MXPA06002118A - Pyrimidothiophene compounds - Google Patents

Abstract

Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, cancer:wherein R2 is a group of formula -(Ar1)m-(Alk1)P-(Z)r-(Alk2)S-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk'and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is -0-, -S-, -(C=O)-, -(C=S)-, -S02-, -C(=O)O-, -C(=O) NR A- , -C(=S)NR A-, -S02NR A-, -NR AC(=O)_, -NR AS02- or-NR A-wherein R A is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical;and R4 is a carboxylic ester, carboxamide or sulfonamide group.

Description

COMPOUNDS OF PYRIMIDOTIOFENO Field of the Invention This invention relates to substituted bicyclic [2,3-d] pyrimidine compounds (hereinafter referred to as "pyrimidothiophene") having HSP90 inhibitory activity, to the use of such compounds in medicine, in relation to diseases that have a response to inhibition of HSP90 activity such as cancers, and to pharmaceutical compositions containing such compounds. BACKGROUND OF THE INVENTION Molecular chaperons maintain the proper folding and conformation of proteins and are crucial in regulating the balance between protein synthesis and degradation. They have proved important in regulating many important cellular functions, such as cell proliferation and apoptosis (Jolly and Morimoto, 2000, et al., 1998, Smith, 2001). Heat Shock Proteins (HSP) Exposure of cells to various environmental stresses, including heat shock, alcohols, metals, heavy and oxidative stress, results in the cellular accumulation of various chaperones commonly known as heat shock proteins ( HSP). The HSP induction protects the cell against injury by Ref. -.170291 initial tension, improves the recovery and leads to the maintenance of a stress-tolerant state. It has also become clear, however, that certain HSPs can also play an important molecular chaperon role under normal stress-free conditions by regulating the correct folding, degradation, localization and function of a growing list of important cellular proteins. There are several families of ultigenes of the HSP, with products of individual genes that vary in the expression, function and cellular location. They are classified according to molecular weight, for example, HSP70, HSP90 and HSP27. Various diseases in humans can be acquired as a result of poor protein folding (reviewed in Tytell et al., 2001, Smith et al., 1998). Thus, the development of therapies which fragment the machinery of molecular chaperones may prove beneficial. In some conditions (for example Alzheimer's disease, prion diseases and Huntington's disease), misfolded proteins can cause protein aggregation that results in neurodegenerative disorders. Also, misfolded proteins can result in loss of function of the wild-type protein, which leads to dysregulated physiological and molecular functions in the cell. HSPs have also been implicated in cancer. For example, there is evidence of the differential expression of HSP which can be related to the stage of tumor progression (Martin et al., 2000, Conroy et al., 1996, Kawanishi et al., 1999, Jameel et al. , 1992; Hoang et al., 2000; Lebeau et al., 1991). As a result of the participation of HSP90 in various critical oncogenic trajectories, and the discovery that certain natural products with anti-cancer activity are targeting this molecular chaperone, the fascinating new concept has developed that by inhibiting the function of HSP it can be useful in the treatment of cancer. The first molecular chaperone inhibitor is currently undergoing clinical trials. HSP90 HSP90 constitutes about 1-2% of the total cellular protein, and is usually present in the cell as a dimer in association with one of several other proteins (see for example, Pratt 1997). It is essential for cell viability and shows dual chaperon functions (Young et al., 2001). It plays a key role in the response to cell stress by interacting with many proteins after their native conformation has been altered by various environmental stresses such as heat shock, ensuring adequate protein folding and avoiding non-specific aggregation (Smith et al. al., 1998). In addition, recent results suggest that HSP90 may also play a role in buffering against the effects of mutation, presumably by correcting the inadequate fold of mutant proteins (Rutherford and Lindquist, 1998). However, HSP90 also has an important regulatory role. Under normal physiological conditions, together with a homolog and GRP94 endoplasmic reticulum, HSP90 plays a maintenance role in the cell, maintaining the conformational stability and maturation of various key client proteins. These can be subdivided into three groups; (a) steroid hormone receptors, (b) Ser / Thr or tyrosine kinases (eg, ERBB2, RAF-1, CDK4, and LCK), and (c) a collection of apparently unrelated proteins, eg mutant p53 and the catalytic subunit of telomerase hTERT. All these proteins play key regulatory roles in many physiological and biochemical processes in the cell. The new HSP90 client proteins are continuously identified. The highly conserved family of HSP90 in humans consists of four genes, nominally the cytopolic HSP90a and HSP90β isoforms (Hickey et al., 1989), GRP94 in the endoplasmic reticulum (Aragón et al., 1999), and HSP75 / TRAP1 in the matrix of the itocondria (Felts et al., 2000). It is believed that all members of the family have a similar mode of action but are linked to different client proteins depending on their location within the cell. For example, ERBB2 is known to be a GRP94 specific client protein (Aragón et al., 1999) and the tumor necrosis factor receptor type 1 (TNFR1) and RB has been shown to be TRAP1 clients (Song et al. ., 1995; Chen et al., 1996). HSP90 participates in a series of complex interactions with a range of regulatory and client proteins (Smith, 2001). Although the precise molecular details remain to be obtained, crystallographic biochemical and X-ray studies (Prodromou et al., 1997; Stebbins et al., 1997) carried out over the last few years have provided increasingly detailed insights into the function of the chaperone of HSP90. After an early controversy on this issue, it is now clear that HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997), with the dimerization of the nucleotide binding domains that are essential for the hydrolysis of ATP, which In turn, it is essential for the function of the chaperone (Prodromou et al, 2000a). The ATP binding results in the formation of a toroidal dimer structure in which the N-terminal domains come into closest contact with one another, resulting in a conformational change known as the 'clamp mechanism' (Prodromou and Pearl, 2000b). Known HSP90 Inhibitors The first class of HSP90 inhibitors to be discovered was in the benzoquinone ansamycin class, which includes the compounds herbimycin A and geldanamycin. They were shown to invert the malignant phenotype of the fibroblasts transformed by the v-Src oncogene (Uehara et al., 1985), and subsequently showed potent antitumor activity both in in vitro models (Schulte et al., 1998) and in animal models in vivo (Supko et al., 1995). Affinity matrix and immunoprecipitation studies have shown that the important mechanism of action of geldanamycin involves binding to HSP90 (Whitesell et al., 1994, Schulte and Neckers, 1998). Additionally, X-ray crystallographic studies have shown that geldamamycin competes in the binding site ATP and inhibits the intrinsic activity of HSP90 ATPase (Prodromou et al., 1997; Panaretou et al., 1998). This in turn prevents the formation of mature multimeric HSP90 complexes able to form chaperones with the client proteins. As a result, the client proteins are targeted for degradation via the protease pathway of uchiquitin. 17-Allylamino, 17-derratoxygelandanamycin (17AAG) retains the property of HSP90 inhibition resulting in suppression of client protein and antitumor activity in cell cultures and in xenoingerto models (Schulte et al, 1998; Kelland et al. al, 1999), but has a significantly lower epatotoxicity than geldanamycin (Page et al, 1997). 17AAG is currently being evaluated in Phase I clinical trials.

Radicicol is a macrocyclic antibiotic that is shown to reverse the malignant phenotype of fibroblasts transformed by v-Src and v-Ha-Ras (Kwon et al, 1992; Zhao et al, 1995). It was shown to degrade various signaling proteins as a consequence of inhibition of HSP90 (Shulte et al., 1998). Crystallographic X-ray data confirmed that radicicol also binds to the N-terminal domain of HSP90 and inhibits the intrinsic activity of ARPase (Roe et al., 1998). Radicicol lacks antitumor activity in vivo due to the unstable chemical nature of the compound. It is known that coumarin antibiotics bind to the gyrase of bacterial DNA at an ATP binding site homologous to that of HSP90. Coumarin, novobiocin, was shown to bind to the carboxy terminus of HSP90, that is, at a site different from that occupied by the benzoquinone and radicicol ansamycins which binds at the N terminus (Marcu et al., 2000b). However, this still results in the inhibition of HSP90 function and the degradation of various signaling proteins that form chaperones with HSP90 (Marcu et al., 2000a). Geldanamycin can not bind subsequent HSP90 to novobiocin; this suggests that there must be some interaction between the N terminal and the C terminal domains, and is consistent with the view that both sites are important for the HSP90 chaperone properties.

An inhibitor of purine-based HSP90, PU3, has been shown to result in the degradation of signaling molecules, including ERBB2, and to arrest cell cycle arrest and differentiation in breast cancer cells (Chiosis et al., 2001). The patent publications WO 2004/050087 and WO2004 / 056782 refer to known classes of pyrazole derivatives which are inhibitors of HSP90. HSP90 As a Therapeutic Objective Because of its role in regulating various signaling pathways that are crucially important in driving the tumor phenotype, and the discovery that certain bioactive natural products exert their effects through HSP90 activity, the HSP90 molecular chaperone is is currently evaluating as a new target for the development of an anticancer drug (Neckers et al., 1999). The predominant mechanism of action of geldanamycin, 17AAG, and radicicol involves the binding of HSP90 to the ATP binding site located in the N-terminal domain of the protein which leads to the inhibition of the intrinsic ATPase activity of HSP90 ( see, for example, Prodromou et al., 1997; Stebbins et al., 1997; Panaretou et al., 1998). The inhibition of HSP90 ATPase activity prevents the recruitment of co-chaperones and encourages the formation of a type of HSP90 heterocomplex from which these client proteins are directed to degradation via the pathway of proteasone ubiquitin (see for example , Neckers et al., 1999; Kelland et al., 1999). Treatment with HSP90 inhibitors leads to the selective degradation of important proteins involved in cell proliferation, cell cycle regulation and apoptosis, processes that are fundamentally important in cancer. The inhibition of HSP90 function has been shown to cause the selective degradation of important signaling proteins involved in cell proliferation, regulation of the cell cycle and apoptosis, processes that are fundamentally important and that are commonly deregulated in cancer (see for example, Hostein et al., 2001). An attractive reasoning to develop drugs against this objective for use in the clinical setting is that by simultaneously suppressing proteins associated with the transformed phenotype, a strong antitumor effect can be achieved and a therapeutic advantage against cancer versus normal cells can be achieved. These events in the downward direction of HSP90 inhibition are believed to be responsible for the antitumor activity of HSP90 inhibitors in cell culture and in animal models (see, eg, Schulte et al., 1998).; Kelland et al., 1999).

Brief Description of the Invention The present invention relates to the use of a class of substituted thieno [2,3-d] pyrimidine compounds (hereinafter referred to as pyrimidotines) as HSP90 inhibitors, for example for the inhibition of the proliferation of cancer cells. A central pyrimidothiophene ring with aromatic substitution at an anil carbon atom are aspects of the principle characterization of the compounds to which the invention relates. Detailed Description of the Invention In a broad aspect, the present invention provides the use of a compound of Formula (I), or a salt, N-oxide, hydrate, or solvate thereof in the preparation of a composition for the inhibition of HSP90 activity in vitro or in vivo: wherein R2 is a group of Formula (IA): - (Ar1) ™ - (Alq1) p- (Z) r- (Alq2) 3-Q (IA) wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C2-C3 alkenylene or C3-C3 alkylene radicals, m, p, r and s independently are 0 or 1, Z is -0-, -S-, - (C = 0) -, - ( C = S) -, -S02-, - (C = 0) 0-, -C (= 0) NRA-, -C (= S) NRA-, -S02NRA-, ~ NRAC (= 0) -, - NRAS02-, or -NRA-wherein R is hydrogen or C? -C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted alkyl (Cx-Cg), aryl or heteroaryl radical; Y R 4 is a carboxylic ester, carboxamide or sulfonamide group. In another broad aspect, the invention provides a method of treating diseases that are responsive to inhibition of HSP90 activity in mammals, which method comprises administering to the mammal an amount of a compound as defined in claim 1 effective for inhibition of HSP90 activity. The in vivo use, and method, of the invention applies to the treatment of diseases in which HSP90 activity is involved, including use for immunosuppression or treatment of viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis. , type I diabetes, lupus, psoriasis and inflammatory bowel disease; disease related to cystic fibrosis angiogenesis such as diabetic retinopathy, hemangiomas and endometriosis; or for the protection of normal cells against the toxicity induced by chemotherapy; or diseases where the failure to experience apoptosis is a fundamental factor; or protection from hypoxia-ischemic injury due to the elevation of Hsp70 in the heart and brain; cenurosis / CJD, Huntingdon or Alzheimer's disease. The use for the treatment of cancer is especially indicated. Publications WO 01/62233, Transition Metal Chemistry Vol. 19, 1994, pages 335-339, Journal of Heterocyclic Chemistry Vol. 30, 1993, pages 1065-1072 and Synthesis No. 5, 1983, pages 402-404, describe compounds specific ones that fall within Formula (I) above, or relate to classes of compounds that encompass some compounds of Formula (I). However, most of the compounds of Formula (I) with which the foregoing broad aspects of the invention refer, are considered novel in their own right. The invention includes such novel compounds, and in particular compounds of the formula (I), and salts, N-oxides, hydrates or solvates thereof: wherein R2 is a group of the Formula (IA): - (Ar1) m - (Alk1) p- (Z) r- (Alk2) ß-Q (IA) wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 Y "Alk2 are optionally substituted divalent C2-C3 alkylene or C2-C3 alkenylene radicals , m, p, rys are independently 0 or 1, Z is -O-, -S-, - (C = 0) -, - (C = S) -, -S02-, C (= 0) 0-, -C (= 0) NRA-, -C (= S) NRA-, -S02NRA-, -NRAC (= 0) -, -NRAS02- or -NRA- wherein RA is hydrogen or C? -C6 alkyl, and Q is hydrogen or an optionally substituted heterocyclic or carbocyclic radical; R3 is hydrogen, an optional substituent, or an alkyl radical (C? -C6), aryl or heteroaryl; and R is a carboxylic ester, carboxamide or sulfonamide group, WITH THE CONDITION THAT (i) R3 is not -NH2 or (ii) when R4 is -C00CH3 and R3 is hydrogen then R2 is not ethylamino, diethylamino, phenylamino or -N (Ph) (C2H5) wherein Ph is phenyl. As used herein: the term "carboxyl group" refers to a group of the Formula -COOH; the term "carboxyl ester group" refers to a group of the formula -COOR, wherein R is a radical currently or by a notion derived from the hydroxyl compound ROH; and the term "carboxamide group" refers to a group of the Formula -C0NRaRb, wherein -NRaRb is an amino group (including cyclic amino) currently or by a notion derived from ammonia or the amine HNRaRb; the term "sulfonamido group" refers to a group of the Formula -S02NRaRb, wherein -NRaRb is an amino group (including cyclic amino) currently or by a notion derived from the ammonia or the amine HNRaRb. As used herein, the term "alkyl (Ca-Cb)" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. As used herein the term "divalent alkylene radical (Ca-Cb)" wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valencies.

