Patent Publication Number: US-6040321-A

Title: Aminothiazole inhibitors of cyclin dependent kinases

Description:
This application claims benefit of Provisional Appl. No. 60/065,195 filed Nov. 12, 1997. 
    
    
     BRIEF DESCRIPTION OF THE INVENTION 
     The present invention is directed to compounds of the formula ##STR2## and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings: 
     R 1  and R 2  are independently hydrogen, fluorine or alkyl; 
     R 3  is aryl or heteroaryl 
     R 4  is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or 
     CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or 
     CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or 
     COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or SO 2  -alkyl, SO 2  -cycloalkyl, SO 2  -aryl, SO 2  -alkyl-cycloalkyl, SO 2  -alkyl-aryl, SO 2  -heteroaryl, SO 2  -alkyl-heteroaryl, SO 2  -heterocycloalkyl, SO 2  -alkyl-heterocycloalkyl; or 
     C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocylcoalkyl; or 
     C(NNO 2 )NH-alkyl, C(NNO 2 )NH-cycloalkyl, C(NNO 2 )NH-aryl, C(NNO 2 )NH-alkyl-cycloalkyl, C(NNO 2 )NH-alkyl-aryl, C(NNO 2 )NH-heteroaryl, C(NNO 2 )NH-alkyl-heteroaryl, C(NNO 2 )NH-heterocyloalkyl, C(NNO 2 )NH-alkyl-heterocycloalkyl; or 
     C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or 
     C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or 
     C(NOR 6 )NH-alkyl, C(NOR 6 )NH-cycloalkyl, C(NOR 6 )NH-aryl, C(NOR 6 )NH-alkyl-cycloalkyl, C(NOR 6 )NH-alkyl-aryl, C(NOR 6 )NH-heteroaryl, C(NOR 6 )NH-alkyl-heteroaryl, C(NOR 6 )NH-heterocylcoalkyl, C(NOR 6 )NH-alkyl-heterocycloalkyl; 
     R 5  is hydrogen or alkyl; 
     R 6  is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; 
     m is an integer of 0 to 2; and 
     n is an integer of 1 to 3. 
     The compounds of formula I are protein kinase inhibitors and are useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such as Alzheimer&#39;s disease, cardiovascular diseases, viral diseases and fungal diseases. 
     DESCRIPTION OF THE INVENTION 
     The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. 
     Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group. 
     It should be noted that any heteroatom with unsatisfied valances is assumed to have the hydrogen atom to satisfy the valances. 
     Carboxylate anion refers to a negatively charged group --COO -- . 
     The term &#34;alkyl&#34; or &#34;alk&#34; refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituent groups, R as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with &#34;branched alkyl group&#34;. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents may include but are not limited to one or more of the following groups: halo (such as F, Cl, Br, I), haloalkyl (such as CCl 3  or CF 3 ), alkoxy, alkylthio, hydroxy, carboxy (--COOH), alkyloxycarbonyl (--C(O)R), alkylcarbonyloxy (--OCOR), amino (--NH 2 ), carbamoyl (--NHCOOR-- or --OCONHR--), urea (--NHCONHR--) or thiol (--SH). Alkyl groups as defined may also comprise one or more carbon to carbon double bonds or one or more carbon to carbon triple bonds. 
     The term &#34;alkenyl&#34; refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon double bond. 
     The term &#34;alkynyl&#34; refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. 
     Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio. 
     The terms &#34;alkoxy&#34; or &#34;alkylthio&#34;, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (--O--) or a sulfur linkage (--S--), respectively. 
     The term &#34;alkyloxycarbonyl&#34;, as used herein, denotes an alkoxy group bonded through a carbonyl group. An alkoxycarbonyl radical is represented by the formula: --C(O)OR, where the R group is a straight or branched C 1-6  alkyl group. 
     The term &#34;alkylcarbonyl&#34; refers to an alkyl group bonded through a carbonyl group. 
     The term &#34;alkylcarbonyloxy&#34;, as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage. 
     The term &#34;arylalkyl&#34;, as used herein, denotes an aromatic ring bonded to an alkyl group as described above. 
     The term &#34;aryl&#34; refers to monocyclic or bicyclic aromatic rings, e.g. phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O) m  (m=O, 1, 2), or thiol. 
     The term &#34;heteroaryl&#34; refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include the following: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl and tetrahydropyranyl. Exemplary substituents include one or more of the following: halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O) m  (m=0, 1, 2), or thiol. 
     The term &#34;heteroarylium&#34; refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. 
     The term &#34;heterocycloalkyl&#34; refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. 
     The term &#34;quaternary nitrogen&#34; refers to a tetravalent positively charged nitrogen atom including, e.g. the positively charged nitrogen in a tetraalkylammonium group (e.g. tetramethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g. trimethylhydroammonium, N-hydropyridinium), the positively charged nitrogen in amine N-oxides (e.g. N-methyl-morpholine-N-oxide, pyridine -N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g. N-aminopyridinium). 
     The term &#34;heteroatom&#34; means O, S or N, selected on an independent basis. 
     The term &#34;halogen&#34; or &#34;halo&#34; refers to chlorine, bromine, fluorine or iodine. 
     When a functional group is termed &#34;protected&#34;, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991). 
     Suitable examples of salts of the compounds according to the invention with inorganic or organic acids are hydrochloride, hydrobromide, sulfate, phosphate. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included. 
     All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. 
     It should be understood that solvates (e.g., hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are generally known in the art. Accordingly, the compounds of the instant invention may be in the free or hydrate form, and may be obtained by methods exemplified by the following schemes. ##STR3## 
     As illustrated in Scheme 1, compounds of formula I where X is S are prepared by reacting 2-aminothiazole (II) with bromine in the presence of sodium or potassium thiocyanate to obtain a thiocyanated aminothiazole, specifically 5-thiocyanatoaminothiazole (III). Compound III is then reacted with R 4  -L, where L is a leaving group such as a halogen, in the presence of a base such as triethylamine to provide a 5-thiocyanatothiazole intermediate (IV), where R 4  is as defined in the specification. The intermediate (IV) is then reduced to a thiol (V) using reducing agents such as dithiothreitol (DTT), sodium borohydride, zinc or other known reducing agents. Compound (V) is then reacted with alkyl, aryl or heteroaryl halides, such as R 3  (CR 1  R 2 ) n  -L, where L is a leaving group such as a halogen, in the presence of a base such as potassium carbonate to obtain compounds of formula I. The steps of reducing the thiocyanothiazole intermediate (IV) to the thiol (V), and the reaction of the reduced thiol (V) to provide compounds of formula I where X is S, may be carried out sequentially without purification. ##STR4## 
     In Scheme 2, 5-thioacetyl-2-acetylaminothiazole of structure VI is reacted with an alkoxide such as potassium t-butoxide in alcohol or THF solvent and the resulting thiol is reacted in situ with a group of formula R 3  (CR 1  R 2 ) n  -L (where L is a leaving group, such as a halogen) such as 2-halomethyloxazole (VII) to provide a compound such as formula VIII, wherein R 1  and R 2  are hydrogen, and R 6  is acetyl. The 2-halomethyloxazole compounds of formula VII may be prepared using several synthetic routes known in the art. Chem. Pharm. Bull. 30, 1865 (1982); Bull. Chem. Soc. Japan (52, 3597 (1979); JCS Chem. Comm. 322 (1981); Comprehensive Heterocyclic Chemistry, vol. 6, 177, edited by A. Katritzky and C. W. Rees, Pergamon Press (1984). 
     Compounds of formula VIII (a compound of formula I where R 4  is acetyl and X is sulfur) can be hydrolyzed in the presence of a base such as sodium hydroxide to provide a compound of formula IX. A compound of formula IX may then be reacted with R 4  -L, in the presence of a base such as triethylamine, where L is a leaving group such as a halogen, to give compounds of formula I where X is sulfur. In this manner, compounds of formula IX, which is a compound of formula I where R 4  is hydrogen, can be treated with agents such as isothiocyanates, halides, acyl halides, chloroformates, isocyanates or sulfonyl chlorides to provide thioureas, amines, amides, carbamates, ureas or sulfonamides. The procedures in Scheme 2 specifically illustrate a methyloxazole group, but are general for all R 3  (CR 1  R 2 ) n  - groups specified by formula I. 
     Alternatively, compounds of formula VII, where L is bromine, may be prepared by halogenation of 2-methyloxazole using N-bromosuccinimide in the presence of dibenzoylperoxide. ##STR5## 
     Scheme 3 lustrates an alternative method of preparing compound VII, which is a compound of formula R 3  (CR 1  R 2 ) n  -L where L is chlorine and n is the integer 1. In this scheme, compound VII is prepared by the reaction of a compound of formula X and formula XI in the presence of a base such as triethylamine to provide compounds of formula XII. Compound XII may be oxidized by an oxidant such as oxalylchloride/DMSO in the presence of a base such as triethylamine to provide a compound of formula XIII which may be cyclized by an agent such as phosphorous oxychloride to provide compounds of formula VII, wherein L is chlorine. Alternatively, compounds of formula XIII may be prepared by reaction of the amino ketone correponding to X with an acid chloride such as XI. ##STR6## 
     Compounds of formula VII, where L is chlorine, may also be prepared from the reaction of diazoketones as illustrated by formula XIV in Scheme 4 with chloronitriles, such as indicated by formula XV, in the presence of BF 3  etherate to provide compounds of formula VII, wherein L is chlorine. ##STR7## 
     In Scheme 5, starting compound XVI denotes a resin-bound benzyl alcohol support used for solid phase synthesis which is prepared from a Merrifield resin denoted as , and 2-methoxy-4-hydroxybenzaldehyde, followed by reduction with reducing agents such as NaBH 4 . In step 1, starting compound XVI is treated with triphosgene and triphenylphosphine (PPh 3 ) in dichloromethane to give the chlorobenzyl resin of formula XVII. In step 2, a thiocyanato trifluoroacetamide (XVIII) is alkylated with the resin-bound benzyl chloride (XVII) in the presence of diisopropylethylamine (DIPEA) to form a resin-bound thiocyanate (XIX). The thiocyanato trifluoroacetamide compound of formula XVII is prepared by reacting 5-thiocyanatoaminothiazole of formula III (Scheme I) with trifluoroacetic anhydride using a base such as 2,6-lutidine. 
     The resin-bound thiocyanate (XIX) is then reduced to a resin-bound thiol (XX) in step 3 with reducing agent such as dithiothreitol (DTT) in tetrahydrofuran (THF) and methanol. The resulting resin-bound thiol (XX) is reacted with R 3  (CR 1  R 2 ) n  -L, where L is a leaving group, in the presence of a base such as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) at 80° C. in dimethylformamide (DMF) to form compounds of formula XXI (step 4). Deprotection of the trifluoroacetyl group of compound XXI is performed in step 5 using sodium borohydride to provide a compound of formula XXII. In step 6, the deprotected compound XXII is reacted with R 6  X, where X is a leaving group, in the presence of a base such as diisopropylethylamine to provide compounds of formula XXIII. The product is then cleaved from the solid phase resin in step 7 with trifluoroacetic acid (TFA) to give compounds of formula I where X is sulfur. Compounds of formula I where X is S(O) m  and m is 1 or 2 may be prepared from compounds of formula I where m is 0 by oxidation with an oxidant such as sodium periodate, meta-chloroperbenzoic acid, or oxone. 
     The starting compounds of Schemes 1-5 are commercially available or may be prepared by methods known to one of ordinary skill in the art. 
     All compounds of formula I may be prepared by modification of the procedures described herein. 
     The preferred compounds of formula I are those where: 
     R 1  and R 2  are independently hydrogen, fluorine or alkyl; ##STR8## wherein Y is oxygen, sulfure or NR 9  ; 
     R 4  is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or 
     CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or 
     CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or 
     COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or 
     SO 2  -alkyl, SO 2  -cycloalkyl, SO 2  -aryl, SO 2  -alkyl-cycloalkyl, SO 2  -alkyl-aryl, SO 2  -heteroaryl, SO 2  -alkyl-heteroaryl, SO 2  -heterocycloalkyl, SO 2  -alkyl-heterocycloalkyl; or 
     C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocylcoalkyl; or 
     C(NNO 2 )NH-alkyl, C(NNO 2 )NH-cycloalkyl, C(NNO 2 )NH-aryl, C(NNO 2 )NH-alkyl-cycloalkyl, C(NNO 2 )NH-alkyl-aryl, C(NNO 2 )NH-heteroaryl, C(NNO 2 )NH-alkyl-heteroaryl, C(NNO 2 )NH-heterocyloalkyl, C(NNO 2 )NH-alkyl-heterocycloalkyl; or 
     C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl -cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or 
     C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or 
     C(NOR 6 )NH-alkyl, C(NOR 6 )NH-cycloalkyl, C(NOR 6 )NH-aryl, C(NOR 6 )NH-alkyl-cycloalkyl, C(NOR 6 )NH-alkyl-aryl, C(NOR 6 )NH-heteroaryl, C(NOR 6 )NH-alkyl-heteroaryl, C(NOR 6 )NH-heterocylcoalkyl, C(NOR 6 )NH-alkyl-heterocycloalkyl; 
     R 5  is hydrogen; and 
     R 6  is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; 
     R 7  and R 8  are independently hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkylheterocycloalkyl or halogen; 
     R 9  is H or alkyl; 
     m is the integer 0; and 
     n is the integer 1. 
