MXPA06008757A - Aminobenzoxazoles as therapeutic agents - Google Patents

Abstract

A compound of Formula (I), wherein the substituents are as defined herein, which are useful as kinase inhibitors.

Description

AMINOBENZOXAZOLES AS THERAPEUTIC AGENTS CROSS REFERENCE TO THE RELATED APPLICATION This application claims the benefit of priority to the application for E. U.A. No. 60/541, 294, filed on February 3, 2004, and at the request of E. U.A. No. 60 / 547,612 filed on February 25, 2004.

BACKGROUND OF THE INVENTION There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. Phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine / threonine kinases. Phosphorylation reactions, and phosphatase neutralization reactions, in the tyrosine, serine and threonine residues are involved in innumerable cellular processes that support responses to various intracellular signals (normally mediated through cellular receptors), the regulation of cellular functions and the activation or deactivation of cellular processes. A cascade of protein kinases frequently participates in intracellular signal transduction and are necessary for the realization of these cellular processes. Due to their ubiquity in these processes, protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or can be located in the nucleus, often as components of enzymatic complexes. In many cases, these protein kinases are an essential element of the enzyme and structural protein complexes that determine where and when a cell process occurs within a cell. The identification of effective small compounds which specifically inhibit signal transduction and cell proliferation by modulating the activity of tyrosine and serine / threonine receptor and non-receptor kinases to regulate and modulate abnormal or inappropriate cellular proliferation, differentiation or metabolism is therefore desirable. In particular, it would be beneficial to identify methods and compounds that specifically inhibit the function of a tyrosine kinase that is essential for anti-angiogenic processes or the formation of vascular hypermeability that leads to edema, ascites, effusions, exudates and macromolecular extravasation and matrix deposition. as associated disorders. The present invention provides novel compounds that inhibit one or more serine / threonine kinases, both receptor and non-receptor.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of Formula (I), (0 pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, indicated as Group A, wherein X is N or CH; A is optionally substituted phenyl, or A is r is 1 and D-i, G ?, J? , Li and W are each independently selected from the group consisting of CRa and N, as long as at least two of Di, G ?, i, L- and i are CRi; or is 0, and one of Di, d, Li and Mi is NRa, one of Di, Gi, ^ yi is CRa and the remainder is independently selected from the group consisting of CRa and N, where Ra is as defined later; L is NH, optionally substituted alkyl, carbonyl, optionally substituted O-alkyl, NH (optionally substituted aliphatic) or S; R1 is -C (= O) -N (R100) 2 wherein R100 for each case is independently hydrogen or alkyl; or R1 is or an optionally substituted group selected from the group consisting of an aliphatic, benzimidazolyl, benzofuranyl, benzisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, cycloalkyl, 2,3-dihydrobenzofuranyl group, 1, 1-di-oxy-benzoisothiazole i, furanyl, 1 H-imidazo [1,2-a] imidazolyl, imidazotl-a-pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [2, 1-b] [ 1,3-thiazolyl, indazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyl, oxadiazolyl, oxazolyl, phenylsulfonyl, phthalazinyl, piperidinyl, pyrazolyl, H-pyridinone, pyridinyl, pyrido-oxazolyl, pyrido-thiazolyl, dirimido-oxazolyl, dirido-thiazolyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, qunolinyl, quinoxalinyl, quinazolinyl, tetrahydrofuranyl, tetrahydronaphthyl, tetrahydropyranyl, thiadiazolyl, thiazolylthienyl, wherein the optionally substituted above groups are optionally substituted by one or more R; u is 1 and D2, G2, J2, L2 and 2 are each independently selected from the group consisting of CRa and N, provided that at least two of D2l G2, J2, L2 and 2 are CRa or ou is 0, and one of D2, G2, L2 and 2 is NRa, one of D2, G2, L2 and M2 is CRa and the remainder is independently selected from the group consisting of CRa and N; Ra and Rb each represents one or more substituents and for each case is independently selected from the optionally substituted group consisting of an aliphatic, alkoxy, alkylamino, aliphatic carbonyl, aliphatic cycloalkyl, aliphatic heterocyclyl, alkyl-S-, alkyl-S ( O) p-, amido, amino, aminoalkyl, carboxamido, -CF3, -CN, -C (O) -aiphatic, -C (O) -cycloalkyl, -C (O) -heterocyclyl, -C (O) H groups , C (O) OH, -C (O) O-aliphatic, C (O) OC (O) O-heterocyclyl, cycloalkyl, aliphatic cycloalkyl, cycloalkyl-S, cycloalkyl-S (O) p, cycloalkylthio, dialkylaminoalkoxy, halo, heterocyclyl, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heterocycle-S, heterocycle-S (O) p, heterocyclic, heterocycloalkyl-S, hydrogen, -NO2, -OCF3, -OH, tetrazolium, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, -Z105-C ( O) N (R) 2, -Z105-N (R) -C (O) -Z200, -Z105-N (R) -S (O) 2-Z200, -Z105-N (R) -C (O ) -N (R) -Z200, -N (R) -C (O) R, -N (R) -C (O) OR, ORC (O) -heterocyclyl-OR, Rc and -CH2ORc; wherein Rc for each case is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, - (d-CeI-NRdRe, -W- (CH2) t-RdRe, -W- (CH2) tO-alkyl, -W- ( CH2) tS-alkyl or -W- (CH2) t-OH; Z105 for each case is independently a covalent bond or an aliphatic group; Z200 for each case is independently selected from an optionally substituted group, selected from the group consisting of aliphatic group, phenyl aliphatic phenyl earth, d and e for each case are independently H, an aliphatic, alkanoyl or SO2-alkyl group, or Rd, Re and the nitrogen atom to which they join together form a five or six membered heterocyclic ring; t for each case is independently a whole number of 2 to 6; W for each case is independently a bond or O, S, S (O), S (O) 2 or NRf, where Rf for each case is independently H or an aliphatic group; or Ra is an optionally substituted cycloalkyl or heterocyclyl ring combined with the ring to which it is attached; B is a bond or a) hydrogen; b) optionally substituted trityl; c) optionally substituted cycloalkyl; d) azaheterocyclyl substituted with an optionally substituted aliphatic group; e) azacycloalkyl which is substituted with one or more substituents selected from the optionally substituted group consisting of - (C? -C6) -alkyl, - (d-CeJ-alkyl-OR, -C (O) - (C? C6) -alkyl-N- (R) 2, - (d-CeJ-alkyl-NÍRJz, - (C? -C6) -alkyl-cycloalkyl, tetrahydrothienyl and tetrahydrothiopyranyl; f) a group of the formula wherein E-, is selected from an optionally substituted group consisting of amido, amino, imidazolyl, morpholino, piperazinyl, piperidinyl, pyrrolidinyl or tetrahydrothiazolyl, and wherein Ei is optionally substituted with one or more substituents selected from - (C0-C6) ) -alkyl-OR, - (C1-C6) -alkyl-C (O) OR, (d-C6) alkyl-heterocyclyl- (C? -C6) -afyl-heterocycloalkyl, - (d-C6) -alkyl- N (R) 2, cyclohexanone, alkoxyalkyl and pyranyl, g) (d-C6) -alternatively substituted alkyl, h) optionally substituted cycloalkyl, i) optionally substituted alkoxyalkoxy, j) optionally substituted alkylamino, k) optionally substituted dialkylamino, I) alkyl ester, m) alkenyl, n) optionally substituted alkoxy, o) optionally substituted heterocyclyl, p) optionally substituted phenyl, q) 1,4-dioxa-spiro [4.5} optionally substituted decane, s) [1, 3] optionally substituted dioxolane, t-R200-O- (R200) 2-Si (R200.}. 3, u) a bond, provided that B, Z and E are not each one a bond, v) alkoxyalkyl ow) phenylalkyl; Z is a bond, carbonyl, R200-O, amino, -O-, -S- or SO2; E is a bond or H, or is a group optionally substituted from the group consisting of alkoxy, aliphatic alkoxy, alkoxyamino, alkoxyalkoxy, aliphatic alkoxycarbonyl, aliphatic, aliphatic-aminoaliphatic, aliphatic carbonyl, alkylsulfonyl, amino, aliphatic, amino aliphatic-carbonyl, aminocarbonyl, aminocarbonyl-aliphatic, aminosulfonyl-aliphatic, CH2-C (CHs) 2 (0H), -C (CH3) 2N (CH3) (H), cycloalkyl, di-aliphatic-amino, di-aliphatic-amino-aliphatic, di-aliphatic-amino-aliphatic-amino, di-aliphatic-aminocarbonyl, di-aliphatic- aminocarbonyl-aliphatic, heterocyclyl, heterocyclic-aliphatic, morpholinocarbonyl-aliphatic, phenyl, piperidinyl-alkoxy, tetrahydropyranyl-aliphatic, tipiranyl, tetrahydrothiopyran-1, -diioxide, triazolyl-aliphatic and urea; or E is -CH (R200) -C (O) -N (C1-C6) -N (R200) 2, -N. { R200) - (dC6) -C (O) -N (R200) 2, -N (R200) - (C1-C6) -C (O) -OH, -N (R200) - (d-C6) -C (O) morpholinyl, - (d-C6) -S-CH3) -C (R200) (CH2OH) - (d-C6) -OH, -C (R200) 2-N (R200) 2, -C (O) -OH, -C (R200) 2 (OH), -C (R200) 2-O- (C? -C6) -C (R20 ()) 2 (OH), -C (R200) 2C ( R200) 2 (OH), wherein R200 is independently hydrogen or alkyl; R2 is H, -NH2 -Syd-Cajalkyl, -SOa d-Ce ^ alkyl, optionally substituted alkyl, -OR7, -N (H) SO2R7, -N (R7) SO2R7, -N (R7) C (O) N (H) R7, -N (R7) C (O) N R7, -N (H) C (O) R7, -N (R7) 2, -N (R7) C (O) R7, -NHC (O) N HR7, or -NHR7; R7 is (C? -C6) -aliphatic optionally substituted by one or more substituents each independently selected from the group consisting of (C? -C6) aikoxy, heterocyclyl, hydroxyl, -NR5Rd optionally substituted phenyl, -C (O R4 and heterocyclyl; wherein any alkoxy, aliphatic and heterocyclyl can be optionally substituted; wherein Rd and R6 are independently H or (d-C-alkyl, -NHS (O) 2R4, -N HC (O) R4 or -NHC (= NH) R4, wherein R4 is selected from (C? -C6) alkyl and H; Y is H, OR3 or N (R3) 2 wherein R3 is independently selected from H or an optionally substituted group consisting of aliphatic, - (CH2) 2-C (O) -NH2, -C (O) -aiiphatic, -C (O) -cycloalkyl and -C (O) -heterocyclyl; wherein R for each case is independently H or is selected from an optionally substituted group consisting of aliphatic, heterocyclyl and heterocycle-aliphatic; is an integer from 1 to 6, and p is 1 or 2, as long as > ^ when A-L-R1 is then B-Z-E is not a pyrrolidinyl which is replaced with 2-methoxyethyl, N, N-dimethylaminomethyl, N, N-dimethylamino-1-oxoetiyl or 2- (N-methylamino) -1-oxopropyl; when X is N; And it's NH2; R2 is H; L is NH: A is phenyl optionally substituted with fluoro or methoxy; B is cyclohexyl; Z is a bond and E is piperazinyl substituted with methyl, then R 1 is not: phenyl optionally substituted by C 2 H 4 OH or chloro, benzofuranyl optionally substituted by chloro, imidazoiyl optionally substituted by methyl, benzoxazolium optionally substituted by one or two methyl, benzoxazolyl optionally substituted by one or two chloro, benzoxazolyl optionally substituted by methoxy, benzoxazolyl optionally substituted by ethyl, benzoxazolyl optionally substituted by carbonitrile, benzoxazoiyl optionally substituted by isopropyl, benzothiazolyl optionally substituted by one or two methyl, benzothiazolyl optionally substituted by propyl, benzothiazolyl optionally substituted by isopropyl, benzothiazolyl optionally substituted with ethyl and phenyl, thiazolyl substituted with ethyl, thiazolyl optionally substituted with phenyl, thiazolyl optionally substituted with phenylmethyl, thiazolyl optionally substituted with nitrophenyl, thiazolyl optionally substituted with two methyls, thiazolyl substituted with phenyl and methyl, thiazolyl substituted with phenyl and propyl, thiazolyl substituted with phenyl and isopropyl, thiazolyl substituted with ethyl and methylphenyl, benzisothiazolyl optionally substituted with CF3, benzisothiazolyl optionally substituted with one or two oxo, benzoisoxazolyl substituted with CF3, indazolyl or pyrimidinyl; or when X is N; Y is NH2; R2 is H; L is N H; A is phenyl optionally substituted with fluoro; R1 is benzoxazolyl substituted with one or two methyl, benzothiazolyl or ethyl; Z is a link; and E is COOH, piperazinyl substituted with methyl, piperazinyl substituted with oxo, or ethyl substituted with oxo; then B is not ethyl, cyclohexyl, piperidinyl substituted with dimethylamin, or phenyl substituted with CN; or when X is N; And it is N H2: R2 is H; L is N H; A is phenyl; B is a link; Z is a link; and R1 is benzofuranyl, benzoisoxazolyl, piperidinyl, pyrrolyl, isooxazolyl substituted with phenyl, isoxazolyl substituted with triloforomethyl, benzoxazolyl optionally substituted by one or two methyl, benzoxazolyl optionally substituted by ethyl, benzoxazolyl optionally substituted by chloro, or benzoxazolyl optionally substituted by isopropyl then E is not: piperidinyl optionally substituted with substituted alkyl, piperazinyl, pyrrolidinyl optionally substituted by methoxyethyl, piperidinyl optionally substituted by dihydroxypropyl, piperidinyl optionally substituted by hydroxyethyl, piperidinyl optionally substituted by methoxyethyl, piperidinyl optionally substituted by methylsulfanylethyl, piperidinyl optionally substituted by optionally substituted ethyl, piperidinyl optionally substituted by optionally substituted propyl, imidazolyl optionally substituted by methyl, imidazolyl optionally substituted by amino, aminoalkylcarb onyl, cyclohexancarboxylate or pyrimidinyl substituted with CN; or when X is N; And it's NH2; R2 is H; A is phenyl; R is phenyl; B is cyclohexyl; Z is a link; and E is piperazinyl substituted with methyl; then L is not methyl substituted by = N-OCH3, = N-OH, N H2 or CN; or when X is N; And it's N H2; R2 is H; L is NH; A is phenyl; R1 is benzoxazolyl substituted with two methyl; B is pyrrolidinyl optionally substituted by methylaminomethyl and ethyl, or pyrrolidinyl optionally substituted by methylaminomethyl and ethyl, or pyrrolidinium optionally substituted by dimethylamino and ethyl; and Z is carbonyl; then E is not dialkylamino, a bond or alkyl substituted with methylamino; or when X is N; L is NH; A is phenyl; R1 is benzoxazolyl optionally substituted with two methyl; B is cyclohexyl; and Z is a link; then E is not dimethylamino or morpholino; or when X is N; L is NH; it is phenyl; R1 is benzoxazolyl optionally substituted with two methyl; B is cyclohexyl; and Z is NH; then E is not methoxyethyl or methyl; or when X is N; And it's NH2; R2 is H; L is NH; A is phenyl; R1 is benzoxazolyl substituted with two methyl; B is piperidinyl; and Z is a link; then E is not a link; or when X is N; L is O-alkyl; A is phenyl; B is cyclohexyl or a bond; Z is a link; and E is cyclopentyl or piperzinyl substituted with methyl; then R1 is not phenyl optionally substituted with benzenesulfonamide or phenyl optionally substituted with benzylurea; or when X is N, Y is N H2, R2 is H, L is N H, A is phenyl optionally substituted with fluoro, R1 is benzoxazolyl substituted with ethyl, bnzoxazolyl substituted with chloro, or benzoxazolil substituted with one or two methyl; B is piperidinyl, azetidinyl, pyrrolyl or cyclohexyl; and Z is a link; then E is not: methoxyethyl, methoxypropyl, methyl, ethyl optionally substituted by hydroxyl, piperazinyl substituted by oxo, or imidazolyl optionally substituted by amino; or when X is N; And it's NH2; R2 is H; L is NH; A is phenyl; B is piperidinyl; Z is carbonyl; and R1 is benzoxazolyl optionally substituted with two methyl or benzoxazolyl optionally substituted with chloro; then E is not: morpholinoalkyl, dimethylaminomethyl, piperidinyl optionally substituted by methyl, isopropyl substituted by methylamine, pyrrolidinyl, ethyl optionally substituted by methyl and methylamino, or ethyl optionally substituted by substituted alkyl; or when X is N; And it's NH2; R2 is H; L is carbonyl; A is phenyl; Z is a link; E is piperidinyl or pyridinyl; and B is a link; then R1 is not: oxazolyl, isoxazolyl optionally substituted by methyl, isoxazolyl optionally substituted by phenyl, pyrazolyl optionally substituted by benzyl, pyrazolyl optionally substituted by benzoyl, pyrazolyl optionally substituted by methyl or pyrazolyl optionally substituted by ethanone; or when X is N; And it's NH2; R2 is H; L is carbonyl; A is phenyl; Z is a link; R1 is phenyl; and B is cyclohexyl; then E is not piperazinyl substituted with methyl; or when X is N; L is alkyl optionally substituted with OH; A is phenyl optionally substituted with methoxy; R1 is benzoxazolyl or benzimidazolyl; B is cyclohexyl; and Z is a link; then E is not piperazinyl substituted with methyl. A preferred embodiment of Formula I, pharmaceutically acceptable salts thereof, isomers thereof, or prodrugs thereof, is wherein Y is -N (R3) 2- A more preferred embodiment of the compound of any of the inventions previous where: X is N; A is optionally substituted phenyl; R1 is optionally substituted benzoxazolyl or optionally substituted benzothiazolyl; B is a bond or is selected from an optionally substituted group consisting of alkenyl, alkyl, alkoxyalkyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 3 to 7 carbon atoms, heterocyclyl, phenyl, 1, 4-dioxa spiro [4.51dec-2-ene, 2,2-dipropyl [1, 3] dixolano, 1-oxa-2-azaspiro [4.5] dec-2-ene, 1, 4-dioxa-spiro [4, 5] decane and 2,2-di propyl [1, 3] dioxol anus; E is H or is selected from an optionally substituted group consisting of alkoxy, alkoxyalkyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, azetidinyl, benzimidazolyl, -C (CH3) (CH2OH) -CH2-OH, -C (CH3) 2, -NH (CH3), -C (CH3) 2-O-CH2- C (CH3) 2 (OH) I -CH2-C (CH3) 2 (OH), - (CH2) 2-S-CH3, COOH, cycloalkyl, diazepanyl, dimethylamino, dimethylamino-, dimetilaminoalquilamino, dimethylaminocarbonyl, dimetilaminocarbonilalquilo, furanyl, imidazolinyl, imidazolyl, imidazolyl, isoxazolyl, morfoiinilo, morpholinyl, -N (CH3) - CH2-C (= 0) alkylmorpholinyl, -N (CH3) - CH2-C (= O) -N (CH3) 2, -N (CH3) -CH2- C (= O) -OH, oxadiazolyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiopyranyl, thienyl, triazolyl and triazolylalkyl; R2 is H, SCH3, N H2 or S (O) 2-CH3; and R3 for each case is independently H or - (CH2) 2-C (= O) NH2. A more preferred embodiment of the compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof of any of the foregoing inventions wherein: A is optionally substituted by one or more substituents selected from the group it consists of alkyl, alkoxy, chloro and fluoro; R1 is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, alkoxyalkoxy, alcoxicarbonilpiperidinilalcoxi, alquiicarbonilo, aminocarbonyl, bromo, CF3, chloro, C (= O) -O (CH3) 3, dialkylaminoalkoxy dialkylaminocarbonyl, dialquilaminocarbonilaleoxi, fluoro, -OH, -morfolinoalcoxi, NO2, OCF3, S-fenii-alkoxy, optionally substituted piperidinylalkoxy, piridinilalcoxi optionally substituted pirrolidinilalcoxi optionally substituted, and optionally substituted tienilalcoxi; B is a bond or an optionally substituted from the group consisting of alkoxyalkyl, alkyl, azetidinyl, cycloalkenyl, cycloalkyl, isoxazolyl, phenyl, piperidinyl, pyranyl, pyridinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, 1, 4-dioxa spiro [4.53dec-2-ene, [1, 3] dioxolane, 1 -oxa-2-aza-spiro [4.5] dec-2-ene, and 1,4-dioxa-spiro [4.5] decane; E is H, dimethylamino-, dimethylaminocarbonyl or an optionally group selected from the group consisting of alkyl, alkoxyalkyl, azetidinyl, benzimidizolilo, diazepanyl, furanyl, imidazolidinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, phenyl, piperidinyl, piperazinyl, pyrazinyl, pyrazolyl , pyridinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, 1, 1-dioxide tetrahydrothiopyran, tetrazolyl, thiadiazolyl, thienyl, thiopyranyl and traiazolilo; and wherein the group is optionally substituted by one or more substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, dialquilamnosulfoniio, fluoro, hydroxy, hydroxyalkyl, nitrile, oxo, S (O) 2CH3 and S (O) 2CF3. A more preferred embodiment of the compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs of the mime or any of the foregoing inventions wherein L is NH, C (OH) H or carbonyl; B is a bond or is selected from the optionally substituted group consisting of alkyl, azetidinyl, cycloalkyl, isoxazolyl, phenyl, piperidinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxa-spiro [4.5] dec-2-ene, [1, 3] dioxolane 1 -oxa-2-aza-spiro [4.5] dec-2-ene and 1,4-dioxa-is pyro [4.5] decane; wherein the group is substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, CF3, C = N, cycloalkyl, fluoro and hydroxyl. A more preferred embodiment of the compound, pharmaceutically acceptable salts thereof, metabolites thereof, or prodrugs thereof, of any of the foregoing inventions wherein R2 is H. A more preferred embodiment of the compound, pharmaceutically acceptable salts thereof, metaboiites thereof, isomers thereof, or prodrugs thereof, of any of the foregoing inventions wherein R3 for each case is H. A still more preferred mode of the compound, salts pharmaceutically acceptable thereof, metabolites thereof, isomers thereof, or prodrugs thereof, any of the above inventions wherein R 1 is benzoxazolyl or benzothiazolyl, each optionally substituted by one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, bromine, CF3, chloro, dimethylaminocarbonyl, fluoro, hydroxyl, OCF3 and nitrile. A more preferred embodiment of the compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, any of the foregoing inventions wherein A is phenyl optionally substituted by fluoro or alkoxy; L is NH; R1 is benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of CF3, CH3 and chloro; Z is a bond, carbonyl, R200-O-, -O- or-S-; and E is H or is selected from the optionally substituted group consisting of alkoxyalkylalkoxyamino, alkyl, COOH, cycloalkyl, diazepanyl, dimethylaminocarbonyl, furanyl, imidazolylalkyl, imidazolidinyl, imidazolyl, isoxazolyl, morpholino, -N (R200) -R200-C (= O) -N (R200) 2, -N (R200) -R200-C (= O) -OH, -N (R200) -R200-C (= O) - morpholinyl, OH, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thienyl and triazolyl; wherein R200 is alkyl. The compound of any of the preceding inventions wherein the compound is 3- [3- (fluoro-4- (5-trifluoromethyl-benzoxazol-2-ylamino) -phenyl] -1- [4- (2-methoxy-ethoxy) -cyclohexyl] -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine, 3- [4- (7-chloro-5-methyl-benzoxazol-2-y-aminophenyl] -1- [4- ( 2-methoxy-ethoxy) -cyclohexyl] -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine, or 1 - (4-. {4-amino-3- [4- (5-chloro -benzoxazol-2-ylamino) -3-fluoro-f-enyl] -pyrazolo [3,4-d] pyrim idin-1-yl]. -cyclohexyloxy) -2-m eti-l-propan-2-ol.

The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, of Group A, indicated as Group B, wherein: X is CH; A is optionally substituted phenol; R1 is optionally substituted benzoxazolyl; B is H or is selected from the optionally substituted group consisting of alkoxyalkyl, alkyl, cycloalkyl and heterocyclyl; E is H, or is selected from the optionally substituted group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, phenyl, piperazinyl, tetrazolyl and urea; R2 is H, N H2, SCH3 or SO2CH3; and R3 for each case is H. A preferred embodiment of the compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof from the group wherein: A is optionally substituted by fluoro; R is an optionally substituted benzoxazolyl substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, bromo, chloro, CF3, dialkylaminoethoxy, fluoro, morpholinyl alkoxy, morpholinyl alkyl and nitrile; B is H or is selected from the optionally substituted group consisting of cycloalkyl, alkyl, piperidinyl and pyrrolidinyl; wherein the substituents are selected from the group consisting of alkyl, hydroxyl, oxo, nitrile and nitro; E is H or is selected from the optionally substituted group consisting of alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, piperazinyl, phenyl, tetrazolyl and urea; wherein the group is optionally substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, cycloalkyl, hydroxyl, nitrile, nitro, N H2 and oxo; and Z is a bond, R200-O-, NH or -O-. A preferred embodiment of any of the above Group B inventions, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof wherein L is NH or N (alkenyl). A preferred embodiment of any of the foregoing Group B inventions pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof wherein R2 is H. A preferred embodiment of any of the foregoing group inventions. B, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, wherein R 1 is optionally substituted benzoxazolyl, substituted by one or more substituents selected from the group consisting of alkyl, bromine , CF3, chlorine, fluoro and nitrile. A preferred embodiment of any of the foregoing Group B inventions, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, wherein A is phenyl or phenyl substituted by fluoro; L is NH; R1 is benzoxazolyl substituted by one or more substituents selected from the group consisting of alkyl, bromine, CF3 and chlorine; Z is a bond u -O-; and E is optionally substituted alkyl, alkoxyalkyl, diazepanyl, piperazinyl or tetrazolyl. A preferred embodiment of any of the foregoing Group B inventions, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, wherein: X is CH; A is optionally substituted phenyl; R1 is optionally substituted benzoxazolyl; B is H or a bond or is selected from the optionally substituted group consisting of alkyl and cycloalkyl; Z is a bond, -R200-O-, amino or -O-; E is H, a bond or an optionally substituted group selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, dialkylamino, hetrocyclyl, phenyl and urea; R2 is H, N H2, -S (d-C6) alkyl or -SO2 (d-C6) alkyl; and R3 for each case is H. A more preferred embodiment of any of the foregoing Group B inventions, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, wherein A is substituted optionally by one or more fluoro; R1 is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, aminoalkoxy, bromine, CF3, chloro, fluoro, morpholinoalkoxy, morpholinoalkyl and nitriio; E is H or an optionally substituted group selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, phenyl, piperazinyl, pyridinyl, pyrrolidinyl, tetrazolyl and urea; wherein the optionally substituted group is optionally substituted by one or more alkoxy, alkyl, amine, bromine, cycloalkyl, dimethylamino, hydroxyl, oxo, nitrile, NO2 or sulfonyl; and R2 is H. An even more preferred embodiment of any of the above Group B inventions, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, wherein L is NH or N- alkenyl; R1 is replaced by one or more alkyl, bromine, CF3, chlorine, fluoro or nitrile; A is phenyl optionally substituted by fluoro; B is a bond or is selected from the optionally substituted group consisting of alkyl, cycloalkenyl, cyclopentyl or cyclohexyl; Z is a bond, -O- or -R200-O-; and E is H, or is selected from the optionally substituted group consisting of alkoxy, alkenyl, alkyl, cycloalkyl, diazepanyl, piperazinyl and tetrazolyl. A more preferred embodiment of any of the foregoing inventions of the Group B compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, wherein: R 1 is substituted by alkyl, bromine or chlorine; L is NH; B is cyclohexyl; Z is a bond or -R 00-O-; wherein R200 is alkyl; E is optionally substituted alkoxy or piperazinyl; and Y is NH. The compound of any of the above Group B inventions wherein the compound is 4- (4-. {4-Amino-5- [4- (5-cyoro-benzoxazo-2-ylamino) -3-fluoro-phenyl) ] -pyrrolyl [2,3-d] pyrimidin-7-yl.} - cyclohexyl-1-methyl-piperazin-2-one 5- [4- (5-chloro-benzooxazol-2-ylamino) -pheni] -7- [4- (2-methoxy-ethoxy) -cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine; or 5- [4- (5-Bromo-7-methyl-benzooxazole- 2-amino) -phenyl] -7- [4- (2-methoxyethoxy) -cyclohexy] -7H-pyrrolo [2,3-d] pyrimidin-4-ylane The compounds of this invention are useful for treating a disease or condition in a patient in need thereof, which comprises administering a compound of Formula I to such a patient, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, thyroiditis, diabetes of the type 1, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis, systemic lupus erythematosus, psoriasis, rejection of organ transplantation, benign and neoplastic proliferative diseases, lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, rectal cancer, hematopoietic malignancies, diabetic retinopathy, premature retinopathy, choroidal neovascularization due to age-related macular degeneration, infantile hemangiomas, edema, ascites, effusions, exudates, cerebral edema, acute lung damage, respiratory anxiety syndrome in adults, proliferative blood vessel disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, effects secondary coronary , cerebral side effects, ischemic limb angiogenesis, ischemia / reperfusion injury, wound healing, diseases related to Helicobacter peptide ulcer, virally induced angiogenic disorders, fractures, Crow-Fukase syndrome (POEMS), pre-eclampsia, menometrorrhagia, fever due to cat scratch, rubeosis, neovascular glaucoma, retinopathies, malignant ascites, von Hippel Lindau disease, hematopoietic cancers, hyperproliferative disorders, burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic inflammation, allergic inflammation, delayed type hypersensitivity , ovarian hyperstimulation syndrome, angina, ankylosing spondylitis, asthma, congestive obstructive pulmonary disease (COPD), hepatitis C virus (HCV), idiomatic pulmonary fibrosis,. myocardial infarction, psoriatic arthritis, restenosis and sciatica. A pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier or excipient. In a further embodiment, the present invention is directed to a method for making an optionally substituted 2-aminobenzoxazole comprising the step of: reacting an optionally substituted N- (2-hydroxyphenyl) thiourea with an oxidant and a base, but not including a toxic metal until the reaction is substantially complete; wherein the oxidant is selected from the group consisting of acid peroxide; oxygen, perishable, chlorine, sodium periodate, potassium periodate, butyl peroxide, fer-butyl hypochlorite, sodium perborate, sodium percarbonate, peroxide adduct urea acid, sodium hypochlorite, potassium hypochlorite, hypobromite of sodium, potassium hypobromite, sodium bromate, potassium bromate, potassium permanganate and barium manganate; and the base is selected from the group consisting of metal hydroxides and tetraalkylammonium; metal carbonates and tetraalkylammonium, metal bicarbonates and tetraalkylammonium, metal and tetraalkylammonium alkoxides, metal and tetraalkylammonium phosphates, dibasic metal and tetraalkylammonium phosphates.

DETAILED DESCRIPTION OF THE INVENTION Protein tyrosine kinases. Protein tyrosine kinases (PTKs) are enzymes which catalyze the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes themselves, act as a molecular switch that regulates cell proliferation, activation or differentiation (for review, see Shlessinger and UHrich, 1992, Neuron 9: 383-391). Aberrant or excessive PTK has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (eg, autoimmune disorders), allograft rejection, and graft against host disease. In addition, endothelial cell-specific PTK receptors such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in sustaining the progress of cancers and other diseases that involve inappropriate vascularization (eg, diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, premature retinopathy, and infantile hemangiomas) . Tyrosine kinases can be of the receptor type (which have extracellular transmembrane and intracellular domains) or of the non-receptor type (which is completely intracellular). Tyrosine Receptor Cyanases (RTKs). RTKs comprise a large family of transmembrane receptors with diverse biological activities. Currently, at least nineteen (19) different RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ulrrch, Ann. Rev. Biochem. 57: 433-478, 1988; Ullrich and Schlessinger, Cell 61: 243-254, 1990). The intrinsic function of RTKs is activated in the ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich &Schlessinger, 1990m Cell 61: 203-212). In this way, signal transduction mediated by receptor tyrosine kinase is initiated by extracellular interaction with a specific growth factor (ligand), usually followed by receptor dimerization, stimulation of intrinsic protein tyrosine kinase activity and trans-phosphorylation receiver The binding sites are therefore created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (eg, cell division, differentiation, metabolic effects and changes in the extracellular microenvironment, see Schlessinger and Ullrich, 1992, Neuron 9: 1 -20). Proteins with SH2 (homology -2 src) or phosphotyrosine binding (PTB) domain bind activated tyrosine kinase receptors and their substrates with high affinity to propagate signals within cells. Both of the domains recognize phosphotyrosine. (Fanal et al., 1992, Ce // 69: 413-423, Songyang et al., 1994, Mol Cell Cell Biol. 14: 2777-2785, Songyang et al., 1993, Cell 72: 767-778; and Koch et al., 1991, Science 252: 668-678, Shoelson, Curr Opin, Chem. Biol. (1997), 1 (2), 227-234, Cowburn, Curr. Opin. Struct. Biol. (1997). ), 7 (6), 834-838). Several intracellular substrate proteins that are associated with receptor tyrosine kinases (RTK) have been identified. These can be divided into two main groups: (1) substrates which have a catalytic domain; and (2) substrates that lack such a domain, but serve as adapters and associate with catalytically active molecules (Songyang et al., 1993, Cell 72: 767-778). The specificity of the interactions between the receptors or proteins and SH2 or PTB domains of their substrates is determined by the amino acid residues that immediately surround the phosphorylated tyrosine residue. In this way, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by the specific growth factor receptors, as well as the receptors of the differentiation factor. It has been suggested that several receptor tyrosine kinases such as FGFR-1, PDGFR, TIE-2 and c-Met, and the growth factors that bind to them, play a role in angiogenesis, although some can indirectly promote angiogenesis (Mustonen and Alitalo, J. Cell Biol. 129: 895-898, 1995). One of the receptor tyrosine kinase, known as fetal liver kinase-1 (FLK-1) is a member of the subclass of type ll l RTKs. An alternative designation for human FLK-1 is receptor (KDR) that contains the kinase insert domain (Terman et al., Oncogene 6: 1677-83, 1991). Another alternative designation for FLK-1 / KDR is a vascular endothelial cell growth factor receptor-2 (VEGFR-2) since it binds VEGF with high affinity. The murine version of FLK-1 / VEGFR-2 has also been called NYK (Oelrich et al., Oncogene 8 (1): 11-15, 1993). Numerous studies such as those reported in Millauer et al., Cell 72: 835-846, 1993, suggest that VEGF and FLK-1 / KDR / VEGFR-2 are a pair of ligand-receptor that play an important role in the proliferation of Vascular endothelial cells, and the formation and outbreak of blood vessels, called vasculogenesis and angiogenesis, respectively. Another subclass of RTK type lll designated fms-like tyrosine kinase-1 (Flt-1) is related to FLK-1 / KDR (DeVries et al., Science 255; 989-991, 1992; Shibuya et al., Oncogene 5: 519-524, 1990). An alternative designation for Flt-1 is receptor-1 of the endothelial cell growth factor (VEGFR-1). So far, members of the FLK-1 / KDR / VEGFR-2 and Flt-1 / VEGFR-1 subfamilies have been found to be expressed mainly on endothelial cells. These members of the subclass are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) family of ligands (Kglgsburn and D'Amore, Cytokine &; Growth Factor Reviews 7: 259-270, 1996). Vascular endothelial cell growth factor (VEGF) binds to Flt-1 with higher affinity than to FLK-1 / KDR and is mitogenic towards vascular endothelial cells (Terman et al., 1992, supra: Mustonen et al. DeVries et al., Supra). It is believed that Flt-1 is essential for endothelial organization during vascular development. The expression of Flt-1 in monocytes, osteoclasts and osteoblasts, as well as in adult tissues such as kidney glomerula suggests an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra). As previously established, recent evidence suggests that VEGF plays a role in the stimulation of both normal and pathological angiogenesis (Jakeman et al., Endocrinology 133: 848-859, 1993; Kolch et al., Breast Cancer Research and Treatment 36: 139 -155, 1995, Ferrara ef aL, Endrocrine Reviews 18 (1), 4-25, 1997, Ferrara et al., Regulation of Angiogenesis (ed. LD Goldberg and EM Rosen), 209-232, 1997). In addition, VEGF has been implicated in the control and improvement of vascular permeability (Connolly, et al., J. Biol. Chem. 264: 20017-20024, 1989; Brown et al., Regulation of Angiogenes (ed. and EM Rosen), 233-259, 1997). Different forms of VEGF originating from alternative splicing of mRNA have been reported, including the four species described by Ferrara et al. (J. Cell. Biochem. 47:21 1-218, 1991). Several related VEGF homologs have recently been identified. Placental growth factor (PIGF) has an amino acid sequence that exhibits remarkable homology to the VEGF sequence (Park et al, J. Biol. Chem. 269: 25646-54, 1994; Maglione et al., Oncogene 8: 925 -31, 1993). As with VEGF, different species of PIGF originate from the alternative splicing of mRNA, and the protein exists in the dimeric form (Park ef al., Supra). PIGF-1 and PIGF-2 bind to Flt-1 with high affinity, and PlGF-2 also binds avidly to neuropilin-1 (Migdal et al., J. Biol. Chem. 273 (35): 22272-22278) , but none is linked to FLK-1 / KDR (Park et al., supra). It has been reported that PIGF potentiates both vascular permeability and the mitogenic effect of VEGF on endothelial cells when VEGF occurs at low concentrations (presumably due to heterodimeric formation) (Park et al., Supra). VEGF-B is produced as two isoforms (167 and 185 residues) that also appear to bind Flt-1 / VEGFR-1 (Peppert ef al., Proc. Nati. Acad. Sci. USA (1998), 95 (20): 1 1709-11714). VEGF-C, in its fully processed form, can also bind KDR / VEGFR-2 and stimulate proliferation and migration of endothelial cells in vitro and angiogenesis in in vivo models (Lymboussaki ef al, Am. J. Pathol. (1998), 153 (2): 395-403; Witzenbichler ef al, Am. J. Pathoi. (1998), 153 (2), 381-394). The transgenic overexpression of VEGF-C causes the proliferation and lengthening of only lymphatic vessels, while the blood vessels are not affected. The most recently discovered VEGF-D is structurally very similar to VEGF-C. It is reported that VEGF-D binds and activates at least two VEGFRS, VEGFR-3 / FIÍ-4 and KDR / VEGFR-2 (Achen et al, Proc. Nati. Acad. Sci. USA (1998), 95 (2), 548-553 and references herein). A novel virally coded type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF7), has recently been reported, which preferably uses the KDR / Flk-1 receptor and carries a potent mitotic activity without heparin binding domain (Meyer ef al, EMBO J. (1999), 18 (2), 363-374, Ogawa et al, J. Biol. Chem. (1998), 273 (47 (, 31273-31282). E possess 25% homology to mammalian VEGF and are encoded for parapoxvirus Orf (OV) virus.As VEGF165, an isoform of VEGF-A, VEGF-E was found to bind with high affinity to VEGF receptor-2 ( KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2 + concentrations, whereas in contrast to VEGF165, VEGF-E does not bind to VEGF receptor-1 (Flt-1). Based on the emerging findings of other VEGF and VEGFRs homologs and the foregoing for ligand and receptor heterodimerization, the actions of such VEGF homologs may involve the formation of VEGF ligand heterodimers, and / or receptor heterodimerization, or the binding to a VEGFR not yet discovered (Witzenbichler et al., supra). Also, recent reports suggest that neuropilin- (Migdal ef al., Supra) or VEGFR-3 / Flt-4 (Witzenbichler et al., Supra), or different receptors of KDR / VEGFR-2 may be involved in the induction of vascular permeability (Stacker, SA, Vitali.A., Domagala, T., Nice, E., and Wilks, AF, Angiogenesis and Cancer Conference, Amer. Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetology 40: S1 18-129 (1997)). Tie-2 (TEK) is a member of a newly discovered family of receptor-specific tyrosine kinases of endothelial cells which is involved in critical angiogenic processes, such as branching, sprouting, remodeling, maturation and blood vessel stability. Tie-2 is the first mammalian receptor tyrosine kinase for which both agonist ligands (eg, Angiopoietin 1 ("Ang1"), which stimulates receptor autophosphorylation and signal transduction) and antagonist ligands (eg, Angiopoietin2 ( "Ang2")), have been identified. The translocation and transgenic manipulation of Tie-2 expression and its ligands indicates spatial and temporal tight control of Tie-2 signaling is essential for the proper development of new vasculature. The current model suggests that the stimulation of Tie-2 kinase by the ligand Ang1 is directly involved in the branching, budding and production of new vessels, and the recruitment and interaction of periendothelial support cells important in maintaining the integrity of the blood vessel. induce latency The absence of Tie-2 Ang1 stimulation or the inhibition of Tie-2 autophosphorylation by Ang2, which occurs at high levels in vascular regression sites, can cause a loss in vascular structure and matrix contacts resulting in death endothelial cell, especially in the absence of growth / survival stimulus. The situation is however more complex, since at least two Tie-2 ligands (Ang3 and Ang4) have recently been reported, and the capacity for heterooligomerization of the various agonistic and antagonistic angiopoietins, so that their activity is modified, has been demonstrated. The ligand-receptor interactions of target Tie-2 as an anti-angiogenic therapeutic approach is thus less favored and a kinase inhibitor strategy is preferred.

Recently, remarkable over-regulation of Tie-2 expression has been found within the synovial pannus of arthritic joints of humans, consistent with a role in inappropriate neovascularization. Point mutations that produce constitutively activated forms of Tie-2 have been identified in association with human venous malformation disorders. Non-receptor tyrosine kinases. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular or transmembrane sequences. At present, more than twenty-one individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LI MK) have been identified . At present, the Src subfamily of non-receptor tyrosine kinases comprises a large number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis and immune responses. A more detailed discussion of non-receptor tyrosine kinases is provided in Bohlen, 1993, Oncogene 8: 2025-2031, which is incorporated herein by reference. It has been found that many of the tyrosine kinases, either an RTK or non-receptor tyrosine kinase, are involved in the signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis and other proliferative disorders or hyper-immune responses.

