C (NCN) NH-heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocylcoalkyl ; or C (NNO2) NH-alkyl, C (NNO2) NH-cycloalkyl, C (NNO2) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NN02) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocyloalkyl, C (NN02) 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 (NOR6) NH-alkyl, C (NOR6) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (NOR6) NH-heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocylcoalkyl, C (NOR6) NH-alkyl-heterocycloalkyl ; Rs is hydrogen or alkyl ; R6 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'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"alkyl"or"alk"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"branched alkyl group". 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 CC13 or CF3), alkoxy, alkylthio, hydroxy, carboxy (-COOH), alkyloxycarbonyl (-C (O) R), alkylcarbonyloxy (-OCOR), amino (-NH2), 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"alkenyl"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"alkynyl"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"alkoxy"or"alkylthio", as used herein, denote an alkyl group as described above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.

The term"alkyloxycarbonyl", 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 Cl 6 alkyl group.

The term"alkylcarbonyl"refers to an alkyl group bonded through a carbonyl group.

The term"alkylcarbonyloxy", as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage.

The term"arylalkyl", as used herein, denotes an aromatic ring bonded to an alkyl group as described above.

The term"aryl"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"heteroaryl"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"heteroarylium"refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge.

The term"heterocycloalkyl"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"quaternary nitrogen"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"heteroatom"means O, S or N, selected on an independent basis.

The term"halogen"or"halo"refers to chlorine, bromine, fluorine or iodine.

When a functional group is termed"protected", 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.

Scheme 1 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 R4-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 R4 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 R3 (CRlR2) 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.

Scheme 2 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 R3 (CRiR2) 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 Ri and R2 are hydrogen, and R6 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 R4 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 R4-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 R4 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 R3 (CRlR2) 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.

Scheme 3

Scheme 3 illustrates an alternative method of preparing compound VII, which is a compound of formula R3 (CRiR2) 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.

Scheme 4 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 BF3 etherate to provide compounds of formula VII, wherein L is chlorine.

Scheme 5

0 HNACF3 NA (XVIII) triphosgene SCN J pph3 -O DIPEA OH CHZC12 CI (XVI) (XVII) Step 1 Step 2 (a-o 0 DTT (D-o 0 R3 (CRIR2), i-L -c c ; N CF3 THF/MeoH j DBU, 80 °C N DMF SCN SH SCN SH SCN (XIX) (XX) Step 3 Step 4 0-0 =. - > > NH J base NiA NAs CH2C'2 Step 5 Step 6 (XXI) SXn (XXII) S R3 S Vs Rt. R2Jn Ra TA N i NA CH2C12 4s S Step 7 R3 R^R2) n cxxun

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 NaBH4. In step 1, starting compound XVI is treated with triphosgene and triphenylphosphine (PPhs) 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 R3 (CRlR2) n-LX 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 R6X, 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.

Scheme 6 Ruz N R S S NH2 tBuONO N O R8 S Br R1 R2 N CuBr2 R1 R2 N Ri R2 N base base Ruz S S NHR4 y RiRa-N

Scheme 6 illustrates the preparation of compounds of formula I from a 2- bromo thiazole XXIV. A compound of formula IX is reacted with a diazotizing agent such as tBuONO in the presence of copper bromide to provide the exemplary 2-bromo thiazole of formula XXIV. Compound XXIV may then be reacted with a compound of formula R4NH2, with or without an added base, to provide compounds of formula I.

Scheme 7 S Br NaSCN NCS S NHR4 RaN/S 'NHR4 base N Bz N (XXV) (XXVI) (IV) Br/HOAc as per Scheme 1 Br SNHR4 (XXVII) base base NMR RBSAc r R8 r R, R2 RlR2 NH2 R8 s S NHR4 (1) 0

Compounds of formula I may also be prepared starting from 2- bromothiazole XXV by reaction with a compound of formula R4NH2, with or without an added base, to provide a compound of formula XXVI. The compound of formula XXVI may be reacted with a thiocyanating agent such as sodium thiocyanate in the presence of bromine to provide a compound of formula IV, that may then be converted to a compound of formula I as described in Scheme 1. Alternatively, the compound of formula XXVI may be treated with a brominating agent such as bromine in acetic acid to generate a compound XXVII. Compounds of formula XXVII may be reacted with either XXVIII or XXIX (themselves available from a compound of formula VII) in the presence of base to provide compounds of formula I.

The starting compounds of Schemes 1-7 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 : Ri and R2 are independently hydrogen, fluorine or alkyl ; R3 is wherein Y is oxygen, sulfur or NR9 ; R4 is 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 <BR> <BR> <BR> S02-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, SO2-alkyl-aryl,<BR> <BR> <BR> <BR> S02-heteroaryl, S02-alkyl-heteroaryl, SO2-heterocycloalkyl, S02-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 (NN02) NH-alkyl, C (NNO2) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NNO2) NH-alkyl-aryl, C (NNO2) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NNO2) NH-heterocyloalkyl, C (NN02) 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 (NOR6) NH-alkyl, C (NOR6) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (NOR6) NH-heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocylcoalkyl, C (NOR6) NH-alkyl-heterocycloalkyl ; Rs is hydrogen ; and

R6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl ; R7 and Rs are independently hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkylheterocycloalkyl or halogen ; Rs 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 : Ri is hydrogen ; R2 is hydrogen, fluorine or alkyl ; R3 is a substituted oxazole having the configuration : R4 is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl ; Rs is hydrogen ; R7 is hydrogen ; Rs 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 (cdkl), 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'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'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'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's disease, AIDS-related dementia, Parkinson'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, raf l, 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.

Compounds of formula I may also be useful in combination with modulators of p53 transactivation.

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 14 exhibited cdc2/cyclin B1 kinase activity with ICso values less than 50 pM. The compounds of examples 1 to 14 exhibited cdk2/cyclin E kinase activity with ICso values less than 50 pM.

The compounds of examples 1 to 14 exhibited cdk4/cyclin D1 kinase activity with ICso values less than 50 pM. cdc2/cyclin B1 Kinase Assay cdc2/cyclin B1 kinase activity was determined by monitoring the incorporation Of 32p into histone H1. The reaction consisted of 50 ng baculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclin B1, 1 pg histone HI (Boehringer Mannheim), 0. 2 mCi of 32p g-ATP and 25 mM ATP in kinase buffer (50 mM Tris, pH 8. 0, 10 mM MgCl2, 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 32p 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 32p g-ATP and 25 mM ATP in kinase buffer (50 mM Hepes, pH 8. 0, 10 mM MgCl2, 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 32p 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. 2aCi 32p y-ATP and 25 iM ATP in kinase buffer (50 mM Hepes, pH 8. 0, 10 mM MgCl2, 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 pl6 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.