     The most preferred compounds of formula I are those where: 
     R 1  is hydrogen; 
     R 2  is hydrogen, fluorine or alkyl; 
     R 3  is a substituted oxazole having the configuration: ##STR9## 
     R 4  is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; 
     R 5  is hydrogen; 
     R 7  is hydrogen; 
     R 8  is an alkyl group, such as tert-butyl; 
     m is the integer 0; and 
     n is the integer 1. 
     The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I are inhibitors of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdk1), cdk2, and cdk4. The novel compounds of formula I are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular disease. 
     More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following: 
     carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; 
     hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett&#39;s lymphoma; 
     hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; 
     tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; 
     tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and 
     other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi&#39;s sarcoma. 
     Due to the key role of cdks in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. 
     Compounds of formula I may also be useful in the treatment of Alzheimer&#39;s disease, as suggested by the recent finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). 
     Compounds of formula I may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer&#39;s disease, AIDS-related dementia, Parkinson&#39;s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. 
     Compounds of formula I, as inhibitors of the cdks, can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus). 
     Compounds of formula I may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse. 
     Compounds of formula I may also be useful in inhibiting tumor angiogenesis and metastasis. 
     Compounds of formula I may also act as inhibitors of other protein kinases, e.g., protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl and thus be effective in the treatment of diseases associated with other protein kinases. 
     The compounds of this invention may also be useful in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate. 
     If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent or treatment within its approved dosage range. For example, the cdc2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., 108, 2897 (1995)). Compounds of formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, 57, 3375 (1997). 
     The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which follow have been carried out with the compounds according to the invention and their salts. The compounds of examples 1 to 8 exhibited cdc2/cyclin B1 kinase activity with IC 50  values less than 50 μM. The compounds of examples 1 to 8 exhibited cdk2/cyclin E kinase activity with IC 50  values less than 50 μM. The compounds of examples 1 to 8 exhibited cdk4/cyclin D1 kinase activity with IC 50  values less than 50 μM. 
     cdc2/cvclin B1 Kinase Assay 
     cdc2/cyclin B1 kinase activity was determined by monitoring the incorporation of  32  P into histone H1. The reaction consisted of 50 ng baculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclin B1, 1 μg histone HI (Boehringer Mannheim), 0.2 mCi of  32  P g-ATP and 25 mM ATP in kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl 2 , 1 mM EGTA, 0.5 mM DTT). The reaction was incubated at 30° C. for 30 minutes and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter (Marshak, D. R., Vanderberg, M. T., Bae, Y. S., Yu, I. J., J. of Cellular Biochemistry, 45, 391-400 (1991), incorporated by reference herein). 
     cdk2 cyclin E Kinase Assay 
     cdk2/cyclin E kinase activity was determined by monitoring the incorporation of  32  p into the retinoblastoma protein. The reaction consisted of 2.5 ng baculovirus expressed GST-cdk2/cyclin E, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 mCi  32  p g-ATP and 25 mM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30° C. for 30 minutes and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter. 
     cdk 4/cyclin D1 Kinase Activity 
     cdk4/cyclin D1 kinase activity was determined by monitoring the incorporation of  32  P in to the retinoblastoma protein. The reaction consisted of 165 ng baculovirus expressed as GST-cdk4, 282 ng bacterially expressed as S-tag cyclin D1, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 μCi  32  P γ-ATP and 25 M ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30° C. for 1 hour and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter (Coleman, K. G., Wautlet, B. S., Morissey, D, Mulheron, J. G., Sedman, S., Brinkley, P., Price, S., Wedster, K. R. (1997). Identification of CDK4 Sequences involved in cyclin D, and p16 binding. J. Biol. Chem. 272,30:18869-18874, incorporated by reference herein). 
     Further subject matter of the invention also includes pharmaceuticals for use as described above including controlling cancer, inflammation and arthritis, which contain at least one compound of the formula I as defined above or at least one of its pharmacologically acceptable acid addition salts, and the use of a compound of the formula I as defined above for the preparation of a pharmaceutical having activity against proliferative diseases as described previously including against cancer, inflammation and/or arthritis. 
     The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto. ##STR10## 
    
    
     A. Preparation of 1-benzyloxycarbonylamino-2-butanol 
     A mixture of 1-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate (11.5 g, 67.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to the reaction mixture and the product was extracted with methylene chloride (3×20 mL). The methylene chloride extract was dried over Na 2  SO 4  and concentrated. The residue was passed through a short column (SiO 2 , hexanes: ethyl acetate/10:1; then ethyl acetate) to afford 1-benzyloxycarbonylamino-2-butanol (13.9 g, 100%) as a liquid. 
       1  H NMR (CDCl 3 ) δ7.30 (m, 5 H), 5.45 (s, 1 H), 5.06 (s, 2 H), 3.57 (s, 1 H), 3.31 (m, 1 H), 3.04 (m, 1 H), 2.91 (m, 1 H), 1.43 (m, 2 H), 0.91 (t, J=7.6 Hz, 3 H). 
     B. Preparation of 1-benzyloxycarbonylamino2-butanone 
     To methylene chloride (60 mL) at -78° C. under argon was added oxalyl chloride (37 mL of 2 M solution in methylene chloride, 74 mmol), followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at 78° C. for 20 min. and to this mixture was added a solution of 1-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylene chloride (40 mL). The mixture was stirred at -78° C. for 1 h and triethylamine (21 mL) was added to the mixture. It was warmed to room temperature (rt) and washed successively with 1 N hydrochloric acid and aqueous sodium bicarbonate solution. The methylene chloride solution was dried over MgSO 4  and concentrated to afford 1-benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid, which was enough pure for the next reaction.  1  H NMR (CDCl 3 ) δ7.32 (m, 5 H), 5.50 (s, 1 H), 5.06 (s, 2 H), 4.07 (s, 2 H), 2.43 (q, J=7.6 Hz, 2 H), 1.06 (t, J=7.6 Hz, 3 H). 
     C. Preparation of 1-amino-2-butanone 
     A solution of 1-benzyloxycarbonylamino-2-butanone (9.30 mg, 42 mmol) in ethanol (50 mL) and 1 N hydrochloric acid (46 mL) was stirred under hydrogen atmosphere in the presence of Pd/C (1.5 g, 10%) at rt for 4 h. The mixture was filtered through a celite bed and the filtrate solution was concentrated. The residue was triturated with ethyl ether to afford 1-amino-2-butanone (5.3 g, 102%) as a hydrochloride salt.  1  H NMR (CD 3  OD) δ3.97 (s, 2 H), 2.60 (q, J=7.6 Hz, 2 H), 1.08 (t, J=7.6 Hz, 3 H). 
     D. Preparation of 2-amino-5-thiocyanatothiazole 
     2-Aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM, dried in a vacuum oven at 130° C. overnight) was dissolved in 450 mL of anhydrous methanol and the solution was cooled in a cold water bath. Here was added bromine (23 mL, 445 mM) dropwise with good stirring. After the addition it was stirred for 4 h at rt. To the mixture 500 mL of water was added and it was stirred for 5 minutes, filtered through a celite bed and washed the bed with water. The pH of the filtrate solution was about 1. Most of the methanol was removed under the reduced pressure and pH of the solution was adjusted to about 7 by adding aq. sodium carbonate slowly with stirring. The precipitated solid was filtered and washed with water to obtain 37 g (57%) of the dark brown colored desired product after drying, mp 140-143° C.  1  H NMR (CD 3  OD) δ7.33 (s, 1 H); MS (CI/NH 3 ) m/e 179 (M+Na) + , 158 (M+H) + . 
     E. Preparation of of 2-acetylamino-5-thiocyanatothiazole 
     To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) at rt. The mixture was stirred at rt for 6 h. The mixture was concentrated to dryness and to the residue MeOH (50 mL) was added. The precipitates were collected and washed with water. The solid was dried and recrystallized from MeOH to afford 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212° C.  1  H NMR (CD 3  OD) δ7.79 (s, 1 H), 2.23 (s, 3 H). 
     F. Preparation of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid 1,1-dimethylethyl ester 
     To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) in MeOH (360 mL) under argon was added dithiothreitol (9.26 g, 60 mmol) at rt. The mixture was stirred at rt for 2 h and it was concentrated to afford a reduced solid product. This solid product was dissolved in DMF (30 mL) and to this solution were added tert-butyl bromoacetate (5.85 g, 30 mmol) and potassium carbonate (5.0 g, 36 mmol). The mixture was stirred at rt for 2 h and water (200 mL) was added to the mixture. The precipitates were collected, washed with water and dried. The solid was dissolved in methylene chloride (100 mL) and MeOH (10 mL) and filtered through a silica gel pad. The filtrate solution was concentrated to afford the desired product (7.5 g, 87%) as a solid, mp 162-163° C.  1  H NMR (CDCl 3 ) δ12.2 (s, 1 H), 7.48 (s, 1 H), 3.37 (s, 2 H), 2.32 (s, 3 H), 1.45 (s, 9 H); MS m/e 289 (M+H) + , 287 (M-H) - . HPLC (Column: YMC S3 ODS 4.6×150 mm; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UV: 220 nm): retention time 6.44 min. 
     G. Preparation of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid 
     A solution of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid 1,1-dimethylethyl ester (4.32 g, 15 mmol) in methylene chloride (30 mL) and trifluoroacetic acid (20 mL) was stirred at rt overnight and concentrated in vacuo. To the residue was added ethyl ether (50 mL). The precipitated solid was collected, washed with ethyl ether and dried to afford the desired product (3.38 g, 97%) as a solid, mp 210° C.  1  H NMR (CD 3  OD) δ7.48 (s, 1 H), 3.47 (s, 2 H), 2.20 (s, 3 H) ppm; MS m/e 231 (M-H) -  ; HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2%H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UV: 254 nm): retention time 4.32 min. 
     H. Preparation of [[2(acetylamino)-5-thiazolyl]thio]-N-(2-oxobutyl)acetamide 
     A mixture of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid (9.0 g, 38.8 mmol), HOBT (5.94 g, 38.8 mmol) and ethyldimethylaminopropylcarbodiimide hydrochloride salt (11.16 g, 58.2 mmol) in DMF (50 mL) was stirred at 0° C. for 0.5 h. To this mixture was added 1-amino-2-butanone hydrochloride (5.27 g, 42.7 mmol) followed by triethylamine (15 mL, 107.5 mmol). The mixture was stirred at 0° C. for 0.5 h and at rt for 1 h. Water (200 mL) was added to the mixture and the product was extracted with methylene chloride containing 10% MeOH (5×100 mL). The methylene chloride extract was dried over Na 2  SO 4  and concentrated. The residue was triturated with water and the precipitated solid product was collected by filtration. It was dried to obtain the desired product (10.5 g, 90%), mp 195-196° C. 
       1  H NMR (CDCl 3 ) δ7.53 (s, 1 H), 4.14 (s, 2 H), 3.46 (s, 2 H), 2.50 (q, J=7.6 Hz, 2 H), 2.25 (s, 3 H), 1.12 (t, J=7.6 Hz, 3 H); MS m/e 302 (M+H) + . HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 ml/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UV: 254 nm): retention time 4.36 min. 
     I. Preparation of N[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide 
     To a solution of [[2-(acetylamino)-5-thiazolyl]thio]-N-(2-oxobutyl)acetamide (10.5 g, 34.8 mmol) in acetic anhydride (100 mL) was added conc. sulfuric acid (10 mL). The mixture was stirred at 55-60° C. for 2 h and sodium acetate (15 g, 0.18 mol) was added to the mixture. The mixture was concentrated in vacuo. To the residue was added cold water (100 mL). The precipitated solid was collected, washed with water and dried. It was purified by a flash column chromatography (SiO 2  ; methylene chloride: MeOH/100:5) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (4.2 g, 43%) as a solid, mp 147-148° C.  1  H NMR (CDCl 3 ) δ12.47 (s, 1 H), 7.29 (s, 1 H), 6.61 (s, 1 H), 3.91 (s, 2 H), 2.64 (q, J=7.6 Hz, 2 H), 2.25 (s, 3 H), 1.21 (t, J=7.6 Hz, 3 H) ppm; MS m/e 284 (M+H) +  ; 
     HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UV: 254 nm): retention time 6.50 min. ##STR11## A. Preparation of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole 
     A solution of N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (1.3 g, 4.6 mmol) in 1 N hydrochloric acid (15 mL) was stirred at 80-90° C. for 3 h. It was cooled to rt and the pH of the solution was adjusted to 7 with sodium carbonate. The product was extracted with methylene chloride (3×10 mL). The combined extract was dried over Na 2  SO 4  and concentrated. The residue was triturated with ethyl ether and the precipitated solid was collected to afford 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (610 mg, 55%) as a solid, mp 119-120° C.  1  H NMR (CDCl 3 ) δ6.93 (s, 1 H), 6.61 (s, 1 H), 5.41 (s, 2 H), 3.82 (s, 3 H), 2.62 (q, J=7.6 Hz, 2 H), 1.18 (t, J=7.6 Hz, 3 H); MS m/e 242 (M+H) +  ; 
     HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UV: 254 nm): retention time 3.96 min. 