As used herein the term "alkenyl (Ca-Cb)" wherein a and b are integers refers to a straight or branched chain alkenyl portion having from a to b carbon atoms having at least one double bond of any E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1 and 2-butenyl and 2-methyl-2-propenyl. As used herein, the term "divalent alkenylene radical (Ca-Cb)" refers to a hydrocarbon chain having from a to b carbon atoms, at least one double bond and two unsatisfied valencies. As used herein, the term "cycloalkyl" refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein, the term "cycloalkenyl" refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. As used herein, the term "aryl" refers to a mono, bi or tricyclic carbocyclic aromatic radical. Illustrative of such phenyl, biphenyl and naphthyl radicals are illustrative.

As used herein, the term "carbocyclic" refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic, cycloalkyl, and cycloalkenyl aryl radicals. As used herein, the term "heteroaryl" refers to a mono, bi or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such thienyl, benzthienyl, furyl, benzfurilo, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, piraziolilo, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, tiadazolilo, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, and indazolyl . As used herein, the non-qualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and in particular refers to a non-aromatic mono, bi or tri-cyclic radical containing one or more heteroatoms selected from S, N and O, and for the groups consisting of a non-aromatic monocyclic radical containing one or more such heteroatoms which are covalently linked to another radical or a monocyclic carbocyclic radical. Illustrative of such radicals groups pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, tiadazolilo, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranilo, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl , ethylenedioxyphenyl, maleimido and succinimido. Unless otherwise specified in the context in which this occurs, the term "substituted" is applied to any amount herein that means substituted with at least one substituent, for example selected from alkyl (CL-CS) , alkoxy (C? -C6), hydroxy, hydroxyalkyl (C? -C6), mercapto, mercaptoalkyl (C? -C3), alkylthio (C? -C6), halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, nitro , nitrile (-CN), oxo, phenyl, -COOH, -COORA, -C0RA, -S02RA, -CONH2, -S02NH2, -CONHRA, -S02NHRA, -CONRARB, -S02NRARB, -NH2, -NHRA, -NRARB, -OCONH2, -OCONHRA, -OCONR ?, RB, -NHC0RA, -NHCOORA, -NRBCOORA, -NHS020RA, -NRBS020RA, -NHC0NH2, -NRAC0NH2, -NHC0NHRB, -NRACONHRB, NHCONRARB, or -NRAC0NRARB wherein RA and RB are independently an alkyl group (C? -C6). An "optional substituent" can be one of the above substituent groups. As used herein, the term "salt" includes an addition base, an addition acid and quaternary salts, the compounds of the invention which are acids can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, for example sodium and potassium hydroxides; alkaline earth metal hydroxides eg calcium, barium and magnesium hydroxides; with organic bases for example N-ethyl piperidine, dibenzylamino and the like. Those compounds (I) which are basic to form salts, including pharmaceutically and veterinarily acceptable salts with inorganic acids, for example with hydrohalic acids such as hydrochloric or hydrobromic acids, sulfuric acid, nitric acid or phosphoric acid and the like, and with organic acids for example with acetic, tartaric, succinic, fumaric, maleic, salicylic, citric, methanesulfonic and p-toluenesulfonic acids and the like. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahll and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when the solvent is water. The compounds to which the invention refers that can exist in one or more stereoisomeric forms, due to the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry in each chiral center or as atropisomers with stereochemistry R or S in each chiral axis. The invention includes all of these enantiomers and diastereomers and mixtures thereof. The so-called "prodrugs" of the compounds of Formula (I) are also within the scope of the invention. Thus certain derivatives of the compounds of the Formula (I) which may have little or no pharmacological activity by themselves may, when administered in or on the body, be converted to compounds of the formula (I) having the desired activity, example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. Roche, American Pharmaceutical Association). The prodrugs according to the invention can, for example, be produced by replacing the appropriate functionalities present in the compounds of the formula (I) with certain portions known to those skilled in the art as "proportions" as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo during drug administration. Some examples of metabolites include (i) wherein the compound of the formula (I) contains a methyl group, a hydroxymethyl derivative thereof (-CH3-> -CH20H): (ii) wherein the compound of the formula (I) contains an alkoxy group, a hydroxy derivative thereof (-0R-> -OH): (iii) wherein the compound of the formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NRXR2-> - NHR1 or -NHR2); (iv) wherein the compound of the formula (I) contains a secondary amino group, a primary derivative thereof (-NHR1-> -NH2): (v) wherein the compound of the formula (I) contains a phenyl portion, a phenol derivative thereof (-Ph-> - PhOH); and (v) wherein the compound of the formula (I) contains an amide group, a carboxylic acid derivative thereof (-C0NH2-> COOH). The radical R2 As stated, R2 is a group of the formula (IA): - (Ar1) m- (Alq1) p- (Z) r- (Alq2) sQ (IA) where in any compatible combination Ar1 is a optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, rys are independently 0 or 1, Z is -0-, -S-, - (C = 0) -, - (C = S) -, -S02-, -C (= 0) 0-, -C (0 =) NRA-, -C (= S) NRA-, -S02NRA-, -NRAC ( = 0) -, -NRAS02- or -NRA- where RA is hydrogen or C? -C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical. When it occurs in the radical R2, Ar1 can be, for example, a phenyl, cyclohexyl, pyridyl, morpholino, piperidinyl or piperazinyl ring. It is currently preferred that Ar1, when present, for a phenyl ring; Alk1 and Alk2 can be, for example, optionally substituted divalent radicals selected from -CH2, CH2CH2- or -CH = CH-. Optional substituents on Alk1 and Alq2 include, for example, mono or di (Cx-C3 alkyl) amino and C1-C3 alkoxy; and Z may be, for example, -0- or -NH; and Q is hydrogen. In a simple subclass of the compounds to which the invention relates, m is 1 and each of p, r and s is 0, and Q is hydrogen, so that R2 is aryl or optionally substituted heteroaryl. In such cases, R 2 may be, for example, phenyl, 2 or 3-thienyl, 2 or 3-furanyl, 2, 3 or 4-pyridinyl, morpholinyl or optionally substituted piperidinyl. Presently preferred are compounds wherein R2 is optionally substituted phenyl, for example where the optional substituents are selected from methyl, ethyl, n- or isopropyl, vinyl, allyl, methoxy, ethoxy, n-propyloxy, benzyloxy, allyloxy, cyanomethoxy chlorine, bromine, cyano, formyl, methyl, ethyl, or n-propyl-carbonyloxy, methyl or ethylaminocarbonyl. The groups of substituents more complexed which may occur in the ring R 2 include those (i) of the formula -0 (CH 2) I 1 Z 1 wherein n is 1, 2 or 3 and Z 1 is a primary, secondary, tertiary or cyclic, or an alkoxyC? -C6 group; or (ii) of the formula - (Alq3) mZ1 wherein Alq3 is a straight or branched chain divalent (C-C3) alkylene, m is 0 or 1, and Z1 is a primary, secondary, tertiary or cyclic amino group, or an alkoxyC? -C6 group. The preferred substitution positions in the phenyl ring are positions 2, 4 and 5. In other simple structures, m is 1, p, r and s are each again 0, and Q may be an optionally substituted carbocyclic or heterocyclic ring, for example a phenyl, cyclohexyl, pyridyl, morpholino, piperidinyl, or piperazinyl ring. In such cases Q is a direct substituent on the optionally substituted Ar1 ring. In more complex structures with which the invention relates, one or more of m, p, r and s can be 1 and Q can be hydrogen or an optionally substituted carbocyclic or heterocyclic ring. For example, p and / or s can be 1 and r can be 0, so Q is linked to Ar1 by an alkylene or alkenylene radical, for example a C? -C3 alkylene radical, which is optionally substituted. In other cases each of p, r and s can be 1, in which case, Q is linked to Ar 1 by an alkylene or alkenylene radical which is interrupted by the radical Z containing heteroatom. In still other cases, p and s can be 0 and r can be 1, in which case Q is linked to Ar1 by means of the radical Z containing heteroatom. Specific examples of the R2 groups used in the compounds of the invention include those present in the compounds of the Examples herein. The optional R3 substituent R3 is hydrogen or an optional substituent, as defined above. It is currently preferred that R3 is hydrogen. The group R4 When R4 is a carboxamide or sulfonamide group, examples include those of the formula -C0NRB (Alq) QRA -S02NRB (Alq) nRA wherein Alq is a divalent alkylene, alkenylene or alkynylene radical, for example a -CH2 radical -, -CH2-CH2-, -CH2-CH2-CH2-, -CH2CH = CH-, or -CH2CCCH2-, and the radical Alq can be optionally substituted, n is 0 or 1, RB is hydrogen or an alkyl group C -C5 or C2-C6 alkenyl, for example methyl, ethyl, n- or iso-propyl, or allyl. It is currently preferred that RB is hydrogen. RA is an optional substituent such as hydroxyl, amino (including mono- and di-alkylamino (Cx-C3)), carbamoyl (-C (= 0) NH2), -S020H, trifluoromethyl; or optionally substituted carbocyclic, for example cyclopropyl, cyclopentyl, cyclohexyl, phenyl optionally substituted by hydroxyl, amino, fluoro, chloro, bromo, 3,4 methylenedioxy, sulfamoyl (-S02NH2), -S020H, methoxy, methylsulfonyl, trifluoromethyl; or heterocyclyl, for example pyridyl, furyl, thienyl, diazolyl, N-piperazinyl, pyrrolyl, tetrahydrofuranyl, thiazolyl, 1-aza-bicyclo [2, 2, 2] octanyl, or N-morpholinyl, any of the heterocyclic rings can be substituted, example in a nitrogen ring by (C? -C3) alkyl, or RA and RB when taken together with the nitrogen to which they are bonded form an N-heterocyclic ring which may optionally contain one or more additional heteroatoms selected from O, S and N, and which can optionally be substituted on one or more C or N atoms in the ring, examples of such N-heterocyclic rings include morpholino, piperidinyl, piperazinyl and N-phenylpiperazinyl. It is currently preferred that R 4 is a carboxamide group. When R4 is a carboxylic ester group, examples include those of the Formula -C00RC wherein Rc is a C? -C6 alkyl group or a C2-C6 alkenyl, for example methyl, ethyl, n- or iso-propyl, or allyl; or an optionally substituted aryl or heteroaryl group, for example phenyl, pyridyl or optionally substituted thiazolyl; or an optionally substituted aryl (C 1 -C 6 alkyl) or heteroaryl (C 1 -C 3 alkyl) group such as benzyl or pyridylmethyl; or an optionally substituted cycloalkyl group such as cyclopentyl or cyclohexyl. Specific examples of the R groups used in the compounds of the invention include those presented in the compounds of the examples herein. A preferred subclass of the compounds to which the invention relates have the formula (II) wherein A is a secondary amino group R10 is H, Cl, Br or CH3; R x is hydrogen, Cl, Br, CN, methyl, ethyl, n or isopropyl, vinyl or allyl; R12 is (i) a radical of the formula -0 (CH2) I1Z1 wherein n is 1, 2 or 3 and Z1 is a primary, secondary, tertiary or cyclic amino group, or a C6-C6 alkoxy group; or (ii) a radical of the formula - (Alq3) mZ1 wherein Alq3 is a straight or branched chain divalent (C-1-C3) alkylene, m is 0 or 1 and Z1 is a primary, secondary amino group, tertiary or cyclic, or an alkoxyC? -C6 group. In this subclass of the compounds (II) it is preferred that A is a secondary alkylaminoC-C6 group, for example wherein the C?-C3 alkyl substituent is selected from methyl, ethyl and n- and iso-propyl, and R12 is ( i) a radical of the formula -0 (CH2) IlZ1 wherein n is 1, 2 or 3 and Z1 is di (Cx-C3 alkyl) amino or C? -C3 alkoxy, for example wherein the alkyl C? -C3 are selected from methyl, ethyl and n- and iso-propyl. Specific compounds to which the invention refers include those of the examples, particularly those exemplified compounds having structure (II) above. There are multiple synthetic strategies for the synthesis of the compounds (I) with which the present invention concerns, but everything depends on the known chemistry, which is known to the technician of synthetic organic chemistry. Thus, the compounds according to Formula (I) can be synthesized according to procedures described in the standard literature and are well known to those skilled in the art. Typical literature sources are "Advanced Organic Chemistry", 4th Edition (Wiley), J March, "Comprehensive Organic Transformation", 2nd Edition (Wiley), R.C. Larock, "Handbook of Heterocyclic Chemistry", 2nd Edition (Pergamon), A.R. Katritzky), journal articles such as those found in "Synthesis", "Acc. Chem. Res.", "Chem. Rev", or Primary literature sources identified by the Sources of standard literature online or from secondary sources such as "Chemical Abstracts" or "Beilstein". Such literature methods include those of the Preparative Examples herein, and methods analogous thereto. For example, the following general reaction scheme can be used: The starting material is either commercially available or can be made according to the methods of the literature. Subsequent reactions can be carried out in R2, R3 or R4 to prepare additional compounds of Formula (I). The compounds of the invention are inhibitors of HSP90 and are useful in the treatment of diseases which respond to the inhibition of HSP90 activity such as cancers; viral diseases such as Hepatitis C (HCV) (Waxman, 2002); immunosuppression as in transplant (Bijlmakers, 2000 and Yorgin, 2000); anti-inflammatory diseases (Bucci, 2000) such as rheumatoid arthritis, asthma, MS, type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseases related to angiogenesis (Hur, 2002 and Kurebayashi, 2001); Diabetic retinopathy, hemangiomas, psoriasis, endometriosis and tumor angiogenesis. Also an Hsp90 inhibitor of the invention can protect normal cells against the toxicity induced by chemotherapy and is useful in diseases where the failure to undergo apoptosis is a fundamental factor. Such Hsp90 inhibitor may also be useful in diseases where the induction of a heat shock protein response or cell stress could be beneficial, for example, protection from a hypoxia-ischemic injury due to the elevation of Hsp70 in the heart (Hutter , 1996 and Trost, 1998) and brain (Plumier, 1997 and Rajder, 2000). An increase induced by the Hsp90 inhibitor in Hsp70 levels could also be useful in diseases where the protein does not attach or aggregation is a major cause, for example, neurogenerative disorders such as Cenurosis / CJD, Huntingdon and Alzheimer (Sittler, 2001; Trazelt, 1995 and Winklhofer, 2001). "In this manner, the invention also includes: (i) A pharmaceutical or veterinary composition comprising a compound of formula (I) above, together with a pharmaceutically or veterinarily acceptable carrier. The use of a compound of formula (I) above in the preparation of a composition for the composition for the inhibition of HSP90 activity in vitro or in vivo. (Iii) A method of treating diseases or conditions that respond to inhibition of the activity HSP90 in mammals, which method comprises administering to the mammal an amount of a compound of formula (I) above effective to -inhibit the activity of HSP90. It will be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of administration. excretion, combination of the drug and the mechanism of cause and severity of the particular disease that undergoes therapy. In general, a suitable dose for formulations that are administered orally will usually be in the range of 0.1 to 3000 mg, once, twice or three times a day, or the equivalent daily amount administered by infusion or other routes. However, optimal dose levels and frequency of dosing will be determined by clinical trials as conventional in the art. The compounds to which the invention relates can be prepared for administration by any route consistent with their pharmacokinetic properties. Orally administrable compositions may be in tablets, capsules, powders, granules, dragees, liquid preparations or gels, such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in a unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; filled for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for the formation of tablets, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to a method well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, hydrogenated edible fats of gelatin, emulsifying agents for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and conventional flavoring or coloring agents are desired. For topical application to the skin, the drug can be made in cream, lotion or ointment. The cream or ointment formulations that can be used for the drug are conventional formulations well known in the art, for example as described in standard pharmacy textbooks such as British Pharmacopoeia. The active ingredient can also be administered parenterally in a sterile medium. Depending on the vehicle and the concentration used, the drug can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as anesthetic agents, preservatives and buffers in the vehicle can be dissolved in the vehicle. The following examples illustrate the preparation and activities of the specific compounds of the invention. Example 1 Ethyl ester of 2-amino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid Stage 1 Ethyl ester of 2-amino-4-chloro-tieno [2,3-d] pyrimidine-6-carboxylic acid To a stirred mixture of 2-amino-4,6-dichloro-5-formyl-pyrimidine (1 eq.) And potassium carbonate (1 eq.) In acetonitrile at room temperature was added ethyl-2-mercaptoacetate (0.95 eq.). .) and the mixture was stirred at room temperature for three hours, followed by heating at 80 ° C for one hour. After cooling, the mixture was concentrated to dry in vacuo. Column chromatography on silica, eluting with ethyl acetate and hexanes, gives example 1 as a yellow powder. LC-MS retention time: 2 .371 minutes, [M + H] + 258. 0 Stage 2 (Suzuki reaction): Ethyl ester of 2-amino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid A solution of Example 1 step 1 (1 eq.), Phenyl boronic acid (1.2 eq) and sodium carbonate (1.2 eq) in 1,4-dioxane and water (3.5: 1) were degassed by bubbling through nitrogen gas for 5 mins. The Pd (PPh3) 4 (0.05 eq.) Was added and the mixture is heated in a Personal Chemistry microwave synthesizer at 150 ° C for 10 minutes. After cooling and concentration in vacuo, preparative HPLC gives Example 2 as a white powder. LC-MS retention time: 2545 minutes, [M + H] + 300.10 This compound has 'A' activity in the fluorescence polarization assay described below. Example 2; Ethyl ester of 2-amino-4- (4-trif luoromethyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid prepared as per Example 1. LC-MS retention time: 2768 minutes, [M + H] + 368.1 XH NMR (400MHz, d6-DMSO): d = 1.07 (3H, t, J = 7.1 Hz), 4.09 (2H, q, J = 7.1 Hz), 7.25 (2H, br s), 7.68 (1 H, s ), 7.76 (2H, d, J = 8.0Hz), 7.85 (2H, d, J = 8. OHz). This compound has activity? B 'in the fluorescent polarization assay described below. The following compounds in Table 1 were synthesized and tested in the fluorescent polarization assay described below. Suzuki reactions were carried out as in the Example 1 Step 2. The reductive amination reactions were carried out as per Example 33, as follows: Ethyl ester of 2-amino-4- (4-piperidin-1-methylmethyl-phenyl) -thieno [2, 3-d] pyridine-6-carboxylic acid (Example 33 in Table 1) Pyrrolidine (5 equiv) was added to a suspension of ethyl ester of 2-amino-4- (4-formyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid (1 equiv) in methanol The reaction mixture was heated to reflux for 3.5 hours then cooled to room temperature. Sodium borohydride (3 equiv) was added and stirred for 10 mins. The mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried and evaporated to a yellow solid. The crude product was purified by preparative HPLC. LC-MS retention time: 1,803 minutes, [M + H] + 383.

