.060 mmol) was added to a solution of (4- {4 - [(phenylsulfonyl) amino] phenyl} (1,3-thiazol- (4- {4- [(phenylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine (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) , 7.82-7.79 (m, 2H), 7.65-7.53 (m, 3H), 3.85 (s, 3H), 2.74 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 21} H 18 N 4 O 2 Calcd for _{S 4, 87.0 (M + H} ), Found; 487.7.

Example 136

a) Synthesis of methyl 4- (4- {4- [(trifluoromethylsulfonyl) amino] phenyl} (1,3-thiazol-2- yl)) - 5-methylthiothiophene-2-carboxylate : To a solution of methyl 4- (4- (4-aminophenyl) (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxylate (200 mg, 0.55 mmol) 20 mL). The mixture was cooled in an ice bath and then trifluoromethanesulfonic anhydride (0.5 mL, 3 mmol) was added. The mixture was then stirred at room temperature for 1.5 hours. The same operation as in step (c) of Example 134 was carried out. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate 7: 3 (v: v)) and purified by thin layer chromatography (eluent: dichloromethane: methanol 99/1 )) To obtain 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, 3/2 ratio of the former container, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 8.29 and 7.84 (AB J = 8.7 Hz), 8.10 and 7.37 (AB quartet, 2H, J = 8.7 Hz), 3.87 and 3.86 (s, 2/3 ratio of conformer, 3H) , 2.77 and 2.76 (s, 2/3 ratio of conformer, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 17} H 13 N 2 O 4 S 4 F 4 Calcd for: 4495.0 (M + H), Found; 495.6.

b) 4- (4- {4- [(trifluoromethylsulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene- Methyl) thiophene-2-carboxylate (prepared by reacting methyl 4- (4- {4- [(trifluoromethylsulfonyl) amino] phenyl} mg, 0.061 mmol) was treated in a similar manner to Example 10, step (b) to give 4- (4- {4- [(trifluoromethylsulfonyl) amino] phenyl} Thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine (21.6 mg, 74%). ^{1 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): Theoretical value for C ₁₆ H ₁₃ N ₄ O ₂ S ₄ F ₃ , 479.0 (M + H), experimental value 479.5.

Example 137

a) Methyl 4- (4- {4- [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene- Carboxylate (33 mg, 0.09 mmol) was dissolved in anhydrous dichloromethane (5 mL) and the solution was stirred at room temperature for 3 hours. ). To this was added N-methylmorpholine (10 L, 0.09 mmol) and p-toluenesulfonyl chloride (17 mg, 0.09 mmol) and the mixture was stirred at room temperature for 5 days. The same operation as in step (c) of Example 134 was carried out. Trituration with dichloromethane and methanol afforded methyl 4- (4- {4- [(toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene -2-carboxylate (20 mg, 43%). ^{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), Mass spectrum (MALDI-TOF, CHCA matrix, m / z): 7.68 and 7.35 (AB quartet, 2H, J = 8.2 Hz), 3.85 (s, 3H), 2.74 _{C 23 H 20 N 2 O 4} S 4 theoretical value for, 517.2 (M + H), Found; 517.0.

b) 4- (4- {4- [(Toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene- (15 mg, 0.029 mmol) was added to a solution of (4- {4 - [(toluenesulfonyl) amino] phenyl} (1,3-thiazol- (4- {4- [4- (Toluenesulfonyl) amino] phenyl} (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine (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, 0.3H), 8.08 (s, 1H), 7.93 and 7.20 ( 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): C 22} H 20 N 4 O 2 Calcd for _{S 4: 501.1 (M + H} ), Found; 501.1.

Example 138

a) Methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfinyl) thiophene- To a solution of methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- -Carboxylate (764 mg, 2 mmol) was added 30% hydrogen peroxide (0.45 mL, 4 mmol). The solution was stirred at room temperature for 45 hours. Dichloromethane (10 mL) was added after 2 hours. Additional hydrogen peroxide (2 x 0.45 mL fractions) was added after 4 h and 24 h. The mixture was quenched with 10% sodium persulfate in brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. Was treated with silica gel (45 g) with column chromatography (eluent: dichloromethane: methanol 99: 1 (v: v)) to obtain methyl 4- [4- (4-chlorophenyl) 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, 3 H). Mass spectrum (MALDI-TOF, GA matrix, m / z): Theoretical value for C ₁₆ H ₁₂ NO ₃ S ₃ Cl: 398.0 (M + H), experimental value 397.8.

b) 4- [4- (4-Chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfinyl) thiophene- Thiophene-2-carboxylate (100 mg, 0.25 mmol) was reacted in step (b) of Example 10 with 4- , And the residue was purified by a thin layer chromatography (eluent: dichloromethane: methanol: acetic acid = 9/1 / 0.5 (v: v: v)) to obtain 4- [4- ) (1,3-thiazol-2-yl)] - 5- (methylsulfinyl) thiophene-2-carboxidine (18.2 mg, 19%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.33 (s, IH), 8.22 (s, IH), 8.05 and 7.57 (AB quartet, 2H, J = 8.6 Hz), 3.12 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, _{m / z): C 15 H} 12 N 3 theoretical value for the _{OS 3 Cl: 382.0 (M +} H), Found; 382.1.

Example l39

a) Methyl 4-cyano-5- (methylsulfonyl) thiophene-2-carboxylate Methyl 4-cyano-5-methylthiothiophene- 2- carboxylate (Maybridge, (4.5 g, 21 mmol) was dissolved in dichloromethane (250 mL) and treated with m-chloroperbenzoic acid (15.3 g, 90 mmol) at room temperature for 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. The solvent was removed in vacuo to give methyl 4-cyano-5- (methylsulfonyl) thiophene-2-carboxylate in solid state (4.91 g, 95%). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.44 (s, 1H), 3.91 (s, 3H), 3.58 (s, 3H).

b) Methyl 4-cyano-5-methoxythiophene-2-carboxylate: Methyl 4-cyano-5- (methylsulfonyl) thiophene- Was refluxed with 0.5 M sodium methoxide in methanol (16 mL) for 15 min. The solution was cooled and the crystallized solid was collected in a Buchner funnel and washed with methanol (50 mL) to give methyl 4-cyano-5-methoxythiophene-2-carboxylate (1.145 g, 73% . ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 8.87 (s, 1H), 4.19 (s, 3H), 3.82 (s, 3H).

c) Methyl 4- (aminothioxomethyl) -5-methoxythiophene-2-carboxylate: Methyl 4-cyano-5-methoxythiophene-2-carboxylate (1 g, 5 mmol) Was dissolved in methanol (150 mL), and triethylamine (3.5 mL, 25.4 mmol) was added. The solution was degassed with argon for 10 minutes, and then the solution was bubbled with hydrogen sulfide for 5 hours. After stirring at room temperature for 18 h, the solution was degassed by argon bubbling (6 h) and concentrated to 20 mL before adding acetone (20 mL). The dark colored solid was collected in a Buchner funnel and washed with acetone. The solid was recrystallized with hot ethanol (15 mL) to obtain methyl 4- (aminothioxomethyl) -5-methoxythiophene-2-carboxylate in the form of brown oil (683 mg, 59%). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): Calculated for C ₈ H ₉ NO ₃ S ₂ : 232.0 (M + H), 232.4.

d) Methyl 5-methoxy-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2- carboxylate: Methyl 4- (aminothioxomethyl) Carboxylate was treated with 345 mg (1.73 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, Wis.) In a similar manner to Example 8, step (a) To obtain methyl 5-methoxy-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxylate in the form of solid (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, 3 H), 3.85 (s, 3 H).

e) 5-Methoxy-4- (4-phenyl (l, 3-thiazol-2- yl)) thiophene- Carboxylate (55 mg, 0.16 mmol) was treated in a similar manner to step (b) of Example 10 to give 5-methoxy-4-thiophene- - (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxidine (36 mg, 69%). ^{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, IH), 4.32 (s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 15} H 13 N 3 Calcd 316.5 (M + H) for ₂ OS, 316.1 experimental values.

Example 140

a) Methyl 4-cyano-5- (4-methoxyphenyl) methylthio] thiophene-2-carboxylate: To a solution of methyl 4-cyano-5- (methylsulfonyl) To a stirred solution of 2.5 g (10 mmol) of thiophene-2-carboxylate (example 139, step (a)) p-methoxybenzylmercaptan (3.8 mL, 28 mmol) and triethylamine , 10 mmol). This solution was refluxed for 15 minutes and cooled. The resulting solid was collected in a Buchner funnel and washed with methanol (2 x 25 mL) to give methyl 4-cyano-5 - [(4-methoxyphenyl) methylthio] thiophene- (2.84 g, 89%).

b) Methyl 4- (aminothioxomethyl) -5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate: Methyl 4-cyano- Methylthio] thiophene-2-carboxylate (2.5 g, 7.8 mmol) was treated in the same manner as in step (c) of Example 139 to give methyl 4- (aminothioxomethyl) -5 - [ -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, 2H, 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- A solution of 1.2 g (3.4 mmol) of 5 - [(4-methoxyphenyl) methylthio] thiophene-2-carboxylate was prepared from 2- bromoacetophenone (3-thiazol-2-yl) thiophene) was prepared by reacting methyl 5- (methoxyphenylthio) -4- (4-phenyl -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, 3H).

d) 5- (Methoxyphenylthio) -4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- Carboxylate (100 mg, 0.22 mmol) was treated in a similar manner to step (b) of Example 10 to give an orange solid (94 mg, 91%) of 5-methoxy-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 9.49 (br s, 2H), 9.15 (br s, 2H), 8.70 (s, 1H). 2H, J = 8.7 Hz), 8.21 (s, 1H), 8.07 (m, 2H), 7.49 3.73 (s, 3 H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 22} H 19 N 3 theoretical value for the _{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-To a solution of &lt; RTI ID = 0.0 &gt; 1 g (2) of methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2- carboxylate , 6 mmol) was treated with m-chloroperbenzoic acid (1.94 g, 11.3 mmol) at room temperature for 1.5 hours. The solution was filtered and the solid was 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. The solvent was removed in vacuo to give methyl 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene- (826 mg, 77%). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): C₁₆H₁₂NO₄S₃Theoretical value for Cl: 414.0 (M + H), experimental value 414.8.

b) 4- [4- (4-Chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene- Carboxylate (200 mg, 0.4 mmol) was reacted with (b), (3-thiazol-2-yl) To give 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (methylsulfonyl) thiophene- (85 mg, 53%).

c) 4- [4- (4-Chlorophenyl) (1,3-thiazol-2-yl)] - 5- (phenylmethylthio) thiophene- Yl)] - 5- (methylsulfonyl) thiophene-2-carboximidine To a stirred solution of 80 mg (0.2 mmol) of benzyl mercaptan mmol) was treated in a similar manner to step (a) of Example 140 and purified by silica gel (20 g) column chromatography (eluent: dichloromethane: methanol: acetic acid 9/1/0.5 (v: v: v) The crude product was purified by column chromatography to obtain an orange solid 4- [4- (4-chlorophenyl) (1,3-thiazol-2-yl)] - 5- (phenylmethylthio) , 85%). ^{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 = 8.7Hz), 7.54-7.17 (m, 5H), 4.45 (s, 2H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 21} H 16 N 3 theoretical value for _{S 3 Cl: 442.0 (M +} H), Found; 442.7.

Example 142 [

a) 1- [5- (tert-Butyl) -2-methyl (3-furyl)] - 2-bromoanthan-1-one: 5- (tert- butyl) 6.25 mL (12.5 mmol) 2M trimethylsilyldiazomethane in 1 g (5 mmol) 2-methylfuran-3-carbonyl (Maybridge, Conwell, UK) and hexane (Aldrich, Milwaukee, WI) Was stirred at room temperature for 1.75 hours, and the mixture was cooled in an ice bath for 5 minutes. To this was added 30% hydrogen bromide (2 mL, 10 mmol) in acetic acid dropwise over 10 min. This was further stirred in an ice bath for an additional 20 minutes. The solvent was evaporated to give 1- [5- (tert-butyl) -2-methyl (3-furyl)] - 2-bromoanthan-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): C 11 H 15 O Calcd for ₂ Br, 259 1, and 261.1 (M + H), Found; 259.1 and 261 1.

b) Preparation of methyl 4- {4- [5- (tert-butyl) -2-methyl (3-furyl) carboxylate: methyl 4- (4-amino-thioxo-methyl) -5-methylthio-thiophene-2- carboxylate (United Kingdom Maybridge of Cornwall product material) step of example 8 a solution of 955 mg (3.86 mmol) (a ) Was reacted with 1 g (3.86 mmol) of 1- [5- (tert-butyl) -2-methyl (3-furyl)] - 2-bromoanthan- Yl)} - 5-methylthiothiophene-2-carboxylate (999 mg, , 64%). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 8.14 (s, 1H), 7.74 (s, 1H), 6.46 (s, 1H), 3.86 (s, 3H), 2.74 (s, 3H), 2.66 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 19} H 21 NO 3 Calcd for _{S 3, 408.1 (M + H} ), Found; 408.0.

c) A mixture of 4- {4- [5- (tert-butyl) -2-methyl (3-furyl) pyrimidine: methyl 4- {4- [5- (tert- butyl) -2-methyl (3-furyl)] (1,3-thiazol-2-yl)} - 5-methylthio-thiophene-2- (940 mg, 2.3 mmol) was treated in a similar manner to step (b) of Example 10 to give 4- {4- [5- (tert-butyl) -2-methyl ] (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxidine (930 mg, quantitative yield). ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 9.42 (br s, 2H), 9.03 (br s, 2H), 8.59 , 2.78 (s, 3H), 2.68 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 18} H 21 N 3 theoretical value for the _{OS 3, 392.1 (M + H} ), Found; 392.1.

Example l43

a) 1- [3- (tert-Butyl) -1-benzylpyrazol-5-yl] -2 -bromoanthan- A solution of 1 g (3.6 mmol) carbonyl (1 g, 3.6 mmol, from Maybridge, Conwell, England) was dissolved in anhydrous acetonitrile (4 mL) and a solution of 2 M trimethylsilyldiazomethane in hexane (Aldrich, Milwaukee, WI) 4.5 mL (9 mmol) was added. After stirring at room temperature for 1 hour and 20 minutes, the mixture was cooled in an ice bath for 5 minutes. To this was added 30% hydrogen bromide in acetic acid (2 mL, 10 mmol) dropwise over 15 minutes. This was further stirred in an ice bath for 15 minutes. The precipitated solid was filtered and the solvent was evaporated to give 1- [3- (tert-butyl) -1-benzylpyrazol-5-yl] -2-bromoanthan- Phosphorous 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). Theoretical values for C ₁₆ H ₁₉ N ₂ OBr, 335.1 and 337.1 (M + H), found 335.6 and 337.6.

b) Preparation of methyl 4- {4- [3- (tert-butyl) -1-benzylpyrazol-5-yl] Carboxylate A solution of 823 mg (3.3 mmol) of methyl 4- (aminothioxomethyl) -5-methylthiothiophene-2-carboxylate (Maybridge, ) Was reacted with 1.36 g (3.3 mmol) of 1- [3- (tert-butyl) -1-benzylpyrazol-5-yl] -2-bromoanthan- 5-yl] (1,3-thiazol-2-yl)} - 5-methylthiothiophene-2-carboxylate (1.25 g, 79%). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 8.11 (s, 1H), 8.05 (s, 1H), 7.28-6.99 (m, 5H), 6.70 (s, 1H), 5.88 (s, 2H) , 3.86 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 24} H 25 N 3 O 2 Calcd for _{S 3, 484.1 (M + H} ), Found; 483.9.

c) Preparation of 4- {4- [3- (tert-butyl) -1-benzylpyrazol-5-yl] (1,3- thiazol- Pyrimidine: Methyl 4- {4- [3- (tert-butyl) -1-benzylpyrazol-5-yl] (1,3- thiazol-2-yl)} - 5-methylthiothiophen- (1.2 mg, 2.6 mmol) was treated in a similar manner to step (b) of Example 10 to give 4- {4- [3- (tert-butyl) -1-benzylpyrazole- 5-yl] (1,3-thiazol-2-yl)} -5-methylthiothiophene-2-carboxidine (1.21 g, quantitative yield). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 9.43 (br s, 1H), 9.07 (br s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 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): C 23} H 25 N 5 theoretical value for _{S 3, 468.1 (M + H} ), Found; 468.1.

Example 144

a) 4-Bromo-5-methylthiothiophene-2-carboxylic acid: To a solution of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S., et al.) in anhydrous tetrahydrofuran A stirred solution of 1 g (3.9 mmol) in Heterocycles 20 (10): 2035, 1983) was cooled to -78 ° C and 2 M n-butyllithium in cyclohexane (1.93 mL, 3.87 mmol) . After stirring at -78 占 폚 for 3 minutes, the mixture was added to tetrahydrofuran (100 mL) while being suspended in dry ice. The mixture was stirred and warmed to room temperature. To this was added cautiously 6N hydrochloric acid (50 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 organic layers were washed with water and brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a 85/15 mixture (780 mg, 90%) of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene- . ^{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 Spectrum (m / z): Theoretical values for C ₆ H ₅ O ₂ SBr, 220.9 and 222.9 (M + H), Experiments 221.3 and 223.3. Theoretical values for C ₅ H ₃ O ₂ SBr, 206.9 and 208.9 (M + H), found 207.3 and 209.3.

b) Methyl 4-bromo-5-methylthiophene-2-carboxylate: To a solution of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene- 15 mixture of 780 mg (3.5 mmol) in methanol (50 mL) was treated with 9 mL (18 mmol) of 2M trimethylsilyldiazomethane in hexane (Aldrich, Milwaukee, WI). The solvent was evaporated to give an 8/2 mixture of methyl 4-bromo-5-methylthiophene-2-carboxylate and methyl 5-bromothiophene-2-carboxylate (858 mg, quantitative yield ). Gas Chromatography / Mass Spectrum (m / z): Theoretical values for C ₇ H ₇ O ₂ SBr, 234.9 and 236.9 (M + H), Experiments 235.3 and 237.3. Theoretical values for C ₆ H ₄ O ₂ SBr, 220.9 and 222.9 (M + H), experimental values 221.3 and 223.3.

c) Methyl 4-cyano-5-methylthiophene-2-carboxylate: Methyl 4-bromo-5-methylthiophene-2-carboxylate and methyl 5-bromothiophene- Was dissolved in anhydrous dimethylformamide (5 mL) and refluxed with copper cyanide (345 mg, 3.9 mmol) for 7 hours. The cooled solution was poured into 0.1 M aqueous sodium cyanide solution (200 mL) and extracted with diethyl ether (5 x 30 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The obtained brown solid was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate 9/1 (v: v)) to obtain methyl 4-cyano-5-methylthiophene-2-carboxylate And methyl 5-methylthiophene-2-carboxylate (369 mg, 68%). ^{1 H-NMR (DMSO-d} 6; 300 MHz) δ 8.06 (s, 1H), 8.05 and 7.90 (2H, 0.1H, 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 804 mg (4.4 mmol) methyl 4-cyano-5-methylthiophene- Was treated in a similar manner to step (c) of Example 139, and the unreacted starting nitrile was fractionally crystallized with ethanol to give methyl 4- (aminothioxomethyl) -5-methylthiophene-2- Carboxylate and methyl 4-cyano-5-methylthiophene-2-carboxylate (457 mg, 48%). ¹ H-NMR (DMSO-d ₅ ; 300 MHz)? 9.93 (br s, 1H, small amount), 9.34 (br s, (S, 3H, minor amount), 3.84 (s, 3H, small amount), 3.81 (s, 3H, main amount), 2.68 Mass spectrum (MALDI-TOF, CHCA matrix, m / z): calculated for C ₈ H ₉ NO ₂ S ₂ : 216.0 (M + H), found 216.4.

e) Methyl 5-methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxylate: Methyl 4- (aminothioxomethyl) Carboxylate (200 mg, 0.93 mmol) was reacted with 185 mg (0.93 mmol) of 2-bromoacetophenone in a similar manner to step (a) of Example 8 and purified by thin layer chromatography (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carbaldehyde in solid state (96 mg, 36%) of methyl 4-cyano-5-methylthiophene-2-carboxylate.

f) 5-Methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- Carboxylate (64 mg, 0.23 mmol) was treated in a similar manner to step (b) of Example 10 and purified by high pressure liquid chromatography (Dynaman C18 column, 300 Å pore Methyl-4- (4-phenyl (l, 3-dihydro-lH-pyrrolo [ Thiazol-2-yl)) thiophene-2-carboxidine (0.6 mg, 0.9%). ¹ H-NMR (CD ₃ OD, 300 MHz) 8.44 (s, 1 H), 8.02 (m, 2H), 7.92 s, 3H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 15} H 13 N 3 S Calcd 300.1 (M + H) for _2, experimental data 300.6.

g) 5- (4-Phenyl-1,3-thiazol-2-yl) thiophene-2-carboxamide: Prepared from the HPLC- Thiazol-2-yl) thiophene-2-carboxamide (2 mg) was isolated. 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): C 14} H 11 N 3 theoretical value for the _{S 2: 286.0 (M + H} ), Found; 286.2.

Example 145

a) Methyl 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5- methylthiophene- A solution of 257 mg (0.48 mmol, based on the weight of the mixture containing 60% nitrile) of 2-bromo- (3 ', 4'-dimethoxy) -Methanone was reacted with 124 mg (0.48 mmol) of acetophenone (step (a) of Example 31) in a similar manner to step (a) of Example 8 to obtain methyl 4- [4- Phenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate (95 mg, 53%). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 18} H 17 NO 4 Calcd for _{S 2: 376.1 (M + H} ), Found; 376.3.

b) 4- [4- (3,4-Dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5- methylthiophene- Yl)] - 5-methylthiophene-2-carboxylate (95 mg, 0.25 mmol) was prepared in analogy to example 10, step (b) To give 4- [4- (3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2- carboxamide as a yellow solid , 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, 3 H), 2.95 (s, 3 H). Mass spectrum (MALDI-TOF, CHCA _{matrix, m / z): C 17} H 17 N 3 O 2 Calcd 360.1 (M + H) for S _2, 360.2 experimental values.

Example 146

methylthiophene-2-carboxylic acid: 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S., Heterocycles 20 (10): A solution of 27.65 g (108 mmol) in tetrahydrofuran (20 mL, 2035, 1983) was dissolved in anhydrous tetrahydrofuran (280 mL), cooled to -78 ° C and then 2 M n- butyllithium in cyclohexane Was added for 10 minutes. After stirring for 20 minutes at -78 [deg.] C, the mixture was allowed to warm to room temperature while bubbling anhydrous carbon dioxide gas for 1.5 hours. To this, 6N hydrochloric acid (100 mL) was carefully added. The layers were separated and the aqueous layer was extracted with diethyl ether (4 x 50 mL). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ ; 300 MHz)? 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 was dissolved in anhydrous dichloromethane 200 mL), and the mixture was reacted with oxalyl chloride (2 mL, 22.6 mmol) and dimethylformamide (100 μL) for 30 minutes while stirring in an ice bath, followed by stirring at room temperature for 2.5 hours. The solvent was removed in vacuo and the residue was passed through silica gel (eluent: hexane: ethyl acetate 7/3 (v / v), ethyl acetate and dichloromethane). The solvent was removed in vacuo and the oil obtained was dissolved in anhydrous dichloromethane (100 mL). This solution was reacted with anhydrous pyridine (9 mL, 113 mmol) and anhydrous isopropanol (40 mL, 522 mmol) for 88 hours. The solvent was removed in vacuo and the residue 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) and brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography (eluent: hexane: ethyl acetate 9/1 (v / v)) to give isopropyl 4-bromo-5-methylthiophene -2-carboxylate (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 = 6.2 Hz ). Mass spectrum (ESI, m / z): Theoretical value for C ₉ H ₁₁ O ₂ SBr 264.2 (M + H), found 264.8.

c) isopropyl 4-cyano-5-methylthiophene-2-carboxylate: Isopropyl 4-bromo-5-methylthiophene-2-carboxylate (1.9 g, 7.3 mmol) Was dissolved in dimethylformamide (30 mL) and refluxed with copper cyanide (785 mg, 8.8 mmol) for 16 hours. The cooling solution was poured into 0.1 M aqueous sodium cyanide solution (300 mL) and extracted with diethyl ether (4 x 40 mL). The organic layer was washed with brine (2 x 40 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate 9/1 (v: v)) to give isopropyl 4-cyano-5-methylthiophen- -Carboxylate (960 mg, 63%). ^{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 = 6.2 Hz ).

d) isopropyl 4- (aminothioxomethyl) -5-methylthiophene-2-carboxylate: Isopropyl 4-cyano-5-methylthiophene-2-carboxylate 960 mg (4.59 mmol) (Aminothioxomethyl) -5-methylthiophene-2-carboxylate (623 &lt; RTI ID = 0.0 &gt; mg, 56%). ¹ H-NMR (DMSO-d ₆ , 300 MHz)? 9.93 (br s, 1 H), 9.34 (br s, 1 H), 7.54 (s, 3H), 1.29 (d, 6H, J = 6.2 Hz). Mass spectrum (MALDI-TOF, GA _{matrix, m / z): C 10} H 13 NO 2 Calcd for _{S 2 244.0 (M + H)} , Found; 243.8.

e) Isopropyl 5-methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxylate: Isopropyl 4- (aminothioxomethyl) (1.54 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, Wis.) And 307 mg (1.54 mmol) of thiophene- Yl) thiophene-2-carboxylate (347 &lt; RTI ID = 0.0 &gt; 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): C 18 H 17 NO 2 Calcd for _{S 2 344.1 (M + H)} , Found; 344.1.

f) 5-Methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- Carboxylate (340 mg, 0.99 mmol) was treated in a similar manner to Example 10, step (b) to give 5-methyl-4- ( 4-phenyl (1,3-thiazol-2-yl)) thiophene-2-carboxidine (360 mg, quantitative yield). This material was dissolved in anhydrous methanol (20 mL) and treated with 1 M HCl (g) in diethyl ether. The solvent was evaporated in vacuo and recrystallized from methanol to give the hydrochloride salt of 5-methyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- 252 mg, 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, IH), 2.93 (s, 3H). Mass spectrum (ESI, m / z): C 15 H 13 N 3 S Calcd 300.1 (M + H) for _2, experimental data 300.2.

Example 147

(a) 2-Methyl-5 - [(methylethyl) oxycarbonyl] thiophene-3-carboxylic acid: And tetrafluorophthalic acid (570 mg, 2.39 mmol) was heated in a glass bomb at 160 &lt; 0 &gt; C for 66 h. The cooled residue was immersed in hot chloroform (30 mL), treated with norite, and filtered through celite. The celite was washed with hot chloroform (30 mL). The cooled chloroform extract was filtered and extracted with saturated sodium bicarbonate (4 x 10 mL). The basic extract was washed with chloroform, filtered through celite, and acidified to pH 1 with concentrated hydrochloric acid. The solid was collected by filtration and washed with water (3 x 10 mL) to give 2-methyl-5- [(methylethyl) oxycarbonyl] thiophene-3-carboxylic acid (288 mg, 53% It was obtained in solid form. ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 13.03 (br s, 1H), 7.85 (s, 1H), 5.08 (septet, 1H, J = 6.2 Hz) 29 (d, 6H, J = 6.2 Hz). Mass spectrum (ESI, m / z): C 10 H 12 O 4 Calcd for S 229.1 (M + H), Found; 228.8.

(b) Isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate: 2-Methyl-5 - [(methylethyl) oxycarbonyl] thiophene- A stirred solution of 300 mg (1.3 mmol) in anhydrous dichloromethane (10 mL) was treated with oxalyl chloride (174 L, 2 mmol) and dimethylformamide (50 L). The mixture was stirred at room temperature for 1.25 h, the solvent was removed in vacuo and the resulting residue was filtered through silica gel (1 mL thick in a 60 mL silica glass Buchner funnel) followed by elution with dichloromethane (150 mL). This material was treated in a similar manner to step (a) of Example 142 to give isopropyl 4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (266 mg, 67% &Lt; / RTI &gt;

(c) Synthesis of isopropyl 4- (2-amino (1,3-thiazol-4-yl)) - 5-methylthiophene- (0.85 mmol) of thiourea was reacted with 65 mg (0.85 mmol) of thiourea in a similar manner to step (a) of Example 8 to give isopropyl 4- (1,3-thiazol-4-yl)) - 5-methylthiophene-2-carboxylate (257 mg, quantitative yield) as a white solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 7.90 (s, 1H), 6.93 (s, 1H), 5.09 (septet, 1H, 6.2Hz), 2.61 (s, 3H), 1.29 (d, 6H , J = 6.2 Hz). Mass spectrum (ESI, m / z): C 12 H 14 N 2 O 2 Calcd for _{S 2 283.1 (M + H)} , Found; 283.1.

(d) Preparation of 4- (2-amino (1,3-thiazol- 4-yl) -4-yl)) - 5-methylthiophene-2-carboxylate (240 mg, 0.85 mmol) was treated in a similar manner to Example 10, step (b) -Thiazol-4-yl)) - 5-methylthiophene-2-carboximidine (20 mg, 10%) as a solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 9.30 (br s, 2H), 8.99 (bs, 2H), 8.28 (s, 1H), 6.78 (s, 1H), 2.71 (s, 3H). Mass spectrum (ESI, m / z): C 9 H 10 N 4 S 2 Calcd 238.8 (M + H), Found; 239.2 for.

Example 148

(a) 4-Bromo-5-ethylthiophene-2-carboxylic acid: To a solution of 4,5-dibromothiophene-2-carboxylic acid (lanthanide from Windham, New Hampshire, USA) in anhydrous THF Castor product) was cooled to -78 &lt; 0 &gt; C. To this was added 35 mL (70 mmol) of 2.0 M n-butyllithium in cyclohexane (Aldrich, Milwaukee, Wisconsin, USA) over 15 minutes and the reaction was stirred at -78 <0> C for 15 minutes. The mixture was quenched with ethyl iodide (2.8 mL, 35 mmol) and warmed to room temperature. The mixture was poured into 6N hydrochloric acid (100 mL), and extracted with diethyl ether (4 x 50 mL). The organic layer was washed with water (2 x 50 mL), brine (50 mL), and then dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, 2-ethyl-3-bromo-thiophene-5-carboxylate (7 g, 85%) was obtained in the form of a dark colored solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 13.25 (br s, 1H), 7.62 (s, 1H), 2.80 (q, 2H, J = 7.5Hz), 1.23 (t, 3H, J = 7.5 Hz).

(b) isopropyl 4-bromo-5-ethylthiophene-2-carboxylate: A solution of 7 g (30 mmol) of 4-bromo-5-ethylthiophene-2-carboxylic acid was dissolved in anhydrous dichloromethane (200 mL) and treated with oxalyl chloride (3.2 mL, 36 mmol) and dimethylformamide (0.5 mL) for 18.5 hours. The solvent was removed in vacuo and the resulting residue brown oil was passed through silica gel (2-inches thick in 350 mL silica glass Buchner funnel) and eluted with 700 mL of hexane: ethyl acetate 9/1 (v: v). The eluate was concentrated in vacuo and the resulting oil was dissolved in anhydrous dichloromethane (200 mL). This solution was treated with pyridine (12 mL, 150 mmol) and anhydrous isopropanol (60 mL, 750 mmol) at room temperature for 4 h. The solvent was removed in vacuo and the resulting residue was partitioned between dichloromethane (100 mL) and water (200 mL). The aqueous layer was extracted with dichloromethane (2 x 30 mL). The collected organic layer was extracted with sodium bicarbonate (2 x 30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. Ethyl-3-bromo-thiophene-5-carboxylate (4 g, 48 mmol) was purified by column chromatography on silica gel (250 g) eluting with hexane: ethyl acetate 95/5 %) As a yellow oil. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 7.66 (s, 1H), 5.89 (septet, 1H, J = 6.2Hz), 2.80 (q, 2H, J = 7.5Hz), 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- Was refluxed with copper cyanide (1.94 g, 22 mmol) in anhydrous dimethylformamide (50 mL) for 8 hours. The cooled mixture was poured into 0.1 M sodium cyanide (500 mL) and extracted with diethyl ether (4 x 50 mL). The organic layer was washed twice with brine (50 mL) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo. Ethyl-3-cyano-thiophene-5-carboxylate (1.7 g, 53%) was obtained by purification by column chromatography on silica gel (400 g) eluting with hexane: ethyl acetate 9/1 %) As a pale yellow oil. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 8.03 (s, 1H), 5.10 (septet, 1H, J = 6.2Hz), 3.04 (q, 2H, J = 7.5Hz), 1.3 1 (t, 3H, J = 7.5 Hz), 1.30 (d, 6H, J = 6.2 Hz). Mass spectrum (ESI, m / z): Theoretical value for C ₁₁ H ₁₃ NO ₂ S 224.1 (M + H), found 224.0.

(d) Isopropyl 4- (aminothioxomethyl) -5-ethylthiophene-2-carboxylate: Isopropyl 4-cyano-5-ethylthiophene-2-carboxylate 1.7 g (7.6 mmol) (1.45 g, 74%) of isopropyl 5-ethyl-4- (aminothioxomethyl) -5-ethylthiophene-2-carboxylate was treated as in Example 139 Step (c) Was obtained in the form of a yellow solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 9.93 (br s, 1H), 9.39 (br s, 1H), 8.04 (s, 1H), 5.08 (septet, 1H, J = 6.2Hz), 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) Synthesis of isopropyl 5-ethyl-4- (4-phenyl (1,3-thiazol-2-yl)) thiophene- Carboxylate (450 mg, 1.75 mmol) was reacted with 2-bromoacetophenone (Aldrich, Milwaukee, Wisconsin, USA) in the manner analogous to step (a) Yl) thiophene-2-carboxylate (303 mg, 49%) was reacted with 348 mg (1.75 mmol) As an off-white solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 8.22 (s, 1H), 8.07 (s, 1H), 8.03 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 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): Theoretical value 358.1 (M + H) for C ₁₉ H ₁₉ NO ₂ S ₂ , experimental value 358.1

(f) 5-ethyl-4- (4-phenyl (l, 3-thiazol-2- yl)) thiophene- Carboxylate (250 mg, 0.70 mmol) was treated in a similar manner to step (b) of Example 10 to give 5-ethyl-4- (4-phenylphenyl) (L, 3-thiazol-2-yl)) thiophene-2-carboxamide (148 mg, 67%) as a yellow solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 = 7.4Hz), 1.42 (t, 3H, J = 7.4Hz). Mass spectrum (ESI, m / z): Theoretical value 314.1 (M + H) for C ₁₆ H ₁₅ N ₃ S ₂ , experimental value 314.2.