Inhibitors of P1 k-1 Kinase Plk-1 is a serine / threonine kinase which is regulated at its important pH of cell cycle progress. This plays critical roles in the assembly of the dynamic function of the mitotic rod apparatus. Plk-1 and the related kinases have also shown that they are closely related in the activation and deactivation of others regulated in their cell cycle pHes, such as cyclin-dependent kinases. Elevated levels of Plk-1 expression are associated with cell proliferation activities. It is frequently found in malignant tumors of various origins.

Inhibitors of Cdc2 / Cyclin B Kinase (Cdc2 is also known as cdkl) Cdc2 / cyclin B is another serine / threonine kinase enzyme which belongs to the cyclin dependent kinase family (cdks). These enzymes are involved in the critical transition between various phases of cell cycle progress. Inhibitors of kinases involved in mediating or maintaining disease states represent novel therapies for these disorders. Examples of such kinases include, but are not limited to: (1) the inhibition of c-Src (Brickell, Critical Reviews in Oncogenesis, 3: 401-406 (1992); Courtneidge, Seminars in Cancer Biology, 5: 236-246 (1994) raf (Powis, Pharmacology &Therapeutics, 62: 57-95 (1994)) and cyclin dependent kinases (CDKs) 1, 2 and 4 in cancer (Pines, Current Opinion in Cell Biology, 4: 144- 148 (1992); Lees, Current Opinion in Cell Biology, 7: 773-780 (1995); Hunter and Pines, Celi, 79: 573-582 (1994)), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger et al., Proceedings of the National Academy of Science USA, 92: 2258-2262 ( 1995)), (3) inhibition of CDK5 and GSK3 kinases in Alzheimers (Hosoi et al., Journal of Biochemistry (Tokyo), 117: 741-749 (1995); Aplin ef ai., Journal of Neurochemistry, 67: 699- 707 (1996), (4) inhibition of c-Src kinase in osteoporosis (Tanaka ef al., Nature, 383: 528-531 (1996), (5) inhibition of GSK-3 kinase in type 2 diabetes (Borthwick ef al., Biochemical &Biophysical Research Communications, 210: 738-745 (1995), (6) Inhibition of p38 kinase in inflammation (Badger et al., The Journal of Pharmacology and Experimental Therapeutics, 279: 1453-1461 ( 1996)), (7) inhibition of VEGF-r 1 -3 and T1E-1 and 2-kinases in diseases which involve angiogenesis (Shawver et al., Drug Discovery Today, 2: 50-63 (1997)), ( 8) Inhibition of UL97 kinase in viral infections (He et al., Journal of Virology, 71: 405-411 (1997)), (9) inhibition of CSF-1 R kinase in bone and hematopoietic diseases (Myers et al., Bioorganic & amp; amp;; Medicinal Chemistry Letters, 7: 421-424 (1997) and (10) inhibition of Lck kinase in autoimmune diseases and transplant rejection (Myers et al., Bioorganic &Medicinal Chemistry Letters, 7: 417-420 (1997)). It is also possible that inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not de-regulated, but nevertheless it is essential for the maintenance of the disease state. In this case, the inhibition of kinase activity would act as either a cure or a palliative for these diseases. VEGFs are unique because they are the only known angiogenic growth factors to contribute to vascular hyper-vascularity and edema formation. Therefore, VEGF mediated hypermeability can contribute significantly to disorders with these etiological characteristics. Due to blastocyst implantation, placental development and embryogenesis are dependent on angiogenesis, certain compounds of the invention are useful as contraceptive agents and antifertility agents. The compounds of this invention have inhibitory activity against one or more protein kinases listed herein, as well as members of the family thereof which are not specifically listed. That is, these compounds modulate signal transduction by protein kinases. The compounds of this invention inhibit protein kinases from classes of serine / threonine and tyrosine kinase. In particular, these compounds selectively inhibit the activity of the Tie2- / Tie-1 tyrosine kinases. Certain compounds of this invention also inhibit the activity of additional tyrosine kinases such as kinases of the subfamily Flt-1 / VEGFR-1, Flt-4, Tie-1, Tie-2, FGFR, PDG FR, IGF-1 R, c -Met, Src such as Lck, Src, hck, fgr, fyn, yes, etc. Additionally, some inventive mushroom compounds significantly inhibit serine / threonine kinases such as PKC, MAP kinases, erk, CDKs, Plk-1, or Raf-1 which play an essential role in cell proliferation and cell cycle progress. In addition, the metabolites and pro-drugs of certain compounds may also possess significant protein kinase inhibitory activity. The compounds of this invention, when administered to individuals in need of such compounds, inhibit vascular hypermeability and the formation of edema in these individuals. In one embodiment, the present invention provides a method for treating a condition mediated by protein kinase in a patient, comprising administering to the patient a therapeutically or prophylactically effective amount of one or more compounds of the Formula. A "protein kinase-mediated condition" or a "condition mediated by protein kinase activity" is a medical condition, such as a disease or other undesirable physical condition, the genesis or the progress of which depends, at least in part, on the activity of at least one protein kinase. The protein kinase can be, for example, a protein tyrosine kinase or a protein serine / threonine kinase. The patient being treated can be any animal, and is preferably a mammal, such as a domesticated animal or a livestock animal. More preferably, the patient is a human being. The method of the present invention is useful in the treatment of any of the conditions described above. In one embodiment, the condition is characterized by unwanted angiogenesis, edema, or stromal deposition. For example, the condition may be one or more ulcers, such as ulcers caused by bacterial and fungal infections, Mooren ulcers and ulcerative colitis. The condition may also be due to a microbial infection, such as Lyme disease, sepsis, septic shock or infections by Herpes simplex, Herpes Zoster, human immunodeficiency virus, protozoa, toxoplasmosis or prapoxivirus; an angiogenic disorder, such as von Hipper Lindau disease, polycystic kidney disease, pemphigoid, Paget's disease and psoriasis; a reproductive condition, such as endometriosis, ovarian hyperstimulation syndrome, pre-eclampsia or menometrorrhagia; a fibrotic and edemic condition, such as sarcoidosis, fibrosis, cirrhosis, thyroiditis, systemic hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma and edema after burns, trauma, radiation, stroke, hypoxia or ischemia; or an inflammatory / immunological condition such as systemic lupus, chronic inflammation, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis, and graft rejection. Other suitable conditions also include sickle cell anemia, osteoporosis, osteopetrosis, tumor-induced hypercalcemia and bone metastasis. Additional conditions which can be treated by the method of the present invention include ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt's disease and Eales disease, in addition to retinopathy and macular degeneration. The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, vascular occlusion and obstructive carotid disease. The compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Swing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcoma, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, pleural or pericardial effusions. induced by tumor and malignant ascites. The compounds of the present invention are also useful in the treatment of Corw-Fukase syndrome (POEMS) and diabetic conditions such as glaucoma, diabetic retinopathy and microangiopathy. The Src, Tec, Jak, Map, Csk, NF? B and Syk families of kinases play pivotal roles in the regulation of immune function. The Src family currently includes Fyn, Lck, Fgr, Fes, Lyn, Src, Yrk, Fyk, yes, Hck and BIk. It is currently understood that the Syk family includes only Zap and Syk. The TEC family includes Tec, Btk, Rlk and Itk. The Janus family of kinases is involved in the transduction of growth factor and pro-inflammatory cytokine signals through a number of receptors. The Csk family is currently understood to include Csk and Chk. The RIP, 1RAK-1, I RAK-2, NIK, p38 MAP kinases, Jnk, IKK-1 and lKK-2 kinases are involved in the signal transduction pathways for key pro-inflammatory cytokines, such as TN F and IL -1. The compounds of Formula I can function as useful immunomodulatory agents for the maintenance of allografts, the treatment of autoimmune disorders and the treatment of sepsis and septic shock. Through their ability to regulate the migration or activation of T cells, B cells, mast cells, monocytes and neutrophils, these compounds could be used to treat such autoimmune diseases and sepsis. The prevention of transplant rejection, whether graft versus host for solid organs or host versus bone marrow graft, is limited by the toxicity of currently available immunosuppressive agents and would benefit from an effective drug with improved therapeutic index. The objective genetic experiments have demonstrated the essential role of Src in the biology of osteoclasts, the cells responsible for bone resorption. The compounds of formula I, through their ability to regulate Src, may also be useful in the treatment of osteoporosis, osteopetrosis, Pager's disease, tumor-induced hypercalcemia and in the treatment of bone metastases. The compounds of the formula I, which inhibits the kinase activity of members of the c-kit family, c-met, c-fms, normal or aberrant src, EGFr, erbB2, erbB4, BCR-Abl, PDGFr, FGFr, IGF1-R and other receptor or cytosolic tyrosine kinases may be of value in the treatment of benign proliferative diseases and neoplastic In many pathological conditions (eg, primary solid tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inappropriate neovascularization, psoriasis, and atherosclerosis) disease progression is contingent on persistent angiogenesis. Certain compounds of formula I capable of blocking the kinase activity of specific endothelial cell kinases could therefore inhibit the progress of the disease. The vascular destabilization of the Tie-2 antagonist ligand (Ang2) is believed to induce an unstable "plastic" state in the endothelium. In the presence of elevated VEGF levels a solid angiogenic response may result; however, in the absence of VEGF or a VEGF-related stimulus, open blood vessel regression and endothelial apoptosis may occur (Genes and Devel, 13: 1055-1066 (1999)). In an analogous manner, a Tie-2 kinase inhibitor can be proangiogenic or antiangiogenic in the presence or absence of a VEGF-related stimulus, respectively. Therefore, Tie-2 inhibitors can be employed with an appropriate proangiogenic stimulus, such as VEGF, to promote therapeutic angiogenesis in situations such as wound healing, infarction and ischemia. The compounds of the formula I, a salt thereof, a prodrug thereof or pharmaceutical compositions containing a therapeutically effective amount thereof can be used in the treatment of conditions mediated by protein kinase, such as benign proliferative diseases and disorders and Neoplasms of the immune system, as described above. For example, such diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammation disease of! bowel, Crohn's disease, myasthenia gravis and systemic lupus erythematosus, psoriasis, rejection of organ transplantation (eg, kidney rejection, host disease against graft), benign and neoplastic proliferative diseases, human cancers such as lung cancer, breast, stomach, bladder, colon, pancreas, ovary, prostate and rectal and hematopoietic malignancies (leukemia and lymphoma) and diseases involving inappropriate vascularization eg diabetic retinopathy, premature retinopathy, choroidal neovascularization due to age-related macular degeneration and hemangiomas children in humans. In addition, such inhibitors may be useful in the treatment of disorders such as edema, ascites, effusions and exudates, including for example, macular edema, cerebral edema, acute lung damage and respiratory distress syndrome in adults (ARDS). The compounds of the formula I, or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof, are additionally useful in the treatment of one or more diseases that afflict mammals which are characterized by cell proliferation in the of blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. Blood vessel proliferative disorders include restenosis. Fibrotic disorders include liver cirrhosis and atherosclerosis. Mesangial cell proliferative disorders include glomerulonephritis, diabetic neuropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, rejection of organ transplantation and glomerulopathies. Metabolic disorders include diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases. The compounds of this invention have anti-angiogenic properties. For this reason, these compounds can be used as active agents against such disease states as arthritis, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral side effects, ischemic limb angiogenesis, ischemia / reperfusion injury, wound healing. , diseases related to Helicobacter peptic ulcer, virally induced angiogenic disorders, fractures, Crow-Fukase syndrome (POEMS), pre-eclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, or macular degeneration related to age. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease) and cysts (such as stromal characteristic hypervascularity). of ovary of polycystic ovary syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and / or metastasis., some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, cerebral edema associated with brain tumor, high altitude, edema cerebral or pulmonary induced by trauma or hypoxia, ocular and macular edema, ascites, glomerulonephritis and other diseases where vascular hypermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful for treating disorders in which protein extravasation leads to fibrin deposition and extracellular matrix, promoting stromal proliferation (e.g., keloid, fibrosis, cirrhosis and carpal tunnel syndrome). The increased VEGF production potentiates inflammatory processes such as monocyte recruitment and activation. The compounds of this invention will also be useful for treating inflammatory disorders such as inflammatory bowel disease (IBD) and Crohn's disease. It is further possible that inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not de-regulated, but is not essential for the maintenance of the disease state. In this case, the inhibition of kinase activity would act as either a cure or a palliative for these diseases. For example, many viruses, such as human papillomavirus, interrupt the cell cycle and harvest cells within the S phase of the cell cycle (Vousden, FASEB Journal, 7: 8720879 (1993)). The prevention of cells from the entry of DNA synthesis after viral infection by the inhibition of activities that initiate the essential S-phase such as CDK2, can interrupt the viral life cycle by preventing viral replication. This same principle can be used to protect normal cells of the body from the toxicity of cycle-specific chemotherapeutic agents (Stone et al., Cancer Research, 56: 3199-3202 (1996)).; Kohn et al, Journal of Cellular Biochemistry, 54: 44-452 (1994)). The inhibition of CDKs 2 or 4 will prevent progression within the cycle in normal cells and limits the toxicity of cytotoxics which act in the S, G2 or mitosis phase. In addition, the activity of CDK2 / cyclin E has also been shown to regulate NF-kB. Inhibition of CDK2 activity stimulates N F-kB-dependent gene expression, an event mediated through interactions with the p300 co-activator (Perkins et al., Science, 275: 523-527 (1997)). N F-kB regulates genes involved in inflammatory responses (such as hematopoietic growth factors, chemokines, and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of Immunology, 12: 141-179 (1994)) and may be involved in the suppression of apoptotic signals within the cell (Beg and Baitimore, Science, 274: 782-784 (1996); Wang ef al., Science, 274: 784-787 (1996); VanAntwerp ef aL, Science, 274: 787- 789 (1996)). In this way, the inhibition of CDK2 can suppress apoptosis induced by cytotoxic drugs through a mechanism which involves N F-kB. This therefore suggests that the inhibition of CDK2 activity may also be useful in other cases where the regulation of NF-kB plays a role in the etiology of the disease. Aspergillosis is a common infection in immunocompromised patients (Armstrong, Clinical Infectious Diseases, 16: 1-7 (1993)). Inhibition of the Aspergillus kinase Cdc2 / CDC28 or Nim A (Osmani et al., EMBO Journal, 10: 2669-2679 (1991); Osmani et al., Cell. 67: 283-291 (1991)) may cause arrest or death in the fungus, improving the therapeutic production for patients with these infections. The compounds of the present invention may also be useful in the prophylaxis of the above diseases. In another aspect, the present invention provides compounds of formula 1 as initially defined above for use as medicaments, particularly as inhibitors of protein kinase activity for example, tyrosine kinase activity, serine kinase activity and threonine activity kinase In still another aspect, the present invention provides the use of compounds of the formula I as initially defined in the above in the manufacture of a medicament for use in the inhibition of protein kinase activity. In this invention, the following definitions are applicable: A "therapeutically effective amount" is an amount of a compound of Formula I or a combination of two or more such compounds, which inhibit, in whole or in part, the progress of the condition or relieves at least partially, one or more symptoms of the condition. A therapeutically effective amount may also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend on the size and gender of the patient, the condition being treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art. "Physiologically acceptable salts" refer to those salts which retain the effectiveness and biological properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid ( for example, (+) or (-) - tartaric acid or mixtures thereof), amino acids (eg, (+) or (-) - amino acids or mixtures thereof) and the like. These salts can be prepared by methods known to those skilled in the art. Certain compounds of formula 1 which have acidic substituents can exist as salts with pharmaceutically acceptable bases. The present invention includes such salts. Example of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts can be prepared by methods known to those skilled in the art. Certain compounds of the formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I and their salts may also exist in the form of solvates, for example, hydrates, and the present invention includes each solvate and mixtures thereof.

Certain compounds of formula 1 may contain one or more chiral centers, and exist in different optically active forms. When the compounds of the formula I contain a chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers can be resolved by methods known to those skilled in the art, for example, by formation of diastereomeric salts which can be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific enantiomer reagent, for example, enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation methods described above, an additional step is required to release the desired enantiomeric form. Alternatively, the desired enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysis or solvents, or by converting one enantiomer into the other by asymmetric transformation. When a compound of formula I contains more than one chiral center, it can exist in diastereomeric forms. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example, chromatography or crystallization and the individual enantiomers within each pair can be separated as described above. The present invention includes each diastereomer of compounds of the formula I and mixtures thereof. Certain compounds of the formula I can exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and / or geometric isomer of compounds of the formula I and mixtures thereof. Certain compounds of the formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation around a single asymmetric bond, for example, due to the spherical impediment or ring strain, may allow the separation of different confomers. The present invention includes each conformational isomer of compounds of the formula I and mixtures thereof. Certain compounds of the formula I can exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of the formula I and mixtures thereof. As used herein, the term "prodrug" refers to an agent that is converted into the parent drug in vivo by some chemical physiological process (e.g., a prodrug that rekindles the physiological pH is converted to the desired drug form). ). Prodrugs are often useful, because, in some cases, they may be easier to administer than the parent drug. These may, for example, be bioavailable by oral administration, while the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions on the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate transmission through a cell membrane wherein the aqueous solubility is not beneficial, but is then metabolically hydrolyzes the carboxylic acid once inside the cell where the aqueous solubility is beneficial. Prodrugs have many useful properties. For example, a prodrug may be more soluble in water than the last drug, so that the intravenous administration of the drug is facilitated. A prodrug may also have a higher level of oral bioavailability than the last drug. After administration, the prodrug is cleaved enzymatically or chemically to deliver the last drug in the blood or tissue. Exemplary prodrugs in the cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention, include, but are not limited to, carboxylic acid substituents (eg, R1 is - (CH2) qC (O) X6 wherein X6 is hydrogen, or R2 or A1 contains carboxylic acid) wherein the free hydrogen is replaced by (C? -C) alkyl, (C2-C12) alkanoyloxymethyl, (C4-C9) - (alkanoyloxy) ethyl , 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, -methyl-1 - (alkoxycarbonyloxy) etiio having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonlactonyl, gamma-butyrolacton-4-yl, di-N, N- (C? -C2) alkylamino (C2-C3) alkyl iIo (such as ß-dimethylaminoethyl), carbamoyl- (C? -C2) alkyl, N, N-di (d-C2) -alkylcarbamoyl- (C -? - C2) alkyl and piperidino-, pyrrolidino or morpholino (C2-) C3) alkyl. Other exemplary prodrugs release an alcohol of Formula 1 wherein the free hydrogen of the hydroxyl substituent (eg, R 1 contains hydroxyl) is replaced by (Ci-β-β-alkanoyloxymethyl, 1 - ((d-CB) alkanoyloxy) ethyl, 1-methyl- 1 - ((C? -C6) alkanoyloxy) ethyl, (Ci-C?) To I coxy, iloxy methyloxy, N- (C? -C6) alkoxycarbonylamino-methyl, succinoyl, (d-C6) alkane, a-amino (C? -C4) alkanoyl, arylactyl and a-aminoacyl or a-aminoacyl-a-aminoacyl wherein such a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in the proteins, P (O) (OH ) 2, -P (O) (O) (C? -C6) alkyl) 2 or glycosyl (the radial resulting from the shedding of the hydroxyl of the hemiacetal of a carbohydrate). The term "heterocyclic" or "heterocyclyl" as used herein, includes aromatic and non-aromatic ring systems, including, but not limited to monocyclic, bicyclic and tricyclic rings, which may be completely saturated or which may contain one or more unsaturation units and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention: azaindole, azetidinyl, benzo (b) thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furans, imidazoles, imidazopyridine, indole, indazoles, isoxazoles, isothiazoles, oxadiazoles, oxazole piperazines, piperidines, purines, pyrans, pyrazines, pyrazoles, pyridines, pyrimidines, pyrroles, pyrrolidines, pyrrolo [2,3-d] pyrimidine, pyrazolo [3,4-d] pyrimidine), quinolines, quinazolines, triazoles, thiazoles, tetrahydroindole, tetrazoles, thiadiazoles, thienyls, thiomorpholines or triazoles. When the term "substituted heterocyclic" (or heterocyclyl) is used, which means that the heterocyclic group is substituted with one or more substituents that can be made by someone of ordinary skill in the art and results in a molecule that is a kinase inhibitor. . For purposes of exemplification, which should not be construed as limiting the scope of this invention, preferred substituents for the heterocyclyls of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl groups, alkoxycarbonylheterocyclealkoxy, alkyl, alkylcarbonyl, alkyl ester, aikyl-OC (O) -, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl nitrile, alkynyl, amido, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, CF3, CN, -C (O) OH, -C (O) H, -C (O) -) (CH3) 3 , -OH, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-heterocyclyl, -C (O) -alkyl, -C (O) -cycloalkyl, -C ( O) -heterocyclyl, cycloalkyl, dialkylaminoalkoxy, dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, halogen, heterocyclyl, a heterocycloalkyl, heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, NO2, OCF3, oxo, phenyl, -SO2CH3, -SO2CR3, tetrazolyl, thienylalkoxy, trifluoromethylcarbonylamino, trifluoro methylsulfonamido, heterocyclylalkoxy, heterocyclyl-S (O) p, cycloalkyl-S (O) p, alkyl-S-, heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl, heterocyclic, cycloalkylthio, -Z105-C (O) N (R) 2 , -Z105-N (R) -C (O) -Z200, -Z105-N (R) -S (O) 2-Z200, -Z105N (R) -C (O) -N (R) -Z200- -N (R) -C (O) R, -N (R) -C (O) OR, OR-C (O) -heterocyclyl-OR, Rc and -CH2ORc; wherein Rc for each case is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, - (C? -C6) -NRdRc, -W- (CH2) -NRdRc, -W- (CH2) tO-alkyl, -W- (CH2) tS-alkyl, or -W- (CH2) t-OH; Z105 for each case is independently a covalent bond, alkyl, alkenyl or alkynyl; and Z200 for each case is independently selected from an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkyl-phenol, alkenyl-phenyl or alkynyl-phenyl. A "heterocycloalkyl" group, as used herein, is a heterocyclic group that is linked to a compound by an aliphatic group having from one to about eight carbon atoms. For example, a preferred heterocycloalkyl group is an imidazolylethyl group. As used herein, "aliphatic" or "an aliphatic group" or notations such as "(C0-C8)" include straight chain or branched hydrocarbons which are fully saturated or which contain one or more units of unsaturation and thus they include alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of single, double and triple bonds. When the group is a Co, it means that the portion is not presented or in other words, it is a link. As used herein, "alkyl" means Ci-Cβ and includes straight or branched chain hydrocarbons which are completely saturated. Preferred alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. As used herein, "alkenyl" and "alkynyl" mean C2-Cs and include straight or branched chain hydrocarbons which contain one or more unsaturation units, one or more double bonds for alkenyl and one or more triple bonds for alkynyl. As used herein, "cycloalkyl" means C3-C12 monocyclic or multicyclic hydrocarbons (eg, bicyclic, tricyclic, etc.) which is fully saturated or has one or more unsaturated bonds but is not equivalent to an aromatic group. Preferred examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl. As used herein, amido group means -N HC (= O) -. As used herein, acyloxy groups are -OC (O) R. As used herein, many portions or substituents are referred to as either "substituted" or "optionally substituted." When a portion is modified by one of these terms, it denotes that any portion of the half that is known to one skilled in the art as being available for substitution may be substituted, which includes one or more substituents, wherein if there are more than a substituent then each substituent is independently selected. Such means for substitution are well known in the art and / or are taught by the current description. For purposes of exemplification, which should not be construed as limiting the scope of this invention, some examples of groups that are substituents are: alkenyl groups, alkoxy group (which itself may be substituted, such as -Od-Cβ-aiquito- OR, -Od-C6-alkyl-N (R) 2 and OCF3), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinylalkoxy, alkyl groups (which themselves may also be substituted, such as -Ci-Ce-alkyl-OR, -C1- C6-alkyl-N (R) 2, and -CF3), alkylamino, alkylcarbonyl, alkyl ester, alkyl nitrile, alkylsulfonium, amino, aminoalkoxy, CF3, COH, COOH, CN, cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonyl, dialkylaminocarbonylalkoxy, dialkylaminosulfonyl, esters (-C (O) -OR, where R is groups such as alkyl, heterocycloalkyl (which can be substituted) heterocyclyl, etc., which can be substituted), halogen group or halo (F, Cl, Br, i) , hydroxy, morpholinoalkoxy, morpholinoalkyl, nitro, oxo, OCF 3, optionally substituted phenyl, S (O) 2CH3, S (O) CF3, and sulfonyl, N-alkylamino or N-dialkylamino (in which the alkyl groups may also be substituted). As used herein, "toxic metal" means a metal that is considered to be toxic to animals in trace amounts.

Pharmaceutical Formulations One or more compounds of this invention may be administered to a human patient by themselves or in pharmaceutical compositions wherein they are mixed with biologically-suitable carriers or excipients in doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. A therapeutically effective dose refers to that amount of the sufficient compound or compounds that result in the prevention or attenuation of a disease or condition as described herein. The techniques for formulation and administration of the compounds of the present application can be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition.

Routes of Administration Appropriate routes of administration may, for example, include oral administration, eye drops, rectal, transmucosal, topical or intestinal; parenteral delivery including intramuscular, subcutaneous, intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections. Alternatively, the compound can be administered in a local rather than systemic form, for example, by injection of the compound directly into an edematous site, often in a depot or sustained release formulation. In addition, the drug can be administered in a target drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody. Composition / Formulation The pharmaceutical compositions of the present invention can be manufactured in a manner that is itself known, for example, by means of mixing, dissolving, granulating, dragee-making, powder-reducing, emulsifying, encapsulating, entrapping or lyophilized conventional. The pharmaceutical compositions for use according to the present invention can thus be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation is dependent on the chosen route of administration. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible pH regulators such as Hank's solution, Ringer's solution or physiological saline pH regulator. For transmucosal administration, the appropriate penetrants to the permeating barrier are used in the formulation. Such penetrants are generally known in the art. For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient being treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee centers. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, the disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee centers are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, varnish solutions, and suitable organic solvents or solvent mixtures. The dyes or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of the active compound doses. Pharmaceutical preparations which can be used orally include soft-fit capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The soft-fit capsules may contain the active ingredients in admixture with the filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration must be in adequate dosage for such administration. For buccal administration, the compositions may take the form of tablets or diamonds formulated in conventional manner. For administration by inhalation, the compounds for use according to the present invention are conveniently supplied in the form of an aerosol spray presentation from pressurized packets or a nebulizer, with the use of a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of the pressurized aerosol, the dose unit can be determined by providing a valve to supply a measured quantity. Capsules and cartridges of for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, eg, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampules or in multi-dose containers, with an added preservative. The compositions may have such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or suitable agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water., before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds can also be formulated as an injectable preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as moderately soluble derivatives for example, as a moderately soluble salt. An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, an organic water-miscible polymer and an aqueous phase. The co-solvent system can be the VPD co-solvent system. The VPD is a solution of 3% w / v of benzyl alcohol, 8% w / v of polysorbate 80 of non-polar surfactant and 65% w / v of polyethylene glycol 300, integrated in volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) consists of VPD diluted 1: 1 with 5% dextrose in aqueous solution. This co-solvent system dissolves hydrophobic compounds suitably, and by itself produces low toxicity in systemic administration. Naturally, the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the components of the co-solvent can be varied: for example, other non-polar surfactants of low toxicity can be used in place of polysorbate 80; the fraction size of the polyethylene glycol can be varied; other biocompatible polymers can replace polyethylene glycol, for example, polyvinyl pyrrolidone; and other sugars or polysaccharides can be substituted for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples for supplying vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be used, although usually at a cost of more toxicity. Additionally, the compounds can be delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known to those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release compounds for a few weeks to more than 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization can be employed. The pharmaceutical compositions may also comprise suitable solid phase or gel carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Many of the compounds of the invention can be provided as salts with pharmaceutically compatible counterions. The pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be more soluble in aqueous or other protonic solvents which are the corresponding free base forms.

Effective Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent the development of or alleviate the existing symptoms of the subject being treated. The determination of the effective amounts is adequate within the capacity of those skilled in the art. For any compound used in a method of the present invention, the therapeutically effective dose can be estimated initially from cellular assays. For example, a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes IC5o as determined in cellular assays (i.e., the concentration of the test compound which achieves a medium-maximal inhibition of an activity of given protein kinase). In some cases it is appropriate to determine 1C50 in the presence of 3 to 5% serum albumin since such determination approximates the binding effects of the plasma protein in the compound. Such information can be used to more accurately determine useful doses in humans. In addition, the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are certainly feasible in plasma. A therapeutically effective dose refers to that amount of the compound that results in the progression of symptoms in a patient. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the maximum tolerated dose (MTD) and ED50 (effective dose for 50% maximum response). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the relationship between BAT and ED50. Preferred are compounds which exhibit therapeutic indices. The data obtained from these cell culture assays and animal studies can be used to formulate a range of doses for use in humans. The dose of such compounds is preferably within a range of circulating concentrations that include the ED5o with little or no toxicity. The dose may vary within this range depending on the dosage form used and the route of administration used. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (See for example, Fingí et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pl). In the treatment of crisis, the administration of an acute bolus or an infusion that focuses on BAT may be required to obtain a rapid response. The amount and range of doses can be adjusted individually to provide plasma levels of the active portion which are sufficient to maintain the effects of kinase modulation, or the minimum effective concentration (MEC). The MEC will vary for each compound, but can be estimated from in vitro data; for example, the concentration necessary to achieve 50-90% inhibition of the protein kinase using the assays described herein. The doses needed to achieve MEC will depend on the individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. The dose ranges can be determined using the MEC value. The compounds should be administered using a regimen which maintains the plasma levels on the ECM for 10-90% of the time, preferably between 30-90% and more preferably between 50-90% until the desired progress of symptoms is achieved. In cases of local administration or selective incorporation, the effective local concentration of the drug can not be related to plasma concentration. The amount of compositions administered will of course depend on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

Packaging The compositions may, if desired, be presented in a package or dispensing device which may contain one or more dosage unit forms containing the active ingredient. The package may comprise for example metal or plastic sheets, such as a blister. The package or distributor device can be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition. In some formulations, it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example, as obtained by grinding fluid energy.

The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description, the term "active compound" denotes any compound of the invention, but particularly any compound which is the final product of one of the preceding Examples. a) Capsules In the preparation of capsules, 10 parts by weight of the active compound and 240 parts by weight of the lactose can be deagglomerated and mixed. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound. b) Tablets Tablets can be prepared, for example, from the following ingredients. Parts by weight Active compound 10 Lactose 190 Corn starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, lactose and some of the starch can be de-agglomerated, mixed and the resulting mixture can be granulated with a solution of the polyvinyl-pyrrolidone in ethanol. The dried granulate can be mixed with the magnesium stearate and the rest of the starch. The mixture was then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of the active compound. c) Enteric coated tablets The tablets can be prepared by the method described in (b) above. The tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanoL-dichloromethane (1: 1). d) Suppositories In the preparation of suppositories, for example, 100 parts by weight of the active compound can be incorporated in 1300 parts by weight of a suppository of triglyceride base and the mixture is formed into suppositories each containing a therapeutically effective amount of the active ingredient. In the compositions of the present invention, the active compound can, if desired, be associated with other compatible pharmacologically active ingredients. For example, the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein. For example, with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuates intracellular responses to VEGF or angiopoietins, blocks intracellular signal transduction, inhibits vascular hypermeability, reduces inflammation, or inhibits or prevents edema formation or neovascularization. The compounds of the invention can be administered before, subsequent to or at the same time with the additional pharmaceutical agent, in any appropriate administration course. Additional pharmaceutical agents include, but are not limited to, anti-edaemic steroids, NSAIDS, ras inhibitors, anti-NTF agents, anti-I L1 agents, antihistamines, PAF antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase, Akt / PTB inhibitors, IGF-IR inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants. The compounds of the invention and the additional pharmaceutical agents act either additively or synergistically. In this way, administration of such a combination of substances that inhibit angiogenesis, vascular hypermeability and / or inhibit the formation of edema may provide greater relief from the deleterious effects of a hyperproliferative disorder, angiogenesis, vascular hypermeability or edema than the administration of any substance alone. In the treatment of combinations of malignant disorders with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention. The present invention also comprises the use of a compound of formula I as a medicament. A further aspect of the present invention provides the use of a compound of formula 1 or a salt thereof in the manufacture of a medicament for treating vascular hypermeability, angiogenesis-dependent disorders, diseases and / or proliferative disorders of the immune system in mammals, particularly human beings. The present invention also provides a method for treating vascular hypermeability, inappropriate neovascularization, diseases and / or proliferative disorders of the immune system which comprises administering a therapeutically effective amount of a compound of the formula I to a mammal, particularly a human , with need of it.

Biological Assays The in vitro potency of the compounds to inhibit one or more protein kinases discussed herein or described in the art can be determined by the procedures detailed below. The potency of the compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (eg, synthetic peptide (Z. Songyang et al., Nature, 373: 536-539) by a test compound relative to the control. KDR Tyrosine Kinase Production Using Baculovirus System: The coding sequence for the intracellular domain of human KDR (aa789-1354) was generated by PCR using cDNAs isolated from HUVEC cells. A poly-Hisd sequence was introduced in the N-terminus of this protein as well. This fragment was cloned into the transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using BacuIoGold Transfection Reagent (PharMingen). The recombinant BV was purified on plates and verified by Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106 / ml, and infected in 0.5 plaque-per-cell units (MOI). The cells were harvested 48 hours after infection.

Purification of KDR SF-9 cells expressing (His) 6KDR (aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis pH buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMFS, 10 μg / ml aprotinin, 1 μg / ml leupeptin) to the cell granule from 1 I of the cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 minutes at 4 ° C. The cell lysate was applied to a chelating sepharose column of 5 ml of N iCI2, equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. The KDR was eluted using the same pH buffer containing 0.25 M imidazole. The column fractions were analyzed using SDS-PAGE and an ELISA assay (subsequent) which measures the activity of the kinase. The purified KDR was exchanged in 25 mM H EPEs, pH 7.5, 25 mM NaCl, 5 mM pH regulator DTT and stored at -80 ° C.

Production and Purification of Human Tie-2 Kinase The coding sequence for the intracellular domain Tie-2 (aa775-1 124) was generated by PCR using cDNAs isolated from human placenta as a template. A poly-His6 sequence was introduced at the N-terminus and this construct was cloned into the pVL 1939 transfection vector at the Xba 1 and Not 1 site. The recombinant BV was generated through co-transfection using the BaculoGold Transfection Reagent. (PharMingen). The recombinant BV was purified on plates and verified by Western analysis. For protein production, SF-9 insect cells were cultured in SF-900-I medium at 2 x 106 / ml, and infected at MOI of 0.5. The purification of the His tagged kinase used for selection was analogous to that described for KDR.

Production and Purification of Human Flt-1 Tyrosine Kinase The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 51 was placed in the nucleotide region encoding the complete intracellular kinase domain Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated through PCR using cDNA libraries isolated from HVCVC cells. The histidine residues allowed affinity purification of the protein in a manner analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a multiplicity of 0.5 and harvested 48 hours after infection.

EGFR Tyrosine Kinase Source Sigma EGFR was purchased (Catalog # E-3641; 500 units / 50 μ) and the EGF ligand was purchased from Oncogene Research Products / Calbiochem (Cat # PF011-100).

Expression of ZAP70 The baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca). The nucleotide sequence encoding amino acids M (H) 6 LVPR3S was placed 5 'in the region encoding all of ZAP70 (amino acids 1-619). The nucleotide sequence encoding the ZAP70 coding region was generated by PCR using cDNA libraries isolated from Jurkat immortalized T cells. The histidine residues allow the affinity purification of the protein (vide infra). The LVPRgS bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, allowing the removal of the affinity tag from the enzyme. SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours after infection.

Extraction and purification of ZAP70 SF-9 cells were lysed in a pH regulator consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 μg / ml leupeptin, 10 μg / ml aprotinin and 1 mM sodium orthovanadate. The soluble lysate was applied to a HiTrap column of chelating sepharose (Pharmacia) equilibrated in 50 mM H EPES, pH 7.5, 0.3 M NaCl. The fusion protein was eluted with 250 mM imidazole. The enzyme was stored in pH buffer containing 50 mM of HEPES, pH 7.5, 50 mM of NaCl and 5 mM of DTT.

Protein kinase source Lck, Fyn, Src, BIk, Csk and Lyn, and truncated forms thereof can be obtained commercially (for example, from Upstate Biotechnology Inc. (Saranac Lake, N.Y.) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca)) or purified from known natural or recombinant sources using conventional methods.

Enzyme Linked Immunosorbent Assay (ELISA) for PTKs Enzyme-linked immunosorbent assays were used (ELISA) to detect and measure the presence of tyrosine kinase activity. ELISAs were conducted according to known protocols which are described in, for example, Soller et al., 1980, "Enzyme-Linked Immunosorbent Assay" in: Manual of Clinical Immunology, 2nd edition, edited by Rose and Friedman, pp 359- 371 Am. Soc. Of Microbiology, Washington, DC The described protocol was adapted to determine the activity with respect to a specific PTK. For example, preferred protocols for conducting ELISA experiments are provided below. The adaptation of these protocols to determine an activity of the compound for other members of the recipient PTK family, as well as non-receptor tyrosine kinases, are well within the capabilities of those in the art. For purposes of determining the inhibitory selectivity, a universal PTK substrate (eg, random polyol copolymer (Glu4 Tyr), 20,000-50,000 MW) was used together with ATP (typically 5 μM) in concentrations of approximately two times the Km apparent in the trial. The following procedure was used to evaluate the inhibitory effect of the compounds of this invention on the tyrosine kinase activity KDR, Flt-1, Flt-4 / VEGFR-3, Tie-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, BIk, Csk, Src, Lyn, Fyn and ZAP70: PH regulators and Solutions: PGTPoly (Glu, Tyr) 4: 1 Store powder at -20 ° C. Powder dissolved in saline regulated at its phosphate pH (PBS) for 50 mg / ml of solution.

Store 1 ml of aliquots at -20 ° C. When plates are made diluted at 250 μg / ml in Gibco PBS. Reaction pH regulator: 100 mM Hepes, 20 mM MgCl2, 4 mM MnCl2, 5 mM DTT, 0.02% BSA, 200 μM NaVO4, pH 7.10 ATP: Store 100 mM aliquots at -20 ° C . Dilute to 20 μM in water Wash pH Controller: PBS with 0.1% Tween 20 Antibody Dilution pH Regulator: 0.1% bovine serum albumin (BSA) in PBS TMB Substrate: mix the TMB substrate and solutions Peroxide 9: 1 just before use o Use substrate Neogen Blue K Detention Solution: 1 M Phosphoric Acid Procedure 1. Plate Preparation Dilute the PGT strains (50 mg / ml, frozen) in PBS to 250 μg / ml. Add 125 μl per well of Corning modified high-background flat affinity ELISA plates (Corning # 25805-96).

Add 125 μl of PBS to empty cavities. Cover with sealing tape and incubate overnight at 37 ° C. Wash 1x with 250 μl washing pH regulator and dry for approximately 2 hours at 37 ° C of the dry incubator. Store coated plates in sealed bags at 4 ° C until used. 2. Tyrosine Kinase Reaction: - Prepare inhibitor solutions in a 4x concentration in 20% DMSO in water. - Prepare the reaction pH regulator - Prepare the enzyme solution so that the desired units are in 50 μl, for example, for KDR at 1 ng / μl for a total of 50 ng per cavity in the reactions. Store on ice. - Realize a 4x solution of ATP at 20 μM of 100 mM strains in water. Store on ice. - Add 50 μl of the pro-enzyme solution (usually 5-50 ng of enzyme / well depending on the specific activity of the kinase) - Add 25 μl of the 4x inhibitor - Add 25 μl of ATP 4x for inhibitor test - Incubate for 10 hours. minutes at room temperature - Stop the reaction by adding 50 μl 0.05N HCl per well - Wash the plate ** Final Concentrations for Reaction: 5 μM ATP, 5% DMSO 3. Antibody Link - Dilute 1 mg / ml aliquot of PY20-H RP antibody (Pierce) (a phosphotyrosine antibody) at 50 ng / ml in 0.1% BSA and PBS for a 2-step dilution (100x, then 200x) - Add 100 μl Ab per well. Incubate 1 hour at room temperature. Incubate 1 hour at 4 ° C. - Wash the 4x plate 4. Color reaction - Prepare the TMB substrate and add 100 μl per well - Monitor OD at 650 nm until it reaches 0.6 - Stop with 1 M phosphoric acid. Shake on the plate reader. - Read OD immediately at 450 nm. The optimal incubation times and the enzymatic reaction conditions vary slightly with enzyme preparations and are determined empirically for each batch. For Lck, the Reaction pH regulator used was 100 mM MOPSO, pH 6.5, 4 mM MnCl2, 20 mM MgCl2, 5 mM DTT, 0.2% BAS, 200 mM NaV04 under the analogous assay conditions. The compounds of the formula I may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of the formula 1. All compounds exemplified in the present they significantly inhibit either FGFR, PDGFR, KDR, Tie-2, Lck, Fyn, BIk, Lyn or Src at concentrations of 50 micromolar or below. Some compounds of this invention also significantly inhibit other tyrosine or serine / threonine kinases such as cdc2 (cdkl) at concentrations of 50 micromolar or below.

Cdc2 source The human recombinant enzyme and the assay pH regulator can be obtained commercially (New England Biolabs, Beverly, Mass., USA) or purified from known natural or recombinant sources using conventional methods.

Cdc2 assay The protocol used was that provided with the reactants acquired with minor modifications. In brief, the reaction was carried out in a pH regulator consisting of 50 mM behind pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCI2 (commercial pH regulator) supplemented with 300 μM of fresh ATP (31 μCi / ml) and final concentrations of 30 μg / ml of histone type ll lss. A reaction volume of 80 μl, containing enzyme units, was operated for 20 minutes at 25 ° C in the presence or absence of the inhibitor. The reaction was terminated by the addition of 120 μl of 10% acetic acid. The substrate was separated from an unincorporated label by staining the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75 mM phosphoric acid. The counts were measured by a beta counter in the presence of a liquid scintillation.