Example 1 N- [5- [ [ (5-ethyl-2-oxazolyl) methyl] thio]-2-thiazolyl] acetamide 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 (3x20 mL). The methylene chloride extract was dried over Na2SO4 and concentrated. The residue was passed through a short column (SiO2, hexanes : ethyl acetate/10 : 1 ; then ethyl acetate) to afford 1- benzyloxycarbonylamino-2-butanol (13. 9 g, 100%) as a liquid.

1H NMR (CDC13) 5 7. 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-benzyloxycarbonylamino-2-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 MgSO4 and concentrated to afford 1- benzyloxycarbonylamino-2-butanone (11. 2 g, 82%) as a solid, which was enough pure for the next reaction.

1H NMR (CDC13) 8 7. 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.

1H NMR (CD30D) 8 3. 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 (41g, 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.

1H NMR (CD30D) 8 7. 33 (s, 1H) ; MS (CI/NH3) 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.

1H NMR (CD30D) 8 7. 79 (s, 1H), 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.

1H NMR (CDCl3) 8 12. 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. 6xl50mm ; flow rate : 2. 5 mL/min ; solvent system : 0-100% B in 8 min. Solvent A : 10% MeOH-90% water- 0. 2% H3PO4 ; Solvent B : 90% MeOH-10% Water-0. 2% H3PO4 ; W : 220 nm) : retention time 6. 44 min.

G. Preparation of [ [2- (acetylamino)-5-thiazolyl] thio] acetic acid A solution of [[2-(acetylamino)-6-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.

1H NMR (CD30D) 8 7. 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% H3PO4 ; Solvent B : 90% MeOH-10% Water-0. 2% H3PO4 ; W : 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 (5x100 mL).

The methylene chloride extract was dried over Na2SO4 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.

1H NMR (CDC13) 8 7. 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% H3PO4 ; Solvent B : 90% MeOH-10% Water-0. 2% H3PO4 ; 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 (Si02 ; methylene chloride :

MeOH/100 : 5) to afford N-[5-[[(5-ethyl2-oxazolyl)methyl]thio]-2- thiazolyl] acetamide (4. 2 g, 43%) as a solid, mp 147-148 °C.

1H NMR (CDC13) 8 12. 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% H3PO4 ; Solvent B : 90%MeOH-10%Water-0.2%H3PO4 ; UV : 254 nm) : retention time 6. 50 min.

Example 2 N- [5- [ [ (5-ethyl-2-oxazolyl) methyl] thio]-2-thiazolyl] benzamide 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 (3x10 mL). The combined extract was dried over Na2SO4 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.

1H NMR (CDC13) 8 6. 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% H3PO4 ; Solvent B : 90% MeOH-10% Water-0. 2% H3PO4 ; UV : 254 nm) : retention time 3. 96 min.

B. Preparation of N-[5-[[(5-ethyl-2-oxazolyl)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 (Si02 ; 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.

1H NMR (CDC13) 8 12. 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% H3PO4 ; Solvent B : 90% MeOH-10% Water-0. 2% H3PO4 ; UV : 254 nm) : retention time 7. 94 min.

Example 3 N- [5- [ [ (4, 5-dimethyl-2-oxazolyl) methyl] thio]-2-thiazolyl] acetamide

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 NaHCO3 (20 mL) and concentrated. The residue was purified by flash column chromatography (Si02 ; hexanes : ethyl acetate/4 : 1) to afford 2- (bromomethyl)-4, 5- dimethyloxazole (64 mg) as an yellow oil.

1H NMR (CDCl3) 5 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) methyl] 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 NaHCO3 solution (20 mL) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layers was concentrated. The residue was purified by flash column chromatography (Si02 ; 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. 1H NMR (CDC13) 8 11. 78 (s, 1 H), 7. 38 (s, 1 H), 3. 90 (s, 2 H), 2. 30 (s, 3H), 2. 22 (s 3H), 2. 05 (s, 3H) ; 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% CH30H/90% H20/0. 2%

H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3PO4 ; UV : 254 nm) : retention time 5. 87 min.

Example 4 N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2-thiazolyl] acetamide 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'-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 silica, 25 x 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).

1H NMR 8 (CDCl3) : 1. 30 (s, 9H), 4. 58 (s, 2H), 6. 68 (s, 1H) ; MS 174 (M+H) + ; TLC : Rf (silica gel, dichloromethane) =0. 33 ; HPLC : tR (YMC S-3 ODS 4. 6x50mm rapid resolution ; 2. 5 ml/min, gradient 0-100% B over 8 min, Solvent A : 10% CH30H190% H20/0. 2% H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3PO4 ; 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 rt for 16 h, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 25 x 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.

1H NMR 8 (CDC13) 1. 27 (s, 9H), 2. 27 (s, 3H), 3. 95 (s, 2H), 6. 59 (s, 1H), 7. 31 (s, 1H), 11. 03 (broad s, 1H) ; MS 312 (M+H) + ;

TLC : Rf (silica gel, ethyl acetate) =0. 53, UV ; HPLC : retention time (YMC S-3 ODS 4. 6x50mm rapid resolution ; 2. 5 ml/min, gradient 0-100% B over 8 min, Solvent A : 10% CHgOH/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3P04 ; W : 254 nm) = 6. 8 min.

Example 5 N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl] trimethylacetamide A. Preparation ofN- [ (5-thiocyanato)-2-thiazolyl] 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.

1H-NMR (CDCl3) 8 12. 4 (br, 1H), 7. 83 (s, 1H).

B. Preparation of 4-hydroxymethyl-3-methoxyphenyloxy Merrifield 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 (2x), 50% dimethylformamide in water (3x), dimethylformamide (2x), and methanol (5x), 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 (3x), dimethylformamide (2x), methanol (2x), and dichloromethane (5x), 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 (6x) and dried in vacuo.

D. Preparation of 4- [N- [ (5-thiocyanato)-2- thiazolyltrifluoroacetamido] methyl]-3-methoxyphenyloxy Merrifield resin (XIX) A mixture of 4-chloromethyl-3-methoxyphenyloxy Merrifield resin (15g), 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 (2x), methanol (2x), dichloromethane (4x), and dried in vacuo.

E. Preparation of 4- [ [N- [ (5-mercapto)-2-thiazolyll trifluoroacetamido] methyl]-3-methoxyphenyloxy Merrifield resin (XX) A mixture of4- [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 (2x), methanol (2x), dichloromethane (4x), 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] trifluoroacetamido] methyl-3-methoxyphenyloxy Merrifield resin (XM) A stream of argon was bubbled 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 (2x), methanol (2x), dichloromethane (4x), 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 (XN, 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 (2x), dimethylformamide (2x), methanol (2x), dichloromethane (4x), 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 (2x), methanol (2x), dichloromethane (4x), and used in the next step without drying.