     B. Preparation of N-[5-[[(5-ethyl-2oxazolyl)methyl]thio]-2-thiazolyl]benzamide 
     A mixture of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine (35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at rt for 10 min. The organic solution was washed with water and concentrated. The residue was purified by a flash column (SiO 2  ; hexanes: ethyl acetate/2:1) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide (41 mg, 59%) as a solid, mp 122-123° C.  1  H NMR (CDCl 3 ) δ12.65 (s, 1 H), 7.96 (m, 2 H), 7.61 (m,, 1 H), 7.49 (m, 2 H), 6.88 (s, 1 H), 6.56 (s, 1 H), 3.93 (s, 2 H), 2.61 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3 H); MS m/e 346 (M+H) +  ; 
     HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UV: 254 nm): retention time 7.94 min. ##STR12## 
     A mixture of 2-amino-6-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (24.1 mg, 0.1 mmol), benzenesulfonyl chloride (19.4 mg, 0.11 mmol) and triethylamine (22 mg, 0.21 mmol) in methylene chloride (0.3 mL) was stirred at rt for 10 h. The product of the reaction mixture was purified by preparative HPLC (column: YMC pack ODSA S3 20×100 mm; method: gradient from 0% B to 100% B in 20 min and flow rate 20 mL/min; Uw: 254 nm; solvent A: 10% MeOH-90% water-0.1% TFA; solvent B: 90% MeOH-10% water-0.1% TFA) to obtain N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzsulfoneamide (2.5 mg) as a solid after drying via lyophilization. 
       1  H NMR (CDCl 3 ) δ7.88 (d, J=8.0 Hz, 1 H), (s, 2 H), 7.49 (m, 3 H), 6.89 (s, 1 H), 6.64 (s, 1 H), 4.01 (s, 2 H), 2.68 (q, J=7.4 Hz, 2 H), 1.27 (t, J=7.4 Hz, 3 H); MS m/e 382 (M+H) +  ; 
     HPLC (column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H 3  PO 4  ; Solvent B: 90% MeOH-10% Water-0.2% H 3  PO 4  ; UW: 254 nm): retention time 6.84 min. ##STR13## A. Preparation of 2-(bromomethyl)-4,5-dimethyloxazole 
     A mixture of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86 mmol) in carbon tetrachloride (4 mL) was heated at 76° C. under nitrogen atm for 3 hrs. After cooling to rt, the solid was removed by filtration. The filtrate solution was washed with saturated aqueous NaHCO 3  (20 mL) and concentrated. The residue was purified by flash column chromatography (SiO 2  ; hexanes:ethyl acetate/4:1) to afford 2-(bromomethyl)-4,5-dimethyloxazole (64 mg) as an yellow oil.  1  H NMR (CDCl 3 ) 67 4.4 (s, 2 H), 2.25 (s, 3 H), 2.05 (s, 3 H). 
     B. Preparation of N-[5-[[(4,5-dimethyl-2-oxazolyl)meihyl]thio]-2-thiazolyl]acetamide 
     N-[5-(Acetylthio)-2-thiazolyl]acetamide (0.050 g, 0.23 mmol) was dissolved in dry THF (10 ml) and here potassiumtert-butoxide (1.0 M solution in THF, 0.25 ml, 0.25 mmol) was added to the mixture. The reaction mixture was stirred at rt for 15 min., and 2-(bromomethyl)-4,5-dimethyloxazole (0.064 g, 0.34 mmol) was added to this mixture. The reaction mixture was stirred at rt for 3 h and saturated aqueous NaHCO 3  solution (20 mL) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers was concentrated. The residue was purified by flash column chromatography (SiO 2  ; methanol:dichloromethane/1:20) to afford N-[5-[[(4,5-dimethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (15 mg, 23%) as a yellow solid. 
       1  H NMR (CDCl 3 ) δ11.78 (s, 1 H), 7.38 (s, 1 H), 3.90 (s, 2 H), 2.30 (s, 3H), 2.22 (s 3 H), 2.05 (s, 3 H); MS m/e 284 (M+H) +  ; 
     HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 ml/min; solvent system: 0-100% B in 8 min. Solvent A: 10% CH 3  OH/90% H 2  O/0.2% H 3  PO 4  ; Solvent B: 90% CH 3  OH/10% H 2  O/0.2% H 3  PO 4  ; UV: 254 nm): retention time 5.87 min. ##STR14## A. Preparation of diazomethane 
     To a mixture of 15 ml of 40% aqueous KOH solution and 50 mL of diethyl ether at 0° C. was added 5 g (68 mmol) of N-methyl-N&#39;-nitro-N-nitrosoguanidine in portions with stirring. The resulting mixture was stirred at 0° C. for 0.5 h. The organic phase was decanted into a dry flask and dried over solid KOH pellets to give 50 mL of diazomethane solution (ca 0.5 M, by titrating with acetic acid). 
     B. Preparation of 1-diazo-3,3-dimethyl-2-butanone 
     To the diazomethane solution at 0° C. was added a solution of 1.23 mL (1.21 g, 10 mmol, Aldrich) of trimethylacetyl chloride in 1 mL of diethyl ether dropwise with stirring. The resulting mixture was kept at 0° C. for 16 h. The solution was sparged with argon to remove the excess diazomethane and diethyl ether was removed under reduced pressure to give 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone as a yellow liquid. 
     C. Preparation of 2-chloromethyl-5-t-butyloxazole 
     To a solution of 2 mL (2.3 g, 16 mmol) of boron trifluoride etherate in 20 mL of chloroacetonitrile at 0° C. was added a solution of 1.33 g (10 mmol) of 1-diazo-3,3-dimethyl-2-butanone in 5 mL of chloroacetonitrile dropwise. The resulting solution was stirred at 0° C. for 0.5 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times with dichloromethane. The combined extracts was dried (sodium sulfate), concentrated and purified by flash column chromatography (Merck silic a, 25×200 mm, dichloromethane) to give 1.1 g of 2-(chloromethyl)-5-t-butyloxazole as a yellow liquid (6.4 mmol, 64% overall from the acid chloride).  1  H NMR δ (CDCl 3 ): 1.30 (s, 9 H), 4.58 (s, 2 H), 6.68 (s, 1 H); MS 174 (M+H) +  ; TLC: R f  (silica gel, dichloromethane)=0.33; 
     HPLC: t R  (YMC S-3 ODS 4.6×50 mm rapid resolution; 2.5 ml/min, gradient 0-100% B over 8 min, Solvent A: 10% CH 3  OH90% H 2  O/0.2% H 3  PO 4  ; Solvent B: 90% CH 3  OH/10% H 2  O/0.2% H 3  PO 4  ; UV:254 nm)=6.5 min. 
     D. Preparation of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide 
     To a solution of 50 mg (0.23 mmol, Applied Chemical Laboratory) of N-[5-(acetylthio)-2-thiazolyl]acetamide in 10 mL of THF was added 0.25 mL of potassium tert-butoxide solution (1 M solution, 0.25 mmol) at rt under argon. The resulting suspension was stirred for 15 min at rt, then a solution of 59 mg of 2-(chhloromethyl)-5-t-butyloxazole (0.34 mmol) in 1 mL of THF was added. The resulting mixture was stirred at ft for 16 h, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 25×200 mm, 1:1 EtOAc/hexanes followed by 100% EtOAc) to give 44 mg (0.14 mmol, 61%) of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide as a white solid. 
       1  H NMR δ (CDCl 3 ) 1.27 (s, 9 H), 2.27 (s, 3 H), 3.95 (s, 2 H), 6.59 (s, 1 H), 7.31 (s, 1 H), 11.03 (broad s, 1 H); MS 312 (M+H) +  ; 
     TLC: R f  (silica gel, ethyl acetate)=0.53, UV; 
     HPLC: retention tim (YMC S-3 ODS 4.6×50 mm rapid resolution; 2.5 ml/min, gradient 0-100% B over 8 min, Solvent A: 10% CH 3  OH/90% H 2  O/0.2% H 3  PO 4  ; Solvent B: 90% CH 3  OH/10% H 2  O/0.2% H 3  PO 4  ; UV: 254 nm)=6.8 min. ##STR15## A. Preparationof N-[(5-thiocyanato)-2-thiazoy]trifluoroacetamide (XVIII) 
     To a mixture of 5-thiocyanato-2-aminothiazole (30 mmol) and 2,6-lutidine (35 mmol) in tetrahydrofuran (25 mL) and dichloromethane (50 mL) at -78° C. under argon was slowly added trifluoroaceticanhydride (33 mmol). After addition, the mixture was allowed to warm up to rt and stirred overnight. The mixture was diluted with dichloromethane (100 mL), and the organic solution was washed with 5% aqueous citric acid followed by brine, dried over magnesium sulfate and passed through a pad of silica gel. The product containing eluent was concentrated to afford 5.3 g of light brown solid.  1  H -NMR (CDCl 3 ) δ12.4 (br, 1 H), 7.83 (s, 1 H). 
     B. Preparation of 4-hydroxymethyl-3-methoxyphenyloxy Merriffeld resin (XVI) 
     To the suspension of sodium hydride (11.7 g, 60% in mineral oil, 293 mmol) in dimethylformamide (30 mL) at 0° C. under argon was slowly added a solution of 4-hydroxy-3-methoxybenzyldehyde (44.5 g, 292.5 mmol) in dimethylformamide (100 mL). To the resulting mixture Merrifield resin (1% DVB, from Advanced Chemtech, loading 1.24 mmol/g, 50 g, 62 mmol) and catalytic amount of tetra-n-butylammonium idodide were added, and it was heated at 65° C. for a day. The resin was filtered, washed with water (2×), 50% dimethylformamide in water (3×), dimethylformamide (2×), and methanol (5×), and dried in vacuo. The dried resin (15 g) was treated with sodium borohydride (3.4 g, 90 mmol) in tetrahydrofuran (50 mL) and ehthanol (50 mL) overnight. The resin was filtered, washed with 50% dimethylformamide in water (3×), dimethylformamide (2×), methanol (2×), and dichloromethane (5×), and dried in vacuo. 
     C. Preparation of 4-chloromethyl-3-methoxyphenyloxy Merrifield resin (XVII) 
     To a solution of triphenylphosphine (17 g, 65 mmol) in dichloromethane (200 mL) at 0° C. was slowly added triphosgene (9.2 g, 31 mmol) portionwise over a period of 30 minutes. After addition, the reaction mixture was stirred at 0° C. for 10 minutes. The solvent was removed in vacuo and the residue was redissolved in dichloromethane (200 mL). To this mixture was added 4-hydroxymethyl-3-methoxyphenyloxy Merrifield resin (12 g). The resulting mixture was agitated for 4 h. The resin was washed with dry dichloromethane (6×) and dried in vacuo. 
     D. Preparation of 4-[N-[(5-thiocyanato)-2-thiazolytryfluoroacetamido]methyl]methoxyphenyloxy Merrifield resin (XIX) 
     A mixture of 4-chloromethyl-3-methoxyphenyloxy Merrifield resin (15 g), N-[(5-thiocyanato)-2-thiazolyl]trifluoroacetamide (14 g, 55.3 mmol) and diisopropylethylamine (7.8 mL, 45 mmol) in dimethylformamide (50 mL) and dichloromethane (100 mL) was agitated overnight. The resin was washed with dimethylformamide (2×), methanol (2×), dichloromethane (4×), and dried in uacuo. 
     E. Preparation of 4-[[N-[(5-mercapto)-2-thiazolyl]trifluoroacetamido]methyl]-3-methoxyphenyloxy Merrifield resin (XX) 
     A mixture of 4-[N-[(5-thiocyanato)-2-thiazolyltrifluoroacetamido]methyl]-3-methoxyphenyloxy Merrifield resin (XIX, 18.5 g) and dithiothreitol (12 g, 78 mmol) in tetrahydrofuran (100 mL) and methanol (100 mL) was agitated overnight. The resin was washed with dimethylformamide (2×), methanol (2×), dichloromethane (4×), and dried in vacuo and stored under argon at -20° C. 
     F. Preparation of 4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trifloroacetamnido]methyl-3-methoxyphenyloxy Merrifield resin (XX) 
     A stream of argon was bubb led through a mixture 4-[[N-[(5-Mercapto)-2-thiazolyl]trifluoroacetamido]methyl]-3-methoxyphenyloxy Merrifield resin (XX, 500 mg), halide (2.0 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1.5 mmol) in dimethylformamide (3 mL) for 5 min., and the mixture was heated at 80° C. for 2 h. The resin was washed with dimethylformamide (2×), methanol (2×), dichloromethane (4×), and dried in vacuo. 
     G. Preparation of 4-N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]methyl-3-methoxyphenyloxy Merrifield resin (XXII) 
     A mixture of 4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trifluoroacetamido]methyl-3-methoxyphenyloxy Merrifield resin (XXI, 500 mg ) and sodium borohydride (4 mmol) in tetrahydrofuran (2 mL) and ethanol (2 mL) was agitated overnight. The resin was washed with 50% dimethylformamide in water (2×), dimethylformamide (2×), methanol (2×), dichloromethane (4×), and dried in vacuo. 