Example 149

(a) Isopropyl 4- [4- (3-hydrophenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene-2-carboxylate: Methylthiophene-2-carboxylate (1.97 g, 8.1 mmol) was reacted with 3'-hydroxy-2-bromoacetophenone (prepared according to the procedure of Example 8, step Reaction with Example 40 step (a)) and purification by silica gel column chromatography eluting with hexane: ethyl acetate 7/3 (v: v) followed by crystallization with 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, 300MHz): 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 = Mass spectrum (ESI, m / z): C 18 H 17 NO 3 Calcd 360.1 (M + H) for S _2, 360.1 experimental values.

(b) 4- [4- (3-Hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene- Carboxylate (1.4 g, 3.89 mmol) was treated in a similar manner to step (b) of Example 10 to give the title compound as a white solid To give 360 mg (31%) of 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiophene- &Lt; / RTI &gt; ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 9.62 (br s, 1H), 9.45 (br s, 2H), 9.09 (br s, 2H), 8.53 (s, 1H), 8.16 (s, 1H ), 7.47 (m, 2H), 7.27 (m, IH), 6.80 (m, IH), 2.93 (s, 3H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₅ H ₁₃ N ₃ OS ₂ 316.1 (M + H), found 316.2.

Example 150

(3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methyl (2-thienyl)} - imino-methyl) carboxamide: 4- [4- (3-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methyl-thiophene-2-carboxamide 320 mg (1 mmol ) Was dissolved in anhydrous dimethylformamide (50 mL), and 262 mg (1.2 mmol) of di-tert-butyl dicarbonate (product of Acros, Inc., Pittsburgh, Pa.) And 261 , 1.5 mmol) at room temperature for 64 hours. The 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 then dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and purified by column chromatography on silica gel (100 g) eluting with dichloromethane: methanol 95/5 (v: v) to give (tert-butoxy) -N - ({4- [4- Yl)] - 5-methyl (2-thienyl)} iminomethyl) carboxamide (247 mg, 59%) was obtained in the form of a yellow oil . ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, 1 H), 6.78 (m, 1 H), 2.83 (s, 3 H), 1.45 (s, 9 H). Mass spectrum (ESI, m / z): C 20 H 21 N 3 O 3 Calcd for _{S 2 416.1 (M + H)} , Found; 415.7

(b) Synthesis of methyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) Yl)] - 5-methyl (2-methoxyphenyl) -acetic acid: (tert-butoxy) -N - ({4- [4- (297 mg, 0.89 mmol) and methyl bromoacetate (136 mg, 0.89 mmol) were dissolved in anhydrous dimethylformamide (4 mL) mg, 0.89 mmol) at 60 &lt; 0 &gt; C for 3 hours. The mixture was poured into water (50 mL) and extracted with dichloromethane (9 x 10 mL). The organic extracts were washed with brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and purified by column chromatography on silica gel (50 g) eluting with dichloromethane: methanol 98/2 (v: v) to give methyl 2- {3- [2- (5 - {[ -Butoxyl) carbonylamino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (178 mg, 61% . Mass spectrum (ESI, m / z): Theoretical values for C ₂₃ H ₂₅ N ₃ O ₅ S ₂ 488.1 (M + H), 388.1 ((M-BOC) + H), 487.8, 388.2.

(c) Methyl 2- {3- [2- (5-Amino-2-methyl-3-thienyl) -1,3-thiazol- Thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (prepared from 15- [ mg, 0.031 mmol) was treated with dichloromethane: trifluoroacetic acid 1/1 (v: v) and water was added at room temperature for 1.5 h. The solvent was removed in vacuo to give methyl 2- {3- [2- (5-amidino-2-methyl-3-thienyl) -1,3-thiazol- 52%) as a brown solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, IH), 6.96 (m, IH), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H). Mass spectrum (ESI, m / z): C 18 H 17 N 3 O 3 Calcd for _{S 2 388.1 (M + H)} , Found; 388.3.

Example 151

(a) 2- {3- [2- (5 - {[(tert-Butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) Phenoxy} acetic acid: Methyl 2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl- Thiazol-4-yl] phenoxy} acetate (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with 2 M aqueous sodium hydroxide solution (2 mL) at room temperature for 1 hour and 10 minutes Respectively. The solvent was removed in vacuo. The solid was purified on silica gel (1 inch thick in a 60 mL silica glass Buchner funnel) eluting with dichloromethane: methanol 8/2 (v / v) to give 2- {3- [2- (5 - {[ Yl) phenoxy} acetic acid (44 mg, 88%) was obtained as a yellow solid in the form of a white solid . ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, IH), 6.96 (m, IH), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H). Mass spectrum (ESI, m / z): C 22 H 23 N 3 O 5 S Calcd 474.1 (M + H), 374.1 ((M-BOC) + H) for a _second experimental values 374.2, 473.7.

(b) 2- {3- [2- (5-Amidino-2-methyl-3-thienyl) -1,3-thiazol-4- yl] phenoxy} acetic acid Methyl 2- {3- [ Thienyl) -1,3-thiazol-4-yl] phenoxy} acetate (4 mg, , 0.0084 mmol) was treated with dichloromethane: trifluoroacetic acid 1/1 (v: v) and 2.5% water was added at room temperature for 2 hours and 35 minutes. The solvent was removed in vacuo, and then 2- {3- [2- (5-amidino-2-methyl-3-thienyl) -1,3-thiazol-4- yl] phenoxy} 71%) as a white solid. Mass spectrum (ESI, m / z): C 17 H 15 N 3 O 3 Calcd 373.1 (M + H) for S _2, 374.2 experimental values.

(c) Preparation of tert-butyl 4- (2- {3- [2- (5 - {[(tert- butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) 2- {3- [2- (5 - {[(tert-butoxy) carbonyl ] -piperazinecarboxylate dissolved in anhydrous dimethylformamide (3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetic acid (40 mg, 0.084 mmol) was added to a solution of hydroxybenzotriazole 23 mg, 0.17 mmol), 32 mg (0.17 mmol) of N-tert-butoxycarbonyl-piperazine (Lancaster, New Hampshire, NH), O- (7-azabenzotriazol- ) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) 65 mg (0.17 mmol) at room temperature for 20 hours. The mixture was partitioned between dichloromethane (50 mL) and brine (50 mL). The aqueous layer was extracted twice with dichloromethane (50 mL), and the collected organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was dried in vacuo. Purified by thin layer chromatography for purification eluting with dichloromethane: methanol 95/5 (v / v) to give tert-butyl 4- (2- {3- [2- (5 - {[(tert-butoxy) Amino] iminomethyl} -2-methyl-3-thienyl) -1,3-thiazol-4-yl] phenoxy} acetyl) piperazinecarboxylate (25 mg, 46%) as a white solid . ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 9.13 (br s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.63 (m, 2H), 7.39 (m, 1H), 3H), 1.45 (s, 9H), 1.42 (s, 9H). Mass spectrum (ESI, m / z): Theoretical value for C ₃₁ H ₃₉ N ₅ O ₆ S ₂ 642.3 (M + H), 542.3 ((M-BOC) H), found 642.0, 542.2, 442.3.

(d) Preparation of 5-methyl-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3-thiazol- : tert -butyl 4- (2- {3- [2- (5 - {[(tert-butoxy) carbonylamino] iminomethyl} -2-methyl-3-thienyl) (25 mg, 0.039 mmol) was treated with dichloromethane: trifluoroacetic acid 1/1 (v: v) and 2.5% water was added to a solution of 2 Lt; / RTI &gt; The solvent was removed in vacuo to give 5-methyl-4- {4- [3- (2-oxo-2-piperazinylethoxy) phenyl] (1,3- thiazol- 2-carboxydine (27.4 mg, quantitative yield) was obtained as an off-white solid. ¹ H-NMR (methanol-d ₄ , 300 MHz):? 8.41 (s, IH), 7.94 (s, IH), 7.67 (s, 2H), 3.88 (m, 4H), 3.25 (m, 4H), 2.95 (s, 3H). Mass spectrum (ESI, m / z): C 21 H 23 N 5 O 2 Calcd 442.1 (M + H) for S _2, 442.4 experimental values.

Implementation 152

Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate

From 0 ℃ of N ₂ under CH ₂ Cl ₂ 28 mL containing 0.8 mL DMF 2- methylthio-stirred slurry of thiophene-3-carboxylic acid (2.0 g, 8.61 mmol) - (5- carboxylic bome ethoxy) (1.9 eq, 16.3 mmol) was added dropwise via syringe. The reaction was allowed to warm to room temperature after 1 hour, and then stirred for an additional 1 hour. The reaction mixture was passed through a 20 cm silica gel pad in a 30 mL silicic acid glass funnel which had been soaked with 50% ethyl acetate-hexane and further eluted with the same solvent system until UV absorber showed no product by UV visualization. The solvent was concentrated in vacuo, azeotroped with toluene (1x) and dried in vacuo to give the acid chloride (1.52 g) in the form of a pale yellow solid. The acid chloride was dissolved in 20 mL CH ₃ CN, cooled to 0 ° C and treated slowly with TMSCHN ₂ (2.1 eq, 6.3 mL, 2 M in hexanes) by syringe. The reaction was allowed to warm to room temperature (0.5 h), cooled back to 5 &lt; 0 &gt; C and then immediately treated with 30% HBr-acetic acid (0.66 mL) through a dropping funnel. After 15 min, the reaction was diluted with 20 mL of ether at 0 &lt; 0 &gt; C, filtered, and washed well with ether (3 x 20 mL). The yellow solid was dried in vacuo 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, 300MHz) δ 2.66 (s, 3H), 3.84 (s, 3H), 5.03 (s, 2H), 8.29 (s, 1H).

Example 153

Isopropyl-4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate

From 0 ℃ of N ₂ under CH ₂ Cl ₂ 15 mL containing 0.8 mL DMF 2- methyl-stirred slurry of thiophene-3-carboxylic acid (0.40 g, 1.75 mmol) - (5- carboxylic boyiso propoxy) (1.9 eq, 3.32 mmol) was slowly added via syringe. The reaction was allowed to warm to room temperature after 1 hour and then stirred for an additional hour. The solvent was concentrated in vacuo, azeotroped with toluene (1x) and dried in vacuo to give the acid chloride (0.397 g, 1.60 mmol) as a pale yellow solid. Acid chloride was dissolved in CH ₃ CN 7 mL and cooled to 0 ℃, TMSCHN ₂ was treated slowly dropwise via syringe with (2.1 eq., 2 M in 1.68 mL, hexane). The reaction was allowed to warm to room temperature (0.5 h), cooled back to 5 &lt; 0 &gt; C and immediately treated with 30% HBr-acetic acid (0.5 mL) through a dropping funnel. After 15 minutes, the reaction mixture was passed through a 10 cm silica gel pad in a 15 mL silica glass funnel, which had been soaked with 50% ethyl acetate-hexane at 0 &lt; 0 &gt; C, And further eluted with a solvent system. The solvent was concentrated to dryness in vacuo to afford isopropyl-4- (2-bromoacetyl) -5-methylthiophene-2-carboxylate (0.329 g, 61% yield) as an oil, &Lt; / RTI &gt; ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 1.31 (d, 6H, J = 6.3Hz), 2.71 (s, 3H), 4.60 (s, 2H), 5.09 (m, 1H), 8.08 (s , 1H).

Example 154

(a) Methyl 5-methylthio-4- [2- (phenylamino) - (1,3-thiazol-4-yl)] - thiophene- 2-carboxylate Bromate: Methyl 4- 5-methylthiothiophene-2-carboxylate (60.5 mg, 0.19 mmol) was slurried in 4 mL acetone with phenylthiourea (1 eq, 30 mg) and heated to 70 & . After 3 hours, the reaction was cooled to room temperature, filtered and then dried in vacuo to give methyl 5-methylthio-4- [2- (phenylamino) - (1,3-thiazol- 2-carboxylate bromate (69% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 16 H 14 N 2 O 2 Calcd for _{S 3 362.49 (M + H)} , Found; 363.7.

(b) 5- methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxamide hydrochloride, pyrimidine: Under N ₂ NH ₄ Cl 57.8 mg (8 Equiv., 1.08 mmol) was charged with 1.3 mL of toluene. AlMe ₃ (8 eq., 2 M / hexane, 0.54 mL) was added dropwise to the stirring slurry over 3 minutes and further stirred for 5 minutes. At this time, a solution of methyl 5-methylthio-4- [2- (phenylamino) - (1,3-thiazol-4-yl)] - thiophene- 2- carboxylate bromate mmol) was quickly added at once, and the resulting mixture was immersed in an oil bath at 120 ° C. After 2 hours and 10 minutes, TLC (silica gel 60F ₂₅₄ , Merck KGaA, Merck product of Darmstadt, Germany, 9: 1: 0.5 CH ₂ Cl ₂ -MeOH-AcOH eluent) And implied that it was completed. The reaction was cooled to ambient temperature and then added via pipette to a stirred slurry of 1.3 g of SiO ₂ in 20 mL of CHCl ₃ . The residue remaining in the flask was washed with 4 mL of MeOH, briefly sonicated and then added to the SiO ₂ slurry. The slurry was stirred for 10 minutes and then filtered through a 15 mL silicified glass funnel containing 20 cm of SiO ₂ with 50% CHCl ₃ -MeOH. The yellow fractions were collected and the others discarded. According to TLC, the product was in a fairly pure state. The solvent was removed in vacuo and the residue obtained was triturated with 10% MeOH-CH ₂ Cl ₂ . The solid was removed by filtration. The solvent was concentrated in vacuo to afford 30.1 mg (66% yield) of 5-methylthio-4- [2- (phenylamino) - (1,3- thiazol-4- yl)] thiophene- As a reddish brown powder. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.73 (s, 3H), 6.94-7.00 (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 Mass spectrum (ESI, m / z): C 15 H 14 N 4 S Calcd for ₃ 346.50 (M + H), Found; 347.2.

Example 155

(a) Methyl 4- {2- [(2-chlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 5-methylthiothiophene-2-carboxylate (50 mg) was reacted with 2-chlorophenylthiourea (26.7 mg) as described in step a) of Example 154 to give (75%) of methyl 4- {2- [(2-chlorophenyl) amino] - (1,3-thiazol-4-yl)} - 5-methylthiothiophene- . ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.66 (s, 3H), 3.82 (s, 3H), 7.04 (m, 1H), 7.32-7.38 (m, 2H), 7.47 (dd, 1H, J = 1.4, 8.7 Hz), 8.12 (s, 1H), 8.56 (dd, 1H, J = 1.4, 8. 3 Hz), 9.75 (s, 1H). Mass spectrum (ESI, m / z): C 16 H 13 ClN 396.94 Calcd for _{2 O 2 S 3 (M +} H), Found; 397.1.

(b) 4- {2- [(2-Chlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (40 mg, 0.08 mmol) was added to a solution of (3-chloro-phenyl) Was treated as described in step b) to give 4- {2- [(2-chlorophenyl) amino] - (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carbamidine hydrochloride (24 mg, 71.8%). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.71 (s, 3H), 7.04 (td, 1H, J = 1.4, 7.8 Hz), 7.21 2H), 9.26 (s, 1H), 8.57 (dd, 1H, J = 1.3, Mass spectrum (ESI, m / z): C 15 H 14 N 4 S 3 Cl, 380.94 (M + H), Found; 381.1.

Example 156

(a) Methyl 4- (2-amino (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate Bromate: Methyl 4- (2-bromoacetyl) -5 (50 mg, 0.16 mmol) was reacted with thiourea (12 mg) as described for example 154 step (a) to give methyl 4- (2-amino- Thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate bromate (70% yield). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.69 (s, 3H), 3.83 (s, 3H), 7.00 (s, Mass spectrum (ESI, m / z): C 10 H 10 O 2 S 3 Calcd for _{N 2 286.4l (M + H)} , Found; 287.1

(b) 4- (2-Amino- (1, 3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxydin hydrochloride: Methyl 4- -Thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate bromate (110 mg, 0.29 mmol) was treated as described in example 154 step (b). The prepared amidine (74 mg) was stirred in 3 mL of anhydrous methanol under N ₂ and treated with about 1 mL of ether saturated with anhydrous HCl gas. Subsequently, the reaction mixture to which anhydrous ether (1.5 mL) was added was allowed to stand at room temperature for 2 hours and then filtered to obtain 4- (2-amino- (1,3-thiazol-4-yl) Octane-2-carboxamide hydrochloride (40 mg, 45% yield). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.69 (s, 3H), 6.90 (s, 1H), 8.44 (s, 1H), 9.20,9.42 (s, 4H, NH). Mass spectrum (ESI, m / z): Theoretical value for C ₉ H ₁₀ N ₄ S ₃ 270.4 (M + H), experimental value 271.2.

Example 157

(a) Methyl 4- {2 - [(2,5-dimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate Bromate: Carboxylate (49.4 mg, 0.15 mmol) was reacted with 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate as described in step a) of Example 154 using 2,5- dimethoxyphenyl Thiourea (37.2 mg) to obtain methyl 4- {2 - [(2,5-dimethoxyphenyl) amino] (1,3-thiazol- carboxylate bromate 65.5 mg (87% ^{yield), 1 H-NMR (DMSO-} d 6, 300MHz): δ2.66 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 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): C 18 H 18 N 2 O 4 S Calcd for ₃ 422.54 (M + H), Found; 423.1.

(b) 4- {2 - [(2,5-dimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (45.5 mg, 0.09 mmol) was added to a solution of {2- [(2,5-dimethoxyphenyl) amino] - (1,3- the embodiment of step 154 was processed as described in (b), purified by thin layer chromatography (500 mm silica gel plate, NJ JT Baker of Phillipsburg product material, 10% for methanol -CH ₂ Cl ₂ - Saturated NH ₃ eluant) to give 4- {2 - [(2,5-dimethoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophen- 9.9 mg (27% yield) of radiantine was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.60 (s, 3H), 3.73 (s, 3H), 3.81 (s, 3H), 6.48 (dd, 1H, J = 3.1,8.8Hz), 6.92 (d, IH, J = 7.9 Hz), 7.05 (s, IH), 7.5 (bs, 2H), 8.04 (s, IH), 8.34 ). Mass spectrum (ESI, m / z): C 17 H 18 N 4 O 2 Calcd for _{S 3 406.55 (M + H)} , Found; 407.1.

Example 158

(a) Methyl 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- (53.3 mg, 0.17 mmol) was reacted with 2-methoxyphenylthiourea as described in step a) of Example 154 (34.5 mg, mg) to obtain 61 mg of methyl 4- {2- [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate (76% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.67 (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 6.53 (d, 1H, J = 6.8Hz), 7.13-7.24 (m, 2H), 7.29 (s, 3H), 7.59 (m, IH), 8.16 (s, 3H), 10.32 (s, IH). Mass spectrum (ESI, m / z): C 17 H 16 N 2 O 3 S 3 Calcd 392.52 (M + H) for, Found; 393.2.

(b) 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 2-carboxamidine bromide (54.6 mg, 0.11 mmol) was carried out in the same manner as in Reference Example 1, except for using 2-amino-2- (3-methoxyphenyl) (3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 25.2 mg (56%) of 2-carboxydin hydrochloride was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ2.71 (s, 3H), 3.77 (s, 3H), 6.54 (m, 1H), 7.15 (s, 3H), 7.l9-7.28 (m 2H), 7.47 (m, 1H), 8.46 (s, 1H), 8.86 (bs, 2H), 9.28 (bs, 2H), 10.36 Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₆ N ₄ OS ₃ 376.52 (M + H), found 377.2.

Example 159

(a) Methyl 4- {2- [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- (41.3 mg, 0.13 mmol) was reacted with 5-methoxyphenylthiourea (26.8 mg, 0.13 mmol) as described in step a) of Example 154, mg) to obtain 25 mg of methyl 4- {2- [4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate (41% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.64, 2.68 (s, 3H rotomer), 3.72, 3.73 (s, 3H rotomer), 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, 1H, J = 9.0 Hz), 8.05, 8.13 (s, 1H rotomer), 10.16, bs, 1H, rotomer). Mass spectrum (ESI, m / z): C 17 H 16 N 2 O 2 S 3 Calcd 392.52 (M + H) for, Found; 393.1.

(b) 4- {2- [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (22 mg, 0.046 mmol) was reacted with 5-methylthiophene-2-carboxylate (B), to give 4- {2- [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carbamidine hydrochloride (61% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.72 (s, 3H), 3.73 (s, 3H), 6.91 (d, 2H, J = 9.0Hz), 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 Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₆ N ₄ OS ₃ 376.52 (M + H), experimental value 377.1.

Example 160

(a) Methyl 4- (2 - {[4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate Bromate: 5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was reacted with 4-N, N-dimethyl- (3-thiazol-4-yl) -5-methylthiothiophene (31.5 mg) was reacted with methyl 4- (2- To obtain 53.2 mg (75% yield) of 2-carboxylate bromate. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 18 H 19 N 3 O 2 S 3 Calcd 405.56 (M + H) for, Found; 406.1.

(b) 4- (2- {[4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene- 5-methylthiothiophene-2-carboxylate bromate (50 mg, 0.10 mmol) was added to a solution of (2 - {[4- (dimethylamino) Was treated as described in step b) of Example 154 to give 4- {2- [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5- 2-carboxydin hydrochloride (22% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J = 9.2Hz), 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 Bromate: Methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was reacted with 2-methyl-4-chlorobenzoate as described for example 154, step (a) (3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate was obtained by reacting methyl 4- {2- [ -Carboxylate bromate (79% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.28, 2.29 (s, 3H rotomer), 2.62, 2.66 (s, 3H rotomer), 3.82 (s, 3H), 7.21-7.29 (m, 3H), 1H, J = 8.4Hz), 9.44 (s, 1H), 9.59 (s, 1H). Mass spectrum (ESI, m / z): C 17 H 15 ClN 2 O 2 S 3 Calcd 410.96 (M + H), Found; 41l.1 on.

(b) 4- {2 - [(4-Chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (55 mg, 0.17 mmol) was added to a solution of (2-methyl-2- Was treated as described in step b) of Example 154 to give 4- {2- [(4-chloro-2-methylphenyl) amino] (1,3- 16 mg (22% yield) of thiothiophene-2-carboxydin hydrochloride was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.30 (s, 3H), 2.70 (s, 3H), 7.15 (s, 1H), 7.23-7.29 (m, 2H), 8.34 (d, 1H, J = 8.6 Hz), 8.44 (s, 1H), 8.86 (bs, 2H), 9.29 (bs, 2H), 9.47 (s, Mass spectrum (ESI, m / z): theoretical value for C ₁₆ H ₁₅ ClN ₄ S ₃ 394.97 (M + H), experimental value 395.1.

Example 162

(a) Methyl 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- (50 mg, 0.16 mmol) was reacted with diphenylmethane thiourea (38 mg) as described for example 154, step (a) After removal of the solvent in vacuo, methyl 4- {2- [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate 145 mg (100% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ2.50 (s, 3H), 2.80 (s, 3H), 6.13, 6.18 (d, 1H rotomer, J = 7.9Hz), 7.23-7.41 (m, 11H), 8.00, 8.02 (s, 1H rotomer), 8.73, 8.86 (d, 1H, rotomer, J = 8.0 Hz). Mass spectrum (ESI, m / z): C 23 H 20 N 2 O 2 S 3 Calcd 452.62 (M + H) for, Found; 453.0.

(b) 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 5-methylthiothiophene-2-carboxymidine bromate (96.3 mg, 0.18 mmol) was reacted with 4- [(diphenylmethyl) amino] (b) to give 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride 16 mg (20% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 2.59 (s, 3H), 6.23 (d, 1H, J = 7.9Hz), 6.84 (s, 1H), 7.22-7.40 (m, 10H), 8.09 ( bs, 3H), 8.12 (s, IH), 8.68 (d, IH, J = 84 Hz). Mass spectrum (ESI, m / z): C 22 H 20 N 4 S 3 Calcd 436.62 (M + H) for, Found; 437.1.

Example 163

(a) methyl 5-methylthio-4- {2 - [(3-phenylpropyl) amino] (131 mg, 0.42 mmol) was added to a solution of propylphenylthiourea (82.3 mg) in DMF as described in step a) of Example 154, and reacting then with 10% methanol -CHCl ₃ and filtered on silica gel pad of the 15 mL glass pupation (fritted) within the funnel 5 cm. The solvent was removed in vacuo and concentrated to give methyl 5-methylthio-4- {2- [(3-phenylpropyl) amino] (1,3-thiazol-4- yl)} thiophene- 203 mg (100% yield) of levorbromate was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 19 H 20 N 2 O 2 Calcd for _{S 3 404.57 (M + H)} , Found; 405.1

(b) 5-Methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thiophene- Carboxylate bromide (112 mg, 0.23 mmol) was reacted in the same manner as in Example 154, step (d), except that thiophene-2-carboxylate (b) to give 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride after obtaining 16 mg (16% yield), 20% methanol -CH ₂ Cl ₂ - using saturated NH ₃ as eluent and further purified by thin layer chromatography for purification. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 1.89 (m, 2H), 2.54 (s, 1H), 2.66 (at, 2H, J = 7.3Hz), 3.31 (m, 2H), 6.69 (bs (S, 3H), 6.76 (s, 1H), 7.15-7.31 (m, 5H), 7.69 (m, Mass spectrum (ESI, m / z): C 18 H 20 N 4 S Calcd for ₃ 388.58 (M + H), Found; 389.2.

Example 164

(a) methyl 5-methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene- Methylthiothiophene-2-carboxylate (60 mg, 0.21 mmol) was reacted with 2,4,5-trimethylcyclohexylamine as described for example 154, step (a) Methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carbaldehyde 42% yield (41% yield) of the phosylate bromate. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.16 (s, 3H), 2.18 (s, 3H), 2.19 (s, 3H), 2.64 (s, 3H), 3.82 (s, 3H), 6.97 (s, IH), 7.18 (s, IH), 7.86 (s, IH), 8.12 (s, IH), 9.29 Mass spectrum (ESI, m / z): C 19 H 20 N 2 O 2 Calcd for _{S 3 404.57 (M + H)} , Found; 405.1

(b) 5-Methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene- Thiophene-2-carboxylate bromate (37.3 mg, 0.07 mmol) was added to a solution of 5-methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] mmol) was treated as described in step (b) of Example 154 to give 5-methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] Yl)} thiophene-2-carboxidine hydrochloride (95% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.16 (s, 3H), 2.19 (s, 3H), 2.20 (s, 3H), 2.68 (s, 3H), 6.97 (s, 1H), 7.03 (s, IH), 7.84 (s, IH), 8.41 (s, IH), 8.84 (bs, 2H), 9.26 (bs, 3H). Mass spectrum (ESI m / z.): C 18 H 20 N 4 S Calcd for ₃ 388.58 (M + H), Found; 389.2.

Example 165

(a) Methyl 4- {2- [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 2-carboxylate Bromate: Methyl 4- (60 mg, 0.19 mmol) was reacted with 2-fluorophenylthiourea as described for example 154, step (a), to give the title compound 55.6 mg (70% yield) of methyl 4- {2- [(2-fluorophenyl) amino] (1,3-thiazol- ). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 rotomer). 8.61 (td, 1H rotomer, J = 1.5, 8.5 Hz), 10.14. 10.30 (s, 1H rotomer). Mass spectrum (ESI, m / z): C 16 H 13 FN 2 O 2 S 3 Calcd 380.48 (M + H), Found; 381.1 for

(b) 4- {2- [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (55.6 mg, 0.13 mmol) was reacted with 5-methylthiothiophene-2-carboxylate bromide in the same manner as in Example 154 Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2- carboxylic acid ethyl ester was prepared as described in step (b) Carboxamide hydrochloride (12.4 mg, 24% yield). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.72 (s, 3H), 3.16 (s, 3H), 6.97-7.08 (m, 1H), 7.18-7.36 1H), 8.70 (td, IH, 1.4, 8.4 Hz), 8.92 (bs, 2H), 9.32 (bs, 2H), 10.18 Mass spectrum (ESI, m / z): C 15 H 13 FN 4 theoretical value for _{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 Bromate: Methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-methyl-3-chloro-benzaldehyde as described for example 154, step (a) (3-chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- -Carboxylate bromate (66.8% yield). Mass spectrum (ESI, m / z): C 17 H 15 ClN theoretical value for the _{2 O 2 S 3 410.96 (M} + H), Found; 411.1.

(b) 4- {2- [(3-Chloro-2-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (61.8 mg, 0.12 mmol) was added to a solution of (3-chloro-2-methylphenyl) amino] Was treated as described in step (b) of Example 154 to give 4- {2- [(3-chloro-2-methylphenyl) amino] 46.7 mg (90% yield) of thiothiophene-2-carboxydin hydrochloride was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.34 (s, 3H), 2.69 (s, 3H), 7.15 (s, 1H), 7.18-7.26 (m, 2H), 8.12 (d, 1H, J = 7.9 Hz), 8.41 (s, 1H), 8.84 (bs, 2H), 9.27 (bs, 2H), 9.61 (s, 1H). Mass spectrum (ESI, m / z): theoretical value for C ₁₆ H ₁₅ ClN ₄ S ₃ 394.97 (M + H), experimental value 395.1.

Example 167

(a) methyl 4- (2- {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl) Methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-isopropylphenylthiourea as described for example 154, step (a) (40 mg) to give methyl 4- (2- {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene- (36% yield) of &lt; RTI ID = 0.0 &gt; ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 1.17 (d, 6H, J = 6.7Hz), 2.60, 2.65 (s, 3H rotomer), 3.27 (s, 1H), 3.82 (s, 3H), (S, 1H), 7.14-7.25 (m, 2H), 7.34-7.37 (m, 1H), 7.78 rotomer). Mass spectrum (ESI, m / z): C 19 H 20 N Calcd about _{2 O A S 3 404.57 (M} + H), Found; 405.1.

(b) 4- (2- {[2- (methylethyl) phenyl] amino} (1,3-thiazol- Carboxylate bromide (33.1 mg, 0.06 mmol) in anhydrous tetrahydrofuran (3 ml) was added to a solution of (2-methyl-2- Was treated as described in example 154 step b) to give 4- (2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol- 22.4 mg (88%) of thiothiophene-2-carboxydin hydrochloride was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 1.19 (d, 6H, J = 6.8Hz), 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, Mass spectrum (ESI, m / z): C 18 H 20 N 4 S Calcd for ₃ 388.58 (M + H), Found; 389.2.

Example 168

(a) methyl 5-methylthio-4- (2 - {[4- (phenylmethoxy) phenyl] amino} Methylthiothiophene-2-carboxylate (336.3 mg, 1.08 mmol) was reacted with 4- benzyloxyphenylthiourea as described for example 154, step (a) (279 mg) to obtain methyl 4- (2 - {[4-phenylmethoxyphenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene- 450 mg (76% yield). Mass spectrum (ESI, m / z): C 23 H 20 N 2 O 3 S 3 Calcd 468.61 (M + H) for, Found; 469.2.

(b) 5-Methylthio-4- (2- {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) thiophene- 5-methylthiothiophene-2-carboxylate (100 mg, 0.18 mmol) was added to a solution of 4- (2- {[4-phenylmethoxyphenyl] amino} 4- (2 - {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl) ) Thiophene-2-carboxydin hydrochloride (23.9 mg, 27% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 6 2.73 (s, 3H), 5.08 (s, 2H), 7.00 (d, 2H, J = 8.2Hz), 7.09 (s, 1H), 7.31-7.47 (m, 5H), 7.70 (d, 2H, J = 8.0Hz), 8.47 (s, 1H), 8.88 (bs, 2H), 9.30 (bs, 2H), 10.20 Mass spectrum (ESI, m / z): C 22 H 20 N 4 theoretical 452.62 (M + H) for ₃ OS, 453.1 experimental values.

Example 169

(a) Methyl 4- {2- [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- (60 mg, 0.19 mmol) was added to a solution of 2-bromophenylthiourea (44 mg, 0.19 mmol) as described for example 154, step (a) mg) to obtain 63.1 mg of methyl 4- {2- [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate (64% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 rotomer), 8.27, 8.37 (dd, 1H), 9.60, 9.80 (bs, 1H rotomer, J = 1.5, 8.2 Hz) spectrum (ESI, m / z): C 16 H 13 BrN 2 O 2 S 3 Calcd 441.39 (M + H), Found; 441.1 for.

(b) 4- {2- [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (63.1 mg, 0.12 mmol) was treated in the same manner as Example 154 (1), except that 2-bromo-2- Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2- carboxylic acid ethyl ester was prepared as described in step (b) Carboxamide hydrochloride (47.9 mg, 86% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.70 (s, 3H). 1H, J = 1.5, 8.0), 8.38 (dd, 1H, J = 1.5, 8.3 Hz), 7.01 (m, 8.44 (s, 1H), 8.89 (bs, 2H), 9.30 (bs, 2H), 9.62 (s, 1H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₅ H ₁₃ BrN ₄ S ₃ 425.39 (M + H), found 425.1.

Example 170

(a) Methyl 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate Bromate: Methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2,6-dichlorophenylthiourea as described for example 154, step (a) (42 mg) to obtain methyl 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate 63.1 mg (65% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.59 (s, 3H), 3.8 (s, 3H), 7.15 (s, 1H), 7.36 (m, 1H), 7.61 (m, 2H), 7.97 (s, 1 H). Mass spectrum (ESI, m / z): C 16 H 12 Cl 2 N 2 O 2 Calcd for _{S 3 431.38 (M + H)} , Found; 431.0.

(b) 4- {2- [(2,6-Dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (43 mg, 0.08 mmol) was added to a solution of (2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} -5-methylthiothiophene- The title compound was prepared as described in Example 154, step (b) to give 4- {2- [(2,6-dichlorophenyl) amino] (1,3-thiazol- -2-carboxamide hydrochloride (40% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, 1 H), 8.84 (bs, 2H), 9.27 (bs, 2H), 9.61 (bs, 1H). Mass spectrum (ESI, m / z): C 15 H 12 Cl 2 N 4 theoretical 415.39 (M + H) for S _3, experimental data 415.1.