I. Preparation of 4-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) +.

Example 6 N- [5- [ [ (4-Ethyl-2-oxazolyl) methyl] thio]-2-thiazolyl] acetamide A. Preparation of 2- (2-chloroacetamido)-l-butanol To a mixture of 2-amino-l-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, i58 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 x 30 mL). The combined organic layers was concentrated to afford 2- (2-chloroacetamido)-l-butanol (8. 6 g, 98%) as a brown solid.

1H NMR (CDCl3) 8 6. 75 (bs, 1 H), 4. 10 (s, 2 H), 4. 08 (dd, 1H), 3. 90 (m, 1 H), 3. 68 (m, 2H), 2. 98 (bs, 1H), 1. 60 (m, 2H), 0. 97 (t, 3H).

B. Preparation of 2- (2-chloroacetamido)-l-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 1N HCl (2 x 100 mL), saturated aqueous NaHCO3 (1 x 10 mL) and concentrated to afford 2- (2-chloroacetamido)-1-butyraldehyde (3. 7 g, 95%) as a brown oil.

1H NMR (CDC13) 8 9. 60 (s, 1 H), 4. 52 (q, 1 H), 4. 12 (s, 2H), 2. 05 (m, 1 H), 1. 80 (m, 1H), 0. 97 (t, 3H).

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 POC13 (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 5N NaOH. The toluene layer was separated and the aqueous layer was washed with dichloromethane (3 x 20 mL). The combined organic solution was concentrated and distilled to afford 2-chloromethy-4-ethyloxazole (1. 1g, 31%) as a colorless liquid.

1H NMR (CDC13) 5 7. 30 (s, 1H), 4. 22 (s, 2 H), 2. 50 (q, 2 H), 1. 22 (t, 3H).

D. Preparation of N- [5- [ [ (4-ethyl-2-oxazolyl) methyl] thio]-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 NaHCO3 solution (5 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (3 x 10 mL). The combined organic layers was concentrated. The residue was purified by flash chromatography (Si02 ; methanol : dichloromethane/1 : 20)

to afford N- [5- [ [ (4-ethyl-2-oxazolyl) methyl] thio]-2-thiazolyl] acetamide (5 mg, 36%) as a white solid.

1H NMR (CDC13) 8 11. 25 (s, 1 H), 7. 34 (s, 1 H), 7. 31 (s, 1H), 3. 95 (s, 2 H), 2. 50 (q, 2H), 2. 27 (s, 3H), 1. 19 (t, 3H) ; 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% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CHgOH/10% H20/0. 2% H3PO4 ; UV : 254 nm) : retention time 6. 14 min.

Example 7 Preparation of N-[5-[[(5-t-Butyl-2-oxazolyl)methyl]thio]-2- thiazolyl]-N'-cyano-N"- (2, 6-difluorophenyl) guanidine.

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"- (2, 6-difluorophenyl) thiourea, 52 mg of ethyl-3 (3- dimethylamino) propyl carbodiimide hydrochloride and 48 uL 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+ iH NMR (400 MHz, CDCI3) : d 1. 27 (9H, s), 4. 19 (2H, s), 6. 69 (1H, s), 7. 03 (2H, m), 7. 35 (1H, m), 8. 74 (1H, s).

Example 8 Preparation of N-[5-[[(5-isopropyl-2-oxazolyl)fluoromethyl]thio]-2- thiazolyl acetamide.

To a stirred mixture of 2-acetamido-5-thiazole thiol acetate (141 mg) in 3 mL of dry THF under argon was added 1N 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 NH4C1 solution (2x25 mL), saturated NaHCOs solution (1x25 mL) and brine (1x25 mL). The organic layer was dried (MgS04), 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 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3PO4 ; UV : 220 nM).

Example 9 Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2- thiazolyl] aminophenyl-4- (2-hydroxyethyl) sulfonamide A. Preparation of 5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-bromo thiazole.

To a solution of CuBr2 (5. 14 g in acetonitrile (100 mL) at 0° C was added tBuONO (4 mL, 1. 2 eq) followed by 5-[[(5-t-butyl-2-oxazolyl) methyl] thio]- 2-thiazolyl) amine (5. 2 g). The mixture was stirred at 0° C for one hour, then at room temperature for one hour, ethyl acetate was added and the organic mixture washed with hydrochloric acid (2 X 50 mL), dried over magnesium sulfate, filtered through a pad of silica gel, and concentrated in vacuo. The residue was chromatographed on silica gel to give the bromide as an orange oil (3. 9 g).

MS : (M+H) + 334 HPLC retention time 4. 04 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH3OH/90%

H20/0. 2% H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3PO4 ; UV : 220 nM).

B. Preparation of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2- thiazolyl] aminophenyl-4-(2-hydroxyethyl) sulfonamide A mixture of the 2-bromothiazole from Part A (0. 85 g) in dimethyl acetamide (4 mL) and 4-aminophenyl-N- (2-hydroxyethyl) sulfonamide (2. 5 g, 5 eq) was stirred at 145° C for 6 hours, cooled and ethyl acetate (80 mL) was added. The reaction mixture was washed with water (2 X 20 mL), the combined aqueous solution was extracted with ethyl acetate, and the combined organic layers dried over sodium sulfate, evaporated in vacuo, and the residue was chromatographed on silica gel, then purified by reverse phase chromatography to give N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2-thiazolyl] aminophenyl-4-(2-hydroxyethyl) sulfonamide as a yellow solid (0. 61 g).

MS : (M+H) + 469 HPLC retention time 3. 80 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH3OH/10% H20/0. 2% H3PO4 UV : 220 nM).

Example 10 Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2- thiazolyl] aminophenyl-4-sulfonamide A mixture of the 2-bromothiazole from Example 9, Part A (106 mg) in dimethyl acetamide (0. 5 mL) and 4-aminobenzenesulfonamide (275 mg, 5 eq) was stirred at 140° C for 6 hours, cooled and the solvent was removed under reduced pressure to provide a dark red oil which was purified by preparative reverse phase HPLC (YMC S5 ODS) to give N- [5- [ [ (5-t-butyl- 2-oxazolyl) methyl] thio]-2-thiazolyl] aminophenyl-4-sulfonamide (94 mg).

MS : (M+H) + 425 HPLC retention time 3. 74 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH3OH/10% H20/0. 2% H3PO4 ; UV : 220 nM).