The chloride shift reactions were carried out as per Example 22 as follows: Methyl ester of 2-amino-4-benzylamino-thieno [2,3-d] pyrimidine-6-carboxylic acid (Example 22 in the Table 1) The methyl ester of 2-amino-chloro-thieno [2,3-d] pyrimidine-6-carboxylic acid (10 Omg, 0. 39mmol), benzylamine (100μl) in 4mL of THF are exposed to MW irradiation at 110 ° C for 35 mins. The reaction was cooled to room temperature and worked (acid) and purified using standard conditions for a neutral compound. LC-MS: RT = 2.391 mins; MS m / z = 329 (M + 1). Note: The intensity and reaction time depends on the reactivity of the amine. For example, for less reactive amines (such as N-methyl aniline), suitable reaction conditions are MW 160 ° C for 30 mins and 0.5mL amine. The fourth column of Table 1 establishes the activity of the compound in the fluorescent polarization assay described below.

Table 1 the he Example 42; 2-Amino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid amide The compound of Example 1 was suspended in concentrated ammonium hydroxide and heated on a Personal Chemistry microwave synthesizer at 140 ° C for 20 minutes. Concentration in vacuo gives example 42 as a white solid. LC-MS retention time: 1824 minutes, [M + H] + 271.10.

Example 43 2-Amino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid ethylamide Step 1: 2-Amino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid Sodium hydroxide (0.66 g, 16.5 mmol) was added to a suspension of 2-amino-phenyl-thieno [2,3-d] irimidine-6-carboxylic acid ethyl ester (Example 1) (1.00 g). 3.34 mmol) in ethanol (20 ml) and water (2 ml). The mixture was refluxed for 1 hour (providing a homogeneous pale yellow solution) and allowed to cool to room temperature.

The solvents were removed in vacuo and the solid residue was dissolved in water (30 mL) and cooled with an ice-water bath. The mixture was stirred and adjusted to pH 1-2 by the dropwise addition of concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water, then ethanol and finally diethyl ether. The opaque white product was dried in vacuo to give 2-amino-4-phenyl-t-ene [2,3-d] pyrimidine-6-carboxylic acid as a colorless solid (0.784 g, 87%). LC / MS RT = 1845 min; m / z = 272 (M + H) + Step 2 2-Amino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid ethylamide 0- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.380 g, 1.0 mmol) was added to 2-amino-4-phenyl-thieno acid [2, 3-d] pyrimidine-6-carboxylic acid (0.187 g, 0.69 mmol). This mixture was suspended in dimethylformamide (DMF) (5.0 mL) and diisopropylethylamine (0.696 mL, 4.0 mmol) was added to provide a yellow solution. Diethylamine hydrochloride (0.122 g, 5.0 mmol) was added and the reaction mixture was heated for ten minutes at 100 ° C in a sealed vial on a microwave synthesizer. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml). The phases were separated and the organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate. The mixture was filtered and the filtered solvents were removed in vacuo to leave a yellow solid which was adsorbed on silica gel and purified by flash chromatography on silica gel (20 g), eluting with a solvent gradient of 15 to 50%. ethyl acetate in hexane. This gives the ethylamide of 2-amino-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid as a pale yellow solid (0.051 g, 25%).

LCMS RT = 2.08 min; m / z = 299 (M + H) + 1 H NMR (400MHz, d 6 DMSO) 6 1.11 (t, 3H), 3.26 (m, 2H), 7.12 (s, 2H), 7.61 (m, 3H), 7.86 ( m, 2H), 8.03 (s, 1 H), 8.71 (t, 1 H). The compound of Example 43 has activity? A 'in the fluorescent polarization assay described below. The following compounds (Table 2) are made by the method of Example 43 from the corresponding ester (Table 1) and the appropriate amine. The final column of Table 2 establishes the activity of the compound in the fluorescent polarization assay described below.

Table 2 Example 74 Ethyl ester of 2,5-diamino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl ester Stage 1 2-amino-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5-carbonitrile Benzaldehyde (15g, 141.3mmol, leq), guanidine carbonate (25.47g, 141.3mmol, leq), ethyl cyanoacetate (15.99g, 141. 3mmol, leq) and anhydrous sodium acetate (11.59g, 141.3mmol, leq) ) were added to 300ml of anhydrous pyridine and refluxed for 4 hours. The reaction was then cooled to room temperature and the solvent was removed under reduced pressure. The brown residue was triturated with 400 ml of aqueous acetic acid (30%) and filtered thoroughly. The yellow solid was then triturated with 300 ml of diethyl ether and filtered thoroughly to give 2-amino-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5-carbonitrile as an opaque white solid. Yield: 14.46g (48%) LCMS retention time = 1.34min, m / z calculated for C ??H9N40 213.22 (M + H), found 213.1 Step 2 2 -Amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-sarbonitrile 2-Amino-6-oxo-4-phenyl-1, 6-dihydro-pyrimidine-5-carbonitrile (0.200g, 0.942mol, leq) and phosphorus pentasulfide (0.838g, 3.770mol, 4eq) were dissolved in 5ml of pyridine. The reaction was heated under reflux for 2 hours, cooled to room temperature and drained in 100 ml of water. The mixture was boiled for 1 hour, cooled to room temperature and extracted with dichloromethane. The combined organic extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the orange residue was triturated with diethyl ether to give 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile as a yellow solid. Yield: O.lldg (55%) CLEM retention time = 1.94min, m / z calculated for C11H9 4S 229.29 (M + H), found 229.1 Step 3 Ethyl ester of 2,5-diamino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid ester Sodium (O.OlOg, 0.438 mmol, leq) was dissolved in 4 ml of anhydrous ethanol under nitrogen. 2-Amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile (O.lOOg, 0.438 mmol, leq) was added and the reaction was stirred at room temperature for 1 hour. The 2-bromoethylacetate (0.073 g, 0.438 mmol, 1 eq) was added. The reaction was stirred for an additional 30 minutes at room temperature. Then the sodium (O.OlOg, 0.438mmol, leq) dissolved in lml of anhydrous ethanol was added. The reaction was then refluxed for 5 hours. The reaction was cooled to room temperature and quenched with water. The precipitate was completely filtered and triturated with diethyl ether to give the ethyl ester of 2,5-diamino-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid as a yellow solid. Yield: 0.059g (43%) LCMS retention time = 2.42min, m / z calculated for C? 5H? 5N402S 315.38 (M + H), found 315.1 aH NMR (DMSO-d6, 2.50) d 1.19 (t, 3H , J = 7.1) # 4.13 (q, 2H, J = 7.1), 5.79 (bs, 2H), 7.29 (bs, 2H), 7.50-7.56 (m, 5H) This compound has activity B in the polarization test of fluorescence described below.