Example 171

(a) Methyl 4- {2 - [(2-bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2-bromo-4-methoxybenzaldehyde as described for example 154 step (a) -Methylphenylthiourea (47 mg) to obtain methyl 4- {2- [(2-bromo-4-methylphenyl) amino] (1,3- -2-carboxylate bromate (61% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.28 (s, 3H), 3.82 (s, 3H), 7.21 (m, 1H), 7.27 (s, 1H), 7.48 (m, 1H), 8.14 , 8.17 (s, 1H rotomer), 9.52, 9.72 (bs, 1H rotomer). Mass spectrum (ESI, m / z): C 17 H 15 BrN 2 O 2 S 3 Calcd 455.42 (M + H) for, Found; 455.0.

(b) 4- {2 - [(2-Bromo-4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 4-methylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate (62 mg, 0.11 mmol) was treated as described in example 154 step (b) to give 4- {2- [(2-bromo-4-methylphenyl) amino] To obtain 26 mg (50% yield) of 5-methylthiothiophene-2-carboxidine hydrochloride. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.28 (s, 3H), 2.70 (s, 3H), 7.14 (s, 1H), 7.21 (dd, 1H, J = 1.6,8.5Hz), 7.49 (d, 1H, J = 1.5 Hz), 8.16 (d, IH, 8.3 Hz), 8.41 (s, IH), 8.85 (bs, 2H), 9.28 (bs, 2H), 9.53 Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₅ BrN ₄ S ₃ 439.42 (M + H), experimental value 439.1.

Example 172

(a) Synthesis of methyl 5-methylthio-4- {2- [(2-morpholin-4- ylethyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate bromate : Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (100 mg, 0.32 mmol) was added to a solution of 1-ethylmorpholin (2-morpholin-4-ylethyl) amino] (1,3-thiazol-4-yl)} thiophene (61.2 mg) -2-carboxylate bromate (yield 79%). ¹ H-NMR (CD ₃ OD, 300 MHz):? 2.64 (s, 3H), 3.43-3.52 (m, 5H), 3.83-3.86 ). Mass spectrum (ESI, m / z): C 16 H 21 N 3 O 3 S Calcd for ₃ 399.55 (M + H), Found; 400.1.

(b) 5-Methylthio-4- {2- [(2-morpholin-4- ylethyl) amino] (1, 3-thiazol-4-yl)} thiophene-2-carboxylate bromate (62 mg, 0.12 mmol) was treated as described in step b) of Example 154 to give 5-methylthio-4- {2- [(2-morpholin-4- ylethyl) amino] Thiazol-4-yl)} thiophene-2-carboxidine hydrochloride (52% yield). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.69 (s, 3H), 3.16-3.95 (m, 15H), 6.96 (s, , 8.84 (bs, 2H), 9.28 (bs, 2H), 10.49 (bs, 1H). Mass spectrum (ESI, m / z): C 15 H 21 N 5 OS 3 Calcd 383.56 (M + H) for, 384.2 Found;

Example 173

(a) Methyl 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate Bromate: - (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2,3- dichlorophenylthiourea as described for example 154 step (42 mg) to obtain methyl 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Bromide (62% yield). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.66 (s, 3H), 3.82 (s, 3H), 7.27 (dd, 1H, J = 1.5, 6.5 Hz), 7.36 1H), 8.14 (s, 1H), 8.62 (dd, 1H, J = 1.5, 8.4 Hz), 9.95 (bs, 1H). Mass spectrum (ESI, m / z): C 16 H 12 Cl 2 N 2 O 2 Calcd for _{S 3 431.38 (M + H)} , Found; 431.1.

(b) 4- {2 - [(2,3-Dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (60.5 mg, 0.11 mmol) was carried out in the same manner as in Example 1, except that the title compound was synthesized from {2- [(2,3-dichlorophenyl) amino] (1,3-thiazol- The title compound was prepared as described in Example 154, step (b) to give 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol- -2-carboxamide hydrochloride (15 mg, 30% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 15 H 12 Cl 2 N 4 S Calcd for ₃ 415.34 (M + H), Found; 415.1

Example 174

(a) Synthesis of methyl 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- Bromoacetyl ) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 2,3, Methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4 Yl)} thiophene-2-carboxylate bromate (63.8% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.67 (s, 3H), 3.81 (s, 6H), 3.82 (s, 3H), 7.11 (s, 2H), 7.25 (s, 1H), 8.19 (s, 1 H), 10.25 (s, 1 H). Mass spectrum (ESI, m / z): C 18 H 20 N 4 O 3 S 3 Calcd 436.56 (M + H) for, Found; 437.1.

(b) Preparation of 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- : Methyl 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate bromate 61.8 mg, 0.11 mmol) was treated as described in step b) of Example 154 to give 5-methylthio-4- {2 - [(3,4,5-trimethoxyphenyl) amino] Thiazol-4-yl)} thiophene-2-carboxidine hydrochloride (27% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 18 H 20 N 4 O 3 Calcd 436.56 (M + H) for S _3, 437.1 Found;

Example 175

(a) Methyl 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene- - (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (100 mg, 0.32 mmol) was reacted with N- ethylpiperidylthiourea as described for example 154 step (60.6 mg) to obtain methyl 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4- yl)} thiophene- Bromine 90 mg (59% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 1.41 (m, 2H), 1.70-1 79 (m, 6H), 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 (at, 1H, J = 5.3Hz), 8.09 (s, Mass spectrum (ESI, m / z): C 17 H 23 N 3 O 2 Calcd for _{S 3 397.6 (M + H)} , Found; 398.1.

(b) 5-Methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene- Thiophene-2-carboxylate bromate (72 mg, 0.15 mmol) was subjected to a reaction in the same manner as in [ (5-methylthio-4- {2- [(2-piperidylethyl) amino] (1,3-thiazol-4-yl)} thiophene -2-carboxydin hydrochloride (43.8% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 (s, IH), 8.07 (t, 1H, J = 5.5Hz) , 1H), mass spectrum (ESI, m / z): C 16 H 23 N 5 S 3 Calcd 381.1 (m + H for a), experimental data 382.2.

Example 176

(a) methyl 4- (2 - {[(4-methylphenyl) methyl] amino} (1,3-thiazol- - (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (111 mg, 0.35 mmol) was reacted with 4-methylphenylmethylthiourea as described for example 154 step 125 mg (81%) of methyl 4- (2 - {[(4-methylphenyl) methyl] amino} (1,3-thiazol- Yield). Mass spectrum (ESI, m / z): C 18 H 18 N 2 O 2 Calcd for _{S 2 358.5 (M + H)} , Found; 359.1.

(b) 4- (2 - {[(4- methylphenyl) methyl] amino} (1,3-thiazol- (118 mg, 0.26 mmol) was added to a solution of (2 - {[(4-methylphenyl) methyl] amino} (1,3-thiazol- (4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene -2-carboxamide hydrochloride (58.2 mg, 54% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.27 (s, 3H), 2.66 (s, 3H), 4.49 (d, 2H, J = 5.7Hz), 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, , 2H). Mass spectrum (ESI, m / z): C 17 H 18 N 4 S Calcd for ₃ 374.55 (M + H), Found; 375.2.

Example 177

(a) Amino {[4- (4-chlorophenoxy) phenyl] amino} methane-2-thione: Unless stated otherwise, all thioureas, isothiocyanates, thioamides, and amines are commercially available from Maybashi Chemical Company (TM), &lt; / RTI &gt; Transwell Chemical Company (Rockville, Md.), Or Aldrich Chemical Company (Milwaukee, Wis.). (i) 4-Amino-4 &apos; -chlorodiphenyl ether (TCI America product, 520 mg, 2.03 mmol from Longley, USA) was slurried in 10 mL of ether and treated with about 1 mL of ether saturated with HCl gas Respectively. After 5 minutes, the solvent was removed in vacuo. At room temperature, thiophosgene (1.2 eq, 2.4 mmol) in 5 mL of CHCl ₃ was added dropwise via a dropping funnel to a stirred two-phase solution of amine-HCl salt in 20 mL of CHCl ₃ -saturated NaHCO ₃ (1: 1, v / v) . By vigorous stirring for 1 hour the reaction (TLC (50% ethyl acetate - according to the hexane), more apparently converted to higher Rf spot), then layers are separated, and the aqueous layer is extracted with CHCl ₃ (1 × 20 mL) the collected organic layer was washed with brine (1 × 20 mL), dried over Na ₂ SO _4. The solvent was removed in vacuo and concentrated to give crude 4- (4-chlorophenoxy) -phenyl isothiocyanate (414 mg). (ii) 4- (4-Chlorophenoxy) -phenyl isocyanate was transferred to an Ace Glass pressure tube equipped with a Teflon coated stirring bar and a 2.0 M solution of NH ₃ in 5 mL of methanol (Aldrich Chemical Company, Milwaukee, Wis.). The tube was sealed and immersed in an 80 ° C oil bath. After 2 h, the reaction was cooled to 0 &lt; 0 &gt; C in an ice bath. The precipitate was filtered and dried in vacuo to give amino {[4- (4-chlorophenoxy) phenyl] amino} methan-1-thione (328 mg, 79%). ^{1 H-NMR (DMSO-d} 6, 300 N1Hz): δ 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H). Mass spectrum (ESI, m / z): theoretical value for C ₁₃ H ₁₁ ClN ₂ OS 278.8 (M + H), experimental value 279 4.

(b) Synthesis of methyl 4- (2- {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol- Bromoacetyl ) -5-methylthiothiophene-2-carboxylate (309 mg, 1.0 mmol) was added to a solution of amino {4 (4-chlorophenoxy) phenyl] amino} (1,3-propanediyl) amino] methane- Thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate bromate (72% yield). Mass spectrum (ESI, m / z): C 22 H 17 ClN 2 O 3 S Calcd for ₃ 489.1 (M + H), Found; 489.1.

(c) 4- (2 - {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl)} - 5-methylthiothiophene- : Methyl 4- (2- {[4- (4-chlorophenoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene-2-carboxylate bromate 300 mg, 0.52 mmol) was treated as described in step (b) of Example 154 to give 4- (2- {[4- (4-chlorophenoxy) phenyl] amino} ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.72 (s, 3H),? 2H), 7.07 (m, 2H), 7.15 (s, 1H), 7.40 (m, 2H), 7.85 (m, 2H), 8.46 (bs, 2H), 10.43 ( bss, 1H) mass spectrum (ESl, m / z): . C 21 H 17 ClN 4 OS 3 Calcd 473.1 (m + H) for, Found; 473.2, 475.1.

Example 178

(a) Synthesis of methyl 5-methylthio-4- [2 - ({4- [5- (trifluoromethyl) (2- pyridyloxy)] phenyl} amino) ) Thiophene-2-carboxylate: Methyl 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (70 mg, 0.23 mmol) Methylthio-4- [2 - ({4- [2- (4-fluorophenyl) ethyl] (98% yield) of 5- (trifluoromethyl) (2-pyridyloxy)] phenyl} amino) (1,3-thiazol-4-yl)] thiophene- . ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.70 (s, 3H), 3.85 (s, 3H), 7.38 (dd, 1H, J = 2.7, 8.8 Hz), 8.32 (s, 1H), 8.60 (m, 1H). Mass spectrum (ESI, m / z): C 22 H 15 F 3 N 2 O 3 S 3 Calcd 508.56 (M + H) for, Found; 509.2.

(b) Synthesis of 5-methylthio-4- [2- ({4- {5- (trifluoromethyl) (2- pyridyloxy)] phenyl} amino) ] Thiophene-2-carboxaldehyde hydrochloride: To a solution of methyl 5-methylthio-4- [2- ({4- [5- (trifluoromethyl) Thiophene-2-carboxylate (95 mg, 0.18 mmol) was treated as described in step b) of Example 154 to give 5-methylthio-4- [2- ] Thiophene-2-carboxamide hydrochloride (30.3 mg, 32 &lt; RTI ID = 0.0 &gt; % Yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.75 (s, 3H), 7.34 (d, 1H, J = 8.7Hz), 741 (m, 2H), 8.01 (s, 1H), 8.10-8.14 (m, 2H), 8.29 (dd, 1H, J = 2.5, 8.4Hz), 8.60 (m, 1H), 8.63 (s, 1H), 8.91 (bs, 2H), 9.31 (bs, 2H). Mass spectrum (ESI, m / z): Theoretical value 492.6 (M + H) for C ₂₁ H ₁₅ F ₃ N ₄ OS ₃ , experimental value 493.1.

Example 179

(a) Methyl 4- (2 - {[4-phenoxyphenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene- (200 mg, 0.64 mmol) was reacted with 4-phenoxyphenylthiourea (158 mg) as described for example 154, step (a) (3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate bromate 300 mg (88% yield). Mass spectrum (ESI, m / z): C 22 H 18 N 2 O 3 S Calcd for ₃ 492.6 (M + H), Found; 493.1.

(b) 4- (2 - {[4-phenoxyphenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene- 2-carboxylate bromide (230 mg, 0.42 mmol) was carried out in the same manner as in Reference Example 1, except that 2 - {[4- (phenoxy) phenyl] amino} was treated as described in step (b) of example 154, and purified by thin layer chromatography (20% methanol -CH ₂ Cl ₂ - saturated NH _3, 500 mm silica gel plate, NJ JT Baker of Phillipsburg product material) To give 86 mg (47% yield) of the product. 46 mg of the aliquot was dissolved in 1 mL of methanol and treated with 3 drops of ether saturated with HCl and concentrated in vacuo with toluene (2 x 5 mL) to give 4- (2 - {[4- phenoxyphenyl] amino } (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxidine hydrochloride (21.3% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.71 (s, 3H), 6.97-7.11 (m, 4H), 7.l5 (s, 1H), 7.36 (m, 2H), 7.72, 7.85 ( d, 2H rotomer, J = 8.7 Hz), 8.36, 8.55 (s, 1H rotomer), 9.00 (bs, 2H), 9.35 (bs, 2H), 10.49 (s, 1H). Mass spectrum (ESI, m / z): C 21 H 18 N 4 Calcd 438.6 (M + H) for ₃ OS, 439.2 experimental values.

Example 180

4- aminodiphenylamine (500 mg, 2.71 mmol) was treated as described in step (a) of Example 177, starting from (a) amino {[4- (phenylamino) phenyl] amino} And recrystallized from toluene to obtain 350 mg (53% yield) of amino {[4- (phenylamino) phenyl] amino} methan-1-thione. ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 6.80 (m, 1H), 7.01-7.24 (m, 8H), 8.15 (s, 1H), 9.45 (s, 1H). Mass spectrum (ESI, m / z): C 13 H 13 N 3 S, 243.33 (M + H), Found; 244.2.

(b) methyl 5-methylthio-4- (2 - {[4- (phenylamino) phenyl] amino} Carboxylate (90 mg, 0.28 mmol) was reacted with 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate as described in step a) of Example 154 to give amino { Amino) phenyl] amino} methan-1-thione (70.8 mg) to obtain methyl 5-methylthio-4- (2- {[4- (phenylamino) -Yl)) thiophene-2-carboxylate bromate (47 mg, 47% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 22 H 19 N 3 O 2 S 3 Calcd 453.60 (M + H) for, Found; 454.2.

(c) 5-Methylthio-4- (2- {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene- -Thiophene-2-carboxylate bromate (71 mg, 0.13 mmol) was added to a solution of 4- (2- {[4- (phenylamino) phenyl] amino} Was treated as described in step b) of Example 154 to give 5-methylthio-4- (2- {[4- (phenylamino) phenyl] amino} (1,3- ) Thiophene-2-carboxydin hydrochloride (23.3 mg, 38% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.72 (s, 3H), 6.74 (t, 1H, J = 7.3Hz), 6.98 (d, 1H, J = 7.6Hz), 7.08 (m, 2H 2H), 7.66 (d, 2H, J = 8.9 Hz), 7.99 (s, 1H), 8.45 (s, 1H), 9.03 (bs, 4H) 1H). Mass spectrum (ESI, m / z): C 21 H 19 N 5 S 3 Calcd 437.59 (M + H) for, Found; 438.2.

Example 181

benzylphenylamine (500 mg, 2.73 mmol) was treated as described in step (a) of Example 177 to give amino {[(4-benzylphenyl) 4-benzylphenyl] amino} methan-1-thione (yield: 62%). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ3.89 (s, 2H), 7.14-7.28 (m, 9H), 9.59 (s, 1H). Mass spectrum (ESI, m / z): C 14 H 14 N 2 S 3 Calcd 242.1 (M + H) for, Found; 243.2.

(b) Methyl 5-methylthio-4- (2 - {[4-benzylphenyl] amino} (90 mg, 0.28 mmol) was added to a solution of amino {[4-benzylphenyl] amino} -5-methylthiophene-2-carboxylate Methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene- Carboxylate bromate (47% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 22 H 19 N 3 O 2 S 3 Calcd 453.6 (M + H) for, Found; 454.2.

(c) 5-Methylthio-4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl) thiophene- 2-carboxydin hydrochloride: Carboxylate bromide (82.2 mg, 0.15 mmol) was reacted in the same manner as in Example 154, step (d), except that thiophene was used instead of 2- (b) to give 5-methylthio-4- (2- {[4- benzylphenyl] amino} (1,3-thiazol-4-yl) thiophene- 33.4 mg (47% yield) of hydrochloride were obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.72 (s, 3H), 3.89 (s, 2H), 7.12 (s, 1H), 7.16-7.29 (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): C 22 H 20 N 4 S Calcd for ₃ 436.6 (M + H), Found; 437.2.

Example 182

4-aminophenylsulfonylpiperidine (500 mg, 2.08 mol) was added to a solution of (4-aminothiomethyl ) amino] phenyl} sulfonyl) piperidine: To obtain 382 mg (61% yield) of {{4- [(aminothioxomethyl) amino] phenyl} sulfonyl) piperidine. ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 1.34 (m, 2H), 1.53 (m, 4H), 2.85 (bs, 1 H). Mass spectrum (ESI, m / z): C 12 H 17 N 3 O 2 Calcd 299.4 (M + H) for S _2, 300.2 experimental values.

(b) Synthesis of methyl 5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} (1,3-thiazol-4-yl) thiophene-2-carboxylate bromate methyl 4- (2-bromoacetyl) -5-methylthio-thiophene-2-carboxylate ({4 as described in step (a) of a (90 mg, 0.28 mmol) example 154 [ (2 - {[4- (piperidylsulfonyl) phenyl] amino} (1 (1-methylthioxomethyl) amino] phenyl} sulfonyl) piperidine , 3-thiazol-4-yl)) thiophene-2-carboxylate bromate (63% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, (Mass spectrum (ESI, m / z): theoretical value 509.69 (M + H) for C ₂₁ H ₂₃ N ₃ O ₄ S ₄ , experimental value 510.2.

(c) 5-Methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} Methyl 5-methylthio-4- (2 - {[4- (piperidylsulfonyl) phenyl] amino} , 0.17 mmol) was treated as described in step b) of Example 154 to give 5-methylthio-4- (2- {[4- (piperidylsulfonyl) phenyl] amino} Yl)) thiophene-2-carboxidine hydrochloride (34.3% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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), 8.84 (bs, 2H) . Mass spectrum (ESI, m / z): C 20 H 23 N 5 O 2 S 5 theoretical 493.69 (M + H) for, Found; 494.2.

Example 183

( 500 mg, 3.46 mmol) was treated as described in step (a) of Example 177 to give amino (3-quinolylamino) methan- Amino) methane-1-thione (41% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 7.57 (m, 1H), 7.67 (m, 1H), 7.94 (m, 2H), 8.4l (d, 1H, J = 2.4Hz), 8.85 ( d, 1 H, J = 2.5 Hz), 10.03 (s, 1H). Mass spectrum (ESI, m / z): C 10 H 9 N 3 S Calcd 203.3 (M + H) for, Found; 204.1.

(b) Methyl 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene- (90 mg, 0.28 mmol) was reacted with amino (3-quinolylamino) methan-1-thione as described in step a) of Example 154 (59.1 mg) to obtain 107.5 mg (yield) of methyl 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate bromate 78% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.75 (s, 3H), 3.84 (s, 3H), 7.52 (s, 1H), 7.92-8.05 (m, 2H), 8.22 (s, 1H) , 9.22 (m, 2H). Mass spectrum (ESI, m / z): C 19 H 15 N 3 O 2 S 3 Calcd 413.54 (M + H), Found; 4l4.1 on.

(c) 5-Methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxydin hydrochloride: Thiophene-2-carboxylate bromate (107.5 mg, 0.21 mmol) was reacted in the same manner as in step (b) of Example 154 except that thiophene- 4.5 mg (4.9%) of 5-methylthio-4- [2- (3-quinolylamino) Yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, IH), 9.16 (m, IH), 9.29 (bs, 2H), 10.97 Mass spectrum (ESI, m / z): C 18 H 15 N 5 S 3 Calcd 397.5 (M + H), Found; 398.1 for.

Example 184

(a) methyl 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4- yl)] thiophene- (65 mg, 0.21 mmol) was reacted with 2-naphthylthiourea (42.4 mg) as described for example 154, step (a) (80% yield) of methyl 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxylate bromate . ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.67 (s, 3H), 3.83 (s, 3H), 7.31 (s, , 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): C 20 H 16 N 2 O 2 Calcd for _{S 3 412.6 (M + H)} , Found; 413.1.

(c) 5-Methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene-2-carboxydin hydrochloride: -Thiophene-2-carboxylate bromate (42.7 mg, 0.086 mmol) was reacted in step (b) of Example 154 with 2- (16%) of 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4- yl)] thiophene- Yield). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.72 (s, 3H), 7.12-7.27 (m, 3H), 7.50-7.68 8.35 (m, 1H), 8.51 (s, 1H), 8.97 (bs, 2H), 9.34 (bs, 2H), 10.26 (s, 1H). Mass spectrum (ESI, m / z): C 19 H 16 N 4 S Calcd for ₃ 396.6 (M + H), Found; 397.2.

Example 185

(a) methyl 4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) Carboxylate (65 mg, 0.21 mmol) was reacted with 4- (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate Methylene dioxyphenylthiourea (41.2 mg) as described to give methyl 4- [2- (2H-benzo [3,4-d] (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxylate bromate as white crystals. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 rotomer, J = 2.2, 8.5 Hz), 7.25 (s, 1H), 7.46, 7.60 (d, 1H rotomer, J = 2.1 Hz), 8.05, 8.13 (s, 1H rotomer), 10.19, , 1H, rotomer). Mass spectrum (ESI, m / z): C 17 H 14 N 2 O 4 S Calcd for ₃ 406.5 (M + H), Found; 407.1.

(b) Synthesis of 4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) 2-carboxamidine hydrochloride: Methyl 4- [2- (2H-benzo [3,4-d] 1,3-dioxolan-5-ylamino) ] -5-methylthiothiophene-2-carboxylate bromate (51 mg, 0.10 mmol) was treated as described in step b) of Example 154 to give 4- [2- (2H- 4-d] 1,3-dioxolan-5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene- 2-carboxidine hydrochloride 16.6 mg (39% &Lt; / RTI &gt; ^{1 H- NMR (DMSO-d6,} 300MHz): δ 2.71 (s, 3H), 5.98 (s, 2H), 6.87 (d, 1H, J = 8.2Hz), 7.09-7.13 (m, 2H), 7.67 ( (d, IH, J = 2.4 Hz), 8.50 (s, IH), 8.95 (bs, 2H), 9.33 (bs, 2H), 10.30 Mass spectrum (ESI, m / z): C 16 H 14 N 4 O 2 S 3 Calcd 390.51 (M + H) for. Experiment 391.2

Example 186

amino -7-bromomfluorene (500 mg, 1.90 mmol) was added to a solution of the title compound as described in step (a) of Example 177 (21% yield) of amino [(7-bromofluoren-2-yl) methane-1-thione was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 3.35 (s, 2H), 7.35 (d, 1H, J = 8.3Hz), 7.54 (d, 1H, J = 8.0Hz), 7.66 (s, 1H ), 7.77-7.87 (m, 3H), 9.80 (s, 1 H). Mass spectrum (ESI, m / z): Theoretical value 319.2 (M + H) for C ₁₄ H ₁₁ BrN ₂ S, found 320.1, 321.1.

(b) Synthesis of methyl 4- {2 - [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- bromate: methyl 4- (2-bromoacetyl) -5-methylthio-thiophene-2-carboxylate, amino as described in (90 mg, 0.28 mmol) step of the example 154 (a) [(7 (92.8 mg) was reacted with methyl 4- {2- [(7-bromo fluoren-2-yl) amino] Thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate (82% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.70 (s, 3H), 3.83 (s, 3H), 3.93 (s, 2H), 7.33 (s, 1H), 7.51 (dd, 1H, J = 1H, J = 8.4 Hz), 8.18 (s, 1H), 7.74 (d, 1H, J = , 8.23 (d, IH, J = 1.4 Hz), 10.47 (s, IH).

(c) 4- {2 - [(7-Bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- : Methyl 4- {2- [(7-bromofluoren-2-yl) amino] (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxylate bromate 100 mg, 0.15 mmol) was treated as described in example 154 step (b) to give 4- {2- [(7-bromofluoren-2-yl) amino] (1,3- 4-yl)} - 5-methylthiothiophene-2-carboxidine hydrochloride (3.3 mg, yield 4%). ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.76 (s, 3H), 3.95 (s, 2H), 7.18 1H, J = 8.2 Hz), 8.23 (s, 1H), 8.50 (s, 1H), 10.53 (s, 1H). Mass spectrum (ESI, m / z): C 22 H 17 BrN 4 S 3 Calcd for 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 Bromate: (65 mg, 0.21 mmol) was reacted with 4-cyclohexylphenylthiourea (49.2 mg, 0.21 mmol) as described for example 154 step (a) mg) to obtain methyl 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxylate bromate (41% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ1.23-1.39 (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), 8.14 (s, 1H), 10.19 (s, 1H). Mass spectrum (ESI, m / z): C 22 H 24 N 2 O 2 S 3 Calcd for 444.64 (M + H), Found; 445.2.

(b) 4- {2- [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Carboxylate bromide (31.1 mg, 0.059 mmol) was reacted with 5-methylthiophene-2-carboxylate in the same manner as in Example 154 (3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamide was prepared as described in step (b) Carboxamide hydrochloride (47% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 = 8.7Hz), 7.68 (d, 2H, J = 8.7Hz), 8.47 (s, 1H), 8.85 (bs, 2H), 9.32 28 (s, 1H). Mass spectrum (ESI, m / z): C 21 H 24 N 4 S 3 Calcd 428.64 (M + H) for, Found; 429.2.

Example 188

( 314 mg, 1.30 mmol) was added to a solution of (a) amino {[4- (phenyldiazenyl) phenyl] amino} methan- (88% yield) of amino {[4- (phenyldiazenyl) phenyl] amino} methan-1-thione was obtained as described in part ii) above. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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): C 13 H 12 N 4 S, 256.3 (M + H), Found; 257.2.

(b) methyl 5-methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} Methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was reacted with amino {[4- ( (Phenyldiazenyl) phenyl] amino} methan-1-thione (53.8 mg) to obtain methyl 5-methylthio-4- (2- Yl)) thiophene-2-carboxylate bromate (yield: 70%). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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 _{(ES1) m / z C 22} H 18 N 4 O 2 Calcd for _{S 3 466.6 (M + H)} , Found; 467.1.

(c) 5-Methylthio-4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene- 4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene-2-carboxylate bromate (47.7 mg, 0.087 mmol) was treated as described in step (b) of Example 154 to give 5-methylthio-4- (2- {[4- (phenyldiazenyl) phenyl] amino} -Yl)) thiophene-2-carboxamide hydrochloride (77% yield). ^{1 H-NMR (DMSO-d} 6, 300 ldHz): 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, 3 H), 8.60 (s, 1 H), 11.02 (bs, 1 H). Mass spectrum (ESI, m / z): C 21 H 24 N 6 S 3 Calcd 450.6 (M + H), Found; 45l.1 on.

Example 189

3- aminobenzyl alcohol (550 mg, 4.46 mmol) was treated as described in step (a) of Example 177, starting from (3-aminothiomethyl) To give 618 mg (76% yield) of {3 - [(aminothioxomethyl) amino] phenyl} methan-1-ol. ^{1 H-NMR (DMSO-d6} , 300MHz): δ 4.47 (d, 2H, J = 5.6Hz), 5.19 (t, 1H, J = 5.7Hz), 7.06 (d, 1H, J = 6.2Hz), 7.18 -7.30 (m, 3 H), 9.73 (s, 1 H).

(b) Synthesis of methyl 5-methylthio-4- (2- {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol- methyl 4- (2-bromoacetyl) -5-methylthio-thiophene-2-carboxylate (1.01 g, 3.26 mmol) of example 154 as described in the step (a) {3 - [( Methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazole- -Yl)) - thiophene-2-carboxylate bromate (92% yield). ^{1 H-NMR (DMSO-d} 1, 300 N1Hz): 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, IH), 7.81 (bs, IH), 8.17 (s, IH), 10.29 (bs, IH).

(c) 5-Methylthio-4- (2 - {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol- Methyl 5-methylthio-4- (2- {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene- 2-carboxylate bromate , 1.47 mmol) with 1: 9: 1 methanol -CH ₂ Cl ₂ phase of the example 154 using -DMF as eluent (b) by a process as described in 5-methyl-4- (2- (32% yield) of {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene-2-carboxidine hydrochloride. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.71 (s, 3H), 4.50 (s, 2H), 6.93 (d, 1H, J = 7.6Hz), 7.15 (s, 1H), 7.21-7.27 (s, 1H), 8.94 (bs, 2H), 9.32 (bs, 1H), 7.38 (bs, 2H), 10.37 (s, 1 H). Mass spectrum (ESI, m / z): Theoretical value 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] Thienyl)) iminomethyl] -carboxamide: A mixture of 5-methylthio 4- (2- {[3- (hydroxymethyl) phenyl] amino} (103 mg, 0.27 mmol) was slurried in THF (4 mL) and treated with 0.5 mL of 0.5 N NaOH. tert-Butyl dicarbonate (0.40 mmol) was added in one portion and the resulting mixture was stirred overnight. The reaction was partitioned between CH ₂ Cl ₂ and water. After to the organic layer was separated, washed with brine (1 × 20 mL), dried over Na ₂ SO _4. The solvent was removed in vacuo and then purified by thin layer chromatography (500 mm silica gel plate, TJ Baker, Phillipsburg, NJ, 1% methanol-CH ₂ Cl ₂ ) to give ((tert-butoxy) -N - [(4- {2 - [(3-hydroxymethylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthio (2-thienyl)) iminomethyl] . to give the mid-45 mg (35% ^{yield) 1 H-NMR (DMSO-} d 6, 300MHz): δ 1.44 (s, 9H), 2.66 (s, 3H), 4.49 (d, 2H, J = 5.7Hz) , 5.15 (t, IH, J = 5.5 Hz), 6.92 (d, IH, J = 7.5 Hz), 6.96 (s, IH), 7.26 (m, IH), 7.66-7.75 s, 1 H), 8.98 (bs, 2 H), 10.24 (s, 1 H).

(b) (tert-butoxy) -N- (imino {4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl} amino) yl)] - 5-methylthio (2-thienyl)} methyl) carboxamide: N ₂ under ((tert- butoxy) -N - [(4- {2 - [(3- hydroxy-phenyl) amino Yl]} - 5-methylthio (2-thienyl)) iminomethyl] -carboxamide (45 mg, 0.094 mmol) in tetrahydrofuran The reaction was stirred for 1 hour and the reaction was quenched with CH ₂ Cl (10 mL) and the reaction was quenched by addition of CH3CN ₂ and water. The organic layer was washed with brine (20 mL), filtered through a pad of 5 cm silica gel in a 15 mL glass funnel, dried over Na ₂ SO _{4, and} the solvent removed in vacuo to give the crude Mesylate (44 mg) was obtained, which was used immediately without further purification. Mesylate in 0.5 mL of DMF 3-Methylpiperidine (0.18 mmol, 21.4 [mu] l) was added to 25.3 mg (0.045 mmol) and the resulting mixture was heated in an oil bath for 4 h at 65 [deg.] C. The reaction was concentrated in vacuo, to give (250 mm silica gel plate, 10% methanol -CH ₂ Cl _2, NJ TJ Baker of Phillipsburg product material) (tert- butoxy) -N- (imino {4- [2 - ({3 Methyl] phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthio (2-thienyl)} methyl) carboxamide % yield) mass spectrum. (ESI, m / z) : C 27 H 35 N 5 O 2 Calcd 557.8 (m + H), Found; 557.9, 458.2 (-C (O to S ₃₎ OC (CH ₃ ) ₃ ).

(c) 4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene- carboxamide pyrimidine hydrochloride: (tert- butoxy) -N- (imino {4- [2 - ({3 - [(3-methyl-piperidyl) methyl] phenyl} amino) (1, 3-thiazol- Yl)] - 5-methylthio (2-thienyl)} methyl) carboxamide (8.2 mg, 0.014 mmol) was stirred in 2 mL of 10% 3N HCl-ethyl acetate solution at 0 ° C for 30 minutes, The solvent was removed in vacuo to give 4- [2 - ({3 - [(3-methylpiperidyl) methyl] phenyl} amino) (1,3-thiazol- -2-carboxamide hydrochloride (100% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 0.83 (d, 3H, J = 5.6Hz), 1.54-2.48 (m, 5H), 2.52-2.63 (m, 4H), 2.66 (s, 3H) 1H), 4.23 (d, 2H, J = 4.8Hz), 7.15-7.23 (m, 2H), 7.41 (t, 1H, J = 7.8Hz), 7.86-7.92 9.01 (bs, 2H), 9.42 (bs, 2H), 10.63 (s, 1H). Mass spectrum (ESI, m / z): C 22 H 27 N 5 S 3 Calcd 457.7 (M + H) for, 458.2 Found;

Example 191

(a) Methyl 5-methylthio-4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - thiophene- - (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was reacted with 3-hydroxyphenylthiourea 32.6 mg) to obtain methyl 5-methylthio-4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - thiophene-2-carboxylate bromate 80.2 mg (92% yield) was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.67 (s, 3H), 3.83 (s, 3H), 6.38 (d, 1H, J = 76Hz), 7.06-7.12 (m, 2H), 7.20- 7.29 (m, 2 H), 8.14 (s, 1 H), 10.17 (s, 1 H).

(b) 4- {2- [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxydin hydrochloride: Thiophene-2-carboxylate bromate (460 mg, 1.0 mmol) was added to a solution of the compound of Example 154 (3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} 5-methylthiothiophene-2-carbaldehyde Pyridine hydrochloride (54% yield). Mass spectrum (ESI, m / z): Theoretical value for C ₁₅ H ₁₄ N ₄ OS ₃ 362.5 (M + H), found 363.2.