Example 11 Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyllthiol-2-, thiazolyl]-4-aminopyrimidine To a 50 mL single necked flask was added 4-aminopyrimidine (142 mg) in dry tetrahydrofuran (5 mL). A sodium hydride dispersion (60%, 60 mg) was added, followed by heating to 60° C for one hour. The solution of the

anion was cooled to room temperature and the 2-bromothiazole from Example 9, Part A (100 mg) was added. The reaction was heated for 24 hours at 60° C, cooled to room temparature, quenched with hydrochloric acid and partitioned between water and ethyl acetate (25 mL each). The organic layer was washed with water (2 X 25 mL), brine (25 mL), dried over sodium sulfate and concentrated in vacuo to give a solid, which was purified by trituration with 1 : 1 ethyl acetate : hexanes to give N- [5- [ [ (5-t- butyl-2-oxazolyl) methyl] thio]-2-thiazolyl]-4-aminopyrimidine (42 mg).

MS : (M+H) + 348 HPLC retention time 3. 63 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3PO4 ; IN : 220 nM).

Example 12 Preparation of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2- thiazolyl]-3- (hydroxymethyl) aniline A. Preparation of N-2- [3- (hydroxymethyl) phenyl] aminothiazole To a solution of 3-hydroxymethyl aniline (2. 46 g) in dry tetrahydrofuran (50 mL) at-78° C was added methyl lithium-lithium bromide solution in ether (27 mL of 1. 5 M solution). The reaction mixture was stirred at-78°

C for 10 minutes, warmed to room temperature for 10 minutes, and then cooled to-78° C and 2-bromothiazole (1. 31 g) was added. The reaction mixture was stirred at 0° C for one hour, then at room temperature for 3 hours, quenched by addition of hydrochloric acid (20 mL of 2N solution), concentrated and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, concentrated and chromatographed on silica gel to give N-2- [3- (hydroxymethyl) phenyl] aminothiazole (0. 68 g).

B. Preparation of N-2- [3- (hydroxymethyl) phenyl] aminothiazole-5-thiocyanate To a cooled solution (ice-salt bath) of the compound of part A (680 mg) and ammonium thiocyanate (500 mg) in methanol (35 mL) was added portionwise bromine (0. 21 mL). After disappearance of the bromine color the reaction was concentrated and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, concentrated and chromatographed on silica gel to give N-2- [3- (hydroxymethyl) phenyl] aminothiazole-5-thiocyanate as a yellow solid (490 mg).

C. Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2- thiazolyl]-3- (hydroxymethyl) aniline To a dark red solution of the thiocyanate of part B (490 mg) in tetrahydrofuran/ethanol was added sodium borohydride portionwise (84

mg). After gas evolution had ceased, acetone (0. 65 mL) was added the reaction stirred for 8 minutes, followed by addition of 2-chloromethyl-5-t- butyl-oxazole (Example 5, Part C compound, 0. 5 g) and the reaction stirred for one hour at room temperature. The reaction was concentrated, extracted with ethyl acetate, the combined organic extracts dried over sodium sulfate, and filtered through a pad of silica gel to provide the product (0. 69 g).

MS : (M+H) + 376 HPLC retention time 3. 84 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CHsOH/10% H20/0. 2% H3PO4 ; UV : 220 nM).

Example 13 Preparation of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2- thiazolyl]-2-aminopyridine A. Preparation of N-2-[pyridinyl] aminothiazole To a suspension of sodium hydride (60% suspension, 1. 8 g) in tetrahydrofuran (200 mL) was added portionwise 2-aminopyridine (4. 23 g), and the mixture was slowly heated to 55° C for 30 minutes. The reaction mixture was then cooled to-10 deg C and a solution of 2-

bromothiazole (2. 46 g) in tetrahydrofuran (2 mL) was added dropwise.

The reaction mixture was stirred at 55° C for 5 hours, cooled and quenched with hydrochloric acid (2N, 20 mL), concentrated, and ethyl acetate was added. The resulting solid was filtered to give N-2- [pyridinyl] aminothiazole (1. 41 g).

B. Preparation of N-2- [pyridinyl]-5-bromo-aminothiazole To a solution of the compound of Part A (0. 88 g) in acetic acid (15 mL) was added bromine (0. 22 mL in 2 mL acetic acid) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours, the was solvent removed under reduced pressure, and the resulting solid was triturated with ether to provide N-2- [pyridinyl]-5-bromo- aminothiazole (1. 6 g) as the hydrobromide salt.

C. Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2- thiazolyl]-2-aminopyridine To a solution of N-2- [pyridinyl]-5-bromo-aminothiazole (8 g) and 2- thioacetyl-5-t-butyl oxazole (8 g) in methanol (500 mL) under argon was added a degassed solution of sodium hydroxide (25 mL of 3 N solution) at room temperature. The reaction mixture was stirred for 20 minutes and then heated to 60° C for one hour, concentrated in vacuo, partitioned between water (125 mL) and ethyl acetate (500 mL) and the aqueous layer was back-extracted (2 X 125 mL) with ethyl acetate. The combined organic layers were washed with brine (25 mL), dried over sodium

sulfate, filtered through a pad of silica gel, and the solvents removed in vacuo. The solid residue was recrystallized form ethyl acetate to provide N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2-thiazolyl]-2-aminopyridine (7. 5 g).

MS : (M+H) + 347 HPLC retention time 4. 01 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH3OH/10% H20/0. 2% H3PO4 ; W : 220 nM).

Example 14 Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2- thiazolyl]-2- [5- [ ( ( (3-hydroxy-2, 2-dimethyl) propyl) amino) methyl]] aminopyridine A. Preparation of N-2- [ (5-bromo) pyridinyl] aminothiazole To a suspension of sodium hydride (60% suspension, 5. 2 g) in tetrahydrofuran (150 mL) was added portionwise 2-amino-4- bromopyridine (15 g), and the mixture was stirred at room temperature for 15 minutes. 2-Bromothiazole (3. 8 mL) was added, and the reaction mixture was stirred at room temperature for one hour and then heated at reflux temperature for 2. 5 hours, cooled, quenched with 6% citric acid and

extracted with ethyl acetate (2 X 100 mL). The organic layers were concentrated, dried over magnesium sulfate and the filtrate concentrated in vacuo to give a dark brown residue which was triturated with ether/hexanes to provide N-2- [ (5-bromo) pyridinyl] aminothiazole as a yellow solid (8. 9 g) B. Preparation of N-2-[(5-carboxaldehyde) pyridinyl] aminothiazole A suspension of the Part A compound (6. 4 g) in tetrahydrofuran (300 mL) was heated to reflux to effect dissolution, the reaction mixture was cooled to-70° C and treated with t-BuMgCl (13 mL of 2M solution in ether) dropwise over 10 minutes. The temperature was raised to-55° C, and t- BuLi (36 mL of 1. 7 M solution in hexanes) was added dropwise, and the reaction mixture stirred for 20 minutes. The reaction mixture was then cooled to-70° C and DMF (8 mL) was added, the resulting mixture was stirred at-50° C for one hour and then warmed to 0° C over one hour, quenched with acetic acid (8 mL) and partitioned between ethyl acetate and water (300 mL each). The aqueous layer was back extracted with ethyl acetate (2 X 200 mL) and the combined organic layers dried over magnesium sulfate and concentrated, the solid washed with ethyl acetate and ether, and dried to give N-2- [ (5-carboxaldehyde) pyridinyl] aminothiazole (3. 15 g).