EXAMPLE 75 2-Amino-5-methyl-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid amide Step 1: 5-Amino-4-benzoyl-3-methyl-thiophene-2-carboxylic acid ethyl ester Prepared by the literature method Bryan P. McKibben, Craig H. Cart right, Arlindo L. Castelhano Tetrahedron Lett. 1999, 44, 5471 Step 2 2-Amino-5-methyl-4-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid amide The guanidine carbonate was added to a solution of the 5-amino-4-benzoyl-3-methylthiophene-2-carboxylic acid ethyl ester, and the suspension was heated, 175 ° C, for ~ 3hrs., Under an atmosphere of nitrogen. The suspension was allowed to cool and the water was added. The mixture was extracted with ethyl acetate, the extracts were washed and dried. The solution was concentrated and the residue was purified by chromatography eluting with mixtures of ethyl acetate and hexane. CL holding time 2.17 minutes [M + H] + 285.1 (Run time 3.75mins). This compound has activity B in the fluorescent polarization assay described below. Additional examples prepared by methods similar to those described above are listed in Table 3. The fourth column of Table 3 establishes the activity of the compound in the fluorescence polarization assay described ab j o.

Table 3 Example 184 Ethyl ester of 2-amino-4- (4-hydroxy-2-methyl-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid Step 1 Ethyl ester of 2-amino-4- (4-benzyloxy-2-methyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid 2-Methyl-4-benzyloxyphenylboronic acid (225 mg, 0.93 mmol) was added to the ethyl ester of 2-amino-4-chloro-thieno [2,3-d] pyrimidine-6-carboxylic acid (Example 1; Stage 1) (200 mg, 0.776 mmol) in DMF (10 mL). NaHCO3 (1.0M aqueous solution, 2.33 mL) was added and the mixture was degassed with N2. The Pd (PPh3) 2Cl2 was added and the reaction mixture was heated to 80 degrees C for 5 hours. The reaction mixture was allowed to cool to room temperature and the DMF was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated NaCl (aq) (50 mL). The organic phase was dried over Na2SO4 and filtered, the filtered solvents were removed in vacuo to give a yellow oil which was purified by ion exchange chromatography (IST SCX-2 column) to give the product as a brown yellow solid ( 230 mg, 71%). CL-EM retention time: 2.852 minutes, [M + H] + 420 (Run time 3.75mins) Step 2: 2-Amino-4- (4-hydroxy-2-methyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl ester To a solution cooled in an ice bath of the ethyl ester of 2-amino-4- (4-benzyloxy-2-methyl-phenyl-thieno [2,3-d] pyrimidine-6-carboxylic acid (211 mg; 0.5 mmol) in dichloromethane (8 mL), BC13 (solution 1. OM in DCM, 1.51 mL, 1.5 mmol) was added. The reaction mixture was stirred for 30 mins and then aqueous ammonia was added (20 mL) and the reaction mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried over Na2SO4 and filtered, the filtered solvents were removed in vacuo to give a yellow solid which was purified by flash chromatography on silica gel (10g IST Flash, eluting 10 to 40% ethyl acetate in hexane) to provide the product as a colorless solid (102 mg, 62%). LC-MS retention time: 2,852 minutes, [M + H] + 420 (Run time 3.75mins). This compound has activity A in the fluorescent polarization assay described below.

Example 185 Ethyl ester of 2-amino-4- (2-methyl-4-propoxy-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid 1-Bromopropane (15 uL, 0.17 mmol) was added to a solution of the ethyl ester of 2-amino-4- (4-hydroxy-2-methyl-phenyl) -thieno [2,3-d] pyrimidine. -6-carboxylic acid (50 mg: 0.152 mmol) and potassium carbonate (25 mg, 0.18 mmol) in DMF (15 mL). The reaction mixture was heated to 50 degrees C for 18 hours. The reaction mixture was allowed to cool and the solvent was removed in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). The organic phase was dried over NaSO and filtered, the filtered solvents were removed in vacuo to give a yellow solid which was purified by flash chromatography on silica gel (eluting with ethyl acetate in hexane) to give the product as a yellow solid. (45mg, 80%). CL-EM retention time: 2821 minutes, [M + H] + 372 (Run time 3.75mins). This compound has activity A in the fluorescent polarization assay described below. The following compounds (Table 4) are made by the method of Example 185, substituting the appropriate alkylating agent for bromopropane. The fourth column of Table 4 establishes the activity of the compound in the fluorescent polarization assay described below.

Table 4 Example 196 Ethyl ester of 2-amino-4- (5-formyl-2-methyl-phenyl) thieno [2,3-d] pyrimidine-6-carboxylic acid Stage 1 3 -Bromo-4-methyl-benzaldehyde Prepared as described by Eizenber and Ammons, Org Prep and Reactions Int., 6 (5), 251-253 (1974) from p-tolualdehyde (12.0Og) Yield: 10.97 g (55%) LCMS retention time = 2.57min; without ionization. XR NMR (400 MHz; CDCl3) d 2.50 (s, 3H), 7.43 (d, 1H, J = 7. 8Hz), 7.75 (dd, 1H, J = 7.8 and 1.6 Hz), 8. 05 (d, 1 H, J = 1. 6 Hz), 9.94 (s, 1 H). Step 2 4-Methyl-3- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzaldehyde To the mixture of 3-bromo-4-methyl-benzaldehyde (3.105 g; . 6 mmol), bis (pinacolato) diboro (4.29 g, 16.86 mmol) and potassium acetate (4.59 g, 46.8 mmol) in dimethylformamide (60 mL) was degassed by nitrogen-evacuation purge (3 cycles), followed by bubbling nitrogen gas through the stirred reaction mixture for 5 minutes. The palladium acetate (0.120 g, 0.536 mmol) was added and the reaction mixture was heated to 85 degrees C (oil bath temperature) for 2.5 hours. The reaction mixture was allowed to cool to room temperature and the DMF was removed in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL) and the mixture was filtered through a pad of celite to remove the black Pd solids. The filter cake was washed with ethyl acetate (2 x 50 mL) and the combined filtrates were separated and the organic phase was washed with water (2 x 150 mL) then saturated sodium chloride solution (150 mL). Organic phase was dried over Na2SO4 and filtered, the filtered solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel (50g IST Flash, eluting with 0 to 10% ethyl acetate in hexane). ) to provide the product as a colorless solid Yield: 4.58 g, 85% LC-MS retention time = 2799 min; [M + H] + 247 XH NMR (400 MHz, CDC13) d 1.36 (s, 12H), 2.62 (s, 3H), 7.31 (d, 1H, J = 7.88 Hz), 7. 83 (dd, 1H, J = 7.88 and 1.9 Hz), 8.25 (d, 1H, J = 1.9 Hz), 9.98 (s) , 1 HOUR) .

Step 3 Ethyl ester of 2-amino-4- (5-formyl-2-methyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid The ethyl ester of 2-amino-4-chloro-thieno [2,3-d] pyrimidine-6-carboxylic acid (7.62 g, 29.57 mmol) was added to 4-methyl-3- (4.4, 5). , 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzaldehyde (7.28 g, 29.57 mmol) followed by sodium hydrogen carbonate (7.45 g, 88.71 mmol). DMF (110 mL) was added followed by water (22 mL) and the suspension was degassed by nitrogen-evacuation purge (3 cycles), followed by bubbling of nitrogen gas through the stirred reaction mixture for 5 minutes. The bis (triphenylphosphine) palladium (II) chloride (500 mg, 0.739 mmol) was added and the reaction mixture was heated to 85 degrees C (oil bath temperature) for 18 hours. The reaction mixture was allowed to cool to room temperature and the DMF was removed in vacuo. The residue was partitioned between ethyl acetate (500 mL) and water (400 mL) and the mixture was stirred vigorously for 15 min before filtering through a pad of celite to remove the Pd solids. The filter cake was washed with ethyl acetate (2 x 50 mL) and the combined filtrates were separated and the organic phase was washed with water (1 x 300 mL) then a saturated sodium chloride solution (250 mL). The organic phase was dried over Na 2 SO and filtered, and the filtered solvents were removed in vacuo to give a brown oily solid which was triturated with ethyl acetate to give the product as a brown solid (5.42 g, 56%). CL-EM retention time = 2.436 min; [M + H] + 342. X H NMR (400 MHz, d 6 -DMSO) 1.30 (t, 3 H), 2.38 (s, 3 H), 4.32 (q, 2 H), 7.48 (s, 2 H), 7.71 (d, 2H), 7.91 (s, 1H), 7.97 (d, 1H), 10.11 (s, 1H). This compound has activity A in the fluorescent polarization assay described below.

Example 197 2-Amino-4- (2-methyl-5-propylaminomethyl-phenyl) -thieno [2,3-d] irimidine-6-carboxylic acid ethylamide Methanol (5mL) was added to the ethyl ester of 2-amino-4- (5-formyl-2-methyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid ester (100 mg, 0.29). mmol) and propylamine (0.586 mmol) was then added to the resulting suspension. The reaction mixture was heated to reflux (providing a homogenous brown solution) for 4 hours then allowed to cool to room temperature. Sodium borohydride (23 mg, 0. 58 mmol) was added and the reaction mixture was stirred for 30 mins. The methanol was removed in vacuo and the residue was partitioned between water (20 mL) and ethyl acetate. (20 mL). The phases were separated and the organic phase was dried over Na 2 SO and filtered, and the filtered solvents were removed in vacuo to give a brown solid which was suspended in ethylamine 2.0M in methanol solution. (5.0 mL, 10 mmol) and heated in a sealed tube at 85 degrees C overnight. The reaction mixture was allowed to cool and the solvents were removed in vacuo to give a brown solid which was triturated in hot ethyl acetate, filtered and dried to give the title product as a light brown solid (50 mg , Four. Five%) . LC-MS retention time = 2.436 min; [M + H] + 342. ^ • H NMR (400 MHz, d6-DMSO) d 0.79 (t, 3H, J = 7.4 Hz), 1.01 (t, 3H, J = 7.2 Hz), 1.35 (m, 2H ), 2.12 (s, 3H), 2.39 (m, 2H), 3.13 (m, 2H), 3.25 (s, 2H), 3.65 (s, 2H), 7.02 (s, 2H), 7.2-7. 38 (m, 3H), 7.48 (s, 1H), 8.52 (t, 3H, J = 5. 4 Hz) This compound has activity A in the fluorescence polarization assay described below. The following compounds (Table 5) are made by the method of Example 197, replacing the appropriate amine with propylamine. The fourth column of Table 5 establishes the activity of the compound in the fluorescent polarization assay described below.