(c) (tert-butoxy) -N - [(4- {2 - [(4-hydroxyphenyl) amino] thienyl)) imino-methyl] _{carboxamide: CH 2 Cl 2 -DMF (3} : 1, v / v) 4 mL of 4- {2 - [(3-hydroxyphenyl) amino] (1,3- Diisopropylethylamine (1.2 eq) was added to a stirred solution of 5-methyl-thiazol-4-yl) Subsequently, di-tert-butyl dicarbonate (1.2 eq., 127 mg, Aldrich Chemicals, Milwaukee, Wis.) Was added dropwise to 1 mL of CH ₂ Cl ₂ and slowly added dropwise via a funnel. The reaction was stirred overnight and then partitioned between CH ₂ Cl ₂ and H ₂ O to separate the layers. The organic layer was dried over Na ₂ SO _4, and concentrated in vacuo. The residue was purified by flash chromatography (1% methanol -CH ₂ Cl ₂₎ (tert- butoxy) -N - [(4- {2 - [(4- hydroxyphenyl) amino] (1,3- Thiazol-4-yl)} - 5-methylthio (2-thienyl)) iminomethyl] carboxamide was obtained in a yield of 27%. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, IH), 8.35 (s, IH), 9.00 (bs, 2H), 9.28 (s, IH), 10.11 (s, IH). Mass spectrum (ESI, m / z): C 20 H 22 N 4 O 3 S Calcd for 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} (2-thienyl)] iminomethyl) carboxamide: To a solution of (tert-butoxy) -N - [(4- {2 - [(4-hydroxyphenyl) amino] Cs ₂ CO ₃ (1.5 eq., 60.1 mg, 0.14 mmol) was added to a stirred solution of 5-methyl-thiazol-4-yl) (1.2 equivalents, 20.4 mg, from Aldrich Chemicals, Milwaukee, Wis.) And a catalytic amount of KI were continuously added to the reaction mixture. The reaction mixture was allowed to warm to 58 ° C in an oil bath, then stirred for 48 hours and 0.6 eq. Of bromoacetamide was further added. Stirring was continued for another 24 h, and the reaction was filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (50% ethyl acetate-hexane) for purification to give (tert-butoxy) -N - {[4- (2- {[3- (carbamoylmethoxy) phenyl] Thiazol-4-yl)) - 5-methylthio (2-thienyl)] iminomethyl} carboxamide was obtained in a yield of 12%. Mass spectrum (ESI, m / z): C 22 H 25 N 5 O 4 Theoretical value 519.7 to S ₃ (M + H), Found; 519.7, 420.7 [-C (O) OC (CH 3) 3].

(e) Synthesis of 4- (2 - {[4- (carbamoylmethoxy) phenyl] amino} (1,3-thiazol-4-yl) -5-methylthiothiophene- in acetate at _{0 ℃ CH 2 Cl 2 -DMF (} 4 mL, 3: 1 v / v) of (tert- butoxy) -N - {[4- (2 - {[3- ( carbamoyl-methoxy) Phenyl] amino} (1,3-thiazol-4-yl) -5-methylthio (2-thienyl)] iminomethyl} carboxamide (about 4 mg, 0.007 mmol) 1 mL of rosacet acid was added. The homogeneous solution was further stirred at this temperature for 40 minutes, the temperature was allowed to warm to room temperature over 30 minutes and then concentrated in vacuo to give 4- (2- {[4- (carbamoylmethoxy) phenyl] amino} Thiazol-4-yl)) - 5-methylthiothiophene-2-carboxymidine trifluoroacetate (100% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.75 (s, 3H), 4.21 (d, 2H, J = 5.7Hz), 6.64 (dd, 1H, J = 2.4,8.2Hz), 6.97 (dd 1H, J = 1.1, 8.2 Hz), 7.16 (s, IH), 7.22 (m, IH), 7.60-7.63 = 2.1 Hz), 8.42 (s, 1 H). Mass spectrum (ESI, m / z): C 17 H 17 N Calcd for _{5 O 2 S 3 419.6 (M} + H), Found; 420.1.

Example 192

(a) Synthesis of isopropyl 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- bromate: isopropyl 4- (2-bromoacetyl) -5-methylthio-thiophene-2-carboxylate 3, 4 as described in (84 mg, 0.27 mmol) step (a) of the example 154 (66.5 mg) was reacted with isopropyl 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazole- 4-yl)} thiophene-2-carboxylate bromate (48% yield). Mass spectrum (ESI, m / z): C 21 H 24 N 2 O 5 S Calcd 448.56 (M + H) for _2, experimental data 449.0.

(b) 5-Methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- Methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate bromate mg, 0.11 mmol) was treated as described in step (b) of Example 154 to give 5-methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] Thiazol-4-yl)} thiophene-2-carboxidine hydrochloride (50.4% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.81 (s, 3H), 3.61 (s, 3H), 3.77 (s, 6H), 7.04 (s, 2H), 7.09 (s, 1H), 8.40 (s, 1 H). Mass spectrum (ESI, m / z): C 18 H 20 N 4 O 3 Calcd 404.5 (M + H) for S _2, 405.2 experimental values.

Example 193

(a) isopropyl 5-methyl-4- {2 - [(4-phenoxyphenyl) amino] - (2-bromoacetyl) -5-methylthiothiophene-2-carboxylate (91 mg, 0.29 mmol) was reacted with 4-phenoxyphenylthiourea as described for example 154 step (4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene-2-carboxylate bromate 115 mg (75% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 1.28 (d, 6H, J = 6.2Hz), 2.70 (s, 3H), 6.06 (quintet, 1H, J = 6.2Hz), 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): C 24 H 22 N 2 O 3 S 2 Calcd 450.6 (M + H), Found; 451.2, 409.2 for _{[-CH (CH 3) 2]} .

(b) 5-Methyl-4- {2 - [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- 2-carbamidine hydrochloride: Thiophene-2-carboxylate bromide (95.5 mg, 0.17 mmol) was added to a solution of the title compound of Example 154, (4-phenoxyphenyl) The title compound was prepared from 5-methyl-4- {2- [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- (32% yield) of the title compound. ^{1 H-NMR (DMSO-d} 6, 300MHz): 62.76 (s, 3H), 6.95-7.12 (m, 6H), 7.34-7.39 (m, 2H), 7.72-7.78 (m, 2H), 8.33 (s , &Lt; / RTI &gt; 1H), 8.98 (bs, 3H), 10.29 (bs, 1H). Mass spectrum (ESI, m / z): Theoretical 406.5 (M + H) for C ₂₁ H ₁₈ N ₄ O ₂ S ₃ , experimental value 407.2.

Example 194

(a) isopropyl 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene- (64 mg, 0.21 mmol) was reacted with phenylthiourea (32.1 mg) as described for example 154 step (a) to give isopropyl 5 &lt; RTI ID = 0.0 &gt; -Methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2- carboxylate bromate was obtained in a yield of 87%. Mass spectrum (ESI, m / z): C 18 H 18 N 2 O 2 Calcd for _{S 2 358.5 (M + H)} , Found; 359.2.

(b) 5-Methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2-carboxidine hydrochloride: - (phenylamino) (1,3-thiazol-4-yl)] - thiophene-2-carboxylate bromate (74.5 mg, 0.16 mmol) was reacted with phenyl (28%) of 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] - thiophene- Yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.79 (s, 3H), 6.96 (t 1H, J = 7.2Hz), 7.09 (s, 1H), 7.33 (t, 2H, J = 7.5Hz) , 7.71 (d, 2H, J = 7.7 Hz), 8.39 (s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H), 10.37 (s, Mass spectrum (ESI, m / z): C 15 H 14 N 4 S Calcd for ₃ 314.4 (M + H), Found; 315.2.

Example 195

(a) Methyl 4- (4-isoxazol-5-yl (1,3-thiazol-4-yl) Methylthiothiophene-2-carboxylate (872 mg, 2.51 mmol) was reacted with 2-bromo-1-isoxazol-5-ylethanone as described for example 154, step (a) One (737 mg, prepared from isoxazole-5-carbonyl chloride as described in step (a) of Example 177 [manufactured by Meibridge Chemicals, Cornwall, UK] (83% yield) of (4-isoxazol-5-yl (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxylate. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.75 (s, 3H), 3.85 (s, 3H), 6.93 (d, 1H, J = 1.8Hz), 8.22 (s, 1H), 8.38 (s , &Lt; / RTI &gt; 1H), 8.70 (d, 1H, J = 1.8 Hz).

(b) 4- (4-Isoxazol-5-yl (1,3-thiazol-4-yl)) - 5-methylthiothiophene- (350 mg, 1.03 mmol) was reacted as described in step (b) of Example 154 with 3- (4-fluorophenyl) -5-methylthiophene- (78% yield) of 4- (4-isoxazol-5-yl (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxydin hydrochloride , And the aliquots thereof were further purified by recrystallization from methanol-isopropanol-water (3: 1: 0.2, v / v / v). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.79 (s, 3H), 6.93 (d, 1H, J = 1.9Hz), 8.45 (s, 1H), 8.74 (m, 2H), 9.23 (bs , 2H), 9.53 (bs, 2H). Mass spectrum (MALDI-TOF, CHCA matrix, m / z): theoretical value 322.4 (M + H) for C ₁₂ H ₁₀ N ₄ OS ₃ , experimental value 323.3.

Example 196

(a) Methyl 4- [4- (2-hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- Carboxylate (808 mg, 3.26 mmol) was reacted with 2- (2-bromoacetyl) hydroxybenzene (925 mg, prepared as described in step (a) of Example 177, from 2- (chlorocarbonyl) phenylacetate [from Aldrich Chemical Company, Milwaukee, Wisconsin] Hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene-2-carboxylate (37% yield). ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, 1 H). Mass spectrum (ESI, m / z): Theoretical value 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- Carboxylate (400 mg, 1.1 mmol) was reacted in the same manner as described in step (b) of Example 154 with the exception of using 173 mg (41% yield) of 4- [4- (2- hydroxyphenyl) (1,3-thiazol-2-yl)] - 5-methylthiothiophene- ). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ2.8l (s, 3H), 6.92-7.02 (m, 2H), 7.22 (m, 1H), 8.20 (dd, 1H, J = 1.7,7.8Hz ), 8.27 (s, IH), 8.65 (s, IH), 9.00 (bs, 2H), 9.41 (bs, 2H), 10.58 Mass spectrum (ESI, m / z): Theoretical value for C ₁₅ H ₁₃ N ₃ OS ₃ 347.48 (M + H), experimental value 348.2.

Example 197

5-methylthio-4- (6-quinolylamino) thiophene-2-carboxymidine hydrochloride

(a) Methyl 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxylate: To an oven-dried glass vial equipped with a stir bar was added methyl 4-bromo-5-methylthiothiophene- 65.2 mg (0.244 mmol) of 2-carboxylate (prepared as in Example 241 step a), 5.2 mg (9.5 mol%) of palladium (II) acetate, A mixture of 22.2 mg (14.6 mol%) of bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 125 mg (0.384 mmol) of cesium carbonate and 50.3 mg (0.349 mmol) of 6-aminoquinoline was added. The vial was transferred to a glove bag and was purged with anhydrous argon and then anhydrous toluene (488 [mu] l) was added. The vial was sealed with a threaded stopper with Teflon and heated at 100 ° C for 48 hours. To the cooled suspension was added ethyl acetate (4 mL) and the resulting mixture was filtered through celite, washed with ethyl acetate (2 x 2 mL) and the solvent removed in vacuo. The residue using a gradient of 5-12% ethyl acetate -CH ₂ Cl ₂ 10-g is purified by chromatography on a silica SPE column to give the title compound 53.3 mg (66%) as a pale yellow resin. _{^{1 H-NMR (CDCl 3,}} 400 MHz): δ 8.77 (dd, 1H, J = 4.2,1.6Hz). 8.04 (d, 1H, J = 9.4 Hz), 8.02 (d, 1H, J = 8.4 Hz), 7.90 , J = 8.3, 4.2 Hz). 7.27 (d, IH, J = 2.6 Hz), 3.92 (s, 3H) and 2.45 (s, 3H). Mass spectrum (ESI, m / z): C 16 H 15 N 2 O 2 Calcd 331.1 (M + H) for S _2. Experiment 331.2.

(b) 5-Methylthio-4- (6-quinolylamino) thiophene-2-carboxydin hydrochloride: A suspension of ammonium chloride (85.6 mg, 1.60 mmol) in anhydrous toluene (0.76 mL) Was added trimethylaluminum (2.0 M in toluene, 0.76 mL, 1.52 mmol) dropwise. The mixture was stirred at 25 &lt; 0 &gt; C for 30 min, then 50.2 mg (0.152 mmol) of methyl 5-methylthio-4- (6- quinolylamino) thiophene- Was added. The reaction mixture was slowly heated to 100 &lt; 0 &gt; C and stirred for 4 hours. The cooled mixture was added to a vigorously stirred slurry of silica gel (3 g) in chloroform (15 mL). The suspension was filtered through celite and washed with 25% MeOH-CH ₂ Cl ₂ (2 × 5 mL), 50% MeOH-CH ₂ Cl ₂ (2 × 5 mL) and 75% MeOH-CH ₂ Cl ₂ mL). The residue obtained by concentrating the washings collected was purified by 5-g silica SPE column using a gradient of 10-15% MeOH-CH ₂ Cl ₂ to give 42.2 mg (79%) of the title compound as a yellow solid. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 9.39 (br s, 2H), 9.12 (br s, 2H), 8.63 (dd, 1H, J = 4.2,1.6Hz), 8.44 (s, 1H) (Dd, 1H, J = 8.3, 4.2 Hz), 7.20 (d, d, 1 H, J = 2.5 Hz) and 2.55 (s, 3H). Mass spectrum _{(ESI, rWz): C 15} H 14 N 4 Calcd 315.1 (M + H) for S _2, 315.2 experimental values.

Example 198

Methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxidine hydrochloride

(a) Methyl 5-methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboxylate: In the same procedure as in Example 197, step (a), methyl 4-bromo- 62.2 mg (0.233 mmol) of 5-methylthiothiophene-2-carboxylate (prepared as in Example 241 step a), 4.7 mg (9.0 mol%) of palladium (II) acetate, BINAP 20.0 mg (13.8 mol%) , a reaction was carried out using cesium carbonate 140 mg (0.430 mmol), 3- amino-biphenyl 48.2 mg (0.285 mmol) and toluene ㎕ 466, and 20 to 40% as before CH ₂ After purification by chromatography using Cl ₂ -hexane, 52.3 mg (63%) of the title compound was obtained as a yellow resin. _{^{1 H-NMR (CDCl 3 400MHz}} ): 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): C 19 H 17 NO 2 Calcd 356.1 (M + H) for S _2, 356.2 experimental values.

methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboximidine hydrochloride: Following the same procedure as in Example 197, step (b) 46.7 mg (0.131 mmol) of 4 - [(3-phenylphenyl) amino] thiophene-2-carboxylate (prepared as in the previous step), 0.76 mL of trimethylaluminum (2.0 M in toluene, 1.57 mmol) The reaction was carried out using 87.7 mL (1.64 mmol) of ammonium and 0.79 mL of toluene and 46.8 mg (95%) of the title compound after purification on a 5 g silica SPE column using 5-10% CH ₂ Cl ₂ -hexane. As a yellow resin. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 9.04 (br s, 4H), 8.10 (s, 1H), 8.06 (s, 1H), 7.62 (m, 2H), 7.46 (m, 2H), (D, 1H, J = 7.8, 1.9 Hz), 2.53 (s, 3H), 7.35 (m, 2H), 7.19 ). Mass spectrum (ESI, m / z): C 18 H 17 N 3 S Calcd 340.1 (M + H) for _2, experimental data 340.2.

Example 199

5-methylthio-4- (3-quinolylamino) thiophene-2-carboxymidine hydrochloride

(a) Methyl 5-methylthio-4- (3-quinolylamino) thiophene-2-carboxylate: According to the same procedure as in the step a) of Example 197, methyl 4-bromo-5- 104 mg (0.389 mmol) of the thiophene-2-carboxylate (prepared as in Example 241 step a), 7.1 mg (8.1 mol%) of palladium (II) acetate, 29.3 mg The reaction was carried out using 192 mg (0.589 mmol) of cesium carbonate, 70.5 mg (0.489 mmol) of 3-aminoquinoline and 778 μl of toluene, and 3-8% CH ₂ Cl ₂ -hexane To give 34.4 mg (27%) of the title compound as a yellow resin. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 8.73 (d, 1H, J = 2.5Hz), 8.04 (d, 1H, J = 8.2Hz), 7.85 (d, 1H, J = 4.0Hz), 7.71 ( 1H, J = 7.9 Hz), 7.62 (m, IH), 7.56 (m, 2H), 6.34 (s, IH), 3.93 (s, 3H) Mass spectrum (ESI, m / z): C 16 H 14 N 2 O 2 Calcd for _{S 2 331.1 (M + H)} , Found; 331.3

(b) 5-Methylthio-4- (3-quinolylamino) thiophene-2-carboxydin hydrochloride: By the same procedure as in the step b) of Example 197, methyl 5-methylthio-4- (2.0 M, 1.17 mmol in toluene), 65.8 mg (1.26 mmol, 1.0 mmol) of ammonium chloride were added to a solution of the title compound ) And 0.59 mL of toluene and purified on a 5 g silica SPE column using 5-12% MeOH-CH ₂ Cl ₂ followed by concentration once from MeOH-MeCN (1: 1) to give the title 17.3 mg (51%) of the compound was obtained in the form of a pale crystalline solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz):? 9.09 (br s, 4H), 8.79 (s, 7.79 (m, IH), 7.56 (s, IH), 7.50 (m, 2H) and 2.55 (s, 3H). Mass spectrum (ESI, m / z). Theoretical value 315.1 (M + H) for C ₁₅ H ₁₄ N ₄ S ₂ , experimental value 315.4.

Example 200

5-Methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboxymidine hydrochloride

(a) Methyl 5-methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboxylate: Methyl 4-bromo-5-methylthiothiophene- 50 mg (0.191 mmol) of palladium (II) acetate (as prepared in step a) of Example 241, 2.7 mg (6.3 mol%) of acetic acid palladium (II), 11.3 mg (9.5 mol%) of racemic BINAP, The reaction was carried out by the same procedure as in the step (a) of Example 197, using 25.9 mg (0.270 mmol) of 2-aminopyrimidine and 381 디 of dioxane, and the reaction was carried out with 5-10% ethyl acetate- To give 16.7 mg (31%) of the title compound as a yellow crystalline solid. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 8.72 (s, 1H), 8.49 (d, 1H, J = 4.8Hz), 6.80 (t, 1H, J = 4.8Hz), 3.92 (s, 3H), 2.42 (s, 3H) and 1.28 (br s, 2H). Mass spectrum (ESI, m / z): C 11 H 11 N 3 O 2 Calcd for _{S 2 282.0 (M + H)} , Found; 282.3.

(b) 5-Methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboximidine hydrochloride: Methyl 5-methylthio-4- (pyrimidin- (0.328 mmol), trimethylaluminum (2.0 M in toluene, 0.648 mmol), ammonium chloride (36.4 mg, 0.680 mmol) and 0.32 mL of toluene The reaction was carried out by the same procedure as in step 197 (b) of Example 197 and purification on a 2-g silica SPE column using 5-15% MeOH-CH ₂ Cl ₂ then eluted with 1: 1 from MeOH-MeCN (1:10) And concentrated to give 11.4 mg (70%) of the title compound as a pale yellow crystalline solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz): 9.24 (br s, 2H), 8.85 (br s, 2H), 8.45 t, 1 H, J = 4.8 Hz) and 2.53 (s, 3H). Mass spectrum (ESI, m / z): C 10 H 11 N 5 theoretical 266.1 (M + H) for S _2, 266.2 experimental values.

Example 201

4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxidine hydrochloride

(a) Methyl 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxylate: Methyl 4-bromo-5-methylthiothiophene-2-carboxylate 122 mg (0.457 mmol) of palladium (II) acetate 9.9 mg (9.7 mol%), racemic-BINAP 42.3 mg (14.9 mol%), cesium carbonate 206 mg 0.632 mmol), 4- cyclohexyl-aniline 102 mg (0.582 mmol), and toluene using a 913 ㎕ to carry out the reaction in the same procedure as step (a) of example 197, and 20 to 40%, such as in front of CH ₂ Cl ₂ -Hexane, 73.8 mg (45%) of the title compound was obtained as a pale green resin. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 7.74 (s, 1H), 7.15 (d, 2H, J = 8.4Hz), 6.98 (d, 2H, J = 8.4Hz), 6.l2 (s, 1H 1H, J = 12.5 Hz), 1.41 (m, 4H), 3.88 (s, 3H) 4H) and 1.28 (m, 1 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₉ H ₂₃ NO ₂ S ₂ 362.1 (M + H), found 362.4

(b) 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxidine hydrochloride: (2.0 M, 1.94 mmol in toluene), 109 mg (2.04 mmol) of ammonium chloride and 0.97 mL of toluene was used as the starting material , The reaction was carried out by the same procedure as in the step b) of Example 197 and chromatographed on a 10-g silica SPE column using 4-8% MeOH-CH ₂ Cl ₂ to obtain 57.7 mg (78 %) In the form of a yellow foam. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 8.45 (br s, 4H), 7.97 (s, 1H), 7.86 (s, 1H), 7.08 (d, 2H, J = 8.5Hz), 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). Theoretical value for C ₁₈ H ₂₃ N ₃ S ₂ 346.1 (M + H), experimental value 346.4.

Example 202

Methyl 4-amino-5-methylthiothiophene-2-carboxylate

A solution of 1.0 g (4.30 mmol) of 5- (methoxycarbonyl) -2-methylthiothiophene-3-carboxylic acid (prepared as in Example 95), 1.01 mL of diphenylphosphoryl azide 4.73 mmol) and 1.57 mL (2.1 eq, 9.03 mmol) of N, N-diisopropylethylamine (Aceglass, New Brunswick, NJ) was charged with 7 mL of t-butanol. The resulting mixture was sealed and heated to 80 [deg.] C in an oil bath for 6 hours. The dark reaction mixture was cooled to room temperature and concentrated in vacuo. After dissolving the crude oil in _{CH 2 Cl 2 3 mL, 1} : 1 CH 2 Cl 2 - was treated with trifluoroacetic acid 2 mL, then 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 over Na ₂ SO ₄ and eluted through a pad of silica gel with 50% ethyl acetate-hexanes. The crude amine obtained by concentrating the solvent in vacuo purified by thin layer chromatography for - to give (20% ethyl acetate in hexane, 2000 ㎛ SiO ₂ gel) methyl 4-amino-5-methylthio-thiophene-2-carboxylate 210 mg (24%) was obtained as a honey colored oil. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.28 (s, 3H), 3.77 (s, 3H). 5.36 (bs, 2H), 7.24 (s, 1 H). Mass spectrum (ESI, m / z): C 7 H 9 NO 2 Calcd 204.02 (M + H) for S _2, 204.0 Found;

Example 203

Methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate

To a stirring mixture of 98 mg (0.48 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate in 5 mL of _2- phase CH ₂ Cl ₂ -NaHCO ₃ (1: 1, v / v) was added thiophosgene (Aldrich Chemical Co., Wisconsin, USA)) (1, 2 eq, 0.57 mmol). The reaction was stirred vigorously overnight and diluted with CH ₂ Cl ₂ (50 mL) to separate the layers. The organic layer was washed with NaHCO ₃ (1 × 15 mL), brine (1 × 15 mL), and dried over Na ₂ SO ₄ . Concentration of the solvent in vacuo the obtained crude isothiocyanate, was dissolved in 2 M NH ₃ 5 mL of MeOH was stirred overnight. The volume of the reaction was concentrated to ½ and filtered. The filtered solid was washed with acetone and dried to give methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate as a light brown solid. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.51 (s, 3H), 3.81 (s, 3H), 7.41 (bs, 2H), 8.03 (s, 1H) and 9.27 (bs, 1H). Mass spectrum (ESI, m / z): C 8 H 10 N 2 O 2 S 3 Calcd 263.00 (M + H) for, Found; 263.2.

Example 204

Methylthio-4 - [(4-phenyl (1,3-thiazol-4-yl)) amino] thiophene-

(a) methyl 5-methylthio-4 - [(4-phenyl (1,3-thiazol-2- yl)) amino] thiophene- To a 25 mL round bottom flask containing 40 mg (0.15 mmol) of the amino-5-methylthiothiophene-2-carboxylate and 30.3 mg (1 eq, 0.15 mmol) of bromoacetophenone, 2 mL of acetone was added The resulting mixture was refluxed for 18 hours. The reaction was cooled to room temperature and filtered to give 50 mg (92%) of methyl 5-methylthio-4 - [(4-phenyl (1,3-thiazol- ) Which was used without further purification. ^{1 H-NMR (DMSO-d} 6, 300MHz): 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, 1 H), 10.06 (bs, 1 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₄ LN ₂ O ₂ S ₃ 363.03 (M + H). Experiment 363.4.

(b) 5-Methylthio-4 - [(4-phenyl (1,3-thiazol-2-yl)) amino] thiophene-2-carboximidine: 47 mg (0.13 mmol) of methyl 5-methylthio-4 - [(4-phenyl (1,3-thiazol-2-yl)) amino] thiophene- 2-carboxylate was reacted with AlMe ₃ / NH ₄ Cl reagent (0.5 eq., 1.04 mmol) and purified by thin layer chromatography (20% MeOH-CHCl ₃ -saturated NH ₃ , 500 쨉 m SiO ₂ gel plate) 19 mg (42%) of 4 - [(4-phenyl (1,3-thiazol-2-yl)) amino] thiophene- ¹ H-NMR (DMSO-d ₆ , 300 MHz):? 2.43 (s, 3H), 7.27-7.42 (m, 4H), 7.90 (d, 2H, J = 7.1Hz), 8.41 (s, 1H). Mass spectrum (ESI, m / z): C 15 H 14 N 4 S 3 Calcd 347.05 (M + H) for, Found; 347.1.

Example 205

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

(a) Methyl 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboxylate: 53 mg (0.2 mmol) of methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate was treated with 4-phenyl-bromoma Methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carbaldehyde was reacted with 55.6 mg (0.2 mmol) 57 mg (65%) of a heterocyclic compound was obtained. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.51 (s, 3H), 3.86 (s, 3H), 6.93 (s, 1H rotomer), 7.10 (s, 1H rotomer), 7.27 (s, 1H rotomer ), 7.37-7.50 (m, 3H rotomer), 7.72-7.76 (m, 4H rotomer), 8.4 (d, 2H, 8.4 Hz), 8.66 (s, 1H rotomer), 10.10 (bs, 1H). Mass spectrum (ESI, m / z): C 22 H 18 N 2 O 2 S3 Calcd 439.06 (M + H) for, Found; 439.2.

(b) 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2- yl)] amino} thiophene- amino} thiophene-2-carboxylate &lt; RTI ID = 0.0 &gt; 57 &lt; / RTI &gt; (0.12 mmol) was reacted with 6.7 equivalents (0.87 mmol) of AlMe ₃ / NH ₄ Cl reagent and was purified by thin layer chromatography (20% MeOH-CHCl ₃ -saturated NH ₃ , 500 μm SiO ₂ plate) (40.7%) of methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene-2-carboximidine. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.51 (s, 3H), 6.93 (s, 1H), 7.10 (s, 1H), 7.27 (s, 1H), 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 (ESI, m / z): C 21 H 18 N 4 S 3 Calcd 423.08 (M + H) for, Found; 423.2.

Example 206

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

(a) Methyl 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene-2-carboxylate: 51 mg (0.19 mmol) of methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate was reacted with 2-bromopropoxy Was reacted with 41.4 mg (0.38 mmol) of paddy (Aldrich Chemical Co., Milwaukee, WI) for 4 hours. The reaction mixture was concentrated in vacuo to afford 73 mg (4-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene- 100%). Mass spectrum (ESI, m / z): C 17 H 16 N 2 O 2 S 3 Calcd 377.05 (M + H) for, Found; 377.2.

(b) 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene-2-carboximidine: ) Was prepared in analogy to the procedure described for the synthesis of methyl 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5-methylthiothiophene- 0.19 mmol) was reacted with 8 equivalents (1.55 mmol) of AlMe ₃ / NH ₄ Cl reagent and was purified by thin layer chromatography (20% MeOH-CHCl ₃ -saturated NH ₃ , 500 μm SiO ₂ plate) (5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5- methylthiothiophene-2-carboximidine was obtained in an amount of 17.9 mg (26%). ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.40 (s, 3H), 2.5I (s, 3H rotomer), 2.73 (s, 3H rotomer), 7.29-7.44 (m, 2H rotomer), 7.64- 7.73 (m, 3H rotomer), 7.95 (s, 1Hrotomer), 8.06 (s, 1H rotomer). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₆ N ₄ S ₃ 361.06 (M + H), found 361.2.

Example 207

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

(a) methyl 4 - {[4- hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5- methylthiothiophene- 56 mg (0.21 mmol) of methyl 4 - [(aminothioxomethyl) amino] -5-methylthiothiophene-2-carboxylate was reacted with bromotrifluoroacetic acid using a procedure analogous to that of Example 204, (4-hydroxy-4- (trifluoromethyl) (1, 3-thiazolin-2-yl) -2-methylpropionic acid was prepared by reacting 40 mg (0.21 mmol) of acetone (Aldrich Chemical Company, Milwaukee, Wis. Yl)] amino} -5-methylthiothiophene-2-carboxylate (40.3 mg, 54%). Mass spectrum (ESI, m / z): C 11 H 11 F 3 N 2 O 3 S 3 Calcd 373.00 (M + H) for, Found; 373.0.

(b) 4 - {[4-Hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5-methylthiothiophene-2-carboximidine: (Trifluoromethyl) (l, 3-thiazolin-2-yl)] amino} -5-methyl &lt; / RTI &gt; 40 mg (0.11 mmol) of thiothiophene-2-carboxylate was reacted with 8 equivalents (0.89 mmol) of AlMe ₃ / NH ₄ Cl reagent and purified by preparative thin layer chromatography (20% MeOH-CHCl ₃ -saturated NH ₃ , to give 500 ㎛ SiO ₂ plates) 4 - {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazol 2-yl)] amino} -5-methylthio thiophene -2 11 mg (28%) of carboxymidine was obtained in the form of a mixture of cyclic amine and ring-opened iminomethane to 1: 1 mixture. ^{1 H-NMR (DMSO-d} 6, 300MHz): δ 2.73 (s, 3H tautomer), 2.89 (s, 3H tautomer), 3.36 (d, 2H, J = 6.5Hz), 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): C 10 H 11 F 3 N 4 theoretical 357.01 (M + H) for ₃ OS, 357.2 experimental values.

Example 208

5-methylthio-4- (2-naphthylamino) thiophene-2-carboxidine

(a) Methyl 5-methylthio-4- (2-naphthylamino) thiophene-2-carboxylate: To an oven dried round bottom flask equipped with a Teflon coated stir bar and rubber septum was added methyl 4-amino- (2 equiv., 1.86 mmol) and Cu (OAc (2 eq)) were added to a solution of 190 mg (0.93 mmol) ) ₂ (from Aldrich Chemical Company, Milwaukee, WI) was added 168 mg (1 eq, 0.93 mmol). The flask was purged with Ar and then charged in the order of 4 mL of CH ₂ Cl ₂ followed by 259 μL of NEt ₃ (2 eq, 1.86 mmol). The mixture was vigorously stirred for 48 h and then filtered through a SiO ₂ small pad, eluting with 50% ethyl acetate-hexane. After concentration of the solvent in vacuo, the residue was thin-layer chromatography for purification - to give (25% ethyl acetate in hexane, 100 μM SiO ₂ plate) methyl 5-methylthio-4- (2-naphthylamino) thiophene Carboxylate (54 mg, yield: 28%) and 170 mg (55%) of recovered methyl 4-amino-5-methylthiothiophene-2-carboxylate. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 2.43 (s, 3H), 3.92 (s, 3H), 6.29 (s, 1H), 7.21 (dd, 1H, J = 2.35,8.7Hz), 7.33-7.37 (m, 2H), 7.45 (m, 1H), 7.71 (d, 1H, J = 8.2 Hz), 7.78 (m, 2H), 7.88 Mass spectrum (ESI, m / z). Theoretical value for C ₁₇ H ₁₅ NO ₂ S ₂ 330.06 (M + H), 330.1.

(b) 5-Methylthio-4- (2-naphthylamino) thiophene-2-carboximidine hydrochloride: Using a procedure similar to step (b) 2-naphthylamino) thiophene-2-carboxylate 730 mg (2.21 mmol) of AlMe ₃ / NH ₄ Cl 8 equivalents of reagent (17.7 mmol) and the reaction, thin layer chromatography (20% MeOH-CHCl ₃ for tablets - saturated NH _3, got 1000 ㎛ SiO ₂ plate) to yield 5-methylthio-4- (2-naphthylamino a) thiophene-2-carboxamide, pyrimidine, was dissolved in anhydrous MeOH 4 mL to 0 ℃ After cooling, it was carefully treated with 1.6 mL of 2 M HCl in ether (1.5 eq, 3.31 mmol). The reaction was stored at 5 &lt; 0 &gt; C overnight and then concentrated in vacuo using successive portions of toluene (3 x 10 mL) and hexane (2 x 10 mL). The yellow solid was dried in vacuo to give 415 mg (53.6%) of 5-methylthio-4- (2-naphthylamino) thiophene-2- carboxydin hydrochloride. ^{1 H-NMR (DMSO-d6} , 400MHz): δ 2.53 (s, 3H), 7.20 (d, 1H, J = 2.2Hz), 7.24-7.31 (m, 2H), 7.38 (m, 1H), 7.69 ( (d, IH, 8.1 Hz), 7.75-7.79 (m, 2H), 8.13 (s, IH), 8.24 (s, IH), 9.06 (bs, 2H), 9.33 (bs, 2H). Mass spectrum (ESI, m / z). Theoretical value 314.08 (M + H) for C ₁₆ H ₁₅ N ₃ S ₂ , experimental value 314.5.

