MXPA01009290A - 6-o-substituted macrolides having antibacterial activity - Google Patents

Abstract

The instant invention provides novel macrolide compounds and compositions useful in treating bacterial infections. Also provided are processes for preparing same. These macrolides are substituted on the 6-O-position with X'-Y'-Z', wherein X'is selected from the group consisting of C1-C10 alkyl, C3-C10 alkenyl, and C3-C10 alkynyl;Y'and Z'are independently selected from the group consisting of:(c) optionally substituted aryl, and (d) optionally substituted heteroaryl, with the proviso that both Y'and Z'are not both phenyl, and with the further proviso that Y'is not isoxazole when Z'is thiophenyl.

Description

ACROID 6-O-SUBST.TUlPOS THAT HAVE ANTIBACTERIAL ACTIVITY TECHNICAL FIELD This invention relates to novel macrolide compounds having antibacterial activity, to pharmaceutical compositions comprising these compounds, to methods for treating bacterial infections using said compounds, and to methods for making these novel compounds.

BACKGROUND OF THE INVENTION Erythromycins A to D are represented by the following formula: Erythromycin The R "A -OH-CH3 B -H -CH3 C -OH -HD -H -H and are well known and potent antibacterial agents.These compounds are widely used to treat and prevent bacterial infections.However, as with others antibacterial agents, bacterial strains have been identified that have insufficient resistance or susceptibility to erythromycin Erythromycin A has only a weak activity against Gram-negative bacteria Therefore, there is a continuing need to identify new macrolide compounds, which possess Improved antibacterial activity, which are less potential to develop resistance, possess the desired Gram-negative activity, and / or have unexpected selectivity against target microorganisms, Consequently, numerous researchers have prepared chemical derivatives of erythromycin in an attempt to obtain analogues having modified profiles or improved antibiotic activity The patent of E. U. A. No. 5,444,051 discloses 6-O-substituted 3-oxoerythromycin A derivatives, wherein the substituents are selected from alkyl, -CON H2, -CONHC (O) alkyl and -CONHSO2alkyl. WO 97/10251, published March 20, 1997, describes 6-O-methyl-3-descladinous erythromycin derivatives. European patent application 596802, published on May 1, 1994, describes derivatives of bicyclic 6-O-methyl-3-oxoerythromycin A. WO 92/09614, published June 1, 1992, describes derivatives of tricyclic 6-O-methylerythromycin A.