Table 5 Example 235 Ethyl amide of 2-amino-4- [2,4-dichloro-5- (2-diethylamino-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid Stage 1 l-Benzyloxy-2/4-dichloro-5-nitro-benzene Potassium carbonate (12g, 87mmol) was added to a solution of 2,4-dichloro-5-nitrophenol (15.6g, 75mmol) in acetone. The benzyl bromide (9ml, 76mmol) was added and the suspension heated, oil bath temperature 75 ° C, for ~ 3hrs. The resulting suspension was allowed to cool and water (500ml) was added, the mixture was extracted with dichloromethane (2x200ml). The combined extracts were washed with aqueous sodium hydroxide (150ml, 2M), water (2x200ml) and saturated aqueous sodium chloride solution (150mol). The solution was dried over anhydrous sodium sulfate and concentrated to a pale yellow solid (21.5g, 96%) Rf 0.73 CH2C12 (SiO2) Step 2 5-Benzyloxy-2,4-dichloro-phenylamine Iron powder (21g, 376mmol) was added to a suspension of nitrobenzene (21.5g, 72mmol) in acetic acid (300ml) / water (150ml) and the mixture was heated, oil bath temperature 85 ° C, for ~ 90mins. The resulting suspension was filtered. The filtrate was allowed to cool, the water (750ml) was added and the mixture was extracted with dichloromethane (3xl50ml). The combined extracts were washed with aqueous sodium hydroxide (300ml, 2M), water (2x500ml) and saturated aqueous sodium chloride solution (200ml). The solution was dried over anhydrous sodium sulfate and concentrated to a pale brown solid (18.6g, 96%). Rf 0.57 CH2C12 (Si02) Stage 3 1-Benzyloxy-2,4-dichloro-5-iodo-benzene Hydrochloric acid (60ml, 6M) was added to an aniline solution (16.2g, 60mmol) in acetic acid (240ml) and the resulting suspension was cooled (ice / water / salt). Aqueous sodium nitrate (4.8g, 69.5mmol in 40ml) was added slowly (keeping the temperature <5 ° C). Upon completion of the addition the resulting solution was stirred for ~ 30mins. The resulting solution was emptied into a solution of potassium iodide (20g, 120mmol) and iodine (4g, lßramol) in water (200ml), and the mixture was stirred for 90mins. The water (800ml) was added and the mixture was extracted with dichloromethane (3x250ml). The combined extracts were washed with aqueous sodium thiosulfate solution (2x15 Oml, 10%), aqueous sodium hydroxide. (250ml, 2M), water (2x250ml) and saturated aqueous sodium chloride solution (200ml). The solution was dried over anhydrous sodium sulfate and concentrated to a pale brown oil, solidified at rest (20.6g, 90%). Rf 0.82 CH2C12 (SiOa) Step 4 2-Amino-4- (5-benzyloxy-2,4-dichloro-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl ester Potassium acetate (16g, 163mmol) was added to a solution of iodobenzene (20.6g, 54mmol) and bis (pinacolato) diboro (14.5g, 57mmol) in DMF (50ml), under a nitrogen atmosphere. The palladium acetate (450 mg, cat.) Was added and the mixture was heated, oil bath temperature 90 ° C, for ~ 18 hrs. The resulting solution was concentrated and the residue was taken up in ethyl acetate (200ml), the solution was washed with water (3x200ml) and saturated aqueous sodium chloride solution (150ml). The solution was dried over anhydrous sodium sulfate and concentrated to a pale brown gum. The residue was taken in 1,4-dioxan (160ml) and 2-amino-4-chloro-thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl ester. (12.85g, 50mmol) and aqueous potassium phosphate (40ml, 2M) was added, under a nitrogen atmosphere. The dichloro bis (triphenylphosphine) palladium (II) (cat.) Was added and the mixture was heated, temperature of the oil bath 100 ° C, for ~ 3hrs. The mixture was allowed to cool and ethyl acetate (400ml) was added. The mixture was washed with saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous sodium sulfate and concentrated to a pale yellow solid. The solids were washed with diethyl ether / hexane (1: 1), to give an opaque white solid. It was dried in vacuo (40 ° C). 10.7g (45%) Rf 0.13 EtOAc / Hex (1: 3) (SiO2) LC retention time 2891 min [M + H] + 474.1 / 476. 1 (run time 3.75 min).

Stage 5 2-amino-4- (2,4-dichloro-5-hydroxy-phenyl) thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl amide A suspension of ethyl ester of 2-amino-4- (5-benzyloxy-2,4-dichlorophenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid methylamine (-2M) was heated, ~ 75 ° C, during ~ 18hrs. The resulting solution was concentrated and the residue was triturated with diethyl ether / hexane to give a pale brown powder. CL retention time 2654 minutes [M + H] + 475.1 / 473.1 (Running time 3.75 minutes) To the solution of boron trichloride (1 M in dichloromethane) was added to a suspension of 2-amino acid ethyl amide. 4- (5-benzyloxy-2,4-dichlorophenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid in dichloromethane at -78 ° C under a nitrogen atmosphere. The suspension was stirred for ~ 3hrs at room temperature. The suspension was cooled in ice and methanol was added, the resulting mixture was stirred for 1 hr. and concentrated to a yellow-green solid. The solids were suspended in aqueous sodium acetate (10%) and extracted with ethyl acetate. The extracts were washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a pale brown solid, washed with hexane, dried in vacuo. CL holding time 2180 minutes [M + H] + 385/383 (Run time 3.75mins).

Step 6: 2-Amino-4- [2,4-dichloro-5- (2-diethylamino-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl amide The cesium carbonate was added to a solution of 2-amino-4- (2,4-dichloro-5-hydroxyphenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl amide in DMF, 2-Bromo-N, N-diethylethylamine hydrobromide was added and the suspension was heated to ~ 140 ° C for ~ 2hrs. The resulting suspension was allowed to cool and dichloromethane was added. The mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a dark brown gum. The crude product was purified by chromatography on silica eluting with mixtures of dichloromethane and methanol.

XH NMR (400 MHz, d6-DMSO) d 0.96 (t, 6H, J = 7.1 Hz), 1.07 (t, 3H, J = 7.2 Hz), 2.55 (q, 4H, J = 7.1 Hz), 2.81 (t , 2H, J = 5.8 Hz), 3.22 (m, 2H), 4.12 (t, 2H, J = 5.8 Hz), 7.23 (s, 2H), 7.38 (s, 1 H), 7.57 (s, 1 H) , 7.80 (s, 1 H), 8.54 (t, 1H, J = 5.5 Hz). CL retention time 1774 minutes [M + H] + 484/482 (Run time 3.75mins). This compound has activity A in the fluorescent polarization assay described below.

Example 236 Ethyl amide of 2-amino-4- [2,4-dichloro-5- (2-morpholin-4-yl-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid Step 1: 2-Amino-4- [2,4-dichloro-5- (2,2-diethoxy-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl amide Potassium tert-butoxide was added to a suspension of 2-amino-4- (2,4-dichloro-5-hydroxyphenyl) -thieno [2,3-d] irimidine-6-carboxylic acid ethyl amide in acetonitrile. , bromoacetaldehyde diethyl acetal was added and the suspension was heated under reflux for ~ 8hrs. The resulting suspension was allowed to cool and water was added, the mixture was extracted with ethyl acetate and the extracts were washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a red / brown gum. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane. CL retention time 2614 minutes [M + H] + 501/499 (Run time 3.75mins).

Step 2: 2-Amino-4- [2,4-dichloro-5- (2-morpholin-4-yl-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid ethyl amide Hydrochloric acid was added to a solution of 2-amino-4- (2,4-dichloro-5- (2,2-diethoxyethoxy) -phenyl) -thieno [2,3-d] pyrimidine-ethyl 2-amide solution. -carboxylic acid in THF and the solution was stirred for ~ 18hrs. The morpholine was added and the solution was stirred, sodium triacetoxyborohydride was added and the resulting suspension was stirred for 118 hrs. The dichloromethane was added and the mixture was washed with aqueous ammonium (0.880), water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a pale yellow solid. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane. CL retention time 1,795 minutes [M + H] + 498/496 (Run time 3.75mins). This compound has activity A in the fluorescent polarization assay described below.

EXAMPLE 237 2-Amino-4- [2,4-dichloro-5- (2-diethylamino-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid isopropyl amide Step 1: 2-Amino-4- (5-benzyloxy-2,4-dichloro-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid Sodium hydroxide (0.190 g, 4.75 mmol) was added to ethyl ester of 2-amino-4- (5-benzyloxy-2,4-dichloro-phenyl) -thieno [2,3-d] pyrimidine- 6-carboxylic acid (step 4, example 235). Ethanol (25 ml) was added followed by water (2.5 ml) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool and the solvents were removed in vacuo. The resulting residue was dissolved in water and stirred in an ice-water bath and neutralized by the dropwise addition of a 37% hydrochloric acid (aqueous) solution. The reaction mixture was dried by freezing to give the product as a yellow powder (containing 2 equivalents of NaCl) 1.33 g; 100% CL holding time 2,579 minutes [M + H] + 448/446 (Run time 3.75mins).

Stage 2 2-Amino-4- (5-benzyloxy-2,4-dichloro-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid isopropamide 0- (7-Azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1176 g, 3.07 mmol) was added to 2-amino-4- (5-benzyloxy-2) acid , 4-dichloro-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid .2NaCl (1.33 g, 2.38 mmol) then DMF (25 mL) was added to give a cloudy brown solution. Isopropyl amine (1.01 ml); 11.9 mmol) was added and the reaction mixture was heated to 60 ° C (oil bath temperature) for 18 hours. The reaction mixture was allowed to cool to room temperature and DMF was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, filtered and the filtered solvents were removed in vacuo to give a yellow solid. The crude product was purified by flash chromatography on silica gel (cartridge 50g IST Flash Si) eluting with a solvent gradient of 20 to 50% ethyl acetate in hexane. This gives the product as a colorless solid (0.612 g, 53%). CL holding time 2756 minutes [M + H] + 489/487 (Run time 3.75mins).

Stage 3 2-Amino-4- (2,4-dichloro-5-hydroxy-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid isopropylamide Prepared as per step 5 example 235 of 2-amino-4- (5-benzyloxy-2,4-dichloro-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid isopropylamide (0.594 g) . The product was purified by flash chromatography on silica gel (20 g IST Flash Si cartridge) eluting with a solvent gradient of 20 to 100% ethyl acetate in hexane. This gives the product as a colorless solid (0.350 g, 72%). CL retention time 2353 minutes [M + H] + 399/397 (Run time 3.75mins). 2-amino-4- [2 # 4-dichloro-5- (2-diethylamino-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid isopropyl amide Prepared as per step 6 of Example 235 of 2-amino-4- (2,4-dichloro-5-hydroxy-phenyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid isopropylamide (0.100 g) ). The product was purified by preparative HPLC. CL holding time 1965 minutes [M + H] + 498/496 (Run time 3.75mins). This compound has activity A in the fluorescent polarization assay described below. The following compounds (Table 6) were made using the methods of Examples 235, 236 and 237. The fourth column of Table 6 establishes the activity of the compound in the fluorescence polarization assay described below.

Table 6 Example 272 2-Amino-4- [2,4-dichloro-5- (2-hydroxy-ethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid ethylamide The hydrochloric acid was added to a solution of 2-amino-4 - (2,4-dichloro-5- (2,2-diethyethoxy) -phenyl) -thieno [2,3-d] pyrimidine-ethyl-2-amide. 6-carboxylic acid in THF and the solution was stirred for ~ 18hrs. The dichloromethane was added and the mixture was stirred, the sodium borohydride was added and the resulting suspension was stirred for ~5hrs. The dichloromethane was added and the mixture was washed with saturated ammonium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a pale yellow solid. The crude product was purified by preparative HPLC, to give the product as an opaque white solid. CL holding time 2.124 minutes [M + H] + 428.9 / 426 (Run time 3.75mins).

Example 273 2-Amino-4- [2,4-dichloro-5- (1-methyl-piperidin-2-ylmethoxy) -phenyl] -thieno [2,3-d] pyrimidine-6-carboxylic acid ethylamide To the mixture of 2-amino-4- (2,4-di chloro-5-hydroxy-phenyl) -thieno [2, 3d] pyrimidine-6-carboxylic acid ethylamide (30 mg, 0.08 mmol) and (1- Methyl-piperidin-2-yl) -methanol (12 mg, 0.09 mmol) in dry tetrahydrofuran (10 ml) was added triphenylphosphine. (33 mg, 0.13 mmol). The diethylazodicarboxylate (0.021 ml, 0.13 mmol) in dry tetrahydrofuran (1 ml) was added dropwise during the space of 30 seconds at room temperature. The mixture was then stirred at room temperature for 30 minutes at which time ethyl acetate (30 ml) was added and the resulting solution was washed with 1M sodium bicarbonate solution (30 ml), followed by saturated brine (30 ml). . The resulting organics were dried with sodium sulfate and concentrated to give a yellow oil which was purified by preparative LCMS to give a white solid (20.4 mg, 53%). CL retention time 1.84 minutes, [M + H] + 494. This compound has activity A in the fluorescence polarization assay described below.

Example 274 2-Amino-4- (2,4-dimethyl-phenyl) thieno [2,3-d] pyrimidine-6-sulfonic acid cyclopropylamide Stage 1 2-amino-4-chloro-6- (2,4-dimethyl-phenyl) -pyrimidine-5-carbaldehyde The aqueous potassium phosphate was added to a suspension of 2,4-dimethylbenzene boronic acid and 2-amino-4,6-dichloro-5-pyrimidinecarbaldehyde (3 eq) in 1,4-dioxane, under a nitrogen atmosphere. Dichlorobis (triphenylphosphine) palladium (II) (cat.) Was added and the mixture was heated, ~ 100 ° C, for ~90mins. The resulting mixture was allowed to cool and dichloromethane was added, the mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a pale yellow solid. The crude solid was purified by column chromatography on silica eluting with the mixtures of diethyl ether and hexane. CL retention time 2.354 minutes [M + H] + 262.0 (Run time 3.75mins).