Example 209

4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxidine

(a) Methyl 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step 208a) (4-chlorophenyl) amino] -5-methylthiophene-2-carboxylate was prepared by reacting 66.6 mg (0.32 mmol) of 4-chlorophenylboronic acid with 100 mg (11.7%) of methylthiothiophene-2-carboxylate and 21 mg (31.5%) of unreacted starting material. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 2.41 (s, 3H), 3.89 (s, 3H), 6.09 (bs, 1H), 6.94 (d, 2H, J = 8.6Hz), 7.25 (d, 2H , J = 8.6 Hz), 7.70 (s, 1H).

(b) 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboximidine hydrochloride: (4-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate was reacted with 8 eq. Of AlMe ₃ / NH ₄ Cl reagent (2.96 mmol) Amino] -5-methylthiothiophene-2-carboxymidine (13 mg, 100%). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.41 (s, 3H), 6.91-6.95 (m.2H). 2H), 7.69 (s, 1H), 7.99 (s, 1H). Mass spectrum (ESI, m / z): theoretical value 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-carboxidine

(a) Methyl 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate: Using a procedure analogous to step (a) 55.7 mg (0.27 mmol) of methylthiothiophene-2-carboxylate was reacted with 73.4 mg (2 eq., 0.54 mmol) of 3-methylphenylboronic acid to obtain methyl 4 - [ Thiophene-2-carboxylate (29.2 mg, 36.8%). _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, 1 H), 7.77 (s, 1 H). Mass spectrum (ESI, m / z): C 14 H 15 NO 2 Calcd 294.06 (M + H) for S _2, 294.1 experimental values.

(b) 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboximidine: Carboxylate (29.2 mg, 0.098 mmol) was reacted with 8 equivalents of AlMe ₃ / NH ₄ Cl reagent (0.78 mmol) and purified by preparative thin layer chromatography (20% MeOH-CHCl 3 ₃ -saturated NH ₃ , 500 쨉 m SiO ₂ plate) to obtain 27 mg (100%) of 4 - [(3-methylphenyl) amino] -5- methylthiothiophene-2-carboxidine. _{^{1 1H-NMR (CDCl 3,}} 400MHz): δ 2.24 (s, 3H), 2.50 (s, 3H), 6.65 (d, 1H, J = 7.3Hz), 6.74-6.76 (m, 2H), 7.10 (m , 7.88 (s, 1H), 7.97 (s, 1H), 9.07 (bs, 3H). Mass spectrum (ESI, m / z): C 13 H 15 N 3 Calcd 278.08 (M + H) for S _2, 278.2 experimental values.

Example 211

4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxidine

(a) Methyl 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate: Using a procedure analogous to step (a) (3-methoxyphenyl) amino] -methylthiophene-2-carboxylate was reacted with 73 mg (0.35 mmol) of 3-methoxyphenylboronic acid with 109 mg -5-methylthiothiophene-2-carboxylate (25.2 mg, 23%). _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, 1 H), 7.78 (s, 1 H). Mass spectrum (ESI, m / z): C 14 H 15 NO 3 Calcd 310.06 (M + H) for S _2, 310.1 experimental values.

(b) 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboximidine hydrochloride: Using methyl 4 - [(3 Carboxylate (25.2 mg, 0.081 mmol) was reacted with 8 equivalents of AlMe ₃ / NH ₄ Cl reagent (0.64 mmol) to give 4 - [(3-methoxyphenyl) ) Amino] -5-methylthiothiophene-2-carboximidine (27 mg, 100%). ^{1 H-NMR (DMSO, 400MHz} ): δ 2.49 (s, 3H), 3.71 (s, 3H), 6.4l (dd, 1H, J = 2.l, 8.0Hz), 6.49 (m, 1H), 6.50 2H), 7.31 (s, 2H), 7.99 (s, 1H). Mass spectrum (ESI, m / z): C 13 H 15 N 3 Calcd 294.07 (M + H) for ₂ OS, 294.1 experimental values.

Example 212

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

(a) Methyl 4 - {[(3-methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step (a) 74.4 mg (0.36 mmol) of amino-5-methylthiothiophene-2-carboxylate was reacted with 118 mg (2 eq, 0.72 mmol) of 3-isopropylphenylboronic acid to give methyl 4 - [ ) Amino] -5-methylthiothiophene-2-carboxylate (22.6 mg, 19.5%). _{^{1 H-NMR (CDCl 3,}} 400MHz): δ l.27 (d, 6H, J = 6.9Hz), 2.40 (s, 3H), 2 89 (m, 1H), 3.88 (s, 3H), 6.15 ( s, 1 H), 6.86-6.89 (m, 3H), 7.24 (m, 1 H), 7.77 (s,

(b) 4 - {[3- (Methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboximidine: Carboxylate (22.6 mg, 0.07 mmol) was reacted with 8 equivalents of AlMe ₃ / NH ₄ Cl reagent (0.56 mmol) to give 4 - {[(3-methylethyl) 3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxidine (18.9 mg, 78.8%). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 1.18 (d, 6H, J = 9.2Hz), 2.51 (s, 3H), 2 81 (m, 1H), 6.71-6.77 (m, 2H), 2H), 8.85 (s, 1H), 7.14 (m, 1H), 7.98 (s, 1H), 8.32 (s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H). Mass spectrum (ESI, m / z): C 15 H 19 N 3 S Calcd 306.11 (M + H) for _2, experimental data 306.2.

Example 213

Methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxidine

(a) Methyl 5-methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboxylate: Using a procedure similar to step (a) Methylthio-4 - [(3-nitrophenyl) methyl] thiophene-2-carboxylate was reacted with 120 mg (2 equiv., 0.72 mmol) of 3-nitrophenylboronic acid. Amino] thiophene-2-carboxylate (12.5%). _{^{1 H-NMR (CDCl 3,}} 400MHz): 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-carboximidine : Using an analogous procedure to step (b) 14.5 mg (0.04 mmol) of [(3-nitrophenyl) amino] thiophene-2-carboxylate was reacted with 8 equivalents (0.35 mmol) of AlMe ₃ / NH ₄ Cl reagent to give 5-methylthio- Mass spectrum (ESI, m / z): Theoretical value for C ₁₂ H ₁₂ N ₄ O ₂ S ₂ 309.05 (M + H), &lt; / RTI &gt;

Example 214

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

(a) Methyl 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step 74.4 mg (0.36 mmol) of amino-5-methylthiothiophene-2-carboxylate was reacted with 118 mg (2 eq, 0.72 mmol) of 4-isopropylphenylboronic acid to give methyl 4 - [ ) Amino] -5-methylthiothiophene-2-carboxylate (14.5 mg, 12.5%). _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 1.26 (d, 6H, J = 6.2Hz), 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-carboximidine: (4-methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxylate was reacted with 8 equivalents of AlMe ₃ / NH ₄ Cl reagent (0.36 mmol) 4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxidine (11.4 mg, 74%). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 1.17 (d, 6H, J = 9.2Hz), 2.51 (s, 3H), 2.81 (m, 1H), 6.92 (d, 2H, J = l1. (Bs, 2H), 7.10 (d, 2H, J = 11.2Hz), 7.88 (s, 1H), 7.96 Mass spectrum (ESI, m / z): C 15 H 19 N 3 S Calcd 306.11 (M + H) for _2, experimental data 306.2.

Example 215

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

(a) Methyl 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step Carboxylate was reacted with 118 mg (2 eq, 0.72 mmol) of 3,4-dimethylphenylboronic acid to obtain methyl 4 - [(3,4-dimethyl Phenyl) amino] -5-methylthiothiophene-2-carboxylate (135.9 mg, 32.4%). _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, IH, J = 7.9 Hz), 7.71 (s, IH).

(b) 4 - [(3,4-Dimethylphenyl) amino] -5-methylthiothiophene-2-carboximidine: Using a procedure analogous to step (3, 4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxylate was reacted with 8 eq. Of AlMe ₃ / NH ₄ Cl reagent (0.93 mmol) 4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboxidine (26.1 mg, 68.5%). ^{1 H-NMR (DMSO-d} 6, 400MHz): 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, IH), 7.91 (s, IH), 8.82 (bs, 2H), 9.17 (bs, 2H). Mass spectrum (ESI, m / z): C 14 H 17 N 3 S Calcd 292.09 (M + H) for _2, experimental data 292.2.

Example 216

Methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxidine

(a) Methyl 5-methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxylate: Using a procedure similar to step (4-phenylphenyl) amino] -5-methylthiophene-2-carboxylate (74.4 mg, 0.36 mmol) was reacted with 142.5 mg (2 eq., 0.72 mmol) -Methylthiothiophene-2-carboxylate (24.5 mg, 19.1%). _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H), 7.08-7.14 (m, 2H), 7.33 (m, 1H), 7.43 -7.46 (m, 2H), 7.54-7.60 (m, 4H), 7.82 (s, 1H).

(b) 5-Methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxamidine: Using a procedure similar to step Carboxylate (24.5 mg, 0.07 mmol) was reacted with 8 eq. (0.56 mmol) AlMe ₃ / NH ₄ Cl reagent to give 5-methylthio-4 - [(4 -Phenylphenyl) amino] thiophene-2-carboxymidine (16.9 mg, 64.1%). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.51 (s, 3H), 7.03 (d, 2H, J = 8.6Hz), 7.26-7.61 (m, 7H), 8.04 (s, 1H), 8.15 (s, 1 H), 8.88 (bs, 2H), 9.25 (bs, 2H). Mass spectrum (ESI, m / z): C 18 H 17 N 3 S Calcd 340.09 (M + H) for _2, experimental data 340.2.

Example 217

4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-

(a) Methyl 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step 74.4 mg (0.36 mmol) of 4-amino-5-methylthiothiophene-2-carboxylate was reacted with 155.5 mg (2 eq., 0.72 mmol) of 3-fluoro- (3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxylate was obtained in an amount of 50.6 mg (41.6%). _{^{1 H-NMR (CDCl 3,}} 400MHz): 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 = 6.9Hz), 7.82 (s, 1H).

(b) 4 - [(3-Fluoro-4-phenylphenyl) amino] -5-methylthiothiophene-2-carboxamide: Using a procedure similar to step 50.6 mg (0.13 mmol) of [(3-fluoro-4-phenylphenyl) amino] -5- methylthiothiophene-2-carboxylate was reacted with 8 equivalents (1.08 mmol) of AlMe ₃ / NH ₄ Cl reagent 39 mg (76.1%) of 4 - [(3-fluoro-4-phenylphenyl) amino] -5- methylthiothiophene-2-carboximidine was obtained. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.5l (s, 3H), 6.75-6.87 (m, 2H), 7.30-7.50 (m, 6H), 8.06 (s, 1H), 8.37 (s , &Lt; / RTI &gt; 1H), 8.90 (bs, 2H), 9.27 (bs, 2H). Mass spectrum (ESl, m / z): C 18 H 16 theoretical 358.08 (M + H) for FN ₃ S _2, 358.2 Found;

Example 218

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

(a) Methyl 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene-2-carboxylate: 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 24.4 mg (20.9%) of methyl 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene- _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, IH, J = 2.2 Hz), 6.76 (d, IH, J = 8.3 Hz), 7.59 (s,

(b) 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene- 24.4 mg (0.075 mmol) of methyl 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene- 2- carboxylate was dissolved in AlMe ₃ / NH ₄ Cl (29.7%) of 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5-methylthiothiophene- &Lt; / RTI &gt; ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.51 (s, 3H), 5.95 (s, 2H), 6.46 (dd, 1H, J = 3.0,11.2Hz), 6.65 (d, 1H, J = 2H), 6.79 (d, 1H, J = 11.0 Hz), 7.80 (s, 1H), 7.87 (s, 1H), 8.91 (bs, 2H), 9.24 (bs, 2H). Mass spectrum (ESl, m / z): C 13 H 13 N 3 O 2 Calcd 308.05 (M + H) for S _2. Experiment 308.2.

Example 219

4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxidine

(a) Methyl 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step (4-butylphenyl) amino] -5-methylthiophene-2-carboxylate was reacted with 128 mg (2 eq, 0.72 mmol) -Methylthiothiophene-2-carboxylate (22.2 mg, 18.3%). _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 0.97 (t, 2H, J = 7.4Hz), 1.38 (m, 2H), 1.59 (m, 2H also obscure by water), 2.39 (s, 3H) , 2H, J = 7.6 Hz), 3.90 (s, 3H), 6.12 (bs, 1H), 6.97 (d, 2H, J = 8.2 Hz), 7.12 7.73 (s, 1 H).

(b) 4 - [(4-Butylphenyl) amino] -5-methylthiothiophene-2-carboximidine: Carboxylate (22.2 mg, 0.06 mmol) was reacted with 8 eq. (0.52 mmol) of AlMe ₃ / NH ₄ Cl reagent to give 4 - [(4-butylphenyl) amino ] -5-methylthiothiophene-2-carboximidine (18.9 mg, 88%). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 0.89 (t, 2H, J = 9.7Hz), 1.23-1.33 (m, 2H), 1.51 (m, 2H), 2.47-2.50 (m, 2H DMSO also obscured by a _{-d 6), 2.51 (s,} 3H), 6.90 (d, 2H, J = 11.3Hz), 7.05 (d, 2H, J = 11.2Hz), 7.86 (s, 1H), 7 94 ( s, 1 H), 8.78 (bs, 2H), 9.21 (bs, 2H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₂₁ N ₃ S ₂ 320.13 (M + H), found 320.2.

Example 220

5-methylthio-4- [benzylamino] thiophene-2-carboxidine

(a) Methyl 5-methylthio-4- [benzylamino] thiophene-2-carboxylate: To a 2-drop vial equipped with a stir bar and a septum stopper was added methyl 4-amino-5-methylthiothiophene- (60 mg, 0.29 mmol) and benzaldehyde (30.7 mg, 0.29 mmol) were weighed and charged. The vial was charged with 1 mL of CH ₂ Cl ₂ -DMF (2: 1, v / v) and 135 mg of NaHB (OAc) ₃ (2.2 eq, 0.63 mmol). The reaction was diluted with Ar and stirred for 48 hours. At this time, the reaction product obtained by adding 2 mL of CH ₃ OH was further stirred for 15 minutes, and diluted with 20 mL of CH ₂ Cl ₂ . The organic layer was washed with water (2 × 20 mL), dried over Na ₂ SO _4, and concentrated to an oven dried 2 Dram vial under vacuum the crude methyl 5-methyl-4- [benzylamino] thiophene -2-carboxylate with unreduced imine. The crude reaction mixture was converted to the amidine without further purification. Mass spectrum (ESI, m / z): C 14 H 15 NO 2 S 2 Calcd 294.06 (M + H), Found; 292.2 (imine), for, 294.2.

(b) 5-Methylthio-4- [benzylamino] thiophene-2-carboximidine: A stirring bar and methyl-5-methylthio-4- [benzylamino] thiophene- 2 mL of toluene was added followed by the addition of 8 equivalents of AlMe ₃ / NH ₄ Cl reagent (2.32 mmol). After the formed yellow mixture was heated for 3 hours at 110 ℃, cooled to room temperature, was added to a slurry of 10 mL of CHCl ₃ SiO ₂ gel 1 g. After stirring for 15 minutes, through a 15 mL sintered glass funnel to a slurry containing a silica gel pad eluted with 50% CHCl ₃ -CH ₃ OH. The solvent was removed in vacuo and the residue obtained was triturated with 10% CH ₃ OH-CHCl ₃ and filtered. The solvent was removed in vacuo and the crude product was purified by thin layer chromatography (500 쨉 m SiO ₂ , 20% CH ₃ OH-CHCl ₃ - saturated NH ₃ ) to give 5-methylthio-4- [benzylamino] (18.3% from methyl 4-amino-5-methylthiothiophene-2-carboxylate). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.49 (s, 3H), 4.35 (d, 2H, J = 6.7Hz), 5.9l (t, 1H, J = 6.8Hz), 7.20-7.38 ( m, 6H). Mass spectrum (ESl, m / z): C 13 H 15 N 3 S Calcd 278.08 (M + H) for _2, 278.3 Found;

Example 221

4- (Indan-5-ylamino) -5-methylthiothiophene-2-carboxidine

(a) Methyl 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step 220 a of Example 220, methyl 4-amino- methylthio-thiophene-2-carboxylate 60 mg (0.29 mmol), 5- indan-carboxaldehyde ₃ 42.3 mg (0.29 mmol) and NaHB (OAc) 135 mg was reacted with (2.2 eq, 0.63 mmol) of methyl 4 (Indan-5-ylamino) -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): C 17 H 19 NO 2 Calcd for _{S 2 334.09 (M + H)} , Found; 332.3 (imine), 333.4.

(b) 4- (Indan-5-ylamino) -5-methylthiothiophene-2-carboximidine: Using a procedure analogous to the step of Example 220, step (b) (27.3% from methyl 4-amino-5-methylthiothiophene-2-carboxylate) was obtained. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 1.94-2.01 (m, 2H), 2.49 (s, 3H), 2.77-2.82 (m, 4H), 4.29 (d, 2H, J = 5.6Hz) 1H, J = 7.5 Hz), 7.20 (s, 1H), 7.23 (s, 1H) 1H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₉ N ₃ S ₂ 318.11 (M + H), found 318.3.

Example 222

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

(a) Methyl 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboxylate: 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate and 42.9 mg (0.29 mmol) of 2,3-dihydrobenzo [b] furan- and _{NaHB (OAc) 3 135 mg (} 2.2 equiv., 0.63 mmol) by reaction of methyl 4- (2,3-dihydrobenzo [b] furan-5-yl) -5-methylthio-thiophene-2- To obtain a chelate rate. Mass spectrum (ESI, m / z): theoretical value for C ₁₆ H ₁₇ NO ₃ S ₂ 336.07 (M + H), experimental value 334.3 (for imine), 335.3.

(b) 4- (2,3-Dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene-2-carboximidine: Using an analogous procedure to step (b) (Methyl 4-amino-5-methylthiothiophen-2-one) was obtained in the same manner as in Example 1, except that 21.8 mg of methyl 4- thiophene- -Carboxylate (23.5%). ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.49 (s, 3H), 3.13 (t, 2H, J = 8.7Hz), 4.24 (d, 2H, J = 6.6Hz), 4.48 (t, 2H 1H, J = 8.7 Hz), 5.69 (t, IH, J = 6.7 Hz), 6.68 7.26 (s, 1 H). Mass spectrum (ESI, m / z): C 15 H 17 N 3 Calcd 320.09 (M + H) for ₂ OS, 320.3 Found;

Example 223

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

(a) Methyl 5-methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboxylate: ₃ 135 mg of methyl 4-amino-5-methylthio-thiophene-2-carboxylate 60 mg (0.29 mmol), 4- formyl-2-phenyl-imidazole 49.9 mg (0.29 mmol) and NaHB (OAc) ( 2.2 equivalents, 0.63 mmol) were reacted to give methyl 5-methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboxylate. Mass spectrum (ESI, m / z): C 17 H 17 N 3 O 2 S 2 Calcd for 360.08 (M + H), Found; 360.0.

(b) 5-Methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene-2-carboximidine: 30.9 mg (prepared from 30 mg of methyl 4-amino-5-methylthiothiophene-2-carboxylate in 30 ml of methyl thio-4 - [ %). ^{1 H-NMR (DMSO-d} 6, 400MHz): 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), 7.43 (bs, 3H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₇ N ₅ S ₂ 344.00 (M + H), experimental value 344.2.

Example 224

Methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxidine

(a) Methyl 5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxylate: Using a procedure similar to step 220 a) 2-carboxylate, 45.5 mg (0.29 mmol) of 2-quinolinecarboxaldehyde and 135 mg (2.2 eq, 0.63 mmol) of NaHB (OAc) ₃ were reacted to give methyl 5 -Methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboxylate. Mass spectrum (ESI, m / z): C 17 H 16 N 2 O 2 Calcd 345.07 for ₂ S (M + H), Found; 343.3 (imine), 345.2.

(b) 5-Methylthio-4 - [(2-quinolylmethyl) amino] thiophene-2-carboximidine: 2.5 mg (2.6% from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of 2.5 mg of [(2-quinolylmethyl) amino] thiophene- Mass spectrum (ESI, m / z): theoretical value for C ₁₆ H ₁₆ N ₄ S ₂ 329.09 (M + H), found 329.3

Example 225

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

(a) Methyl 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxylate: Using a procedure similar to step 220 a) -amino-5-methylthio-thiophene-2-carboxylate 61.6 mg (0.30 mmol), 3- acetoxy benzaldehyde 49.5 mg (0.30 mmol) and _{NaHB (OAc) 3 135 mg (} 2.2 equiv., 0.63 mmol) and the reaction Methyl 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m / z): C 14 H 16 NO 3 352.07 theoretical value for _{S 2 (M + H),} 350.2 ( imine), 352.1 Found;

(b) 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2-carboxylate: 7.9 mg (8.9% from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of . Mass spectrum (ESI, m / z). Theoretical value for C ₁₃ H ₁₅ N ₃ OS ₂ 294.07 (M + H), experimental value 294.3.

Example 226

5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxidine

(a) Methyl 5-methylthio-4- (phenyl-carbonyl-amino) thiophene-2-carboxylate: from 0 ℃ CH ₂ Cl ₂ 4 mL of methyl 4-amino-5-methylthio-thiophene-2 (1.5 eq, 0.82 mmol) of N, N-diisopropylethylamine was added via syringe to 71 mg (1.1 eq, 0.61 mmol) of benzoyl chloride, . The reaction was allowed to warm to room temperature and stirred for additional 4 h. At this time, the reaction was partitioned between 40 mL of 1: 1 CH ₂ Cl ₂ -saturated NaHCO ₃ (v / v) and the organic layer was separated, washed with 20 mL of brine, dried over Na ₂ SO ₄ , Concentration afforded 113 mg (66.8%) of methyl 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxylate which was used without further purification. _{^{1 H NMR (DMSO-d 6}} , 400MHz): 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, 1 H). Mass spectrum (ESI, m / z): C 14 H 13 NO 3 Calcd for _{S 2 308.04 (M + H)} , Found; 308.2.

(b) 5-Methylthio-4- (phenylcarbonylamino) thiophene-2-carboxamide: Methyl 4 - {[4- (methylethyl) Phenyl] amino} -5-methylthiothiophene-2-carboxylate was reacted with 8 equivalents (2.58 mmol) of AlMe ₃ / NH ₄ Cl reagent to obtain 5-methylthio- (100%) of the title compound was obtained. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ2.59 (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): C 13 H 14 N 3 Calcd 292.06 (M + H) for ₂ OS, 292.2 experimental values.

Examples 227-240

A series of 2 diram vials with stirring bar and Teflon septum was added with amounts between 0.3-0.6 mmol of acid chloride (1 eq.), Respectively, followed by the addition of 1 equivalent of methyl 4-amino-5-methylthiothiophene- Was added as a 1 M CH ₂ Cl ₂ solution. To each vial was added another 2 mL of CH ₂ Cl ₂ followed by 1.5 equivalents of N, N-diisopropylethylamine. Each vial was cleaved with Ar and stirred for 3 hours. At this time, 4 mL of saturated NaHCO ₃ was added to each vial and stirred for 5 minutes. The aqueous layer was removed by pipette and Na ₂ SO ₄ was added. After the vials were stirred overnight, the contents were eluted with 0.5% MeOH-CH ₂ Cl ₂ in a 5-g silica gel (SPE column) cartridge. The amide was concentrated in vacuo and placed in a pre-weighed 2-drop vial equipped with a stir bar and Teflon septum for subsequent amidation reaction. The vial was cleared of Ar and 2 mL of toluene was charged and then 8 equivalents of AlMe ₃ / NH ₄ Cl reagent was charged as a 1 M solution in toluene. The reaction was heated to 110 &lt; 0 &gt; C for 3 hours in a heating block. This was then cooled to room temperature and each was pipetted into a slurry of 1.5 g of silica gel in 15 mL of CH ₂ Cl ₂ . Each slurry was stirred vigorously, and filtered to 50% on a 15 mL sintered glass funnel containing silica gel, 20 cm CHCl ₃ -MeOH for 15 minutes. The yellow fractions were collected and concentrated in vacuo. After pulverizing the solid in 10% MeOH-CHCl _3, and filtered. And concentrated in vacuo to obtain the crude amidine, this thin layer chromatography for purification (20% MeOH-CHCl ₃ - saturated MH _3, 500 ㎛SiO ₂₎ to thereby give each of the amidine as a representative free base form of this .

Example 227

4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene-

(a) Methyl 4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene-2-carboxylate: Yield 100%. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.49 (s, 3H), 3.83 (s, 3H), 7.12 (d, 1H, J = 15.7Hz), 7.41-7.66 (m, 6H), 8.24 (s, 1 H), 9.92 (s, 1 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₅ NO ₃ S ₂ 334.06 (M + H), 334.1.

¹ H-NMR (DMSO-d ₆ , 400 MHz):? - ( 2-methoxyphenyl) propionylamino] -5-methylthiothiophene- 2H), 8.40 (s, 1H), 8.81 (bs, 3H), 7.51-7.66 (m, 2H) ), 10.02 (bs, 1H) mass spectrum (ESI, m / z): C 15 H 15 N 3 Calcd 318.07 (M + H for the OS _2), 318.2.

Example 228

4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine

(a) Methyl 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate: Yield 53%. ^{1 H-NMR (DMSO-d} 6, 400N1Hz): δ 2.55 (s, 3H), 3.83 (s, 3H), 7.62 (d, 2H, J = 8.5Hz). 7.87 (s, 1H), 7.97 (d, 2H, J = 8.5 Hz), 10.21 (s, 1H).

(b) 4 - [(4- chlorophenyl) carbonyl-amino] -5-methylthio-thiophene-2-carboxamide ^{pyrimidine: 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 (ESI, m / z): C 13 H 12 ClN 3 Calcd 326.02 (M + H) for ₂ OS, 326.2 Found;

Example 229

4- (Cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxidine

(a) Methyl 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxylate: Yield 69.9%. ¹ H-NMR (DMSO-d ₆ , 400 MHz):? 1.22-1.81 (m, 11H), 2.51 (s, 3H), 3.82 . Mass spectrum (ESl, m / z): C 14 H 19 NO 3 Calcd for _{S 2 314.09 (M + H)} , Found; 314.2.

(b) 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2 -carboximidine : ¹ H-NMR (DMSO-d ₆ , 400 MHz):? 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 (ESI, m / z): C 13 H Theoretical value for ₂₀ N ₃ OS 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, 400MHz): δ 2.56 (s, 3H), 2.61 (s, 3H), 3.82 (s, 3H), 7.70 (d, 1H, J = 8.1Hz), 7.86 (s , 8.19 (dd, 1H, J = 1.7, 8.0 Hz), 8.56 (d, 1H, J = 1.7 Hz), 10.41 (s, 1H). Mass spectrum (ESI, m / z): C 15 H 14 N 2 O 5 S Calcd 367.42 (M + H) for _2, experimental data 367.2.

(b) Methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate: ¹ H-NMR (DMSO-d _6. 400 MHz) (s, 3H), 2.61 (s, 3H), 7.12 (bs, 3H), 7.69-7.73 (m, 2H), 8.20 (dd, = 1.6 Hz). Mass spectrum (ESI, m / z): C 14 H 14 N 4 O 3 Calcd 351.06 (M + H) for S _2, 351.2 experimental values.

Example 231

4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxidine

(a) Methyl 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxylate: Yield 100%. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.54 (s, 3H), 3.83 (s, 3H), 6.71 (dd, 1H, J = 1.8, 3.4Hz), 7.33 (d, 1H, J = 3.5 Hz), 7.87 (s, 1H), 7.95 (m, 1H), 9.93 (s, 1H). Mass spectrum (ESl, m / z): C 12 H 11 NO 4 Calcd 298.02 (M + H) for S _2, 298.3 experimental values.

(b) 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboximidine: ¹ H-NMR (DMSO-d ₆ , 400 MHz):? 2.51 (s, 3H), 6.71 1H, J = 1.8, 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): C 11 H 11 N 3 O 2 Calcd 282.04 (M + H) for S _2, 282.2 experimental values.

Example 232

4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxidine

(a) Methyl 4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxylate: Yield 93.4%. ^{1 H-NMR (DMSO-d} 6, 400MHz): 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): Theoretical value for C ₁₂ H ₁₇ NO ₃ S ₂ 288.07 (M + H), found 288.1.

(b) 4- (2,2- dimethyl propanoyl) -5-methylthio-thiophene-2-carboxamide ^{pyrimidine: 1 H-NMR (DMSO-} d 6, 400MHz): δ 1.24 (s, 9H) , 2.55 (s, 3H), 8.05 (s, IH), 9.0 (bs, 3H), 9.1 (s, IH). Mass spectrum (ESI, m / z): Theoretical value for C ₁₁ H ₁₇ N ₃ OS ₂ 272.09 (M + H), found 272.2.

Example 233

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

(a) Methyl 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene-2-carboxylate: Yield 96.9%. Mass spectrum (ESI, m / z): 457.97 (M + H) for C ₁₈ H ₁₃ C ₁₂ NO ₅ S ₂ , experimental value 457.9.

(b) 4 - {[5- (3,5- dichlorophenoxy) (2-furyl)] carbonyl} amino-5-methylthio-thiophene-2-carboxamide ^{pyrimidine: 1 H-NMR (DMSO-} d _{6, 400MHz): δ 2.53 (} s, 3H), 6.12-6.17 (m, 1H), 6.79 (d, 1H, J = 1.8Hz), 7.40-743 (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): C 17 H 14 Cl 2 N 3 O 3 Calcd 441.99 (M + H) for S _2, 442.2 experimental values.

Example 234

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

(a) Methyl 5-methylthio-4- (naphthylcarbonylamino) thiophene-2-carboxylate: Yield 80.8%. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 7.59-7.67 (m, 3H), 7.80 (d, 1H, J = 6.8Hz), 8.02-8.34 (m, 4H), 10.38 (s, 1H) .

(b) 5- methyl-4- (naphthyl-carbonyl-amino) thiophene-2-carboxamide ^{pyrimidine: 1 H-NMR (DMSO-} d 6, 400MHz): δ 2.50 (s, 3H), 7.60 (m 1H, J = 6.8Hz), 8.09 (d, 1H, 8.3Hz), 8.30 (d, 1H, , J = 8.8 Hz). Mass spectrum (ESI, m / z): C 17 H 15 N 3 Calcd 342.07 (M + H) for ₂ OS, 342.2 experimental values.

Example 235

5-methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboxidine

(a) Methyl 5-methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboxylate: Yield 80.9%. ^{1 H-NMR (DMSO-d} 6, 400MHz): 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), &lt; / RTI &gt; 10.63 (s, 1H).

(b) 5-Methylthio-4- (2-quinolylcarbonylamino) thiophene-2-carboximidine: ¹ H-NMR (DMSO-d ₆ , 400 MHz): 隆 2.53 (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): Theoretical value for C ₁₆ H ₁₄ N ₄ OS ₂ 343.45 (M + H), experimental value 343.1.

Example 236

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

(a) Methyl 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate: Yield 90.3%. ^{1 H-NMR (DMSO-d} 6, 400MHz): 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, 1 H), 10.09 (s, 1 H). Mass spectrum (ESI, m / z): C 15 H 15 NO 4 Calcd 338.05 (M + H) for S _2, 338.3 experimental values.

(b) 4 - [(3- methoxyphenyl) carbonyl amino] -5-methylthio-thiophene-2-carboxamide ^{pyrimidine: 1 H-NMR (DMSO-} d 6, 400MHz): δ 2.58 (s, 3H (D, 1H, J = 2.1, 8.1 Hz), 7.45-7.57 (m, 3H), 8.15 (s, 1H), 9.11 (bs, 4H), 10.32 1H). Mass spectrum (ESI, m / z): C 14 H 15 N 3 O 2 S Calcd 322.07 (M + H) for _2, experimental data 322.2.

Example 237

4- [2- (2,5-dimethoxyphenyl) acetylamino] -5-methylthiothiophene-2-carboxidine

¹ H-NMR (DMSO-d ₆ , 400 MHz):? 2.47 (a) Methyl 4- [2- (2,5-dimethoxyphenyl) acetylamino] -5-methylthiothiophene- (d, 1H, J = 3.0, 8.8 Hz), 6.87 (s, 3H), 3.80 d, 1H, J = 3.0 Hz), 6.93 (d, 1H, J = 8.9 Hz), 8.04 (s, 1H), 962 (s, 1H).

(b) 4- [2- (2,5-dimethoxyphenyl) acetylamino] -5-methylthiothiophene-2 -carboximidine : ¹ H-NMR (DMSO-d ₆ , 400 MHz) (s, 3H), 3.76 (s, 3H), 3.76 (s, 3H), 6.81 (dd, 1H, J = 3.3, 8.0Hz), 6.88-6.94 7.91 (s, 1H), 9.42 (bs, 1H).

Example 238

4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine

(a) Methyl 4 - [(4-ethoxyphenyl) carbonyl amino] ^{-5-methylthio-thiophene-2-carboxylate: 1 H-NMR (DMSO-} d 6, 400MHz): δ 1.36 (t, 2H, J = 7.0 Hz), 7.05 (d, 2H, J = 8.8 Hz), 7.87 (s, 3H) 1H), 7.93 (d, 2H, J = 8.8 Hz), 9.93 (s, 1H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₆ H ₁₇ NO ₄ S ₂ 352.07 (M + H), experimental value 352.2.

(b) 4 - [(4- ethoxyphenyl) carbonyl amino] -5-methylthio-thiophene-2-carboxamide ^{pyrimidine: 1 H-NMR (DMSO-} d 6, 400MHz): δ 1.36 (t, 3H 2H, 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 ), 8.73 (bs, 3H), 10.01 (bs, 1H). Mass spectrum (ESI, m / z): C 15 H 17 N 3 O 2 Calcd 336.08 (M + H) for S _2, 336.2 experimental values.

Example 239

5-methylthio-4- (2-phenoxyacetylamino) thiophene-2-carboxidine

(a) Methyl 5-methylthio-4- (2-phenoxyacetylamino) thiophene-2-carboxylate: Yield 79%. ^{1 H-NMR (DMSO-d} 6, 400MHz): 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, 1 H), 9.80 (s, 1 H).

(b) 5-Methylthio-4- (2-phenoxyacetylamino) thiophene-2 -carboximidine : ¹ H-NMR (DMSO-d ₆ , 400 MHz): 隆 2.52 (s, 3H) (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): C 14 H 15 N 3 O 2 Calcd 322.43 (M + H) for S _2, 322.2 experimental values.