     H. Preparation of 4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamido]methyl-3-methoxyphenyloxy Merrifield resin (XXIII) 
     A mixture of 4-N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]methyl-3-methoxyphenyloxy Merrifield resin (XXII, 100 mg), diisopropylethylamine (1.2 mmol) and trimethylacetyl chloride (1 mmol) in dichloromethane (2 mL) in a polypropylene tube fitted with a polyethylene frit and a luer stopcock was agitated overnight. The resin was washed with dimethylformamide (2×), methanol (2×), dichloromethane (4×), and used in the next step without drying. 
     I. Preparation of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamide 
     4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamido]methyl-3-methoxyphenyloxy Merrifield resin (XXIII) was treated with 60% trifluoroacetic acid in dichloromethane (2 mL) in a polypropylene tube fitted with a polyethylene frit and a luer stopcock for 4 hours. The solution was decanted to a tube and the resin was washed with dichloromethane. The combined organic solution was concentrated in Speed Vac. The residue was purified by preparative-HPLC to afford 11.3 mg of the desired product. 
     MS m/e 354 (M+H) + . ##STR16## A. Preparation of 2-(2-chloroacetamido)-1-butanol 
     To a mixture of 2-amino-1-butanol (5.0 mL, 53 mmol) and triethyl amine (15.0 mL, 111 mmol) in dichloromethane (20 mL) at -70° C. was added chloroacetyl chloride (4.6 mL, 58 mmol) dropwise. The reaction mixture was stirred at -70° C. for 15 min. and then was allowed to warm to rt. It was diluted with EtOAc (50 mL) and the reaction was quenched by adding water (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers was concentrated to afford 2-(2-chloroacetamido)-1-butanol (8.6 g, 98%) as a brown solid.  1  H NMR (CDCl 3 ) δ6.75 (bs, 1 H), 4.10 (s, 2 H), 4.08 (dd, 1 H), 3.90 (m, 1 H), 3.68 (m, 2 H), 2.98 (bs, 1 H), 1.60 (m, 2 H), 0.97 (t, 3 H). 
     B. Preparation of 2-(2-chloroacetamido)-1-butyraldehyde 
     To a solution of oxalyl chloride (14.5 mL, 29.0 mmol) in dichrolomethane (30 mL) at -78° C. DMSO (2.75 mL, 38.8 mmol) was added dropwise over 5 min. After stirring for 10 min. at -78° C., here was added a solution of 2-(2-chloroacetamido)-1-butanol (4.0 g, 24 mmol) in 20 mL of dichrolomethane dropwise over 15 min. The reaction mixture was stirred for 40 min. at -78° C. and here was added triethyl amine (9.4 mL, 68 mmol) dropwise over 5 min. and the reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The solid was removed by filtration and washed with EtOAc. The organic phase was washed with 1 N HCl (2×100 mL), saturated aqueous NaHCO 3  (1×10 mL) and concentrated to afford 2-(2-chloroacetamido)-1-butyraldehyde (3.7 g, 95%) as a brown oil. 
       1  H NMR (CDCl 3 ) δ9.60 (s, 1 H), 4.52 (q, 1 H), 4.12 (s, 2 H), 2.05 (m, 1 H), 1.80 (m, 1 H), 0.97 (t, 3 H). 
     C. Preparation of 2-chloromethy-4-ethyloxazole 
     To a solution of 2-(2-chloroacetamido)-1-butyraldehyde (3.7 g, 23 mmol) in toluene (10 mL) was added POCl 3  (6.3 mL, 68 mmol). The reaction mixture was heated at 90° C. for 1 h under nitrogen. After cooling the reaction mixture to room temperature it was poured into ice water (10 mL) and the pH of the solution was adjusted to 7 with 5 N NaOH. The toluene layer was separated and the aqueous layer was washed with dichloromethane (3×20 mL). The combined organic solution was concentrated and distilled to afford 2-chloromethy-4-ethyloxazole (1.1 g, 31%) as a colorless liquid. 
       1  H NMR (CDCl 3 ) δ7.30 (s, 1 H), 4.22 (s, 2 H), 2.50 (q, 2 H), 1.22 (t, 3 H). 
     D. Preparation of N-[5-[[(4-ethyl-2-oxazolyl)methyl]thiol]-2-thiazolyl]acetamide 
     To a solution of 2-acetylamino-5-thiazolylthiol (0.010 g, 0.050 mmol) in dry THF (5 mL) was added potassium tert-butoxide (1.0 M solution in THF, 0.060 mL, 0.060 mmol). The reaction mixture was stirred at room temperature for 15 min. and here was added 2-chloromethyl-4-ethyloxazole (0.015 g, 0.10 mmol). After 3 h, saturated aqueous NaHCO 3  solution (5 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (3×10 mL). The combined organic layers was concentrated. The residue was purified by flash chromatography (SiO 2  ; methanol:dichloromethane/1:20) to afford N-[5-[[(4-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (5 mg, 36%) as a white solid. 
       1  H NMR (CDCl 3 ) δ11.25 (s, 1 H), 7.34 (s, 1 H), 7.31 (s, 1 H), 3.95 (s, 2 H), 2.50 (q, 2 H), 2.27 (s, 3 H), 1.19 (t, 3 H); MS m/e 284 (M+H) +  ; HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 ml/min; solvent system: 0-100% B in 8 min. Solvent A: 10% CH 3  OH/90% H 2  O/0.2% H 3  PO 4  ; Solvent B: 90% CH 3  OH/10% H 2  O/0.2% H 3  PO 4  ; UV: 254 nm): retention time 6.14 min. 
     Using the procedures described herein or by modification of the procedures described herein as known to one or ordinary skill in the art, the following additional compounds have been prepared and disclosed in Table 1: 
     
                                           TABLE 1                                 
__________________________________________________________________________
Example                                                                   
     Structure                              Molecular Formula             
                                                     (M                   
__________________________________________________________________________
                                                     + H)+                
 8                                                                        
      ##STR17##                             C9H11N3OS2                    
                                                     242                  
 9                                                                        
      ##STR18##                             C12H15N3O2S2                  
                                                     298                  
 10                                                                       
      ##STR19##                             C13H17N3O2S2                  
                                                     312                  
 11                                                                       
      ##STR20##                             C10H13N3O3S3                  
                                                     320                  
 12                                                                       
      ##STR21##                             C11H10F3N3O2S2                
                                                     338                  
 13                                                                       
      ##STR22##                             C14H19N3O2S2                  
                                                     326                  
 14                                                                       
      ##STR23##                             C21H17N3O2S2                  
                                                     408                  
 15                                                                       
      ##STR24##                             C17H24N4O2S2                  
                                                     381                  
 16                                                                       
      ##STR25##                             C17H17N3O2S2                  
                                                     360                  
 17                                                                       
      ##STR26##                             C15H19N3O2S2                  
                                                     338                  
 18                                                                       
      ##STR27##                             C17H17N3O3S2                  
                                                     376                  
 19                                                                       
      ##STR28##                             C17H23N3O2S2                  
                                                     366                  
 20                                                                       
      ##STR29##                             C14H19N3O2S2                  
                                                     326                  
 21                                                                       
      ##STR30##                             C13H15N3O2S2                  
                                                     310                  
 22                                                                       
      ##STR31##                             C15H13N3O2S2                  
                                                     332                  
 23                                                                       
      ##STR32##                             C13H11N3O2S2                  
                                                     306                  
 24                                                                       
      ##STR33##                             C10H11N3O2S2                  
                                                     270                  
 25                                                                       
      ##STR34##                             C12H15N3O2S2                  
                                                     298                  
 26                                                                       
      ##STR35##                             C13H16BrN3O2S2                
                                                     391                  
 27                                                                       
      ##STR36##                             C15H12FN3O2S2                 
                                                     350                  
 28                                                                       
      ##STR37##                             C13H15N3O4S2                  
                                                     342                  
 29                                                                       
      ##STR38##                             C15H21N3O2S2                  
                                                     340                  
 30                                                                       
      ##STR39##                             C19H21N3O2S2                  
                                                     388                  
 31                                                                       
      ##STR40##                             C18H17N3O4S2                  
                                                     404                  
 32                                                                       
      ##STR41##                             C15H19N3O4S2                  
                                                     370                  
 33                                                                       
      ##STR42##                             C14H17N3O4S2                  
                                                     356                  
 34                                                                       
      ##STR43##                             C16H19N3O3S2                  
                                                     366                  
 35                                                                       
      ##STR44##                             C16H21N3O4S2                  
                                                     384                  
 36                                                                       
      ##STR45##                             C15H19N3O4S2                  
                                                     370                  
 37                                                                       
      ##STR46##                             C16H21N3O4S2                  
                                                     384                  
 38                                                                       
      ##STR47##                             C18H17N3O4S2                  
                                                     404                  
 39                                                                       
      ##STR48##                             C15H19N3O4S2                  
                                                     370                  
 40                                                                       
      ##STR49##                             C16H14FN3O2S2                 
                                                     364                  
 41                                                                       
      ##STR50##                             C16H14ClN3O2S2                
                                                     380                  
 42                                                                       
      ##STR51##                             C16H13Cl2N3O2S2               
                                                     415                  
 43                                                                       
      ##STR52##                             C18H19N3O4S2                  
                                                     406                  
 44                                                                       
      ##STR53##                             C18H19N3O4S2                  
                                                     406                  
 45                                                                       
      ##STR54##                             C18H19N3O4S2                  
                                                     406                  
 46                                                                       
      ##STR55##                             C18H19N3O2S2                  
                                                     374                  
 47                                                                       
      ##STR56##                             C18H20N4O2S2                  
                                                     503                  
 48                                                                       
      ##STR57##                             C17H17N3O2S2                  
                                                     360                  
 49                                                                       
      ##STR58##                             C18H19N3O2S2                  
                                                     374                  
 50                                                                       
      ##STR59##                             C18H19N3O2S2                  
                                                     374                  
 51                                                                       
      ##STR60##                             C18H20N4O2S2                  
                                                     503                  
 52                                                                       
      ##STR61##                             C18H20N4O2S2                  
                                                     503                  
 53                                                                       
      ##STR62##                             C19H16N4O2S2                  
                                                     511                  
 54                                                                       
      ##STR63##                             C18H16N4O2S2                  
                                                     499                  
 55                                                                       
      ##STR64##                             C18H16N4O2S2                  
                                                     499                  
 56                                                                       
      ##STR65##                             C16H13F2N3O2S2                
                                                     382                  
 57                                                                       
      ##STR66##                             C17H15ClFN3O2S2               
                                                     412                  
 58                                                                       
      ##STR67##                             C19H19N3O4S2                  
                                                     418                  
 59                                                                       
      ##STR68##                             C18H16F3N3O2S2                
                                                     428                  
 60                                                                       
      ##STR69##                             C17H16FN3O2S2                 
                                                     378                  
 61                                                                       
      ##STR70##                             C17H16N4O4S2                  
                                                     405                  
 62                                                                       
      ##STR71##                             C17H16N4O4S2                  
                                                     405                  
 63                                                                       
      ##STR72##                             C19H21N3O4S2                  
                                                     420                  
 64                                                                       
      ##STR73##                             C19H17N3O3S2                  
                                                     400                  
 65                                                                       
      ##STR74##                             C12H15N3O3S2                  
                                                     314                  
 66                                                                       
      ##STR75##                             C13H17N3O3S2                  
                                                     328                  
 67                                                                       
      ##STR76##                             C15H14N4O2S2                  
                                                     461                  
 68                                                                       
      ##STR77##                             C16H19N3O2S2                  
                                                     350                  
 69                                                                       
      ##STR78##                             C15H17N5O2S2                  
                                                     364                  
 70                                                                       
      ##STR79##                             C13H14F3N3O2S2                
                                                     366                  
 71                                                                       
      ##STR80##                             C15H15N3O2S3                  
                                                     366                  
 72                                                                       
      ##STR81##                             C17H23N3O2S2                  
                                                     366                  
 73                                                                       
      ##STR82##                             C16H16N4O2S2                  
                                                     475                  
 74                                                                       
      ##STR83##                             C12H16N4O2S2                  
                                                     427                  
 75                                                                       
      ##STR84##                             C18H19N3O3S2                  
                                                     390                  
 76                                                                       
      ##STR85##                             C18H18N4O3S2                  
                                                     403                  
 77                                                                       
      ##STR86##                             C22H19N3O3S2                  
                                                     438                  
 78                                                                       
      ##STR87##                             C17H17N3O3S2                  
                                                     376                  
 79                                                                       
      ##STR88##                             C22H19N3O2S2                  
                                                     422                  
 80                                                                       
      ##STR89##                             C16H14ClN3O2S2                
                                                     380                  
 81                                                                       
      ##STR90##                             C17H17N3O3S2                  
                                                     376                  
 82                                                                       
      ##STR91##                             C16H14ClN3O2S2                
                                                     380                  
 83                                                                       
      ##STR92##                             C17H17N3O3S2                  
                                                     376                  
 84                                                                       
      ##STR93##                             C17H15N3O4S2                  
                                                     390                  
 85                                                                       
      ##STR94##                             C17H14N4O2S3                  
                                                     403                  
 86                                                                       
      ##STR95##                             C17H16ClN3O2S2                
                                                     394                  
 87                                                                       
      ##STR96##                             C18H19N3O3S2                  
                                                     390                  
 88                                                                       
      ##STR97##                             C19H19N3O2S2                  
                                                     386                  
 89                                                                       
      ##STR98##                             C21H23N3O2S2                  
                                                     414                  
 90                                                                       
      ##STR99##                             C17H16ClN3O2S2                
                                                     394                  
 91                                                                       
      ##STR100##                            C18H19N3O3S2                  
                                                     390                  
 92                                                                       
      ##STR101##                            C17H16ClN3O2S2                
                                                     394                  
 93                                                                       
      ##STR102##                            C18H17N3O4S2                  
                                                     404                  
 94                                                                       
      ##STR103##                            C25H22N4O2S2                  
                                                     589                  
 95                                                                       
      ##STR104##                            C14H17N3O3S2                  
                                                     340                  
 96                                                                       
      ##STR105##                            C14H17N3O3S2                  
                                                     340                  
 97                                                                       
      ##STR106##                            C15H14N4O2S2                  
                                                     461                  
 98                                                                       
      ##STR107##                            C16H21N3O2S2                  
                                                     352                  
 99                                                                       
      ##STR108##                            C18H17N3O3S2                  
                                                     388                  
100                                                                       
      ##STR109##                            C16H16N4O2S2                  
                                                     475                  
101                                                                       
      ##STR110##                            C19H18N4O2S2                  
                                                     513                  
102                                                                       
      ##STR111##                            C17H14N4O2S2                  
                                                     371                  
103                                                                       
      ##STR112##                            C20H17N3O2S2                  
                                                     396                  
104                                                                       
      ##STR113##                            C21H18N4O3S2                  
                                                     553                  
105                                                                       
      ##STR114##                            C23H21N3O3S2                  
                                                     452                  
106                                                                       
      ##STR115##                            C20H21N3O2S2                  
                                                     400                  
107                                                                       
      ##STR116##                            C22H23N3O3S2                  
                                                     442                  
108                                                                       
      ##STR117##                            C17H15N5O2S2                  
                                                     500                  
109                                                                       
      ##STR118##                            C18H18N4O3S2                  
                                                     403                  
110                                                                       
      ##STR119##                            C17H17N5O2S3                  
                                                     420                  
111                                                                       
      ##STR120##                            C17H16BrN3O2S2                
                                                     439                  
112                                                                       
      ##STR121##                            C17H16FN3O2S2                 
                                                     378                  
113                                                                       
      ##STR122##                            C17H15Cl2N3O2S2               
                                                     429                  
114                                                                       
      ##STR123##                            C17H15N3O3S2                  
                                                     374                  
115                                                                       
      ##STR124##                            C18H19N3O2S2                  