COMPENDIUM OF THE INVENTION The present invention relates to compounds selected from the group consisting of a compound of the formula I: I; A compound of the formula I I: II; and a compound of the formula III: or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein either: (a) Y and Z taken together define a group X, and X is selected from the group consisting of: (1) = O (2) = N-OH, (3) = NOR 1, wherein R 1 is selected from the group consisting of: (a) alkyl of 1 to 12 unsubstituted carbon atoms, (b) alkyl of 1 to 12 carbon atoms substituted with aryl, (c) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (d) alkyl of 1 to 12 carbon atoms substituted with heteroaryl, (e) alkyl of 1 to 12 carbon atoms substituted with substituted heteroaryl, (f) cycloalkyl of 3 to 12 carbon atoms, and (g) -Si- (R2) (R3) (R4), wherein R2, R3 and R4 are each independently selected from alkyl and aryl of 1 to 12 atoms of carbon; and (4) = NOC (R5) (R6) -OR \ wherein R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 12 unsubstituted carbon atoms, (c) alkyl of 1 to 12 carbon atoms substituted with aryl, (d) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (e) alkyl of 1 to 1 2 carbon atoms substituted with heteroaryl, and (f) alkyl of 1 to 12 carbon atoms substituted with substituted heteroaryl, or Rs and R6 taken together with the atom to which they are attached form a cycloalkyl ring of 3 to 12 carbon atoms; or (b) one of Y and Z is hydrogen and the other is selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) N R7R8 wherein R7 and R8 are independently select hydrogen and alkyl of 1 to 6 carbon atoms, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a ring of 3 to 7 members, which, when the ring is a ring of 5 to 7 members, can optionally contain a heterogeneous function selected from the group consisting of -O-, -N H-, -N- (alkyl of 1 to 6 carbon atoms) -, -N (aryl) -, -N (aryl-alkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with aryl) -, -N (heteroaryl) -, - N (heteroaryl alkyl of 1 to 6 carbon atoms) -, -N (aikyl of 1 to 6 carbon atoms substituted with heteroaryl) -, and -S- or -S (O) n-, where n is 1 or 2; Ra is hydrogen or hydroxy; Rb is hydrogen or a protective hydroxy group; L is methylene or carbonyl, provided that L is methylene, T is -OR-; T is selected from the group consisting of -O-, -N H-, and -N (W-Rd) -, where W is absent or selected from the group consisting of -O-, -N H-CO- , -N = CH- and -NH-, and Rd is selected from the group consisting of: (1) hydrogen, (2) alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of of: (a) aryl (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) hydroxy, (f) alkoxy of 1 to 6 carbon atoms, (g) NR7R8, wherein R7 and R8 they are as previously defined, and (h) -CH2-M-R9, wherein M is selected from the group consisting of: (i) -C (O) -NH-, (ii) -NH-C (O) -, (iii) -N H-, (iv) -N =, (v) -N (CH3) -, (vi) -N HC (O) -0-. (vii) -N HC (O) -N H- (viii) -OC (O) -N H- (ix) -OC (O) -O-, (x) -o-, (xi) -S ( O) n-, where n is 0, 1 or 2, (x? I) -C (O) -O-, (xiii) -OC (O) -, and (xiv) -C (O) -; and wherein R9 is selected from the group consisting of: (i) alkyl of 1 to 6 carbon atoms, optionally, substituted with a substituent selected from the group consisting of: (aa) aryl, (bb) substituted aryl, (ce) heteroaryl, and (dd) substituted heteroaryl; (ii) aryl, (iii) substituted aryl, (iv) heteroaryl, (v) substituted heteroaryl, and (vi) heterocycloalkyl; and (3) cycloalkyl of 3 to 7 carbon atoms, (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) heteroaryl its substituted; X 'is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, and alkynyl of 3 to 10 carbon atoms; Y 'and Z' are independently selected from the group consisting of: (a) optionally substituted aryl, and (b) optionally substituted heteroaryl, provided that both Y 'and Z' are both not phenyl, and with the proviso that Y ' it is not isoxazole when Z 'is thiophenol; and A, B, D and E are independently selected from the group consisting of: (a) hydrogen; (b) alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of: (i) aryl; (ii) substituted aryl; (iii) heteroaryl; (iv) substituted heteroaryl; (v) heterocycloalkyl; (vi) hydroxy; (vii) alkoxy of 1 to 6 carbon atoms; (viii) halogen consisting of Br, Cl, F or I; and (ix) NR7R8, wherein R7 and R8 are as previously defined; (c) cycloalkyl of 3 to 7 carbon atoms; (d) aryl; (e) substituted aryl; (f) heteroaryl; (g) substituted heteroaryl; (h) heterocycloalkyl; and (i) a group selected from option (b) above also substituted with -M-R9, wherein M and R9 are as previously defined, provided that at least two of A, B, D, and E are hydrogen; or any pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3-7 membered ring optionally containing a hetero function selected from the group which consists of -O-, -NH-, -N (alkyl of 1 to 6 carbon atoms) -, -N (arylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms) substituted with aryl) -, -N (heteroarylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with heteroaryl) -, -S- or -S (O) n-, in where n is 1 or 2, -C (O) -NH, -C (O) -NR 12-, wherein R 12 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, -NH-C (O) -, and -NR 12 -C (O) -.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically effective amount of a compound of the formulas I, II or II as defined above in combination with a pharmaceutically acceptable carrier. The present invention also relates to processes for preparing compounds of the formulas I, II or III. The invention further relates to methods for treating bacterial infections in a host mammal with the need for such treatment, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I, II or III, as defined above.

DETAILED DESCRIPTION OF THE INVENTION As used throughout the specification and the claims, the following terms have the specified meanings. The terms "alkyl of 1 to 3 carbon atoms", "alkyl of 1 to 6 carbon atoms", and "alkyl of 1 to 12 carbon atoms", as used herein, refer to chain hydrocarbon radicals straight or branched, saturated, derived from a hydrocarbon portion containing between 1 and 3, 1 and 6 and 1 and 12 carbon atoms, respectively, through the removal through a single hydrogen atom. Examples of alkyl radicals of 1 to 3 carbon atoms include methyl, ethyl, propyl and isopropyl, examples of alkyl radicals of 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl. Examples of alkyl radicals of 1 to 12 carbon atoms include all the above examples, as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-docecyl. The term "C 1-6 alkoxy", as used herein, refers to an alkyl group of 1 to 6 carbon atoms, as previously defined, attached to the parent molecular moiety through a oxygen atom. Examples of alkoxy of 1 to 6 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. The term "alkenyl of 3 to 12 carbon atoms" denotes a monovalent or divalent group derived from a hydrocarbon portion containing from 2 to 12 carbon atoms and having at least one carbon-carbon double bond through the removal of one carbon atom. only hydrogen atom. Alkenyl groups include propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. The term "C 3 -C 12 alkynyl", as used herein, refers to a monovalent or divalent group derived from a hydrocarbon containing from 2 to 12 carbon atoms and having at least one triple carbon bond -carbon through the removal of a single hydrogen atom. Representative alkynyl groups include 2-propynyl (propargyl), 1-propynyl, and the like.