Example 240

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

(a) Methyl 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboxylate: Yield 79%. ^{1 H-NMR (DMSO-d} 6, 400MHz): 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): Theoretical value for C ₁₅ H ₁₅ NO ₃ S ₂ 322.06 (M + H), found 322.2

(b) 4 - [(3- methylphenyl) carbonyl amino] -5-methylthio-thiophene-2-carboxamide ^{pyrimidine: 1 H-NMR (DMSO-} d 6, 400MHz): δ 2.40 (s, 3H), 1H), 2.55 (s, 3H), 7.43-7.44 (m, 2H), 7.75-7.78 (m, 2H), 8.05 (s, Mass spectrum (ESI, m / z): C 14 H 15 N 3 Calcd 306.07 (M + H) for ₂ OS, 306.2 experimental values.

Example 241

(a) Methyl 4-bromo-5-methylthiothiophene-2-carboxylate: To a solution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol) Prepared according to the procedure of EP 0676395 A2 (Klehnmann et al.)) Was added thionyl chloride (7 mL, 96 mmol) dropwise. After stirring at room temperature for 10 minutes, the solution was refluxed and stirred for 7.5 hours. The solution was cooled and the solvent was removed in vacuo. The solid formed was dissolved in dichloromethane (1500 mL), washed with saturated sodium bicarbonate (2 x 300 mL), water (300 mL), saturated brine (300 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The solid formed was recrystallized twice with hexane / ethyl acetate to give methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).

methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboxylate The methyl 4-bromo-5-methylthiothiophene (6 mol%), rac-2, 2 ' -bis (diphenylsulfonyl) -2, 12 mg (9 mol%), cesium carbonate (Aldrich Chemical Company, Milwaukee, Wisconsin) 110 mg (0.34 &lt; RTI ID = 0.0 & mmol, 1.5 eq.) and 54 mg (0.29 mmol, 1.3 eq.) of 3-benzyloxyaniline (Aldrich Chemical Company, Milwaukee, Wis.) were added to an oven-dried 1 dir glass vial. The vial was eluted with anhydrous argon in a glove bag, and the vial to which anhydrous toluene (450 [mu] L, 0.5 M) was added was heated at 100 [deg.] C for 36 hours. To the cooled suspension was added ethyl acetate (4 mL) and the mixture was passed through 1-inch celite, then washed with ethyl acetate (2 x 4 mL) and the solvent was removed in vacuo. Purification by preparative thin layer chromatography (1: 1 dichloromethane: hexane) gave 13 mg (15%) of the title compound as a pale yellow solid. _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, 3 H). Mass spectrum (ESI, m / z): C 20 H 19 NO 3 Calcd 386.1 (M + H) for S _2, 386.3 experimental values.

(c) 5-Methylthio-4 - {[3- (3-phenylmethoxy) phenyl] amino} thiophene-2-carboximidine: To a suspension of ammonium chloride (216 mg) in toluene Aluminum (2.0 M in toluene, 2 mL) was added dropwise over 5 minutes and stirred at 0 &lt; 0 &gt; C under anhydrous nitrogen. The mixture was stirred at 25 &lt; 0 &gt; C for 30 minutes, and when most of the solids had dissolved, the mixture was taken up with a syringe to give methyl 5-methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} -Carboxylate (13 mg, 0.03 mmol). The reaction mixture was heated to reflux in several steps and stirred for 2 hours and 10 minutes. The cooled mixture was poured into a vigorously stirred slurry of silica gel (2 g) in chloromethane (20 mL). Methanol (50 mL) was added to the suspension, and the mixture was passed through a 1-inch silica gel in a silica glass Buchner funnel, washed with methanol (50 mL), and then the solvent was removed in vacuo. The crude product was first washed with dichloromethane and then purified on a 5 g silica gel SPE column eluting the product with 10% methanol in dichloromethane. The product was purified by high pressure liquid chromatography (HPLC) (Dynamax (Dynamax) C18 column, pore size 60 Å, pore size 10 μM, gradient of methanol from 40% to 100% in 0.1% trifluoroacetic acid over 30 min) To give 5.4 mg (45%) of the title compound. _{^{1 H-NMR (CD 3 OD}} , 400MHz): δ 7.84 (s, 1H), 7.44-6.60 (m, 9H), 5.08 (s, 2H), 2.48 (s, 3H). Mass spectrum (ESI, m / z): C 19 H 19 N 3 Calcd 370.1 (M + H) for ₂ OS, 370.2 experimental values.

Example 242

(a) Methyl 5-methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboxylate: To a solution of methyl 4-bromo-5-methylthiothiophene- (0.299 mmol) and 72 mg (0.389 mmol, 1.3 eq.) Of 3-phenoxyaniline (Aldrich, Milwaukee, Wis.) Was treated as in Example 241, step (b). The product was further purified by thin layer chromatography for purification, eluting with 10% ethyl acetate in hexanes to give 36 mg (32%) of the title compound as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 7.76 (s, 1H), 7 40-6.65 (m, 9H), 6.26 (s, 1H), 3.89 (s, 3H), 2.40 (s, 3H). Mass spectrum (ESI, m / z): C 19 H 17 NO 3 Calcd for _{S 2 372.1 (M + H)} , Found; 372.2

(b) 5-methylthio-4 - [(3-phenoxyphenyl ) amino] thiophene- 2-carboxylate (36 mg, 0.097 mmol) was treated as in Example 241, step (c) but without HPLC purification afforded 30 mg (86%) of the title compound as an orange glass. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ9.28 (s, 2H), 8.11 (s, 2H), 7.99 (s, 1H), 7.34-6.50 (m, 9H), 6.29 (s, 1H), 2.35 (s, 3 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₈ H ₁₇ N ₃ OS ₂ 356.1 (M + H), experimental value 356.2.

Example 243

(a) 5-Methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboximide: 80 mg of methyl 4-bromo-5-methylthiothiophene- A stirred suspension of 72 mg (0.389 mmol, 1.3 eq.) Of 4-phenoxyaniline (from Aldrich, Milwaukee, WI) was treated as in Example 241, step (b). The product was further purified by thin layer chromatography for purification, eluting with 10% ethyl acetate in hexanes to give 53 mg (48%) of the title compound as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 7.70 (s, 1H), 7.34-7.00 (m, 9H), 6.11 (s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Mass spectrum (ESI, m / z): C 19 H 17 NO 3 Calcd 372.1 (M + H) for S _2, 372.1 experimental values.

(b) 5-methylthio-4 - [(4-phenoxyphenyl ) amino] thiophene- 2-carboxylate (53 mg, 0.14 mmol) was processed as in Example 241, step (c) but without purification by HPLC to provide 58 mg (quantitative yield) of the title compound as orange glass. _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, 3 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₈ H ₁₇ N ₃ OS ₂ 356.1 (M + H), experimental value 356.2.

Example 244

(a) Methyl 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate: Methyl 4-bromo-5-methylthiothiophene- A stirred suspension of 57 mg (0.46 mmol, 1.2 equiv) of 2-methoxyaniline (from Aldrich, Milwaukee, Wis.) Was treated in a similar manner to step (b) of Example 241 to give the title compound 78 mg (65%) as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ7.82 (s, 1H), 7.12-6.52 (m, 4H), 6.52 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.40 (s, 3 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₄ H ₁₅ NO ₃ S ₂ 310.1 (M + H), found 310.2.

(b) 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene- 2-carboxylate (78 mg, 0.25 mmol) was treated as in Example 241, step (c) but without HPLC purification afforded 75 mg (quantitative yield) of the title compound as orange glass. ¹ H-NMR (CD ₃ OD, 400 MHz):? 7.91 (s, 1H), 7.15-6.93 (m, 4H), 3.93 (s, 3H), 2.48 (s, 3H). Mass spectrum (ESI, m / z): C 13 H 15 N 3 Calcd 294.1 (M + H) for ₂ OS, 294.2 experimental values.

Example 245

(a) Methyl 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2- carboxylate: 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene- 51 mg (14.9 mol%) of tris (dibenzylideneacetone) dipalladium (Lancaster, Pelham, NH), racemic 2,2'-bis (diphenylphosphino) -1,1 (0.56 mmol, 1.5 eq.) And cesium carbonate (Aldrich Chemical Company, Milwaukee, Wisconsin, USA) and 2 ' -naphthyl (Strept products from Newberry Report, (0.49 mmol, 1.3 eq.) Of methyl aniline (Aldrich Chemical Company, Milwaukee, Wis.) Was added to an oven-dried 1 dir glass vial. The vial was eluted with anhydrous Ar in a glove bag and the vial to which anhydrous toluene (750 L, 0.5 M) was added was heated at 100 DEG C for 40 hours. To the cooled suspension was added ethyl acetate (4 mL) and the mixture was passed through 1 inch of celite, washed with ethyl acetate (2 x 4 mL) and the solvent was removed in vacuo. Purification by preparative thin layer chromatography (1: 1 dichloromethane / hexanes) afforded 67 mg (61%) of the title compound as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): 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, 3 H). Mass spectrum (ESI, m / z): C 14 theoretical value for _{1H 15 NO 2 S 2 294.1 (} M + H), Found; 294.2

(b) 4 - [(2-methylphenyl) amino] -5-methylthiothiophene- 2-carboxylate (67 mg, 0.23 mmol) was processed as in Example 241, step (c) but without HPLC purification afforded 20 mg (30%) of the title compound as an orange glass. ¹ H-NMR (CD ₃ OD, 400 MHz):? 7.56 (s, 1H), 7.24-6.99 (m, 4H), 2.49 (s, 3H), 2.29 (s, 3H). Mass spectrum (ESI, m / z): C 13 H 15 N 3 S Calcd 278.1 (M + H) for _2, experimental data 278.2.

Example 246

(a) Methyl 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboxylate: 80 mg of methyl 4-bromo-5-methylthiothiophene- (0.389 mmol, 1.3 eq.) Of 3-chloroaniline (Aldrich, Milwaukee, Wis.) Was treated in a similar manner to step (b) of Example 241 to give 47 mg 50%) as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): 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): C 13 H 12 NO 2 Calcd for _{S 2 Cl 314.0 (M + H} ), Found; 314.1.

(b) 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene- 2- Carboxylate (47 mg, 0.15 mmol) was treated in the same manner as in step (c) of Example 241 to give 33 mg (75%) of the title compound as a pale yellow solid. ^{1 H-NMR (DMSO-d} 6, 400MHz): 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, 3 H). Mass spectrum (ESI, m / z): C ₁₂ H ₁₂ N ₃ S ₂ Cl, 298.0 (M + H), found 298.3.

Example 247

(a) Methyl 4- (methylphenylamino) -5-methylthiothiophene-2-carboxylate: 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene- A stirred suspension of 72 μL (0.487 mmol, 1.3 eq.) Of methyl aniline (Aldrich, Milwaukee, Wis.) Was treated in a similar manner to step (a) of Example 245 to afford 23 mg (21%) of the title compound as yellow In the form of oil. ¹ H-NMR (CDCl ₃ , 400 MHz):? 7.61 (s, 1H), 7.26-6.68 (m, 5H), 3.89 (s, 3H), 3.25 (s, 3H), 2.50 Mass spectrum (ESl, m / z): C 11 H 15 NO 2 Calcd 294.l (M + H) for S _2, 294.3 experimental values.

(b) 4- (Methylphenylamino) -5-methylthiothiophene-2-carboximide: Methyl 4 - [(2- methylphenyl) amino] , 0.078 mmol) was treated as in Example 241 step (c) but without HPLC purification afforded 5.6 mg (26%) of the title compound as an orange glass. _{^{1 H-NMR (CD 3 OD}} , 400MHz): δ 7.83 (s, 1H), 7.24-6.71 (m, 4H), 3.27 (s, 3H), 2.57 (s, 3H). Mass spectrum (ESI, m / z): C 13 H 15 N 3 theoretical value for the _{S 2 278.1 (M + H)} , Found; 278.3.

Example 248

(a) Methyl 5-methyl-4- (phenylamino) thiophene-2-carboxylate: To a solution of 400 mg (1.7 mmol) of methyl 5-methyl-4-bromo- thiophene- (2.1 mmol, 1.25 eq.) Was treated in a similar manner to step (b) of Example 241 to give 66 mg (16%) of the title compound as a brown glass. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 7.70 (s, 1H), 7.56 (s, 1H), 7.17 (m, 2H), 6.72 (m, 3H), 3.79 (s, 3H), 2.31 (s, 3 H). Mass spectrum (MALDI, Gentis acid matrix, m / z): Theoretical value for C ₁₃ H ₁₃ NO ₂ S 248.1 (M + H), found 247.5.

(b) 5-Methyl-4- (phenylamino) thiophene-2-carboximidine: Methyl 4- (methylphenylamino) -5-methylthiothiophene- 2-carboxylate (66 mg, 0.27 mmol) (C) of Example 241 but treated without purification by HPLC to afford the title compound (57 mg, 91%) as a brown glass. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 9.17 (s, 2H), 8.85 (s, 2H), 7.98 (s, 1H), 7.85 (s, 1H), 7.21-6.73 (m, 5H) , &Lt; / RTI &gt; 2.39 (s, 3H). Mass spectrum (ESI, m / z): Theoretical value 232.1 (M + H) for C ₁₂ H ₁₃ N ₃ S, found 232.2.

Example 249

(a) Methyl 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboxylate: Methyl 5-methyl-4-bromo- thiophene- A stirred suspension of 66 mg (0.35 mmol, 1.3 eq.) Of 100 mg (0.267 mmol) of 4-amino-N, N-dimethylaniline (product of Fluka, Milwaukee, WI) 1 ethyl acetate / hexane to give 86 mg (quantitative yield) of the title compound as an orange glassy phase. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 7.53 (s, 1H), 7.16 and 6.62 (AB quartet, 4H, J = 8.9Hz), 5.99 (s, 1H), 3.86 (s, 3H), 2.94 ( s, 6H), 2.39 (s, 3H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₅ H ₁₈ N ₂ O ₂ S ₂ 323.1 (M + H), found 323.3.

(b) 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2-carboximidine: Methyl 4- (methylphenylamino) -5-methylthiothiophene- (86 mg, 0.267 mmol) was processed as in Example 241, step (c) but without purification by HPLC. This material was purified by passing through 1-inch basic alumina and eluting with 10% methanol in dichloromethane (15 mL) to give 62 mg (76%) of the title compound as a brown glass. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 8.95 (s, 4H), 7.75 (s, 1H), 7.56 (s, 1H), 6.97 and 6.72 (AB quartet, 4H, J = 8.9Hz), 2.83 (s, 6 H), 2.44 (s, 3 H). Mass spectrum (ESI, m / z): C 14 H 18 N 4 Calcd 307.1 (M + H) for S _2, 307.3 experimental values.

Example 250

4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxidine hydrochloride

(a) Methyl 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboxylate: To an oven-dried glass vial equipped with a stir bar was added methyl 4-bromo- Carboxylate 100 mg (0.374 mmol) (as prepared in step 24a of Example 241), 5.8 mg (6.9 mol%) palladium (II) acetate, and rac-2,2'- A mixture of 21.7 mg (9.3 mol%) of bis (diphenylphosphino) -1,1'-binaphthyl, 171.5 mg (0.526 mmol) of cesium carbonate and 59 mg (0.487 mmol) of 4-ethylaniline was added. The vial was transferred to a glove bag, which was purged with anhydrous argon and then anhydrous toluene (749 [mu] l) was added. The vial was sealed with a threaded stopper with Teflon and heated at 100 ° C for 48 hours. The cooled suspension was filtered through celite, washed with ethyl acetate (2 x 2 mL) and then the solvent was removed in vacuo. The remaining residue was purified on a 1 mm silica tablet plate eluting with 40% methylene chloride-hexane to give 14 mg (12 mg) of methyl 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene- %) As a pale yellow resin, which was used immediately in the next step.

( 19 mg, 0.363 mmol) in anhydrous toluene (1 mL) at 0 &lt; 0 &gt; C under Ar was added dropwise to a solution of 4- (4-ethylphenyl) amino- Was added trimethylaluminum (2.0 M in toluene, 0.182 mL, 0.363 mmol) dropwise. The mixture was stirred at 25 &lt; 0 &gt; C for 30 minutes and then 14 mg (0.036 g) of methyl 4- [(4-ethylphenyl) amino] -5- methylthiothiophene- mmol). The reaction mixture was slowly heated to 100 &lt; 0 &gt; C and stirred for 4 hours. The cooled mixture was added to a vigorously stirred slurry of silica gel (1.3 g) in chloroform (20 mL). The suspension was filtered through silica and washed with 50% MeOH-CH ₂ Cl ₂ (2 x 50 mL). The residue obtained by concentrating the washings was purified on a 0.5 mm silica eluting plate eluting with 10% MeOH-CH ₂ Cl ₂ to give 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene- 8 mg (67%) of the title compound as a yellow solid. _{^{1 H-NMR (CD 3 OD}} , 400MHz): δ 7.84 (s, 1H), 7.14 (d, 2H, 8Hz), 7.01 (d, 2H, 8Hz), 2.55 (q, 2H, 65.5Hz), 2.48 ( s, 3H), 1.23 (t, 3H, 15.2 Hz). Mass spectrum (ESI, m / z): C 14 H 17 N 3 S Calcd 292.1 (M + H) for _2, experimental data 292.5.

Example 251

Methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxidine hydrochloride

(a) Methyl 5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxylate: 100 mg (0.374 mmol) of 5-methylthiothiophene-2-carboxylate (prepared as in Example 241 step a), 5.5 mg (6.5 mol%) of palladium (II) acetate, 23.6 mg (10.1 mol%) of semi-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 194 mg (0.595 mmol) of cesium carbonate, 97.3 mg ) And 749 [mu] l of toluene and chromatographed using 40% CH ₂ Cl ₂ -hexane as before, to give methyl 5-methylthio-4 - {[4- (phenylmethoxy) Phenyl] amino} thiophene-2-carboxylate as a yellow resin, which was used as such in the next step.

(b) 5-Methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboximidine hydrochloride By the same procedure as in the step b) of Example 250, 7 mg (0.018 mmol) of trimethylaluminium (2.0 M in toluene, 0.182 mmol), and triethylamine were added to a solution of 7 mg (0.018 mmol) of thio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene- mmol), 10 mg (0.182 mmol) of ammonium chloride and 1 mL of toluene, and purified on a 0.5 mm silica plate with elution with 10% MeOH-CH ₂ Cl ₂ to give 5-methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene-2-carboxidine hydrochloride as a yellow oil. _{^{1 H-NMR (CD 3 OD}} , 400MHz): δ 7.72 (s, 1H), 7.45 (d, 2H, 7Hz), 7.39 (t, 2H, 9Hz), 7.37 (d, 1H, 12Hz), 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): C 19 H 19 N 3 Calcd 370.1 (M + H) for ₂ OS, 370.3 experimental values.

Example 252

Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxamide hydrochloride

(a) Methyl 5-methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboxylate: By the same procedure as in the step a) of Example 250, methyl 4-bromo -5-methylthiothiophene-2-carboxylate (prepared as in step 241 of Example 241), 5.5 mg (6.5 mol%) of palladium (II) acetate, (9.3 mol%), cesium carbonate (173 mg, 0.533 mmol), N-phenyl-1,4-phenylenediamine The reaction was carried out using 92.3 mg (0.500 mmol) and 749 [mu] l of toluene and chromatographed using 40% CH ₂ Cl ₂ -hexane as before, to give methyl 5-methylthio- (Phenylamino) phenyl] amino} thiophene-2-carboxylate as a brown solid. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 7.85 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.14 (t, 2H, 16Hz), 6.99 (d, 2H, 16Hz), 6.90 (q, 4H, 44Hz), 6.70 (t, 2H, 4Hz), 3.77 (s, 3H), 2.43 (s, 3H).

(b) 5-Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene-2-carboximidine hydrochloride: By the same procedure as in the step b) of Example 250, 58 mg (0.156 mmol) of trimethylaluminium (2.0 M in toluene, 1.56 mmol), 4 - {[4- (phenylamino) phenyl] amino} thiophene- The reaction was carried out using 0.783 mL of ammonium chloride 84 mg (0.156 mmol) and 10 mL of toluene and purification via silica pad eluting with 50% MeOH-CH ₂ Cl ₂ gave 5-methylthio-4 - {[4- (Phenylamino) phenyl] amino} thiophene-2-carboxidine hydrochloride (50 mg, 75%) as a yellow oil. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 7.91 (d, 2H, 12Hz), 7.78 (s, 1H), 7.20 (t, 3H, 12Hz), 7.04-6 94 (m, 5H), 6.71 (m, 1 H), 2.47 (s, 3 H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₈ H ₁₈ N ₄ S ₂ 355.1 (M + H), experimental value 355.4.

Example 253

4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxidine hydrochloride

(a) Methyl 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxylate: To an oven-dried glass vial equipped with a stir bar was added methyl-4-bromo- A mixture of 120 mg (0.449 mmol) of thiothiophene-2-carboxylate (prepared as in Example 241 step a), 7.1 mg (7 mol%) of palladium (II) acetate, A mixture of 29.4 mg (10.5 mol%) of bis (diphenylphosphino) -1,1'-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 69.1 mg (0.561 mmol) of p- . The vial was transferred to a glove bag, which was then dehydrated with anhydrous argon and then anhydrous toluene (0.9 mL) was added. The vial was sealed with a threaded stopper with Teflon and heated at 100 ° C for 48 hours. To the cooled suspension was added ethyl acetate (4 mL) and the mixture was filtered through celite, washed with ethyl acetate (2 x 2 mL) and the solvent was removed in vacuo. The remaining residue was purified by thin layer chromatography (40% CH ₂ Cl _{2 in} hexane) for purification of the silica gel to give 83 mg (60%) of the title compound as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 2.39 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 6.03 (s, 1H), 6.89 (m, 2H), 7.03 (m , &Lt; / RTI &gt; 2H), 7.58 (s, 1H).

( 216 mg, 4 mmol) in anhydrous toluene (1 mL) at room temperature under Ar was added dropwise to a stirred solution of 4- (4-methoxyphenyl) amino-5-methylthiothiophene- Was added trimethylaluminum (2.0 M in toluene, 2 mL, 4 mmol) dropwise. The mixture was stirred at 25 &lt; 0 &gt; C for 30 min and then a solution of methyl 4 - [(4-methoxyphenyl) amino] -5- methylthiothiophene- 2-carboxylate (prepared in the previous step) in anhydrous toluene Was added 80 mg (0.259 mmol). The reaction mixture was slowly heated to 100 &lt; 0 &gt; C and stirred for 2.5 hours. The cooled mixture was added to a vigorously stirred slurry of silica gel (3 g) in chloroform (20 mL). The suspension was filtered and washed with MeOH (4 x 5 mL) and 50% MeOH-CH ₂ Cl ₂ (4 x 5 mL). The collected washings were concentrated and the residue was purified on a 2 g silica gel column with 5% MeOH-CH ₂ Cl ₂ to give 50 mg (59%) of the title compound as an orange solid. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 2.44 (s, 3H), 3.69 (s, 3H), 6.84 (m, 2H), 6.98 (m, 2H), 7.73 (s, 1H), 7.84 (s, 1 H), 9.01 (br s, 2H), 9.24 (brs, 2H). Mass spectrum (ESI, m / z): C 13 H 15 N 3 Calcd 294.1 (M + H) for ₂ OS, 294.2 experimental values.

Example 254

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

(a) Methyl 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboxylate: Methyl 4-bromo-5-methylthiothiophene- A solution of 120 mg (0.449 mmol) of the intermediate (as prepared in step a) of Example 241, 41 mg (10 mol%) of tris (dibenzylidineacetone) dipalladium, (15 mol%), cesium carbonate 205 mg (0.629 mmol), and 3-fluoro-4-methyl (diphenylphosphino) -1,1'-binaphthyl (Strept product, Aniline (70 mg, 0.56 mmol) was added to an oven-dried 1 dir glass vial with a stir bar. The vial was transferred to a glove bag, which was then dehydrated with anhydrous argon and then anhydrous toluene (0.9 mL) was added. The vial was sealed with a threaded stopper with Teflon and heated at 100 ° C for 48 hours. To the cooled suspension was added ethyl acetate (4 mL) and the mixture was filtered through celite, washed with ethyl acetate (2 x 2 mL) and the solvent was removed in vacuo. The remaining residue was purified by preparative thin layer chromatography (10% Et ₂ O in hexanes) to give 103 mg (78%) of the title compound as a yellow oil. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 2.22 (d, 3H, J = 1.6Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 (s, 1H), 6.68 (m, 1H ), 6.71 (s, 1 H), 7.08 (m, 1 H), 7.72 (s, 1 H).

(b) 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene-2-carboximidine: In the same manner as in the method of Example 253, 103 mg (0.349 mmol) of trimethylaluminium (2.0 M in toluene, 4 mmol) was added to a solution of 3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene- The reaction was carried out using 2 mL of ammonium chloride, 216 mg (4 mmol) of ammonium chloride and 2 mL of toluene and purification on a 2-g silica SPE column with 5% MeOH-CH ₂ Cl ₂ to give 45 mg (44%) of the title compound It was obtained in the form of a yellow foam. ^{1 H-NMR (DMSO-d} 6; 400MHz): δ 2.13 (s, 3H), 2.50 (s, 3H), 6.70 (m, 2H), 7.10 (m, 1H), 7.98 (s, 1H), 8.09 (s, 1 H), 9.16 (br s, 4H). Mass spectrum (ESI, m / z): C 13 H 14 theoretical 296.1 (M + H) for FN ₃ S _2, 296.2 experimental values.

Example 255

4- (Indan-5-ylamino) -5-methylthiothiophene-2-carboxidine

(a) Methyl 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboxylate: By the same procedure as in the step a) of Example 254, methyl 4-bromo- A solution of 120 mg (0.449 mmol) thiothiophene-2-carboxylate (prepared as in Example 241 step a), 41 mg (10 mol%) tris (dibenzylidineacetone) dipalladium, Aminoindan in 900 [mu] l of toluene and 205 mg (0.629 mmol) of cesium carbonate were added to a mixture of 42 mg (15 mol%) of 2,2'-bis (diphenylphosphino) 0.56 mmol) and chromatographed using 40% CH ₂ Cl ₂ -hexane as before to give 100 mg (78%) of the title compound as yellow resin. _{^{1 H-NMR (CDCl 3,}} 400MHz): 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-carboximidine: Following the same procedure as step (b) 2 mL of trimethylaluminum (2.0 M in toluene, 4 mmol) and 216 mg (4 mmol) of ammonium chloride were added to a solution of 2-amino-2-methylthiophene- mmol) and 2 mL of toluene and purified on a 2-g silica SPE column using 5% MeOH-CH ₂ Cl ₂ to give 65 mg (65%) of the title compound as a yellow foam. ¹ H-NMR (DMSO-d ₆ , 400 MHz):? 1.99 (m, 2H), 2.48 (s, 3H), 2.78 (m, 4H), 6.77 (dd, (S, 1 H), 9.13 (br s, 4H) mass spectrum (ESI, m / z): 6.86 (s, : C ₁₅ H ₁₇ N ₃ S Calcd 304.1 (M + H) for _2, experimental data 304.3.

Example 256

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

(a) Methyl 4- [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboxylate: By the same procedure as in the step a) of Example 254, methyl 4- A solution of 120 mg (0.449 mmol) of bromo-5-methylthiothiophene-2-carboxylate (prepared as in Example 241 step a), 41 mg of tris (dibenzylidineacetone) dipalladium 42 mg (15 mol%) of racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate, and 3 -Amino-9-ethylcarbazole (118 mg, 0.56 mmol) and chromatographed using 40% CH ₂ Cl ₂ -hexane as before to give 80 mg (47 %) As a yellow resin. _{^{1 H-NMR (CDCl 3,}} 400MHz): δ1.46 (t, 3H, J = 7.2Hz), 2.44 (s, 3H), 3.85 (s, 3H), 4.39 (q, 2H, J = 7.2Hz) , 7.25 (s, 1H), 7.28 (s, 1H), 7.40 (m, 2H), 7.49 = 2.1 Hz), 8.06 (d, 1H, J = 7.8 Hz).

(b) 4 - [(9-Ethylcarbazol-3-yl) amino] -5-methylthiothiophene-2-carboximidine: By the same procedure as in the step b) of Example 253, methyl 4- 80 mg (0.21 mmol) of trimethylaluminium (2.0 M in toluene, 0.5 mmol) in toluene, 4 mmol), 216 mg (4 mmol) of ammonium chloride and 2 mL of toluene and purified on a 2-g silica SPE column using 5% MeOH-CH ₂ Cl ₂ to give 56 mg (70%) as a yellow foam. ^{1 H-NMR (DMSO-d} 6, 400MHz): δ 1.31 (t, 3H, J = 7.0Hz), 2.50 (s, 3H), 4.42 (q, 2H, J = 7.0Hz), 7.14 (m, 1H 1H), 7.72 (d, 1H, J = 8.7, 2.1 Hz), 7.43 (s, 1H), 8.10 (d, 1H, J = 7.7 Hz), 9.11 (br s, 4H). Mass spectrum (ESI, m / z): C 20 H 20 N 4 Calcd 381.1 (M + H) for S _2, 381.3 experimental values.

Examples 257 and 258

(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamide trifluoroacetate and 4- { 5-methylthiothiophene-2-carboxyridine trifluoroacetate

(a) methyl 5-methylthio-4 - [(4-phenylsulfonyl) amino] thiophene- Methylthiothiophene-2-carboxylate To an oven-dried round bottom flask equipped with a stir bar was added methyl 4-amino-5-methylthiothiophene-2-carboxylate (prepared as in Example 202) A mixture of mg (0.24 mmol), 4-biphenylsulfonyl chloride 68 mg (0.27 mmol) and 4-dimethylaminopyridine 50 mg (0.49 mmol) was added. The flask was purged with anhydrous argon and then anhydrous acetonitrile (3 mL) was added. The reaction was refluxed for 3 hours and then the solvent was removed in vacuo. The crude reaction product was extracted with ethyl acetate (2 x 25 mL) and 1N HCl (50 mL). The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a foam which was then subjected to silica chromatography purification with 30% ethyl ether-hexane to give methyl 5-methylthio-4 - [(4-phenyl Sulfonyl) amino] thiophene-2-carboxylate and methyl 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxylate . This mixture was used in the next reaction without further purification. Mass spectrum (ESI, m / z): C 19 H 17 NO 4 Calcd 420.0 (M + H) for S _3, experimental data 419.7.

(4-phenylphenyl) sulfonyl] amino} thiophene-2-carboxamide trifluoroacetate and 4- {[bis (4-phenylphenyl) sulfonyl] Amino} -5-methylthiothiophene-2-carboxymidine trifluoroacetate: To a suspension of ammonium chloride (155 mg, 2.89 mmol) in anhydrous toluene (2.0 mL) under Ar at 0 <0> C was added trimethylaluminum (2.0 in toluene M, 1.36 mL, 2.72 mmol). The mixture was stirred at 25 ° C for 30 minutes and then a solution of methyl 5-methylthio-4 - [(4-phenylsulfonyl) amino] thiophene-2-carboxylate and methyl 4- { (4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxylate (prepared as in the previous step). The reaction mixture was slowly heated to 100 &lt; 0 &gt; C and stirred for 4 hours. The cooled mixture was added to a vigorously stirred slurry of silica gel (3 g) in chloroform (15 mL). The suspension was filtered and washed with 25% MeOH-CH ₂ Cl ₂ (2 × 5 mL), 50% MeOH-CH ₂ Cl ₂ (2 × 5 mL) and 75% MeOH-CH ₂ Cl ₂ And washed. The collected washings were concentrated and the residue was purified on a 10-g silica SPE column with a gradient of 10-15% MeOH-CH ₂ Cl ₂ saturated with ammonia to give 66 mg of the title compound as a yellow oil. The mixture was treated with a Rainin SD-1 Dynamax system and a 2-inch C18 reverse phase Dynamax 60A column using a gradient from 30% MeOH / 0.1% TFA to 100% MeOH and a flow rate of 50 mL / HPLC to obtain 15 mg of 5-methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene-2- carboxymidine trifluoroacetate and 4- { Phenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxymidine trifluoroacetate. Electronic spectrum (ESI, m / z): C 18 H 17 N 3 O 2 Calcd for _{S 3 404.0 (M + H)} , Found; 404.1. The latter spectrum (ESI, m / z): C 30 H 25 N 3 O 4 S 4 Calcd 619.8 (M + H) for, 620.2 Found;

Examples 259 to 282

The following compounds were synthesized using the same method as in Example 257 and Example 258.?

compound reagent compound The Mass spectroscopy, ESI. m / z Theoretical value M + H Experimental value 259 1-naphthalenesulfonyl chloride Methylthio-4 - [(2-naphthylsulfonyl) -amino] thiophene-2-carboxidine C ₁₆ H ₁₅ N ₃ O ₂ S ₃ 378.0 378.1 260 1-naphthalenesulfonyl chloride 4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine C ₂₆ H ₂₁ N ₃ O ₄ S ₄ 568.0 568.1 261 7-Bromonaphthalenesulfonyl chloride 4 - {[(6-bromo (2- naphthyl)) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₆ H ₁₄ BrN ₃ O ₂ S ₃ 455.9 * 262 7-Bromonaphthalenesulfonyl chloride 4- {bis [(6-bromo (2-naphthyl)) sulfonyl] amino} -5-methylthiothiophene- C ₂₆ H ₁₉ Br ₂ N ₃ O ₄ S ₄ 723.9 * 263 2-naphthalenesulfonyl chloride 5-methylthio-4 - [(naphthylsulfonyl) -amino} thiophene-2-carboxidine C ₁₆ H ₁₅ N ₃ O ₂ S ₂ 378.0 378.1 264 2-naphthalenesulfonyl chloride 4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine C ₂₆ H ₂₁ N ₃ O ₄ S ₄ 568.7 568.3 265 O-toluenesulfonyl chloride 4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₃ H ₁₅ N ₃ O ₂ S ₃ 342.4 342.1 266 O-toluenesulfonyl chloride 4- {bis [(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₂₀ H ₂₁ N ₃ O ₄ S ₄ 496.6 496.1 267 M-toluenesulfonyl chloride 4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₃ H ₁₅ N ₃ O ₂ S ₃ 342.0 342.1 268 M-toluenesulfonyl chloride 4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₂₀ H ₂₁ N ₃ O ₄ S ₄ 496.6 496.0 269 P-toluenesulfonyl chloride 4 - {[(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₃ H ₁₅ N ₃ O ₂ S ₃ 342.0 342.1 270 P-toluenesulfonyl chloride 4- {bis [(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₂₀ H ₂₁ N ₃ O ₄ S ₄ 496.6 496.1 271 Alpha -toluenesulfonyl chloride 5-methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboxidine C ₁₃ H ₁₅ N ₃ O ₂ S ₃ 342.0 342.1

compound reagent compound The Mass spectroscopy, ESI. m / z Theoretical value M + H Experimental value 272 4-methoxybenzenesulfonyl chloride 4 - {[(4-methoxyphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₃ H ₁₅ N ₃ O ₃ S ₃ 358.0 358.1 273 4-methoxybenzenesulfonyl chloride 4 - {[bis (4-methoxyphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₂₀ H ₂₁ N ₃ O ₆ S ₄ 528.0 528.0 274 4-iodobenzenesulfonyl chloride 4 - {[(4-iodophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₂ H ₁₂ IN ₃ O ₂ S ₃ 453.9 454.0 275 3,4-dimethoxybenzenesulfonyl chloride 4 - {[(3,4-dimethoxyphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₄ H ₁₇ N ₃ O ₄ S ₃ 388.0 388.1 276 3,4-dimethoxybenzenesulfonyl chloride 4- {bis {(3,4-dimethoxyphenyl (sulfonyl) amino} -5-methylthiothiophene-2-carboxidine C ₂₂ H ₂₅ N ₃ O ₈ S ₄ 588.0 588.1 277 2-chlorobenzenesulfonyl chloride 4 - {[(2-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₂ H ₁₂ ClN ₃ O ₂ S ₃ 361.9 362.1 278 3-Chlorobenzenesulfonyl chloride 4 - {[(3-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₂ H ₁₂ ClN ₃ O ₂ S ₃ 361.9 362.1 279 3-Chlorobenzenesulfonyl chloride 4- {bis [(3-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₈ H ₁₅ Cl ₂ N ₃ O ₄ S ₄ 535.9 537.9 280 4-chlorobenzenesulfonyl chloride 4 - {[(4-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₂ H ₁₂ ClN ₃ O ₂ S ₃ 361.9 362.1 281 4-chlorobenzenesulfonyl chloride 4- {bis [(4-chlorophenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₈ H ₁₅ Cl ₁₂ N ₃ O ₄ S ₄ 535.9 * 282 Benzenesulfonyl chloride 5-methylthio-4 - [(phenylsulfonyl) amino] -thiophene-2-carboxidine C ₁₂ H ₁₃ N ₃ O ₂ S ₃ 328.0 328.1

compound reagent compound The Mass spectroscopy, ESI. m / z Theoretical value M + H Experimental value 283 Benzenesulfonyl chloride 4- [bis (phenylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine C ₁₈ H ₁₇ N ₃ O ₄ S ₄ 468.0 467.9 284 4-tert-Butylbenzenesulfonyl chloride 4 - ({[4- (tert-butyl) phenyl] sulfonyl} amino) -5-methylthiothiophene- C ₁₆ H ₂₁ N ₃ O ₂ S ₃ 384.0 384.2 285 4-tert-Butylbenzenesulfonyl chloride 4- (bis {[4- (tert-butyl) phenyl] sulfonyl} amino) -5-methylthiothiophene- C ₂₆ H ₃₃ N ₃ O ₄ S ₄ 580.1 580.2 286 Trans-β-styrenesulfonyl chloride 4 - {[((1E) -2-phenylvinyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine C ₁₄ H ₁₅ N ₃ O ₂ S ₃ 354.0 * 287 4-benzenesulfonyl-thiophene-2-sulfonyl chloride Methylthio-4 - ({[4- (phenylsulfonyl) (2-thienyl)] sulfonyl} amino) thiophene- C ₁₆ H ₁₅ N ₃ O ₄ S ₅ 473.9 474.1 * Mass spectral data is not deterministic.