                                                     374                  
116                                                                       
      ##STR125##                            C17H16BrN3O2S2                
                                                     439                  
117                                                                       
      ##STR126##                            C18H19N3O2S2                  
                                                     374                  
118                                                                       
      ##STR127##                            C17H16BrN3O2S2                
                                                     439                  
119                                                                       
      ##STR128##                            C18H19N3O2S2                  
                                                     374                  
120                                                                       
      ##STR129##                            C18H16N4O2S2                  
                                                     499                  
121                                                                       
      ##STR130##                            C17H15F2N3O2S2                
                                                     396                  
122                                                                       
      ##STR131##                            C17H15F2N3O2S2                
                                                     396                  
123                                                                       
      ##STR132##                            C17H15F2N3O2S2                
                                                     396                  
124                                                                       
      ##STR133##                            C20H23N3O2S2                  
                                                     402                  
125                                                                       
      ##STR134##                            C18H19N3O3S2                  
                                                     390                  
126                                                                       
      ##STR135##                            C17H18N4O2S2                  
                                                     489                  
127                                                                       
      ##STR136##                            C14H17N3O2S2                  
                                                     324                  
128                                                                       
      ##STR137##                            C13H17N3O3S2                  
                                                     328                  
129                                                                       
      ##STR138##                            C14H13N3O3S2                  
                                                     336                  
130                                                                       
      ##STR139##                            C14H13N3O3S2                  
                                                     336                  
131                                                                       
      ##STR140##                            C15H21N3O2S2                  
                                                     340                  
132                                                                       
      ##STR141##                            C15H21N3O2S2                  
                                                     340                  
133                                                                       
      ##STR142##                            C15H21N3O2S2                  
                                                     340                  
134                                                                       
      ##STR143##                            C15H21N3O2S2                  
                                                     340                  
135                                                                       
      ##STR144##                            C14H13N5O2S2                  
                                                     348                  
136                                                                       
      ##STR145##                            C15H15N3O3S2                  
                                                     350                  
137                                                                       
      ##STR146##                            C14H17N3O4S2                  
                                                     356                  
138                                                                       
      ##STR147##                            C14H15N5O2S2                  
                                                     464                  
139                                                                       
      ##STR148##                            C19H21N3O2S2                  
                                                     388                  
140                                                                       
      ##STR149##                            C16H16N4O2S2                  
                                                     475                  
141                                                                       
      ##STR150##                            C19H18N4O2S2                  
                                                     513                  
142                                                                       
      ##STR151##                            C15H17N5O2S2                  
                                                     478                  
143                                                                       
      ##STR152##                            C19H21N3O3S2                  
                                                     404                  
144                                                                       
      ##STR153##                            C12H16N4O2S2                  
                                                     427                  
145                                                                       
      ##STR154##                            C20H20N4O2S2                  
                                                     527                  
146                                                                       
      ##STR155##                            C13H18N4O2S2                  
                                                     441                  
147                                                                       
      ##STR156##                            C19H18N4O4S2                  
                                                     431                  
148                                                                       
      ##STR157##                            C14H17N3O2S2                  
                                                     324                  
149                                                                       
      ##STR158##                            C15H21N3O2S2                  
                                                     340                  
150                                                                       
      ##STR159##                            C13H14N4O3S3                  
                                                     371                  
151                                                                       
      ##STR160##                            C15H20N4O2S2                  
                                                     467                  
152                                                                       
      ##STR161##                            C17H22N4O3S2                  
                                                     395                  
153                                                                       
      ##STR162##                            C14H17N3O2S2                  
                                                     324                  
154                                                                       
      ##STR163##                            C19H18N4O2S2                  
                                                     513                  
155                                                                       
      ##STR164##                            C14H19N3O2S2                  
                                                     326                  
156                                                                       
      ##STR165##                            C19H21N3O2S2                  
                                                     388                  
157                                                                       
      ##STR166##                            C16H13Cl2N3O2S2               
                                                     415                  
158                                                                       
      ##STR167##                            C17H17N3O2S2                  
                                                     360                  
159                                                                       
      ##STR168##                            C16H12F3N3O2S2                
                                                     400                  
160                                                                       
      ##STR169##                            C20H18N4O2S2                  
                                                     525                  
161                                                                       
      ##STR170##                            C20H18N4O2S2                  
                                                     525                  
162                                                                       
      ##STR171##                            C19H21N3O2S2                  
                                                     388                  
163                                                                       
      ##STR172##                            C19H21N3O4S2                  
                                                     420                  
164                                                                       
      ##STR173##                            C17H16FN3O2S2                 
                                                     378                  
165                                                                       
      ##STR174##                            C20H23N3O5S2                  
                                                     450                  
166                                                                       
      ##STR175##                            C18H16F3N3O2S2                
                                                     428                  
167                                                                       
      ##STR176##                            C19H21N3O2S2                  
                                                     388                  
168                                                                       
      ##STR177##                            C19H21N3O2S2                  
                                                     388                  
169                                                                       
      ##STR178##                            C18H19N3O2S2                  
                                                     374                  
170                                                                       
      ##STR179##                            C17H17N3O3S2                  
                                                     376                  
171                                                                       
      ##STR180##                            C19H22N4O2S2                  
                                                     517                  
172                                                                       
      ##STR181##                            C19H21N3O2S2                  
                                                     388                  
173                                                                       
      ##STR182##                            C19H21N3O4S2                  
                                                     420                  
174                                                                       
      ##STR183##                            C17H15F2N3O2S2                
                                                     396                  
175                                                                       
      ##STR184##                            C14H15N5O2S2                  
                                                     350                  
176                                                                       
      ##STR185##                            C15H14N3O2S2                  
                                                     461                  
177                                                                       
      ##STR186##                            C18H19N3O3S2                  
                                                     390                  
178                                                                       
      ##STR187##                            C18H19N3O4S2                  
                                                     406                  
179                                                                       
      ##STR188##                            C22H19N3O3S2                  
                                                     438                  
180                                                                       
      ##STR189##                            C17H16N4O4S2                  
                                                     405                  
181                                                                       
      ##STR190##                            C20H23N3O2S2                  
                                                     402                  
182                                                                       
      ##STR191##                            C23H21N3O2S2                  
                                                     436                  
183                                                                       
      ##STR192##                            C24H23N3O2S2                  
                                                     450                  
184                                                                       
      ##STR193##                            C23H21N3O2S2                  
                                                     436                  
185                                                                       
      ##STR194##                            C - 21H19N3O2S2               
                                                     410                  
186                                                                       
      ##STR195##                            C21H19N3O2S2                  
                                                     410                  
187                                                                       
      ##STR196##                            C17H15Cl2N3O2S2               
                                                     429                  
188                                                                       
      ##STR197##                            C19H21N3O4S2                  
                                                     420                  
189                                                                       
      ##STR198##                            C18H19N3O2S2                  
                                                     374                  
190                                                                       
      ##STR199##                            C19H18F3N3O3S2                
                                                     458                  
191                                                                       
      ##STR200##                            C22H27N3O2S2                  
                                                     430                  
192                                                                       
      ##STR201##                            C18H19N3O2S2                  
                                                     374                  
193                                                                       
      ##STR202##                            C12H15N3O2S2                  
                                                     298                  
194                                                                       
      ##STR203##                            C18H26N4O4S2                  
                                                     427                  
195                                                                       
      ##STR204##                            C12H13N3O4S2                  
                                                     328                  
196                                                                       
      ##STR205##                            C11H13N3O4S2                  
                                                     316                  
197                                                                       
      ##STR206##                            C11H13N3O3S2                  
                                                     300                  
198                                                                       
      ##STR207##                            C11H15N3OS2                   
                                                     270                  
199                                                                       
      ##STR208##                            C10H13N3OS2                   
                                                     256                  
200                                                                       
      ##STR209##                            C17H16N4O4S2                  
                                                     405                  
201                                                                       
      ##STR210##                            C19H20N4O2S2                  
                                                     401                  
202                                                                       
      ##STR211##                            C16H15BrN4O2S2                
                                                     440                  
203                                                                       
      ##STR212##                            C17H16N6O2S2                  
                                                     515                  
204                                                                       
      ##STR213##                            C19H17N5O2S2                  
                                                     526                  
205                                                                       
      ##STR214##                            C20H23N5O3S2                  
                                                     560                  
206                                                                       
      ##STR215##                            C16H16N4O2S2                  
                                                     361                  
207                                                                       
      ##STR216##                            C16H14F2N4O2S2                
                                                     397                  
208                                                                       
      ##STR217##                            C16H15ClN4O2S2                
                                                     395                  
209                                                                       
      ##STR218##                            C17H18N4O3S2                  
                                                     391                  
210                                                                       
      ##STR219##                            C17H18N4O2S2                  
                                                     375                  
211                                                                       
      ##STR220##                            C16H15BrN4O2S2                
                                                     440                  
212                                                                       
      ##STR221##                            C16H15ClN4O2S2                
                                                     395                  
213                                                                       
      ##STR222##                            C16H14Cl2N4O2S2               
                                                     430                  
214                                                                       
      ##STR223##                            C17H17ClN4O3S2                
                                                     425                  
215                                                                       
      ##STR224##                            C17H18N4O3S2                  
                                                     391                  
216                                                                       
      ##STR225##                            C16H15BrN4O2S2                
                                                     440                  
217                                                                       
      ##STR226##                            C16H15FN4O2S2                 
                                                     379                  
218                                                                       
      ##STR227##                            C17H18N4O2S2                  
                                                     375                  
219                                                                       
      ##STR228##                            C17H18N4O3S2                  
                                                     391                  
220                                                                       
      ##STR229##                            C16H15ClN4O2S2                
                                                     395                  
221                                                                       
      ##STR230##                            C18H19N5O3S2                  
                                                     418                  
222                                                                       
      ##STR231##                            C17H18N4O3S2                  
                                                     391                  
223                                                                       
      ##STR232##                            C18H21N5O2S2                  
                                                     518                  
224                                                                       
      ##STR233##                            C16H15FN4O2S2                 
                                                     379                  
225                                                                       
      ##STR234##                            C16H15FN4O2S2                 
                                                     379                  
226                                                                       
      ##STR235##                            C17H18N4O2S2                  
                                                     375                  
227                                                                       
      ##STR236##                            C17H17N5O3S2                  
                                                     404                  
228                                                                       
      ##STR237##                            C17H15N5O2S3                  
                                                     418                  
229                                                                       
      ##STR238##                            C17H16N6O2S2                  
                                                     401                  
230                                                                       
      ##STR239##                            C16H15N7O2S2                  
                                                     402                  
231                                                                       
      ##STR240##                            C16H17N5O2S2                  
                                                     490                  
232                                                                       
      ##STR241##                            C15H20N4O2S2                  
                                                     353                  
233                                                                       
      ##STR242##                            C17H17ClN4O2S2                
                                                     409                  
234                                                                       
      ##STR243##                            C17H19N5O2S2                  
                                                     504                  
235                                                                       
      ##STR244##                            C17H19N5O2S2                  
                                                     504                  
236                                                                       
      ##STR245##                            C19H18N6O2S3                  
                                                     459                  
237                                                                       
      ##STR246##                            C15H16N4O2S3                  
                                                     381                  
238                                                                       
      ##STR247##                            C15H20N4O3S2                  
                                                     369                  
239                                                                       
      ##STR248##                            C16H20N6O2S2                  
                                                     507                  
240                                                                       
      ##STR249##                            C18H25N5O4S2                  
                                                     440                  
241                                                                       
      ##STR250##                            C17H24N4O2S2                  
                                                     381                  
242                                                                       
      ##STR251##                            C18H20N4O2S2                  
                                                     389                  
243                                                                       
      ##STR252##                            C17H18N4O2S2                  
                                                     375                  
244                                                                       
      ##STR253##                            C18H20N4O2S2                  
                                                     389                  
245                                                                       
      ##STR254##                            C19H22N4O2S2                  
                                                     403                  
246                                                                       
      ##STR255##                            C17H19N5O2S2                  
                                                     504                  
247                                                                       
      ##STR256##                            C17H17ClN4O2S2                
                                                     409                  