Certain compounds of this invention significantly inhibit cdc2 at concentrations below 50 μM.

Source of PKC kinase The catalytic subunit of PKC can be obtained commercially (Calbiochem). PKC Kinase Assay A radioactive kinase assay was used after a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3: 166, 1220-1227 (1990)). In brief, all reactions were performed in a kinase pH regulator consisting of 50 mM back-HCl pH 7.5, 10 mM MgCl 2, 2 mM DTT, 1 mM EGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and 33P ATP (8Ci / mM). The compound and the enzyme were mixed in the reaction vessel and the reaction initiated by the addition of ATP and the substrate mixture. After completion of the reaction by the addition of 10 μl of the stop pH buffer (5 mM ATP in 75 mM phosphoric acid), a portion of the mixture stained phosphocellulose filters. The stained samples were washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. The incorporation of the radiolabel was quantified by liquid scintillation counting.

Erk2 enzyme source The recombinant murine enzyme and the assay pH regulator (New England Biolabs, Beverly MA, USA) can be obtained commercially or purified from known natural or recombinant sources using conventional methods.

Erk2 Enzyme Assay In brief, the reaction was carried out in a pH regulator consisting of 50 mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM of MgCl (commercial pH regulator) supplemented with 100 μM of fresh ATP (31 μCi / ml) and 30 μM of myelin basic protein under conditions recommended by the supplier. The reaction volumes and the method for evaluating the incorporated radioactivity were described and described for the PKC assay (vide supra).

In Vitro Models for Activation of the T Cell In activation by mitogen or antigen, T cells are induced to secrete IL2, a growth factor that supports its subsequent proliferative phase. Therefore, both the production of IL-2 from or the cell proliferation of primary T cells or appropriate T cell lines can be measured as a substitute for T cell activation. Both of these assays are well described in the literature and its well-documented parameters (in Current Protocols in Immunology, Vol 2, 7.10.1 -7.1 1 .2). Briefly, T cells can be activated by co-culture with allogeneic stimulator cells, a process called mixed lymphocyte reaction in one direction. Responsive and stimulatory peripheral blood mononuclear cells are purified by Ficoll-Hypaque gradient (Pharmacia) by manufacturer directions. Stimulatory cells are mitotically inactivated by treatment with mitomycin C (Sigma) or gamma irradiation. The responder and stimulator cells are co-cultured in a ratio of two to one in the presence or absence of the test compound. Normally, the 105 responders are mixed with 5 x 104 stimulators and formed into plates (200 μl volume) in a U-bottom microtiter plate (Costar Scientific). The cells are cultured in RMPI 1640 supplemented with any inactivated fetal bovine serum (Hyclone Laboratories) or human AB serum pooled from male donors, 5 x 105 M 2 mercaptoethanol and 0.5% DMSO. The cultures are pulsed with 0.5 μCi of 3H thymidite (Amersham) one day before harvest (usually day three). The crops are harvested (Betaplate harvester, Wallac) and the incorporation of the isotope is evaluated by liquid scintillation (Betaplate, Wallac). The same culture system can be used to assess the activation of the T cell by measuring the production of I L-2. Eighteen to twenty-four hours after the start of the culture, the supernatants are removed and the concentration of IL-2 is measured by ELISA (Systems R and D) following the directions of the manufacturer.

Autoforosphorylation Test Protocol H UVEC KDR Culture of HUVEC cells from Frozen strains: 1. Thaw a bottle with HUVEC cells (Clonetics, cc-2519) inside a 100 mm plate (Falcon for tissue culture) containing 10 ml of complete EBM medium (all supplements added) (Clonetics, cc-41-43) . This is passage one (P1). 2. The next day, change the medium. 3. Two-three days later, the plate should be 90-100% confluent. Divide into 3-4 100 mm plates (P2). To divide either the use of Clonetics trypsin or dilute our trypsin / EDTA (Gibco, 25500-056) 1: 5 in PBS1 X, add 2 ml per plate and observe the cells under the microscope. Most will detach in 1 minute. 4. 3-4 days later, divide 3 or 4 plates into 12-14 plates of 100 mm (P3). 5. Continue the passage of cells in this way through P8. Autophosphorylation induced by HUVEC VEGF: 1. 3-4 days after forming in P3 plates, the plates should be 90-100% confluent. 2. Remove serum overnight, all but 2 or 3 plates for use in the assay (non-suppressed plates are used for the next passage). For suppressed serum plates: Extract by aspirate means; rinse in 5-10 ml of PBS; add 10 ml of EBM base medium (without added supplements). 3. TEST DAY: integrate all RIPA drug and pH regulator dilutions just before use. Treatment Conditions; (a) 0 = untreated suppressed serum (b) 10 'VEGF (1X) - 2 ml at 50 ng / ml * * VEGF is kept in the freezer at -80 ° C in 100 μl aliquots in 10 μg / ml of PBS / 1% BSA for 1X VEGF - aliquot of 100 μl is added to 20 ml of EBM base for 2X VEGF - add 100 μl aliquot to 10 ml of EBM base medium (c) Inhibitors - (1) add 2 ml of 25 μM or 5 μM of drug dilution for 1 hour at 37 ° C. (2) After 1 hour, add 2 ml of 2X VEGF for 10 minutes. (d) Extract by aspiration, rinse in 5-10 ml of PBS + 1 mM of ortho Vanadate of Na (e) Dissolve the plate in 500 μl of cRIPA ** and scrape place on ice for 15 minutes. (f) After 15 minutes, place the lysate in a labeled eppendorf tube and continue dilution on ice for 2-4 hours. (g) centrifuge at 14,000 rpm for 30 minutes, to compress the core (h) Pour the lysate into the fresh tube (i) Take 10 ul for a BCA Protein Determination (team by Pierce). You can freeze at this point until you are ready for (immuno) precipitate or Western blot. (j) Protein Precipitation is done by adding 3 times the volume (of lysate) of cold Ethanol as ice. The samples are placed in the freezer overnight. Samples can be stored in this way until ready for use. 4. Day to activate gels: (a) Centrifuge the samples at 14,000 rpms for 30 minutes @ 4 ° C (b) Pour supernatant. Air Drying Granule 1 -2 hours. (c) Add 2X + 2Me Sample pH Regulator (Sigma M7154). (d) Boiling samples 5 minutes. (e) Activate gels. ** pH REGULATOR PA PA Modified CONCENTRATION FI NAL 50 mM Tris-HCl pH7.5 150 mM NaCI 1% NP-40 0.25% NaDOC (deoxycholic acid) (Sigma D4297) 1 mM EDTA (Sigma E1644) QS To 1000 ml Add just before use for 10 ml Conc Final 100 mM PMSF (diluted in 100 ul 1 mM EtOH (Sigma P7626) 1 mg / ml Aprotinin (Sigma A3428) 10 μl 1 μg / ml 1 mg / ml of Pepstatin (Sigma P5318) 10 μl 1 μg / ml 1 mg / ml Leupeptin (Sigma L9783) 10 μl 1 μg / ml 100 mM Na orthovanadate (Sigma S9265) 100 μl 1 mM 100 mM Nafluoride ( Sigma S7920) 100 μl 1 mM 10 mg / ml DNase (Sigma D4527) 10 μl 1 μg / ml Intracellular Calcium Induced VEGF Calcium Protocol Assay (stimulation &Counterscreen) PH Regulators: pH A Regulator Hanks Balanced Salt Solution (Gibco / BRL # 14175-095 without phenol red) + 1% Hepes 1 M (final concentration 10 mM) (Gibco / BRL # 15630-080). PH regulator B pH regulator A + 5% BSA (Sigma # A-7030) pH C regulator pH regulator B + 10 μg / ml DNase (Sigma # D-4527). PH regulator FACS 0.1% BSA in HBSS (+ 0.01% of Sodium Azide (Sigma S20021)) Versene Gibco / BRL # 15040-066 (# P-300 Molecular Probes) HUVEC cells Grouped Donors (Clonetics # cc-2519) Medium EC medium EBM (Clonetics # cc-3121) + supplements (Clonetics # cc-4133). VEGF R &S Systems (# 293-VE050) μg / ml strain in PBS lonomycin Sigma (# 1-0634) 10 mM DMSO Strain Histain Sigma (# H-7125) 10 mM DMSO Strain Thrombin Sigma (# T-6884) 1000 undiads / ml Strain from PBS Bovine Insulin Strain Gibco / BRL (# 13007-018) and dH2O Cell Culture HUVEC: 1. Thaw a vial of HUVEC cells within 10 ml of complete EC medium in a tissue culture dish (Falcon # 25-3003) . 2. The next day, the medium is withdrawn by aspirate, fed back. 3. 3-4 days later, once the plate is 80-90% confluent, divide the cells. 4. Dilute Trypsin / EDTA (Gibco / BRL # 252000-056) 1: 5 in 1X PBS without calcium or magnesium (Gibco / BRL # 14190-144). 5. Leave on cells that have been rinsed once in PBS, for 1 -2 minutes. Tap the plate against the end of the hook to release cells. 6. Divide into 4 100 mm of TC plates. 7. 3-4 days later, expand in 4-6 flasks of 4-6 T150 cm2 (Corning # 430825). 8. Divide every 3-4 days, a T150 in 5-6 TI50cm2. 9. Use only by passage 10 after defrosting. Labeling Fluo4 / AM Cells: 1. Rinse 1X PBS cells. 2. Add 5 ml of Versene per flask. 3. Allow the cells to detach at room temperature, 3-5 minutes. 4. Add the pH A Regulator to cells at twice the cell volume. 5. Count cells using the Tripane Blue Exclusion method, you need 1x106 cells / ml. 6. Calculate the number of my necessary dye and cells turned down. It is resuspended at 1x106 cells / ml in 5 uM of Fluo4 / AM + 0.025% of P127. 7. Remove at RT 20 minutes 8. Add equal volume of pH B regulator, incubate at RT for 10 minutes. 9. Centrifuge at 1000 rpms for 5-10 minutes. 10. Extract by vacuum. 1 1. The cells can be washed 1X in pH C Regulator before the addition of the FACS pH Regulator. HUVECS does not tolerate this additional stage and can be excluded, without causing increased background problems. 12. Resuspend 1x106 cells / ml in FACS pH Regulator. Place 1 ml in Falcon # 35-2025. 5 ml polystyrene, round bottom tubes to be read in FACS machine. 13. The cells are "alive" and will only last for about an hour, therefore everything has been organized and the FACSscan machine will warm up while the cells are labeled. 14. Read using the Becton Dickinson FACscan machine with Cellquest software using a density plot against time.

Intracellular Calcium Flow Test (by FACS): 1. The FACSscan machine (BEckton Dickenson) must be turned on to heat 10-20 minutes before use. 2. Check the level of the pH regulator before start, a container of full pH regulator is recommended and a waste container is emptied. 3. Fluo4 has an emission similar to FTTC, so it reads in FL1 at -350 nm. 4. Once the FACS machine has been formed from a density diagram (fluorescence versus time), start reading the controls. Specifics for KDR VEGF 50 ng / ml Non-specific Yonomicin 10 μM Histamine 10 μM Thrombin 1 unit Bovine Insulin 500 μg / ml . For test compounds, make dilutions of the 10 mM DMSO strain within pH A Regulator, just before the experiment. Add the compound to the tube during a 5-minute pre-incubation before taking a background reading of 10-15 seconds. Add VEGF and read for 3 minutes. If the compound is inhibited, a change as with VEGF alone will not be observed. Make a dose titration until no inhibition is observed. 6. The specificity test was done by adding the compound, in a concentration that gives complete inhibition, simultaneously with each non-specific stimulant. Then, it is tested by adding VEGF reading for 2.5-3 minutes, until peak flow is observed; add the compound, in a concentration that gives complete inhibition; read for 2-3 minutes, then add Yonomicin to see if the cells can still flow calcium.

PDGF-ß Cellular Assay Protocol Means: cDMEM = DMEM + 10% HI-FBS + 1% Hepes + 1% L-glutamine + 1% non-essential amino acids + 1% sodium pyruvate • Form plaque cells N IH / 3T3 @ 3x105 cells / well in a 12 well plate (costar # 3513) and incubate overnight @ 37 ° C / 5% CO2. • The next day, remove serum from the cells by aspirating the media from plates and replacing it with pre-warmed cDMEM (37 ° C) without FBS and incubated for one hour at 37 ° C / 5% CO2. • Make dilutions of the desired drug in DMEM + 1% DMSO, ensuring 1 ml of each dilution for cell cover. • After serum suppression, add 1 ml of dilutions in serum to each well and incubate cells with drug for 30 minutes @ 37 ° C / 5% CO2. • During the incubation prepare lysis pH regulator: 50 ml of RIPA base (keep on ice) 500 μl 100 mM of vanadate 500 μl 100 mM of NaF 50 μl 1 mg / ml of Leupeptin 50 μl 1 mg / ml of A-protinin 50 μl 1 mg / ml of Pepstatin A 500 μl of PMFS (add just before lysis) • Thaw PDGF-BB (Prepotech # 100-14B 2 μg) (This is done at 10 μg / ml in 200 μl 10 mM acetic acid). For each well, 100 ng / ml (5 μl of previous solution) is needed. • After the drug incubation, add 5 μl / well of PDGF-BB and incubate @ 37 ° C / 5% CO2 for 10 minutes. • Carefully remove the media from the wells and add 500 μl of lysis pH regulator. Mix on ice for 30 minutes. • Place the lysates in Eppendorf tubes and centrifuge them @ 14,000 rpm for 20 minutes. • Place 150 μl of the protein in new Eppendorf tubes and place a total volume of 500 μl (can store @ -20C and continue later). • Pre-rinse: For each tube add 30 μl of G protein / agarose and mix @ 4 ° C for 30 minutes. • Centrifuge at 14,000 rpm for 2 minutes @ 4 ° C. Place the supernatant in new Eppendorfs and add 10 μl of IP antibody. (Santa Cruz SC-432 polyclonal rabbit PDGFR-ß) and mix @ 4 ° C for 2 hours (or overnight). • Add 50 μl of G protein / agarose to each tube and mix for 2 hours (or overnight) • Wash beads x3 q 14,000 rpm, 2 minutes, 4 ° C with 800 μl of PBS + 1 mM of vanadate + Sigma cocktail Pl (in 50 ml of PBS add 500 μl of 100 mM of vanadate and 500 μl of cocktail Sigma Pl) • After the last wash add 50 μl of 5x sample buffer and heat the samples @ 95 ° C for 5 minutes • Centrifuge q 14, 000 rpm, 2 minutes, 4 ° C and the supernatant is transferred to new Eppendorfs (this can be stored at -20 ° C until the gels are ready to activate). • Activate 10 μl of each sample in 8-16% Tris-glycine gels (Novex 1.5 mm, 15 well)), activate the duplicate gles to check the equal load. Activate @ 40 mA per gel for -1.5 hours using Novex 1 x activation pH regulator. • Balance the gels within the transfer pH regulator: 1600 ml MeOH 800 ml 10x tris-glycine 5600 ml H2O • Transfer onto nitrocellulose membrane ECL hybond for 1 hour @ 100 volts / 4 ° C • Blockade at night @ 4 ° C stain block PDGF-B in 5% milk / PBST Stain block p-Tyr in 3% BSA / PBST • Rinse stains 2x quickly and 5x for one hour in PBS / 0.1% tween-20 • Primary antibody : p-Tyrblots-4g 10-HRP (quantity determined by the number of lots in 10 ml of PBST (Upstate Biotech # 16-105) PDGF-β-use spots PDGFR-β from Santa Cruz (SC-432) -use -10 μl in 10 ml of PBST per spot • Incubate primary antibody for one hour at room temperature, gently swinging • Wash 5x for one hour in PBST • Secondary antibody: PDGF-β stains - Use H RP of anti-rabbit IgG Amersham (NA # 934) 1 uL in 10 ml of PBST per spot p-Tyr- without maintaining the necessary secondary balancing in PBST • Incuba r in secondary antibody for one hour at room temperature, gently rocking. • Wash 5x for one hour in PBST • Develop using ECL Detection Equipment CSF1 Cell ELISA Protocol -R Day # 1 Cell Plate Formation: form 25,000 clone 5.5 cells in plates (see Nature (1986) 320, 277- 80) per well in 96-well round bottom plates Costar # 3799 in 150 μl / well of growth medium. 2 cell plates are needed per set of compounds that are tested. The medium is DMEM + 10% FBS + 1% L-glutamine + 1% HEPEs + 500 μg / ml G418. Formation of antibody plates: Form 1 μg / well of Encogen GR12L (anti-cfms / rat monoclonal antibody CASF1 R) in 150 μl of Na Pierce carbonate (# 28382) / bicarbonate pH9.0 pH regulator. It can be coated overnight at 4 ° C in refrigeration or 1 hour at 37 ° C in the incubator.

Day # 2 Formation of antibody plates: wash using the TECAN plate washer (in 2047) in PBST (PBS + Tween 20 from an average kitchen inside the house). Add 200 ul of 5% N FDM (defatted milk powder, Carnation) in PBS to block the plate, incubating at RT until ready to add the lysate. It can be incubated overnight at 4 ° C under refrigeration. Formation of the drug plate 2X: Prepare a drug plate for every 2 cell plates. Dilute the compounds in DMEM + 1% DMSO (aka medium).

Working the Strain (WS) is 200 μM which is a 1: 5 dilution of 10 mM DMSO strain. Serial Dilution Scheme: Medium 20 μl WS + 180 μl = 20 μM Medium 20 μl 20 μM + 180 μl = 2 μM Medium 20 μl 2 μM + 180 μl = 0.2 μM Medium 20 μl 0.2 μM + 180 μl = 0.02 μM Medium 20 μl 0.02 μM + 180 μl = 0.002 μM 2XMCSF (R &D Systems 216-MC): 200 ng / ml is the necessary concentration. 200 cavities x 25 μl / cavity = 5 ml 5 ml x 200 ng / ml = 1000 mg = 1 μg Therefore 1 μg of MCSF in the middle of 5 ml is added 25 ul / well to both cell plates. Sampling Protocol: Removal media from plates, vacuuming with plate washer when discarding the medium inside the sink. Add 25 μl / well from 2X Drug Plate. Incubate 20 minutes. 37 ° C in incubator. Add 25 μl / well 2X MCSF, incubate 10 minutes at 37 ° C. Add 50 μl / well of Lysis pH regulator (see below) Wash antibody X2 plate with plate washer in PBST. Add 170 μl of combined cell lysate (combine 100 ul of each plate into one of the cell plates) to the washed antibody plate. Incubate 2 hours at RT. Wash the 5X plate in PBST. To detect p-Tyr: Add 150 μl / well of antibody 4G10-Biotin (Upstate # 16- 103) diluted 1: 2000 in PBS. Incubate 1.5 hours at RT. Wash x5 in PBST. Add 150 μl / well of Streptavidin-HRP (Upstate # 18-152) diluted in PBS. Incubate 1 hour, TA. Add 100 μl / well of the Improved Blue-K Substrate (Neogen # 308177). The color reaction is blue. Read the plate at 650 nm until the control wells (+) read 0.6 OD Add 100 μl of 1 M Phosphoric Acid (Sigma # P6560). Read the tach at 450 nm. Lysis pH Reagent Lysis Pierce pH Regulator (Extraction Reagent Mammalian Protein M-PER # 78501). Add just before use: for 10 ml Final Conc. 100 mM PMSF (diluted in EtOH) 100 μl 1 mM (Sigma P7626) 1 mg / ml Aprotinin (Sigma A3428) 10 μl 1 μg / ml 1 mg / ml Pepstatin (Sigma P5318) 10 μl 1 μg / ml 1 mg / ml Leupeptin (Sigma L9783) 10 μl 1 μg / ml 100 mM Na orthovanadate (Sigma S9265) 100 μl 1 mM 100 mM Na fluoride (Sigma S7920) 100 μl 1 mM 10 mg / nl DNase ( Sigma D4527) 10 μl 1 μg / ml Cell assay of C-kit 1. 2 x 107 H526 cells (SCLC; ATCC) were removed from serum overnight in 0.1% Fetal Calf Serum (Premium) 2. It was incubated with dilutions of the compounds for one hour (except two controls). 3. It was stimulated with SCF (Stem Cell Factor, R &D cat # 255-SC) @ 250 ng / ml for 10 minutes (including a control). 4. Cell lysates were immunoprecipitated with 1 DC3 @ 10 μg / mg protein. 5. Immune complexes were harvested using Protein G + agarose beads, (100 μl). 6. 8% Tris glycine gels were used for protein separation. 7. Protein transferred in membrane (PVDF or Nitrocellulose) using 40 volts for 2 hours. 8. The membrane is blocked in 3% BASA in 1X PBS. 9. The Western blot was made using an anti-C-kit (1: 500; AF332 SCFR anti human from R &D Systems) as a primary antibody and anti-goat (1: 2000) as a secondary antibody for detection of the C-kit protein. 4G10 as an anti-phosphotyrosine (1: 5000) as a primary antibody and anti-mouse (1: 10000) as a secondary antibody for the detection of phosphorylation. The stains were developed using a chemo-luminescent Lumiglo kit of cellular signaling. The Western blot of C-kit uses KDR-Kit Chimera The cKit-KDR cells are formed on plates @ 0.5 X 106 in 6-well plates. The next day the cells were suppressed from serum in 0.1% FCS in DMEM overnight. The following day the compound was added for one hour 50 ng / ml of added VEGF for 30 minutes Protein lysates made Protein assays done Western transfers activate 20 μg / vial. Antibodies used: Fosfo c-kit (Tyr71) catalog number 3391 (1: 500) Cell signaling technology Flk-1 / KDR // VEGFR2 anti Human mouse catalog number RDI- FLKl Eabmx Research Diagnostics, Inc. (1: 500) In vitro homogeneous time-resolved fluorescence kinase (HTRF) assay in vitro (mathis.G., HTRF (R) Technology, J Biomol Screen, 1999, 4 (6): p.309-314) : For example, the purified enzyme was mixed with 4 μM of N-biotinylated substrate (for example, poly (Glu Tyr)) and various concentrations of the inhibitor in reaction pH buffer (50 M H EPES, pH 7.0, 10 mM MgCl 2, 2 mM MnCl 2, 0.1% BSA and 1 mM DTT, 40 L final volume). The quinaa reaction was initiated by the addition of ATP (1 mM final concentration) in a 96-well black plate (Packard). After 30-60 minutes of incubation at room temperature, the reaction was quenched by the addition of an EDTA solution regulated in its pH (approximate final concentrations: 30 mM EDTA, 0.1% BSA, 0.1% Triton X- 100 and 0.24 M of KF) and a solution of revealing agents (pair give 0.084 ng / well of streptavidin-XL-665 (Cis-Bio) and 6.5 ng / well of antiphosphotyrosine mAb pT66-K of Europinium kriptate) was added to the reaction mixture. The quenched reaction was allowed to stand at room temperature for 3 hours and then read in a time resolved fluorescence detector (Discovery, Packard) at 620 nm and 665 nm simultaneously. A 337 nm nitrogen laser was used for excitation. The relation between the signal of 620 nm and 665 nm was used in the calculation of the IC50. More specific details for the various enzymes are included later: PH regulator MOPSO pH regulator: HEPES pH regulator: 50 mM MOPSO pH 6.5 50 mM HEPES pH7.1 2.5 mM DTT 2.5 mM 10 mM DTT 10 mM MgCl2 2 mM MgCl2 10 mM MgCl2 0.01% BSA 0.01% BSA 100 μM Na3VO 100 μM Na3VO4 Peptide Substrates Bio-fgfr (Biotin-Ahx-AEEEYFFLFA-amide) Peptide Bio-Ick (Biotin-Ahx-GAEEIYAAFFA-COOH) Bio-PGT purchased from CIS- bio One well contains a total of 40 μl reagents Enzyme ELISA Protocol PDGFRβ ELISA plates (single-layered high-cost 96-well costar plate # 3369 EIA / RIA) pre-coated with anti-PDGFRβ antibody 0.0625 μg / well (Santa Cruz # SC-432) are washed four times in TPBS then blocked with 2% milk powder in PBS. After blocking, the plates were stained dry. 30 μl of 0.667 ng / μl of PDGFR enzyme (20 ng / final well) is added together with 20 μl of drug solution in concentrations ranging from 200 μM to 0.0128 μM. The drug samples are diluted in 20% DMSO with Reaction pH regulator (50 mM Hepes pH 7.1, 100 mM MgCl2, 20 mM MnCl2, 2.5 mM DTT, 0.01% BSA, 0.1 mM Vanadate sodium). The enzyme and the drug solution are incubated for 30 minutes. 30 μl of 2.67 mM ATP (1 mM final) is added to start the reaction. After 8 minutes, the reaction was stopped with 20 μl of 0.5 M EDTA pH 7.9 and the plates are incubated for an additional 1.5 hours at room temperature. The lacquers are washed four times with TPBS. 100 μl of anti-phosphotyrosine HRP conjugate antibody diluted 1/1000 in 2% milk / PBS is added to wells and the plates are incubated for one hour at room temperature. The plates are washed four times with TBPS, then 100 μl of K-Blue substrate is added to wells. 10 μl of 2N sulfuric acid is added after 10 minutes and the OD is determined at 450-570 nm. The background OD from the minor PDGFRβ control is subtracted from all data, and the data is converted to percent activity by division by OD of PDGFRβ samples lacking the inhibitor. The values of 1C50 are determined by adjusting the percentage of activity against the data of inhibitory concentration established to the Percent of Activity = 1 / (1 + [lj7IC5o) by adjustment of curve of less-averages-nonlinear squares.

In vivo models of T Cell Activation The in vivo efficacy of the compounds can be tested in known animal models to directly measure T cell activation or for which T cells have demonstrated effectors. T cells can be activated in vivo by ligation of the constant portion of the T cell receptor with a monoclonal anti-CD3 antibody (Ab). In this model, BALB / c mice are given 10 μg of anti-CD3 Ab intraperitoneally two hours before bleeding. The animals receiving a test drug were pre-treated with a single dose of the compound one hour before the administration of anti-CD3 Ab. The serum levels of interferon-? of proinflammatory cytokines (I FN-?) and tumor necrosis factor-a (TNF-a), T cell activation indicators, are measured by ELISA. A similar model employs T cell priming with a specific antigen such as keyhole limpet hemocyanin (KLH) followed by a secondary in vitro stimulation of lymph node drainage cells with the same antigen. As in the above, the measurement of cytokine production is used to evaluate the activation state of the cultured cells. In brief, C57BL / 6 mice are immunized subcutaneously with 100 μl of KLH emulsified in complete Freund's adjuvant (CFA) on day zero. Animals were pre-treated with the compound one day before immunization and subsequently on days one, two and three after immunization. The draining lymph nodes are harvested on day 4 and their cells cultured at 6 x 106 per ml in tissue culture medium (RPMl 1640 supplemented with heat inactivated fetal bovine serum (Hyclone Laboratories) 5 x 10"5 M 2-mercaptoethanol and 0.5% DMSO) for both twenty-four and forty-eight hours.The culture supernatants are then evaluated for interleukin-2 (IL-2) of the T cell growth factor and / or IFN-α levels. by ELISA The compounds can also be tested in animal models of a human disease, exemplified by experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), EAE models which mimic aspects of multiple sclerosis in humans. have been described in both rats and mice (reviewed FASEB J.5: 2560-2566, 1991; murine model; Lab. Invest. 4 (3): 278, 1981), rodent model; J. Immunol 146 (4): 1 163-8, 1991). Briefly, mice or rats are immunized with an emulsion of myelin basic protein (MBP) or neurogenic peptide derivatives thereof and CFA. Acute disease can be induced with the addition of bacterial toxins such as Bordetella pertussis. Recurrence / remission disease is induced by adoptive transfer of T cells from animals immunized with MBP / peptide. The CIA can be induced by DBA / 1 mice by immunization with type II collagen (J. Immunol: 142 (7): 2237-2243). Mice develop signs of arthritis as previously as ten after stimulation of the antigen and can be classified as many as ninety days after immunization. In both EAE and Cia models, a compound can be administered either prophylactically or at the time of onset of the disease. Effective drugs should reduce the severity and / or incidence. Certain compounds of this invention which inhibit one or more of the angiogenic PTK receptor, and / or a protein kinase such as Ick involved in mediating inflammatory responses can reduce the severity and incidence of arthritis in these models. The compounds can also be tested in mouse allograft models, either skin (reviewed in Ann. Rev. Immuno., 10: 333-58, 1992; Transplantation: 57 (12): 1701-17D6, 1994) or heart (Am. J. Anat.: 113-273, 1963). In brief, full-thickness skin grafts are transplanted from C57BL / 6 mice to BALB / c mice. Grafts can be examined daily, beginning on day six, for evidence of rejection. In the mouse neonatal heart transplant model, the neonatal hearts are ectopically transplanted from C57BL / 6 mice into the ear foliole of adult CBA / J mice. Hearts begin to throb four to seven days after transplantation and rejection can be assessed visually using a dissection microscope for the cessation of pulsation.

Cellular Receptor PTK Assays The following cellular assay was evaluated to determine the level of activity and the effect of different compounds of the present invention on KDR / VEGFR2. Similar receptor PTK assays employing a specific ligand stimulus can be designed along the same lines for other tyrosine kinases using techniques well known in the art. Phosphorylation of KDR Induced by VEGF in Human Umbilical Vein Endothelial Cells (H UVEC) as measured by Western transfers: 1. HUVEC cells (from pooled donors) were purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer's directions. Only previous passages (3-8) were used for this trial. Cells were grown in 100 mm plates. (Falcon for tissue culture; Becton Dickinson; Pymouth, England) using complete EBM media (Clonetics). 2. To evaluate an inhibitory activity of the compound, they were trypsinized and plated at 0.5 x 1.0 x 10 5 cells / well in each well of 6-well cluster plates (Costar, Cambridge, MA). 3. 3-4 days after sowing, the plates were 90-100% confluent. The medium was removed from all wells, the cells were rinsed with 5-10 ml of PBS and incubated 18-24 hours with 5 ml of EBM base medium without added supplements (ie, serum suppression). 4. Dilutions or serial inhibitors were added in 1 ml of EBM medium (final concentration of 25 μM, 5 μM or 1 μM to cells and incubated for one hour at 37 ° C.) The recombinant human VEGF165 (R & D Systems ) was then added to all the wells in 2 ml of EBM medium in a final concentration of 50 ng / ml and incubated at 37 ° C for 10 minutes.The control cells not treated or treated with VEGF were only used to evaluate phosphorylation of background and induction by VEGF phosphorylation All cavities were then rinsed with 5-10 ml of cold PBS containing 1 nM of sodium orthovanadate (Sigma) and the cells were dissolved and scraped in 200 μl of pH regulator RIPA (50 mM of Tris-HCl) pH7, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA) containing protease inhibitors (1 mM PMSF, 1 μg aprillin / ml, 1 μg pepstatin / ml, 1 μg / ml leupeptin, 1 mM Na vanadate, 1 mM Na fluoride) and 1 μg / ml Dnase (all of which of Sigma Chemical Company, St. Louis, MO). The lysate was centrifuged at 14,000 rpm for 30 minutes to remove the core. Equal amounts of protein were then precipitated by the addition of cold ethanol (-20 ° C) (2 volumes) for a minimum of 1 hour or a maximum overnight. The granules were reconstituted in a Laemli sample pH buffer containing 5% -mercaptoethanol (BioRad, Hercules, CA) and boiled for 5 minutes. The proteins were re-analyzed by polyacrylamide gel electrophoresis (6%, 1.6 mm, Novex, San Diego, CA) and transferred onto a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), the proteins were examined overnight with polyclonal anti-KDR antibody (C20, Anta Cruz Biotechnology; Santa Cruz CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology , Lake Placid, NY) at 4 ° C. After washing and incubation for 1 hour with F (ab) 2 conjugated with HRP of goat-anti-rabbit IgG or goat-anti-mouse bands were visualized using the emission chemiluminescence system (ECL) (Amersham Life Sciences, Ariington Height , IL). Certain examples of the present invention significantly inhibit KDR tyrosine kinase phosphorylation induced by VEGF at concentrations of less than 50 μM.

Uterine Edema Model In vivo This test measures the ability of the compounds to inhibit the acute increase in uterine weight in mice which occurs in the first hours after estrogen stimulation. This early onset of uterine weight gain is known to be due to edema caused by increased permeability of the uterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993), Í33; 829-837J demonstrated a close temporal relationship of uterine edema stimulated by estrogen with increased expression of VEGF mRNA in the uterus. These results have been shaped by the use to neutralize monoclonal antibody to VEGF which significantly reduces the acute increase in uterine weight after the estrogen stimulation (WO 97/42187). Therefore, this system can serve as a model for in vivo inhibition of VEGF signaling and associated hypermeability and edema. Materials: All hormones were purchased from Sigma (St.

Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to the supplier's instructions. Vehicle components (DMSO, Cremaphor EL) were purchased from Sigma (St. Louis, MO). Mice (Balb / c, 8-12 weeks of age) were purchased from Taconic (Germantown, NY) and were housed in a pathogen-free animal facility in accordance with the Guidelines of the Animal Use and Care Committee. Method: Day 1: Balb / c mice were given an intraperitoneal (i.p.) injection of 12.5 units of serum gonadotropin for pregnant mare (PMSG). Day 3: Mice received 15 units of human chorionic gonadotropin (hCG) i.p. Day 4: Mice were randomized and divided into groups of 5-10. Test compounds were administered by i.p., i.v. or p.o. depending on the solubility and vehicle in doses ranging from 1 -100 mg / kg. The vehicle control group received only vehicle and two groups were left untreated. Thirty minutes later, the experimental groups, vehicle and one of the untreated ones were given an i.p. of 17-estradiol (500 g / kg). After 2-3 hours, animals were sacrificed by CO2 inhalation. After a midline incision, each uterus was isolated and removed by cutting just below the cervix and in the connections of the uterus and the oviducts. Fat and connective tissue were removed with care without altering the integrity of the uterus before weight (wet weight). The uterus was dyed to remove the fluid by pressing between two sheets of filter paper with a one liter glass bottle filled with water. The uterus was weighed after staining (spotted weight). The difference between wet and spotted weights was taken as the fluid content of the uterus. The average fluid content of irate groups was compared to treated or untreated vehicle groups. Transcendence was determined by Student's test. The unstimulated control group was used to monitor the estradiol response. The results demonstrate that certain compounds of the present invention inhibit the formation of edema when administered systemically by several routes. Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases may also be known to be active in a Matrigel implant model of neovascularization. The Matrigel neovascularization model involves the formation of new blood vessels within a clear marble of extracellular matrix implanted subcutaneously which is induced by the presence of the proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al., Lab. Investig. (1992), 67 (4), 519-528; Anat. Rec. (1997), 249 (1), 63-73; Int. J. Cancer (1995), 63 (5), 694-701; Vasc. Biol. (1995), 15 (11), 1857-6). The model is preferably activated for 3-4 days and the endpoints include macroscopic visual / imaging of neovascularization, microscopic microvessel density determinations, and hemoglobin quantification (Drabkin method) following removal of the implant against controls from animals not treated with inhibitors. The model can alternatively use bFGF or HGF as the stimulus. Certain compounds of this invention which inhibit one or more oncogenic, protooncogenic or proliferation-dependent protein kinases, or angiogenic receptor PTK inhibit the growth of murine, rat or primary human xenograft tumors in mice, or inhibit metastasis in murine models. EXAMPLES ABREVIATU RAS Boc fer-Butoxycarbonyl Dba dibenzylidene acetone DCM Dichloromethane DEAD Diethyl Azodicarboxylate DIAD Diisopropyl Axodicarboxylate DME 1,2-Dimethoxyethane DMF? /,? / - Dimethylformamide EtOAc Ethyl acetate Ms Methansulfonyl NMP? / - Methylpyrrolidin-2-one r.t. room temperature TBAF Fer-Butylammonium Fluoride TEA Triethylamine THF Tetrahydrofuran Ts for-Toluenesulfonyl PROCEDURES GENERAL AND EXAMPLES Most of the following examples are ordered according to the last final general procedure used in their preparations. Synthetic routes to any novel intermediaries are listed by sequentially listing the general procedures (key letter) in parentheses after their name. A solved example of this protocol is given later. The analytical data is defined either within the experimental conditions or the tables of examples. Unless otherwise stated, all 1 H or 13 C NMR data were collected on Varian Mercury plus 400 MHz or a Broker DRX 400 MHz, chemical changes are quoted in parts per million (ppm). The liquid chromatography of high pressure, the analytical data are detailed either within the experimental or referenced to the table of HPLC conditions using the lowercase letter method in parentheses (Table 1).

Table 1. List of HPLC methods GENERAL NON-SPECIFIC ROUTES The synthetic schemes that were used to construct the majority of the compounds included in this application are described below (Schemes 1-3). Scheme 1. General synthetic routes to pyrrolo [2,3-c /] pyrimidyl aminobenzoxazoles through a final stage aminolysis reaction (General procedures are observed in parentheses).

Scheme 2. General synthetic routes to pyrrolo [2,3-o '] pyrimidyl and pyrazolo [3,4-d] pyrimidyl aminobenzoxazoles through a final phase aminobenzoxazole formation (General procedures are observed in parentheses) Boronate Formation (D) Amhobenzaxazole (E, F, and H) Synthetic Processing of the Substitute (W, K, L,, N, PQ, S, T, U, VW? Y? AA, BB.CC, DD. EE) Scheme 3. General synthetic routes to pyrrolo [2,3-d] pyrimidiio and pyrazolo [3,4-d] pyrimidyl amidobenzoxazole through a Suzuki coupling reaction of the final stage. (General procedures are observed in parentheses).

Buttonalo faith formation (D) Aplnabepzaxazol (E, F, and H) Synthetic elaboration of the Eus8tuyßnlB O.J.K.MÍ.N.PAS.T.U.V.WXVPZ ^ W.BB.CC.DD.YEE) LIST OF GENERAL PROCEDURES General Procedure A: Mitsunobu coupling of a pyrazolo [3,4-cf] pyrimidine or pyrroIo [2,3-d] pyrimidine with an alcohol. General procedure B: Aminolysis of chloropyrimidine General procedure C: Suzuki coupling of halide with a boronate ester or boronic acid General procedure D: Conversion of a bromide to a borate General procedure E: Cyclization of an aminoalcohol to a benzoxazole General procedure F: Nitration of phenols General procedure G: Transformation of an aniline to an aminobenzoxazole General procedure H: Reduction of a nitroaromatic compound to an aniline General procedure I: Alkylation of nucleophile based on nitrogen General procedure J: Reductive coupling of an amine with a ketone Procedim General K: Ketalization of a Ketone General Procedure L: Removal of a Boc Protection Group General Procedure M:? - lactam alkylation General procedure N: Debenzylation of a benzyl ester compound General procedure O: Mitsunobu coupling of a pyrazolo [3,4-cf] pyrimidine or a pyrroium [2,3-] pyrimidine with an alcohol using a phosphine source attached to resin. General procedure P: Ester hydrolysis General procedure Q: EDC coupling of an acid with an amine General procedure R: Boc protection of an amine General procedure S: a-Alkylation of hydroxyalkyl carboxylate. General procedure T: Desq ueta lization of a protected cyclohexanone General procedure U: Reduction of ketone or ester to an alcohol General procedure V: Mesylation of an alcohol and subsequent displacement of the mesylate group General procedure W: Acylation of an amine with an acid chloride, sulfonyl chloride or an anhydride. General procedure Y: O-alkylation of an alcohol General procedure Y: Synthesis of 2,5-diketopiperazine General procedure Z: Synthesis of homoketopiperazine General procedure AA: Carbonilative cyclization of diamines and amino alcohols General procedure BB: Synthesis of quetomorfoline General procedure CC: Deprotection of a silyl protected alcohol General procedure DD. Synthesis of a trifluoromethyl ether General procedure EE: Oxidation of a sulphide to a sulphoxide or a sulfone General procedure FF: Ring closure to form substituted aminobenzoxazoles in a one-step protocol.

EXAMPLE RESOLVED USING GENERAL PROCEDURES The letter of the key of the general procedure constitutes a synthetic route to the final product. A solved example of how the route is determined is given later using Example # 1 as the legal precedent. The synthesis of Example # 1 was completed using general procedure B as detailed in Table 2, that is, prepared using US 6001839 C (F, H, G, D) In this case, the chloropyrimidine starting material, Compound A, was prepared using the route US 6001839, C (F, H, G, D) (as detailed in Table 2). This is translated in the following sequence, in which the reagent used in general procedure C is the product of the following procedures F, H, G and D, so these steps are designated in additional parentheses.

General Procedure D General Procedure A: M itsunobu coupling of a pyrazolo [3,4-d] pyrimidine or pyrrolo [3,4-d] pyrimidine with an alcohol A mixture of pyrazolo [3,4-d] pyrimidine or pyrrolo [2, 3-d] pyrimidine (preferably 1 equivalent), an alcohol (1-5 equivalents, preferably 3 equivalents), a phosphine (for example, triphenylphosphine) (1-5 equivalents, preferably 3 equivalents) and an azodicarboxylate (eg example, diisopropylazodicarboxylate) (1-5 equivalents, preferably 3 equivalents) in an anhydrous solvent (preferably tetrahydrofuran) at about 0-100 ° C (preferably about 20 ° C) for about 0.5-24 hours (preferably 4 hours ) under an inert atmosphere. The solvent is removed under reduced pressure. The resulting residue is divided between an organic solvent and an aqueous solution. The organic layer is separated and the aqueous layer is further extracted with an organic solvent. The combined organic extracts are dried on a desiccant. The solvent is evaporated under reduced pressure to produce the product, which can be further purified by crystallization or chromatography.