C. Preparation of N-2- [ (5-carboxaldehyde) pyridinyl]-5-bromo- aminothiazole A solution of N-2- [ (5-carboxaldehyde) pyridinyl] aminothiazole (0. 5 g) in acetic acid (6 mL) and dichloromethane (20 mL) was treated with bromine (0. 12 mL) in dichloromethane (3 mL). The reaction mixture was stirred for 30 minutes at room temperature, ether was added, and the resulting precipitate was collected by filtration, washed with ether to give N-2- [ (5- carboxaldehyde) pyridinyl]-5-bromo-aminothiazole (0. 69 g).

D. Preparation of N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2- thiazolyl]-2-aminopyridine-5-carboxaldehyde To a solution of the compound of Part C (3. 8 g) and 5-t-butyl-2- (S- isothiourea) methyl oxazole (3. 06 g) in methanol (300 mL) under nitrogen was added degassed sodium hydroxide (6. 4 g of 50% w/w solution). The reaction mixture. was heated at 76° C for 6 hours, the methanol was removed in vacuo, water was added, and the solid was collected by filtration, washed with water and ethyl acetate, and dried to give N- [5- [ [ (5-t-butyl-2-oxazolyl) methyl] thio]-2-thiazolyl]-2-aminopyridine-5- carboxaldehyde (0. 53 g). The filtrate was extracted with ethyl acetate (4 X 200 mL), dried over magnesium sulfate, and concentrated in vacuo and

triturated with ether/ethyl acetate to give an additional 2. 02 g of the desired compound.

E. Preparation of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2- thiazolyl]-2- [5- [ ( ( (3-hydroxy-2, 2-dimethyl) propyl) amino) methyl]] aminopyridine To a solution of the aldehyde of Part D (1. 5 g) and 3-amino-2, 2-dimethyl propanol (2. 06 g) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (6. 0 g), followed by acetic acid (5 mL). The reaction mixture was stirred for 30 minutes at room temperature, and the solvents removed in vacuo to give a yellow solid which was purified by column chromatography to give N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2- thiazolyl]-2- [5- [ ( ( (3-hydroxy-2, 2-dimethyl) propyl) amino) methyl]] aminopyridine (1. 08 g).

MS : (M+H) + 462 HPLC retention time 3. 22 min. (Column : YMC ODS S05 4. 6 X 50 mm column, 0% to 100% B gradient in 4 min. Solvent A : 10% CH30H/90% H20/0. 2% H3PO4 ; Solvent B : 90% CH30H/10% H20/0. 2% H3PO4 ; UV : 220 nM).