248                                                                       
      ##STR257##                            C16H17N5O2S2                  
                                                     490                  
249                                                                       
      ##STR258##                            C17H25N5O2S2                  
                                                     510                  
250                                                                       
      ##STR259##                            C16H17N5O2S2                  
                                                     490                  
251                                                                       
      ##STR260##                            C17H25N5O2S2                  
                                                     510                  
252                                                                       
      ##STR261##                            C18H20N4O2S2                  
                                                     389                  
253                                                                       
      ##STR262##                            C15H16N4O3S2                  
                                                     365                  
254                                                                       
      ##STR263##                            C17H16F2N4O2S2                
                                                     411                  
255                                                                       
      ##STR264##                            C15H22N4O2S2                  
                                                     355                  
256                                                                       
      ##STR265##                            C14H18N4O2S2                  
                                                     339                  
257                                                                       
      ##STR266##                            C14H20N4O2S2                  
                                                     341                  
258                                                                       
      ##STR267##                            C15H22N4O2S2                  
                                                     355                  
259                                                                       
      ##STR268##                            C17H17ClN4O2S2                
                                                     409                  
260                                                                       
      ##STR269##                            C18H20N4O2S2                  
                                                     389                  
261                                                                       
      ##STR270##                            C18H20N4O3S2                  
                                                     405                  
262                                                                       
      ##STR271##                            C18H20N4O3S2                  
                                                     405                  
263                                                                       
      ##STR272##                            C18H20N4O3S2                  
                                                     405                  
264                                                                       
      ##STR273##                            C16H22N4O3S2                  
                                                     341                  
265                                                                       
      ##STR274##                            C14H20N4O2S2                  
                                                     512                  
266                                                                       
      ##STR275##                            C17H27N5O2S2                  
                                                     353                  
267                                                                       
      ##STR276##                            C16H22N4O3S2                  
                                                     425                  
268                                                                       
      ##STR277##                            C18H24N4O4S2                  
                                                     401                  
269                                                                       
      ##STR278##                            C19H20N4O2S2                  
                                                     383                  
270                                                                       
      ##STR279##                            C17H26N4O2S2                  
                                                     355                  
271                                                                       
      ##STR280##                            C15H22N4O2S2                  
                                                     433                  
272                                                                       
      ##STR281##                            C19H20N4O4S2                  
                                                     512                  
273                                                                       
      ##STR282##                            C16H21N5O3S2                  
                                                     353                  
274                                                                       
      ##STR283##                            C15H20N4O3S2                  
                                                     367                  
275                                                                       
      ##STR284##                            C16H22N4O2S2                  
                                                     389                  
276                                                                       
      ##STR285##                            C16H21N5O3S2                  
                                                     425                  
277                                                                       
      ##STR286##                            C18H24N4O4S2                  
                                                     369                  
278                                                                       
      ##STR287##                            C13H18N4O2S2                  
                                                     465                  
279                                                                       
      ##STR288##                            C13H14N6O2S2                  
                                                     493                  
280                                                                       
      ##STR289##                            C15H18N6O2S2                  
                                                     466                  
281                                                                       
      ##STR290##                            C12H13N7O2S2                  
                                                     366                  
282                                                                       
      ##STR291##                            C14H15N5O3S2                  
                                                     366                  
283                                                                       
      ##STR292##                            C13H14N6O2S3                  
                                                     409                  
284                                                                       
      ##STR293##                            C17H17ClN4O2S2                
                                                     387                  
285                                                                       
      ##STR294##                            C18H18N4O2S2                  
                                                     375                  
286                                                                       
      ##STR295##                            C17H18N4O2S2                  
                                                     405                  
287                                                                       
      ##STR296##                            C18H20N4O3S2                  
                                                     389                  
288                                                                       
      ##STR297##                            C17H16F2N4O2S2                
                                                     490                  
289                                                                       
      ##STR298##                            C16H17N5O2S2                  
                                                     476                  
290                                                                       
      ##STR299##                            C15H15N5O2S2                  
                                                     510                  
291                                                                       
      ##STR300##                            C15H14ClN5O2S2                
                                                     490                  
292                                                                       
      ##STR301##                            C16H17N5O2S2                  
                                                     490                  
293                                                                       
      ##STR302##                            C16H17N5O2S2                  
                                                     476                  
294                                                                       
      ##STR303##                            C15H15N5O2S2                  
                                                     526                  
295                                                                       
      ##STR304##                            C15H15N5O2S2                  
                                                     540                  
296                                                                       
      ##STR305##                            C18H29N5O2S2                  
                                                     526                  
297                                                                       
      ##STR306##                            C14H19N3O2S2                  
                                                     326                  
298                                                                       
      ##STR307##                            C21H23N3O2S2                  
                                                     414                  
299                                                                       
      ##STR308##                            C19H25N3O2S2                  
                                                     392                  
300                                                                       
      ##STR309##                            C22H21N3O2S2                  
                                                     424                  
301                                                                       
      ##STR310##                            C22H21N3O2S2                  
                                                     424                  
302                                                                       
      ##STR311##                            C15H19N3O2S2                  
                                                     338                  
303                                                                       
      ##STR312##                            C16H23N3O2S2                  
                                                     354                  
304                                                                       
      ##STR313##                            C18H19N3O2S2                  
                                                     374                  
305                                                                       
      ##STR314##                            C18H16N4O2S2                  
                                                     385                  
306                                                                       
      ##STR315##                            C20H23N3O2S2                  
                                                     402                  
307                                                                       
      ##STR316##                            C18H17F2N3O2S2                
                                                     410                  
308                                                                       
      ##STR317##                            C21H23N3O2S2                  
                                                     414                  
309                                                                       
      ##STR318##                            C18H16N4O2S3                  
                                                     417                  
310                                                                       
      ##STR319##                            C19H19N3O4S2                  
                                                     418                  
311                                                                       
      ##STR320##                            C20H23N3O3S2                  
                                                     418                  
312                                                                       
      ##STR321##                            C18H18N4O4S2                  
                                                     419                  
313                                                                       
      ##STR322##                            C18H18N4O4S2                  
                                                     419                  
314                                                                       
      ##STR323##                            C18H18N4O4S2                  
                                                     419                  
315                                                                       
      ##STR324##                            C19H21N3O4S2                  
                                                     420                  
316                                                                       
      ##STR325##                            C19H21N3O4S2                  
                                                     420                  
317                                                                       
      ##STR326##                            C18H19N5O2S3                  
                                                     434                  
318                                                                       
      ##STR327##                            C18H19N5O2S3                  
                                                     434                  
319                                                                       
      ##STR328##                            C19H18F3N3O2S2                
                                                     442                  
320                                                                       
      ##STR329##                            C18H18BrN3O2S2                
                                                     453                  
321                                                                       
      ##STR330##                            C21H25N3O5S2                  
                                                     464                  
322                                                                       
      ##STR331##                            C23H28N4O4S2                  
                                                     489                  
323                                                                       
      ##STR332##                            C20H21N3O2S2                  
                                                     400                  
324                                                                       
      ##STR333##                            C18H25N3O2S2                  
                                                     380                  
325                                                                       
      ##STR334##                            C19H21N3O2S2                  
                                                     388                  
326                                                                       
      ##STR335##                            C27H26N4O3S2                  
                                                     519                  
327                                                                       
      ##STR336##                            C19H21N3O3S2                  
                                                     404                  
328                                                                       
      ##STR337##                            C20H23N3O2S2                  
                                                     402                  
329                                                                       
      ##STR338##                            C19H21N3O2S2                  
                                                     388                  
330                                                                       
      ##STR339##                            C19H21N3O2S2                  
                                                     388                  
331                                                                       
      ##STR340##                            C19H21N3O3S2                  
                                                     404                  
332                                                                       
      ##STR341##                            C26H28N4O4S3                  
                                                     557                  
333                                                                       
      ##STR342##                            C19H27N3O2S2                  
                                                     394                  
334                                                                       
      ##STR343##                            C22H22N4O3S2                  
                                                     455                  
335                                                                       
      ##STR344##                            C22H25N3O4S2                  
                                                     460                  
336                                                                       
      ##STR345##                            C20H21N3O3S2                  
                                                     416                  
337                                                                       
      ##STR346##                            C15H19N3O4S2                  
                                                     370                  
338                                                                       
      ##STR347##                            C20H18F3N3O2S2                
                                                     454                  
339                                                                       
      ##STR348##                            C24H26N4O3S2                  
                                                     483                  
340                                                                       
      ##STR349##                            C18H19N3O3S2                  
                                                     390                  
341                                                                       
      ##STR350##                            C18H19N3O3S2                  
                                                     390                  
342                                                                       
      ##STR351##                            C20H20N4O2S2                  
                                                     413                  
343                                                                       
      ##STR352##                            C18H19N3O2S2                  
                                                     374                  
344                                                                       
      ##STR353##                            C19H18N4O2S2                  
                                                     399                  
345                                                                       
      ##STR354##                            C17H18N4O2S2                  
                                                     489                  
346                                                                       
      ##STR355##                            C17H18N4O2S2                  
                                                     489                  
347                                                                       
      ##STR356##                            C20H20N4O2S2                  
                                                     413                  
348                                                                       
      ##STR357##                            C20H24N4O2S2                  
                                                     531                  
349                                                                       
      ##STR358##                            C21H22N4O2S2                  
                                                     427                  
350                                                                       
      ##STR359##                            C16H17N5O4S2                  
                                                     408                  
351                                                                       
      ##STR360##                            C19H18N6O2S3                  
                                                     687                  
352                                                                       
      ##STR361##                            C11H15N3OS2                   
                                                     270                  
353                                                                       
      ##STR362##                            C17H19N3OS2                   
                                                     346                  
354                                                                       
      ##STR363##                            C13H19N3OS2                   
                                                     298                  
355                                                                       
      ##STR364##                            C22H25N3O2S2                  
                                                     428                  
356                                                                       
      ##STR365##                            C20H27N3O2S2                  
                                                     406                  
357                                                                       
      ##STR366##                            C23H23N3O2S2                  
                                                     438                  
358                                                                       
      ##STR367##                            C23H23N3O2S2                  
                                                     438                  
359                                                                       
      ##STR368##                            C16H21N3O2S2                  
                                                     352                  
360                                                                       
      ##STR369##                            C17H25N3O2S2                  
                                                     368                  
361                                                                       
      ##STR370##                            C19H21N3O2S2                  
                                                     388                  
362                                                                       
      ##STR371##                            C19H18N4O2S2                  
                                                     399                  
363                                                                       
      ##STR372##                            C21H25N3O2S2                  
                                                     416                  
364                                                                       
      ##STR373##                            C19H19F2N3O2S2                
                                                     424                  
365                                                                       
      ##STR374##                            C22H25N3O2S2                  
                                                     428                  
366                                                                       
      ##STR375##                            C19H18N4O2S3                  
                                                     431                  
367                                                                       
      ##STR376##                            C20H21N3O4S2                  
                                                     432                  
368                                                                       
      ##STR377##                            C21H25N3O3S2                  
                                                     432                  
369                                                                       
      ##STR378##                            C19H20N4O4S2                  
                                                     433                  
370                                                                       
      ##STR379##                            C19H20N4O4S2                  
                                                     433                  
371                                                                       
      ##STR380##                            C20H23N3O4S2                  
                                                     434                  
372                                                                       
      ##STR381##                            C20H23N3O4S2                  
                                                     434                  
373                                                                       
      ##STR382##                            C19H21N5O2S3                  
                                                     448                  
374                                                                       
      ##STR383##                            C19H21N5O2S3                  
                                                     448                  
375                                                                       
      ##STR384##                            C19H20BrN3O2S2                
                                                     467                  
376                                                                       
      ##STR385##                            C22H27N3O5S2                  
                                                     478                  
377                                                                       
      ##STR386##                            C24H30N4O4S2                  
                                                     503                  
378                                                                       
      ##STR387##                            C21H23N3O2S2                  
                                                     414                  
379                                                                       
      ##STR388##                            C19H27N3O2S2                  
                                                     394                  