Illustration of General Procedure A Preparation # 1: c / s-3-Iodo-1 - [4- (2-methoxyethoxy) -cidohexyl] -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine Preparation # 2 : Ira /? s-3-Iodo-1 - [4- (2-methoxyethoxy) -cycOhexyl] -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine To a solution of 3-iodo-1 r -pyrazolo [3,4-d] -pyrimidin-4-ylamine (0.626 g, 2.40 mmol) in anhydrous tetrahydrofuran was added triphenylphosphine (1.51 g, 5.76 mmol) and diisopropylazodicarboxylate (1.16 g, 5.76 mmole). The mixture was stirred for about five minutes at room temperature under a nitrogen atmosphere and 4- (2-methoxyethoxy) -cyclohexanol (JP 6122986, mixture of cis and trans isomers, 1.04 g, 5.98 mmol) was added. The reaction mixture was stirred at room temperature for about three hours. Tetrahydrofuran was removed under reduced pressure and the unpurified mixture was stirred in a mixture of acetone (15 ml) and aqueous hydrochloric acid (2 N, 15 ml) for two hours at room temperature. The acetone was removed under reduced pressure and the aqueous mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution so that the pH was about 8. The aqueous mixture was extracted with ethyl acetate (3 x 25 ml) and the The combined organic fractions were dried over anhydrous magnesium sulfate. The crude mixture was purified by flash column chromatography on silica gel using ethyl acetate as the mobile phase to give pure white solids of both trans-3-iodo-1- [4- (2-methoxyethoxy) -cyclohexyl] - 1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (200 mg, 0.480 mmol); 1 H NMR (DMSO-d 6), 400 MHz) 58.18 (s, 1 H), 4.59 (m, 1 H), 3.56 (dd, 2 H), 3.46 (dd, 2 H), 3.36 (t t, 1 H), 3.25 (s, 3H), 2.08 (d, 2H), 1.92 (m, 4H), 1.33-1.37 (qd, 2H); m / z: (M + H) + 418, and cis-3-iodo-1- [4- (2-methoxyethoxy) -cyclohexyl-1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (120 mg 0.288 mmole); 1 HN MR (DMSO-d6), 400 MHz) 68.18 (s, 1 H), 4.63 (tt, 1 H), 3.58 (t, 1 H), 3.52 (td, 2H), 3.50 (td, 2H), 3.29 (s, 3H), 2.15 (q, 2H), 1.95 (d, 2H), 1.61 (m, 4H); m / z: (M + H) + 418.

General Procedure B: Aminolysis of a Chloropyrimidine A mixture of a 4-chloro-5-iodo-7-pyrrolo [2,3-d-pyrimidine (preferably 1 equivalent) and aqueous ammonium hydroxide (28% ammonia by weight) was heated. (100-300 equivalents, preferably 300 equivalents) in dioxane in Parr mini-reactor at about 80-150 ° C (preferably about 120 ° C) for about 1 -48 hours (preferably about 12 hours). The mixture was allowed to cool to room temperature and the solvents are removed under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

Illustration of General Procedure B Preparation # 3: Ipsap-7- (4-Cyclopropylmethoxy-cyclohexyl) -5-iodo-7H-pyrroIo [2,3-d] pyrimidin-4-ylamine A mixture of frans-4-chloro-7- (4-cyclopropylmethoxy-cyclohexy!) - 5-iodo-7H-pyrrolo [2,3-d] pyrimidine (prepared by general procedures X, T, U and A was heated. ) (0.357 g, 0.00083 moles) in aqueous ammonium hydroxide (28% ammonia by weight, 15 ml, 0.247 moles, 298 equivalents) in dioxane (15 ml) in a Parr mini-reactor at approximately 120 ° C for approximately 12 hours. hours. The mixture was allowed to cool to room temperature and the solvents were removed under reduced pressure to give trans-7- (4-cyclopropylmethoxy-cyclohexyl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as a white solid (0.509 g, 0.00083 moles, containing ammonium chloride); LC / MS (30% to 95% acetonitrile / 0.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column, 120 A, 3 μm, 30 x 4.6 mm; Electrospray ionization method that observes both positive and negative ions) Rt 2.80 minutes; m / z: (M + H) +413. Other products obtained using general procedure B are shown (Table 2). The method used to determine the retention time H PLC is given in a lowercase letter in parentheses (see Table 1).

Table 2: Examples synthesized using general procedure B General Procedure C: Suzuki coupling of a halide with boronate ester or boronic acid A boronate ester or boronic acid mixture (1-5 equivalents, preferably 1.5 equivalents), a halide (for example, a bromide or a iodide, preferably an iodide) (preferably 1 equivalent) and a base (eg, sodium carbonate or cesium carbonate, preferably sodium carbonate) (1 -10 equivalents, preferably 2 equivalents) is heated in a mixture of an organic solvent (for example, ethylene glycol dimethyl ether,? /,? -dimethylformamide, or toluene, preferably ethylene glycol dimethyl ether) and water at about 20-120 ° C (preferably about 80 ° C). A palladium catalyst (for example, palladium acetate (ll), tris (dibenzylidene ketone) dipalladium (0), tetrakis (triphenylphosphine) palladium (Q), preferably 0.05 equivalents) is added and the reaction mixture is allowed to stir for approximately 1-48 hours (preferably about 12 hours) under an inert atmosphere. The mixture is allowed to cool to room temperature and the solvents are removed under reduced pressure. The residue is divided between water and an organic solvent, the organic layer is separated and the aqueous layer is further extracted with organic solvent. The combined extracts are dried on a desiccant. The solvents are evaporated under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

Illustration of General Procedure C Example # 3: c / s-. { 4- (4-. {4-Amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl}. -cyclohexyl)} -1-methyl-piperazin-2-one To a mixture of c / s-. { 4- [4- (4-amino-3-iodo-pyrazolo [3,4-djpyrim idin-1-yl] -cyclohexyl]} -1-methyl-piperazin-2-one (prepared using general procedures A, T and J (employing a ketopiperazine described in US Pat. No. 4,251,438)) (80 mg, 0.18 mmol) (5,7-dimethyl-benzoxazole- 2-yl) - [4- (4,4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) phenyl] -atin (G, D) (80 mg, 0.22 mmol) and carbonate sodium (47 mg, 0.44 mmol) in N, N-dimethylformamide (4 ml) and water (2 ml) was added tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.017 mmol), at room temperature, under one atmosphere of nitrogen. The reaction mixture was heated to about 80 ° C for about 16 hours. The mixture was allowed to cool to room temperature and the solvents were removed under reduced pressure. The residue was partitioned between water (25 ml) and dichloromethane (25 ml), the organic layer was separated and the aqueous layer was further extracted with dichloromethane (2 x 2 ml). The combined organic extracts were dried over magnesium sulfate, then evaporated under reduced pressure. The residue was purified by flash column chromatography on silica using a dichloromethane / methanol / ammonium hydroxide mixture (28-30% solution) (95: 4.95: 0.05) as the mobile phase to give cis-. { 4- (4- { 4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) ~ phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl] -cyclohexyl )} -1-methyl-piperazin-2-one as a white solid (56.0 mg, 0.099 mmol), 1 H NMR (DMSO-d6, 400 MHz) d 10.85, 8.23, 7.92, 7.64, 7.11, 6.80, 4.81, 3.17, 3.07, 2.84, 2.72, 2.40, 2.35, 2.12-2.08 and 1.72-1.60; RP-HPLC (5% to 85% acetonitrile / O.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes at 1 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) R, 16.73 minutes. Other products obtained using general procedure C are shown (Table 3). The method used to determine the retention time of H PLC is given in lowercase letters in parentheses (see Table 1).

Table 3. Examples synthesized using general procedure C General Procedure D: Conversion of a bromide to a boronate A mixture of bis (pinaco! Ato) diboro (1-1.5 equivalents, preferably 1.3 equivalents), an aryl bromide (preferably 1 equivalent), adduct of dicioro dichloromethane [1, 1'-bis (diphenyphosphino) ferrocene] -palladium (II) (0.03-0.15 equivalents, preferably 0.10 equivalents) and a base (eg, sodium acetate or potassium acetate, preferably sodium acetate). potassium) (1.5-3.0 equivalents, preferably 2.5 equivalents) is heated in an organic solvent (eg,? /, V-dimethylformamide, dioxane or tetrahydrofuran, preferably? /,? / -dimethylformamide) to about 50 -100 ° C (preferably 80 ° C) for about 1 -24 hours (preferably 15 hours) under an inert atmosphere. The mixture is allowed to cool to room temperature, and the solvent is removed under reduced pressure. The solid residue can then be purified by flash column chromatography or crystallization.

Illustration of General Procedure D Preparation # 4: 2-Methyl-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-i!) - phenylamine A mixture of 4-bromo-2-methylaniline (0.2509 g, 1.34 mmol), bis (pinacolato) diboro (0.442 g, 1.747 mmol), dichloromethane adduct of 1,2-bis (diphenylphosphino) - ferrocen] palladium (II) (0.1 10 g, 0.134 mmol) and potassium acetate (0.329 g, 3.357 mmol) in / V, ?? -di methylphormamide (5 ml) at about 80 ° C for about 15 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and purified by flash column chromatography on silica gel using ethyl acetate / heptane (3: 7) as the mobile phase to give 2-methyl-4- (4.4, 5, 5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -phenylamine as a yellow oil (0.213 g, 0.914 mmol); RP-HPLC (25% to 100% acetonitrile / O.1 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 10 minutes at 1.0 ml / min;? = 254 nm; Hypersil C18 column, 100A, 5 μm, 250 x 4.6 mm) Rt 11.02 minutes.

General Procedure E: Cyclization of an amino alcohol to a benzoxazole An aminophenol (1-2 equivalents, preferably 1 equivalent) is added to a solution of an aryl isothiocyanate (1-2 equivalents, preferably 1 equivalent) in an organic solvent ( for example, tetrahydrofuran or pyridine) at about -40 to 50 ° C. The mixture is stirred at about 0 to 50 ° C for about 1-24 hours, 1- (3-dimethyaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1-2 equivalents, preferably 1 equivalent) is added to the reaction and the mixture is heated to about 40-80 ° C for about 1-24 hours (preferably 15 hours). The mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

Illustration of Route E General Preparation # 5: (4-Bromo-phenyl) - (5-chloro-benzoxazol-2-yl) -amine To a solution of 4-bromophenyl isothiocyanate (46.2 g, 0.216 mol) in tetrahydrofuran (750 ml) was added 2-amino-4-chlorophenol (31.0 g, 0.216 mol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (49.7 g, 0.259 mol) and the mixture was stirred at about 50 ° C for about 15 hours. The solvent was removed under reduced pressure and the residue was partitioned between 0.1 N aqueous hydrochloric acid (250 ml) and dichloromethane (300 ml). The resulting unpurified precipitate was collected by filtration and washed with water (200 ml). The remaining organic layer of the filtrate was separated and the aqueous layer was extracted with additional dichloromethane (2 x 200 ml). The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product (30 g) was then purified by flash column chromatography on silica using hepato / ethyl acetate (90: 10 to 75:25) as a mobile phase to produce (4-bromo-phenyl) - (5- chloro-benzoxazol-2-yl) -amine as a pink solid (15.8 g, 0.048 moles); RP-HPLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 10 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100A, 5 μm, 250 x 4.6 nm) Rt 12.984 min.

General Procedure F: Nitration of phenols A substituted phenol (preferably 1.0 equivalents) is dissolved in an organic solvent (for example, diethyl ether and ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether) and the resulting solution is cooled to about -60 °. C (preferably about -50 ° C). Nitronium tetrafluoroborate (1-2 equivalents, preferably 1.02 equivalents) is added and the reaction mixture is gradually heated to room temperature while stirring under a nitrogen atmosphere for about 2-96 hours. The organic solvent is removed under reduced pressure and the residue can be further purified by chromatography or crystallization.

I lustration of General Procedure F Preparation # 6: 5-Bromo-2-hydroxy-3-nitrobenzonitrile -Bromo-2-hydroxybenzonitrile (5.04 g, 0.0254 mol) was dissolved in ethylene glycol dimethyl ether (60 ml) and the resulting solution was cooled to about -55 ° C. Nitronium tetrafluoroborate (3.58 g, 0.0259 mol) was added immediately and the reaction mixture was gradually warmed to room temperature while stirring under continuous nitrogen flowing for about 24 hours. Ethylene glycol dimethyl ether was removed under reduced pressure and the residue was passed through a pad of silica gel (40 g) eluting with ethyl acetate (800 ml). Ethyl acetate was removed under reduced pressure and the residue was triturated with cold ether (15 ml). The precipitate was collected by filtration and dried to yield 5-bromo-2-hydroxy-3-nitrobenzonitrile (3.30 g, 0.0136 mol) as a yellow solid; m / z: (M-H) "241 and 243.

General Procedure G: Transformation of an aniline to an aminobenzoxazole To an aniline solution (preferably 1 equivalent) in an organic solvent (for example, dichloromethane, acetonitrile or pyridine, preferably pyridine) at about 0-25 ° C (preferably 25 ° C) was added to the thiocarbonyl (for example 1,1'-thiocarbonyldi-2 (1 H) -pyridone or 1,1'-thiocarbonyl-dimidazole, preferably 1,1'-thiocarbonyldiimidazole (1-5 equivalents, preferably 1.05 equivalents) for about 0.5-2 hours (preferably about 1 hour), and the mixture was stirred at about 0-50 ° C (preferably about 25 ° C) for about 1 -5 hours (preferably about 2 hours) A 2-aminophenol (1-2 equivalents, preferably 1 equivalent) is added to the reaction mixture and stirred for about 1 -12 hours (preferably 2 hours) at about 0-50 ° C (preferably about 25 ° C.) Carbodiimide is added (preferably 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (1-5 equivalents, preferably 1.2 equivalents) to the reaction and the mixture is stirred at about 25-70 ° C (preferably about 50 ° C). ) for approximately 1 -48 hours (preferably approximately 12 hours). The mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is divided between an aqueous acidic solution and an organic solvent, the organic layer is separated and the aqueous layer is further extracted with an organic solvent. The combined organic extracts are dried on a desiccant. The solvents are evaporated under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

Illustration of General Procedure G Preparation # 7: (4-bromo-2-f luoro-f-enyl) - (5,7-d i -methyl-benzoxazol-2-yl) -amine To a solution of 4-bromo-2-fluoroaniline (5 g, 26.3 mmol) in pyridine (150 ml) at room temperature was added 1, 1'-thiocarbonyldiimidazole (4.92 g, 27.6 mmol). The reaction was stirred, under a nitrogen atmosphere, for about 1 hour. 2,4-Dimethyl-6-aminophen (3.61 g, 26.3 mmol) was added to the reaction mixture and the mixture was stirred at room temperature, under nitrogen, for an additional 45 minutes. The pyridine was removed from the reaction mixture under reduced pressure. The residue was incorporated in acetonitrile (200 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (6.05 g, 31.6 mmol) was added, and the mixture was stirred at room temperature for about 20 hours, before being heated to about 60 ° C for about 5 additional hours. The acetonitrile was removed under reduced pressure and the residue was taken up in ethyl acetate (100 ml), then washed with 0.5N hydrochloric acid (4 x 100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The crude product was triturated in hot methanol to yield (4-bromo-2-fluoro-phenyl) - (5,7-dimethyl-benzoxazol-2-yl) -amine as a pink solid (4.24 g, 12.6 mmol); 1 H NMR (DMSO-d6), 400 MHz) d 10.51, 8.28, 7.60, 7.47, 7.07, 6.79, 2.38, 2.33; RP-HPLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5 for 10 minutes at 1 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm , 250 x 4.6 mm) Rt 10.36 minutes. Other products obtained using the general procedure G are shown (Table 4). The method used to determine the HPLC retention time is given in lowercase letters in parentheses (see Table 1).

Table 4. Examples Synthesized using the general procedure C General Procedure H: Reduction of a nitroaromatic compound to an aniline A mixture of a nitroaromatic compound (preferably 1 equivalent), sodium dithionite (1 -10 equivalents, preferably 4 equivalents), ethylviologen dibromide (0-1 equivalent, preferably 0.04 equivalents) and potassium carbonate (0) is heated. -5 equivalents, preferably 5 equivalents) in a mixture of an organic solvent (preferably ethanol or dichloromethane) and water at about 20-80 ° C (preferably about 60 ° C) for about 1-120 hours (preferably about 2 hours) under an inert atmosphere. The mixture is allowed to cool to room temperature and the organic solvent is removed under reduced pressure. The resulting aqueous mixture is extracted with an organic solvent. The organic layer is separated and washed with saturated brine solution. The retained organic layer is then dried on a desiccant. The solvent is evaporated under reduced pressure to produce the product that can be easily used or further purified by crystallization or chromatography.

Illustration of General Procedure H Preparation # 8: 3-Amino-5-bromo-2-hydroxy-benzonitrile A mixture of 5-bromo-2-hydroxy-3-nitro-benzonitrile (prepared using general procedure F) (4.01 g, 16.5 mmol) and sodium dithionite (15.5 g, 66 mmol) in a mixture was heated. of ethanol (200 ml) and water (100 ml) at about 60 ° C for about 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and the organic solvent was removed under reduced pressure. The aqueous mixture was extracted with dichloromethane (200 ml). The organic extracts were combined and washed with saturated brine solution (100 ml). The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-amino-5-bromo-2-hydroxy-benzonitrile as an oxidized pink solid (2.14 g, 10.0 mmol): RP-H PLC (5% to 95% acetonitrile / 0.05M of aqueous ammonium acetate, regulated in its pH to pH 4.5, for 10 minutes at 1.7 ml / min;? = 254 nm; Column Hypersil C18, 100 μA 5 μM, 250 X 4.6 mm) R, 8.5 min; 11 H NMR (400 MHz, DMSO-dβ),) d 6.99 (1 H, s) and 6.92 (1 H, s).

General Procedure I: Nitrogen-based Nucleophile Alkylation A mixture of an alkylating agent, such as mesylate, tosylate, chloride, iodide or bromide, preferably mesylate (1 -15 equivalents, preferably 1 equivalent), a nucleophile based on nitrogen (preferably 1 H-pyrazolo [3,4-d] pyrimidine or a JH-pyrrolo [2,3-d] pyrimidine) and a base (for example, sodium carbonate, sodium hydride, potassium carbonate or sodium carbonate) cesium, preferably sodium carbonate) (1 -10 equivalents, preferably 1.5 equivalents) is heated in an organic solvent (for example, ethylene glycol dimethyl ether,? /,? / - dimethylformamide, 1-methyl-2-pyrrolidinone, or sulfoxide dimethyl, preferably? /,? / - dimethylformamide) at 20-130 ° C (preferably about 100 ° C) for 1-60 hours (preferably about 30 hours) under an inert atmosphere. The mixture is allowed to cool to room temperature and the contents are poured into ice water. The organic layer is separated and the aqueous layer is further extracted with an organic solvent. The combined organic extracts are dried on a desiccant. The solvents are evaporated under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

An Illustration of General Procedure I Preparation # 9: 3- (4-Amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -azetidin-1-carboxylic acid fer-butylester H, C CH, A mixture of 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine (2.68 g, 0.0103 mol), 3-methanesulfonyloxy-azetidine-3-methanesulfonyloxy acid-butylester is heated -carboxylic (described in patent WO 02/080926 A1) (2.58 g, 0.0103 moles) and cesium carbonate (4.36 g, 0.0134 moles) in? /,? / - dimethylformamide (40 ml) at about 90 ° C for about 48 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature then poured into ice water (30 ml) and extracted with 5% methane / dichloromethane (2 x 200 ml). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a stannous solid. The solids were dissolved in dichloromethane and the solution was cooled to about 0 ° C. After 16 hours the resulting precipitation was collected and dried to produce 3- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -zetidine-1-carboxylic acid tert-butylester. as a white solid (2.022 g, 0.00486 moles); RP-HPLC (30% to 95% acetonitrile / O.01 M aqueous sodium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 3.6 mm, electrospray ionization method observing both positive and negative ions) Rt 2.28 min; m / z (M + H) + 417. Other products obtained using general procedure I are shown (Table 5). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 5. Examples synthesized using the general procedure I General Procedure J: Reductive coupling of an amine with a ketone A mixture of (3-20 equivalents, preferably 1 equivalent), an amine (or an amine salt) (1-4 equivalents, preferably 3 equivalents) and acetic acid was stirred. (preferably 4 equivalents) in a mixture of organic solvents (preferably 1,2-dichloroethane and 1-methyl-2-pyrrolidinone) at room temperature for about 2 hours under a nitrogen atmosphere. Then a reduction reagent (preferably sodium triacetoxyborohydride) was added (1.5-14 equivalents, preferably 1. 5 equivalents) and the mixture was stirred at room temperature for about 12 hours to 7 days (preferably about 12 hours). The mixture was quenched with a basic aqueous solution (for example, a solution of saturated aqueous sodium bicarbonate) and extracted with organic solvent. The combined organic extracts were dried on a desiccant. The solvents were evaporated under reduced pressure to provide the product that can be further purified through crystallization or chromatography.

Illustration of General Procedure J Preparation # 10: fraps-. { 4- [4- (4-amino-5-iodo-pyrrolo [2J3-d] pyrimidin-7-yl) -cyclohexyl] -1-methyl-piperazin-2-one} A mixture of 4- (4-amino-5-iodo-pyrrolo [2,3-d] pyrimidin-7-yl) -cyclohexanone (prepared by the general procedures A and T) (17.6 g, 47.2 mmol) was stirred, 4-methyl-3-oxo-piperazin-1 -io monotrifluoroacetate (44.03 g, 193 mmol) and acetic acid (1.05 mL, 193 mmol) was stirred in a mixture of 1,2-dicyoroethane (1000 ml) and 1-methyl-2-pyrrolidinone (50 ml) at room temperature for about 2.5 hours under a nitrogen atmosphere.

Then, sodium triacetoxyborohydride (15,337 g, 72.4 mmol) was added in one portion and the mixture was stirred at room temperature for approximately 12 hours. The mixture was quenched with saturated aqueous sodium carbonate solution until pH > 7 and extracted with dichloromethane / methanol (95: 5, 1000 ml). The combined organic extracts were dried over magnesium sulfate. Dichloromethane and methanol were evaporated under reduced pressure to yield a solid which was purified by flash column chromatography on silica using a gradient of methanol / ethyl acetate / triethylamine (1: 98: 1 to 7:92: 1) as a mobile phase to give fraps-. { 4- [4- (4-amino-5-iodo-pyrrolo [2,3-d] pyrimidin-7-yl) -cyclohexyl] -1-methyl-piperazin-2-one} as a white solid (5.07 g, 11 mmol). 1 H NMR (DMSO-d6, 400 MHz) d 8.08.7.35, 6.51, 5.76, 4.49, 3.29, 3.12, 2.73, 2.45, 1.90, 1.18; RP-HPLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 4.6 mm, electrospray ionization method observing both positive and negative ions) Rt 1.37 min; m / z: (M + H) + 455. Other products obtained using the general procedure J are shown (Table 6). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 6. Examples synthesized using the general procedure J General Procedure K: Cetalization of a Ketone A mixture of a ketone (preferably 1 equivalent), a butanediol (1 -50 equivalents, preferably 20 equivalents), and p-toluenesulfonic acid (0.05-1 equivalents, preferably 0.2) is heated. equivalents) in an organic solvent (preferably toluene) at about 50-120 ° C (preferably at reflux temperature) for 1-10 days (preferably 5 days) under an inert atmosphere. The aqueous by-product is removed (preferably in a Dean-Stark trap filled with activated molecular sieves (3A bead, 4-8 mesh)). The mixture was allowed to cool to room temperature. The solvent is removed under reduced pressure to produce the unpurified product, which can be further purified by distillation, chromatography or crystallization to produce the product.

Illustration of General Procedure K Example # 265:? V2- (4- { 4-amino-1 - [(2ft, 3fl) -2,3-dirnethyl-1,4-dioxaspire [4.5] dec-8 -M] -1 Hp -razolo [3,4-d] pyrimidin-3-yl.] Phenyl) -557-dimethyl-1,3-benzoxazole-2-amine A mixture of 4- (4-amino-3- { 4 - [(5,7-dimethyl-1,3-benzoxazol-2-yl) amino] f en il.} -1-pyrazolo [3 , 4-d] piri mid in-1-yl) -1-cyclohexanone (prepared using general procedures A, T and C) (0.40 g, 0.86 mmol) (r?, /?) -1,2-butanediol ( 0.29 g, 3.22 mmoles) and p-toluenesulfonic acid monohydrate (0.03 g, 0.16 mmol) was heated in toluene (30 ml) under reflux for 5 days, during which time the water was collected in a Dean-Stark trap filled with molecular sieves. (pearl 3A, mesh 4-8). Additional (R, R) -, 2-butanediol (0.87 g, 9.66 mmol) was required for the reaction to reach completion. The reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. The resulting unpurified product was purified by flash chromatography on silica using a gradient of 0% -3% methanol (containing 2% 28% aqueous ammonia) in dichloromethane as the mobile phase to produce N2- (4- { 4-amino-1- [(2R, 3R) -1,2-dimethyl-1,4-dioxaspiro [4, 5] dec-8-yl] -1 H-pyrazoo [3,4-d] pyrimidin-3 -H-Phenyl) -5,7 '-dimethyl-1,3-benzoxazole-2-amine (0.276 g, 0.51 mmol) as a white solid: RP-HPLC (5% to 95% acetonitrile / 0.05 M acetate) aqueous ammonium, regulated in pH at pH 4.5, for 10 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 12.13 min; m / z (M + H) + 540. Other products obtained using the general procedure K are shown (Table 7). The method used to determine the HPLC reaction time is given in a lowercase letter in parentheses (see Table 1).

Table 7: Examples synthesized using the general procedure K General Procedure L: Removal of a Boc protection group A mixture of fer-butyl carbamate (1-1.5 equivalents, preferably 1 equivalent), an organic solvent (eg, 1,4-dioxane or dichloromethane, preferably dichloromethane) and an acid (5-40 equivalents, preferably 20 equivalents) (for example hydrochloric acid or trifluoroacetic acid, preferably trifluoroacetic acid) is mixed at about 0-60 ° C (preferably about 25 ° C) for about 1 -24 hours (preferably about 14 hours) under an inert atmosphere. The mixture is neutralized with an aqueous base (such as sodium carbonate or potassium carbonate, preferably sodium carbonate). The organic layer is separated and the aqueous layer is further extracted with an organic solvent. The combined organic extracts are dried on a desiccant. The solvents are evaporated under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

I lustration of General Procedure L Example # 268: 7-Azetidin-3-yl-5- [4- (5,7-dimethyl-benzoxazol-2-ylammon) -phenyl] -7H-pyrrolo [2,3- d] pirimdin-4-iamine A mixture of 3- acid fer-butylester. { 4-amino-5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-yl} -zetidin-1-carboxylic acid (prepared by general procedures I and C) (1.23 g, 0.002336 moles) and trifluoroacetic acid (1.81 ml, 0.023 moles) was mixed in dichloromethane (18 ml) at room temperature for 24 hours under one atmosphere of nitrogen. The mixture was diluted with aqueous sodium carbonate, the organic layer was separated and dried on a desiccant. The precipitate in the aqueous layer was collected and combined with the organic phase. The solvent was removed under reduced pressure to yield 7-azetidin-3-yl-5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine. -4-ilamine as a stannous solid (1.00 g, 0.00235 moles); RP-H PLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate for 4 minutes at 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 4.6 mm, electrospray ionization method observing both positive and negative ions) Rt 2.13 min; m / z (M + H) + 427.

Other products obtained using the general procedure L are shown (Table 8). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 8: Examples synthesized using the general procedure L General procedure : ? - lactam alkylation The amine functionality of an amine lactam (1-2 equivalents, preferably 1 equivalent) is acylated with an appropriate protection group (eg, di-fer-butyl bicarbonate) (1-2 equivalents, preferably 1.05 equivalents) in tetrahydrofuran at room temperature for 1-24 hours (preferably about 15 hours). The solvent is removed under reduced pressure and the resulting residue is washed with an organic solvent (for example, heptane or ethyl acetate). The residue is dissolved in an organic solvent (for example, a mixture of tetrahydrofuran and? /,? / - dimetha! Formamide) and treated with a base (eg, sodium hydride) (1-2 equivalents, preferably 1 .5 equivalents) at room temperature for about 0.5-12 hours (preferably 1 hour), then an alkyl halide (1-4 equivalents, preferably 1.05 equivalents) (eg, iodomethane) is added. The reaction mixture is stirred at about 0.75 ° C (preferably at room temperature) for about 1-24 hours (preferably 15 hours). The solvent is removed and the extractive development produces a product that can be further purified by chromatography. The protection group in the amine functionality is removed (for example, the removal of the Boc group is detailed in the general procedure L) to produce the product or the salt of the product which can be further purified by crystallization or chromatography.

Illustration of the General Procedure Preparation # 11: 4-methyl [1,4] diazepan-5-one monotrifluoroacetate Di-fer-butyl bicarbonate (3.162 g, 0.01447 mol) was added to a suspension of [1,4 Jdiazepan-2-aone (1.562 g, 0.01338 mol) in tetrahydrofuran (90 ml) and the mixture was stirred at room temperature for approximately 15 hours. The solvent was removed under reduced pressure. The residue was washed with ethyl acetate to give 5-oxo- [1,4] diazepane-1-carboxylic acid fer-butylester as a white solid (2.866 g, 0.01338 mol). The solid was dissolved in a mixture of tetrahydrofuran (80 ml) and N, N-dimethylformamide (30 ml) and sodium hydride (60% dispersion in mineral oil, 0.849 g, 0.0212 mol) were added. After about 1 hour, iodomethane was slowly added to the reaction mixture. The mixture was stirred at room temperature for about 15 hours, then the solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous ammonium chloride solution (100 ml) and dichloromethane. The organic layer was separated and the aqueous layer was further extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate. The solvent was evaporated under reduced pressure to leave a dark brown solid which was purified by flash column chromatography on silica gel using ethyl acetate as a mobile phase to give 4-methyl-5-oxo-tert-butyl ester - [1,4] Dizepan-1-carboxylic acid as a white solid (2.70 g, 0.0122 mol). The solid was dissolved in dichloromethane (20 ml), the solution was cooled to 0 ° C, and trifluoroacetic acid (10 mm, 0.1298 mol) was added. The reaction mixture was allowed to warm to room temperature. The solvent was evaporated under reduced pressure to produce 4-methyl- [1, 4] diazepan-5-one monotrifluoroacetate as a brown oil (2962 g, 0.01223 mol); 1 H N M R (DMSO-d 6, 400 MHz) d 3.64 (m, 2 H), 3.23 (m, 4 H), 2.89 (s, 2 H), 2.74 (m, 2 H).

General Procedure N: Debenzylation of the benzyl ether compound A mixture of benzylether (preferably 1 equivalent) and palladium on carbon (10% by weight) (0.01 -0.50 equivalents, preferably 0.10 equivalents) in an organic solvent is stirred (e.g., ethanol, ethyl acetate, ethylene glycol dimethyl ether, or toluene, preferably ethanol) under a hydrogen atmosphere at about 20-120 ° C (preferably about 20 ° C) for about 1 -48 hours (preferably 12 hours). The mixture is filled through a column of Celite which is washed with additional organic solvent. The solvent is removed under reduced pressure to give the desired product which can be further purified by crystallization or chromatography.

Illustration of General Procedure N Preparation # 12: c / s-4- (2-Cyclopropoxy-ethoxy) -cyclohexanol A mixture of c / s- [4- (2-cyclopropoxy-ethoxy) -cyclohexyloxymethyl-benzene (prepared by general procedure X) (0.580 g, 0.0020 mol) and palladium on carbon (10% by weight (0.212 g) was stirred. , 0.10 equivalents) in ethanol (25 ml) under an atmosphere of hydrogen at about 20 ° C for about 12 hours, then filtered through a column of Celite.The solvent was removed under reduced pressure to give cis-4- ( 2-cyclopropoxy-ethoxy? '-cyclohexanol (0.441 g, 0.0020 moles); 1 H NMR (DMSO-d6, 400 MHz) d 3.74, 3.64-3.66, 3.55-3.57, 3.44, 3.35, 1.76-1.88, 1 .63 -1 .68, 1 .55-1 .59, 0.58-0.59, 0.45-0.46; TLC (dichloromethane / ethyl acetate = 4: 1) Rf 0.10.

General Procedure O: M itsunobu coupling of a pyrazolo [3,4-d] pyrimidine or a pyrrolo [253-d] pyrimidine with an alcohol using a resin-bound phosphine source. A mixture of pyrazolo [3,4-d] pyrimidine or pyrro! Or [2,3-djpirim idine (preferably 1 equivalent), an alcohol (1-5 equivalents, preferably 2 equivalents), a resin-bound phosphine ( 1-5 equivalents, preferably 2.2 equivalents) and an azodicarboxylate (for example, diisopropylazodicarboxylate (1-5 equivalents, preferably 2.2 equivalents) is stirred in an anhydrous solvent (for example, tetrahydrofuran) at about 0-100 ° C (from preferably about 20 ° C) for about 1 -48 hours (preferably about 2 hours) under an inert atmosphere.The unpurified mixture is filtered through a pad of Celite to remove the resin-bound phosphine reagent. it is collected and the solvent is removed under reduced pressure to produce the unpurified product which can be further purified by crystallization or chromatography.

Illustration of General Procedure O Preparation # 13. 1 - (2-fIuoro-1-fluoromethyl-ethyl) -3-iodo-1 H-pyrazoium [3,4-d] pyrimidin-4-ylamine A mixture of 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine (0.1250 g, 0.958 mmol) and triphenylphosphine bound to polystyrene (0.7 g, 3 mmol phosphine / g resin, 2.10 mmol) were added. charged to a reaction vessel equipped with a magnetic stir bar. The flask was flushed with nitrogen, and anhydrous tetrahydrofuran (10 ml) and diisopropylazodicarboxylate (0.424 g, 2.10 mmol) were added. 1,3-Difluoro-2-propanol (0.182 g, 1.89 mmol) was added and the mixture was stirred for about 2 hours at room temperature. The crude mixture was then filtered through a pad of Celite and the solid was washed with tetrahydrofuran (3 x 3 mL). The filtrate was concentrated under reduced pressure to give 1- (2-fluoro-1-fluoro-methyl-ethyl) -3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-ylamine; RP-HPLC (5% -95% acetonitrile / O.05 M ammonium acetate for 10 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 5 μm, 100 A, 250 x 4.6 mm) Rt 7.92 min; m / z: (M + H) +340.

General Procedure P: Ester Hydrolysis A ester (preferably 1 equivalent) and a base (lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide) are heated in a water mixture (1 -3 equivalents, preferably 1.2 equivalents) and an organic solvent (for example, methanol or dimethyl sulfoxide, preferably methane) at about 50-100 ° C (preferably about 60 ° C) for about 1 -24 hours (preferably about 12 hours) ). After cooling to room temperature, the volatile solvents are removed under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

Illustration of General Procedure P Example # 272. acid fra? s-4-. { 4-Amino-3- [4- (5) 7-dimethyl-benzoxazole -2-i i -no) -f -enyl] -pyrazole or [3,4-d] pyrimidin-1 -i 1.}. -1-ethyl-cyclohexanecarboxylic A solution of trans-4-ethyl ester was heated at about 100 ° C for about 15 hours. { 4-amino-3- [4- (5, 7-dimethyl-benzoxazol-2-ylammo) -phenyl] -pyrazolo [3,4-] pyrimidin-1-yl} -1-ethyl-cyclohexanecarboxylic acid (prepared by the general procedures S, A and C) (3.94 g, 7.13 mmol) in aqueous potassium hydroxide (1 N, 16.4 ml, 16.4 moles) and dimethyl sulfoxide (20 ml). The reaction mixture was cooled to room temperature and aqueous hydrochloric acid (1 N, 20 ml, 20 mmol) was added to produce a precipitate. The solid was filtered, rinsed sequentially with water, and ether, and dried under vacuum to yield trans-4- acid. { 4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pt-razol [3, 4-d] pi rimidin-1 -i l} - 1-ethyl-cyclohexane carboxylic acid as an orange solid; RP-HPLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 4.6 mm, electrospray ionization method observing both positive and negative ions) Rt 2.28 min; m / z (M + H) + 526. Other products obtained using the general procedure P are shown (Table 9). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 9. Examples synthesized using the general procedure P Procedure Generally Q: Coupling EDC of an acid with an amine A mixture of a carboxylic acid (preferably 1 equivalent), an amine (free base or salt) (preferably an amine) (1-5 equivalents, preferably 3) equivalents), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1-3 equivalents, preferably 1.3 equivalents) and a hydroxybenzotriazole (1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole, preferably 1-hydroxy) -7-azabenzotriazole) (1 -1.5 equivalents preferably 1 equivalent) is stirred in an organic solvent (dichloromethane or N, N-dimethylformamide, preferably?,? / - dimethylformamide) at about 20 ° C-60 ° C (from room temperature preference) for about 15-48 hours (preferably about 15 hours). The solvent is evaporated under reduced pressure, and the mixture is extracted from water with an organic solvent. The organic extracts are dried on a desiccant, evaporated and the product can be further purified by crystallization or chromatography.

Illustration of the General Procedure Q Example # 275. fra /? S- (4- { 4-Amino-3- [4- (5,7-dimethyl-benzoxazol-2-i lam i) -f in il] -pyrazolo [3,4-d] piri mid in-1 -i I.} -1 -eti I-cyclohexy I) -morfoIin-4-ii-methanone To a solution of the acid f / "a /? S-4- { 4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazzo [3J 4-d ] pyrimidin-1-yl.] -1-ethyl-cyclohexanecarboxylic acid (example # 272, 3.74 g, 7.13 mmole) in N, N-dimethylformamide (50 ml) was added 1- (3-dimethylaminopropyl) -3- hydrochloride. ethylcarboiimide (1.85 g, 9.65 mmol), morpholine (2.79 ml, 32.0 mmol) and 1-hydroxy-7-azabenzotriazole (0.97 g, 7.13 mmol) The mixture was stirred at room temperature for approximately 15 hours. stirring under reduced pressure, and the product was extracted from water with methanol / ethyl acetate (1: 9) .The organic fractions were dried over magnesium sulfate, filtered and concentrated.The product was purified by column chromatography. instant silica gel pretreated with triethylamine, using methanol / dichloromethane (1:24) as the mobile phase, to produce trans s- (4-. {4-amino-3- [4- (5, 7- dimethyl-benzoxazol-2-yla mi no) -f-enyl) -phenyl] -piraz olo [3,4.}. dJpyrimidin-1-il} -1-ethyl-cyclohexyl) -morpholin-4-yl-methanone as a yellow solid (1.2 g, 2.04 mmol). RP-HPLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 4.6 mm; electrospray ionization method / * / observing positive and negative ions) Rt 3.03 min; m / z (M + H) + 595. Other products obtained using general procedure Q are shown (Table 10). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 10. Examples synthesized using the general procedure Q General Procedure R: Boc protection of an amine To a solution of the amine (preferably 1 equivalent) in an organic solvent (for example, (dioxane / water or tetrahydrofuran) in the absence or presence of a base (e.g. sodium, cesium carbonate, preferably sodium carbonate) (1-5 equivalents, preferably 2.4 equivalents) is added di-fer-butyldicarbonate (1-5 equivalents, preferably 1.2 equivalents) The reaction mixture is stirred at approximately 0-50 ° C (preferably about 25 ° C) for about 1 -48 hours (preferably about 12 hours) The organic solvent is removed under reduced pressure The residue is divided between water and an appropriate organic solvent, the layer The organic layer is separated and the aqueous layer is further extracted with an organic solvent.The combined organic extracts are dried over a desiccant.The solvents are evaporated under reduced pressure to produce the product which can additionally by crystallization or chromatography.

Illustration of General Procedure R Preparation # 14. (f?) - 3-h? droxi-piperidin-1-carboxylic acid-butylester To a solution of (?) - 3-hydroxypiperidine hydrochloride (10.3 g, 0.075 mol) in dioxane / water (80 ml each) was added di-fger-butyldicarbonate (20 g, 0.091 mol) and sodium carbonate (19 g, 0.182 mol). The mixture was stirred at room temperature for approximately 16 hours. The organic solvent was removed under reduced pressure and the aqueous layer was extracted with diethylether (3 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried over magnesium sulfate, and the solvent was removed under reduced pressure to produce (R) -3-hydroxy-piperidine-1-carboxylic acid tert-butylester (15.1 g, 0.075 moles) as a colorless oil; m / z (M + H) + 202.

General Procedure S: a-Alkylation of a hydroxyalkyl carboxylate A mixture of hydroxyalkyl carboxylate (preferably 1 equivalent), a silylating agent (fer-butyldimethylsilyl chloride or triethylsilyl chloride, preferably tert-butyldimethylsilyl chloride) (1 -3 equivalents, preferably 1 .15 equivalents), a base (imidazole or triethylamine, preferably imidazole) and a catalyst (pyridine or 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine) (0.01 to 1.0 equivalents, preferably 0.04 equivalents) they are stirred in an organic solvent (dichloromethane or? /,? / - dimethylformamide, preferably N, N-dimethylformamide) at room temperature for about 1-24 hours (preferably 15 hours). The solvent is removed under reduced pressure, and the product is extracted from water with an organic solvent. The organic extracts are dried on a desiccant and concentrated to produce the silyl ether which can be further purified by chromatography. The resulting silyl ether (preferably 1 equivalent) is dissolved in an organic solvent (ether or tetrahydrofuran, preferably tetrahydrofuran) and enolized with a strong base (preferably lithium diisopropylamide) (2-4 equivalents, preferably 2.5 equivalents) to about -78 to 25 ° C (preferably 0 ° C). An alkyl halide (preferably methyl iodide or ethyl iodide) (1-10 equivalents, preferably 3.5 equivalents) is added and the reaction is stirred at about -78 to 25 ° C (preferably about 25 ° C) during about 2-24 hours (preferably about 4 hours). The solvents are removed under reduced pressure and the alkylated ester can be further purified by chromatography. The alkylated ester (preferably 1 equivalent) is mixed with a fluoride source (potassium fluoride or tetrabutylammonium fluoride, preferably tetrabutylammonium fluoride) (1-2 equivalents, preferably 1.2 equivalents) in an organic solvent (preferably tetrahydrofuran) ) at about 0.50 ° C (preferably about 25 ° C) for about 1-24 hours (preferably about 15 hours). The solvent is removed under reduced pressure, and the product is extracted from water with an organic solvent, and can be further purified by chromatography or crystallization.