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 : Example Structure Molecular Formula (M+H) + y"' 15 \S . C9H11N30S2 242 , l H j 17 C13Hl7N302S2 312 ) N H -- 17 -./C13H17N302S2 312 A N 18 CllHlOF3N302S2 338 Fuzz I 0 , (N H i 19 326 0 I - 'H w I 20 S ! C21H17N302S2 408 ° ' ! U ; N i N I 21 X > C17H24N402S2 3BI 0 N razz 22 SH C17H17N302S2 360 yo Example Structure Molecular Formula (M+H) + i-. 23 H C15Hl9N302S2 338 W I 0", o , JL., 24 S" (, C17H17N303S2 376 s po N 25 366 0 N Jl. l ruz 26 326 0 zens II --N 27 ~ s H C13H15N302S2 310 J 28 ! NtS S C15H13N302S2 332 ) | o 0 N 29 N ; \ C13H11N302S2 306 Ho I H S 30 \Irk,-S CloHllN302S2 270 I 31 C12H15N302S2 S95 N Example 7 Structure MolecularFormula (M+H) + H Br VS FNt5 04 C13H16BrN302S2 391 Z H 33 N\o C15Hl2FN302S2 350 I F ZAPF vs 34 \= (5 C13H15N304S2 342 35 C15H21N302S2 340 0 Ll JO N 36 Cl C19H21 N302S2 388 X 37 LJL C18H17N304S2 404 wo 38/,-N.,/s ° C15H19N304S2 370 0 OU 39 cN <rNH O C14H17N304S2 1 356 IN ( 0 I 40 C16H19N303S2 366 0 N 0 Example Structure Molecular Formula I (M+H) + -____. am 41 49 o C16H21N304S2 384 ' \my" 01i I cN <rNH O C15H19N304S2 370 N j q, / OH _r, NH/\ 0 I 43 (N NH O. C1 6H21 N304S2 384 I 44 ° C18H17N304S2 404 NU ins OH 45 NH i C15H19N304S2 370 N nu 0 F S 46 L. N C16H14FN302S2 364 ii a q_fo 47 C16Hl4CIN302S2 380 H I H | | C16 H13 CI2 N3 0252 415 \ S N H 49 0 C18H19N304S2 406 N Example Structure Molecular Formula (M+H) + o I 50 Ln C18H19N304S2 406 W ? d 51 sg C18 H19 N304S2 406 ho \ N S 52 H C18 H19 N3 02 S2 374 o-) p Ls 53 @N C18 H20 N402 S2 503 Q M- 0 N S 54 H C17 H17 N3 02 S2 360 o NCN / 55 H C18 H19 N3 02 S2 0 N oR) 56 H C18 H19 N3 02 S2 374 T Hz 57 M-H t J C18H20N402S2 503 S ion 'N 0 Example Structure I Molecular Formula (M+H) + ~ , o 58 C18H20N402S2 503 X avé I I 59 ANH C19 H16 N402 S2 511 CL 0 0 -S i I o i 60 SH C18 H16 N402 S2 499 H I H 0 61 H C18 H16 N4 02 S2 499 N I- ( zozo N 0 I 0 62 ! f C16H13F2N302S2 382 ton I U 0 ; 63 C17H1saFN302S2 412 ChM ! N 64 C19 H19 N3 04 S2 418 shill hr ° F FS y MI \ I F I 65 C18 H16 F3 N3 02 S2 428 i i n Example Structure Molecular Formula (M+H) + 0 N zon 66 sfi-S H C17 H16 F N3 02 S2 378 \-'Hz 0., )) -t, N 0 67 s^ o C17 H16 N4 04 S2 405 i iso o N 68 H C17 H16 N4 04 S2 405 --U-', o 0 , 69 H Cl 9 H21 N3 04 S2 420 -ll lS n S N 70 H C19 H17 N3 03 S2 400 0 o 71 ir s C12Hl5N303S2 314 N N 11 _/I 72 1 N/0 C13 H17 N3 N H I \-0 jN 73 AN O C16 H14 N4 02 S2 461 N ZON 0 I N 0 //S \N 0 N H Example ! ecu) ar Formuta ! (M+H) + ." I 75 i C15 H17 N5 02 S2 364 N 0 --\StIN N su 76 N/", C13 H14 F3 N3 02 S2 366 9 N F 0 77 XN S HX C15 H15 N3 02 S3 366 o s i I 78 9 C17 H23 N3 02 S2 366 N '<r- N N n A/\ 79 \< ; C16 H16 N4 02 S2 475 lob \ -N 80 zu 427 N -H 0 81 <</SFH Q C18H19 N3 03 S2 390 O' i NH o " 82 N i C18 H18 N4 03 S2 403 0 403 ° o i 0 83 4 9 ? C22 H19 N3 03 S2 D Example Structure ; Molecular Formula i (M+H) + O SS i o 's 84 t C17H17N303S2 376 I 85 N C22 H19 N3 02 S2 422 ls H zon IN i o 86 DNA C16 H14 CIN302 S2 380 Q a ! cr 87 DN C17 H17 N303 S2 376 I i- cri --- i I CI I 88 \-H C16 H14 CIN302 S2 380 f N I 0/-\ i 89 X C17 H17 N3 03 S2 376 N S IN 0 0 0 90 H C17 H15 N3 04 S2 390 N . N O Dz I ___ 91 H C17 H14 N4 02 S3 403 N N I N Example Structure Molecular Formula (M+H) + o '1 ° i 92 N 5J4t C17 H16CIN3 02S2 394 i-N 0 ; o i L/s-'C II o i 93 N C18 H19 N3 03 S2 390 i I I, I I N 94 C19 H19 N3 02 S2 386 I ? 0 I i 95 <Y"C21H23N302S2 414 í S _ _ a y I I 96 e C17 H16CIN3 02S2 394 X I, _ i i i 97 r C18 H19 N3 03 S2 390 _I \ o N N 98 \>HX C17 H16 CIN3 02S2 394 ; s I ce j o I 99 SH/\ C18 H17 N3 04 S2 404 o-z-S/s I I Example l Structure ! Molecular Formula (M+H) + o I 1'S-- I i I H 5 100 C25 H22 N4 02 S2 589 1< b 101 N C14 H17 N3 03 S2 340 N S-saH 102 9 N C14 H17 N3 03 S2 340 r H N y 103 gN C15 H14 N4 02 S2 461 /H -N P 104 C16 H21 N3 02 S2 352 r H N fo 105 C18 H17 N3 03 S2 388 Y " VN 106 C16 H16 N4 02 S2 475 g NH ZON <<s C19 H18 N4 02 S2 513 zon Example ; Structure ; Molecular Formula (M+H) + i- ; _ o I i s 108 (t 9t C17 H14 N4 02 S2 371 N I I N S i 0 N \ S I N 109 H C20 H17 N3 02 S2 396 0 I o 110 @ C21 H18N403S2 551 N b 111 C23 H21 N3 03 S2 452 O, e 0 112 C20 H21 N3 02 S2 400 ' " 113 C22 H23 N3 03 S2 442 I I 114'C17H15N502S2 500 lI !'" N CNrNH JY O 115 H C18H18N403S2 403 Example Structure Molecular Formula (M+H) + <Y 116 $ C17 H17 N5 02 S3 420 i N 0 439 I o 117'"'H1 C17H16BrN302S2 ; 439 Br 0 /1-N 0 118 N C17 H16 F N3 02 S2 378 i . \ I I I N 0 v */i-N 0 119 N SJ49 C17 H15 Cl2 N3 02 S2 429 1 i mu f ssAo'\ 120 C17 H15 N3 03 S2 374 i 0 0 /v ; i 121 N- (C18H19N302S2 374 S4 0 t-N but N i I /Ar I-I 122 r'C17H16BrN302S2 439 r 1 i i 123 Xo C18 H19 N3 02 S2 374 o i s w zon Example i Structure i Molecular Formula (M+H) + f"h. I N, 124 zu H C17 H16 Br N3 02 S2 439 bu ber i 125 X 0 C18 H19 N3 02S2 374 N-' o 0 N N , _ 126 \-/Y ! 