Step 2 2 -amino-4- (2,4-dimethyl-phenyl) -β-mercapto-pyrimidine-S-carbaldehyde The 2-amino-4-chloro-6- (2,4-dimethylphenyl) -pyrimidine-5-carbaldehyde was added to a suspension of sodium sulphide (5eq.) In DMF and the mixture was stirred for ~ 60mins, Give a yellow suspension. The suspension was poured into water, and the solution was filtered. The filtrate was acidified with acetic acid, to give a yellow precipitate. The solids were removed by filtration and washed with water and hexane, dried in vacuo, to give a yellow powder. CL retention time 2048 minutes [M + H] + 260.0 (Run time 3.75mins). Step 3 C- [2-amino-6- (2,4-dimethyl-phenyl) -5-formyl-pyrimidin-4-ylsulfanyl] -N-cyclopropyl-methanesulfonamide The sodium acid carbonate was added to a solution of 2-amino-4- (2,4-dimethylphenyl) -6-mercapto-pyrimidine-5-carbaldehyde in DMF and the suspension was stirred. The sulfonamide of C-bromo-N-cyclopropyl-methane was added, and the mixture was heated, ~ 85 ° C, for ~ 3hrs. The resulting suspension was allowed to cool and ethyl acetate was added, the mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a pale yellow solid. The crude solid was purified by column chromatography on silica eluting with the mixtures of ethyl acetate and hexane. CL retention time 2413 minutes [M + H] + 393.0 (Run time 3.75mins) Step 4 2-Amino-4- (2,4-dimethyl-phenyl) -thieno [2,3-d] pyrimidine acid cyclopropylamide -6-sulfdnico The pyridine was added to a sulfonamide suspension of C- [2-amino-6- (2, -dimethylphenyl) -5-formyl-pyrimidin-4-ylsulfanyl] -N-cyclopropyl-methane in dichloromethane and the mixture was cooled , ice water. The trifluoroacetic anhydride was added and the mixture was stirred for ~ 2 hrs and heated under reflux for ~ 24 hrs. The resulting dark red solution was allowed to cool and aqueous ammonium (0.880) was added and the mixture was stirred for ~30mins. The dichloromethane was added and the mixture was washed with dilute hydrochloric acid, water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to a red / orange solid. The crude solid was purified by preparative HPLC. ? E NMR (400 MHz, de-DMS0) d 0.40-0.45 (m, 2H), 0.50-0.55 (m, 2H), 2.22 (s, 3H), 2.27 (m, 1H), 2.36 (s, 3H), 7.17 (bd, 1H, J = 7.6 Hz), 7.18 (s, 1H), 7.21 (bs, 1H), 7. 28 (d, 1H, J = 7.6 Hz), 7.34 (s, 2H), 8.16 (bs, 1H). CL holding time 2478 minutes [M + H] + 375.0 (Run time 3.75mins). This compound has activity A in the fluorescent polarization assay described below. Example 275 Ethyl ester of 2-amino-4-phenethyl-thieno [2,3-d] pyridin-6-carboxylic acid Stage 1 Ethyl ester of 2-amino-4-styryl-thieno [2,3-d] pyrimidine-6-carboxylic acid To a solution of 2-amino-4-chlorotiene [2,3-d] pyrimidine-6-carboxylic acid ethyl ester (0.193g, 0.75trr. L.) And alpha-phenyl vinyl boronic acid (0.17g, 1.5 equiv. ) in DF at room temperature was added a solution of 1M sodium acid carbonate (1.88 ml, 2.5 equiv.) followed by bis (triphenylphosphine) palladium (II) chloride (26 mg, 0.05 equiv.). Nitrogen was bubbled through the mixture for 5 minutes before heating to 85 ° C and stirred for 10 hours. The cold solution was partitioned between ethyl acetate and water, the combined organics were washed with water and brine before being loaded directly onto an isolute SCX II ion exchange column. On elution with 1M ammonium in methanol and evaporation in vacuo, the pure product was recovered as an orange powder (0.169g, 70%). ^ H NMR (CDC13) d = 8.03 (1H, s); 8.03 (1H, d, J = 15Hz); 7.59 (2H, m); 7.41-7.30 (4H, m); 5.19 (2H, broad s); 4.31 (2H, q, J = 7.1 Hz) and 1.35 (3H, t, J = 7.1 Hz). CLEM holding time 7.47 mins, [M + H] + = 326.12 (run time 15 minutes).

This compound has A 'activity in the fluorescent polarization assay described below. Stage 2 Ethyl ester of 2-amino-4-phenethyl-thieno [2,3-d] pir: imidine-6-carboxylic acid To a solution of the ethyl ester of 2-amino-4-styryl-thieno [2,3-d] pyrimidine-6-carboxylic acid ester (78 mg, O.ldmmol) in ethanol was added palladium in 5% charcoal ( 51 mg) which was stirred overnight under a hydrogen atmosphere. The suspension was filtered through celite, the volatiles were removed in vacuo and the residue was purified using semi-preparative HPLC to provide the pure compound as an orange powder. X H NMR (CDC13) d = 7.82 (1 H, s); 7.35-7.11 (5H, m); 5.33 (2H, broad s); 4.40 (2H, q, J = 7.1 Hz); 3.26 (2H, m); 3.22 (2H, m) and 1.43 (3H, t, J = 7.1 Hz). CLEM holding time 7.11 mins, [M + H] + = 327.92 (run time 15 minutes). This compound has activity "A" in the fluorescent polarization assay described below.

The following compounds (Table 7) are made by the methods of Example 275 substituting the appropriate boronic acid or boronate ester. The corresponding amides were synthesized directly from the ester (example 235, step 5) or by hydrolysis (example 43, step 1) followed by amine coupling (eg 43, step 2) and purified by semi-semi-preparative HPLC. The fourth column of Table 7 establishes the activity of the compound in the fluorescent polarization assay described below. Table 7 Hsp90 FP Comment Example Structure MH + of synthesis IC50 279 356.1 Suzuki 280 360.0 Suzuki 281 360.1 Suzuki 282 344.2 Suzuki Suzuki, 283 325.1 hydrolyze, then amidation Example 294 Ester. of ethyl 2-amino-4- (lH-indol-3-yl) -thieno [2,3-d] irimidine-6-carboxylic acid Stage 1 Ethyl ester of 2-amino-4- (1-benzenesulfonyl-lH-indol-3-yl) -thieno [2,3-d] pyrimidine-6-carboxylic acid Using 1- (phenylsulfonyl) -3 -indole boronic acid and the method of Example 275 step 1, the desired product was synthesized as an orange solid (105g, 29%). LCMS retention time 7.72 min, [M + H] + = 478. (run time 15 mins).

Step 2: 2-Amino-4- (lH-indol-3-yl) -thieno [2,3-d] pyrimidine-6-carboxylic acid A solution of the ethyl ester of 2-amino-4- (1-benzenesulfonyl-1H-indol-3-yl) -thieno [2,3-d] pyrimidine-6-carboxylic acid ester (80 mg, 0.17 mmol) in ethanol ( 6ml) was heated to 65 ° C, 2M potassium hydroxide (0.25ml, 3 equiv.) Was added and stirred overnight. The water was added and the volatile was removed in vacuo. The solution was then neutralized and dried by freezing. LCMS retention time 5.72 min, [M + H] + = 311.07 (run time 15 minutes).

Step 3 Ethyl ester of 2-amino-4- (lH-indol-3-yl) -thieno [2,3-d] pyrimidine-6-carboxylic acid The crude 2-amino-4- (lH-indol-3-yl) -thieno [2,3-d] irimidine-6-carboxylic acid was dissolved in ethanol (2 ml) and concentrated sulfuric acid (5 drops) was added. . The solution was refluxed overnight before adding the water and the volatiles were removed in vacuo. The aqueous solution was partitioned with 1 M sodium hydrogen carbonate solution and ethyl acetate. The organics were combined, dried over sodium sulfate and evaporated to dryness. The pure compounds are obtained after preparative CCD as an opaque white colorless powder. X H NMR (d 6 -DMS0) d = 11.93 (1 H, broad s); 8.62 (1 H, d, J = 7.5 Hz); 8.43 (1H, s); 8.27 (1H, s); 7.53 (1H, d, J = 7.5 Hz); 7.27-7.15 (1H + 1H + 2H, m); 4.34 (2H, q, J = 7.1 Hz) and 1.34 (3H, t, J = 7.1 Hz). LCMS retention time 6.70 min, [M + H] + = 339.08 (run time 15 minutes). This compound has activity? B 'in the fluorescent polarization assay described below.

Example 294 2-Amino-4-benzyloxy-thieno [2,3-d] pyrimidine-6-carboxylic acid ethylamide Step 1: 2-Amino-4-benzyloxy-thieno [2,3-d] pyrimidine-6-carboxylic acid A benzyl alcohol was added to a nitrogen-filled flask containing sodium hydride (0.5mmol, 60% in mineral oil) in anhydrous THF (5ml). (0.5mmol). The suspension was stirred vigorously for 10 minutes until no more gas evolves before transferring to a microwave reaction tube containing 2-amino-4-chlorotiene-2-ethyl ester., 3-d] pyrimidine-6-carboxylic acid (0.129g, 0.5mmol). The sealed tube was heated to 90 ° C for 5 mins using 300W in a CEM microwave oven (BEWARE!). The reaction mixture was partitioned between DCM and water, the water layer was neutralized and evaporated to dry in vacuo to leave the pure product. LCMS retention time 6.35 min, [M + H] + = 301.93 (run time 15 minutes) Stage 2 2-amino-4-benzyloxy-thieno [2,3-d] pyrimidine-6-carboxylic acid ethylamide The amide was synthesized using the HATU coupling conditions given in Example 43, step 2 and purified by column chromatography. X H NMR (CDC13) d = 7.49 (1H, s); 7.39-7.25 (5H, m); 6.03 (1H, broad t, J = 5 Hz); 5.39 (2H, s); 5.15 (2H, broad s); 3.38 (2H, dq, J = 5.7 Hz and J = 7.2 Hz); 1.14 (3H, t, J = 7.2 Hz).

LCMS retention time 6.34 min, [M + H] + = 329.05 (run time 15 minutes). This compound has activity? B 'in the fluorescent polarization assay described below.

Example 295 Ethyl ester of 2-amino-4- (4-chloro-benzoyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid To a solution of 2-amino-4-chloro-thieno [2,3-d] pyrimidine-6-carboxylic acid (1 mol eq.), P-chlorobenzaldehyde (1 mol eq.) And 3-ethyl-1-bromide methyl-3H-imidazol-l-inio (0.3 mol eq.) in DMF at room temperature, sodium hydride (1.1 mol eq., 60% in mineral oil) was added. The solution turned dark immediately and was stirred for 3 hours during which it turned into an orange solution. This was filtered through a sintered glass funnel, brine was added and the resulting precipitate was filtered and dried. The resulting yellow solids were purified either by preparative CCD or preparative HPLC. X H NMR (ds-acetone) d = 8.11 (2H, d, J = 8.8 Hz); 8. 03 (1H, s); 7.57 (2H, d, J = 8.8 Hz); 6.86 (2H, s); 4.33 (2H, q, J = 7.0 Hz) and 1.34 (3H, t, J = 7.0 Hz). LCMS retention time 7.49 min, [M + H] + = 362.06 (run time 15 minutes). This compound has activity "A" in the fluorescent polarization assay described below. The following compounds (Table 8) are made by the method of Example 295 substituting the appropriate benzaldehyde. The fourth column of Table 8 establishes the activity of the compound in the fluorescent polarization assay described below.

Table 8 Hsp90 FP Comment Example Structure MH + of synthesis IC50 302 362.0 Aroilation 303 346.0 Aroilation 304 362.1 Aroilation 305 346.0 Aroilation 306 356.1 Aroilation Example 315 Ethyl ester of 2-amino-4- (1-benzo [1,3] dioxol-5-yl-1-hydroxy-ethyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid The ethyl ester of 2-amino-4- (benzo [1,3] dioxol-5-carbonyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid (example 312) (lOOmg) was dissolved in THF Anhydrous under a nitrogen atmosphere before adding methyl magnesium bromide (solution 3. OM in diethyl ether, 5 equiv.). The solution was stirred at 40 ° C overnight before being partitioned between 10% aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give the crude product which was purified by preparative CCD to give the desired compound as a yellow powder. X H NMR (de-acetone) d = 8.04 (1H, s); 6.94 (1H, d, J = 7.7 Hz); 6.91 (1H, s); 6.64 (1H, d, J = 7.7 Hz); 6.50 (2H, broad s); 5.81 (2H, s); 5.46 (1H, s); 4.17 (2H, q, J = 7.1 Hz); 1.81 (3H, s) and 1.19 (3H, t, J = 7.1 Hz). LCMS retention time 6.37 min, (elimination of H20 in LCMS) [M + H] + = 370.07 (run time 15 minutes). This compound has activity "A" in the fluorescent polarization assay described below. Example 316 Ethyl ester of 2-amino-4- (benzo [1,3] dioxol-5-yl-cyano-methyl) -thieno [2,3-d] pyrimidine-6-carboxylic acid To a solution of the ethyl ester of 2-amino-chloro-tieno [2,3-d] pyrimidine-6-carboxylic acid (1 equiv.) And benzo [1,3] dioxol-5-yl-acetonitrile (1 mol eq.) in DMF at room temperature, sodium hydride (1.1 mol eq., 60% in mineral oil) was added. The mixture was stirred at this temperature overnight under argon. After this, it was diluted with brine and extracted with ethyl acetate. The combined organic portions were washed with brine and water and dried with sodium sulfate. After filtration and evaporation of the solvent, brown solids are obtained, which were purified either by preparative CCD or preparative HPLC. 1 H NMR (d6-acetone) d = 7.76 (1H, s); 6.84 (1H, d, J = 8.0 Hz); 6.56 (1H + 1H + 1H, m); 6.10 (1H, d, J = 1.0 Hz); 6.05 (1H, d, J = 1.0 Hz); 4.3? (2H, q, J = 7.0 Hz) and 1.30 (3H, t, J = 7.0 Hz). LCMS retention time 7.04 min, [M + H] + = 383.06 (run time 15 minutes). This compound has activity "A" in the fluorescent polarization assay described below. The following compounds (Table 9) are made by the method of Example 316 substituting the appropriate acetonitrile. The fourth column of Table 9 establishes the activity of the compound in the fluorescent polarization assay described below.