Illustration of General Procedure S Preparation # 15. ethylester of urae /? s-1-Ethyl-4-hydroxy-cyclic or hexan carboxylic acid A mixture of etii-4-hydroxycyclohexanecarboxylate (16.0 g, 92.9 mmol), fer-butyldimethylsilylchloride (16.1 g, 106.8 mmol) imidazole (8.41 g, 123.5 mmol) and 4-dimethylaminopyridine (0.453 g, 3.71 mmol) in? /? / -dimethylformamide (150 ml) was stirred at room temperature for about 15 hours. The solvent was evaporated under reduced pressure and the product was extracted from aqueous ammonium chloride using ether / petroleum ether (1: 1). The organic extracts were dried over magnesium sulfate and concentrated, and the residue was purified by flash column chromatography on silica gel using ether / petroleum ether (1: 14) as the mobile phase to produce ethyl ester of 5- ( fer-butyl-dimethyl-silyloxy) cyclohexanecarboxylic acid (25.8 g, 90.2 mmol) as a colorless oil; m / z (M + H) + 287. An ice-cooled solution of the above compound (25.8 g, 90.2 mmol) in tetrahydrofuran (50 mL) was added to a solution of lithium diisopropylamide (225 mmol) in tetrahydrofuran (200 mL). ) at approximately -78 ° C. The mixture was stirred at about -78 ° C for about 1 hour, heated to about 0 ° C for about 5 minutes and cooled again to about -78 ° C. Ethyl iodide (25.2 ml, 316 mmol) was added via syringe, and the mixture was allowed to warm to room temperature. After 1 hour at room temperature, the excess base was quenched with aqueous ammonium chloride, and the volatile solvents were removed under reduced pressure. The product was extracted from water with ether and concentrated and purified by column chromatography on silica gel, using ether / petroleum ether (1: 15) as the mobile phase to produce ethyl ester of 4- (ferric) acid. butyl-dimethyl-silyloxy) -1-ethyl-cyclohexanecarboxylic acid (27.3 g, 86.9 mmol) as a colorless oil. The above product (27.3 g, 86.9 mmol) was mixed with a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 144 mL, 144 mmol) at about 0 ° C, and the reaction mixture was allowed to warm to room temperature for 15 minutes. hours. The tetrahydrofuran was removed under reduced pressure, and the residue was extracted from water (500 ml) with ether (5 x 500 ml). The combined organic extracts were dried over magnesium sulfate and concentrated. The product was purified by flash column chromatography on silica gel, using ether / petroleum ether (4: 1) as the mobile phase to produce trans-1-ethyl-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (17.39 g, 87.0 mmoles) as a colorless oil; 1 H NMR (400 MHz, DMSO-d6) d: 4.45, 4.10, 2.05, 1.69, 1.41, 1.18, 1.11, 0.73.

General Procedure T: De-ketalization of a protected cyclohexanone A mixture of 1,4-dioxa-spiro [4.5] decane 8-substituted (preferably 1 equivalent) and an acid (for example, hydrochloric acid, sulfuric acid, oxalic acid or trifluoroacetic acid, preferably oxalic acid) (1 -10 equivalents, preferably 3 equivalents) is heated in a mixture of water and an organic solvent (for example, acetone, ethanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, toluene or a mixture of the listed solvents, preferably tetrahydrofuran / water 2: 1) at about 0 ° C-120 ° C (preferably about 70 ° C) for about 1 -48 hours (preferably 6 hours). The solvent is removed under reduced pressure. The residue is divided between an aqueous solution and an organic solvent, the organic layer is separated and the aqueous layer is further extracted with organic solvent. The combined organic extracts are dried on a desiccant. The solvents are evaporated under reduced pressure to produce the desired product which can be further purified by crystallization or chromatography.

Illustration of General Procedure T Preparation # 16. 4- (4-Chloro-5-iodo-pyrrolo [253-tl] pyrimidin-7-yl) -cyclohexanone To a suspension of 4-chloro-7- (1,4-dioxa-spiro [4.5] dec-8-yl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidine (prepared by the general procedure A) (0.230 g, 0.0010 mol) in acetone (20 ml) at about 0 ° C, hydrochloric acid (6.0 M, 0.55 ml, 0.0033 mol) was added slowly through a dropping funnel. The reaction mixture was stirred at about 0 ° C for about 1 hour, at room temperature for about 25 hours. The additional hydrochloric acid (6.0 N, 0.25 ml, 0.0015 mol) was added and the reaction mixture was stirred at room temperature for an additional 3 days. The solvent was removed under reduced pressure, and the residue was washed with water. The resulting precipitate was filtered and washed with water (100 ml). Drying under reduced pressure yielded 4- (4-chloro-5-iodo-pyrrolo [2,3-d] -pi? Midin-7-yl) cyclohexanone (0.319 g, 0.0085 mol); H N MR (DMSO-d6 l 400 MHz) d 8,674, 8,167, 5,263, 2,710-2,777, 2,295-2,392, 2,086; RP-HPLC (30% to 95% acetonitrile / 0.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column, 120 A, 3 μm, 30 x 4.6 mm) Rt 2.80 min.

General Procedure U: Reduction of a Ketone or Ester to an Alcohol A reducing agent (sodium borohydride, lithium tri-sec-butylborohydride, lithium-aluminum hydride, or lithium triethylborohydride, preferably sodium borohydride, for ketones and lithium aluminum hydride for esters) (1 -10 equivalents, preferably 2 equivalents) is added in portions to a solution of a ketone or an ester (preferably 1 equivalent) in an organic solvent (methane or tetrahydrofuran, tetrahydrofuran preference) at about -78 ° C at room temperature (preferably at about -70 ° C). The reaction is stirred at room temperature for about 1 -72 hours (preferably about 2 hours) until it reaches completion. The excess reducing agent is quenched by the addition of a small amount of water. The resulting mixture is divided between an aqueous layer and an organic solvent. The organic phase is separated, washed with a saturated brine solution and dried over a desiccant. The solvent is then removed under reduced pressure to produce the unpurified product which can be purified by crystallization or chromatography.

Illustration of General Procedure U. Example # 310. fra /? s-4-. { 4-Amino-3- [4- (5,7-dimethyl-benzoxazole-2-Hamino-phenyl-pyrazoloyl S -d-pyrimidin-1-phenyl-cyclohexanol Example # 31 1. c s-4- { Amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -p? Razolo [3,4-d] pyrimidin-1-yl.} - cyclohexanol A mixture of 4- (4-amino-3- { 4 - [(5,7-dimetiI-1,3-benzoxazol-2-yl) amino] pheny1} -1 H-pyrazolo [3,4 -d] pyrimidin-1-yl) -1-cyclohexanone (0.15 g, 0.32 mmol) and sodium borohydride (0.015 g, 0.38 mmol) was stirred in methanol (10 ml) at room temperature for approximately 72 hours, during which the additional sodium borohydride (0.055 g, 1.45 mmol) was added in portions to drive the reaction to completion. The reaction was then quenched by the addition of water (0.1 ml), and the solvent was removed under reduced pressure. The unpurified solid was purified by flash chromatography on silica using a gradient of 0% -6% methanol (containing 2% of 28% aqueous ammonia) in dichloromethane as the mobile phase to produce a slower running fraction containing trans -4-. { 4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl} -hexanol cycle (0.053 g, 0.1 1 mmol) as a white solid; RP-HPLC (5% to 95% acetonitrile / O.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 10 minutes at 1 ml / min;? = 254 nm; Hypersil C18 column, 100 A , 5 μm, 250 x 4.6 mm) Rt 10.05 min; m / z (M + H) + 470.3; and a faster execution fraction containing cis-4-. { 4- amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d-pyrimidin-1-yl} -cyclohexane \ (0.023 g, 0.05 mmol) as a white solid; RP-HPLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 10 minutes at 1 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 10.29 min; m / z (M + H) + 470.3. Other products obtained using the general procedure U are shown (Table 11). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 1 1. Examples synthesized using the general procedure U General Procedure V: Extraction of an alcohol and the subsequent displacement of the mesylate group An alcohol (preferably 1 equivalent) is dissolved in a mixture of an organic solvent (preferably dichloromethane) and an organic base (sodium hydride, pyridine, preferably pyridine). Methanesulfonyl chloride (1-6 equivalents, preferably 1.6 equivalents) is added and the reaction mixture is stirred at about 10-60 ° C (preferably about 25 ° C) under continuous nitrogen flow for about 10-80 hours (preferably about 40 hours). The solvents are removed under reduced pressure and the residue is triturated with water. The precipitate is collected by filtration and washed with water. The precipitate is dried under reduced pressure and optionally purified by trituration, crystallization or chromatography. A mesylate (preferably 1 equivalent) is dissolved in an organic solvent (α / - methylpyridinidone, dimethyl sulfoxide or N, N-dimethylformamide, preferably? /? / - dimethylformamide) and an organic base (cesium carbonate, carbonate sodium or sodium hydride, preferably sodium hydride) (1-10 equivalents, preferably 5 equivalents) is added, followed by the addition of the nucleophile (1-10 equivalents, preferably 5 equivalents). The reaction mixture is heated to about 30-70 ° C (preferably about 55 ° C) for about 10-100 hours (preferably 24 hours) under continuous nitrogen fiow. The reaction mixture is concentrated under reduced pressure and the residue is purified by crystallization or chromatography.

Illustration of General Procedure V Preparation # 17: Irans-3-iodo-1- (4-pyrazol-1-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine Methanesulfonyl chloride (0.72 ml, 0.00930 mol) was added to a mixture of c / s-4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -cyclohexanol (2, 00 g, 0.00557 moles), dichloromethane (20 ml) and pyridine (20 ml). The reaction mixture was stirred at about * 25 ° C under continuous nitrogen flow for about 30 hours. The solvents were removed under reduced pressure and the residue was triturated with water (25 ml). The precipitate was collected by filtration, washed with water, dried under reduced pressure for 24 hours, placed on a glass filter, washed with ethyl acetate, and dried under reduced pressure for 24 hours to produce cis-4. - (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -cyclohexylmethanesulfonate (1.46 g, 0.003 mol) as an off-white solid; RP-HPLC (5% to 85% acetonitrile / 0.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes to 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) R t 12.14 min, cis-4- (4-Amino-3-iodo-pyrazolo [4,5-d] pyrimidin-1-yl) cyclohexyl methanesulfonate (0.68 g, 0.00156 moles) in? / ,? dimethylformamide (40 ml) and sodium hydride (60% dispersion in mineral oil, 0.31 g, 0.00764 mol) and pyrazole (0.53 g, 0.00778 mol) were added sequentially. The reaction mixture was heated to about 55 ° C for about 24 hours under continuous nitrogen flow. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to produce trans-3-iodo-1- (4-pyrazol-1-yl-cyclohexyl) -1H-pyrazolo [3,4-d] pyrimidine. -4-ylamine (0.152 g, 0.000371 moles) as a white solid; m / z (M + H) + 410.

General Procedure W: Acylation of an amine with an acid chloride, sulfonyl chloride and an anhydride. A mixture of an amine (1 -1.25 equivalents, preferably 1 equivalent), a base (e.g., pyridine, triethylamine or diisopropylamine, preferably triethylamine (1-5 equivalents, preferably 4 equivalents) and either an acyl chloride , sulfonyl chloride or an acid anhydride (1 -1.25 equivalents, preferably 1.04 equivalents) is stirred in an organic solvent (for example, dichloromethane or tetrahydrofuran, preferably dichloromethane) at about -10 ° to 50 ° C (preferably about 0 ° C) for about 2-10 hours (preferably about 5 hours). The reaction is quenched with an alcohol (for example, methanol or ethanol, preferably methanol) or water and the mixture is allowed to warm to room temperature. The solvents are removed under reduced pressure and the residue is optionally purified by chromatography or crystallization.

Illustration of General Procedure W Example # 313. 1 - (4-. {4-Amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl}. -piperidin -1 -il) -2-methyl ropan-1 -one To a mixture of 3- [4- (5,7-dimethylbenzoxazol-2-ylamino) -phenyl] -1-piperidin-4-yl-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine (0.0585, 0.13 mmol) and triethylamine (0.0547, 0.54 mmol) in anhydrous dichloromethane (2 ml) at about 0 ° C, a solution of isobutyryl chloride (0.0144 g, 0.135 mmol) in anhydrous dichloromethane (2 ml) was added and The resulting mixture was stirred for about 5 hours at about 0 ° C. Methanol (1 ml) was added and the resulting mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the residue was purified by preparative RP-H PLC driven by mass (25% to 75% acetonitrile / 0.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 7 hours). minutes at 25 ml / min, 100% acetonitrile for 2 minutes, 100% at 25% acetonitrile / O.05 M ammonium acetate for 1.5 minutes; column Hypersil BDS C18, 100 A, 5 μm, 100 x 21.2 mm ) to produce 1- (4-. {4-amino-3- [4- (5,7-di-methyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1 - I.) .piperidin-1-yl) -2-methypropan-1-one (0.043 g, 0.08 mmol) as a white solid; RP-HPLC (5% to 95% acetonitrile / 0.05 M ammonium acetate, regulated in its pH to pH 4.5, 3.5 minutes at 2 ml / min;? = 250-470 nm; Pecosphere C18 column, 3 μm, 33 x 4.6 mm, electrospray ionization method observing both positive and negative ones) Rt 2.8 min; m / z (M + H) + 525. Other products obtained using the general procedure W are shown (Table 12). The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 12. Examples synthesized using the general procedure W General Procedure X: O-alkylation of an alcohol A mixture of an alcohol (preferably 1 equivalent) and a base (eg, sodium hydride, sodium hydroxide, potassium hydroxide, or sodium, preferably potassium hydroxide) ( 1 -10 equivalents, preferably 4 equivalents) in an organic solvent (e.g., acetone, ethanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, or dimethyl sulfoxide, preferably dimethyl sulfoxide) is treated with an electrophilic compound (e.g., an alkyl bromide, iodide of alkyl, alkyl tosylate or an epoxide, preferably an alkyl bromide) (1-10 equivalents, preferably 3 equivalents) at about 0-120 ° C (preferably about 20 ° C)) for about 1 -48 hours (preferably 18 hours). The reaction mixture is divided between an aqueous solution and an organic solvent, the organic layer is separated, and the aqueous layer is further extracted with an organic solvent. The combined organic extracts are dried on a desiccant. The solvents are evaporated under reduced pressure to produce the desired product which can be further purified by crystallization or chromatography.

Illustration of General Procedure X Preparation # 18. c s-4- (2-Hydroxy-2-methypropoxy) -cyclohexanol 2,2-dimethyi-oxirane (4.69 ml, 0.0526 mol) was slowly added to a mixture of c / s-cyclohexane-1,4-diol (J. Org. Chem. 1962, 27, 4708-2709) (5.55 g). , 0.0478 moles) and potassium hydroxide (3.22 g, 0.0573 moles) in dimethyl sulfoxide (50 ml). The reaction mixture was heated to about 50 ° C for 18 hours. The solvent was removed under reduced pressure. Water (100 ml) was added and the aqueous layer was extracted with diethyl ether (6 x 75 ml), then dichloromethane (3 x 100 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate / dichloromethane (1: 1) as the mobile phase to produce cis-4- (2-hydroxy-2-methyl-propoxy) -cciohexane (3.55 g, 0.0189 moles); m / z 189 (M + H) +.

General Procedure Y: Synthesis of 2,5-Dicetopiperazine A mixture of a 2-halo-acetylaminoacetate (preferably 1 equivalent) and a primary amine (for example, methylamine, ethylamine, 2-propylamine) (1-10 equivalents, preferably 4 equivalents) is stirred in an organic solvent (for example, acetone, ethanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, preferably tetrahydrofuran) at about 0-120 ° C (preferably about 20 ° C) for about 1 -48 hours (preferably 18 hours). The precipitate from the reaction mixture is filtered, and washed with water. The solid is dried under reduced pressure to produce the desired product which can be further purified by crystallization or chromatography.

Illustration of the General Procedure and Preparation # 19: cis-1 - [4- (4-Chloro-5-ydo-pyrrolo [2,3-d] pyrimidin-7-yl) -cycOhexyl] -4-methyl-piperazine -2,5-diona A mixture of c / s - [(2-chloro-acetyl) - [4- (4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidin-7-yl) cyclohexyI] amino} Methyl acetate (0.200 g, 0.00038 mol) and methylamine (2.0 M in tetrahydrofuran, 0.76 ml, 0.0015 mol) was stirred in tetrahydrofuran (8 ml) at about 20 ° C for about 18 hours. The precipitate was filtered and washed with water. The solid was dried under reduced pressure to produce cis-1- [4- (4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidin-7-yl) cyclohexyl} -4-methyl-piperazine-2,5-dione (0.152 g, 0.00031 mol), RP-HPLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min; ? = 190-700 nm; Genesis C column 18, 120 A, 3 μm, 30 x 4.6 mm; Electrospray ionization method observing both positive and negative ones) Rt 2.13 min; m / z 488 (M + H) +.

General Procedure Z: Synthesis of homocetopiperazine A mixture of a diamine (2 equivalents) and a haloacetate (1 equivalent) in ethanol are allowed to stir overnight at room temperature and the resulting precipitate is removed by filtration. Sodium ethoxide (1 equivalent) is added to the filtrate and heated to reflux for 1 -48 hours (preferably 16 hours). The mixture is allowed to cool to room temperature and the solvent is removed under reduced pressure to produce the product which can be further purified by crystallization or chromatography.

Illustration of General Procedure Z Preparation # 20. [1, 4] -Diazepan-2-one A mixture of propan-1,3-diamine (10.00 g, 0.135 mol) and bromoacetic acid ethyl ester (1.260 g, 0.067 mol) in ethanol (100 ml) was allowed to stir at room temperature under a nitrogen atmosphere overnight . The precipitate was removed by filtration and sodium ethoxide (5.200 g, 0.076 mol) was added to the resulting filtrate. The mixture was heated to reflux for about 16 hours. The mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure to leave a black oil which was purified by flash column chromatography on silica gel eluting ethyl acetate, followed by ethyl acetate / methanol (70:30 ) as the mobile phase to give [1,4] -diazepan-2-one as a white solid (2.051 g, 0.0180 moles): 1 H NMR (DMSO-d6, 400 MHz) d 7.37 (s 1 H) m 3.20 (s, 2H), 3.09 (t, 2H), 2.83 (t, 2H), 1.53 (m, 2H); m / z (M + H) + 1 15.

General Procedure AA: Carbonylative cyclization of diamines and aminoalcohols. Di-imidazol-1-yl-methanone solution (1-2 equivalents, preferably 1.5 equivalents) of an amino alcohol or diamine (preferably 1 equivalent) in a solution is added to a solution. organic solvent, such as tetrahydrofuran or? ,? -dimethylformamide. The mixture was stirred for about 1 -24 hours at about 0-50 ° C. The solvent was removed under reduced pressure to supply the product which can be further purified by chromatography or crystallization.

Illustration of General Procedure AA Preparation # 21. 3- [4- (4-Amino-3-iodo-pyrazolo [3,4-d] pyrimid in-1 L-cyclohexyl] -oxazo l id in-2-one Carbonyldiimidazoi (1326 g, 8.16 mmol) was added to a solution of 2- [4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -cyclohexylamino-ethanol (2188 g, 5.44 mmol. ) in tetrahydrofuran (150 ml). The mixture was stirred for about 15 hours at room temperature. The solvent was removed under reduced pressure to produce the product which was purified by flash column chromatography on silica gel using dichloromethane / methanol / 28% aqueous ammonia (98: 1 .9: 0.1) as the mobile phase to produce 3. - [4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-H) cyclohexyl] -oxazolidin-2-one as a white solid (0.800 g, 1.87 mmoles); RP-HPLC (10% to 80% acetonitrile / O.01 M ammonium acetate, regulated in its pH to pH 4.5, for 6 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column, 120 A, 3 μm, 30 x 4.6 mm, electrospray ionization method observing both positive and negative ions) Rt 4.42 min; m / z (M + H) + 429.

General Procedure BB: Synthesis of cetomorpholine To a solution of a substituted amino-ethanol (1-2 equivalents, preferably 1 equivalent) in an organic solvent at room temperature (preferably toluene), methylester of chloroacetic acid (1- 2 equivalents, preferably 1 equivalent) and sodium hydride (1-2 equivalents, preferably 1.1 equivalents). The reaction mixture was stirred for about 10-30 minutes (preferably about 15 minutes) at room temperature, then brought to reflux for about 8-16 hours (preferably about 8 hours). After cooling to room temperature, the solvent was removed under reduced pressure. The residue was divided between an aqueous basic solution (for example, saturated potassium carbonate solution) and an organic solvent. The organic layer was separated and the aqueous layer was further extracted with organic solvent. The combined organic extracts were dried over desiccant and the solvent was removed under reduced pressure to produce the product which can be further purified by chromatography or crystallization.

Illustration of General Procedure BB Preparation # 22. 4- (1, 4-Dioxa-spiro [4.5] dec-8-yl) -morpholin-3-one Chloroacetic acid methyl ester (2.8 m! 32 mmole) and sodium hydride (60% oil dispersion, 1.4 g, 35 mmole) were added to a solution of 2- (1,4-dioxa-spiro [4.5] dec-8-ylamino) ethanol (6.42 g, 32 mmol) in toluene (100 ml) at room temperature under stirring. The reaction mixture was stirred for about 15 minutes at room temperature, then refluxed for 8 hours. After cooling to room temperature, the toluene is removed under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate solution (40 ml) and ethyl acetate (50 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 4- (1,4-dioxa-spiro [4.5] dec-8-yl) -morpholin-3-one (6.7 g, 27.8 g. mmoles) as a yellow oil. 1 H NMR (CDCl 3, 400 MHz) d 4.18, 3.95, 3.85, 3.30, 1.72.

General Procedure CC: Deprotection of a silyl protected alcohol A mixture of a silyl protected alcohol and a fluoride source (eg, tetrabutylammonium fluoride) (10-20 equivalents, preferably about 16 equivalents) was stirred for about 24-72 hours (preferably about 48 hours) at about 25-60 ° C (preferably about 40 ° C). The solvent was removed under pressure eluted and the residue was partitioned between the aqueous basic solution (eg, saturated sodium carbonate solution) and an organic solvent. The organic layer was separated and the aqueous layer was further extracted with organic solvent. The combined organic extracts were dried on a desiccant and the solvents were removed under reduced pressure. The compound can be further purified by chromatography or crystallization.

Illustration of General Procedure CC Preparation # 23. c / s-. { 2- (4-Benzyloxy-cyclohexyloxy) -ethanol} A mixture of c / s-. { [2- (4-benzyloxy-cyclohexyloxy) -ethoxy] -tert-butyl-dimethyl-silane} (3.49 g, 0.58 mmol) and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 153 mL, 153 mmol) was stirred for about 48 hours at about 40 ° C. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution (40 ml) and dichloromethane (50 ml). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (3 x 50 ml). The combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to produce a yellow oil. The compound was further purified by flash chromatography on silica gel eluting ethyl acetate / heptane (1: 1) as the mobile phase to produce cis-. { 2- (4-benzyloxy-cyclohexyloxy) ethanol (2.3 g, 9.2 mmol). 1 H N MR (chloroform-di, 400 MHz) d 7.34, 4.52, 3.70, 3.54, 3.51, 3.40, 2.48, 1.85, 1.60; TLC (ethyl acetate / heptane 1: 1) Rf 0.30.

General Procedure DD: Synthesis of a trifluoromethoxy ether A mixture of primary alcohol (preferably 1 equivalent), sodium hydride (1-10 equivalents, preferably 1.3 equivalents), imidazole (0.02-0.04 equivalents, preferably 0.03 equivalents) and a dry organic solvent (for example, dimethyl sulfoxide or tetrahydrofuran, preferably tetrahydrofuran) was brought to reflux under a nitrogen atmosphere for about 3-5 hours (preferably about 3 hours). After cooling to room temperature, carbon disulfide (4-10 equivalents, preferably 5 equivalents) was added and the reaction heated to reflux for about 30 minutes. The reaction mixture was again cooled to room temperature and iodomethane (2-7 equivalents, preferably 4.8 equivalents) was added. The resulting mixture was refluxed for about 30 minutes then neutralized with an acid (preferably acetic acid), washed with water, and extracted with an organic solvent. The combined organic extracts were dried on a desiccant and the solvent was removed under reduced pressure. The compound is further purified by flash chromatography to produce an S-methyl ester of dithiocarbonic acid. A polypropylene container was charged with 1,3-dibromo-5,5-dimethylhydantoin (2-5 equivalents, preferably 3 equivalents) and dichloromethane. The suspension was cooled to about -78 ° C and acid fluoride (70% acid fluoride in pyridine, 50-100 equivalents, preferably 80 equivalents) was added. The resulting suspension was stirred at about -78 ° C. A solution of S-methyl ester of dithiocarbonic acid (1 equivalent) in dichloromethane was added at -78 ° C. After completing the addition, the dry ice bath in acetone was replaced by an ice-cold salt bath. The resulting red-brown reaction mixture was stirred at that temperature for about 30 minutes, then diluted with ether (30 ml) at about 0 ° C, and quenched by the careful addition of an ice-cooled solution of a hydrosulfite aqueous sodium / sodium bicarbonate / hydroxide (pH 10) until the reddish-brown color disappears. The pH value was readjusted to 10 at about 0 ° C by the slow addition of ice-cold sodium hydroxide (30% aqueous solution) and the resulting mixture was diluted with diethyl ether. The organic layer was separated, and the aqueous layer was extracted with diethyl ether. The combined organic phase was washed with brine, dried over desiccant and the solvent was removed under reduced pressure and further purified by chromatography or crystallization.

Illustration of General Procedure DD Preparation # 24. c / s-. { [4- (2-Trifluoromethoxy-ethoxy) -cyclohexyloxymethylj-benzene} A mixture of c / s-. { 2 - [(4-benzyloxy) cyclohexyloxy)} -ethanol] (1.14 g, 4.56 mmol), sodium hydride (60 & amp; amp;; dispersion in mineral oil, 237 mg, 5.92 mmol) and imidazole 88.9 mg, 0.136 mmol) in dry tetrahydrofuran (19 ml) was heated to reflux under a nitrogen atmosphere, for about 3 hours. After cooling to room temperature, carbon disulfide (1.37 ml, 22.79 mmol) was washed and the mixture was heated to reflux for about 30 minutes. The reaction mixture was again cooled to room temperature and iodomethane (1.36 ml, 21.88 mmol) was added dropwise. The resulting mixture was heated to reflux for about an additional 30 minutes. The reaction mixture was then neutralized with acetic acid, washed with water (10 ml), and extracted with dichloromethane (4 x 20 ml). The combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to produce an orange oil. The compound was purified by flash chromatography on silica gel using ethyl acetate / heptane (9:91) as a mobile phase to produce cis-S-methyl ester of cis- (2- (4-benzyloxy-cyclohexyloxy) -ethyl] ester S-methyl ester. -. { dithiocarbon } (1.0 g, 2.94 mmol); 1 H NMR (CDCl 3, 400 MHz) d 7.34, 4.76, 4.52, 3.80, 3.42, 2.56, 1.84, 1.59; TLC (ethyl acetate / heptane 3: 7) Rf 0.57. A dry polypropylene round bottom tube was rinsed with nitrogen and charged with 1,3-dibromo-5,5-dimethylhydantoin (2.76 g, 9.46 mmol) and dichloromethane (70 ml). The suspension was cooled to -78 ° C and stirred for about 10 minutes. To the mixture was slowly added acid fluoride (70% acid fluoride in pyridine, 6.31 ml, 252.4 mmol). The resulting suspension was stirred at about -78 ° C and added dropwise to a solution of cis- [dithiocarbonic acid] - [2- (4-benzyloxy-cyclohexyloxy) -ethyl] S-methyl ester} (1.08 g, 3.16 mmol) in dichloromethane (10 ml) at about -78 ° C through a cannula. After the addition was complete, the reaction was heated to about -10 ° C for 30 minutes, diluted with ether (30 ml) at about 0 ° C, then quenched by the addition of an ice-cooled hydrosulfite solution. sodium / sodium bicarbonate / sodium hydroxide (pH 10), until the reddish-brown color of the mixture disappeared at approximately 0 ° C. The pH value was readjusted from 10 to about 0 ° C by the addition of ice-cold sodium hydroxide (30% aqueous solution), and the mixture was diluted with ether (100 ml). The organic layer was separated, and the aqueous layer was extracted with brine (50 ml), dried over magnesium sulfate, and the solvent was removed under reduced pressure to produce a yellow oil. The compound was purified by flash chromatography on silica gel using ethyl acetate / heptane (1: 20) as a mobile phase to produce cis-. { [4- (2-trifluoromethoxy-ethoxy) -cyclohexyloxymethylj-benzene} (571 mg, 1.80 mmol); 1 H NMR (CDCl 3, 400 MHz) d 7.47, 7.24, 4.46, 4.07, 3.65, 3.45, 1.85, 1.58; TLC (ethyl acetate / heptane 1: 10) Rf 0.21.

General Procedure EE: Oxidation of a sulphide to a sulfoxide or sulphite A mixture of a sulfide compound (preferably 1 equivalent), 3-chloroperoxybenzoic acid (1-5 equivalents, preferably 1 equivalent for oxidation for sulfoxide or 2 equivalents for oxidation to sulfota) and calcium carbonate (1-10 equivalents, preferably 4 equivalents) was stirred in an organic solvent (preferably dichloromethane) at room temperature for about 1 -24 hours (preferably about 6 hours) until the reaction reached the termination. The solvent was removed under reduced pressure and the crude product can be further purified by crystallization or chromatography.

Illustration of General Procedure EE Example # 360. 3- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -phenyl] -1- (2, 2-d-xylo-hexahydro-1-thiopyran-4-yl) -1 Hp-irazolo [3,4 -d] pi rimidin-4-ilamine A mixture of 3- [4- (5,7-dimethyl-benzoxazoI-2-ylamino) -phenyl] -1- (tetrah idro-thiopyran-4-yl) -1 H-pyrazolo [3,4-d] pyrmidine The lamina (0.2 g, 0.42 mmol), 3-chloroperoxybenzoic acid (0.183 g, 1.06 mmol) and calcium carbonate (0.17 g, 1.70 mmol) was stirred in dichloromethane (15 ml) at room temperature under an inert atmosphere. for about 2 hours. Additional 3-chloroperoxybenzoic acid (0.136 g, 0.78 mmol) was added and the reaction was stirred at room temperature for approximately 24 hours. The solvent was removed under reduced pressure and the unpurified product was purified by preparative RP-HPLC (10% to 60% acetonitrile / O.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes, then 60% to 100% acetonitrile / 0.05M aqueous ammonium acetate, regulated at its pH to pH 4.5, for 5 minutes at 21 ml / min;? = 254 nm; column Hyperprep® HS C18, 8 μm, 250 x 21.2 mm) to produce 3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -1- (1,1-dioxo-hexahydro-1'-thiopyran-4-yl) -1H -pyrazolo [3,4-d] pyrimidin-4-ylamine (0.080 g, 0.16 mmol) as an off-white solid; RP-HPLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A , 5 μm, 250 x 4.6 mm) Rt 19.00 min; m / z (M + H) + 504.4.

Example # 361 trans-5- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7- [4- (2H-tetrazol-5-l) -cycOhexyl] -7H-pyrrolo [2J3-d] pyrimidin-4-ylamine A mixture of 4- [4-amino-5- (4-amino-3-fluoro-phenyl) -pyrrolo [213-d] pyrimidin-7-yl] -cyclohexanone (prepared by general procedures A, B, T, C and L) (0.200 g, 0.590 mmol) and tosylmethyl isocyanide (0.126 g, 0.645 mmol) in ethylene glycol dimethyl ether (6 ml) and fer-butyl alcohol (3 ml), was cooled to about 0 ° C. Potassium fer-butoxide (0.148 g, 13.2 mmol) was added, and the mixture was warmed to room temperature and allowed to stir at that temperature for about 15 hours. The mixture was diluted with water (10 ml) and the product was extracted with methanol / dichloromethane (1: 9, 3 x 15 ml). The organic fractions were dried over magnesium sulfate and concentrated, and the product was purified by flash column chromatography on silica treated with triethylamine, using methanol / ethyl acetate (1: 28) as the mobile phase to produce fra / 7s- 4- [4-amino-5- (4-amino-3-fluoro-phenyl) -pyrrolo [2,3-d] pyrimidin-7-yl] -cyclohexanecarbonitrile (55 mg, 0.157 mmol) as an orange solid; RP-H P (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate for 10 minutes at 1 ml / min using a Hypersil HS C18 column, 250 x 4.6 mm,? = 254 nm) Rt 7.67 min. When using the general procedure G, the above compound was then used to form fra / 7s-4-. { 4-am i no-5- [4- (5,7-diemtiI-benzoxazol-2-i lamí no) -3-f luoro-f-enyl] -pyrrolo [2,3-d] pyrimidin-7-yl} -carbonitrile cyclohexane (0.038 g, 0.076 mmol); RP-HPLC (25% to 100% acetonitrile / O.1 M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 10 minutes at 10 minutes at 1.0 ml / min; ? = 254 nm; column Hypersil C18, 100 A, 5 μm, 250 x 4.6 mm) Rt 11.43 min. The above compound (0.038 g, 0.076 mmole), sodium azide (30.0 mg, 0.46 mmole) and ammonium chloride (0.45 mmole) were stirred in? / ,? -dimethylformamide (2 ml) in a sealed tube at 1 15 ° C for 4 days. The mixture was cooled to room temperature, filtered and the product was purified by preparative H PLC (25 to 100% acetonitrile / O.1 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes at 21 ml / min;? = 254 nm; Hypersil HS C18 column, 5 μm, 100 A, 250 x 21 mm) to produce trans-5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3 -fluoro-phenyl] -7- [4- (2H-tetrazol-5-H) ccylohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.012 g, 0.022 mmol) as a yellow powder; RP-H PLC (25% to 100% acetonitrile / O.1 M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 10 minutes at 1.0 ml / min;? = 254 nm; column Hypersil C18, 100 A, 5 μm, 250 x 4.6 mm) R t 8.82 min; m / z (M + H) + 539.

Example # 362. 3- [4- (5, 7-Di methy1-benzoxazole-2-ylami no) -f-enyl] -1- (2-triemthyl-silyl-ethoxy-methyl) -1H-pyrazolo [3,4-d] -pyrimidine-4-ylamine A solution of 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine (10 g, 38.31 mmol) in α /, -dimethylformamide (200 ml) was treated. and dimethyl sulfoxide (29 ml) was treated with sodium hydride (60% dispersion in mineral oil, 2.45 g, 61.29 mmol) under an inert atmosphere. After evolution of hydrogen had ceased, the reaction mixture was cooled to about 0 ° C in an ice bath and added slowly. { 2- (cioromethoxy) ethyl} trimethylsilane (7.66 g, 45.97 mmol) for about 30 minutes. The ice bath was stirred and the reaction was stirred at room temperature for about 20 hours. The resulting mixture was poured into ice water (500 ml) and the precipitate was filtered and dried under reduced pressure to yield 3-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazolo [3,4-d] pyrimidine. -4-ylamine (14 g, 35.78 mmol) as a white solid; m / z 392.1 (M + H) + - When using general procedure C, 3-iodo-1 - (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine was reacted (1 g, 2.56 mmole) to produce 3- [4- (5,7-dimethylbenzoxazol-2-ylamino) -phenyl] -1- (2-t-methylsilane-eioxymethyl) - 1 H -pyrazolo [3,4-d-pyrimidin-4-] ilamine (0.60 g, 1.2 mmol) as a light brown solid; RP-HPLC (5% to 95% acetonitrile / O.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 10 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A , 5 μm, 250 x 4.6 mm) Rt 12.6 min; m / z (M + H) + 502.

Example # 363 3- [4- (557-Dimethyl-benzoxazol-2-ylamino) -phenyl] -1 H-pyrazoo [3,4-d] pyrimid i n-4-i lamina A suspension of 3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -f-enyl] -1- (2-trimethylsilylene-ethoxymethyl) -1-pyrazoyl [3, 4-d] pyrimidin-4-ylamine (0.55 g, 1.1 mmol) in a mixture of aqueous hydrochloric acid (6N, 12.5 ml) and ethanol (5 ml) was heated at about 50 ° C for about 24 hours. The reaction mixture was then cooled in an ice bath and aqueous sodium hydroxide (50% or solution w / w) was added dropwise to adjust the pH to 14. The resulting mixture was extracted with dichloromethane (2 x 20 ml. ). The combined organic layers were washed with a saturated brine solution (20 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The unpurified solid was purified by RP chromatography (10% to 60% acetonitrile / O.06 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes, then 60% to 100% acetonitrile / O .05 M aqueous ammonium acetate, regulated in its pH to pH 4.5, for 5 minutes, at 21 ml / min;? = 254 nm; Hyperprep® HS C18 column, 8 μm, 250 x 21.2 mm) to produce 3- [4- (5,7-dimethyl-benzoxazol-2-ylamine) -phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (0.22 g, 0.59 mmol) as a white solid: RP-H PLC (5% to 95% acetonitrile / O.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 10 minutes to 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) R, 9.2 min; m / z (M + Hf 370; and 3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -1-ethoxymethyl-1 H -pyrazolo [3,4-d] pyrimidine-4 -amine (0.022 g, 0.05 mmol) as an off-white solid, RP-HPLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, regulated at pH 4.5, for 10 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 10.9 min; m / z (M + H) + 430.

Example # 365.c / s-3-. { 4-Amino-4- [4- (5,7-dimethyl-benzoxazol-2-yl) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-yl} -cyclopentanol Palladium hydroxide (20% by weight of Pd) in carbon (0.080 g) was slowly added to a cold suspension of c / s-4. { 4-amino-5- [4- (5,7-dimethyl-benzoxazole-2-yl ion) -f -enyl j-pyrrolo [2,3-d] pyri mid in-7-iI} -cyclopent-2-enol (0.1 g, 0.22 mmol) in methanol (100 ml). The mixture was stirred in a sealed tube under hydrogen pressure (50 psi) at room temperature for approximately 18 hours. The resulting mixture was filtered through Celite. The filtrate was concentrated and dried under reduced pressure to produce cis-3-. { 4-amino-5- [4- (5,7-dimethyl-benzoxazol-2-Hamino) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-yl} -cyclopentanol (0.101 g, 0.22 mmol) as a white solid; RP-H PLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH to pH 4.5, for 10 minutes at 1 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 10.8 min; m / z (M + H) + 455.

Example # 366 Salt of acid c / s-3-. { 4-Amino-5- [4- (5-chloro-7-methyl-benzoxazol-2-ylamino) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-yl} -acetic cyclopentanol Palladium hydroxide (20% by weight of Pd) in carbon (0.080 g) was slowly added to a cold suspension of c / s-4. { 4-amino-5- [4- (5-cl or ro-7- methyl-benzoxazol-2-ylami no) -f-enyl] -pyrro [2,3-d] pirim idin-7-iI} -cyclopent-2-enol (0.1 g, 0.21 mmol) in methanol (100 ml). The mixture was stirred in a sealed tube under hydrogen pressure (50 psi) at room temperature for about 2 hours. The resulting mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The unpurified product was then purified through RP chromatography (10% to 60% acetonitrile / O.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes, then 60% to 100% of acetonitrile / O.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 5 minutes at 21 ml / min;? = 254 nm; column Hyperprep® HS C18, 100 A, 8 μm, 250 x 21.2 mm) to produce cis-3- monoacetate. { 4-amino-5- [4- (5-chloro-7-methyl-benzoxazole-2-Hamino) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-H} -cyclopentanol (0.049 g, 0.10 mmol) as a white solid; RP-H PLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 10 minutes at 1 ml / min;? = 254 nm; Hypersil C18 column, 100 A , 5 μm, 250 x 4.6 mm) Rt 1 1 .2 min; m / z (M + H) + 475.

Example # 367. írans-. { 4- [4-Amino-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-3-yl] -phenyl} -benzothiazole-2-yl-methanol Benzothiazole (0.416 g, 3.08 mmol) and anhydrous tetrahydrofuran (15 ml) were charged into a reaction vessel equipped with a magnetic stir bar. The flask was rinsed with nitrogen and the mixture was cooled to about -78 ° C before the addition of n-butyllithium (1.95 M in hexanes, 1.58 ml, 3.09 mmol). The reaction was stirred at about -78 ° C for about 3 hours. Then, 4- [4-amino-1- (4-morpholin-4-yl-cyclohexyl) -1 r -pyrazolo [3,4-d] pyrimidin-3-yl] -benzaldehyde (prepared from 3- Iodine-1 H-pyrazolo [3,4-d] pyrim idin-4-iAmino using general procedures A, T, J and C) (0.50 g, 1.23 mmoles) was added. The reaction was warmed to room temperature and stirred for about 16 hours. The reaction mixture was then quenched by the addition of saturated aqueous ammonium chloride (40 ml). The tetrahydrofuran was removed under reduced pressure and the aqueous mixture was extracted with ethyl acetate (3 x 15 ml). The combined fractions were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The unpurified product was purified through RP-H PLC (10% to 80% acetonitrile / O.05 M aqueous ammonium acetate, adjusted in its pH to pH 4.5, for 25 minutes at 21 ml / min; ? = 254 nm; Hyperprep® C18 column, 100 A, 8 μm, 250 x 21.2 mm) to give the trans-. { 4- (4-Amino-1- (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-3-yl] -phenyl} -benzothiazol-2-yl -methanol as a white solid (0.057 g, 0.105 mmol), RP-H PLC (5% to 85% acetonitrile / 0.05 M ammonium acetate, regulated in its pH at pH 4.5, for 20 minutes at 1 .0 ml / min;? = 254 nm; Hypersil C18 column, 5 μm, 100 A, 250 x 4.6 mm) Rt 14.06 min; m / z (M + H) + 542.