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Structure _Molecular Formula l (M+H) + 142 N C15 H15 N3 03 S2 350 N u o H 0 i-___-__- N 143 C14 H17 N3 04 S2 N H N 0 s"C-N/ Og1/N 144 a Ç8 C14 H15 N50252 464 pli N ° 145 H C19 H21 N3 02 S2 388 f- /j-N 0 o i 0 I 146 N C16 H16 N4 02 S2 475 t 0 o /_ o I i 147 ß si C19 H18 N402 S2 513 v ; ru Xi N ; v ou N N C15 H17 N5 02 S2 478 - l0\ 149 t C19 H21 N3 03 S2 404 ,, CHral N NH, N Chiral 150 C12 H16 N4 02 S2 427 i Example Structure Molecular Formula (M+H) + "" , 151 C20 H20 N4 02 S2 527 i I cr t-M ° NH N H I I ° Y' l53 l C19H18N4 04S2 431 ; il o I 0 I po //S S H i N I or N 0 155 Cl 5 H21 N3 02 S2 340 doh _ _-O- Nu NH I 156 N C13 H14 N4 03 S3 371 zon N XN S H. ! o ! °'"" --\s N I I N 0 N 158 S-1 N C17 H22 N4 03 S2 395 N Cs-H I 0 159" C14 H17 N3 02 S2 ; 324 sa H i l60 9 C19 H18 N402 S2 513 159 \ n/r C14H17N302S2 324 sXN ° i Example Structure 1 Molecular Formula i (M+H) + 0 chiai 161 N3 02 S2 326 sus ZON I i ! 162 g) C19H21 N302S2 388 ' I w I a s^S 163 C16H13Ct2N302S2 415 '0 N N' 164 ! w C17H17N302S2 360 F ! F I 165 ! C16H12F3N302S2'400 I i j7 ! i 166 (j- C20H18N402S2 525 0 ;, i 167 C20 H18 N4 02 S2 525 I N \ N 0 i 'N 0 168 P C19 H21 N302 52 3B8 N o i L o 169'N H C19 H21 N3 04 S2 420 X i i Example | Structure Molecular Formula | (M+H) + /F kJ 170 S C17H16FN302S2. 378 s N 0 N J \i H 171 s C20 H23 N3 05 S2 450 \con i o ; N I ruz 172 s C18 H16 F3 N3 02 S2 428 F F I Q Vj. ui u H21 N3 02 S2 388 t'.' 174 Cl 9 H21 N3 02 S2 388 l N V--N Ihi-w 175 H C18 H19 N3 02 S2 374 N I 0 Choral 76 = (T C17H17N303S2 376 y' 'je Ho 0 N \ N 177 ¢5 X C19 H22 N4 02 S2 517 N N N- Example Structure'Molecular Formula ! (M+H) + 178 H21 N3 02 S2 388 o \_N N 0 179" C19H21N304S2 420 , 0 180 N F C17 H15 F2 N3 02 S2 396 IF N N H 181 N, _C C14 H15 N5 02 S2 350 nu N 0 182/ C15 H14 N4 02 S2 461 Nô c /\ 183 C18 H19 N3 03 62 390 i -o 0 184 C18 H19 N3 04 S2 406 o 0 i 185 \o \ C22H19N303S2 438 mS0 -N 0 - 186 C17 H16 N4 04 S2 405 f Example Structure Molecular Formula (M+H) + _ S j i 187 C20 H23 N3 02 S2 402 l 0 188 C23 H21 N3 02 S2 436 z Ill 189 C24 H23 N3 02 S2 450 s i I i/v i/\ 190 j H C23 H21 N3 02 S2 i 436 I i N 191 I C21 H19 N3 02 S2 I 410 \X N N I j 13 192 C21H19N302S2 410 X N S g C17 H15 C12 N3 02 S2 429 i d or, t+) C19 H21 N3 04 S2 420 kirs Example l Structure Molecular Formula I (M+H) + Clirai I chra j j /\ so 195 I I C18 H19 N3 02 S2 374 I 0 I i I 196 W C19 H18 F3 N3 03 S2 458 ti ! \ 197 H C22H27N302S2 430 0 N I 198 C18 H19 N3 02 S2 374 0 0 N N I N I lW > sF C12 H15 N3 02 52 298 po Nez 0 0 ! 200 t,, » HH C18 H26 N4 04 S2 427 I i o I H H 201 "Ts./° C12H13N304S2 328 0 N N 0 202 Cll H13N304S2 316 zu N 0 203 0 s Cl 1 H13 N3 03 S2 300 ICI 0 1 __j Example Structure _ Molecular Formula | (M+H) + -_.- i f 204 '\\-S. ° C11H15N30S2 270 N 205 205 \ C10H13N30S2 256 206 ,. ! N ! . , c0' 207''. C19H20N402S2 401 s 0 440 S (, ruz Ber zon i I i 209 H C17 H16 N6 02 S2 515 I my I N I. 210 ç C19 H17 N5 02 52 526 I i 211 s C20 H23 N5 03 S2 560 N Example Structure Molecular Formula (M+H) + Q , H NH 212 C16H16N402S2 361 jT 0 r 213 F C16 H14 F2 N4 02 S2 397 I wl I ! p 0 N\ I i i H S (I 214 i"\ C16H15C ! N402S2 395 Q i m I wv I : 215 C17 H18 N4 03 S2 391 , J Q- 216 C17 H18 N4 02 S2 375 JT ou 0 217 i \"s C16H15BrN402S2 440 ber lez '--/, I, H Ss S 218 218 H15 CI N4 02 S2 ! 395 cri a' I i a 219 N H Cl C16 H14 C12 N4 02 S2i430 ! TY' V nez I I Example Structure Molecular Formula (M+H) + . ___ f 220 ! N C17 H17 CIN4 03 S2 425 . \ H I NH T 0 221 | Ns C17 H18 N4 03S2 | . $ ° YO . pu a i NN 222 ! ! C16H15BrN402S2 440 i 0 223 H>a C16 H15F N4 02S2 379 F nom i I NN 224 dNH C17 H18 N4 02 S2 3P5 N I f I 225 C17 H18 N4 03 S2 391 0 N i 226 HN U C16 H15 CIN4 02 S2 395 . X a 1 227 . C18H19N503S2 418 yo , N Example Structure, Molecular Formula | (M+H) + M-y, N 228 C17H18N403S2 391 p H I 229 I C18H21N502S2 518 I vSY ! N NHP/NS 0 230 s HtS C16 H15 F N402 S2 379 zu 0 s F ! 231 6F H C16 H15 F N4 02 S2 379 i i i N NN 232 C17 H18 N4 02 S2 375 swan @° -v 233 C17H17N503S2 404 < r' j-° ou 234 C17 H15 N5 02 S3 418 N I i I H \ j 235 'y C17H16N602S2 401 H Vin 0 Example I Structure ! Molecular Formula (M+H) + I i ____ I N 236 N C16 H15 N7 02 S2 402 " ! VN 0 NH 237 1 C16 H17 N5 02 S2 490 238 N C15 H20 N4 02 S2 353 Jazz 0 H 239"M-GN C17 H17 CI N4 02 S2 409 _i0 a 240 H s N C17 H19 N5 02 S2 504 I=ci 0 r ! 241 N s C17 H19 N5 02 S2 504 vA I o' ! I 242 C19 H18 N6 02 S3 459 N 0 r, N 243 ß < C15 H16 N402 S3 381 , N Zizi 244 ß ! C15H20N403S2 369 Example Structure | Molecular Formula'; (M+H) + _, 245 H20 N6 02 S2 507 ! r- i N 246 i . L C18H25N504S2 440 I HVO c i M 247 tiu C17 H24 N4 02 S2 381 "\ zu q : cl I TN ! ! 