Example 288

5-methylthio-4-phenoxythiophene-2-carboxyridine trifluoroacetate

(a) Methyl 5-methylthio-4-phenoxythiophene-2-carboxylate: To an oven-dried round bottom flask equipped with a stir bar was added methyl 4-bromo-5-methylthiothiophene- (Brewster, RQ and Groening T., Organic Syntheses , Vol. II, Note 1, pp 445-446) and 100 mg (0.37 mmol) mg &lt; / RTI &gt; (0.46 mmol). The flask was purged with anhydrous argon and anhydrous tetrahydrofuran (5 mL) was added. The reaction was refluxed for 48 hours and then the solvent was removed in vacuo. The remaining residue was purified on a 10-g silica SPE column using a gradient of 50-100% CH ₂ Cl ₂ -hexane to give 48 mg (37%) of methyl 5-methylthio-4-phenoxythiophene- ). _{^{1 H-NMR (CDCl 3,}} 400MHz): δ 7.39 (s, 1H), 7.32 (m, 2H), 7.09 (m, 2H), 6.97 (d, 1H, J = 8.4Hz), 3.86 (s, 3H ) And 2.49 (s, 3H).

(b) 5-Methylthio-4-phenoxythiophene-2-carboxymidine trifluoroacetate: In the same procedure as in the step (b) of Example 257, methyl 5-methylthio-4-phenoxythiophene- (2.0 M in toluene, 1.3 mmol) and trimellitic anhydride (3 mL) were added to a stirred solution of the title compound as a colorless solid, 48.0 mg (0.17 mmol), ammonium chloride 78 mg Reaction was carried out using a Rainin SD-1 Dynamax system and a 2-inch C18 reverse phase Dynamax 60A column using a gradient from 30% MeOH / 0.1% TFA to 100% MeOH in water and a flow rate of 50 mL / Lt; RTI ID = 0.0 &gt; HPLC. &Lt; / RTI &gt; _{^{1 H-NMR (CD 3 OD}} , 400MHz): δ 7.66 (s, 1H), 7.39 (t, 2H, J = 7.5Hz), 7.17 (t, 2H, J = 7.4Hz), 7.02 (d, 1H, J = 7.7 Hz) and 2.58 (s, 3H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₂ H ₁₂ N ₂ OS ₂ 265.0 (M + H), found 262.2.

Example 289

5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxymidine trifluoroacetate

(a) 4-Bromo-5-methylthiothiophene-2-carboxylic acid

H ₂ O 10 a-methyl-4-bromo-5-methylthio-thiophene-2-carboxylate (example A prepared in the same as described for step 241 (a)) 1.0 g (3.7 mmol) dissolved in 25 mL MeOH gt; NaOH &lt; / RTI &gt; The reaction was stirred at room temperature for 5 hours and then the solvent was removed in vacuo. The reaction residue was extracted with ethyl acetate (2 x 50 mL) and 1N HCl. The organic layer was collected, dried over NaS ₂ O ₄ , filtered and concentrated in vacuo to afford 833 mg (89%) of 4-bromo-5-methylthiothiophene-2-carboxylic acid as a white solid.

(b) 5-Methylthio-4- (phenylsulfonyl) thiophene-2-carboxylic acid:

To an oven-dried round bottom flask equipped with a stir bar was added 100 mg (0.39 mmol) of 4-bromo-5-methylthiophene-2-carboxylic acid (prepared as in the previous example). The flask was purged with anhydrous argon and anhydrous tetrahydrofuran (3 mL) was added. The solution was then cooled to-78 C and then 511 [mu] l of tert-butyllithium (0.87 mmol, 1.7 M in tetrahydrofuran) was added. After stirring the mixture for 45 minutes, 77 mg (0.39 mmol) of fluorinated benzenesulfonyl was added and the resulting reaction was allowed to warm to room temperature. The reaction was stirred for 12 h and then quenched with H ₂ O cautiously. The solvent was removed in vacuo and the reaction residue was extracted with ethyl acetate (2 x 50 mL) and 1N HCl. Collect the organic layer, Na ₂ was dried by filtration over SO _4, and concentrated in vacuo to give a solid 130 mg. This solid was used in the next step without further purification.

(c) Methyl 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxylate: To a solution of 25 mg of the mixture of the previous step dissolved in 3 mL of MeOH was added trimethylsilyldiazomethane (0.79 mmol, 2 M solution in water) was added dropwise and the resulting reaction was stirred for 1 hour. The solvent was removed in vacuo. The remaining residue was purified on a 10-g silica SPE column with a gradient of 50-100% ethyl acetate-hexane to give 13.8 mg of methyl 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxylate. Mass spectrum (ESI, m / z): C 13 H 12 O 4 Calcd 329.0 (M + H) for S _2, 329.0 experimental values.

(d) 5-Methylthio-4- (phenylsulfonyl) thiophene-2-carboxymidine trifluoroacetate: In the same procedure as in the step b) of Example 257, methyl 5-methylthio-4- Carboxylate (prepared as in the previous step), 20 mg (0.376 mmol) of ammonium chloride and 0.176 mL (2.0 M in toluene, 0.353 mmol) of trimethylaluminum And 3 mL anhydrous toluene and run on a Rainin SD-1 Dynamax system using a gradient from 30% MeOH / 0.1% TFA in water to 100% MeOH and a flow rate of 50 mL / -Inch C18 reverse phase Dynamax 60A column to give 2.3 mg of 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxidine. _{^{1 H-NMR (CD 3 OD}} , 400MHz): δ 8.42 (s, 1H), 8.04 (m, 2H), 7.70 (m, 2H), 7.62 (m, 1H) and 2.70 (s, 3H). Mass spectrum (ESI, m / z): Theoretical value for C ₁₂ H ₁₂ N ₂ O ₂ S ₃ 31.0 (M + H), found 313.2.

Example 209

Tablet manufacture

Tablets each containing 25.0 mg, 50.0 mg and 100.0 mg of the following active compounds a and b were prepared as illustrated below:

a. 4- (4-methylthiazol-2-yl) -5-methylthiothiophene-2-carboxidine

b. 4- [4- (4-phenylphenyl) thiazol-2-yl] -5-methylthiothiophene-2-

Single dose tablets containing 25 mg to 100 mg of active compound Amount - mg Active compound 25.0 50.0 100.00 Microcrystalline cellulose 37.25 100.0 200.0 Modified food corn starch 37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5

Some of the active compound, cellulose and corn starch were mixed together and then granulated with 10% corn starch paste. The granules thus produced were sieved, dried and blended with the remaining corn starch and magnesium stearate. The granules thus prepared were then compression molded into tablets each containing 25.0 mg, 50.0 mg and 100 mg of active ingredient per tablet.

Example 291

Intravenous solution manufacturing

An intravenous dosage form of the indicated active compound was prepared as follows.

Active compound 0.5 mg to 10.0 mg Sodium citrate 5 mg to 50 mg Citric acid 1 mg to 15 mg Sodium chloride 1 mg to 8 mg Water for injection (USP) Up to 1 ml

Using this amount, the active compound is reacted at room temperature with sodium chloride, sodium chloride, sodium chloride, sodium chloride, sodium chloride, sodium chloride, sodium chloride, sodium chloride, sodium chloride and sodium chloride in water for injection (USP, 1995, United States Pharmacopoeia, page 1636, United States State Pharmacopoeial Incorporated, Rockville, Md. Citric acid and sodium citrate.

Example 292

Inhibition of purified enzyme in vitro

Reagents: All buffer salts were purchased from Sigma Chemical Company (St. Louis, Mo.), the highest purity commercially available. N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride (Sigma B2291), Np-tosyl- N-succinyl-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) and N-CBZ-Val-Gly-Arg-p Nitroanilide (Sigma C7271) was purchased from Sigma. (BACHEM L-1720) and N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide Bachem (King of Prussia, Pennsylvania, USA).

Human α-thrombin, human Xa factor, and human plasmin were purchased from Enzyme Research Laboratories, Warth Bend, Indiana, USA. Small alpha-chymotrypsin (Sigma C4129), small trypsin (Sigma T8642) and human kidney cell eukinase (Sigma U5004) were purchased from Sigma. Human white blood cell elastase was purchased from Elastin Products (Pacific, MO).

K _i measurements: All assays are based on the performance of the test compound to inhibit the enzyme catalytic hydrolysis of the peptide p-nitroanilide substrate. In a typical K _i measurement, the substrate is prepared in DMSO and diluted with assay buffer (pH 7.5) consisting of 50 mM HEPES, 200 mM NaCl. The final concentrations for each substrate are described below. In general, the substrate concentration is lower than the experimentally measured value for K _m . Test compounds are prepared as 1.0 mg / mL solutions in DMSO. The diluent is made in DMSO to produce eight final concentrations, including a 200-fold concentration range. Enzyme solutions are prepared in assay buffers at the concentrations listed below.

In a typical K _i measurement, 280 μl of the substrate solution and 10 μl of the test compound solution are pipetted into each well of a 96-well plate, and the plate is thermally paralleled at 37 ° C for 15 minutes or more on a Molyklabisais plate reader. The reaction is initiated by adding 10 [mu] l aliquots of the enzyme and the absorbance increase at 405 nm is recorded for 15 minutes. Data for less than 10% of the total substrate hydrolysis is used for the calculation. The rate of change (rate of change in absorbance as a function of time) to the sample containing no test compound at all is plotted as the concentration function of the test compound divided by the rate of the sample containing the test compound. The data are linearly regression analyzed and the slope values of the lines are calculated. The reciprocal of the slope is the experimentally measured K _i value.

Thrombin: thrombin activity was analyzed as the ability to hydrolyze the substrate N-succinyl-Ala-Ala-Pro-p-nitroanilide. Substrate solutions were prepared at a concentration of 32 μM (32 μM «K _m = 180 μM) in the assay buffer. The final DMSO concentration was 4.3%. Purified human [alpha] -thrombin was diluted to a concentration of 15 nM in assay buffer. The final reagent concentrations were: [thrombin] = 0.5 nM, [substrate N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide] = 32 [mu] M.

Xa Factor [FXa]: FXa activity was analyzed as the ability to hydrolyze the substrate N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride. Substrate solution was prepared in buffer for analysis at a concentration of _{51 μM (51 «K m =} 1.3 mM). The final DMSO concentration was 4.3%. Lt; RTI ID = 0.0 &gt; 300 nM &lt; / RTI &gt; in buffer for analysis of purified human X factor. The final reagent concentrations were as follows: [FXa] = 10 nM, [N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride] = 51 μM.

Plasmin: Plasmin activity was analyzed as the ability to hydrolyze Np-tosyl-Gly-Pro-Lys-p-nitroanilide. Substrate solutions were prepared at 37 μM (37 μM «K _m = 243 μM) in the assay buffer. The final DMSO concentration was 4.3%. The purified human plasmin was diluted to 240 nM in assay buffer. The final reagent concentrations were as follows: [Plasmin] = 8 nM, [Np-tosyl-Gly-Pro-Lys-p-nitroanilide] = 37 μM.

Chymotrypsin: chymotrypsin activity was analyzed as the ability to hydrolyze N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. Substrate solutions were prepared at a concentration of 14 μM (14 μM «K _m = 62 μM) in the assay buffer. The final DMSO concentration was 4.3%. Purified sonicated chymotrypsin was diluted in assay buffer to a concentration of 81 nM. The final reagent concentrations were: [chymotrypsin] = 2.7 nM, [N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide] = 14 μM.

Trypsin: trypsin activity was analyzed as the ability to hydrolyze N-benzoyl-Phe-Val-Arg-p-nitroanilide. Substrate solutions were prepared at a concentration of 13 μM (13 μM «K _m = 291 μM) in the assay buffer. The final DMSO concentration was 4.3%. Purified trypticin was diluted to 120 nM in assay buffer. The final reagent concentrations were: [trypsin] = 4 nM, [N-benzoyl-Phe-Val-Arg-p-nitroanilide] = 13 [mu] M.

Elastase activity : Elastase activity was analyzed as the ability to hydrolyze N-succinyl-Ala-Pro-Val-p-nitroanilide. Substrate solution was prepared in buffer for analysis at a concentration of _{19 μM (19 μM «K m} = 89 μM). The final DMSO concentration was 4.3%. Purified human leukocyte elastase was diluted in assay buffer to a concentration of 750 nM. The final reagent concentrations were: [Elastase] = 25 nM, [N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide] = 19 [mu] M.

The urokinase: urokinase activity was analyzed as the ability to hydrolyze N-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solution was prepared in buffer for analysis at a concentration of _{100 μM (100 μM «K m} = 1.2 mM). The final DMSO concentration was 4.3%. The purified human kidney urokinase was diluted in the assay buffer to a concentration of 1.2 μM. The final reagent concentrations were: [urokinase] = 40 nM, [N-CBZ-Val-Gly-Arg-p-nitroanilide] = 100 mM.

The results of the exemplary analysis are shown in the following table.

Protease inhibition data Protease K _i (μM) Example No. Trypsin 0.858 8 Trypsin 0.474 52 Xa factor 2.73 94 Xa factor 3.00 119 Chymotrypsin 4.90 11 tPA 9.49 One Plasmin 7.31 12 C1S 0.940 283

In addition, the following compounds have a K _i ranging from 0.016 to 3.5 μM against uPA.

Examples 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.

According to the results, the compounds of the present invention are inhibitors of proteases including urokinase.

It will be apparent to those skilled in the art that the present invention may be practiced otherwise than with the scope of the invention or any embodiment thereof, I think. All patents and publications cited herein are incorporated by reference in their entirety.

Claims (76)