Table 9 Example 319 Ethyl ester of 2-amino-4-cyano-thieno [2,3-d] pyrimidine-6-carboxylic acid The ethyl ester of 2-amino-4-chloro-thieno [2,3-d] pyrimidine-6-carboxylic acid (1 equiv.), Zn (CN) 2 (0.6 equiv.), Zn powder (0.12 equiv.) .), Pd2 (dba) 3 (0.02 mol eq.) And 1,1 '-bis (diphenylphosphino) ferrocene (0.04 equiv.) Were mixed in DMA and the mixture was stirred under argon at 120 ° C for 24 hours. The resulting suspension was filtered through a short column of Celite, the filtrate was diluted with brine and extracted with ethyl acetate. The organic layer was then washed with brine, water and dried over sodium sulfate. After evaporation of the solvent, the crude oil was purified by preparative CCD. X H NMR (d g -acetone) d = 7.92 (1 H, s); 7.08 (1H, s); 4.42 (2H, q, J = 7.0 Hz) and 1.40 (3H, t, J = 7.0 Hz). LCMS retention time 6.10 min [M + H] + = 249.04 (run time 15 minutes). This compound has activity "A" in the fluorescent polarization assay described below.

Fluorescence polarization assay Fluorescence polarization (also known as fluorescence anisotropy) measures the rotation of fluorescent species in solution, where the larger the more polarized molecule the fluorescence emission will be. When the fluorophore is excited with polarized light, the emitted light is also polarized. The molecular size is proportional to the polarization of the emission by fluorescence. The probe labeled by fluoroescein RBT0045864-FAM- binds to HSP90 (HSP90 from the N-terminal domain or full length human, full-length yeast) and anisotropy (probe rotation: protein complex) is measured. The test compound is added to the test plate, allowed to equilibrate and the anisotropy is measured again. Any change in anisotropy is due to competitive binding of the compound to HSP90 whereby the probe is released. Materials The chemicals are of the highest purity commercially available and all aqueous solutions are made in AR water. 1) Costar 96-well black test plate # 3915 2) Test buffer of (a) 100 mM Tris pH 7.4; (b) 20 mM KCl; (c) 6 mM MgCl2. Stored at room temperature 3) BSA (bovine serum albumin) 10 mg / ml (New England Biolabs # B9001S) 4) 20 mM probe in a stock concentration of 100% DMSO. Stored in the dark at room temperature. The working concentration of 200 nM diluted in RA water and stored at 4 ° C. The final concentration in the 80 nM assay. 5) Human full length HSP90 protein expressed in E. coli, purified > 95% (see, for example, Panaretou et al., 1998) and stored in aliquots of 50 μL at -80 ° C. Protocol 1) Add 100 μl of Ix buffer to the HA and 12A pellets (= FP BLNK) 2) Prepare the test mixture - all reagents are kept on ice with a lid in the cuvette since the probe is sensitive to the light i. Final concentration Ix Hsp90 FP buffer solution 10 ml lx BSA lOmg / ml (NEB) 5.0 μl 5 μg / ml Probe 200 μM 4.0 μl 80 nM Full length human Hsp90 6.25 μl 200 nM 3) Assay mix 100 μl aliquot to all other wells. 4) Seal the plate and leave in the dark at room temperature for 20 minutes to balance Compound dilution plate - 1 x 3 dilution series 1) In a transparent 96-well v-bottom plate - (# VWR 007/008/257) add 10 μl 100% DMSO to wells Bl to Hll. 2) For the Al a All wells add 17.5 μl 100% DMSO 3) Add 2.5 μl cpd to Al. This gives 2.5 mM (50x) of reserve compound, assuming 20 mM compounds. 4) Repeat for wells A2 to A10. Control in columns 11 and 12. 5) Transfer 5 μl from row A to row B, not column 12. Mix well. 6) Transfer 5 μl from row B to row C. Mix well. 7) Repeat for row G. 8) Do not add any compound to row H, this is row zero. 9) This produces a 1 x 3 dilution series from 50 μM to 0.07 μM. 10) In well B12 prepare 20 μl of a standard compound 100 μM. 11) After the first incubation, the assay plate is read on a Fusion ™ -FP plate reader (Packard BioScience, Pangbourne, Berkshire, UK). 12) After the first reading, 12 μl of diluted compound is added to each well for columns 1 to 10. In column 11 (standard curve is provided) only add compound Bll-Hll.

Add 2 μl of the standard 100 mM compound to the wells B12 - H12 (it is the positive control) 13) The Z 'factor is calculated from the zero controls and the positive wells. Typically gives a value of 0.7-0.9 The compounds tested in the above test were assigned to one of 2 activity ranges in particular A = < 10 μM; B = > 10 μM, and those assignments are reported previously. A growth inhibition assay was also employed for the evaluation of the candidate HSP90 inhibitors: Evaluation of the cytotoxicity of the Solforhodamine B (SRB) assay: calculation of 50% inhibitory concentration (IC50).

Day 1 1) Determine the number of cells by the hemocytometer .. 2) When using an 8-channel multipipette, add 160 μl of the cell suspension (3600 cells / well or 2 x 104 cells / ml) to each well of a 96-well microtiter plate. 3) Incubate overnight at 37 ° C in a C0 incubator.

Day 2 4) Drug reserve solutions are prepared, and serial dilutions of each drug are carried out in a medium to give final concentrations in the wells. 5) Using a multiple pipette, 40 μl of drug (at a final concentration 5 x) is added to the wells in quadruplicate. 6) The control wells are on either side of the 96-well plates, where 40 μl of the medium is added. 7) Incubate the plates in a C02 incubator for 4 days (48 hours).

Day 6 8) remove the tip medium in the sink and slowly submerge the plate in ice cold 10% trichloroacetic acid (TCA). Leave for about 30 minutes on ice. 9) Wash the plates in tap water 3 times by immersing the plates in water baths of the tap and removing the tip. 10) Dry in an incubator. 11) Add 100 μl of 0.4% SRB in 1% acetic acid to each well (except the last row (right side) of the 96-well plate, this is the 0% control, ie without drug, without staining. The first row will be 100% control without drug but with staining). Leave for 15 minutes. 12) Thoroughly wash the SRB stain without binding with 4 washes of 1% acetic acid. 13) Dry the plates in an incubator. 14) Solubilize SRB using 100 μl of 10 mM Tris base and place the plates on a shake plate for 5 minutes. 15) Determine the absorbance at 540 nm using a plate reader. Calculate the mean absorbance for the wells in quadruplicate and express it as a percentage of the value for the control of the untreated wells. 16) Graph the values of. percentage of absorbance against logarithmic concentration of the drug and determine the IC50.

By way of illustration, the compound of Example 2 gave an IC50 in the 'A' range (< 50 uM) for the SRB growth suspension assay.

REFERENCES A number of publications are cited above in order to more fully describe the invention and the state of the art to which the invention pertains.

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Panaretou B, Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW and Pearl LH. 1998"ATP binding and hydrolysis are essential to the function of the HSP90 molecular chaperone in vivo", EMBO J., Vol. 17, pp. 4829-4836. Plumier etal, 1997, Cell. Stress Chap., Vol. 2, pp. 162 Pratt WB. 1997"The role of the HSP90-based chaperone system in signa! Transduction by nuclear receptors and receptors signaling via MAP kinase '", Annu. Rev. Pharmacol. Toxicol , Vol. 37, pp. 297-326. Prodromou C and Pearl LH. 2000a "Structure and in vivo function of HSP90", Curr. Opin. Struct. Biol., Vol. 10, pp. 46-51. Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW and Pearl LH. 1997"Identification and structural characterization of the ATP / ADP-binding site in the HSP90 molecular chaperone", Cell, Vol. 90, pp. 65-75.

Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury JE, Roe SM, Piper PW and Pearl LH. 2000b "The ATPase cycle of HSP90 drives to molecular 'clamp' via transient dimerization of the N-terminal domains", EMBO J., Vol. 19, pp. 4383-4392. Rajder et al, 2000, Ann. Neurol., Vol. 47, pp. 782. Roe SM, Prodromou C, O'Brien R, Ladbury JE, Piper PW and Pearl LH. 1999"Structural basis for inhibition of the HSP90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin", J. Med. Chem., Vol. 42, p. 260-266. Rutherford SL and Lindquist 'S. 1998"HSP90 as a capacitor for morphological evolution, Nature, Vol. 396, pp. 336-342, Schulte TW, Akinaga S, Murakata T, Agatsuma T, Sugimoto S, Nakano H, Lee YS, Simen BB, Argon Y, Felts S, Toft DO, Neckers LM and Sharma SV 1999. "Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones", Mol.Endocrinologv, Vol. 13, pp. 1435-1448 Schulte TW, Akinaga S, Soga S, Sullivan W, Sensgard B, Toft D and Neckers LM 1998. "Antibiotic radicicol binds to the N-terminal domain of HSP90 and shares important biologic activities with geldanamcyin", Cell Stress and Chaperones, Vol. 3, pp. 100-108 Schulte TW and Neckers LM 1998"The benzoquinone ansamycin 17 -allylamino- 17 -deemthoxygeldanamcyin binds to HSP90 and shares important biologic-activities with geldanamycin", Cancer Chemother, Pharmacol., Vol. 42, P. 273-279, Sittler et al, 2001, Hum Mol. Genet., Vol. 10, pp. 1307.

Smith DF 2001"Chaperones in signal transduction", in: Molecular chaperones in the cell (P Lund, ed., Oxford University Press, Oxford and NY), pp. 165-178. Smith DF, Whitesell L and Katsanis E. 1998"Molecular chaperones: Biology and prospects for pharmacological intervention", Pharmacological Reviews, Vol. 50, pp. 493-513. Song HY, Dunbar JD, Zhang YX, Guo D and Donner DB. 1995"Identification of a protein with homology to hsp90 that binds the type 1 tumor receptor necrosis", J. Biol. Chem., Vol. 270, p. 3574-3581. Stebbins CE, Russo A, Schneider C, Rosen N, Hartl FU and Pavletich NP. 1997"Crystal structure of an HSP90-geldanamcyin complex: targeting of a protein chaperone by an antitumor agent", Cell, Vol. 89, pp. 239-250. Supko JG, Hickman RL, Grever MR and Malspeis L. 1995"Preclinical pharmacologic evaluation of geldanamycin as an antitumour agent", Cancer Chemother. Pharmacol., Vol. 36, pp. 305-315. Tratzelt etal, 1995, Proc. Nat. Acad. Sci., Vol. 92, pp. 2944. Trost et al, 1998, J. Clin. Invest., Vol. 101, pp. 855 Tytell M and Hooper P. 2001"Heat shock proteins: new keys to the development of cytoprotective therapies", Emerging Therapeutic Taraets, Vol. 5, pp. 267-287. Uehara U, Hori M, Takeuchi T and Umezawa H. 1986"Phenotypic change from transformed to normal induced by benzoquinoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus", Mol. Cell. Biol., Vol. 6, pp. 2198-2206. Waxman, Lloyd H. Inhibiting hepatitis C virus processing and replication. (Merck &Co., Inc., USA). Sun. Int. PCT (2002), WO 0207761 Winklhofer et al, 2001, J. Biol. Chem., Vol. 276, 45160. Whitesell L, Mimnaugh EG, De Costa B, Myers CE and Neckers LM. 1994"Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation", Proc. Nati Acad. Sci. U S A., Vol. 91, pp. 8324-8328. Yorgin et al. 2000"Effects of geldanamycin, a heat-shock protein 90-binding agent, on T cell function and T cell nonreceptor protein tyrosine kinases", J. Immunol. , Vol 164 (6), pp. 2915-2923. Young JC, Moarefi I and Hartl FU. 2001"HSP90: a specialized but essential protein-folding tool", J. Cell. Biol., Vol. 154, pp. 267-273. Zhao JF, Nakano H and Sharma S. 1995"Suppression of RAS and MOS transformation by radicicol", Oncogene, Vol. 11, pp. 161-173. It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.

Claims (40)

Claims Having described the invention as above, the content of the following claims is claimed as property.