249 H18 N4 02 S2 375 i i i . 250 J C18H20N402S2 389 0 N 0 'tb 'f I 251 Nit C19 H22 N4 02 S2 403 H 1 Iw ! 252 s N C17 H19 N5 02 S2 504 ", N--6 0 753/C17 H17 CI NX a Example Structure Molecular Formula (M+H) + ---, I W 254 0 -S C16 H17 N5 02 S2 490 l l zu . r 255 Cl 7 H25 N5 02 S2 510 t 256 < C16 H17 N5 02 S2 490 0 N 257 N C17 H25 N5 02 S2 ° \/T _ N -N . 0 ' 259 Tsg-N'H C15H16N403S2 365 J p S H N N i H 260 s C17 H16 F2 N4 02 S2 411 po N 261 (\sJ-H C15H22N402S2 355 Jazz 0 I zu "C14 H18 N4 02 S2 339 N N0 non Nazi 263 (ysg-N H \ C14H20N402S2 341 1 S H Example Structure Molecular Formula (M+H) + -_-. 264 H C15 H22 N4 02 S2 355 zu N In o 265 e''N"NC17 H17 Cl N4 02 S2 409 H H ! HH , i 266 'j C18 H20 N4 02 S2 389 Yd-\ ) G 267 C18 H20 N4 03 S2 405 r I d 268 C18 H20 N4 03 S2 40. 5 W _--_. i l zu 269 C18 H20 N4 03 S2 405 N I i s 270) n J C16H22N403S2 341 OU oh 0' s 271 zon 512 r--o _/ 1 272 C17 H27 N5 0. 2 S2 353 N Oh 0 N . -S 273 H'S 'C16 H22 N4 03 S2 425 Example Structure i o i ; 0)-S 274 I'CN N S Cl 8 H24 N4 04 S2 401 J" ; I s 275 \-N C19 H20 N4 02 S2 383 N 276 .. s''C17H26N402S2 355 JJ N 0 277 N C15 H22 N4 02 S2 433 oAo (f J'N oo 278 0 s-sN C19H20N404S2 512 zu 0 S -'o 0 0 N- 279 N'S Cl 6 H21 N5 03 S2 353 Fuzz XI 280 AN'S C15 H20 N4 03 S2 367 i Nß s HQ N S 281 NINCS C16 H22 N4 02 S2 389 /\" N 282 o C16 H21 N5 03 S2 425 in ici S- nu 0 J \ S w \/ 283 C18 H24 N4 04 S2 X 369 Example Structure Molecular Formula (M+H) + N 284 C13 H18 N4 02 S2 465 0 H NCN ZON cl HN N 285 N N C13 H14 N6 02 S2 493 tD sur N 0 j I i i 286 ! , C15H18N602S2 ! 466 0 I NH /N 287 N HN C12 H13 N7 02 S2 366 dz 0 H _. i' HAN 288 ; HN C14 H15 NS 03 S2 i 366 i o 366 i N HO 289 N C13 H14 N6 02 S3 409 N 0 0 H O- 290 s" C17H17CtN402S2 ! 387 _I a i o i 291 % S NXs 9\ S C18 H18 N402 S2 375 292 N 292 H18 N4 02 S2 405 Example Structure Molecular Formula (M+H) + o i 293 ( sySN C18H20N403S2 389 'o 0 i 'N 1 294 WF C17 H16F2 N4 02 52 490 L 1 I W 295 N N C16 H17 N5 02 S2 476 i /" Q I NH I N 296 C15 H15 N5 02 S2 510 V-0 \ O c 297 KN C15 H14 CIN5 02S2 490 HM zu W 298 . C16H17N502S2 490 Q J-o HH 29 ? !. T C16H17N502S2 476 r ° 1 \N I Y \Y T, S NH NH 300 C15 H15 N5 02 S2 526 &"" ! 7" ! - i Example Structure I Molecular Formula (M+H) + nu H nu 301 C15 H15 N5 02 S2 540 cr ! ! \^S vH ;) 302 C18 H29 N5 02 S2 526 NIT S I 303 r C14 H19 N3 02 S2 326 o.. _ I\ srl 304 C21 H23 N3 02 S2 414 i I 0 305 H C19 H25 N3 02 S2 j 392 . N p'I N I I 306 C22H21N302S2 424 N my 0. 1 -M 0 I 307 C22 H21 N3 02 S2 424 dz zon N 308 Cl 5 Hl 9 N3 02 S2 338 Example Structure Molecular Formula (M+H) +- I/*\ N 309 C16 H23 N3 02 S2 354 salz 0 N-% \ - 310 ß/> S ß C18 H19N302 S2 374 NAS ° \ 311 tß< C18 H16 N402 S2 385 I I I I N 312 ° 8 8 312' t ! 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C11H15N30S2 270 0 sain ZON 359 S C17 H19 N3 0 S2 346 s __ 360 C13 H19 N3 0 S2 298 cf s. S I H, 0 N I 361 H C22 H25 N3 02 S2 428 N °"° I 362 C20 H27 N3 02 S2 406 N N 0 363 C23 H23 N3 02 S2 S fYyY° ° I 364 C23 H23 N3 02 S2 438 Nez 365 FN C16 H21 N3 02 S2 352 O 366 C17 H25 N3 02 S2 368 ' s i 1 JLy-s. y 367 N s Cl 9 H21 N3 02 S2 388 Example Structure Molecular Formula (M+H) + __ I 368 C19 H18 N4 02 S2 399 zu N 369 C21 H25 N3 02 S2 416 N N zizi 0 370 C19 H19 F2 N3 02 S2 424 F 0 371 ~ 1 Cz2H25N30Z Sa 428 woo I s 372 C19 H18 N4 02 S3 431 (SHNIN 373 432 P "/' N 374 0 C21 H25 N3 03 S2 432 I 0 0' YYT St° 375 C19H20N404S2 433 Example Structure Molecular Formula I (M+H) + _-i _ N/-\ _ ___ 376 \ C19 H20 N4 04 S2 433 iso 7- o I 377 XNA 8 C20 H23 N3 04 S2 434 w '' II-s I 378 C20 H23 N3 04 S2 434 ZUT i V s 379 Cl JJ'" C19H21N502S3 448 ! 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HE I 432 C16 H23 N3 02 S2 354 Example Structure Molecular Formula (M+H) + i-- o I i s 433 gNjJW C18 H19N3 02S2 374 i zu 434 NNYAS C18H16N4 02S2 385 40 ! i 435 Xu C20 H23N3 02S2 402 e 1 Jo 436 C18H17F2N302S2 410 F 0 zu I n 437 C21 H23 N3 02 S2 414 w lao If 0 I s 438 H s C18 H16 N4 02 S3 417 I a 439 NX C19H19N3 04S2 | 418 Qz 440 C20 H23 N3 03 S2 418 N N thil o 441 e C18 H18 N4 04 S2 j 419 WO I Ex mple Structure j Molecular Formula_ _M+H) + o I o 442 C18H18N404S2 419 ruz s H 0 I yH 443 C18 H18 N4 04 S2 419 ru o i i l j i w w 444 Cl 9 H21 N3 04 S2 420 H w I I o 1 \ I 445 ß C19H21 N304S2 D 0 nez _____, i s ; 446 C18 H19 N5 02 S3 434 J I SN I t H 447 tj C18 H19 N5 02 S3 4y I i NH moi, o _ F I I F F i 1 ° i I yH/\ I 449 453 Bt . !"YTV "Y. 450 C21 H25 N3 05 S2 464 1 i Example Structure Molecular Formula i (M+H) + H N )" fS 451 < C23 H28 N4 04 S2 489 N s 'o°ra ° I/N i 452 °) L C20H21N302S2 400 S ! 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