Example # 368 íraps-. { 4- [4-Amino-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-3-yl] -phenyl} -benzothiazol-2-yl-methanone They were loaded into a trans-reaction flask. { 4- [4-Amino-1- (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-3-yl] -phenyl} -benzothiazol-2-yl-methanol (example # 367) (0.050 g, 0.090 mmol), manganese dioxide (0.040 g, 0.460 mmol) and methanol (15 ml). The mixture was stirred under a nitrogen atmosphere at room temperature for about 48 hours. The crude mixture was filtered through a pad of Celite and washed with methanol (3 x 5 ml). The filtrate was concentrated under reduced pressure and the unpurified product was purified through RP-H PLC (10% to 80% acetonitrile / 0.05M ammonium acetate for 25 minutes at 21 ml / min.; ? = 254 nm; Hyperprep® C18 column, 100 A, 8 μm, 250 x 21 .2 mm) to give trans-. { 4- [4-amino-1- (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d-pyrimidin-3-yl-phenyl]} -benzothiazol-2-yl-methanone as a white solid (0.037 g, 0.0686 mmol); RP-H PLC (5% to 95% acetonitrile / O.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 10 minutes at 1.0 ml / min;? = 254 nm; column Hypersil C18, 5 μm, 100 A, 250 x 4.6 mm) Rt 9.66 min; m / z (M + H) + 540.

Example # 369 [4- (4-Am ino-1-cyclopentyl-1 H-pyrazolo [334-d] pyrimidin-3-yl) -phenyl] benzothiazol-2-yl-methanol Benzothiazole (0.358 g, 2.65 mmol) and anhydrous tetrahydrofuran (10 ml) were charged into a reaction vessel equipped with a magnetic stir bar. The flask was rinsed with nitrogen and the mixture was cooled to about -78 ° C before the addition of n-butyllithium (1.95 M in hexanes, 1.36 ml, 2.66 mmole). The reaction was stirred at about -78 ° C for about 3 hours. Then, 4- (4-amino-1-cyclopentyl-1 H-pyrazolo [3,4-d] pyrimidin-3-yl) -benzaldehyde (prepared from 3-iodo-1-7-pyrazolo [3, 4-d] pyrimidin-4-ylamine through general procedures A and C) (0.325 g, 1.06 mmol). The reaction was allowed to warm to room temperature and was stirred for about 16 hours. The reaction mixture was then quenched by the addition of saturated aqueous ammonium chloride (40 ml). The tetrahydrofuran was removed under reduced pressure and the aqueous mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the crude product was purified through RP-H PLC (10% to 80% acetonitrile / 0.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes at 21 ml / min;? = 254 nm; Hyperprep® C18 column, 100 A, 8 μm, 250 x 4.6 mm) to give [4- (4-amino-1-cyclopentyl-1H-pyrazolo [3, 4-d] pyrimidin-3-yl) phenyl] -benzothiazol-2-yl-methanol as a white solid (0.058 g, 0.131 mmol); RP-HPLC (5% to 95% acetonitrile / 0.05 M aqueous ammonium acetate, regulated at pH 4.5, for 10 minutes at 1.0 ml / min, 15 minutes total activation time; 254 nm; Hypersil C18 column, 5 μm, 100 A, 250 x 4.6 mm) Rt 12.84 min; m / z (M + H) + 443.

Example # 370 [4- (4-Amino-1-cyclopentyl-1 H -pyrazolo [3,4-d] pyrim m idin-3-yl) -phenyl] -benzotaizol-2-l-methanone They were loaded into a reaction flask. { 4- [4-Amino-1-cyclopentyl] -1-pyrazolo [3,4-d] pyrimidin-3-yl] -phenyl} -benzothiazole-2-ylmethanol (example # 369) (0.040 g, 0.090 mmol), manganese dioxide (0.0393 g, 0.452 mmol) and methanol (10 m). The mixture was stirred under a nitrogen atmosphere at room temperature for about 48 hours. The crude mixture was filtered through Celite pad and washed with methanol (3 x 10 ml). The filtrate was concentrated under reduced pressure and the crude product was purified by RP-HPLC (10% to 80% acetonitrile / 0.05 M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes. at 21 ml / min;? = 254 nm; Hyperprep® C18 column, 100 A, 8 μm, 250 x 21.2 mm) to give [4- (4-amino-1-cyclopent-1H-pyrazolo [3,4 .}. d] pyrimidin-3-yl) -phenyl-J-benzothiazol-2-ylmethanone as a white solid (0.0086 g, 0.0195 mmol); RP-HPLC (5% to 85% acetonitrile / O.05 M ammonium acetate, regulated in its pH to pH 4.5, for 20 minutes at 1.0 ml / min, 30 minutes of total activation time;? = 254 nm; Hypersil C18 column, 5 μm, 100 A, 250 x 4.6 mm) Rt 27.96 min; m / z (M + H) + 441.

Preparation # 25. 2-cyclopropo-i-ethyl ester of toluene-4-sulfonic acid A solution of 2-cyclopropoxy-ethanol (0.102 g, 0.0010 mole) and triethylamine (0.153 ml, 0.001 mole), endichloromethane (2 ml) was cooled to about 0 ° C, and slowly treated with a 4-chloro solution. methyI-benzenesulfonyl (0.228 g, 0.0012 mol) in dichloromethane (3 mL). The reaction mixture was stirred at about 0 ° C for 1 hour, then at room temperature for about 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel using ethyl acetate / heptane (1: 7) to yield toluene-4-sulfonic acid 2-cyclopropoxy-ethyl ester (0.129 g, 0.00050 mol) as a light yellow oil; RP-HPLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate, regulated in its pH at pH 4.5, 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column , 120 A, 3 μm, 30 x 4.6 mm, electroaspersion ionization method observing both positive and negative ions) Rt 3.02 min.

Preparation # 26. 3-Bromo-1 -fer-butyl-1 rY-pyrazolo [3,4-d] pyrimidin-4-ylamine.

A suspension of 5-amino-1-fer-butyl-1 H-pyrazole-4-carbonitrile (8.67 g, 0.0528 mol) in formamide (100 ml) was heated at 180 ° C for about 4 hours. The reaction mixture was cooled, poured into ice water (200 ml) and the product extracted with ethyl acetate (4 x 80 ml). The combined organic layers were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was taken up in ether (35 ml) and the precipitate was filtered, washed with ether (50 ml) and dried under educted pressure to yield 1 -fer-butyl-1 H -pyrazolo [3,4-d] pyrimidine. -4-ylamine (3.22 g, 0.0169 mol) as a white solid, RP-H PLC (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column, 120 A, 3 μm, 30 x 4.6 mm) Rt 1.38 min. A mixture of 1-fer-butyl-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine (0.200 g, 0.0010 mol) and bromide (0.134 ml, 0.0026 mol) in H2O (10 ml) was heated to about 90 ° C for about 24 hours. This was neutralized with aqueous sodium hydroxide (2.0 N). The resulting white precipitate was filtered, washed with water, and dried to yield 3-bromo-1-tert-butyl-1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (0.177 g, 0.66 mmol) as a white solid; RP-HPLC (30% to 95% acetonitrile / 0.01 M aqueous ammonium acetate, regulated in its pH to pH 4.5, for 4.5 inutes to 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 4.6 mm) Rt 2.05 min.

Example # 371 Ipses-3- [3- [4- (5-chloro-7-methyl-benzoxazol-2-ylamino) -phenyl] -1- (4-morfoin-4-yl-cyclohexyl) -1 H-pyrazolo acid salt [3J4-d] pyrimidin-4-ylamino] -propionam ida Fra / 7S-3-iodo-1- (4-morpholin-4-yl-cyclohexyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (prepared using general procedures A, T and J) (0.1 g, 0.000234 moles), cesium carbonate (0.299 g, 0.000702 moles) and 3-chloropropionamide (0.025 g, 0.000234 moles) were dissolved in? / ,? dimethylformamide (5 ml). The reaction mixture was stirred for about 40 hours, the insoluble residue was removed by filtration, and the filtrate was concentrated, then purified by preparative RP-HPLC (10% to 60% acetonitrile / 0.05M aqueous ammonium acetate, regulated at pH 4.5, for 25 minutes at 21 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 8 μm, 250 x 21.2 mm) to produce trans-3- [3-iodo-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamino] -propionamide (0.075 g, 0.000151 mol) as a white solid; m / z (M + H) + 500. Frat? s-3- [3-Iodo-1- (4-morpholin-4-yl-cyclohexyl) -1 / - / - pyrazolo [3,4-d] was coupled. ] pyrimidin-4-ylamino] -propionamide (0.075 g, 0.00015 mol) with (5-chloro-7-methyl-benzoxazol-2-yl) - [4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenyl] -amine (0.075 g, 0.000195 moles) (prepared using general procedures G and D) using general procedure C to produce trans-3- [3- [4-monoacetate] - (5-Chloro-7-methyl-benzoxazol-2-ylamino) -phenyl] -1- (4-morpholin-4-yl-cyclohexy l) - 1 H -pyrazolo [3,4-d] pyrimidine-4- ila mio nj-propionamide (0.020 g, 0.0000289 moles) as a white solid. 1 H N MR (DMSO-d6, 400 MHz) d 7.91, 7.60, 7.08, 6.87, 6.50, 4.64, 3.68, 3.54, 2.40, 2.08, 1.88, 1.44; m / z (M-Hf 629.

Example # 372. íraps-4-. { 4-Ami no: 3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl} -1-methyl-cyclohexanol Example # 373. c / s-4-. { 4-Amino-3- [4- (5,7-dimethyl-benzoxazoI-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl} -1-methyl-cyclohexanol They were suspended in toluene (100 ml) 4-. { 4-amino-3- [4- (5,7-di-methyl-l-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrim idin-1-yl} -ciciohexanone (prepared using general procedures A, T and C (G, D)) (5.00 g, 0.0107 moles) and zinc bromide (0.50 g, 0.0022 moles) and stirred at room temperature for 10 minutes under nitrogen flow continuous. A solution of trimethylaluminium in toluene (2 M, 13.38 ml, 0.0267 mol) was added and the stirring was continued for about 2 hours. The addition of trimethylammonium solution (2 M, 13.38 ml) was repeated four more times and the reaction mixture was quenched by a dropwise addition of saturated aqueous ammonium chloride solution (100 ml). The resulting mixture was evaporated to dryness under reduced pressure; the residue was suspended in? ^ / V-dimethylformamide (200 ml) and filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by preparative RP-HPLC (20% to 80% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 30 minutes at 21 ml / min; 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 21.2 mm) to produce trans-4- [4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-Ib} -1-methyl-cyclohexanol 80.052 g, 0.107 mmol) as a white solid: RP-H PLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 19.62 min; 1 H N M R (DMSO-d6, 400 MHz) d 10.85, 8.23, 7.93, 7.67, 7.1 1, 6.79, 4.64, 4.46, 2.89, 2.73, 2.08, 1.91, 1.44; and cis-4-. { 4-amino-3- [4- (5,7-dimethyl-be nzoxa-zol-2-yl-mi-y) -fe nilj-pyrazol or [3,4-d] pyrimidin-1-yl} 1-metho-cyclohexanol (0.104 g, 0.206 mmol) as a white solid; RP-H PLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; column Hypersil C18, 100 A, 5 μm, 250 x 4.6 mm) Rt 20.33 min; H NMR (DMSO-d6, 400 MHz) d 10.86, 8.23, 7.93, 7.67, 7.1 1, 6.79, 4.68, 4.20, 2.89, 2.73, 2.14, 1.83.

Example # 374 Isopropyl ester of 4- acid. { 4-Amino-3- [4- (5,7-dimethyl-l-benzoxazol-2-ylamido) -phenyl] -p-razoIo [3,4-d] pirim idin-1 -i l} -piperidin-1 -carboxylic Triethylamine (0.1 ml, 0.72 mmol) was added to a suspension of 3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -f-enyl] -1-piperidin-4-y1- 1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine (prepared using general procedures A and C (G, D)) (0.109 g, 0.24 mmol) in dichloromethane (5 ml) and the resulting mixture was cooled to 0 ° C while stirring under continuous nitrogen flow. A solution of chloroformate. of isopropyl in toluene (1 M, 0.24 ml, 0.00024 mol) was added dropwise and the reaction mixture was stirred at about 0 ° C for about 1 hour. The solvents were removed under reduced pressure and the residue was purified by preparative RP-HPLC (20% to 90% acetonitrile / O.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 30 minutes to 21 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 8 μm, 250 x 21 .2 mm) to produce 4-isopropylester. { 4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyi] -pyrazolo [3,4-d] pyrimidin-1-yl} -piperidine-1-carboxylic acid (0.080 g, 0.148 mmol) as a white solid: RP-HPLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 15.55 min; 1 H NMR (DMSO-d6, 400 MHz) d 10.86, 8.24, 7.93, 7.67, 7.1 1, 6.79, 4.94, 4.78, 4.12, 3.00, 2.41, 2.34, 2.01, 1.17.

Example # 375 Methyl ester of 4- acid. { 4-Amino-3- [4- (5,7-dimethyl-l-benzoxazole -2-i lamine o) -f-enyl] -pyrazole or [3,4-d] pyrimidin-1 -i 1.}. -pi perid i n-1 -carboxyl Triethylamine (0.1 ml, 0.72 mmol) was added to a suspension of 3- [4- (5,7-d.methyl-benzoxazol-2-ylami no) -f-enyl] -1-piperidin-4-yl-1. f / -pyrazolo [3,4-d] -pyrimidin-4-ylamine (prepared using general procedures A and C (G, D)) (0.1 10 g, 0.24 mmol) in dichloromethane (5 ml) and the resulting mixture was cooled to about 0 ° C while stirring under continuous nitrogen flow. Methyl chloroformate (0.020 ml, 0.254 mmol) was added dropwise and the reaction mixture was stirred at about 0 ° C for about 1 hour. The solvents were removed under reduced pressure and the residue was purified by preparative RP-HPLC (20% to 90% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 30 minutes to 21 ml / min;? = 254 nm; Hypersii C18 column, 100 A, 8 μm, 250 x 21 .2 mm) to produce 4- [4-amino-3 [4- (5,7-dimethyl-benzoxazole-2) methyl ester. -ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl} -pyrimidine-1-carboxylic acid (0.077 g, 0.15 mmol) as a white solid: RP-HPLC (30% to 95% acetonitrile / O.01 of aqueous ammonium acetate, regulated in its pH to pH 4.5, for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column, 120 A, 3 μm, 30 x 4.6 mm) Rt 2.77 min; m / z (M + H) + 513.

Example # 376 ? , / F-4 imethylcarbamate V-d. { 4-Amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -pyrazolo [3,4-d]? Irimidin-1-yl} -cyclohexyl Chloride of? /,? / - dimethylcarbamoyl (0.63 g, 0.00585 mole) was added to a mixture of fra / 7S-4- (4-Amino-3-iodo-pyrazoo [3,4-d] pyrim idin-1- il) -cyclohexanol (prepared using general procedures A, T and U) (0.20 g, 0.000557 moles) in N-methylpyrrole idonone (0.9 ml) and pyridine (0.1 ml). The reaction mixture was heated to about 75 ° C for about 24 hours under a continuous flow of nitrogen. Additional N, N-dimethylcarbamoyl chloride (0.63 g, 0.00585 mole) was added and the reaction was stirred at about 75 ° C for approximately an additional 24 hours. The reaction mixture was cooled to room temperature and purified by preparative RP-HPLC (10% to 60% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes to 21 ml / min;? = 254 nm; Column Hypersil C18, 100 A, 8 μm, 250 x 21.2 mm) to produce N, N-dimethylcarbamate fr / s-4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrim idin-1-yl) -cyclohexy] (0.019 g, 0.0455 mmoles) of an off-white solid: m / z (M + H) + 431. Reaction was made of frans-4- (4-Amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -cyclohexyl / V,? / - dimethylcarbamate (0.06 g, 0.00014 mol) with , 7-dimethyI-benzoxazol-2-yl) - [2-fluoro-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenyl] -amine (0.07 g, 0.000182 moles) (prepared using general procedures G and D) using general procedure C to produce trans-4- [4-amino-3- [4- (5,7-dimethyl-benzoxazole- N, N-dimethylcarbamate; 2-ylamino) -3-fluoro-phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl} -cyclohexyl (0.034 g, 0.000061 moles) as a white solid: RP-H PLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate; regulated at pH 4.5 to 4.5, for 20 minutes at 1.7 ml / min; ? = 254 nm; Column Hypersil C18, 100 A, 5 μm, 250 x 4.6 mm) Rf 16.44 min; 1 H N MR (DMSO-d6, 400 MHz) d 10.58, 8.50, 8.25, 7.52, 7.10, 6.80, 4.75, 4.58, 2.85, 2.41, 2.31, 2.01, 1.61.

Example # 377 fra /? -3- (4- { 4-Amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrim? d? n-1 -yl.}. -cyclohexyl) -4 H- [1,4] oxadiazol-5-one 4- (4-Amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -cyclohexanone (prepared using general procedures A and T) (4.00 g, 0.0112 mol) was added to a mixture of ethylene glycol dimethyl ether (60 ml) and ethanol (2 ml). 1-Isocyanomethoxy-sulfonyl-4-methyl-benzene (2.19 g, 0.01 12 mol) was added and the resulting mixture was cooled to about 0 ° C while stirring under continuous nitrogen flow. Potassium fer-butoxide (2.51 g, 0.0224) was added and the reaction mixture was stirred for approximately 16 hours while heating slowly to room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel using dichloromethane / methanol / triethylamine (98: 1 .1) as the mobile phase to produce 4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidine. -1-yl) -cyclohexanecarbonitrile (1.9 g, 0.00516 mol) as an off-white solid as a mixture of cis and trans isomers: RP-HPLC (5% to 85% acetonitrile / 0.05 M aqueous ammonium acetate, regulated at pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 12.16 min, and 12.53 min. The mixture of cis and frans 4- (4-amino-3-iodo-pyrazolo [3,4- d] pyrimidin-1-yl) -cyclohexylancarbonitrile (1.5 g, 0.00408 mol), hydroxylamine hydrochloride (1.42 g, 0.0204 mol) ) and triethylamine (3.6 ml, 0.0204 moles) was heated in dimethyl sulfoxide (10 ml) at about 75 ° C under a continuous flow of nitrogen for about 16 hours. The reaction mixture was poured into ice water (120 ml) and the precipitate was collected by filtration, washed with water and dried to yield 4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -? / - hydroxy-cyclohexanecarboxamidine (1.20 g, 0.003 mole) as a yellow solid as a mixture of cis and trans isomers: RP-HPLC (5% to 85% acetonitrile / 0.05M acetate) aqueous ammonium, regulated at pH 4.5, for 20 minutes 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 9.00 min, and 9.09 min. The mixture of cis and trans 4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -? / - hydroxy-cyclohexancarboxamidine (0.215 g, 0.000536 moles) and pyridine (0.048 ml) , 0.00059 moles) in? /,? / - d.methylformamide (5 ml) was cooled to about 0 ° C while stirring under a continuous flow of nitrogen and 2-ethylhexyl chloroformate (0.105 ml, 0.000536 moles ) was added in drops. Stirring at about 0 ° C was continued for about an additional 40 minutes and the reaction mixture was poured into ice water (20 ml). The precipitate was collected by filtration and dried. This was triturated in xylenes and the suspension was heated to reflux for about 2 hours under a continuous flow of nitrogen. The solvent was removed under reduced pressure and the yellow residue was purified by preparative RP-HPLC (10% to 50% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes, 21 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 8 μm, 250 x 21.2 mm) to produce trans-3- [4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl] -4H- [1,2,4] oxadiazol-5-one (0.018 g, 0.0423 mmole) as a white solid: RP-HPLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 1 1 .27 . Fra / 7S-3- [4- (4-Amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1 -I) -cyclohexyl] -4H- [1, 2,4] oxadiazole was reacted -5-one (0.032 g, 0.000075 moles) with (5,7-dimethyl-benzoxazol-2-yl) - [4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2 -yl) -phenyl] -amine (0.032 g, 0.0009 mole) (prepared using general procedures G and D) using general procedure C to produce trans-3- (4- [4-amino-3- [4- ( 5, 7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl] -cyclohexyl) -4H- [1, 2, 4] oxadiazol-5-one (0.021 g, 0. 0000384 moles) as a whitish solid; RP-HPLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, 20 minutes to 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 16.63 min; 1 H NMR (DMSO-d6, 400 MHz) d 10.86, 8.24, 7.95, 7.67, 7.1 1, 6.80, 4.71, 2.89, 2.73, 2.41, 2.31, 2.01.

Example # 378 Fra /? S- (4- {4-Ami} -3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] piri mid in-1 -insert hexi I oxy) -acetic Example # 379. Ira /? s-2- (4- { 4-Amino-3- [4- (5,7-dimethyl-benzoxazoi-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1 -yl.}. -cyclohexyloxy) -ethanol A mixture of frat7s-4- (4-amino-3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl) -cyclohexanol (0.50 g, 0.00139 mol) was heated (prepared using general procedures A, T and U) and dimethylformamide dimethylacetal (0.24 ml, 0.00181 mol) in N, N-dimethylformamide (10 ml) at about 85 ° C under continuous nitrogen flow for about 16 hours. The solvent was removed under reduced pressure and the residue was triturated with ethyl acetate (20 ml). The precipitate was collected by filtration, washed with ethyl acetate and dried to yield tran-N '- [1- (4-hydroxy-cyclohexyl) -3-iodo-1-t-pyrazolo [3,4-d] ] pyrimidin-4-yl] -V,? / -dimethyl-formamidine (0.30 g, 0.00075 mol) as a yellow solid; RP-H PLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, regulated at pH 4.5, for 20 minutes at 1.7 ml / min;? = 254 nm; Hypersil C18 column, 100 A , 5 μm, 250 x 4.6 mm) Rt 1 1 .97 min. Ethyl diazoacetate (0.047 ml, 0.046 moles) was added to a mixture of frans-? '- [1 - (4-hydroxycyclohexyl) -3-iodo-1 r / -pyrazolo [3,4-d] pyrimidin-4-yl] -? /,? / - dimethyl-formamidine (0.20 g, 0.483 mmoles) and rhodium acetate dimer (0.01 g, 0.023 mmol) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature under continuous nitrogen flow for about 78 hours. Additional ethyl diazoacetate (0.047 ml, 0.046 moles) was added after 4, 8, 72, 74 and 76 hours. The solvent was removed under reduced pressure and the residue was purified by preparative RP-HPLC (10% to 60% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 25 minutes at 21 ml / min.;? = 308 nm; Hypersil C18 column, 100 A, 8 μm, 250 x 21.2 mm) to produce ethyl ester of fraps- acid. { 4- [4- (dimethylaminomethyl-eneamino) -3-iodo-pyrazolo [3,4-d] pyrimidin-1-yl] -cyclohexyloxy} -acetic (0.044 g, 0.0883 mmole) as a whitish solid; RP-HPLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 10 minutes, regulated in its pH to pH 4.5, for 10 minutes at 1.7 ml / min; ? = 308 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) Rt 10.68 min. The fraps- ethyl ester was coupled. { 4- [4- (dimethylaminomethyl-eneamino) -3-iodo-pyrazoo [3,4-d] pyrimidin-1-yl] -cyclohexyloxy} -acetic (0.27 g, 0.00054 moles) with (5,7-dimethyl-benzoxazol-2-yl) - [2-fluoro-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan -2-yl) -phenyl] -amine (0.236 g, 0.648 mmol) (prepared using the general procedures G and D) using the general procedure G to produce trans- (4- {4-amino-3- [4- (5,7-Dimethyl-benzoxazol-2-ylmethyl) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl] -cyclohexyloxy-acetic acid (0.209 g, 0.397 mmol) as a white solid, RP-HPLC (10% to 80% acetonitrile / O.01 M aqueous ammonium acetate, for 6 minutes at 0.8 ml / min;? = 190-700 nm; Genesis column C18, 120 A, 3 μm, 30 x 4.6 mm) Rt 5.27 min; m / z (M + H) + 528. A solution of aluminum hydride (1 M in tetrahydrofuran, 0.266 ml, 0.266 mmole) was added dropwise to an acid suspension. frans- (4-. {4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylmethyl) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl}. -cyclohexyloxy) -acetic (0.035 g, 0.064 mmol) in tetrahydrofuran (5 ml) and the reaction mixture. The ion was stirred at room temperature under continuous nitrogen flow for about 24 hours. The reaction was quenched by a dropwise addition of ice water (1 ml) and the solvents were removed under reduced pressure and the residue was purified by preparative RP-HPLC (10% to 60% acetonitrile / 0.05M aqueous ammonium acetate , regulated in its pH to pH 4.5, for 25 minutes at 21 ml / min; ? = 308 nm; Hypersil C18 column, 100 A, 8 μm, 250 x 21.2 mm) to produce trans-2- (4. {4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylmethyl ) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl.}. -cyfohexyloxy) -ethanol (0.026 g, 0.051 mmol) as a white solid: RP-HPLC (30% to 95% acetonitrile / 0.01 M aqueous ammonium acetate, 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Genesis C18 column, 120 A, 3 μm, 30 x 4.6 mm) R, 1.99 min; / z (M + H) + 514.

Preparation # 27. c / s-. { 5- (4-Amino-3-fluoro-phenyl) -6-bromo-7- [4- (4-methyl-p-piperazin-1-yl) -cyclohexyl] -7W-pyrrolo [2, 3-d] pyrimidin-4-ylamine} A 25 ml round bottom flask equipped with a nitrogen inlet was charged with c / s-. { 5- (4-amino-3-fluoro-phenyl) -7- [4- (4-methyl-piperazin-1-yl) -cydohexyl] -7W-pyrrolo [2,3-d] pyrimidin-4-ylamine} (prepared using the general procedures A, B, T, J, C and L) (600 ml, 1.42 mmol) and? /,? / - dimethylformamide (10 ml), N-Bromosuccinimide (264 mg, 1.48 mmol) was added in portions to the reaction mixture for about 45 minutes. The reaction mixture was stirred at room temperature for approximately 29 hours. Additional N-bromosuccinimide (240 mg, 1.35 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for about 3 days. The solvent was removed under reduced pressure and the residue was incorporated in? , V-dimethylformamide. The precipitate was filtered and washed with N, N-dimethylformamide. The combined organic washings and filtrate were concentrated to produce a thick orange-brown oil which was purified by preparative RPLC activated by mass (25% to 85% acetonitrile / 0.05M aqueous ammonium acetate regulated at its pH to pH 4.5, for 6.5 minutes at 24 ml / min;? = 254 nm; Hypersil C18 column, 130 A, 5 μm, 100 x 21.2 mm) to produce cís-. { 4- (4-amino-3-f-uoro-f-enyl) -6-bromo-7- [4- (4-methyl-piperazin-1-yl) -cydohexyl] -7H-pyrrolo [3,4-d] ] pyrimidin-4-ylamine} as a pale brown solid (25 mg, 0.0498 mmol); m / z (M + H) + 502.

Example # 380 c / s-. { 4- [4- (7-Ethyl-5-methyl-benzoxazol-2-ylamino) -3-fluoro-phenrl] -7- [4- (4-methyl-piperazin-1-yl) -cyclohexyl] -7H- pyrrolo [2,3-d] pyrimidin-4-ylamine} A 25 ml round bottom flask equipped with a reflux condenser adapted with a nitrogen inlet with c s- was charged. { 5- [4- (7-Bromo-5-methyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7- [4- (4-methyl-piperazin-1-yl) -cyclohexyl] -7H- pyrrolo [2,3-d] pyrimidin-4-ylamine} (prepared using the general procedures A, B, T, J, C, L and G (F, H)) (188 mg, 0.297 mmol), palladium acetate (ll) (3 mg, 0.015 mmol), 2- ( dicyclohexylphosphino) biphenyl (1 mg, 0.030 mmol), sodium carbonate (79 mg, 0.743 mmol), ethylene glycol dimethyl ether (2 ml) and water (1 ml). Triethylborane (1.0 M solution in tetrahydrofuran, 0.60 ml, 0.594 mmol) was added and the mixture was heated to about 80 ° C for about 2 hours. Palladium (II) acetate (3 mg, 0.015 mmol), 2- (cyclohexylphosphino) biphenyl (1.1 mg, 0.030 mmol) and triethylborane (0.25 ml, 0.25 mmol) were added to the reaction mixture and the mixture was stirred to dryness. room temperature for approximately 17 hours. Additional palladium (ll) acetate (3 mg, 0.015 mmol), 2- (cyclohexylphosphino) biphenyl (11 mg, 0.030 mmol) and triethylborane (0.25 ml, 0.25 mmol) were added and the mixture was stirred at approximately 80 ° C. for an additional hour. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous phase was separated and further extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate and the organic solvent was removed under reduced pressure to produce a red-brown oil. The product was purified by preparative reverse phase HPLC (15% to 75% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 30 minutes at 21 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 8 μm, 250 x 21 .2 mm) to produce cis-. { 5- [4- (7-ethyl-5-methyl-benzoxazol-2-ylamino) -3-f luo-ro-phenyl] - / - [4- (4-methyl-piperazin-1-yl) -cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino} (85 mg, 0.146 mmol) as an off-white solid; RP-H PLC (Delta Pak C18, 5 μm, 300 A, 15 cm, 5% to 85% acetonitrile / 50 mM aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes, 1 ml / min) Rt 13.80 min, m / z (M + H) + 538.

Example # 381 c / s-. { 7- [4- (4-cyclopropyl-piperaz? N-1-yl) -cyclohexyl] -5- [4- (5,7-di-methyl-benzoxazo-2-i-min) -3-f luoro -f on I] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine} A 25 ml round bottom flask equipped with a reflux condenser, adapted with a nitrogen inlet was charged with c / s-. { 5- [4- (5,7-DimetiI-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7- (4-piperazin-1-yl-cyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine} (prepared by general procedures A, B, T, J, C, L and G) (100 mg, 0.180 mmol), methanol (3 ml), acetic acid (108 mg, 1.80 mmol) and sodium cyanoborohydride (45 mg) , 0.72 mmole) in methanol (3 ml). [(1-Ethoxycyclopropyl) oxy] -trimethylsilane (157 mg, 0.901 mmol) was added and the mixture was stirred at about 64 ° C for about 21 hours and then cooled to room temperature. The reaction mixture was filtered and the solids were washed with ethyl acetate. The combined organic washings and filtrate were concentrated to produce a thick yellow oil. The product was purified by preparative reverse phase HPLC (15% to 75% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 30 minutes at 21 ml / min;? = 254 nm; column Hypersil C18, 100 A, 8 μm, 250 x 21.2 mm) to produce cis-. { 7- [4- (4-cyclopropyl-piperazin-1-yl) -cyclohexyl] -5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3-f luoro-f eni!] - 7H - pyrrolo [2, 3-d] pyrimidin-4-ylamine} as a whitish solid (15 mg, 0.025 mmol); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm, 5% to 85% acetonitrile / 50 mM ammonium acetate for 20 minutes, 1 ml / min) Rt 13.495 min, m / z (M + H) + 595.

Example # 382 is-. { 6-Bromo-5- [4- (5,7-dimetiI-benzoxazol-2-ylami no) -3-f luoro-phenyl] -7- [4- (4-meth i-piperaz-n-1 -yl) -cyclohexy I] -7H-pyrrolo [2,3-d] pyrim id in-4-i lamina} This compound was prepared from c / s-. { 5- (4-amino-3-f luoro-f en il) -6-bromo-7- [4- (4-metii-piperazin-1-yl) -cyclohexyl] -7 / V-pyrrolo [2,3 -d] pyrimidin-4-yamine} (preparation # 28) and 2-amino-4,6-dimethyphenol, using general procedure G, to produce cis-. { 6-bromo-5- [4- (5,7-dimethyl-benzoxazol-2-yamino) -3-f luoro-f eni] -7 - [4- (4-methyl-piperazin-1-yl) ) -cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine} as a beige solid (4 mg, 0.007 mmol); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm, 5% to 85% acetonitrile / 50 mM aqueous ammonium acetate for 20 minutes, 1 ml / min) Rt 15.45 min, m / z (M + H) + 647.

Example # 383 c / s-. { 5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7- [4- (4-methanesulfonyl-piperazin-1 -I) -cyclohexyl] -7H -pyrrolo [2,3-d] pyrimidin-4-ylamine} Methanesulfonyl chloride (7 μl, 0.093 mmol) was added to a solution of c / s-. { 5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7- (4-piperazin-1-yl-cyclohexyl) -6,7-dihydro-5-pyrrolo [ 2,3-d] pyrimidin-4-ylamine} (prepared using general procedures A, B, T, J, C, L and G) (51 mg, 0.093 mmol) and triethylamine (13 μl, 0.093 mmol) in dichloromethane (7 ml) at about 0 ° C under one atmosphere inert. The solution was slowly warmed to room temperature and the reaction mixture was stirred for about 3 weeks. Additional methanesulfonyl chloride (14 μL, 0.186 mmole) and triethylamine (26 μL, 0.186 mmole) were added to the reaction mixture during this time. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (15 mL) and the crude product was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and the solvent was removed under reduced pressure. The unpurified mixture was purified by preparative reverse phase HPLC (Delta Pak C18, 5 μm, 300 μA, 15 cm, 10% to 60% acetonitrile / 50M aqueous ammonium acetate for 25 min, 20 ml / min) to produce cis-. { 5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3-i: i uoro-f-enyl] -7- [4- (4-methanesulfonyl-piperazin-1-yl) - cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yamine} as a whitish solid (12 mg, 0.019 mmol); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm, 5% to 95% acetonitrile / 50 mM aqueous ammonium acetate for 10 minutes, 1 ml / min) Rt 9.06 min, m / z (M + H) + 633.

Example # 384 3- [4- (5J7-Dimethyl-benzoxazol-2-ylamino) -phenyl] -1- (4-methylene-cyclohexyl) -1 H-pyrazoo [3,4-d] pyrimidin-4-ylamine To a suspension of methyltriphenylphosphonium bromide (7.64 g, 21.4 mmol) in tetrahydrofuran (200 mL) at about -78 ° C was added n-butyllithium (0.69 M in tetrahydrofuran, 31 mL, 21.4 mmol) so that the temperature of the reaction did not exceed approximately -50 ° C. The reaction mixture was slowly warmed to room temperature and stirred for about 2 hours. The mixture was cooled again below about -20 ° C and a solution of 4-. { 4-amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl} -cydohexanone (prepared by the general procedures A, T and C) (5.0 g, 10.7 mmol) in tetrahydrofuran (80 ml) was added. The reaction mixture was then stirred at about 50 ° C for about 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (100 ml) and dichloromethane (150 ml). The organic layer was extracted and the aqueous layer was extracted with additional dichloromethane (2 x 150 mL). The combined organic fractions were washed with brine (150 ml), dried over magnesium sulfate and the solvent was removed under reduced pressure to produce an orange syrup. The crude product was purified by flash column chromatography on silica gel using dichloromethane / acetone (75:25) as the mobile phase to give e- [4- (5,7- dimetH-benzoxazol-2-ylamino) -phenyl) ] -1- (4-methylene-cyclohexyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine as a white solid (4.0 g, 8.59 mmol); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm, 5% to 95% acetonitrile / 50 mM aqueous ammonium acetate for 10 minutes, 1.7 ml / min) R t 12.82 min, m / z (M + H) + 466.

Example # 385 c / s-. { 3- [4- (5,7-Di-methy1-benzoxazole-2-ylamino) -f-enyl] -1- (3-met-il-1 -oxa-2-aza-spiro [4.5] dec-2 -in-8-yl) -1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine} To a solution of acetaldoxime (102 mg, 1.72 mmol) in / V, / V-dimethylformamide (2.5 ml) at about 0 ° C was added N-chlorosuccinimide (230 mg, 1.72 mmol). The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1 hour under a nitrogen atmosphere. A solution of 3- [4- (5, 7-di methylo-be nzoxazoi-2-yla min o) -f-enyl] -1- (4-methylene-cyclohexyl) -1H-pyrazolo [3,4- d] pyrimidin-4-ylamine (Example # 384) (1.00 g, 2.15 mmoles) in? / ,? dimethylformamide (12 ml) was added to the reaction mixture in one portion at room temperature, followed by a solution of triethylamine (250 μl, 1.80 mmol) in? /,? / - dimethylformamide (2 ml), which was added slowly for about 2 hours. The reaction mixture was stirred for 15 hours at room temperature. The unpurified reaction mixture was partitioned between water (25 ml) and dichloromethane (25 ml), the organic layer was separated and the aqueous layer was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure. The unpurified mixture was purified by preparative reverse phase H PLC (C18, 8 μm, 260 x 21.2 mm, 70% to 80% acetonitrile / 50 mM aqueous ammonium acetate for 20 minutes, 21 ml / min) to produce cis-. { 3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -1- (3-methyl-1-oxa-2-aza-spiro [4.5] dec-2-en-8-yl) ) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine} as a light yellow solid (31 mg, 0.059 mmol); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm, 5% to 95% acetonitrile / 50 mM aqueous ammonium acetate for 10 minutes, 1.7 ml / min) R t 12.72 min, m / z (M + H) + 523.

Example # 386 frans-3- (4-Benzoxazol-2-ylmethyl-phenyl) -1 - [4- (4-methyl-piperazin-1-yl) -cyclohexyl] -1 H -pyrazolo [3,4-d] pyrim id in-4-i lamina 2-Aminophenol (0.257 g, 2.36 mmol) and 4-bromophenylacetic acid (0.500 g, 2.36 mmol) were heated together to approximately 200 ° C e a test tube open for 1 hour. The reaction mixture was cooled to room temperature, dissolved in methanol-dichloromethane (1: 20, 50 ml), and extracted with dilute aqueous sodium carbonate (10 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, using ethyl acetate-heptane (15:85) as the mobile phase, to produce 2- (4-bromobenzyl) -benzoxazole (0.347 g, 1. 20 mmol) like yellow flakes; m / z (M + H) + 288, 290. 2- (4-Bromo-benzyl) -benzoxazole (0.100 g, 0.347 mmol) was converted to 2- [4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) ~ benzyl-J-benzoxazole using general procedure D, and the unpurified product was then reacted, using general procedure C, with tra ns-3-iodo-1 - [ 4- (4- meti lp i pe razin- 1 -il) -cid or hexyl] -1H-pyrazole or [3,4-d] pyrimidin-4-ylamine (prepared using general procedures A, T and J) to produce trans-3- (4-benzoxazol-2-ylmethyl-phenyl) -1- [4- (4-methyl-piperazin-1-yl) -cyclohexy] -1H-pyrazolo [3,4- d] pyrimidin-4-ylamine as a white powder (0.102 g, 0.195 mmol); RP-HPLC (25% to 100% acetonitrile / O.1 M aqueous ammonium acetate, regulated at pH 4.5, for 10 minutes at 1.0 ml / min;? = 254 nm; Hypersil C18 column, 100 A, 5 μm, 250 x 4.6 mm) R t 6.83 min; m / z (M + H) + 523.

Preparation # 28. JV- (3-Bromo-1-methyl-1 H-pyrazolo [3,4-d] irimidin-6-ii) -phenethylamine To a solution of 3-bromo-6-methanesulfonyl-1-methyl-1 H-pyrazolo [3,4-d] pyrimidine (WO 03029209) (0.282 g, 0.969 mmol) in 1-methyl-2-pyrrolidinone (10 ml phenethylamine (0.587 g, 4.85 mmol) was added and the reaction mixture was heated to about 50 ° C. After about one hour, water (40 ml) was added, followed by ethyl acetate (40 ml). The layers separated. The aqueous portion was re-extracted with ethyl acetate (2 x 20 ml). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and evaporated. The unpurified yellow residue was purified by flash column chromatography on silica gel, using ethyl acetate / heptane (1: 1) as the mobile phase, to give (3-bromo-1-metH-1 H-pyrazolo [3 , 4-d] pyrimidin-6-yl) -phenethyl-amine as a white solid (0.205 g, 0.636 mmol); RP-H PLC (5% to 95% acetonitrile / 0.05M aqueous ammonium acetate, regulated in its pH at pH 4.5, for 10 minutes at 1.7 ml / min, 15 minutes total activation time; = 254 nm; Hypersil C18 column, 5 μm, 100 A, 250 x 4.6 mm) Rt 1. 1.78 min; m / z (M + H) + 332 and 334.

Preparation # 29. ? - (4-Bromo-phenyl) - [5-methyl-7- (3-morpholin-4-yl-propoxy) benzoxazole -2-il] -a mi na Preparation # 29.1. 2- (3-Bromo-propoxy) -1-methoxy-4-methyl-benzene A solution of 2-methoxy-5-methyl-phenol (5.0 g, 36.2 mmol), 1,3-dibromopropane (40 ml, 360 mmol), tetrabutylammonium hydroxide (16 ml, 24.25 mmol) and 40% w / w of aqueous potassium hydroxide (180 mmol) was stirred at 55 ° C for 1 hour. The solution was diluted with ether, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting oil was subjected to flash chromatography eluting with hexanes and gradually increasing the polarity to 10% ethyl acetate to give 2- (3-bromo-propoxy) -1-methoxy-4-methyl-benzene (6.5 g, 70 g. % of performance).

Preparation # 29.2. 4- (3- (2-Methoxy-5-methyl-phenoxy) -propyl] -morpholine A solution of 2- (3-bromo-propox?) - 1-methoxy-4-methyl-benzene (3.0 g, 1.1 1.6 mmol) and morpholine (5.05 ml, 57.9 mmol) in TH F (60 ml) it was heated at 65 ° C for 2 hours. The solution was cooled to room temperature, diluted with ether, washed with water and brine, dried magnesium sulfate, filtered and concentrated to give 4- [3- (2-methoxy-5-metH-phenoxy) - propyl] -morpholine (3.01 g, 97% yield); m / z: (M +) + 319, 321.