380                                                                       
      ##STR389##                            C20H23N3O2S2                  
                                                     402                  
381                                                                       
      ##STR390##                            C28H28N4O3S2                  
                                                     533                  
382                                                                       
      ##STR391##                            C20H23N3O3S2                  
                                                     418                  
383                                                                       
      ##STR392##                            C19H20N4O5S2                  
                                                     449                  
384                                                                       
      ##STR393##                            C21H25N3O2S2                  
                                                     416                  
385                                                                       
      ##STR394##                            C25H27N3O3S2                  
                                                     482                  
386                                                                       
      ##STR395##                            C20H23N3O2S2                  
                                                     402                  
387                                                                       
      ##STR396##                            C20H23N3O2S2                  
                                                     402                  
388                                                                       
      ##STR397##                            C20H23N3O3S2                  
                                                     418                  
389                                                                       
      ##STR398##                            C18H20N4O2S2                  
                                                     503                  
390                                                                       
      ##STR399##                            C27H30N4O4S3                  
                                                     571                  
391                                                                       
      ##STR400##                            C20H29N3O2S2                  
                                                     408                  
392                                                                       
      ##STR401##                            C23H24N4O3S2                  
                                                     469                  
393                                                                       
      ##STR402##                            C23H27N3O4S2                  
                                                     474                  
394                                                                       
      ##STR403##                            C21H23N3O3S2                  
                                                     430                  
395                                                                       
      ##STR404##                            C16H21N3O4S2                  
                                                     384                  
396                                                                       
      ##STR405##                            C21H20F3N3O2S2                
                                                     468                  
397                                                                       
      ##STR406##                            C25H28N4O3S2                  
                                                     497                  
398                                                                       
      ##STR407##                            C19H21N3O3S2                  
                                                     404                  
399                                                                       
      ##STR408##                            C21H22N4O2S2                  
                                                     427                  
400                                                                       
      ##STR409##                            C20H20N4O2S2                  
                                                     413                  
401                                                                       
      ##STR410##                            C18H20N4O2S2                  
                                                     503                  
402                                                                       
      ##STR411##                            C18H20N4O2S2                  
                                                     503                  
403                                                                       
      ##STR412##                            C21H22N4O2S2                  
                                                     427                  
404                                                                       
      ##STR413##                            C21H26N4O2S2                  
                                                     545                  
405                                                                       
      ##STR414##                            C22H24N4O2S2                  
                                                     441                  
406                                                                       
      ##STR415##                            C16H19N5O2S3                  
                                                     524                  
407                                                                       
      ##STR416##                            C20H23N3O3S2                  
                                                     418                  
408                                                                       
      ##STR417##                            C16H19N5O2S2                  
                                                     492                  
409                                                                       
      ##STR418##                            C17H19N5O4S2                  
                                                     422                  
410                                                                       
      ##STR419##                            C26H34N4O4S2                  
                                                     531                  
411                                                                       
      ##STR420##                            C24H30N4O4S2                  
                                                     503                  
412                                                                       
      ##STR421##                            C25H32N4O4S2                  
                                                     517                  
413                                                                       
      ##STR422##                            C21H26N4O2S2                  
                                                     545                  
414                                                                       
      ##STR423##                            C19H22N4O2S2                  
                                                     517                  
415                                                                       
      ##STR424##                            C20H24N4O2S2                  
                                                     531                  
416                                                                       
      ##STR425##                            C19H22N4O2S2                  
                                                     403                  
417                                                                       
      ##STR426##                            C16H14F2N4O2S2                
                                                     397                  
418                                                                       
      ##STR427##                            C16H14Cl2N4O2S2               
                                                     430                  
419                                                                       
      ##STR428##                            C18H20N4OS3                   
                                                     405                  
420                                                                       
      ##STR429##                            C16H14Cl2N4OS3                
                                                     446                  
421                                                                       
      ##STR430##                            C21H23N3O2S2                  
                                                     414                  
422                                                                       
      ##STR431##                            C19H25N3O2S2                  
                                                     392                  
423                                                                       
      ##STR432##                            C22H21N3O2S2                  
                                                     424                  
424                                                                       
      ##STR433##                            C22H21N3O2S2                  
                                                     424                  
425                                                                       
      ##STR434##                            C15H19N3O2S2                  
                                                     338                  
426                                                                       
      ##STR435##                            C16H23N3O2S2                  
                                                     354                  
427                                                                       
      ##STR436##                            C18H19N3O2S2                  
                                                     374                  
428                                                                       
      ##STR437##                            C18H16N4O2S2                  
                                                     385                  
429                                                                       
      ##STR438##                            C20H23N3O2S2                  
                                                     402                  
430                                                                       
      ##STR439##                            C18H17F2N3O2S2                
                                                     410                  
431                                                                       
      ##STR440##                            C21H23N3O2S2                  
                                                     414                  
432                                                                       
      ##STR441##                            C18H16N4O2S3                  
                                                     417                  
433                                                                       
      ##STR442##                            C19H19N3O4S2                  
                                                     418                  
434                                                                       
      ##STR443##                            C20H23N3O3S2                  
                                                     418                  
435                                                                       
      ##STR444##                            C18H18N4O4S2                  
                                                     419                  
436                                                                       
      ##STR445##                            C18H18N4O4S2                  
                                                     419                  
437                                                                       
      ##STR446##                            C18H18N4O4S2                  
                                                     419                  
438                                                                       
      ##STR447##                            C19H21N3O4S2                  
                                                     420                  
439                                                                       
      ##STR448##                            C19H21N3O4S2                  
                                                     420                  
440                                                                       
      ##STR449##                            C18H19N5O2S3                  
                                                     434                  
441                                                                       
      ##STR450##                            C18H19N5O2S3                  
                                                     434                  
442                                                                       
      ##STR451##                            C19H18F3N3O2S2                
                                                     442                  
443                                                                       
      ##STR452##                            C18H18BrN3O2S2                
                                                     453                  
444                                                                       
      ##STR453##                            C21H25N3O5S2                  
                                                     464                  
445                                                                       
      ##STR454##                            C23H28N4O4S2                  
                                                     489                  
446                                                                       
      ##STR455##                            C20H21N3O2S2                  
                                                     400                  
447                                                                       
      ##STR456##                            C18H25N3O2S2                  
                                                     380                  
448                                                                       
      ##STR457##                            C19H21N3O2S2                  
                                                     388                  
449                                                                       
      ##STR458##                            C27H26N4O3S2                  
                                                     519                  
450                                                                       
      ##STR459##                            C19H21N3O3S2                  
                                                     404                  
451                                                                       
      ##STR460##                            C18H18N4O5S2                  
                                                     435                  
452                                                                       
      ##STR461##                            C20H23N3O2S2                  
                                                     402                  
453                                                                       
      ##STR462##                            C24H25N3O3S2                  
                                                     468                  
454                                                                       
      ##STR463##                            C19H21N3O2S2                  
                                                     388                  
455                                                                       
      ##STR464##                            C19H21N3O2S2                  
                                                     388                  
456                                                                       
      ##STR465##                            C19H21N3O3S2                  
                                                     404                  
457                                                                       
      ##STR466##                            C17H18N4O2S2                  
                                                     489                  
458                                                                       
      ##STR467##                            C26H28N4O4S3                  
                                                     557                  
459                                                                       
      ##STR468##                            C19H27N3O2S2                  
                                                     394                  
460                                                                       
      ##STR469##                            C22H22N4O3S2                  
                                                     455                  
461                                                                       
      ##STR470##                            C22H25N3O4S2                  
                                                     460                  
462                                                                       
      ##STR471##                            C20H21N3O3S2                  
                                                     416                  
463                                                                       
      ##STR472##                            C15H19N3O4S2                  
                                                     370                  
464                                                                       
      ##STR473##                            C20H18F3N3O2S2                
                                                     454                  
465                                                                       
      ##STR474##                            C24H26N4O3S2                  
                                                     483                  
466                                                                       
      ##STR475##                            C18H19N3O3S2                  
                                                     390                  
467                                                                       
      ##STR476##                            C18H19N3O3S2                  
                                                     390                  
468                                                                       
      ##STR477##                            C20H20N4O2S2                  
                                                     413                  
469                                                                       
      ##STR478##                            C15H21N3O2S2                  
                                                     340                  
470                                                                       
      ##STR479##                            C19H18N4O2S2                  
                                                     399                  
471                                                                       
      ##STR480##                            C17H18N4O2S2                  
                                                     489                  
472                                                                       
      ##STR481##                            C17H18N4O2S2                  
                                                     489                  
473                                                                       
      ##STR482##                            C20H20N4O2S2                  
                                                     413                  
474                                                                       
      ##STR483##                            C20H24N4O2S2                  
                                                     531                  
475                                                                       
      ##STR484##                            C21H22N4O2S2                  
                                                     427                  
476                                                                       
      ##STR485##                            C15H17N5O2S3                  
                                                     510                  
477                                                                       
      ##STR486##                            C19H21N3O3S2                  
                                                     404                  
478                                                                       
      ##STR487##                            C15H17N5O2S2                  
                                                     478                  
479                                                                       
      ##STR488##                            C16H17N5O4S2                  
                                                     408                  
480                                                                       
      ##STR489##                            C25H32N4O4S2                  
                                                     517                  
481                                                                       
      ##STR490##                            C23H28N4O4S2                  
                                                     489                  
482                                                                       
      ##STR491##                            C24H30N4O4S2                  
                                                     503                  
483                                                                       
      ##STR492##                            C19H18N6O2S3                  
                                                     459                  
484                                                                       
      ##STR493##                            C20H24N4O2S2                  
                                                     531                  
485                                                                       
      ##STR494##                            C18H20N4O2S2                  
                                                     503                  
486                                                                       
      ##STR495##                            C19H22N4O2S2                  
                                                     517                  
487                                                                       
      ##STR496##                            C13H18N4O2S2                  
                                                     363                  
488                                                                       
      ##STR497##                            C18H18F2N4O2S2                
                                                     425                  
489                                                                       
      ##STR498##                            C18H18Cl2N4O2S2               
                                                     458                  
490                                                                       
      ##STR499##                            C17H18N4O2S2                  
                                                     489                  
491                                                                       
      ##STR500##                            C18H20N4O2S2                  
                                                     389                  
492                                                                       
      ##STR501##                            C14H19N3O2S2                  
                                                     326                  
493                                                                       
      ##STR502##                            C16H21N3O2S2                  
                                                     352                  
494                                                                       
      ##STR503##                            C14H19N3O2S2                  
                                                     326                  
495                                                                       
      ##STR504##                            C14H19N3O2S2                  
                                                     326                  
496                                                                       
      ##STR505##                            C17H17N3O3S2                  
                                                     376                  
497                                                                       
      ##STR506##                            C18H19N3O3S2                  
                                                     390                  
498                                                                       
      ##STR507##                            C14H19N3O3S2                  
                                                     342                  
499                                                                       
      ##STR508##                            C21H31N3O3S2                  
                                                     438                  
500                                                                       
      ##STR509##                            C10H9BrN4O3S2                 
                                                     378                  
501                                                                       
      ##STR510##                            C19H22N4O3S2                  
                                                     419                  
502                                                                       
      ##STR511##                            C18H20N4O2S2                  
                                                     389                  
503                                                                       
      ##STR512##                            C19H22N4O2S2                  
                                                     403                  
504                                                                       
      ##STR513##                            C19H22N4O2S2                  
                                                     403                  
505                                                                       
      ##STR514##                            C15H21N3O3S2                  
                                                     356                  
506                                                                       
      ##STR515##                            C23H27N3O2S2                  
                                                     442                  
507                                                                       
      ##STR516##                            C21H29N3O2S2                  
                                                     420                  
508                                                                       
      ##STR517##                            C24H25N3O2S2                  
                                                     452                  
509                                                                       
      ##STR518##                            C24H25N3O2S2                  
                                                     452                  
510                                                                       
      ##STR519##                            C17H23N3O2S2                  
                                                     366                  
511                                                                       
      ##STR520##                            C18H27N3O2S2                  
                                                     382                  