Claims 1. A compound of formula (I), solvate, hydrate or pharmaceutically acceptable salt thereof, Formula I Wherein, X is O, S or NR ⁷ where R ⁷ is hydrogen, alkyl, aralkyl, hydroxy (C _2-4 ) alkyl, or alkoxy (C _2-4 ) Y is a direct covalent bond, CH ₂ or NH, Z is NR ⁵ R ^6, (in the stage, when Z is hydrogen or alkyl and Y is NH Im) 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 _1-3 alkoxy, R ² and R ³ are independently i. Hydrogen, Ii. halogen, Iii. Hydroxy, Iv. Nitro, V. Cyano, Vi. Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycloamino, diheterocycloamino, Alkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, alkylsulfonylamino, Amino, di (aralkylsulfonyl) amino, di (aralkylsulfonyl) amino, di (arylsulfonyl) amino, di (heteroarylsulfonyl) amino, formylamino, alkanoylamino, Heteroarylamino, H (S) CNH-, or thioacylamino, wherein aryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, Any of the groups-containing heteroaryl which may be substituted optionally may be substituted, but any of the groups containing heterocyclic ring optionally on an aromatic ring), Ⅶ. Monoalkylaminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl, Ⅷ. Aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl, Ⅸ. Monoarylaminocarbonylamino, monoaralkylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, monoaralkylaminocarbonylamino, diaralkylaminocarbonylamino, diarylaminocarbonylamino, X. Monoalkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy or diaralkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, Xi. Monoalkylaminosulfonyl, dialkylaminosulfonyl, monoarylaminosulfonyl, diarylaminosulfonyl, monoaralkylaminosulfonyl or diaralkylaminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, Xii. Alkoxy or alkylthio wherein the alkyl portion of each group may be optionally substituted, 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, aralkylsulfonyl, arylsulfonyl or heteroarylsulfonyl wherein the aryl portion of each group may be optionally substituted, Xvi. Alkenyl or alkynyl, Ⅹⅶ. Optionally substituted aryl, Ⅹⅷ. Optionally substituted alkyl, Ⅹⅸ. Optionally substituted aralkyl, Xx. An optionally substituted heterocycle, or Xxi. Optionally substituted cycloalkyl, R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C _2-10 ) alkyl, dialkylamino (C _2-10 ) Amino, alkoxy, hydroxy or -CO ₂ R ^W , wherein R ^W is alkyl, cycloalkyl, phenyl, benzyl, Wherein R ^d and R ^e are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, or phenyl, and R ^f is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, or phenyl , R ^g is hydrogen, C _1-6 alkyl, C _2-6 alkenyl or phenyl and R ^h is aralkyl or C _1-6 alkyl, However, R ² or at least one of R ³ is (a) optionally substituted alkyl groups, preferably C ₁ -C ₆ alkyl, more preferably C ₁ -C ₃ , (b) alkoxy, aryloxy, alkylthio or arylthio, any of which is optionally substituted, (c) optionally substituted C ₆ -C ₁₄ aryl, or optionally substituted aralkyl, except when R ¹ and R ² are both hydrogen or methyl and R ³ is not nitrophenyl or aminophenyl, (d) optionally substituted heterocycle, and (e) optionally substituted cycloalkyl &Lt; / RTI &gt; 2. A compound according to claim 1 wherein R ² or R ³ is alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl wherein the alkyl moiety of the alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl is optionally substituted with halogen, Thiol, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, Aryloxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy , Alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, Alkylthio, and arylthio, each of which may be optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Lt; RTI ID = 0.0 &gt; 1 to 4 &lt; / RTI &gt; 2. A compound according to claim 1, wherein R &lt; ³ &gt; is optionally substituted alkyl or alkylthio. 3. The method of claim 2, wherein one to four substituents include chloro, hydroxy, amino, mono (C _1-4) alkylamino, di (C _1-4) alkylamino, formylamino, C _2-6 acyl Amino, aminocarbonyl, C _2-8 aminoacyl, C _2-6 thioacylamino, aminothiocarbonyl, C _2-8 aminothioacyl, C _1-6 alkoxy, C _6-14 aryloxy, carboxy, carboxy (C _1-6 ) alkyl, C _2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C _1-6 alkylthio, C _6-14 arylthio, C _1-6 aralkylsulfonylamino, C _1-6, arylsulfonyl, amino, monoalkylamino-carbonyl-oxy, di-alkyl-amino-carbonyl-oxy, mono- (C _6-10) aryl-amino-carbonyl-oxy, di (C _6-10) aryl-amino-carbonyl-oxy, aralkyl mono- wherein it is selected from the group consisting of _10-aryloxy carbonyl amino carbonyl-carbonyl-oxy Kiel, Dia ralkil oxy-carbonyl, C _1-6 alkoxycarbonyl, amino, C _7-15 aralkoxy when carbonyl amino, and C ₆ Ha Is a compound. The compound of claim 1, wherein at least one of R ² and R ³ is selected from the group consisting of halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, Amino, amino, aminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, di Monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonyl Alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonyl Aralkyloxy, arylthio, aralkyl, aryloxy, aralkylthio, alkylthio, arylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, , Aralkylsulfonyl, arylsulfonyl, heterocycle or heterocycloalkyl. The method of claim 5, wherein one to four substituents include chloro, hydroxy, amino, mono (C _1-4) alkylamino, di (C _1-4) alkylamino, formylamino, C _2-6 acyl Amino, amino carbonyl, C _2-8 aminoacyl, C _3-7 cycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _6-14 aryloxy, carboxy, carboxy (C _1-6 ) C _2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C _1-6 alkylthio, C _6-14 arylthio, C _6-14 aryl, tetrazolyl, thienyl, Propylenedioxy, C _1-6 alkylsulfonylamino, C _1-6 aralkylsulfonylamino, C _1-6 arylsulfonylamino, monoalkylaminocarbonyl Mono-C _6-10 arylaminocarbonyloxy, di-C _6-10 arylaminocarbonyloxy, monoaralkylcarbonyloxy, diaralkylcarbonyloxy, C _1-6 alkoxycarbonyl amino, C _7-15 aralkoxy when carbonyl amino, C ₆ - ₁₀ Aryloxy-carbonyl-amino, thio C _2-6 acylamino, amino-carbonyl and C _2-8 alkylthio compound being selected from the group consisting of amino-acyl thio. The method according to claim 1, X is sulfur or oxygen, Y is a covalent bond or -NH-, R &lt; ¹ &gt; is hydrogen, amino, hydroxy or halogen, One of R ² or R ³ is hydrogen, C _1-6 alkylthio, C _1-6 alkyl or C _1-6 alkoxy, R ² or R ³ is selected from the group consisting of aminoacyl, acylamino, aminosulfonyl, sulfonylamino, aminocarbonylamino, alkoxycarbonylamino, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted benzo Thienyl, optionally substituted furanyl, optionally substituted pyrazolyl, or optionally substituted pyridyl. 8. A compound according to claim 7 wherein R &lt; ⁴ &gt;, R &lt; ⁵ &gt; and R &lt; ⁶ &gt; are hydrogen. The method according to claim 1, X is sulfur or oxygen, Y is a covalent bond or -NH-, Z is NR &lt; ⁵ &gt; R &lt; ⁶ & R &lt; ¹ &gt; is hydrogen, amino, hydroxy or halogen, R ² and R ³ is one of hydrogen, C _1-6 alkylthio, C _1-6 alkyl or C _1-6 alkoxy, R &lt; ² &gt; and R &lt; ³ &gt; Wherein Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, tetrazolyl, Wherein R is selected from the group consisting of pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 2-O'Neill and imidazolidin-2 sleepy and O'Neill, R ⁸ and R ⁹ is hydrogen, halogen, amino, mono (C _1-4) alkylamino, arylamino, mono C _6-14 arylamino, di (C _6-14) aryl, amino, mono (C _6-14) aralkyl (C _1-6) alkylamino, di (C _6-14) aralkyl (C _1-6) alkylamino, di (C _1-4) alkylamino , C _2-6 acylamino, aminocarbonyl, C _2-8 aminoacyl, C _2-6 thioacylamino, aminothiocarbonyl, C _2-8 aminothioacyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, carboxy, carboxy (C _1-6) alkyl, C _{2 -8} alkoxycarbonyl, nitro, cyano, trifluoromethyl, tetrazolyl, thienyl, C _6-14 aryloxy, C _1-6 alkylthio, C _6-14 arylthio, C _6-14 aryl, and C _{6-14 ares} (C _1-6) independently selected from the group consisting of alkyl, the aryl portion of the groups any of the groups are halogen, hydroxy, amino, mono (C _1-4) alkylamino, di (C _1-4) alkylamino, formylamino, C _1-4 acylamino, C _1-4 acyl amino, mono (C _1-4) alkylamino-carbonyl, di (C _1-4) alkylamino-carbonyl, thio carbonyl-amino, thio C _1-4 acylamino, amino-thiocarbonyl, C _1-4 alkoxy, C _6-10 aryloxy, amino-carbonyl-oxy, mono (C _1-4) alkyl-amino-carbonyl-oxy, di ( C _1-4) alkyl-amino-carbonyl-oxy, mono- (C _6-10) aryl-amino-carbonyl-oxy, di (C _6-10) aryl-amino-carbonyl-oxy, mono- (C _4-12) aralkyl, aminocarbonyl-oxy , Di (C _4-12 ) aralkylaminocarbonyloxy, C _1-4 alkylsulfonyl , C _6-10 arylsulfonyl, (C _7-12 ) aralkylsulfonyl, C _1-4 alkylsulfonylamino, C _6-10 arylsulfonylamino, (C _7-12 ) aralkylsulfonylamino, C _{1 -4} alkoxycarbonyl, amino, C _7-12 aralkoxy when amino carbonyl, C _6-10 aryloxy carbonyl amino, mono (C _1-4) alkyl-amino-thiocarbonyl, di (C _1-4) alkylamino Thiocarbonyl, C _7-12 aralkoxy, carboxy, carboxy (C _1-4 ) alkyl, C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, 1 to 3 independently selected from the group consisting of C _1-4 alkylthio, C _6-10 arylthio, 3,4-methylenedioxy, 3,4-ethylenedioxy and 3,4-propylenedioxy Lt; / RTI &gt; may optionally be substituted with a substituent, R ⁴ , R ⁵ and R ⁶ are independently hydrogen, C _1-4 alkyl, amino, C _1-4 alkoxy or hydroxy &Lt; / RTI &gt; 10. The method of claim 9, X is sulfur, Y is a covalent bond, Z is NR &lt; ⁵ &gt; R &lt; ⁶ & R &lt; ¹ &gt; is hydrogen, R ² is as defined in formula II Wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, chloro, hydroxy, C _1-4 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, C _6-10 aryl optionally substituted with one to three substituents independently selected from the group consisting of 4-methylenedioxy and 3,4-propylenedioxy, R ³ is methylthio or methyl, R &lt; ⁴ &gt;, R &lt; ⁵ &gt; and R &lt; ⁶ &gt; are hydrogen. The method according to claim 1, X is sulfur, Y is a direct covalent bond, Z is NR &lt; ⁵ &gt; R &lt; ⁶ & R &lt; ¹ &gt; is hydrogen, R ² is alkyl, aryl (alkyl), alkylsulfonyl, -SO ₂ -alkyl, amido, amidino or Formula II Wherein Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl and R ⁸ and R ⁹ are independently selected from hydrogen, carboxy, phenyl, naphthyl, alkyl, Alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, heteroaryl, heteroaryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, A substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkylthio group, And each of said one to three substituents may be optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkyl, halogen, alkyl, amino, acetyl, hydroxy , Dialkylamino, dial And it may be further optionally substituted with one or more selected from an aryl or an aryl group), - Kill aminoacyl, monoalkylamino, acyl, -SO ₂ - heteroaryl, -SO ₂ R ³ is -SO ₂ -alkyl, trifluoromethyl, S (O) -alkyl, hydrogen, alkoxy, alkylthio, alkyl, aralkylthio, R &lt; ⁴ &gt;, R &lt; ⁵ &gt; and R &lt; ⁶ &gt; are hydrogen. 12. A compound according to claim 11, wherein Ar is thiazolyl and at least one of R &lt; ¹⁷ &gt; and R &lt; ¹⁸ &gt; is phenyl. The compound according to claim 11 or 12, wherein the thiazolyl is thiazol-2-yl. 14. The compound of claim 13, wherein R &lt; ² &gt; is a 4-phenylthiazol-2-yl group and the phenyl group is optionally substituted. 13. A compound according to claim 11 or 12, wherein said thiazolyl is thiazol-4-yl. 16. The compound of claim 15, wherein R &lt; ² &gt; is a 2-aminothiazol-4-yl group. 12. The compound of claim 11, wherein the oxazolyl is oxazol-2-yl. 12. The compound of claim 11, wherein the oxazolyl is oxazol-4-yl. 12. Compounds according to claim 11, wherein R &lt; ³ &gt; is methylthio. Claims 1. A compound of formula (I), solvate, hydrate or pharmaceutically acceptable salt thereof, Formula I Wherein, X is sulfur, Y is a covalent bond, Z is NR &lt; ⁵ &gt; R &lt; ⁶ & R &lt; ¹ &gt; is hydrogen, R ² is as defined in formula II Wherein Ar is phenyl, thiazolyl, or oxazolyl, and R ⁸ and R ⁹ are _{independently} selected from the group consisting of hydrogen, and chloro, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, phenyl, , C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3,4-methylenedioxy and 3,4-propylenedioxy, R ³ is methylthio, R ⁴ , R ⁵ and R ⁶ are hydrogen. Claims 1. A compound of formula (I), solvate, hydrate or pharmaceutically acceptable salt thereof, Formula I Wherein, X is sulfur, Y is a covalent bond, R &lt; ¹ &gt; is hydrogen, R ² is as defined in formula II Wherein Ar is thiazolyl and R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen and C _6-10 aryl substituted with a sulfonamide group, R ³ is methylthio, R ⁴ , R ⁵ and R ⁶ are hydrogen. 22. The compound of claim 21, wherein the sulfonamide group is a C _6-10 arylsulfonamide, an alkylsulfonamide, an alkoxysulfonamide or a heteroarylsulfonamide. The method of claim 22, wherein the sulfonamide group is selected from the group consisting of 4-methylphenylsulfonamide, methylsulfonamide, phenylsulfonamide, trifluoromethylsulfonamide, 4-fluorophenylsulfonamide, 4- chlorophenylsulfonamide, (5-chlorothiophene) sulfonamide, butylsulfonamide, and isopropylsulfonamide (4-methoxyphenyl) sulfonamide, &Lt; / RTI &gt; Claims 1. A compound of formula (I), solvate, hydrate or pharmaceutically acceptable salt thereof, Formula I Wherein, X is sulfur, Y is a covalent bond, Z is NR &lt; ⁵ &gt; R &lt; ⁶ & R &lt; ¹ &gt; is hydrogen, R ² is as defined in formula II (Wherein, Ar is a thiazolyl, R ⁸ and R ⁹ is hydrogen and -OCH ₂ C (O) - alkoxy, -OCH ₂ C (O) - amino, -OCH ₂ C (O) -NH- alkyl Or C _6-10 aryl substituted with a group selected from -OCH ₂ C (O) -N (alkyl) ₂ , R ³ is methylthio, R ⁴ , R ⁵ and R ⁶ are hydrogen. Claims 1. A compound of formula &lt; RTI ID = 0.0 &gt; (III) (III) Wherein, A is methylthio or methyl, G 'is -O-, -S-, -NH- or a covalent bond, n is an integer of 1-10, m is an integer 0-1, R ' and R " are independently selected from hydrogen, alkyl, aryl or aralkyl, or R ' and R & To form a heterocyclic ring. The method of claim 25, wherein said 3-8 membered heterocyclic ring may contain a further N atom, said additional N atom of hydrogen, C _1-4 alkyl, C _6-10 aryl, C _6-10 ar ( C _1-4 ) alkyl, C _1-6 alkoxy, alkoxycarbonyl or benzyloxycarbonyl. 26. The compound of claim 25, wherein the 3-8 membered heterocyclic ring is piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl, the rings being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, Alkylamino, alkoxy, alkoxy, aryloxy, aminocarbonyloxy, monoalkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, Monoarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, Alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothio Is further optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, alkyl, alkoxy, carbonyl, alkoxy, carbonyl, alkoxy, carbonyl, alkoxy, carbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio &Lt; / RTI &gt; 12. The method of claim 11, Ar is thiazolyl, One of R ⁸ and R ⁹ is hydrogen and the other of R ⁸ and R ⁹ is an amino group and the amino group is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, , Monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy , Monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonyl Amino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxy Sialic Kiel, alkoxycarbonyl, alkoxycarbonyl-alkyl, nitro, cyano, tri compounds, characterized in that optionally substituted with a methyl, alkylthio and arylthio fluoro. A compound of formula IV: Formula IV Wherein, A is methylthio or methyl, R "'is hydrogen, C _6-14 aryl, C _1-6 alkyl, alkoxy (C _6-14) aryl, amino (C _6-14) aryl, monoalkylamino (C _6-14) aryl, dialkylamino (C _6-14) aryl, C _6-10 ahreu (C _1-6) alkyl, C _1-6 alk (C _6-14) aryl, amino (C _1-6) alkyl, monoalkylamino (C _{1- 6)} alkyl, dialkylamino (C _1-6) alkyl, hydroxy (C _6-14) aryl, or hydroxy (C _1-6) alkyl, any of which is halogen, hydroxy, amino, mono Alkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyl Monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, alkylaminocarbonyloxy, Arylsulfonyl, Alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl Optionally substituted by one to four nonhydrogen substituents selected from the group consisting of alkyl, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, aryloxy, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio. 30. The method of claim 29, 4- {2 - [(3-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 4- {2 - [(4-methoxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 4- (2 - {[4- (dimethylamino) phenyl] amino} (1,3-thiazol-4-yl) Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxidine, 4- {2 - [(diphenylmethyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 5-methylthio-4- {2 - [(3-phenylpropyl) amino] (1,3-thiazol-4-yl)} thiophene- 5-methylthio-4- {2 - [(2,4,5-trimethylphenyl) amino] (1,3-thiazol-4-yl)} thiophene- 4- {2 - [(2-fluorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboxamide, 4- {2- [ 4- (2 - {[2- (methylethyl) phenyl] amino} (1,3-thiazol-4-yl)) - 5- 4- (2 - {[4- (phenylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) thiophene- 4- {2 - [(2-bromophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 4- {2 - [(2,6-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboximidine, 4- {2- [ Amino] (1,3-thiazol-4-yl)} thiophene-2-carboximidine, 4- {2 - [(2,3-dichlorophenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 5-methylthio-4- {2- [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4- yl)} thiophene- 5-methylthio-4- {2 - [(2-piperidylethyl) amino] (1,3- 4- (2 - {[(4-methylphenyl) methyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene- Amino] (1,3-thiazol-4-yl)) - 5-methylthiothiophene-2-carboxamide, 4- (2 - {[4-phenoxyphenyl] amino} (1,3-thiazol-4-yl)) - 5-methylthiothiophene- 4- (2 - {[4- (phenylamino) phenyl] amino} (1,3-thiazol-4-yl)) thiophene- 4- (2 - {[4-benzylphenyl] amino} (1,3-thiazol-4-yl)) thiophene- (3-thiazol-4-yl)) thiophene-2-carboxamide, 5-methylthio-4- [2- (3-quinolylamino) (1,3-thiazol-4-yl)] thiophene- 5-methylthio-4- [2- (2-naphthylamino) (1,3-thiazol-4-yl)] thiophene- 5-ylamino) (1,3-thiazol-4-yl)] - 5-methylthiothiophen-2 - carboxamidine, Amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene-2-carboximidine, 4- {2 - [(7-bromo- 4- {2 - [(4-cyclohexylphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 4- (2 - {[4- (phenyldiazenyl) phenyl] amino} (1,3-thiazol-4-yl)) thiophene- 5-methylthio 4- (2- {[3- (hydroxymethyl) phenyl] amino} (1,3-thiazol-4-yl)) - thiophene- Methyl} phenyl} amino) (1,3-thiazol-4-yl)] - 5-methylthiothiophene-2-carboxidine , 4- {2 - [(3-hydroxyphenyl) amino] (1,3-thiazol-4-yl)} - 5-methylthiothiophene- 4- (2 - {[4- (carbamoylmethoxy) phenyl] amino} (1,3-thiazol-4-yl)) - 5- Methyl-4- {2 - [(3,4,5-trimethoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- 5-Methyl-4- {2 - [(4-phenoxyphenyl) amino] (1,3-thiazol-4-yl)} thiophene- 5-methyl-4- [2- (phenylamino) (1,3-thiazol-4-yl)] thiophene- 5-yl (1,3-thiazol-2-yl)) - 5-methylthiothiophene-2-carboxidine &Lt; / RTI &gt; The method according to claim 1, 4- [4- (4-chlorophenyl) thiazol-2-yl] -5-methylthiothiophene- 4-phenyl-5-methylthiothiophene-2-carboxymidine, 4- [4- (2,4-dichlorophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (4-methylthiazol-2-yl) -5-methylthiothiophene- 4- [4- (3-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3-hydroxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (4-phenylthiazol-2-yl) -5-methylthiothiophene-2-carboxidine, 4- [4- (4-nitrophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3,4-propylene dioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (4- (naphth-2-yl) thiazol-2-yl] -5-methylthiothiophene- 4-isopropylsulfonyl-5-methylthiothiophene-2-carboxidine &Lt; / RTI &gt; or a hydrate, solvate or pharmaceutically acceptable salt thereof. 12. The method of claim 11, 4-phenyl-5-methylthiothiophene-2-carboxymidine, 4- [4- (4-chlorophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (4-phenylphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3-hydroxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (4-phenylthiazol-2-yl) -5-methylthiothiophene-2-carboxidine, 4- [4- (4-nitrophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3,4-ethylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (4-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3,4-propylene dioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4-isopropylsulfonyl-5-methylthiothiophene-2-carboxymidine, 4- (4-methylthiazol-2-yl) -5-methylthiothiophene- 4- [4- (2,4-dichlorophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (2-naphthylthiazol-2-yl) -5-methylthiothiophene-2- 4- [4- (4-chloro-3-methylphenyl) thiazol-2-yl] -5- methylthiothiophene- 4- (5-methyl-4-phenylthiazol-2-yl) -5-methylthiothiophene- 4- [4- (4-chloro-3-nitrophenyl) thiazol-2-yl] -5- methylthiothiophene- 4- (5-phenyloxazol-2-yl) -5-methylthiothiophene-2- 5-methylthiophene-2-carboxamide, 4- [4- (3-fluoro-5-trifluoromethylphenyl) Methyl-thiazol-2-yl] -5-methylthiothiophene-2-carboximidine, 4- [ 4- [4- (3-fluoro-5-trifluoromethylphenyl) thiazol-2-yl] -5- methylthiothiophene- 4- [4- (3-bromophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3,4-methylenedioxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (4-methylphenyl) thiazol-2-yl] -5-methylthiothiophene- 4-f4- (3,5-bis (trifluoromethyl) phenyl) thiazol-2-yl] -5- methylthiothiophene- 4- [4- (2-methoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (4-phenylimidazol-2-yl) -5-methylthiothiophene-2-carboxidine, 4- [4- (2,4-dimethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (4-benzylthiazol-2-yl) -5-methylthiothiophene-2- 4- [4- (3,4-dichlorophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3-methylphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3,5-dimethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (2-methylphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (2,5-dimethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- (4,5-diphenyl) thiazol-2-yl-5-methylthiothiophene- 4- (2-phenyl) thiazol-4-yl-5-methylthiothiophene- 4- [4- (2-chloro-3-pyridyl) thiazol-2-yl] -5- methylthiothiophene- 4- [4- (phenoxymethyl) thiazol-2-yl] -5-methylthiothiophene-2- 4- (4-cyclohexylthiazol-2-yl) -5-methylthiothiophene-2- 4- [4- (4-chlorophenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (2-hydroxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (3-Trifluoromethoxyphenyl) thiazol-2-yl] -5-methylthiothiophene- 4- [4- (2-chloro-4-pyridyl) thiazol-2-yl] -5- methylthiothiophene- 4- (5-phenyl-2-pyridyl) -5-methylthiothiophene- 4- [4- (2-chlorophenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- [2- (3-methoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- [2- (phenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- [2- (2,5-dimethoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- (2-aminothiazol-4-yl) -5-methylthiothiophene-2- 4- [2- (4-chloro-2-methylphenylamino) thiazol-4-yl] -5- methylthiothiophene- 4- [2- (4-dimethylaminophenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- [2- (4-methoxyphenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- [4- (4-hydroxy-3-methoxyphenyl) thiazol-2-yl] -5- methylthiothiophene- 4- [4- (3-hydroxy-4-methoxyphenyl) thiazol-2-yl] -5- methylthiothiophene- 4- [2- (2-fluorophenylamino) thiazol-4-yl] -5-methylthiothiophene- 4- [2- (2,4,5-trimethylphenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (3-chloro-2-methylphenyl) aminothiazol-4-yl] -5- methylthiothiophene- 4- [2- (2-isopropylphenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (4-benzyloxyphenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (2-bromophenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (2,5-dichlorophenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (2-bromo-4-methylphenyl) aminothiazol-4-yl] -5- methylthiothiophene- 4- [2- (2,3-dichlorophenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (3,4,5-trimethoxyphenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (2-piperidinylethyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- [2- (4-methylphenyl) aminothiazol-4-yl] -5-methylthiothiophene- 4- (4-phenyloxazol-2-yl) -5-methylthiothiophene-2- 4- [2- (diphenylmethyl) aminothiazol-4-yl] -5-methylthiothiophene-2- carboximidine, and 4- [2- (3-phenylpropyl) aminothiazol-4-yl] -5-methylthiothiophene- &Lt; / RTI &gt; or a solvate or a pharmaceutically acceptable salt thereof. The present invention provides a method for treating a disease selected from benign prostatic hypertrophy, prostate cancer, tumor metastasis, restenosis, and psoriasis by administering an effective amount of a compound of formula (I), a solvate, hydrate or a pharmaceutically acceptable salt thereof &Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; Formula I Wherein, X is oxygen, sulfur or NR &lt; ⁷ &gt; 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 &lt; ⁵ &gt; R &lt; ⁶ & R ¹ is hydrogen, amino, hydroxy, halogen, cyano, C _1-4 alkyl or -CH ₂ R, wherein R is hydroxyamino or C _1-3 alkoxy, R ² and R ³ are independently i. Hydrogen, Ii. halogen, Iii. Hydroxy, Iv. Nitro, V. Cyano, Vi. Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, alkarylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryl Alkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, formylamino, acylamino, H (S) CNH- or thioacylamino, Ⅶ. Aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, arylaminocarbonyl or aminoacyl, Ⅷ. Aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl, Ⅸ. Monoarylaminocarbonylamino, monoaralkylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, monoaralkylaminocarbonylamino, diaralkylaminocarbonylamino, diarylaminocarbonylamino, X. Monoalkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy or diaralkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, Xi. Monoalkylaminosulfonyl, dialkylaminosulfonyl, monoarylaminosulfonyl, diarylaminosulfonyl, monoaralkylaminosulfonyl or diaralkylaminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, Xii. Alkoxy or alkylthio wherein said alkyl portion of alkoxy or alkylthio may be optionally substituted, Xiii. Aralkyloxy, aralkylthio or arylthio (the aryl portion of the aralkoxy, aryloxy, aralkylthio or arylthio group may be optionally substituted), aralkoxy, Xiv. Alkylsulfonyl (the alkyl portion may be optionally substituted), Xv. Aralkylsulfonyl or arylsulfonyl, wherein the aryl portion of each group may be optionally substituted, Xvi. Alkenyl or alkynyl, Ⅹⅶ. Optionally substituted aryl, Ⅹⅷ. Optionally substituted alkyl, Ⅹⅸ. Optionally substituted aralkyl, Xx. An optionally substituted heterocycle, or Xxi. Optionally substituted cycloalkyl, R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C _2-10 ) alkyl, dialkylamino (C _2-10 ) Carboxyalkyl, cyano, amino, alkoxy or hydroxy. 34. The method of claim 33, wherein said effective amount is from about 0.01 mg to about 50 mg per kg of body weight per day. 35. The method of claim 34, wherein said effective amount is from about 0.1 mg to about 20 mg per kg of body weight per day. 11. A pharmaceutical composition comprising a compound of claims 1 or 11, a pharmaceutically acceptable ester, salt or ether thereof, and a pharmaceutically acceptable carrier. 37. The pharmaceutical composition according to claim 36, wherein said compound is present in an amount of 0.01 mg to 100 mg. C-1 estetase, C-3 convertase, acrosine, thrombin, europaea, leukocyte neutrophil elastase, chymotrypsin, trypsin, pancreatic elastase, cathepsin G, thrombin, Thrombin, calicaine, and pepsin is contacted with the compound of claim 1 or 11. 39. The method of claim 38, wherein the protease is trypsin, chymotrypsin, plasmin or an urokinase. Treatment of adult respiratory distress syndrome, wound healing, gout, rheumatoid arthritis, reperfusion injury, atherosclerosis, recurrent stenosis, tumor formation, metastasis, emphysema, Alzheimer's disease, pancreatitis, benign prostatic hyperplasia, prostate cancer, psoriasis or Parkinson's disease Wherein the effective amount of the compound of claim 1 or 11 is administered to the patient. 37. The pharmaceutical composition according to claim 36, which is suitable for parenteral, oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or intravenous administration. A process for preparing a compound of formula (I), a solvate, hydrate or a pharmaceutically acceptable salt thereof, (a) adding a Lewis acid to a suspension of anhydrous ammonium chloride in an aprotic solvent which is stirred under an inert atmosphere at a temperature near 0 &lt; 0 &gt; C to form a mixture, (b) warming the mixture to room temperature with stirring, followed by stirring the mixture until substantially all solids are dissolved, (c) adding to said mixture a compound of formula (V) (d) refluxing the mixture for a predetermined period of time, and then cooling the mixture to room temperature Comprising the steps of: Formula I Formula V Among the above equations, X is oxygen, sulfur or NR &lt; ⁷ &gt; 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, R ¹ is hydrogen, amino, hydroxy, halogen, cyano, C _1-4 alkyl or -CH ₂ R, wherein R is hydroxyamino or C _1-3 alkoxy, R ² and R ³ are independently i. Hydrogen, Ii. halogen, Iii. Hydroxy, Iv. Nitro, V. Cyano, Vi. Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, alkarylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryl Alkylsulfonylamino, arylsulfonylamino, arylsulfonylamino, formylamino, acylamino, H (S) CNH- or thioacylamino, Ⅶ. Aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, arylaminocarbonyl or aminoacyl, Ⅷ. Aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl, ix. Monoarylaminocarbonylamino, monoaralkylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, diarylaminocarbonylamino, monoaralkylaminocarbonylamino, diaralkylaminocarbonylamino, diarylaminocarbonylamino, x. Monoalkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy or diaralkylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, diarylaminocarbonyloxy, xi. Monoalkylaminosulfonyl, dialkylaminosulfonyl, monoarylaminosulfonyl, diarylaminosulfonyl, monoaralkylaminosulfonyl or diaralkylaminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, xii. Alkoxy or alkylthio wherein said alkyl portion of alkoxy or alkylthio may be optionally substituted, xiii. Aralkoxy, aryloxy, aralkylthio or arylthio (the aryl portion of the aralkoxy, aryloxy, aralkylthio or arylthio group may be optionally substituted), xiv. Alkylsulfonyl (the alkyl portion may be optionally substituted), xv. Aralkylsulfonyl or arylsulfonyl, wherein the aryl portion of each group may be optionally substituted, x vi. Alkenyl or alkynyl, xⅶ. Optionally substituted aryl, xⅷ. Optionally substituted alkyl, xix. Optionally substituted aralkyl, xx. An optionally substituted heterocycle, or xxi. Optionally substituted cycloalkyl, R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C _2-10 ) alkyl, dialkylamino (C _2-10 ) Carboxyalkyl, cyano, amino, alkoxy, hydroxy or hydrazino, R &lt; ⁸ &gt; is selected from alkyl and aryl. 43. The process according to claim 42, wherein the Lewis acid is trimethylaluminum or triethylaluminum. 43. The process according to claim 42, wherein the aprotic solvent is selected from toluene, benzene, xylene or mesitylene. 42. The pharmaceutical composition of claim 41, wherein said compound is present in an amount of from 25 mg to 100 mg. 42. The pharmaceutical composition of claim 41, wherein said compound is present in an amount of 0.5 mg to 10 mg. 2. A compound according to claim 1, wherein X is sulfur. 2. A compound according to claim 1, wherein Y is a covalent bond. 2. A compound according to claim 1, wherein R &lt; ^{1 &gt;} is hydrogen. The method of claim 1, wherein, R ^4, R ⁵ and R ⁶ are both compounds comprising hydrogen. 2. A compound according to claim 1, wherein R &lt; ³ &gt; is methylthio or methyl. The compound of claim 1 wherein the aryl moiety of R ² is 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 Amino, mono (C _1-6 ) alkyl (optionally substituted with one or more substituents selected from the group consisting of _C1-6 alkyl, _C1-6 alkoxy, _C6-10 arylmethoxy, _C1-6 aminoalkyl, carboxy, 3,4-methylenedioxy, Amino, di (C _1-6 ) alkylamino, mono (C _6-10 ) arylamino, di (C _6-10 ) arylamino, C _1-6 alkylsulfonylamino, C _6-10 arylsulfonylamino, C _1-6 alkylamino, C _1-8 acylamino, C _1-8 alkoxycarbonyl, C _1-6 alkanoylamino, C _6-14 aroylamino, C _1-6 hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl and Tetrazole, and tetrazole. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; 52. The compound of claim 52, wherein any of said C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylmethoxy is optionally substituted with chloro, halogen, C _1-6 alkyl, C _1-6 alkoxy, phenyl, Wherein the compound is further substituted by one or two of hydroxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy or amino . 58. The compound of claim 52, wherein said optional substituent is thienyl further substituted with one or two of chloro, amino, methyl, methoxy or hydroxy. The compound according to claim 1, wherein R ² is C _1-6 alkylsulfonylamino, C _6-10 aryl (C _1-6 ) alkylsulfonylamino, C _6-10 aryl (C _2-6 ) alkenylsulfonylamino, C _6-10 aryl-sulfonylamino, heteroaryl sulfonyl amino, di (C _6-10 ahreu (C _1-6) alkylsulfonyl) amino, di (C _6-10 ahreu (C _2-6) alkenyl nilseol sulfonyl ) Amino, di (C _6-10 arylsulfonyl) amino or di- (heteroarylsulfonyl) amino, wherein any of said aryl or heteroaryl containing groups is optionally substituted on the aromatic ring. 56. The method of claim 55 wherein, R ² is C _6-10 aryl-sulfonylamino, di (C _6-10 arylsulfonyl) amino, C _6-10 ahreu (C _1-3) alkylsulfonyl, amino, di (C _{6 -10} aryl (C _1-3 ) alkylsulfonyl) amino or thienylsulfonylamino, wherein any of said aryl or thienyl-containing groups is optionally further substituted. The compound of claim 1, wherein R ² is selected from the group consisting of biphenylsulfonylamino, bis (biphenylsulfonyl) amino, naphth-2-ylsulfonylamino, di (naphth- (Naphth-1-ylsulfonyl) amino, 2-methylphenylsulfonylamino, di-naphthylsulfonylamino, di (4-methylphenylsulfonyl) amino, di- (2-methylphenylsulfonyl) amino, 3- methylphenylsulfonylamino, di- Amino, 4-methoxyphenylsulfonylamino, di- (4-methoxyphenylsulfonyl) amino, 4-iodophenylsulfonylamino, Dimethoxyphenylsulfonylamino, di- (2-chlorophenylsulfonyl) amino, 3-chlorophenylsulfonylamino, di- Di- (3-chlorophenylsulfonyl) 4-chlorophenylsulfonylamino, di- (phenylsulfonyl) amino, 4-tert-butylphenylsulfonylamino, di- (4-chlorophenylsulfonyl) amino, butylphenylsulfonyl) amino, 2-phenylethenylsulfonylamino or 4- (phenylsulfonyl) thien-2-ylsulfonylamino. The compound of claim 1 wherein R ² is selected from the group consisting of amino, mono (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, mono (C _6-10 ) arylamino, di (C _6-10 ) , mono (C _1-6) alkyl, mono (C _6-10) aryl, amino, mono-aralkyl (C _1-6) alkylamino, di (C _6-10) aralkyl (C _1-6) alkylamino, mono (C _1-6) alkyl, mono (C _6-10) aralkyl (C _1-6) alkylamino, mono-heteroaryl-amino, di-heteroaryl-amino, or mono- (C _1-6) alkyl and mono-heterocyclic arylamino, the aryl or Wherein any of the heteroaryl containing groups is optionally substituted on the aromatic ring. The system of claim 58 wherein, R ² is a mono (C _6-10) aryl, amino, mono (C _1-6) alkyl, mono (C _6-10) aryl, amino, mono (C _6-10) aralkyl (C _1-3 ( _C1-6 ) alkylamino, mono ( _C1-6 ) alkylmono ( _C6-10 ) aryl ( _C1-3 ) alkylamino, monoheteroarylamino or mono ( _C1-6 ) _{alkylmonoheteroarylamino} . 60. The method of claim 59 wherein, R ² is 1,3-thiazol-2-ylamino, imidazol-4-yl amino, quinolin-2-ylamino or compound, characterized in that 6-yl-amino. 58. The compound of claim 58, wherein R ² is selected from the group consisting of anilino, naphth-2-ylamino, naphth-1-ylamino, 4- (biphenyl) thiazol- 2-ylamino, 4-phenyl-5-methylthiazol-2-ylamino, 4-hydroxy-4-trifluoromethylthiazol- Phenylphenylamino, 3-fluorophenylamino, 3,4-methylenedioxyphenylamino, n-butylphenylamino, n-butylphenylamino, Methoxyphenylamino, 2-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino, 3-methoxyphenylamino, 3-methoxyphenylamino, 2- (3-fluoro-4-methylphenyl) amino, 4- (indan-5-yl) amino, benzylamino, indanyl Methylamino, 2,3-dihydrobenzofuranylmethylamino, 2-phenylimidazole 4-benzyloxyphenylamino, 4-benzyloxyphenylamino, quinolin-6-ylamino, quinolin-4-ylamino, 4-cyclohexylphenylamino, 4- (9-ethylcarbazol-2-yl) phenylamino, 4- 3-yl) amino, 4- (t-butyl) phenylamino or 4-methylthiophenylamino. The compound of claim 1, wherein R ² is alkanoylamino, alkenoylamino, aroylamino, aralanoylamino, aralkanoylamino, heteroaroylamino, or heteroarylalkanoylamino, &Lt; / RTI &gt; is optionally substituted on the ring. 63. The method of claim 62 wherein, R ² is (C _6-10) arylcarbonyl-amino, C _6-10 ahreu (C _1-3) alkyl-carbonyl-amino, C _6-10 ahreu (C _2-3) alkenyl carbonyl amino carbonyl, C _6-10 aryloxy (C _1-3) alkyl-carbonyl-amino, C _3-8 cycloalkyl-carbonyl-amino, C _1-6 alkyl-carbonyl or heteroaryl-amino carbonyl compounds, characterized in that the amino-carbonyl . 64. The method of claim 63 wherein, R ² is a furanyl-carbonyl-amino and quinolinium compounds, characterized in that carbonyl-carbonyl-amino. 64. The method of claim 63 wherein, R ² is 3-hydroxy-phenyl-carbonyl-amino, 2-phenylethenyl-carbonyl-amino, phenyl-carbonyl-amino, cyclohexyl-carbonyl-amino, 4-methyl-3-nitro-phenyl-amino-carbonyl, Furan-2-ylcarbonylamino, tert-butylcarbonylamino, 5- (3,5-dichlorophenoxy) furan-2-ylcarbonylamino, naphth-1-ylcarbonylamino, quinolin- 4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino or 3-methylphenylcarbonylamino. &Lt; / RTI &gt; The method of claim 1 wherein, R ² is a C _6-10 aryloxy, C _6-10 ahreu (C _1-6) alkoxy, C _6-10 arylsulfonyl, C _6-10 ahreu (C _1-6) alkyl sulfonic sulfonyl or C _6-10 ahreu (C _2-6) alkenyl and nilseol sulfonyl, any of these compounds, characterized in that optionally substituted on an aromatic ring. 67. The method of claim 66 wherein, R ² is a compound which is characterized in that the C _6-10 aryloxy or C _6-10 arylsulfonyl. The method of claim 67 wherein, R ² is phenoxy, naphthyloxy, phenylsulfonyl or compound, characterized in that the naphthoquinone sulfonyl tilseol. The method according to claim 1, 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxymidine, Methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboximidine, 5-methylthio-4- (3-quinolylamino) thiophene-2-carboximidine, 5-methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboximidine, 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxidine, 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- 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene- 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5- methylthiothiophene- 4- {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5- methylthiothiophene- 5-methylthio-4- (2-naphthylamino) thiophene-2-carboxymidine, 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxidine, Methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboximidine, 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2- 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboximidine, Methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxidine, 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene- 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5- methylthiothiophene- 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboximidine, 5-methylthio-4- [benzylamino] thiophene-2-carboxymidine, 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboximidine, 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene- Methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene- 5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene- 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2- 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxymidine, 4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene- 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboximidine, 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxidine, Methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene- 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxymidine, 4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxymidine, 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene- 5-methylthio-4- (naphthylcarbonylamino) -thiophene-2-carboxymidine, 5-methylthio-4- (2-quinolylcarbonyl-amino) thiophene-2-carboximidine, 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine, 4- [2- (2-hydroxy-5-methoxyphenyl) acetylamino] -5-methylthiothiophene- 4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine, 5-methylthio-4- (2-phenoxyacetylamino) -thiophene-2-carboxymidine, 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboximidine, Methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboximidine, Methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboximidine, Methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboximidine, 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboximidine, 4- (methylphenylamino) -5-methylthiothiophene-2-carboxidine, 5-methyl-4- (phenylamino) thiophene-2-carboxidine, 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2- 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboximidine, Methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene- Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene- 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene- 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboximidine, 4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene- Methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene- 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- Methylthio-4 - [(2-naphthylsulfonyl) -amino] thiophene-2-carboximidine, 4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - {[(6-bromo (2-naphthyl)) sulfonyl] amino} -5- methylthiothiophene- 4- {bis [(6-bromo (2- naphthyl)) sulfonyl] amino} -5-methylthiothiophene- Methylthio-4 - [(naphthylsulfonyl) -amino] thiophene-2-carboximidine, 4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- carboximidine, 4- {bis [(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- 4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- 4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- 4 - {[(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- carboximidine, 4- {bis [(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine, Methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboximidine, 5-methylthio-4-phenoxythiophene-2-carboxamidine, or 5-methylthio-4-phenoxythiophene-2-carboxidine &Lt; / RTI &gt; or a salt, solvate, hydrate or prodrug thereof. Claims 1. A compound of formula (I), solvate, hydrate or pharmaceutically acceptable salt thereof, Formula I Wherein, X is oxygen or sulfur, Y is a covalent bond or -NH-, Z is NR &lt; ⁵ &gt; R &lt; ⁶ & R &lt; ¹ &gt; is hydrogen, amino, hydroxy or halogen, R ² is selected from the group consisting of alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di (aralkylsulfonyl) amino, di (aralkylsulfonyl) Sulfonyl) amino or di (heteroarylsulfonyl) amino, wherein any of the aryl or heteroaryl containing groups is optionally substituted on the aromatic ring, Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycloamino, diheterocycloamino, Monoalkyl monoheterocycloamino, wherein any of the aryl or heteroaryl containing groups is optionally substituted, Alkanoylamino, alkenoylamino, alkanoylamino, aroylamino, aralanoylamino, aralkanoylamino, heteroaroylamino, heteroarylalkanoylamino, wherein any of these may be optionally substituted on the aromatic ring Substituted), Alkoxy, alkylthio, aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, any of which is optionally substituted, Alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein any of the aryl-containing groups is optionally substituted on the aromatic ring, &Lt; / RTI &gt; formylamino, H (S) CNH-, or thioacylamino, R ³ is hydrogen; C _1-6 alkyl; C _1-6 alkyl optionally substituted with OH, NH ₂ , COOH or aminocarbonyl; Or C _1-6 alkoxy. A pharmaceutical composition, comprising a compound of claim 70, a pharmaceutically acceptable ester, salt or ether thereof, and a pharmaceutically acceptable carrier. 72. The pharmaceutical composition of claim 71, wherein said compound is present in an amount of 0.01 to 100 mg. C-1 estetase, C-3 convertase, acrosine, thrombin, europaea, leukocyte neutrophil elastase, chymotrypsin, trypsin, pancreatic elastase, cathepsin G, thrombin, Thrombin, calicaine, and pepsin is contacted with the compound of claim 70. A method for inhibiting said protease, comprising contacting said protease with a compound of claim 70. 73. The method of claim 73, wherein the protease is trypsin, chymotrypsin, plasmin, or urokinase. Treatment of adult respiratory distress syndrome, wound healing, gout, rheumatoid arthritis, reperfusion injury, atherosclerosis, recurrent stenosis, tumor formation, metastasis, emphysema, Alzheimer's disease, pancreatitis, benign prostatic hyperplasia, prostate cancer, psoriasis or Parkinson's disease Wherein the effective amount of the compound of claim 70 is administered to the patient. 71. The method of claim 70, 5-methylthio-4- (6-quinolylamino) thiophene-2-carboxymidine, Methylthio-4 - [(3-phenylphenyl) amino] thiophene-2-carboximidine, 5-methylthio-4- (3-quinolylamino) thiophene-2-carboximidine, 5-methylthio-4- (pyrimidin-2-ylamino) thiophene-2-carboximidine, 4 - [(4-cyclohexylphenyl) amino] -5-methylthiothiophene-2-carboxidine, 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- 5-methylthio-4 - {[4- (4-phenylphenyl) (1,3-thiazol-2-yl)] amino} thiophene- 4 - [(5-methyl-4-phenyl (1,3-thiazol-2-yl)) amino] -5- methylthiothiophene- 4- {[4-hydroxy-4- (trifluoromethyl) (1,3-thiazolin-2-yl)] amino} -5- methylthiothiophene- 5-methylthio-4- (2-naphthylamino) thiophene-2-carboxymidine, 4 - [(4-chlorophenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - [(3-methylphenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - [(3-methoxyphenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - {[3- (methylethyl) phenyl] amino} -5-methylthiothiophene-2-carboxidine, Methylthio-4 - [(3-nitrophenyl) amino] thiophene-2-carboximidine, 4 - {[4- (methylethyl) phenyl] amino} -5-methylthiothiophene-2- 4 - [(3,4-dimethylphenyl) amino] -5-methylthiothiophene-2-carboximidine, Methylthio-4 - [(4-phenylphenyl) amino] thiophene-2-carboxidine, 4 - [(3-fluoro-4-phenylphenyl) amino] -5-methylthiothiophene- 4- (2H-benzo [d] 1,3-dioxolen-5-ylamino) -5- methylthiothiophene- 4 - [(4-butylphenyl) amino] -5-methylthiothiophene-2-carboximidine, 5-methylthio-4- [benzylamino] thiophene-2-carboxymidine, 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboximidine, 4- (2,3-dihydrobenzo [b] furan-5-ylamino) -5-methylthiothiophene- Methylthio-4 - [(2-phenylimidazol-4-yl) amino] thiophene- 5-methylthio-4 - [(2-quinolylmethyl) amino] thiophene- 4 - {[(3-hydroxyphenyl) methyl] amino} -5-methylthiothiophene-2- 5-methylthio-4- (phenylcarbonylamino) thiophene-2-carboxymidine, 4 - ((2E) -3-phenylprop-2-enoylamino) -5-methylthiothiophene- 4 - [(4-chlorophenyl) carbonylamino] -5-methylthiothiophene-2-carboximidine, 4- (cyclohexylcarbonylamino) -5-methylthiothiophene-2-carboxidine, Methyl 4 - [(4-methyl-3-nitrophenyl) carbonylamino] -5-methylthiothiophene- 4- (2-furylcarbonylamino) -5-methylthiothiophene-2-carboxymidine, 4- (2,2-dimethylpropanoylamino) -5-methylthiothiophene-2-carboxymidine, 4 - {[5- (3,5-dichlorophenoxy) (2-furyl)] carbonylamino} -5-methylthiothiophene- 5-methylthio-4- (naphthylcarbonylamino) -thiophene-2-carboxymidine, 5-methylthio-4- (2-quinolylcarbonyl-amino) thiophene-2-carboximidine, 4 - [(3-methoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine, 4- [2- (2-hydroxy-5-methoxyphenyl) acetylamino] -5-methylthiothiophene- 4 - [(4-ethoxyphenyl) carbonylamino] -5-methylthiothiophene-2-carboxidine, 5-methylthio-4- (2-phenoxyacetylamino) -thiophene-2-carboxymidine, 4 - [(3-methylphenyl) carbonylamino] -5-methylthiothiophene-2-carboximidine, Methylthio-4 - {[3- (phenylmethoxy) phenyl] amino} thiophene-2-carboximidine, Methylthio-4 - [(3-phenoxyphenyl) amino] thiophene-2-carboximidine, Methylthio-4 - [(4-phenoxyphenyl) amino] thiophene-2-carboximidine, 4 - [(2-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - [(2-methylphenyl) amino] -5-methylthiothiophene-2-carboximidine, 4 - [(3-chlorophenyl) amino] -5-methylthiothiophene-2-carboximidine, 4- (methylphenylamino) -5-methylthiothiophene-2-carboxidine, 5-methyl-4- (phenylamino) thiophene-2-carboxidine, 4 - {[4- (dimethylamino) phenyl] amino} -5-methylthiothiophene-2- 4 - [(4-ethylphenyl) amino] -5-methylthiothiophene-2-carboximidine, Methylthio-4 - {[4- (phenylmethoxy) phenyl] amino} thiophene- Methylthio-4 - {[4- (phenylamino) phenyl] amino} thiophene- 4 - [(4-methoxyphenyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - [(3-fluoro-4-methylphenyl) amino] -5-methylthiothiophene- 4- (indan-5-ylamino) -5-methylthiothiophene-2-carboximidine, 4 - [(9-ethylcarbazol-3-yl) amino] -5-methylthiothiophene- Methylthio-4 - {[(4-phenylphenyl) sulfonyl] amino} thiophene- 4- {bis [(4-phenylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- Methylthio-4 - [(2-naphthylsulfonyl) -amino] thiophene-2-carboximidine, 4- [bis (2-naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - {[(6-bromo (2-naphthyl)) sulfonyl] amino} -5- methylthiothiophene- 4- {bis [(6-bromo (2- naphthyl)) sulfonyl] amino} -5-methylthiothiophene- Methylthio-4 - [(naphthylsulfonyl) -amino] thiophene-2-carboximidine, 4- [bis (naphthylsulfonyl) amino] -5-methylthiothiophene-2-carboxidine, 4 - {[(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- carboximidine, 4- {bis [(2-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- 4 - {[(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- 4- {bis [(3-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- 4 - {[(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2- carboximidine, 4- {bis [(4-methylphenyl) sulfonyl] amino} -5-methylthiothiophene-2-carboxidine, Methylthio-4 - {[benzylsulfonyl] amino} -thiophene-2-carboximidine, 5-methylthio-4-phenoxythiophene-2-carboxidine, and 5-methylthio-4- (phenylsulfonyl) thiophene-2-carboxidine &Lt; / RTI &gt; or a prodrug thereof.