Preparation # 29.3. 4-Methyl-2- (3-orpholin-4-yl-propoxy) -phenol A solution of 4- [3- (2-methoxy-5-methyl-phenoxy) -propyl] -morpholine (3.0 g, 11.31 mmol) in acetic acid (25 ml) and H Br (25 ml) was stirred at 90 ° C for 4 hours. The solution was cooled to room temperature and condensed. The resulting residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate. The organics were combined and the solvent was removed under reduced pressure to give 4-methyl-2- (3-morpholin-4-yl-proxy) -phenol (2.36 g); m / z (M + H) + 251.

Preparation # 29.4. 4-Methyl-2- (3-morpholin-4-yl-propoxy) -6-nitro-phenol A solution of -78 ° C of 4-methyl-2- (3-morpholin-4-yl-propoxy) -phenol (2.36 g, 9.4 moles) in DME (66 ml) was added to a solution of NO2BF4 (1.27. mmoles) in DME (44 ml) at -78 ° C. The solution was stirred and allowed to warm to -10 ° C. Ice was added to extinguish the solution. The solution was condensed to remove DME. The residue was cooled in an ice bath, neutralized with aqueous sodium bicarbonate, and extracted with methylene chloride. The organics were combined, condensed and the residue was subjected to flash chromatography on silica gel eluting with 1% TEA / 1% MeOH / methylene chloride. The first fraction contained the desired product, an orange semi-solid. This material was subjected to a second instantaneous column, eluting with 5: 5: 1 ethyl acetate: hexanes: methanol (to remove triethylamine salt) to give 4-methyl-2- (3-morpholin-4-ii-propoxy) ) -6-nitro-phenol 80.687 g, 25% yield), m / z (M + H) + 297.

Preparation # 29.5. 2-Amino ~ 4 ~ methyl-6- (3-morpholin-4-yl-propoxy) -phenol A solution of 4-metii-2- (3-morpholin-4-yl-propoxy) -6-nitro-phenol (0.687 g, 2.32 mmol) and Pd / C (0.116 mol) in methanol (65 ml) was stirred under a hydrogen atmosphere for 4 hours. The system was purged with nitrogen, filtered through celite and condensed. The residue was triturated with methanol to give 2-amino-4-methyl-6- (3-marfolin-4-yl-propoxy) -phenol (0.315 g, 51% yield); miz: (M + H) + 267.

A solution of 2-amino-4-methyl-6- (3-morpholin-4-yl-propoxy) -phenol (0.315 g, 1.18 mmol) and 1-bromo-4-isothiocyanato-benzene (0.245 g, 1.14 mmol) in THF (6 ml) was stirred at room temperature under a nitrogen atmosphere for 3.5 hours. EDCl (0.262 g, 1.36 mmol) was added and the solution was stirred at 50 ° C overnight, then cooled to room temperature resulting in the oil outside the product. The solution was concentrated and the residue was taken up in acetonitrile, heated to obtain a homogeneous solution and cooled to room temperature. The resulting precipitate was removed by vacuum filtration. The filtrate was condensed and the residue was partitioned between ethyl acetate and water. The organic layer was condensed and the residue was triturated from acetonitrile to give (4-bromo-phenyl) - [5-methoxy-7- (3-morpholin-4-yl-propoxy) -bnzoxazol-2-yl] - amine (0.335 g, 61% yield); m / z (M +) 445, 447.

Preparation # 30. (4-Bromo-phenyl) - [5-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -benzoxazol-2-yl] -amine Preparation # 301. 4- (2-Methoxy-5-methyl-l-f-enoxy-methyl) -1-methylpiperidine A solution at 0 ° C of 2-methoxy-5-methyl-phenol (3.45 g, 25 mmol) in THF (110 ml) was treated with triphenylphosphine (7.87 g, 30.0 mmol), followed by DEAD (4.72 ml, 30.0 mmol). ), stirred for 5 minutes, then treated with a solution of (1-methyl-piperidin-4-yl) -methanol (3.88 g, 30.0 mmol) in THF 8150 ml). The ice bath was stirred and the solution was stirred at room temperature overnight. The solution was condensed and subjected to flash chromatography on silica gel eluting with 5% MeOH / methylene chloride to give 4- (2-methoxy-5-methyl-phenoxymethyl) -1-methyl-piperidine (3.58 g, 57 % yield); m / z (M + H) + 250. The remainder of the synthesis was completed, using the detailed route for preparation # 29, by replacing preparation # 30.1 with preparation # 29.2 to produce (4-bromo-phenyl) - [5-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -benzoxazol-2-yl] -amine; m / z (M) + 429, 431.

Preparation # 31. (7-Allyl-5-methyl-benzoxazol-2-yl) - (4-bromo-phenyl) -amine Preparation # 31.1. 2-Allyl-4-methyl-phenol A solution of allyl para-tolyl ether (1 g) in N, N-diethylaniline (5 ml) was heated at 180 ° C for 18 hours, allowed to cool to room temperature, then partitioned between 1 N HCl and ether (2x). ). The combined ether extracts were dried (Na2SO), concentrated and the residue was purified through silica gel chromatography eluting with 15: 1 hexanes: EtOAc to give 2-allyl-4-ethyl-phenol (0.67 g) . The rest of the synthesis was completed, using the detailed route for preparation # 29, substituting preparation # 31 .1 for preparation # 29.3 to produce (7-allyl-5-methyl-benzoxazole-2-ii) - ( 4-bromo-phenyl) -amine; m / z; (M + H) + 342.9, 344.9.

Preparation # 32. (4-Bromo-phenyI) - [5-methyl-7- (3-morpholin-4-yl-propyI) -benzoxazol-2-yl] -amine * -r? Cr Preparation # 32.1 3- [2- (4-Bromo-phenylamine) -5-methyl-benzoxazol-7-yl] -propan-1-ol Borane-THF (98 ml, 1 M in TH F, 98 mmoles) was added in drops to a 0 ° C solution of preparation # 31 (6.74 g, 19.6 mmol) in THF (300 ml). The resulting mixture was stirred at 0 ° C for 3 hours, carefully treated with NaoH 6? / (13.5 ml), then with 30% H2O2 (27 ml), heated at 60 ° C for 1.2 hours, then extinguished with NaHS? 3 aqueous saturated (added in drops). The acidic mixture (pH 1-2) was neutralized with saturated aqueous NaHCO3 and extracted with ether (2x). The combined ether extracts were dried (Na2SO4), concentrated and the residue was purified through silica gel chromatography eluting with 2: 1 hexanes: EtOAc and subsequent trituration with CH2CI2 yielded 3- [2- (4- bromo-phenylamino) -5-methyl-benzoxazol-7-yl] -propan-1 -ol as a solid (3.98 g, 56% yield); m / z (M + H) + 360.9, 362.9.

Preparation # 32.2. 3- [2- (4-bromo-phenylamino) -5-methyl-benzoxazol-7-yl] -propyl ester of methanesulfonic acid A 0 ° C solution of 3 - [2- (4-bromo-phenylamino) -6-methyl-benzoxazol-7-yl] -propan-1-ol (0.34 g, 0.94 mmol) in pyridine (10 ml) was treated. with methanesulfonyl chloride (0.08 ml), stirred at 0 ° C for 15 minutes, then at room temperature, for an additional 2 hours, then treated with additional methanesulfonyl chloride (0.1 ml) and stirred for 3 hours. The mixture was partitioned between ether and water, and the organic extract was washed with brine, dried (MgSO4), filtered and concentrated to give 3- [2- (4-bromo-phenylamino) -5-methyl-benzoxazole- 7-II] -propyl ester of the crude methanesulfonic acid (0.36 g); m / z (M + H) + 438.9, 440.7.

A solution of the 3- [2- (4-bromo-phenylamino) -6-methyl-benzoxazol-7-yl] -propi-ester of methanesulfonic acid (0.047 g) and morpholine (1 ml) in DMF (2 ml) was heated at 80 ° C for 3 hours, it was allowed to cool to room temperature, then it was partitioned between water and ether. The organic extract was washed with brine, dried (MgSO4), filtered, concentrated and the residue was triturated with ether to give (4-bromo-phenyl) - [5-methyl-7- (3-morfoiin-4- il-propyl) -benzoxazol-2-ii] -amine (0.03 g); m / z (M + H) + 429.8, 431.8.

Preparation # 33.2 2- (4-Bromo-phenylato) -5-methyl-benzoxazoI-7-ol Preparation # 33.1. (4-Bromo-fTil) - (7-methoxy-5-methyl-benzoxazol-2-yl) -amine --oi OjMß Substituting 2-methoxy-4-methyl phenol for preparation # 29.3 and following the detailed steps to complete the synthesis of preparation # 29 produced (4-bromo-phenyl) - (7-methoxy-5- methyl-benzoxazol-2-yl) -amine. A solution of (4-bromo-phenyl) - (7-methoxy-5-methyl-benzoxazol-2-yl) -amine (4.46 g) in acetic acid (60 ml) and 48% HBr (60 ml) was heated refluxed for 6 hours, then stirred at room temperature for 10 hours. The resulting precipitate was collected through filtration to give 2- (4-bromo-phenylamino) -5-methyl-benzoxazol-7-ol (3.66 g); m / z (M + H) + 318.9, 320.8.

Preparation # 34. (4-Bromo-phenyI) - (5-methoxy-benzoxazol-2-yl) -amine By substituting 2-nitro-4-methoxy phenol for preparation # 29.4 and following the detailed steps to complete the synthesis of preparation # 29, (4-bromo-phenyl) - (5-methoxy-benzoxazol-2-yl) was produced. ) -amine; m / z (M + H) + 319, 321.

Preparation # 35. (4-Bromo-phenyl) - [5-methyl-7- (2-pyrrolidin-1-yl-ethoxy?) - benzoxazol-2-yl] -amine -Ot < Cr When using the route described from preparation # 29. 1 to preparation # 29, replacing 1,2-dibromoethane for 1,3-dibromopropane and pyrrolidine by morpholine produced (4-bromo-phenyl) - [5-methyl-7- (2-pyrrolidine) 1-yl-ethoxy) -benzoxazole-2-H] -a mine; m / z (M + H) + 416, 418.

Preparation # 36. (4-Bromo-phenyl) - [7- (2-dimethylamino-ethoxy) -5-methyl I -benzoxazole -2-yl] -a mi na A mixture of preparation # 33 80.09 g, 0.28 mmol), Cs2CO3 (0.37 g, 1.13 mmol) and (2-chloro-ethyl) dimethylamine hydrochloride (0.044 g, 0.3 mmol) in DMF (1.5 ml) was heated at 80 ° C for 8 hours, at room temperature, then it was partitioned between water and ether (2x). The combined extracts were dried (MgSO4), concentrated and the residue was purified through silica gel chromatography eluting with 5: 4: 1 hexanes: EtOAc: methanol to yield (4-bromo-phenyl) - [7- ( 2-dimethylamino-ethoxy) -5-methyl-benzoxazol-2-yl] -amine (0.103 g, 94% yield); m / z (M + H) + 389.9, 391.8.

Preparation # 37. 2- (4-Bromo-phenylamino) -5-chloro-benzoxazole-7-ol Preparation # 37.1. (4-Bromo-phenyl) - (5-chloro-7-methoxy-benzoxazol-2-yl) -amine By substituting 4-chloro-2-methoxyphenol for preparation # 29.3 and completing the synthetic route, for preparation # 29, (4-bromo-phenyl) - (5-chloro-7-methoxy-benzoxazol-2-yl) was produced )-amine.

A mixture of (4-bromo-phenyl) - (5-chloro-7-methoxy-benzoxazol-2-yl) amine (0.687 g, 1.9 mmol), 2,4,6-collidine (10 ml) and Lil (1.04) g, 7.7 mmoles) was heated to reflux overnight, cooled to room temperature, diluted with 1 N HCl and extracted with ether (4x). The combined ether extracts were dried (Na2SO4), filtered and concentrated to give 2- (4-bromo-phenylamino) -5-chloro-benzoxazole-7-ol 80.58 g, 88% yield); m / z (M + H) "336.8, 338.8.

Preparation # 38. 2- (4-Bromo-2-fluoro-phenylamino) -5-cioro-benzoxazole-7-ol Following the steps of preparation # 29.4 to preparation # 29, substituting 4-cyclo-2-methoxyphenol for preparation # 29.3 and 4-bromo-2-fluoro-1-isothiocyanatobenzene for 4-b rom or 1- isothiocyanatobenzene was produced 2- (4-bromo-2-fluoro-phenylamino) -5-chloro-benzoxazol-7-ol; m / z (M + H) + 356.8, 358.8.

Preparation # 39. 5-Iodo-7- (4-nitro-benzyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine Preparation # 39.1. 4-Chloro-5-iodo-7- (4-nitro-benzyl) -7H-pyrrolo [2,3-d] pyrimidine Sodium hydride (0.47 g, 60% oil dispersion, 11.8 mmol) was added in portions to a solution of 4-chloro-5-iodo-7H-pyrroIo [2,3-d] pyrimidine (3.0 g. , 10.7 mmoles) in DMF (50 ml) and the resulting mixture was stirred at room temperature for 40 minutes, then treated with 4-nitrobenzyl bromide (2.58 g, 1.8 mmoles) and stirred for an additional 3 hours. The mixture was diluted with water and extracted with THF-ether (2x). The extract was cooled to -20 ° C for 4 hours, and the resulting precipitate was collected through filtration to give 4-chloro-5-iodo-7- (4-nitro-benzyl) -7H-pyrrolo [2, 3 -d] pyrimidine (3.8 g); / z (M + H) + 414.8.

A mixture of 4-chloro-5-iodo-7- (4-nitro-benzyl) -7H-pyrrolo [2,3-d] pyrimidine (1 g) and concentrated NH OH (15 ml) in dioxane (15 g) was added. ml) was heated at 120 ° C in a sealed tube for 4 hours, allowed to cool to room temperature and then treated with water (30 ml) and stirred for 1 hour. The resulting precipitate was collected through filtration to give 5-iodo-7- (4-nitro-benzyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.83 g, 87% yield); m / z (M + H) + 395.9.

Preparation # 40. 5-Yod o-7- (3,4,5-tri-methoxybenzyl) -7H-pi or R [2, 3-d] pyrimidin-4-ylamine Preparation # 40.1. 4-Chloro-5-iodo-7- (3,4,5-trimethoxy-benzyl). -7H-pyrrolo [2,3-d] pyridine A solution of 4-chloro-5-iodo-7H-pyrrolo [2,3-d-pyrimidine (2.0 g, 7.16 mmol) in THF (75 ml) was treated sequentially with 3,4,5-trimethoxybenzyl alcohol (1.3 ml, 7.87 ml). mmoles), Ph3P (3.8 g, 14.3 mmol), DIAD (2.91 ml, 14.3 mmol) was stirred at room temperature for 18 hours, then diluted with water and extracted with ether, then with CH2Cl2. The combined extracts were dried (MgSO), filtered and concentrated. The residue was triturated from ether, then CH2CI2 to give 4-phosphorus-5-iodo-7- (3,4,5-trimethoxy-benzyl) -7H-pyrrolo [2,3-d] pyrimidine (1.32 g); m / z (M + H) + 459.9. 4-Chloro-5-iodo-7- (3,4,5-trimethoxy-benzyl) -7H-pyrrolo [2,3-d] pyrimidine was reacted using the protocol detailed in the synthesis of preparation # 39.2 to produce 5-iodo-7- (3,4,5-trimethoxy-benzyl) -7H-pyrrolo [2,3-d] pyrmidin-4-ylamine; m / z (M + H) + 441.2.

Preparation # 41. 3-Iodo-1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine By substituting methyl iodide and 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine for 4-nitrobenzyl bromide and 4-chloro-5-iodo-7H-pyrrolo [2,3-d] ] pyrimidine, respectively, in the synthesis of preparation # 39. 1 3-iodo-1-methyl-1H-pyrazolo [3,4- d] pyrimidin-4-iiamina was produced; m / z (M + H) + 275.9.

Preparation # 42. 5-Iodo-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-i lamina By replacing methyl iodide with 4-nitrobenzyl bromide in the synthesis of preparation # 39, 3-iodo-1-methyl-1 H -pyrrolo [3,4-d] pyrimidin-4-yamine is produced; m / z (M + H) + 274.8.

Preparation # 43. N- [4- (4-Amino-5-iodo-pyrroIo [2, 3-d] piri midin-7-i I met i I) -f in i l] -metansu lf ona m ida Preparation # 43.1 7- (4-Amino-benzyl) -S-iodo-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine A mixture of 5-iodo-7- (4-nitro-acyl) -7H-pyrrolo [2,3- d] pyrimidin-4-ylamine (preparation # 39, 0.66 g, 1.67 mmol) and iron powder (0.28 g) in Ethanol (10 ml) and water (5 ml) was stirred at 80 ° C for 1 hour, treated with an additional 0.1 g of iron powder, water (1 ml), THF (0.5 ml) and NH Cl (0.094 g). and stirred for another 4 hours. The resulting suspension was filtered through celite washing with CH2Cl2 and methanol. The filtrate was washed with water, dried (MgSO 4), concentrated and the residue was purified by silica gel chromatography eluting with 3% MeOH: CH 2 Cl 2 to give 7- (4-amino-benzyl) -5- iodine-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.33g); m / z (M + H) + 365.9. Methanesulfonyl chloride (0.033 ml) was added in drops to a solution at 0 ° C of 7- (4-amino-benzyl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.15 g) in CH 2 Cl 2 (10 mL) and pyridine (6 mL) and the resulting suspension was stirred at room temperature for 19 hours, then diluted with water. The precipitate was collected by filtration, then dissolved in THF, dried (MgSO), filtered and concentrated to give N- [4- (4-amino-5-iodo-pyrrolo [2,3-d] pyrimidin-7-ylmethyl) -phene] -metanesulfonamide (0.13 g); m / z (M + H) + 443.8.

Preparation # 44. 1- [4- (4-Amino-5-iodo-pyrrolo [2,3-d] pyrimidin-7-ylmethyl) -phenyl] -3- (2-hydroxyethyl) urea.

A cloudy solution of 7- (4-amino-benzyl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.154 g) and triethylamine (0.065 ml) in THF (8 ml) was added. treated with para-nitrophenylchloroformate (0.097 g) and stirred at 0 ° C for 1.5 hours. The reaction was then treated with ethanolamine (0.051 ml) and triethiamine (0.065 ml) and stirred at room temperature for 4 hours. The mixture was diluted with water (20 ml) was stirred at room temperature for 16 hours, and the resulting precipitate was collected through filtration, washed with water, dried at 50 ° C in a vacuum oven to give 1- [4- (4-amino-5-iodo-pyrroo [2,3-d] pyrimidin-7-methyl) -phenyl-3- (2-hydroxy-ethyl) -urea (0.17 g); m / z (M + H) + 452.9.

Preparation # 45. (4-Amino-5-iodo-pyrrolo [2,3-d] pyrimidin-7-yl) acetonitrile.

Substituting bromoacetonitrile for 4-nitrobenzyl bromide in the synthesis of preparation # 39 produced (4-amino-5-iodo-pyrrolo [2,3-d] pyrimidin-7-yl) -acetonitrO; m / z (M + H) + 299.07.

Preparation # 46. 3-Iodo-1-pyridin-3-ylmethyl-1 H-pirzolo [3,4-d] pyrimidin-4-ylamine Substituting 3-bromomethylpyridine monohydrobromide for 4-nitrobenzylbromide in the synthesis of preparation # 39 produces 3-iodo-1-pyridin-3-ylmethyl-1H-pyrazolo [3,4-d] pyrimidine-4 -amine; m / z (M + H) + 351.9. The following examples (# 387 to # 405) were synthesized by converting the bromides (eg, preparations # 29 to # 38) to the corresponding boronates using the general procedure D and reacting the boronates with the iodides (eg, preparations # 39). a # 46) using the general procedure C.

Example # 387 1-Pe nt i cycle I -3- [4- (5-methoxy-benzoxazole -2- i lami no) -phenyl] -1 H-pyrazoo [3,4-d] pyrimidin-4-ylamine Example # 388 3- [4- (5-Methoxy-benzoxazoI-2-ylamino) -phenyl] -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 389 7-Methyl-5-. { 4- [5-methyl-7- (3-morpholin-4-M-propoxy) -benzoxazole -2-i lamone] -fen i l} -7H -pirrólo [2, 3-d] piri idin -4-i the mine Example # 390 Methyl-3-. { 4- [5-methyl-7- (3-morpholin-4-yl-propoxy) -benzoxazol-2-ylamino] -phenyl} -1 H-pyrazolo [3,4-d] pyrim id n-4-ylamine Example # 391. 1 -Methyl-3-. { 4- [5-methyl-7-. { 1-methyl-p-peridin-4-ylmethoxy) -benzoxazol-2-ylamino] -fen? 'I} -1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 392. 1-Cyclopentyl-3-. { 4- [5-Methyl-7- (2-pyrrolidin-1-yl-ethoxy) -benzoxazo l-2-ylamino] -phenyl} -1 H- irazolo [3, 4-d] pirim idin -4-ilamine Example # 393. 1 -MetiI-3-. { 4- [5-methyl-7-. { 2-pyrrolidin-1-yl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -1 H-pyrazolo [354-d] pyrimidin-4-ylamine Example # 394 7-Cyclopentyl-5-. { 4- [5-methyl-7- (3-morpholin-4-ii-propoxy) -benzoxazole -2-i lami no] -f in i l} -7H-p i rrolo- [2,3-d] p iri mid i n-4-ilamine Example # 395 7-Methyl-4-. { 4- [5-methyl-7- (3-morpholin-4-yl-propyl) -benzoxazol-2-ylamino] -fenii} -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine.

Example # 396 3- [4- (7-AMI-5-methyl-benzoxazol-2-ylamino) -phenyl] -1-cyclopentyl-1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 397. 1-Cyclopentyl-3-. { 4- [7- (2-dimethylamino-ethoxy) -5-methyl-benzoxazol-2-ylamino] -phenyl} -1 H-pyrazolo [3,4-tí] pyrimidin-4-ylamine Example # 398 2- [4- (4-Amino-1-cyclopentyl-1 H -pyrazolo [3,4-d] pyrimin-3-yl) -phenylamino] -5-methyl-benzoxazole-7-ol Example # 399 N- (4-. {4-Amino-5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-ylmethyl}. -phenyl) - methanesulfonamide Example # 400 1 - (4- { 4-Amino-5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -pyrroI [2,3-d] pyrimid-7- ilmetl.}.-phenyl-3- (2-hydroxy-ethyl) -urea Example # 401 5- [4- (5,7-dimethyl-benzoxazoI-2-ylamino) -phenyl] -7- (3,4,5-trimethoxy-benzyl) -7H-pyrrolo [2,3-d] pyrimidi n-4-i lamina Example # 402 5- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -phenyI] -7- (4-nitrobenzyl) -7H-pyrrolo [2,3-d] pyridin-4-ylamine Example # 403 . { 4-Amino-5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -pheni] -pyrrolo [2 > 3-d] pyrimidin-7-yl} -acetonitrio Example # 404 5- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine Example # 405 5- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7-pyridin-3-ylmethyl-7H-pyrrolo [2,3-thi] [pyrimidin-4-ylamine] The method used to determine the HPLC retention time is given in a lowercase letter in parentheses (see Table 1).

Table 13. Summary of the synthesis and analytical data for examples 387 to 405 Example # 406 7- (4-Aminobenzyl) -5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -7H-pyrrolo [2,3-d] p? Rimidin-4-iAmino The reduction of example # 402, using procedure H, yielded 7- (4-amino-benzyl-5- [4- (5, 7-dimetH-benzoxazol-2-ylamino) -phenyl] -7H-? Irrolo [ 2,3-d] pyrimidin-4-ylamine; 1 H NMR (300 M Hz, DMSO-de,) d 2.34 (s, 3H), 2.39 (s, 3H), 5.04 (s, 2H), 5.16 (s, 2H), 6.04 (br s, 2H), 6.49 (d, J = 8.48 Hz, 2H), 6.77 (s, 1 H), 7.04 (d, J = 8.48 Hz, 2H), 7.09 (s, 1 H) , 7.26 (s, 1 H), 7.42 (d, J = 8.48 Hz, 2H), 7.83 (d, J = 8.81 Hz, 2H), 8.71 (s, 1 H), 10.71 (s, 1 H); / z (M + H) + 476.2 Preparations # 47-54. Phenolic aminobenzoxazole analogs The list of aminobenzoxazole phenol analogues (preparations # 47-54) were synthesized using the detailed procedure to prepare example # 387 using reagents detailed in Table 14. The method used to determine the retention time of H PLC is given in a lowercase letter in parentheses (see Table 1).

Table 14. Preparations # 47 to 54 Example # 407. 1-Cyclopentyl-3-. { 4- [5-methyl-7- (2-morpholin-4-yl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine A solution of Example # 398 (0.16 g, 0.36 mmol), 4- (2-chloroethyl) morpholine (0.075 g, 0.4 mmol) and triethylamine (0.160 mL, 0.76 mmol) in DMF (15 mL) was treated with Cs2CO3 (130 mg) ), was stirred at 50 ° C for 3 hours. An additional amount of Cs2CO3 (260 mg) was added and stirred at 50 ° C for an additional 2.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether 3 times. The combined extracts were dried (MgSO), concentrated and the residue was purified by chromatography on silica gel eluting with hexanes: EtOAc: methanol: CH2Cl (5: 4: 1: 1) to give 1-cyclopentyl-3-. . { 4- [5-methyl-7- (2-morpholin-4-yl-ethoxy) -benzoxazo-2-ylamino] -phenyl} - 1 H -pyrazolo [3,4-d] pyrimidin-4-yamine (45 mg, 22% yield); RP-HPLC (5% to 95% acetonitrile / 0.1% H3PO (ac), for 7 minutes at 1.5 ml / min;? = 190-700 nm; column for rapid resolution Zorbax SB-C8; 4.6 mm x 75 mm , 3.5 μm) Rt 1.76 min; m / z (M + H) + 555.2.

Examples # 408-428 were prepared through alkylation of the corresponding phenol with an alkylating agent as described by preparation # 29. 1.

Example # 408 1-cyclopentyl-3-. { 4- (5-Methyl-7- (2-morpholin-4-yl-ethoxy) -benzoxazol-2-ylamido] -f in i 1.} -1 H-pyrazole or [3,4-d] pyri mid i n-4-i the mine Example # 409 4-terbutil ester monotrifluoroacetate. { 2- [4- (4-Amino-1-cyclopentyl-1 H -pyrazolo [3,4-d] -pyrimidin-3-yl) -phenylamino] -5-methyl-benzoxazol-7-yloxymethyl-piperidin-1 -carboxylic Example # 410 7-Methyl-5-. { 4- [5-methyl-7- (2-morpholin-4-yl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -7H-pyrrolo [233-d] pyrimidin-4-ylamine Example # 411. 5-. { 4- [7- (2-Dimeti min o-ethoxy) -5-met i I -benzoxazol-2-ylamino] -phenyl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine Example # 412. 3-. { 4- [5-Chloro-7- (2-dimethylamino-ethoxy) -benzoxazole-2-yle] -f in i l} -1-penti 1-1 H-pyrazolo [3, 4-d] pyrimidin-4-ylamine cycle Example # 413. 3-. { 4- [5-Chloro-7- (2-methoxy-ethoxy) -benzoxazol-2-ylamino] -pheni} -1-cyclopentyl-1 H-pyrazolo [3,4-d] pyrimido-4-ylamine Example # 414 3-. { 4- [5-chloro-7- (2-morpholin-4-yl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -1-cyclopentyl-1 H-pyrazoI [3,4-d] pyrimidin-4-ylamine Example # 415 2-. { 2- [4- (4-Amino-1-cyclopentyl-1 H-pyrrazolo [3,4-d] pyrimidin-3-yl) -phenylamino] -5-chloro-benzoxazol-7-yloxy} -N } N-diethyl acetamide Example # 416. 3-. { 4- [5-chloro-7- (2-pyrrolidin-1-yl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -1-cyclopentyl-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 417 5-. { 4- [5-Chloro-7- (2-morfoin-4-yl-ethoxy) -benzoxazol-2-ylamino] -pheni} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine Example # 418 3-. { 4- [5-Chloro-7- (2-morpholin-4-yl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 419 5-. { 4- [5-Chloro-7- (5-chloro-thiophen-2-ylmethoxy) -benzoxazole -2-i lami no] -f in i I.}. -7-methyl-7H-pyrrolo [2,3-d] pyrim idin-4-ilamine Example # 420 3-. { 4- [5-Chloro-7- (2-phenylsulfanyl-ethoxy) -benzoxazol-2-ylamino] -phenyl} -1-methyl-17H-pyrazolo [3) 4-d] pyrimidin-4-ylamine Example # 421. 3-. { 4- [5-Chloro-7- (6-chloro-pyridin-3-ylmethoxy) -benzoxazol-2-ylamino] -phenyl} -7-cyclopentyl-7H-pyrrolo [233-d] pyrimidin-4-ylamine Example # 422 5-. { 4- [5-Chloro-7- (3-morpholin-4-yl-propoxy) -benzoxazol-2-ylamino] -phenyl} -7-methyl-7H-irrolo [2,3-d] pyrimidin-4-ylamine Example # 423 3-. { 4- [5-Chloro-7- (3-morpholin-4-yl-propoxy) -benzoxazole-2-ymin) -f in i l} -1-penti cycle 1-1 H-pyrazolo [3, 4-d] pyrimidin-4-i lamina Example # 424. 5-. { 4- [5-Chloro-7- (3-morpholin-4-yl-propoxy) -benzoxazole -2-i lami no] -f in i l} -7-methyl-7H-pyrro [2, 3-d] pyrimidin-4-ylamine Example # 425. 5-. { 4- [5-Chloro-7- (3-morpholin-4-yl-propox?) - benzoxazoI-2-ylamino] -3-fluoro-phenyl} -7-methyl-7H-pyrroIo [2,3-d] pyrimidin-4-ylamine Example # 426. 5-. { 4- [5-Chloro-7- (3-morpholin-4-yl-propoxy) -benzoxazol-2-ylamino] -3-fluoro-phenyl} -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine Example # 427 3-. { 4- [5-Chloro-7- (2-morpholin-4-yl-ethoxy) -benzoxazol-2-ylammonyl] -phenyl} -1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 428 3-. { 4- [5-chloro-7- (3-morpholin-4-yl-propoxy) -benzoxazol-2-ylamino] -phenyl} -1 - (4-morpholin-4-yl-cyclohexyl) -1 Hp? Razolo [3,4-d] pyrimidin-4-ylamine The method used to determine the retention time of H PLC is given in a lowercase letter in parentheses (see Table 1).

Example # 429 1-Cyclopentyl-3-. { 4- [5-methyl-7- (piperidin-4-ylmethoxy) -benzoxazol-2-ylamido] -pheni} -1 H-pyrazolo [3,4-d] pyri mid i n-4-i lamina A solution at 0 ° C of example # 409 (0.08 g) in CH2Cl2 (4 ml) and TFA (1 ml) was stirred at 0 ° C for 1 hour, then at room temperature for 4 hours, before concentration. The residue was triturated with ether and the precipitate was collected, dried under vacuum for 24 hours to give 1-cyclopentyl-3- bis-trifluoroacetate. { 4- [5-methyl-7- (piperidin-4-yl-methoxy) -benzoxazol-2-ylaminide] -enyl} -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (52.7 mg); RP-HPLC (5% to 95% acetonitrile / O.1% H3PO (aqueous) for 7 minutes at 1.5 ml / min;? = 190-700 nm; column for rapid resolution Zorbax SB-C8; 4.6 mm x 75 mm, 3.5 μm) Rt 1.74 min; m / z (M + H) + 539.1.

Example # 430. 5- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine 3-Iodo-1 - (2-trimethylsilane-ethoxymethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamine was reacted (as detailed in the synthesis of Example # 362) with (5.7 -dimethyl-benzoxazole-2-ii) - [2-ethyl-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenyl] -amine (G, D ) using general procedure C to produce 5- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -phenyl] -7- (2-trimethylsilyanil-ethoxymethyl) -7H-pyrroium [2,3-d] pyrimidin-4-ylamine. A solution of this compound (0.128 g) in TH F (20 ml) was treated with TBAF (5 ml, 1 M in TH F) was stirred at reflux for 15 hours, cooled to room temperature and partitioned between saturated aqueous NH 4 Cl and ether (2x). The combined organic extracts were dried (MgSO), concentrated and the residue purified by chromatography on silica gel eluting with 5: 4: 1 hexanes: EtOAc: methanol to give 5- [4- (5,7-dimethyl -benzoxazol-2-ylamino) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (9.3 mg); m / z: (M + H) + 371 .1; RP-HPLC (5% to 95% acetonitrile / O.1% H3PO4 (aqueous) for 7 minutes at 1.5 ml / min;? = 190-700 nm; Zorbax SB-C8 rapid resolution column; 4.6 mm x 75 mm, 3.5 μm) Rt 1.74 min.

Example # 431 5- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7-methyl-7H-pyrrolo [253-d] pyrimidine-2,4-diamine By substituting? / - (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-2-yl) -2,2-dimethyl-propionamide (Nucleics Acids Res., 26, 3353, 1998) and dimethisulfate by 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine and 4-nitrobenzyl bromide, respectively in preparation # 39. 1, gave the methylated product which was reacted with ammonium hydroxide, as detailed in general procedure B, to give 5-iodo-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-2 > 4-diamine.

Reacted 5-iodo-7-methyl-7H-pyrrolo [2,3-d] pyrimidine-2,4-diamine with (5,7-dimethyl-benzoxazol-2-yl) - [2-fIuoro-4-] (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenyl] -amine (G, D) using general procedure C, to produce 5- [4- (5, 7-dimethyI-benzoxazol-2-ylammonyl) -3-fluoro-phenyl] -7-methyl-7H-pyrrolo [2,3-d] pyrimidine-2,4-diamine; m / z: (M + H) + 418.2; 1 HN MR (300 MHz, DMSO-d6)) d 2.33 (s, 3H), 2.39 (s, 3H), 3.56 (s, 3H), 5.72 (s, 4H), 6.78 (s, 1 H), 6.91 (s, 1 H), 7.06 (s, 1 H), 7.27 (m, 2H), 8.28 (t, J = 8.31 Hz, 1 H), 10.36 (s, 1 H).

Example # 432 c / s-4- [4- (5,7-Dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -7- (4-morpholin-4-yl-cyclohexyl) -7H-pyrrolo [2, 3-d] pyrimidin-2J4-diamine The reaction of? - (4-chloro-5-iodo-7H-pyrroio [2,3-d] pyrimidin-2-yl) -2,2-dimethyl-propionamide (Nucleic Acids Res., 26, 3353, 1998) with a 4- morpholin-4-yl-cyclohexanol under conditions detailed in general procedure A gave the alkylated product which under wet aminolysis, through general procedure B, produces 5-iodo-7- (4-morpholin-4-yl-cyclohexyl) - 7H-pyrrolo [213-d] pyrimidin-2,4-di-amine. This product was subsequently reacted with (5,7-dimethyl-benzoxazol-2-yl) - [2-fluoro-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2- L) -phenyl] -amine (G, D), using general procedure C, to produce a mixture of diastereoisomers that were separated by chromatography to give cis-5- [4- (5, 7-d / metH-benzoxazo ! -2-Hamino) -3-f lu oro-i: enyl] -7- (4-morpholin-4-i-cyclohexyl) -7 H-pyrro [2, 3-d] pyrimidin-2, 4-diamine; m / z: (M + H) + 571.3; 1 H NM R (300 MHz, DMSO-d 6,) d 1.50 (m, 2H), 1.65 (m, 2H), 2.01 (m, 4H), 2.17 (m, 1 H), 2.33 (s, 3H), 2.39 (m, 7H), 3.64 (m, 4H), 4.49 (m, 1 H), 5.70 (s, 4H), 6.78 (s, 1 H), 6.94 (s, 1 H), 7.06 (s, 1 H), 7.32 (m, 2H), 8.26 (t, J = 8.81 Hz, 1 H), 10.36 (s, 1 H). Examples # 433-446 were synthesized by reacting tra t -s-3-iodo-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrim id in-4- il amine (A, T, J, C) with the appropriately substituted 2-aminopheni, using the general procedure G. 2-aminophenols, which are not commercially available, were synthesized either from the corresponding 2-nitrophenol, using the procedure general Example # 433. Ira /? s-3- [4- (5-Ier-Butyl-7-methyl-I-benzoxazole-2-ylamino) -phenyl] -1- (4-morpholin-4-I-cyclo) hexi l) -1 H-pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 434. trans-3- [4- (7-tert-Butyl-5-ethyl-benzoxazol-2-ylamino) -phenyl] -1- (4-morfoin-4-yl-cyclohexyl) -1 H-pyrazolo [3,4 -d] pyrimidin-4-ilamine Example # 435 trans-3- [4- (5-Ethyl-7-methoxy-benzoxazole -2-ylamino) -phenyl] -1- (4-morpholin-4-yl-cyclohexyl) -1 H-pyrazolo [3,4 -d] pyrimidin-4-ilamine Example # 436 trans-1 - [2-. { 4- [4-Amino-1 -. { 4-morpholin-4-l-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-l] -phenylamino} -7-methyl-benzoxazol-5-yl) -ethanone Example # 437 trans-1 - (2- { 4- [4-Amino-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-3-yl] -phenylamino .}. -5-fluoro-benzoxazol-7-yl) -ethanone Example # 438 trans-3- [4- (7-Methoxy-5-propyl-benzoxazoI-2-ylamino) -phenyl] -1- (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3, 4-d] ] pyrimidin-5-ilamine Example # 439 trans-2-. { 4- [4-Amino-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-3-yl] -f in i lam} -5-bromo-benzoxazole-7-carbonitrile Example # 440 trans- (2- { 4- [4-Amino-1 - (4-morpholine-4-ii-cyclohexyl) -1 H -pyrazolo [3,4-d] pyri mid in-3-yl] -f in i lam ino.}. -7-ethoxy-benzoxazol-5-yl) -acetonitrile Example # 441. trans-3- [4- (7-tert-Butyl-5-methyl-benzoxazol-2-ylamino) -phenyl] -1- (4-morph or I in-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine Example # 442. trans-3- [4- (5-Chloro-7-methoxy-benzoxazol-2-ylamino) -phenyl] -1- (4-morpholin-4-yl-cyclohexyl) -1 H-pyrazolo [3,4-d] ] pyrimidin-4-ilamine Example # 443. trans-3- [4- (7-C] -5-methoxy-benzoxazole -2-i-mino) -phenyl] -1- (4-morpholin-4-yl-cyclohexyl) -1 H-pyrazole or [334 -d] pirim id i n-4-ilamine Example # 444. trans-3- [4- (5-Fluoro-7-methoxy-benzoxazole-2-y) the mino) -phenyl] -1- (4-morpholin-4-yl-cyclohexyl) -1 H-pyrazolo [334-] d] pyrimidin-4-ylamine Example # 445 Trans-2- acid amide. { 4- [4-Amino-1 - (4-morpholin-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-yl] -phenylami no} -5- chloro-benzoxazole-7-carboxylic acid Example # 446 trans- (2- { 4- [4-Amino-1 - (4-morfoyl-4-yl-cyclohexyl) -1 H -pyrazolo [3,4-d] pyra-midin-3- il] phenylamine.} - 7-methoxy-benzoxazol-5-yl) -acetonitrile The method used to determine the retention time of H PLC is given in a lowercase letter in parentheses (see Table 1 ) .

Table 16. Examples # 433 to # 446 General Procedure FF: Ring closure to form substituted aminobenzoxazoles in a one-step protocol A mixture of substituted 2-aminophenol (1-5 equivalents, preferably 1.15 equivalents), and substituted phenyl isothiocyanate (1-5 equivalents, preferably 1.0 equivalents) and anhydrous organic solvent (for example, dichloromethane, dioxane, DME, THF or MTBE, preferably THF was stirred at room temperature under an inert atmosphere for 1-48 hours (preferably 16 hours). it was cooled to about 0 to -30 ° C (preferably about -15 ° C) with a circulation bath, then the solid lithium hydroxide monohydrate (1-5 equivalents, preferably 2 equivalents) was added in one portion The reaction suspension was cooled to about 0 to -30 ° C (preferably about -15 ° C) again.An addition funnel, 30% aqueous acid peroxide (1-10 equivalents, preferably 5 equiv. lenses) was added dropwise at a rate such that the temperature is maintained between about 15 to 25 ° C (preferably about 15 ° C). After 10 minutes to 3 hours (preferably 10 minutes), the reaction was complete, and a solution of sodium sulfite (Na2SO3, 2L, 1M) was added to the stirred reaction mixture. The reaction mixture was transferred to a separatory funnel with an organic solvent. The layers were separated, and the organic layer was washed with brine and water solutions. The combined aqueous washings were extracted again with an organic solvent. The combined organic extracts were concentrated under reduced pressure. The residue was crystallized and dried in a vacuum oven. Other oxidants that can be used include oxygen (O2), peracids (RCO3H, R = aryl or alkyl, or perfluoroalkyl), chlorine (Cl2), sodium periodate (NalO), potassium periodate (KIO), fer-butyl peroxide ( f-BuOOH), fer-butyl hypochlorite (f-BuOCI), sodium perborate (NaBO3_nH2O), sodium percarbonate (Na2CO3_1 .5H202), adduct of urea acid peroxide (H2NCON H2_H2O2), sodium hypochlorite (NaOCI), potassium hypochlorite (Cocí), sodium hypobromide (NaBrO), potassium hypobromide (KBrO), sodium bromate (NaBrO3), potassium bromate (KBrO3), potassium permanganate (KMnO), and barium manganate (BaMnO4).

Other bases that may include metal hydroxides (Na, K or CsOH), metal carbonates (Li, Na, K or Cs2CO3), metal bicarbonates (Li, Na, K or CsHCO3), metal alkoxides (MOR, R = Me, Et etc. .), metal phosphates (Li, Na, K or Cs3PO4), metal dibasic phosphates (Li, Na, K or Cs2H PO) and tetraalkylammonium (RN, where R = Me, Et, Bu, etc.) of all the above.