1. - The use of a compound of the Formula (I), or a salt, N-oxide, hydrate, or solvate thereof in the preparation of a composition for the inhibition of HSP90 activity in vitro or in vivo: wherein R2 is a group of Formula (IA): - (Ar1) ^ (Alqx) p- (Z) r- (Alq

2) BQ (IA) wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alq1 and Alq2 are C2-C3 alkenylene radicals or optionally substituted divalent C3-C3 alkylene, m, p, rys are independently 0 or 1, Z is -O-, -S-, - (C = 0) -, - (C = S ) -, -S02-, - (C = 0) 0-, - C (= 0) NRA-, -C (= S) NRA-, -S02NRA-, -NRAC (= 0) -, -NRAS02-, or -NRA- wherein RA is hydrogen or Ci-Ce alkyl, and Q is hydrogen or a carbocyclic or heterocyclic-optionally substituted radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C? -C3) alkyl, aryl or heteroaryl radical; and R is a carboxylic ester, carboxamide or sulfonamide group. 2. - A method of treating diseases that respond to the inhibition of HSP90 activity in mammals, the method characterized in that it comprises administering to the mammal an amount of the compound according to claim 1, effective to inhibit HSP90 activity.

3. The use according to claim 1 or method according to claim 1, for the immunosuppression or treatment of viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, type I diabetes, lupus, psoriasis. and inflammatory bowel disease; disease related to cystic fibrosis angiogenesis such as diabetic retinopathy, hemangiomas and endometriosis; or for the protection of normal cells against the toxicity induced by chemotherapy; or diseases where the failure to experience apoptosis is a fundamental factor; or protection from hypoxia-ischemic injury due to the elevation of Hsp70 in the heart and brain; cenurosis / CJD, Huntingdon or Alzheimer's disease.

4. The use in accordance with the claim 1, or the method in accordance with the claim 2, for the treatment of cancer.

5. The use or method according to any of the preceding claims, wherein, in the compound (I), m is 1, each of p, r and s is 0, and Q is hydrogen.

6. The use or method according to any of the preceding claims, wherein, in the compound (I), R2 is phenyl, 2 or 3-thienyl, 2 or 3-furanyl, 2, 3 or 4-pyridinyl, morpholinyl or optionally substituted piperidinyl.

7. The use or method according to claim 6, wherein, in the compound (I), R 2 is phenyl, optionally substituted by one or more substituents selected from methyl, ethyl, n- or isopropyl, vinyl, allyl, methoxy, ethoxy, n-propyloxy, benzyloxy, allyloxy, cyanomethoxy chlorine, bromine, cyano, formyl, methyl-, ethyl-, or n-propyl-carbonyloxy, methyl- or ethylaminocarbonyl, and substituents of the formula -0 (CH2) nZ1 in where n is 1, 2 or 3 and Z 1 is a primary, secondary, tertiary or cyclic amino group, or a C 1 -C 3 alkoxy group; or of the formula - (Alq3) mZ1 wherein Alq3 is a straight or branched divalent straight chain alkylene (Ci- C3), m is 0 or 1, and Z1 is a primary, secondary, tertiary or cyclic amino group, or a C6-C6 alkoxy group.

8. The use or method according to claim 7, wherein the optional substituents are in positions 2 and / or 4 and / or 5 of the phenyl ring.

9. The use or method according to any of the preceding claims, wherein, in the compound (I), m is 1, p, r and s are 0, and Q is an optionally substituted carbocyclic or heterocyclic ring.

10. The use or method according to any of the preceding claims, wherein, in the compound (I), Ar1 is a phenyl, cyclohexyl, pyridyl, morpholino, piperidinyl, or piperazinyl ring.

11. The use or method according to any of the preceding claims, wherein, in the compound (I), R3 is hydrogen.

12. The use or method according to any of the preceding claims, wherein in the compound (I) R4 is a carboxamide group of the formula -CONRB (Alq) nRA or a sulfonamide group of the formula -S02NRB (Alq) nRA in where Alk is an optionally substituted divalent alkylene, alkenylene or alkynylene radical, n is 0 or 1, RB. is hydrogen or a C?-C6 alkyl or C2-C6 alkenyl group, hydroxy or carbocyclic RA or optionally substituted heterocyclyl, or RA and RB when taken together with the nitrogen to which they are bonded form an N-heterocyclic ring which may optionally be containing one or more additional heteroatoms selected from 0, S and N, and which may optionally be substituted on one or more C or N atoms in the ring.

13. The use or method according to claim 12, wherein Alq is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2CH = CH-, or -CH2CCCH2- optionally substituted, RB is hydrogen or methyl, ethyl, n- or iso-propyl, or allyl, hydroxy RA or optionally substituted phenyl, 3,4-methylenedioxyphenyl, pyridyl, furyl, thienyl, N-piperazinyl, or N-morpholinyl, or RA and RB when taken together with the nitrogen to which they bond they form an N-heterocyclic ring which may optionally contain one or more additional heteroatoms selected from 0, S and N, and which may optionally be substituted on one or more C or N atoms in the ring.

14. The use or method according to any of claims 1 to 11, wherein, in the compound (I) R4 is a carboxylic ester group of the formula -C00Rc wherein Rc is a C? -C6 alkyl group or a C2-C6 alkenyl, or an optionally substituted aryl or heteroaryl group, or an optionally substituted aryl (C? -C3) alkyl or heteroaryl (Ci-C6 alkyl) -alkyl group or an optionally substituted cycloalkyl group.

15. The use or method according to any of claims 1 to 11, wherein, in the compound (I) R4 is a carboxylic ester group of the formula -C00Rc wherein Rc is methyl, ethyl, n- or iso -propyl, allyl, phenyl, pyridyl, thiazolyl, benzyl, pyridylmethyl, cyclopentyl or optionally substituted cyclohexyl.

16. The use or method according to any of claims 1 to 4, wherein, the compound (I) has the formula (II) wherein A is a secondary amino group R10 is H, Cl, Br or CH3; Rii is hydrogen, Cl, Br, CN, methyl, ethyl, n- or isopropyl, vinyl or allyl; Ra2 is (i) a radical of the formula -IOCH-nZ1 wherein n is 1, 2 or 3 and Z1 is a primary, secondary, tertiary or cyclic amino group, or an alkoxy group Cr-Cs; or (ii) a radical of the formula - (Alk3) ^ 1 wherein Alk3 is a straight or branched chain divalent (C? -C3) alkylene, m is 0 or 1 and Z1 is a primary, secondary, tertiary amino group or cyclic, or a Ci-Cg alkoxy group.

17. The use or method according to claim 16, wherein, in the compound (II), A is a secondary alkylaminoC? -C6 group.

18. The use or method according to claim 16 or claim 17, wherein, in the compound (II), R? 2 is (i) a radical of the formula -OÍCH ^ nZ1 wherein n is 1, 2 or 3 and Z1 is di (C? -C3 alkyl) amino or C? -C3 alkoxy.

19. A compound of the formula (I), or a salt, N-oxide, hydrate or solvate thereof: characterized in that R2 is a group of Formula (IA): - (Ar1) m- (Alq1) p- (Z) r- (Alq2) SQ (IA) wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alq1 and Alk2 are C2-C3 alkylene radicals or optionally substituted divalent C2-C3 alkenylene, m, p, rys are independently 0 or 1, Z is -O-, -S-, ~ (C = 0) -, - (C = S ) -, -S02-, C (= 0) 0-, -C (= 0) NRA-, -C (= S) NRA-, -S02NRA-, -NRAC (= 0) -, -NRAS02- or - NRA- wherein RA is hydrogen or C-? -C6 alkyl, and Q is hydrogen or an optionally substituted heterocyclic or carbocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted aryl or heteroaryl (C? -C3) alkyl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group, with the proviso that (i) R3 is not -NH2 or (ii) when R4 is -COOCH3 and R3 is hydrogen then R2 is not NH2, ethylamino, diethylamino, phenylamino or -N (Ph) (C2H5) wherein Ph is phenyl, and (iii) when R4 is -CONH2 and R2 is hydrogen then R2 is not -NH2.

20. The compound according to claim 19, characterized in that R3 is hydrogen.

21. The compound according to claim 19 or claim 20, characterized in that m is 1, each of p, r and s is 0, and Q is hydrogen.

22. The compound according to claim 21, characterized in that R2 is phenyl, 2 or 3-thienyl, 2 or 3-furanyl, 2, 3 or 4-pyridinyl, morpholinyl or optionally substituted piperidinyl.

23. The compound according to claim 21, characterized in that R is phenyl, optionally substituted by methyl, ethyl, n- or isopropyl, vinyl, allyl, methoxy, ethoxy, n-propyloxy, benzyloxy, allyloxy, cyanomethoxy chlorine, bromine, cyano, formyl, methyl-, ethyl-, or n-propyl-carbonyloxy, methyl- or ethylaminocarbonyl.

24. The compound according to claim 23, characterized in that the optional substituents are in positions 2 and / or 4 and / or 5 of the phenyl ring.

25. The compound according to claim 19 or claim 20, characterized in that m is 1, and p, r and s are 0, and Q is an optionally substituted carbocyclic or heterocyclic ring.

26.- The compound in accordance with the claim 19 or claim 20, characterized in that m is 1 and at least one of p, r and s is 1.

27.- The compound according to any of claims 19 to 26, characterized in that Ar1 is an optionally substituted phenyl ring.

28. The compound according to claim 19 or claim 20, characterized in that it is 0.

29. The compound according to claim 26 or claim 27, characterized in that Alq1 when presented is -CH2-, -CH2. -CH2-, or -CH2CH = CH- optionally substituted; Alk2 when present is -CH2-, -CH2-CH2-, or -CH2CH = CH-optionally substituted; Z when presented is -O- or -NH-; and Q is hydrogen.

30. The compound according to claim 29, characterized in that Z and Alk2 are present, and Alk2 is substituted by di (C? -C3) alkyl amino or C? -C3 alkoxy.

31. The compound according to any of claims 19 to 30, characterized in that R4 is a carboxamide group of the formula -C0NRB (Alq) nRA or a sulfonamide group of the formula -S02NRB (Alq) nRA wherein Alq is a optionally substituted divalent alkylene, alkenylene or alkynylene radical, n is 0 or 1, RB is hydrogen or a C?-C6 alkyl or C2-C6 alkenyl group, RA is hydroxy or optionally substituted carbocyclic, for example hydroxy and / or phenyl substituted with chlorine and 3,4 methylenedioxyphenyl; or heterocyclyl, for example pyridyl, furyl, thienyl, N-piperazinyl, or N-morpholinyl, any of which heterocyclic rings can be substituted, or RA and RB when taken together with the nitrogen to which they are bound form an N-heterocyclic ring which it may optionally contain one or more additional heteroatoms selected from O, S and N, and which may optionally be substituted on one or more C or N atoms in the ring.

32. The compound according to claim 31, characterized in that Alk is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2CH = CH-, or -CH2CCCH2- optionally substituted, RB is hydrogen or methyl , ethyl, n- or iso-propyl, or allyl, hydroxy RA or optionally substituted phenyl, 3,4-methylenedioxyphenyl, pyridyl, furyl, thienyl, N-piperazinyl, or N-morpholinyl, or RA and RB when taken together with nitrogen to which they are linked form an N-heterocyclic ring which may optionally contain one or more additional heteroatoms selected from O, S and N, and which may optionally be substituted on one or more C or N atoms in the ring.

33. The compound according to claim 31 or claim 32, characterized in that R4 is a carboxamide group.

34. The compound according to any of claims 19 to 30, characterized in that R is a carboxylic ester group of the formula -COORc wherein Rc is a C? -Ce alkyl group or a C2-C3 alkenyl group, or a group optionally substituted aryl or heteroaryl, or an optionally substituted aryl (C 1 -C 3) alkyl or heteroaryl (C 6 alkyl) group or an optionally substituted cycloalkyl group.

The compound according to any of claims 19 to 30, characterized in that R4 is a carboxylic ester group of the formula -COORc wherein Rc is methyl, ethyl, n- or iso-propyl, allyl, phenyl, pyridyl, optionally substituted thiazolyl, benzyl, pyridylmethyl, cyclopentyl or cyclohexyl.

36. - The compound according to claim 19, characterized in that it has the formula (II) wherein A is a secondary amino group Rio is H, Cl, Br or CH3; R n is hydrogen, Cl, Br, CN, methyl, ethyl, n- or isopropyl, vinyl or allyl; Ri2 is (i) a radical of the formula -0 (CH2) nZ1 wherein n is 1, 2 or 3 and Z1 is a primary, secondary, tertiary or cyclic amino group, or a C6-C6 alkoxy group; or (ii) a radical of the formula - (Alk3) mZ1 wherein Alq3 is a straight or branched chain divalent (C? -C3) alkylene, m is 0 or 1 and Z1 is a primary, secondary, tertiary or cyclic, or an alkoxyCi-Cg group.

37. The compound according to claim 36, characterized in that A is a secondary alkylaminoC? -C6 group. 38.- The compound in accordance with the claim36 or claim 37, characterized in that Ri2 is (i) a radical of the formula -O (CH2) nZ1 wherein n is 1, 2 or 3 and Z1 is di (C1-C3 alkyl) amino or C1-C3 alkoxy. 39.- The compound according to claim 38, characterized in that it is the subject of any of the Examples, except for Example 74. 40.- A pharmaceutical or veterinary composition, characterized in that it comprises the compound according to any of claims 19 to 39, together with one or more pharmaceutically acceptable carriers and / or excipients.