512                                                                       
      ##STR521##                            C20H23N3O2S2                  
                                                     402                  
513                                                                       
      ##STR522##                            C20H20N4O2S2                  
                                                     413                  
514                                                                       
      ##STR523##                            C22H27N3O2S2                  
                                                     430                  
515                                                                       
      ##STR524##                            C20H21F2N3O2S2                
                                                     438                  
516                                                                       
      ##STR525##                            C23H27N3O2S2                  
                                                     442                  
517                                                                       
      ##STR526##                            C20H20N4O2S3                  
                                                     445                  
518                                                                       
      ##STR527##                            C21H23N3O4S2                  
                                                     446                  
519                                                                       
      ##STR528##                            C22H27N3O3S2                  
                                                     446                  
520                                                                       
      ##STR529##                            C20H22N4O4S2                  
                                                     447                  
521                                                                       
      ##STR530##                            C20H22N4O4S2                  
                                                     447                  
522                                                                       
      ##STR531##                            C20H22N4O4S2                  
                                                     447                  
523                                                                       
      ##STR532##                            C21H25N3O3S2                  
                                                     432                  
524                                                                       
      ##STR533##                            C21H25N3O4S2                  
                                                     448                  
525                                                                       
      ##STR534##                            C20H23N5O2S3                  
                                                     462                  
526                                                                       
      ##STR535##                            C20H23N5O2S3                  
                                                     462                  
527                                                                       
      ##STR536##                            C21H22F3N3O2S2                
                                                     470                  
528                                                                       
      ##STR537##                            C20H22BrN3O2S2                
                                                     481                  
529                                                                       
      ##STR538##                            C23H29N3O5S2                  
                                                     492                  
530                                                                       
      ##STR539##                            C21H24N4O3S2                  
                                                     445                  
531                                                                       
      ##STR540##                            C22H25N3O4S2                  
                                                     460                  
532                                                                       
      ##STR541##                            C20H29N3O2S2                  
                                                     408                  
533                                                                       
      ##STR542##                            C21H25N3O2S2                  
                                                     416                  
534                                                                       
      ##STR543##                            C29H30N4O3S2                  
                                                     547                  
535                                                                       
      ##STR544##                            C22H27N3O3S2                  
                                                     446                  
536                                                                       
      ##STR545##                            C20H22N4O5S2                  
                                                     463                  
537                                                                       
      ##STR546##                            C22H27N3O2S2                  
                                                     430                  
538                                                                       
      ##STR547##                            C26H29N3O3S2                  
                                                     496                  
539                                                                       
      ##STR548##                            C21H25N3O2S2                  
                                                     416                  
540                                                                       
      ##STR549##                            C25H32N4O4S2                  
                                                     517                  
541                                                                       
      ##STR550##                            C26H34N4O4S2                  
                                                     531                  
542                                                                       
      ##STR551##                            C19H22N4O2S2                  
                                                     517                  
543                                                                       
      ##STR552##                            C17H21N5O4S2                  
                                                     424                  
544                                                                       
      ##STR553##                            C21H31N3O2S2                  
                                                     422                  
545                                                                       
      ##STR554##                            C24H26N4O3S2                  
                                                     483                  
546                                                                       
      ##STR555##                            C24H29N3O4S2                  
                                                     488                  
547                                                                       
      ##STR556##                            C22H25N3O3S2                  
                                                     444                  
548                                                                       
      ##STR557##                            C21H25N3O4S2                  
                                                     448                  
549                                                                       
      ##STR558##                            C21H25N3O3S2                  
                                                     432                  
550                                                                       
      ##STR559##                            C26H30N4O3S2                  
                                                     511                  
551                                                                       
      ##STR560##                            C20H23N3O3S2                  
                                                     418                  
552                                                                       
      ##STR561##                            C20H23N3O3S2                  
                                                     418                  
553                                                                       
      ##STR562##                            C20H23N3O3S2                  
                                                     418                  
554                                                                       
      ##STR563##                            C20H22N4O5S2                  
                                                     463                  
555                                                                       
      ##STR564##                            C17H25N3O2S2                  
                                                     368                  
556                                                                       
      ##STR565##                            C20H23N3O4S2                  
                                                     434                  
557                                                                       
      ##STR566##                            C19H22N4O2S2                  
                                                     517                  
558                                                                       
      ##STR567##                            C19H22N4O2S2                  
                                                     517                  
559                                                                       
      ##STR568##                            C22H24N4O2S2                  
                                                     441                  
560                                                                       
      ##STR569##                            C22H28N4O2S2                  
                                                     559                  
561                                                                       
      ##STR570##                            C23H26N4O2S2                  
                                                     569                  
562                                                                       
      ##STR571##                            C17H21N5O2S3                  
                                                     538                  
563                                                                       
      ##STR572##                            C21H25N3O3S2                  
                                                     432                  
564                                                                       
      ##STR573##                            C17H21N5O2S2                  
                                                     506                  
565                                                                       
      ##STR574##                            C18H21N5O4S2                  
                                                     436                  
566                                                                       
      ##STR575##                            C27H36N4O4S2                  
                                                     545                  
567                                                                       
      ##STR576##                            C25H32N4O4S2                  
                                                     517                  
568                                                                       
      ##STR577##                            C26H34N4O4S2                  
                                                     531                  
569                                                                       
      ##STR578##                            C21H22N6O2S3                  
                                                     487                  
570                                                                       
      ##STR579##                            C22H28N4O2S2                  
                                                     559                  
571                                                                       
      ##STR580##                            C20H24N4O2S2                  
                                                     531                  
572                                                                       
      ##STR581##                            C21H26N4O2S2                  
                                                     545                  
573                                                                       
      ##STR582##                            C20H24N4O2S2                  
                                                     531                  
574                                                                       
      ##STR583##                            C21H26N4O2S2                  
                                                     545                  
575                                                                       
      ##STR584##                            C13H15N3O4S2                  
                                                     342                  
576                                                                       
      ##STR585##                            C11H13N3O3S2                  
                                                     300                  
577                                                                       
      ##STR586##                            C11H14N4O2S2                  
                                                     413                  
578                                                                       
      ##STR587##                            C17H23N3O4S2                  
                                                     398                  
579                                                                       
      ##STR588##                            C16H21N3O4S2                  
                                                     384                  
580                                                                       
      ##STR589##                            C15H21N3O3S2                  
                                                     356                  
581                                                                       
      ##STR590##                            C18H18F2N4O3S2                
                                                     441                  
582                                                                       
      ##STR591##                            C18H18F2N4O4S2                
                                                     457                  
583                                                                       
      ##STR592##                            C15H21N3O5S2                  
                                                     388                  
584                                                                       
      ##STR593##                            C15H21N3O4S2                  
                                                     372                  
585                                                                       
      ##STR594##                            C17H17N3O3S2                  
                                                     376                  
586                                                                       
      ##STR595##                            C21H22Cl2N4O2S2               
                                                     498                  
587                                                                       
      ##STR596##                            C21H22F2N4O2S2                
                                                     465                  
588                                                                       
      ##STR597##                            C14H19N3O2S2                  
                                                     326                  
589                                                                       
      ##STR598##                            C10H11N3O3S2                  
                                                     286                  
590                                                                       
      ##STR599##                            C18H19FN4O4S2                 
                                                     439                  
591                                                                       
      ##STR600##                            C18H19FN4O2S2                 
                                                     407                  
592                                                                       
      ##STR601##                            C18H19FN4O3S2                 
                                                     423                  
593                                                                       
      ##STR602##                            C15H21N3O4S2                  
                                                     372                  
594                                                                       
      ##STR603##                            C14H19N3O3S2                  
                                                     342                  
595                                                                       
      ##STR604##                            C14H19N3O4S2                  
                                                     358                  
596                                                                       
      ##STR605##                            C14H20N4O2S2                  
                                                     341                  
597                                                                       
      ##STR606##                            C18H19FN4O2S2                 
                                                     407                  
598                                                                       
      ##STR607##                            C18H18F2N4O2S2                
                                                     425                  
599                                                                       
      ##STR608##                            C18H17F3N4O2S2                
                                                     443                  
600                                                                       
      ##STR609##                            C18H19ClN4O2S2                
                                                     423                  
601                                                                       
      ##STR610##                            C21H26N4O2S2                  
                                                     431                  
602                                                                       
      ##STR611##                            C15H22N4O3S2                  
                                                     371                  
603                                                                       
      ##STR612##                            C16H24N4O3S2                  
                                                     385                  
604                                                                       
      ##STR613##                            C19H22N4O3S2                  
                                                     419                  
605                                                                       
      ##STR614##                            C19H21FN4O3S2                 
                                                     437                  
606                                                                       
      ##STR615##                            C19H22N4O3S2                  
                                                     419                  
607                                                                       
      ##STR616##                            C19H20N4O4S2                  
                                                     433                  
608                                                                       
      ##STR617##                            C18H27N5O2S2                  
                                                     524                  
609                                                                       
      ##STR618##                            C17H22N6O2S2                  
                                                     521                  
610                                                                       
      ##STR619##                            C14H17N702S2                  
                                                     494                  
611                                                                       
      ##STR620##                            C19H21N5O3S2                  
                                                     432                  
612                                                                       
      ##STR621##                            C17H19N5O2S2                  
                                                     504                  
613                                                                       
      ##STR622##                            C22H25N5O2S2                  
                                                     456                  
614                                                                       
      ##STR623##                            C18H24N6O2S2                  
                                                     535                  
615                                                                       
      ##STR624##                            C21H23FN4O2S2                 
                                                     447                  
616                                                                       
      ##STR625##                            C21H22F2N4O2S2                
                                                     465                  
617                                                                       
      ##STR626##                            C21H21F3N4O2S2                
                                                     483                  
618                                                                       
      ##STR627##                            C21H23ClN4O2S2                
                                                     464                  
619                                                                       
      ##STR628##                            C24H30N4O2S2                  
                                                     471                  
620                                                                       
      ##STR629##                            C18H26N4O3S2                  
                                                     411                  
621                                                                       
      ##STR630##                            C19H28N4O3S2                  
                                                     425                  
622                                                                       
      ##STR631##                            C22H26N4O3S2                  
                                                     459                  
623                                                                       
      ##STR632##                            C22H25FN4O3S2                 
                                                     477                  
624                                                                       
      ##STR633##                            C22H26N4O3S2                  
                                                     459                  
625                                                                       
      ##STR634##                            C22H24N4O4S2                  
                                                     473                  
626                                                                       
      ##STR635##                            C21H31N5O2S2                  
                                                     564                  
627                                                                       
      ##STR636##                            C20H26N6O2S2                  
                                                     561                  
628                                                                       
      ##STR637##                            C17H21N7O2S2                  
                                                     534                  
629                                                                       
      ##STR638##                            C23H29N5O2S2                  
                                                     586                  
630                                                                       
      ##STR639##                            C22H25N5O3S2                  
                                                     472                  
631                                                                       
      ##STR640##                            C20H23N5O2S2                  
                                                     544                  
632                                                                       
      ##STR641##                            C25H29N5O2S2                  
                                                     496                  
633                                                                       
      ##STR642##                            C21H28N6O2S2                  
                                                     575                  
634                                                                       
      ##STR643##                            C24H33N3O3S2Si                
                                                     504                  
635                                                                       
      ##STR644##                            C23H28N4O4S2                  
                                                     489                  
__________________________________________________________________________
 ##STR645##
 
    
     A solution of 100 mg of N-[5-[[(5-t-Butyl-2-oxazolyl)methyl]thio]-2-aminothiazole and 68 mg of 2,6-difluorophenyl isothiocyanate was heated at 65° C. for 16 hours under argon. The solution was evaporated to dryness and the residue purified by flash chromatography to give 91 mg of the intermediate thiourea. 
     To a solution of 30 mg of N-[5-[[(5-t-Butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]-N&#34;-(2,6-difluorophenyl)thiourea, 52 mg of ethyl-3(3-dimethylamino)propyl carbodiimide hydrochloride and 48 μL of diisopropylethylamine in 0.5 mL methylene chloride was added a solution of 29 mg of cyanamide in 0.1 mL tetrahydrofuran. After stirring for 1 hr, the solvent was removed and the crude material purified by HPLC to give 8 mg of Example 636 compound. 
     MS: (M+H) +   449 +   
       1  H NMR (400 MHz, CDCl 3 ): d 1.27 (9 H, s), 4.19 (2 H, s), 6.69 (1 H, s), 7.03 (2 H, m), 7.35 (1 H, m), 8.74 (1 H, s). ##STR646## 
     To a stirred mixture of 2-acetamido-5-thiazole thiol acetate (141 mg) in 3 mL of dry THF under argon was added 1 N t-BuOK in THF (0.72 mL). This mixture was stirred at room temperature for 25 min, and a solution of 5-isopropyl-(2-(chlorofluoromethyl))oxazole (116 mg) in 2 mL of dry THF was added. The reaction mixture was stirred at 60° C. for 18 hr, diluted with 150 mL of EtOAc and washed with saturated NH 4  Cl solution (2×25 mL), saturated NaHCO 3  solution (1×25 mL) and brine (1×25 mL). The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo to give Example 637 compound. 
     MS: (M+H)+316 HPLC retention time 3.52 min. (Column: YMC ODS S05 4.6×50 mm column, 0% to 100% B gradient in 4 min. Solvent A: 10% CH 3  OH/90% H 2  O/0.2% H 3  PO 4  ; Solvent B: 90% CH 3  OH/10% H 2  O/0.2% H 3  PO 4  ; UV: 220 nM).