Illustration of General Procedure FF Preparation # 55. (4-Bromo-2-fluorophenyl) - (5-fluorobenzoxazol-2-yl) amine: To a 5-liter, jacketed RB flask, equipped with a nitrogen inlet, a temperature probe, and a mechanical stirrer, 2-amino-4-phiuophenol (64.4 g, 507 mmol, 1.15 equivalents), 2-fluoro-4-bromophenyl isothiocyanate (102.3 g, 440.8 mmol) were charged.; 1.0 equivalents), and TH F anhydrous (1.5. I). The reaction mixture was stirred at room temperature overnight. The reaction (thiourea formation) was completed shown by HPLC analysis. The reaction solution was cooled to about -15 ° C with a circulation bath. Then, solid lithium hydroxide monohydrate (L 2 OH H 2 O, 37.0 g, 882 mmol, 2 equivalents) was added. The reaction suspension was cooled to about -15 ° C again. Using an addition funnel, 30% aqueous acid peroxide (H2O2, 264 ml, 2.2 moles, 5 equivalents) was added dropwise at a rate to maintain the internal temperature between about 15 to 25 ° C. The reaction is very exothermic in the early period of the addition and was reduced towards the end of the addition. After the addition was complete, a sample was incorporated for HPLC analysis, and usually the reaction was completed. A solution of sodium sulfite (Na 2 SO 3, 2 L, 1 M) was added to the stirring reaction mixture while keeping the temperature below 30 ° C. The solution was checked for residual peroxide using a peroxide test strip and no remaining peroxide was shown. The reaction mixture was transferred to a 6-liter separatory funnel. The flask was rinsed with water (3 x 500 ml), EtOAc (4 x 500 ml) and the rinses were transferred to the separatory funnel. The layers were separated, and the organic layer was washed with brine and water solutions (100 + 400 ml, 4 times), brine (1 x 500 ml). The combined aqueous washings were extracted again with EtOAc (2 I). The combined organic extracts were concentrated under reduced pressure. To the obtained residue was added acetonitrile (250 ml), and the suspension was rotated on a rotovap for 30 minutes and left in a refrigerator overnight. The solid was collected and washed with heanos (1 x 300 ml), dried in a vacuum oven. The product obtained (131.5 g, 92% yield), m.p. 188-189 ° C. 1 H NM R (400 MHz, DMSO-d6) d 10.67 (s, 1 H), 8.20 (t, J = 8.8 Hz, 1 H), 7.63 (d, J? = 10.7, 1 H), 7.52- 7.46 (m, 2H), 7.31 (dd, J., = 8.9, J2 = 1.9, 1 H), 6.99-6.94 (m, 1 H); 13C NMR (100 MHz, DMSO-de) 3 159.9 (C), 158.8 (C), 157.6 (C), 153.2 (C), 150.7 (C), 143.1 (C), 142.5 and 142.4 (C), 127.10 and 127.06 (CH), 125.5 and 125.4 (C), 122.4 (CH), 118.4 and 118.2 (CH), 114.0 and 113.9 (C), 109.1 and 109.0 (CH), 108.1 and 107.9 (CH), 103.5 and 103.3 (CH) ). HRMS: cale, for C13H879BrF2N2O 324.9788, 324.9803 (MH +) was found. Anal. Cale, for C 13 H 7 Br 2 N 2 O: C, 48.03; H, 2.17; Br, 24.58; F, 11.69; N, 8.62; was found: C, 47.83; H, 1.95; Br, 24.32; F, 11.80; N, 8.49.

The following examples were synthesized using the general procedure FF: Preparation # 56. (4-Bromo-2-fluorophenyl) (5-chlorobenzoxazol-2-yl) amine. Yield 90%, m.p. 194-195 ° C. 1H NMR (400 MHz, DMSO-d6) d 10.71 (s, 1H), 8.18 (t, J = 8.7 Hz, 1H), 7.63 (dd, J ^ IO.6, .12 = 2.3, 1H), 7.53- 7.46 (m, 3H), 7.17 (dd, ^ = 9.2, J2 = 2.2, 1H). 13C NMR (100 MHz, DMSO-d6) S 158.4 (C), 153.2 (C), 150.8 (C), 145.5 (C), 142.8 (C), 127.8 (CH), 127.13 and 127.09 (C), 125.4 and 125.2 (C), 122.6 (CH), 121.2 (CH), 118.5 and 118.2 (CH), 116.1 (CH), 114.2 and 114.1 (C), 109.8 (CH). HRMS: cale, for C13H879BrC1FN2O 340.9493, 340.9501 (MH +) was found; cale, for C3H881BrClFN2O 342.9472, 342.9470 (MH +) was found. Anal. Cale, for C3H7BrClFN2O: C, 45.71; H, 2.07; Br, 23.39; Cl, 10.38; F, 5.56; N, 8.20; it was found: C, 45.74; H, 2.05; Br, 23.71; Cl, 10.51; F, 5.53; N, 8.16.

Preparation # 57. (4-Bromo-2-fluorophenyl) (5-methylbenzoxazol-2-yl) amine. Yield 89%, m.p. 185-186 ° C. 1H NMR (400 MHz, DMSO-d6) d 10.48 (s, 1H), 8.25 (t, J = 8.5 Hz, 1H), 7.60 (dd, J., = 10.7, J2 = 2.2, 1H), 7.46 (dd) , ^ = 9.3, J2 = 1.0, 1H), 7.35 (d, J = 8.2, 1H), 7.25 (s, 1H), 6.95 (d, .1 = 8.2, 1H), 2.37 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d 157.3 (C), 153.0 (C), 150.5 (C), 144.8 (C), 141.3 (C), 132.8 (C), 127.10 and 127.07 (CH), 125.89 and 125.80 (C), 122.15 and 122.05 (CH), 118.3 and 118.1 (CH), 116.6 (CH), 113.43 and 113.35 (C), 108.1 (CH), 21.1 (CH3). HRMS: cale, for C? 4Hn79BrFN2O 319.9961, 319.9959 (MH +) was found; cale, for C? 4Hn81BrFN2O 321.9940, 321.9949 (MH +) was found. Anal. Cale, for C? 4H10BrFN2O: C, 52.36; H, 3.14; Br, 24.88; F, 5.92; N, 8.72; was found: C, 52.14; H, 3.15; Br, 23.21; F, 5.91; N, 8.62.

Preparation # 58. (4-Bromo-2-fluorophenyl) [5- (trifluoromethyl) benzoxazole -2-l] amine. Yield 88%, m.p. 160-161 ° C. 1 H NMR (400 MHz, DMSO-d 6) d 10.83 (s, 1 H), 8.22 (t, J = 8.8 Hz, 1 H), 7.83 (s, 1 H), 7.76 (d, J = 17.3 Hz, 1 H), 7.61 (dd, J- ^ 10.6, J2 = 2.2, 1H), 7.51-7.46 (m, 2H). 13C NMR (100 MHz, DMSO-d6) S 158.7 (C), 153.3 (C), 150.8 (C), 148.9 (C), 142.0 (C), 128.0 and 124.3 (C). 127.12 and 127.09 (CH), 125.29 and 125.25 and 125.21 and 125.13 (C), 124.9 and 124.6 (C). 122.6 (CH), 119.9, 118.74 and 118.70 (CH), 118.5 (CH) and 118.3 (CH), 114.4, 114.3, 113.2 (CH), 109.4 (CH). Anal. Cale, for O H7BrF4N20: C, 44.83; H, 1.88; Br, 21 .30; F, 20.26; N, 7.47; O, 4.27. was found: C, 44.65; H, 1.71; Br, 21.14; F, 19.42; N, 7.44.

Preparation # 59. Ethyl (5-methylbenzoxazol-2-yl) amine. Yield 89%, m.p. 90-91 ° C. 1 H NMR (400 MHz, DMSO-de) d (t, J = 5.3 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.03-7.02 (m, 1 H), 6.76-6.73 (m, 1 H), 3.34-3.27 (m, 2H), 2.31 (s, 3H), 1 .18 (t, J = 7.2, 3H). 13C NMR (100 MHz, DMSO-d6) d 161.7 (C), 145.6 (C), 143.0 (C), 132.0 (C), 120.0 (CH), 115.3 (CH), 107.4 (CH), 37.1 (CH2), 21.1 (CH3), 14.8 (CH3). HRMS: cale, for C10H12N2O 176.0950, 176.0948 (M +) was found; Anal. Cale, for O0H12N20: C, 68.16; H, 6.86; N, 15.90. it was found: C, 67.97; H, 6.86; N, 15.84.

Example # 447 Trans-4- (4- { 4-amino-5- [3-fluoro-4- (5-methyl-benzoxazole -2-i min) -f in il] -pyrrolo [2, 3-d ] pyrimidin-7-i-1-cyclohexyl) -piperazin-2-one Sodium trisacetoxyborohydride (46.8 mg, 0.22 mmol) was added to a suspension of 2-piperazinone (51.06 mg, 0.51 mmol) and . { 4-amino-5- [3-fluoro-4- (5-methyl-benzoxazol-2-ylamino) -phenyl] -pyrrolo [2,3-d] pyrimidin-7-yl} -cyclohexanone (prepared from 4-chloro-3-iodopyrrolo [2,3-d] pyrimidine and 1,4-dioxa-spiro [4.5] decan-8-ol using general procedures A, C, B, K and G) (80 mg, 0.17 mmol) in glacial acetic acid (0.03 ml, 0.51 mmol) and dichloromethane (5 ml). After about 18 hours of stirring at room temperature, the reaction was still heterogeneous since NMP (2 ml) was added and the reaction was stirred for an additional 24 hours. The reaction was monitored by t. l. c. (using 10% MeOH in dichloromethane as the eluent) and quenched with saturated aqueous sodium hydrogen carbonate (10 ml). The product was extracted into dichloromethane (3 x 50 ml), dried over anhydrous magnesium sulfate and evaporated to dryness to yield the yellow oil which was further purified by chromatography on silica gel using 0.1% N H2OH and 5% MeOH in dichloromethane as the eluent. Further purification using preparative RP-H PLC (5% to 85% acetonitrile / O.1 M ammonium acetate 'aqueous, regulated in its pH to pH 4.5, for 20 minutes, 1 ml / min,? = 254 nm; Deltapak C18 column, 300 A, 5 μm, 150 x 3.9 mm) produces trans-4- (4. {4-amino-d- [3-fluoro-4- (5-methyl-benzoxazol-2-ylamino) phenyl] -pyrrolo [2,3-d] pyrimidin-7-ii.} - cyclohexyl) pperazin-2-one (2 mg); 1 H NMR (DMSO-d 6, 400 MHz) d 8.53 (1 H), 8.30 (1 H), 7.33 (2 H), 7.28 (2 H), 7.00 (2 H), 6.05 (1 H), 5.61 (2 H), 4.69 (2H), 3.38 (2H), 3.34 (2H), 2.79 (2H), 2.45 (3H), 2.23 (2H), 2.17 (2H), 1.87 (2H), and 1.61 (2H); and m / z (M + H) + 555.3.

Example # 448 Trans-4- (4- { 4-Amino-3- [4- (5,7-dimethyl-benzoxazol-2-ylamino) -3-fluoro-phenyl] -pyrazolol [3,4-d] pyrimidine- 1 -yl.} -cyclohexyl-1-piperazin-2-one tetrakistriphenylphosphine (6 mg, 0.005 mmol) was added to a solution of 4- [4- (4-amino-3-iodo-pyrazolo [3,4-] d] pyrimidin-1-yl) -cyclohexyl] -piperazin-2-one (prepared from 4-amino-3-iodo-pyrazolo [3,4-d] pyrimidine and 1,4-dioxa-spiro [4.5] decan-8-oI using general procedures A, K and J) (45 mg, 0.10 mmol) (5,7-dimetiI-benzoxazol-2-iI) - [2-fluoro-4- (4,4,5, 5-tetramethyl- [1, 3,2J-dioxaborolan-2-yl) -phenyl] -amine (prepared using general procedures G and D) (49 mg, 0.13 mmol), and sodium carbonate (27 mg, 0.25 mmole) in DMF (5 ml) and water (2.5 ml) and heated to about 80 ° C for about 12 hours. Additional tetrakistriphenylphosphine (0.015 mmole), (5,7-dimethyl-benzoxazol-2-yl) - [2- (fluoro-4- (4,4,5,5-tetramethyl- [1, 3-2] dioxaborolan) was added. -2-yl) -phenyl] -amine (0.06 mmol) and sodium carbonate (0.25 mmol) and the reaction was heated to about 80 ° C for an additional 16 hours.The solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 ml) and water (100 ml) The organic layer was separated and the aqueous layer was further extracted with dichloromethane (3 x 50 ml) The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by preparative RP-HPLC (5% to 85% acetonitrile / 0.05M aqueous ammonium acetate, adjusted in pH to pH 4.5, for 20 minutes at 1.7 ml / min:? = 254 nm; Hypersil C18 100 Á, 5 μm, 250 x 4.6 mm column) and triturated with ethyl acetate to produce ε-4- (4-. {4-amino-3- [4- (5.7 -di met l-benzoxazoI-2-ylamino) -3-f luoro-f in iljpirazolo- [3,4-d] pyrimidin-1-yl} -cyclohexyl) -piperazin-2-one (4.2 mg) as an off-white solid; LC / MS (30% to 95% acetonitrile / O.01 M aqueous ammonium acetate for 4.5 minutes at 0.8 ml / min;? = 190-700 nm; Gnosis column C18, 120 A, 3 μm, 30 x 4.6 mm, electrospray ionization method observing both positive and negative ions) Rt 2.30 min; m / z (M + H) + 570.4. The contents of all references, patents and published patent applications, in their entirety, cited throughout this application are incorporated herein by reference.

Claims (24)

1. A compound of the formula (I), (0 pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, indicated as Group A, wherein X is N or CH; A is optionally substituted phenyl, or A is r is 1 and D ^ Gi, Ji, Li and Mi are each independently selected from the group consisting of CRa and N, as long as at least two of D-i, Gi, J-i, Li and Mi are CRi; or is 0, and one of Di, Gi, Li and Mi is NRa, one of Di, Gi, Li and Mi is CRa and the rest is independently selected from the group consisting of CRa and N, where Ra is as defined later;

L is NH, optionally substituted alkyl, carbonyl, optionally substituted O-alkyl, N H (optionally substituted aliphatic) or S;

R1 is -C (= O) -N (R100) 2 wherein R100 for each case is independently hydrogen or alkyl; or R1 is or an optionally substituted group selected from the group consisting of an aliphatic, benzimidazolyl, benzofuranyl, benzisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, cycloalkyl, 2,3-dihydrobenzofuranyl, 1,1-dioxobenzisothiazolyl, furanyl, 1 H group -imidazo [1, 2-a] imidazolyl, midazo [1,2-a] pipdyl, imidazo [1,2-a] pyrimidinyl, imidazo [2, 1-b] [1,3] thiazolyl, indazolyl , indolinyl, indolyl, isoquinolinyl, isothiazolinium, isoxazolyl, morpholinyl, naphthyl, oxadiazolyl, oxazolyl, phenylsulfonyl, phthalazinyl, piperidinyl, pyrazolyl, H-pyridinone, pyridinyl, pyrido-oxazolyl, pyrido-thiazolyl, dirimido-oxazolyl, dirimido-thiazolyl, pyrrolidinyl , pyrrolopyridinyl, pyrrolyl, qunolinyl, quinoxalinyl, quinazolinyl, tetrahydrofuranyl, tetrahydronaphthyl, tetrahydropyranyl, thiadiazolyl, thiazolylthienyl,

Or wherein the optionally substituted above groups are optionally substituted by one or more Rb; u is 1 and D2, G2, J2, L2 and M2 are each independently selected from the group consisting of CRa and N, provided that at least two of D2, G2, J2, L2 and M2 are CRa; or u is 0, and one of D2, G2, L2 and M2 is NRa, one of D2, G2, L2 and M2 is CRa and the remainder is independently selected from the group consisting of CRa and N; Ra and b each represents one or more substituents and for each case is independently selected from the optionally substituted group consisting of an aliphatic, alkoxy, alkylamino, aliphatic carbonyl, aliphatic cycloalkyl, aliphatic heterocyclyl, alkyl-S-, alkyl-S (O ) p-, amido, amino, aminoalkyl, carboxamido, -CF3, -CN, -C (O) -aliphatic, -C (O) -cycloalkyl, -C (O) -heterocyclyl, -C (O) H groups, C (O) OH, -C (O) O-aliphatic, C (O) OC (O) O-heterocyclyl, cycloalkyl, aliphatic cycloalkyl, cycloalkyl-S, cycloalkyl-S (O) p, cycloalkylthio, diacylamine noalkoxy, a halo, heterocyclyl, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heterocycle-S, heterocycle-S (O) p, heterocyclethyl, heterocycloalkyl-S, hydrogen, -NO2, -OCF3, -OH, tetrazolyl, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, -Z105-C (O) N (R) 2, -Z105-N (R) -C (O) -Z200,

-Z105-N (R) -S (O) 2-Z200, -Z105-N (R) -C (O) -N (R) -Z200, -N (R) -C (O) R, -N (R) -C (O) OR, ORC (O) -heterocyclyl-OR, Rc and -CH2ORc; wherein Rc for each case is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, - (C? -C6) -NRdRe, -W- (CH2) tN RdRe, -W- (CH2) tO-alkyl, -W- (CH2) tS-alkyl or -W- (CH2) t-OH; Z105 for each case is independently a covalent bond or an aliphatic group; Z200 for each case is independently selected from an optionally substituted group, selected from the group consisting of an aliphatic, phenyl aliphatic earth phenyl group; Rd and Re for each case are independently H, an aliphatic, alkanoyl or SO2-alkyl group; or Rd, Re and the nitrogen atom to which they join together form a five or six membered heterocyclic ring; t for each case is independently an integer from 2 to 6; W for each case is independently a bond or O, S, S (O), S (O) 2 or NRf, where Rf for each case is independently H or an aliphatic group; or Ra is an optionally substituted cycloalkyl or heterocyclyl ring combined with the ring to which it is attached; B is a bond or a) hydrogen; b) optionally substituted trityl; c) optionally substituted cycloalkyl; d) azaheterocyclyl substituted with an optionally substituted aliphatic group; e) azacycloalkyl which is substituted with one or more substituents selected from the optionally substituted group consisting of - (C? -Ce) -alkyl, - (Ci-C6) -alkyl-OR, -C (O) - (C1-) C6) -alkyl-N- (R) 2, - (C1-C6) -alkyl-N (R) 2, - (0-C6) -alkyl-cycloalkyl, tetrahydrothienyl and tetrahydrothiopyranyl; f) a group of the formula wherein Ei is selected from an optionally substituted group consisting of amido, amino, imidazolyl, morpholino, piperazinyl, piperidinyl, pyrrolidinyl or tetrahydrothiazolyl, and wherein Ei is optionally substituted with one or more substituents selected from - (C0-C6) - alkyl-OR, - (C? -C6) -alkyl-C (O) OR, (d-C6) alkyl-heterocyclyl- (C? -Ce) -Ilkyl-heterocycloalkyl, - (O-Ce) -alkyl-N (R) 2, cyclohexanone, alkoxyalkyl and pyranyl, g) (O-Ce) -alternatively substituted alkyl, h) optionally substituted cycloalkyl, i) optionally substituted alkoxyalkoxy, j) optionally substituted alkylamino, k) optionally substituted dialkylamino, 1) alkyl ester , m) alkenyl, n) optionally substituted alkoxy, o) optionally substituted heterocyclyl, p) optionally substituted phenyl, q) 1,4-dioxa-spiro [4.5} optionally substituted decane, s) [1, 3] optionally substituted dioxolane, t-R200-O- (R200) 2-Si (R200) 3, u) a bond, provided that B, Z and E are not each a linkage, v) alkoxyalkyl ow) phenylalkyl; Z is a bond, carbonyl, R200-O, amino, -O-, -S- or SO2; E is a bond or H, or is a group optionally substituted from the group consisting of alkoxy, aliphatic alkoxy, alkoxyamino, alkoxyalkoxy, aliphatic alkoxycarbonyl, aliphatic, aliphatic-aminoaliphatic, aliphatic carbonyl, alkylsulfonyl, amino, aliphatic, amino aliphatic-carbonyl, aminocarbonyl, aminocarbonyl-aliphatic, aminosulfonyl-aliphatic, CH2-C (CH3) 2 (OH),

-C (CH3) 2N (CH3) (H), cycloalkyl, di-aliphatic-amino, di-aliphatic-amino-aliphatic, di-aliphatic-amino-aliphatic-amino, di-aliphatic-aminocarbonyl, di-aubat-aminocarbonyl -aliptic, heterocyclyl, heterocyclo-aliphatic. morpholinocarbonyl-aliphatic, phenyl, piperidinylalkoxy, tetrahydropyranyl-aliphatic, tipiranyl, tetrahydrothiopyran-1, 1-dioxide, triazolyl-aliphatic and urea; or E is -CH (R200) -C (O) -N (C? -C6) -N (R200) 2, -N (R200) - (C? -C6) -C (O) -N (R200) 2, -N (R200) - (C? -Ce) -C (O) -OH, -N (R200) - (C? -C6) -C (O) morpholinyl, - (C? -C6) -S -CH3, -C (R200) (CH2OH) - (C6C6) -OH, -C (R200) 2-N (R200) 2, -C (O) -OH, -C (R200) 2 (OH ), -C (R200) 2-O- (C1-C6) -C (R200) 2 (OH), -C (R200) 2C (R200) 2 (OH), wherein R200 is independently hydrogen or alkyl; R2 is H, -N H2 -S (C? -C6) alkyl, -SO2 (C? -C6) alkyl, optionally substituted alkyl, -OR7, -N (H) SO2R7, -N (R7) SO2R7, -N (R7) C (O) N (H) R7, -N (R7) C (O) N R7, -N (H) C (O) R7, -N (R7) 2, -N (R7) C ( O) R7, -N HC (O) N HR7, or -NH R7; R7 is (Ci-CβJ-aliphatic optionally substituted by one or more substituents each independently selected from the group consisting of (Ci-C-alkyloxy, heterocyclyl, hydroxyl, -NR5R6 optionally substituted phenyl, -C (O) R4 and heterocyclyl; wherein any alkoxy, aliphatic and heterocyclyl can be optionally substituted, wherein R5 and R6 are independently H or (Ci-C6) alkyl, -NHS (O) 2R4, -NHC (O) R4 or -N HC (= NH) R4 wherein R4 is selected from (C? -Ce) alkyl and H; Y is H, OR3 or N (R3) 2 wherein R3 is independently selected from H or an optionally substituted group consisting of aliphatic, - (CH2) 2-C (O) -NH 2, -C (O) -aliphatic, -C (O) -cycloalkyl and -C (O) -heterocyclyl, wherein R for each case is independently H or is selected from an optionally substituted group which consists of aliphatic, heterocyclyl and heterocyclo aliphatic, n is an integer from 1 to 6, and p is 1 or 2, as long as when A-L-R1 is then B-Z-E is not a pyrrolidinyl which is substituted with 2-methoxyethyl, N. N-dimethylaminomethyl, N, N-dimethylamino-1-oxoethyl or 2- (N -meti I to my no) -1-oxopropyl; when X is N; And it's N H2; R2 is H; L is N H: A is phenyl optionally substituted with fiuoro or methoxy; B is cyclohexyl; Z is a bond and E is piperazinyl substituted with methyl, then R1 is not: phenyl optionally substituted with C2H4OH or chloro, benzofuranyl optionally substituted with chloro, imidazolif or optionally substituted with methyl, benzoxazolium optionally substituted with one or two methyls, benzoxazolyl optionally substituted by one or two chlorines, benzoxazolyl optionally substituted by methoxy, benzoxazolyl optionally substituted by ethyl, benzoxazolyl optionally substituted by carbonitrile, benzoxazolyl optionally substituted by isopropyl, benzothiazolyl optionally substituted by one or two methyl, benzothiazolyl optionally substituted by propyl, benzothiazolyl optionally substituted with isopropyl, benzothiazolyl optionally substituted with ethyl and phenyl, thiazolyl substituted with ethyl, thiazolyl optionally substituted with phenyl, thiazolyl optionally substituted with phenylmethyl, thiazolyl optionally substituted with nitrophenyl, thiazolyl optionally substituted with two methyl, thiazolyl substituted with phenyl and methyl , thiazolyl substituted with phenyl and propyl, thiazolyl substituted with phenyl and isopropyl, thiazolyl substituted with ethyl and methylphenyl, benzisothiazolyl optionally substituted with CF3, benzois otiazolyl optionally substituted with one or two oxo, benzoisoxazolyl substituted with CF3, indazolyl or pyrimidinyl; or when X is N; And it's NH2; R2 is H; L is NH; A is phenyl optionally substituted with fluoro; R1 is benzoxazolyl substituted with one or two methyl, benzothiazolyl or ethyl; Z is a link; and E is COOH, piperazinyl substituted with methyl, piperazinyl substituted with oxo, or ethyl substituted with oxo; then B is not ethyl, cyclohexyl, piperidinyl substituted with dimethylamino, or phenyl substituted with CN; or when X is N; And it is NH2: R2 is H; L is NH; A is phenyl; B is a link; Z is a link; and R 1 is benzofuranyl, benzoisoxazolyl, piperidinyl, pyrrolyl, isooxazolyl substituted with phenyl, isoxazolyl substituted with triloforomethyl, benzoxazolyl optionally substituted by one or two methyl, benzoxazolyl optionally substituted by ethyl, benzoxazolyl optionally substituted by chloro, or benzoxazolyl optionally substituted by isopropyl then E is not: piperidinyl optionally substituted with substituted alkyl, piperazinyl, pyrrolidinyl optionally substituted by methoxyethyl, piperidinyl optionally substituted by dihydroxypropyl, piperidinyl optionally substituted by hydroxyethyl, piperidinyl optionally substituted by methoxyethyl, piperidinyl optionally substituted by methylsulfanylethyl, piperidinyl optionally substituted by optionally substituted ethyl, piperidinyl optionally substituted by optionally substituted propyl, imidazolyl optionally substituted by methyl, imidazolyl optionally substituted by a mino, aminoalkylcarbonyl, cyclohexancarboxylate or pyrimidinyl substituted with CN; or when X is N; And it's NH2; R2 is H; A is phenyl; R is phenyl; B is cyclohexyl; Z is a link; and E is piperazinyl substituted with methyl; then L is not methyl substituted by = N-OCH3, = N-OH, N H2 or CN; or when X is N; And it's NH2; R2 is H; L is NH; A is phenyl; R1 is benzoxazolyl substituted with two methyl; B is pyrrolidinyl optionally substituted by methylaminomethyl and ethyl, or pyrrolidinyl optionally substituted by methylaminomethyl and ethyl, or pyrrolidinyl optionally substituted by dimethylamino and ethyl; and Z is carbonium; then E is not dialkylamino, a bond or alkyl substituted with methylamino; or when X is N; L is NH; A is phenyl; R1 is benzoxazolyl optionally substituted with two methyl; B is cyclohexyl; and Z is a link; then E is not dimethylamino or morpholino; or when X is N; L is NH; it is phenyl; R1 is benzoxazolyl optionally substituted with two methyl; B is cyclohexyl; and Z is NH; then E is not methoxyethyl or methyl; or when X is N; And it's N H2; R2 is H; L is NH; A is phenyl; R1 is benzoxazolyl substituted with two methyl; B is piperidinyl; and Z is a link; then E is not a link; or when X is N; L is O-alkyl; A is phenyl; B is cyclohexyl or a bond; Z is a link; and E is cyclopentyl or piperzinyl substituted with methyl; then R1 is not phenyl optionally substituted with benzenesulfonamide or phenyl optionally substituted with benzylurea; or when X is N, Y is N H2, R2 is H, L is N H, A is phenyl optionally substituted with fluoro, R1 is benzoxazolyl substituted with ethyl, bnzoxazolyl substituted with chloro, or benzoxazolil substituted with one or two methyl; B is piperidinyl, azetidinyl, pyrrolyl or cyclohexyl; and Z is a link; then E is not: methoxyethyl, methoxypropyl, methyl, ethyl optionally substituted by hydroxyl, piperazinyl substituted by oxo, or imidazolyl optionally substituted by amino; or when X is N; And it's NH2; R2 is H; L is NH; A is phenyl; B is piperidinyl; Z is carbonyl; and R1 is benzoxazolyl optionally substituted with two methyl or benzoxazolyl optionally substituted with chloro; then E is not: morpholinoalkyl, dimethylaminomethyl, piperidinyl optionally substituted by methyl, isopropyl substituted by methylamine, pyrrolidinyl, ethyl optionally substituted by methyl and methylamino, or ethyl optionally substituted by substituted alkyl; or when X is N; And it's N H2; R2 is H; L is carbonyl; A is phenyl; Z is a link; E is piperidinyl or pyridinyl; and B is a link; then R1 is not: oxazolyl, isoxazolyl optionally substituted by methyl, isoxazolyl optionally substituted by phenyl, pyrazolyl optionally substituted by benzyl, pyrazolyl optionally substituted by benzoyl, pyrazoiyl optionally substituted by methyl or pyrazolyl optionally substituted by ethanone; or when X is N; And it's N H2; R2 is H; L is carbonyl; A is phenyl; Z is a link; R1 is phenyl; and B is cyclohexyl; then E is not piperazinyl substituted with methyl; or when X is N; L is alkyl optionally substituted with OH; A is phenyl optionally substituted with methoxy; R1 is benzoxazolyl or benzimidazolyl; B is cyclohexyl; and Z is a link; then E is not piperazinyl substituted with methyl. 2. The compound, pharmaceutically acceptable salts thereof, mime metabolites, isomers thereof, or prodrugs thereof, of claim 1, wherein Y is -N (R3) 2. 3. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, according to claim 2, wherein: X is N; A is optionally substituted phenyl; R1 is optionally substituted benzoxazolyl or optionally substituted benzothiazolyl; B is a bond or is selected from an optionally substituted group consisting of alkenyl, alkyl, alkoxyalkyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 3 to 7 carbon atoms, heterocyclyl, phenyl, 1,4-dioxa -spiro [4.5] dec-2-ene, 2,2-dipropyl [1, 3] dixolane, 1 -oxa-2-aza-spiro [4.5] dec-2-ene, 1,4-dioxa-spiro [4] , 5] decane and 2,2-dipropyl [1, 3] dioxolane; E is H or is selected from an optionally substituted group consisting of alkoxy, alkoxyalkyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, azetidinyl, benzimidazolyl, -C (CH3) (CH2OH) -CH2-OH, -C (CH3) 2, -NH (CH3), -C (CH3) 2-O-CH2- C (CH3) 2 (OH), -CH2-C (CH3) 2 (OH), - (CH2) 2-S-CH3, COOH, cycloalkyl, diazepanyl, dimethylamino, dimethylaminoalkyl, di methylaminoalkylamino, dimethylaminocarbonyl, dimethylaminocarbonylalkyl, furanyl, imidazolinyl, imidazolyl, imidazolylalkyl, isoxazolyl, morpholinyl, morpholinyl-alkyl, -N (CH3) -CH2-C (= 0) -morphoinyl, -N (CH3) -CH2-C (= O) -N (CH3) 2, -N (CH3) -CH2-C (= O) -OH, oxodiazolite, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolydinyl, pyrrolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiopyranyl, thienyl, triazolyl and triazolylalkyl; R2 is H, SCH3, N H2 or S (O) 2-CH3; and R3 for each case is independently H or - (CH2) 2-C (= O) NH2. 4. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, of claim 13, wherein: A is optionally substituted by one or more substituents selected from the group consisting of alkyl , alkoxy, chloro and fluoro; R1 is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, alkoxyalkoxy, akoxycarbonylpiperidine? Lalkoxy, alkylcarbonyl, aminocarbonyl, bromine, CF3, chlorine, C (= O) -O (CH3) 3 , dialkylaminoalkoxy, dialkylaminocarbonyl, dialquilaminocarbonilalcoxi, fluoro, -OH, -morfolinoalcoxi, NO2, OCF3, phenyl-S-alkoxy, optionally substituted piperidinylalkoxy, piridinilalcoxi optionally substituted pirrolidinilalcoxi optionally substituted, and optionally substituted tienilalcoxi; B is a bond or group optionally substituted from the group consisting of alkoxyalkyl, alkyl, azetidinyl, cycloalkenyl, cycloalkyl, isoxazolyl, phenyl, piperidinyl, pyranyl, pyridinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, 1,4-dioxazole, spiro [4.5] dec-2-ene, [1, 3] dioxolane, 1 -oxa-2-aza-spiro [4.5] dec-2-ene, and 1,4-dioxa-spiro [4.5] decane; E is H, dimethylamino-, dimethylaminocarbonyl or an optionally group selected from the group consisting of alkyl, alkoxyalkyl, azetidinyl, benzimidizolilo, diazepanyl, furanyl, imidazolidinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, phenyl, piperidinyl, piperazinyl, pyrazinyl, pyrazolyl , pyridinium, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-tetrahydrothiopyran dioxide, tetrazolyl, thiadiazolyl, thienyl, thiopyranyl and traiazolyl; and wherein the group is optionally substituted by one or more substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, dialkylamnosulfonium, fluoro, hydroxy, hydroxyalkyl, nitrile, oxo, S (O) 2CH3 and S (O) 2CF3. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 4, wherein L is N H, C (O) H or carbonyl; B is a bond or is selected from the optionally substituted group consisting of alkyl, azetidinyl, cycloalkyl, isoxazolyl, phenyl, piperidinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxa-spiro [4,5] dec-2- eno, [1, 3] dioxolane, 1 -oxa-2-aza-spiro [4.5] dec-2-ene and 1,4-dioxa-spiro [4.5] decane; wherein the group is substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, CF3, C = N, cycloalkyl, fluoro and hydroxyl. 6. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof of claim 5, wherein R2 is H.

7. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, same or pro-drugs thereof, of claim 6, wherein R3 for each case is H.

8. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 7, wherein R 1 is benzoxazolyl or benzothiazolyl, each optionally substituted by one or more substituents selected from the group which consists of alkenyl, alkoxy, alkyl, bromine, CF3, chloro, dimethylaminocarbonyl, fluoro, hydroxyl, OCF3 and nitrile. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 8, wherein A is phenyl optionally substituted by fluoro or alkoxy; L is NH; R1 is benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of CF3, CH3 and chloro; Z is a bond, carbonyl, R200-O-, -O- or -S-; and E is H or is selected from the optionally substituted group consisting of alkoxyalkylalkoxyamino, alkyl, COOH, cycloalkyl, diazepanyl, dimethylaminocarbonyl, furanyl, imidazolylalkyl, imidazolidinyl, imidazolyl, isoxazolyl, morpholino, -N (R200) -R200-C ( = O) -N (R200) 2, -N (R200) -R200-C (= O) -OH, -N (R200) -R200-C (= O) -morpholinyl, OH, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thienyl and triazolyl; wherein R200 is alkyl. The compound of claim 9, wherein the compound is 3- [3- (fluoro-4- (5-trifluoromethyl-benzoxazol-2-ylamino) -f-enyl] -1- [4- (2- methoxy-ethoxy) -cyclohexyl] -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine, 3- [4- (7-chloro-5-methyl-benzoxazol-2-ylamino-phenyl] -1- [4- (2-methoxy-ethoxy) -cyclohexyl] -1 H -pyrazolo [3,4-d] pyrimidin-4-ylamine, or 1 - (4-. {4-amino-3- [4- (5-Chloro-benzoxazole-2-ylamine) -3-fluoro-phenyl] -pyrazolo [3,4-d] pyrimidin-1-yl.} - cyclohexyloxy) -2-methyl-propan-2-ol. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 1, wherein: X is CH; A is optionally substituted phenyl; R1 is optionally substituted benzoxazolyl; is H or is selected from the optionally substituted group consisting of alkoxyalkyl, alkyl, cycloalkyl and heterocyclyl, E is H, or is selected from the optionally substituted group consisting of alkoxy, alkyl, alkyl ilsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, phenyl, piperazinyl, tetrazoline and urea; R2 is H, N H2, SCH3 or SO2C H3; and R3 for each case is H. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 1, wherein: A is optionally substituted by fluoro; R1 is an optionally substituted benzoxazolyl, substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, bromo, chloro, CF3, dialkylaminoethoxy, fluoro, morpholinylcox, morpholinyl alkyl and nitrile; B is H or is selected from the optionally substituted group consisting of cycloalkyl, alkyl, piperidinyl and pyrrolidinyl; wherein the substituents are selected from the group consisting of alkyl, hydroxyl, oxo, nitrile and nitro; E is H or is selected from the optionally substituted group consisting of alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, piperazinyl, phenyl, tetrazolyl and urea; wherein the group is optionally substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, cycloalkyl, hydroxyl, nitrile, nitro, N H2 and oxo; and Z is a bond, R200-O-, NH or -O-. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 12, wherein L is NH or N (alkenyl). 14. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 13, wherein R2 is H. 15. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof. , of claim 14, wherein R 1 is optionally substituted benzoxazolyl, substituted by one or more substituents selected from the group consisting of alkyl, bromine, CF 3, chlorine, fluoro and nitrile. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 15, wherein A is phenyl optionally substituted by fluoro; L is NH; R1 is benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of alkyl, bromine, CF3 and chlorine; Z is a bond u -O-; and E is optionally substituted alkyl, alkoxyalkyl, diazepanyl, piiperazinyl or tetrazolyl. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 2, wherein: X is CH; A is optionally substituted phenyl; R1 is optionally substituted benzoxazolyl; B is H or a bond or is selected from the optionally substituted group consisting of alkyl and cycloalkyl; Z is a bond, -R200-O-, amino or -O-; E is H, a bond or an optionally substituted group selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, dialkylamino, heterocyclyl, phenyl and urea; R 2 is H, N H 2, -O-C 6 -Salt or 0-C 6 -SO 2 alkyl; and R3 for each case is H. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or prodrugs thereof, of claim 17, wherein A is optionally substituted with one or more fluoro; R is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, aminoalkoxy, bromine, CF3, chloro, fluoro, morpholinoalkoxy, morpholinoalkyl, and nitrile; E is H or an optionally substituted group selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, phenyl, piperazinyl, pyridinyl, pyrrolidinyl, tetrazolyl and urea; wherein the optionally substituted group is optionally substituted by one or more alkoxy, alkyl, amino, bromo, cycloalkyl, dimethylamino, hydroxyl, oxo, nitrile, NO2 or sulfonyl; and R2 is H. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 18, wherein L is NH or N-alkenyl; R1 is replaced by one or more alkyl, bromine, CF3, chlorine, fluoro or nitrile; A is phenyl optionally substituted by fluoro; B is a bond or is selected from the optionally substituted group consisting of alkyl, cycloalkenyl, cyclopentyl or cyclohexyl; Z is a bond, -O- or -R200-O-; and E is H, or is selected from the optionally substituted group consisting of alkoxy, alkenyl, alkyl, cycloalkyl, diazepanyl, piperazinyl and tetrazolyl. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof or pro-drugs thereof, of claim 19, wherein: R 1 is substituted by alkyl, bromine or chlorine; L is N H; B is cyclohexyl; Z is a bond or -R200-O-; wherein R200 is alkyl; E is optionally substituted alkoxy or piperazinyl; and Y is NH. twenty-one . The compound of claim 20, wherein the compound is 4- (4-. {4-Amino-5- [4- (5-chloro-benzoxazol-2-ylamino) -3-fluoro-f in il] - pyrrolyl [2,3-d] pyrimidin-7-yl}. -cyclohexyl-1-methyl-piperazin-2-one 5- [4- (5-chloro-benzooxazol-2-ylamino) -phenyl] -7 - [4- (2-methoxy-ethoxy) -cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine; or 5- [4- (5-Bromo-7-methyl-benzooxazole-2- i-amino) -phenyl] -7- [4- (2-methoxyethoxy) -cycolohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine 22. A method for treating a disease or condition in a patient with need thereof, which comprises administering a compound according to claim 1, to such a patient, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammation of the intestine, Crohn 's disease, myasthenia gravis, systemic lupus erythematosus, psoriasis, rejection of organ transplantation, benign proliferative diseases and neoplastic, lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, rectal cancer, hematopoietic malignancies, diabetic retinopathy, premature retinopathy, neovascularization choroidal due to age-related macular degeneration, infantile hemangiomas, edema, ascites, effusions, exudates, cerebral edema, acute lung damage, respiratory anxiety syndrome in adults, proliferative blood vessel disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary side effects, cerebral side effects, ischemic limb angiogenesis, ischemia / reperfusion injury, wound healing, Helicobacter peptide-related diseases, induced angiogenic disorders vi Fractures, Crow-Fukase syndrome (POEMS), pre-eclampsia, menometrorrhage, cat scratch fever, rubeosis, neovascular glaucoma, retinopathies, malignant ascites, von Hippel Lindau disease, hematopoietic cancers, hyperproliferative disorders, burns, disease chronic pulmonary, apoplexy, polyps, anaphylaxis, chronic inflammation, allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, angina, ankylosing spondylitis, asthma, congestive obstructive pulmonary disease (COPD), hepatitis C virus (HCV), idiomatic pulmonary fibrosis, myocardial infarction, psoriatic arthritis, restenosis and sciatica. 23. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient. 24. A method for making an optionally substituted 2-aminobenzoxazole comprising the step of: reacting an optionally substituted N- (2-hydroxyphenyl) thiourea with an oxidant and a base, but not including a toxic metal until the reaction is complete substantially; wherein the oxidant is selected from the group consisting of acid peroxide; oxygen, perishable, chlorine, sodium periodate, potassium periodate, fer-butyl peroxide, fer-butyl hypochlorite, sodium perborate, sodium percarbonate, peroxide adduct urea acid, sodium hypochlorite, potassium hypochlorite, hypobromite of sodium, potassium hypobromite, sodium bromate, potassium bromate, potassium permanganate and barium manganate; and the base is selected from the group consisting of metal hydroxides and tetraalkylammonium; metal carbonates and tetraalkylammonium, metal bicarbonates and tetraalkylammonium, metal and tetraalkylammonium alkoxides, metal and tetraalkylammonium phosphates, dibasic metal and tetraalkylammonium phosphates.