The term "alkylene" denotes a divalent group derived from a saturated straight or branched chain hydrocarbon through the removal of two hydrogen atoms, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,3 -propylene, 2,2-dimethylpropylene, and the like. The term "C 1 -C 3 alkylamino", as used herein, refers to 1 or 2 alkyl groups of 1 to 3 carbon atoms, as previously defined, attached to the molecular portion of origin through of a nitrogen atom. Examples of alkylamino of 1 to 3 carbon atoms include methylamino, dimethylamino, ethylamino, diethylamino and propylamino. The term "oxo" denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group, as defined above, are replaced with a single oxygen atom (e.g., a carbonyl group). The term "aprotic solvent", as used herein, refers to a solvent that is relatively inert to proton activity, for example, that does not act as a proton donor. Examples include hydrocarbons such as hexane and toluene, for example, halogenated hydrocarbons such, for example, methylene chloride, ethylene chloride, chloroform and the like, heteroaryl compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art and it will be obvious to those skilled in the art that solvents or individual mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as the solubility of the reagents, reactivity of the reagents and preferred temperature scales, for example. Other discussions of aprotic solvents can be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4a. ed. Edited by John A. Riddick and others, Vol. II, in the Techniques of Chemistry Series, John Wiley & amp;; Sons, NY, 1986. The term "aryl" as used herein, refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings including phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, substituted lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentrafluorophenyl. The term "cycloalkyl of 3 to 12 carbon atoms" denotes a monovalent group derived from a saturated, monocyclic or bicyclic carbocyclic ring compound through the removal of an individual hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2. 1] heptyl and bicyclo [2.2.2] octyl. The terms "halo" and "halogen" as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine. The term "alkylamino" refers to a group having the structure -N H R ', wherein R' is alkyl, as previously defined. Examples of alkylamino include methylamino, ethylamino, iso-propylamino, and the like. The term "dialkylamino" refers to a group having the structure -N R'R ", wherein R 'and R" are independently selected from alkyl, as previously defined.

In addition, R 'and R "together optionally can be - (CH2) k-, wherein k is an integer from 2 to 6. Examples of dialkylamino include dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino, and the like." The term "haloalkyl" denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and illustrated by groups such as chloromethyl, bromoethyl, trifluoromethyl, and the like The term "alkoxycarbonyl" represents an ester group, for example, an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like The term "thioalkoxy" refers to an alkyl group as previously defined attached to the parent molecular moiety through of a sulfur atom The term "carboxaldehyde" as used herein, refers to a group of the formula -CHO.The term "carboxy" as used herein, refers to a group e the formula -CO2H. The term "carboxamide" as used herein, refers to a group of the formula -CONH R'R ", wherein R 'and R" are independently selected from hydrogen or alkyl, or R' and R "together optionally they can be - (CH2) k-, where k is an integer from 2 to 6. The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from 5 to 10 ring atoms , of which one ring atom is selected from S, O and N, one, two or three ring atoms may be additional heterogeneous atoms independently selected from S, O and N, and the remaining ring atoms are carbon, the radical being attached to the rest of the molecule through any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiophenol, furanyl , quinolinyl, isoquinolinyl, and the like. ethocycloalkyl ", as used herein, refers to a non-aromatic, partially unsaturated or fully saturated ring system of 3 to 10 members, which includes individual rings of 3 to 8 atoms in size and bi or tricyclic ring systems , which may include aromatic, 6-membered aryl or heteroaryl rings, fused to a non-aromatic ring. These heterocycle rings include those having 1 to 3 heterogeneous atoms independently selected from oxygen, sulfur and nitrogen, wherein the heterogeneous nitrogen and sulfur atoms may optionally be oxidized and the heterogeneous nitrogen atom optionally quaternized. Representative heterocycles include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinium, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. Specific heterocycloalkyl rings include 3-methylpiperidine, 4- (diphenylmethyl) piperazine, 4- (2- (bis- (2-propenyl) amino) ethyl) piperazine, 4- (2- (diethylamino) ethyl) piperazine, 4- (2-chlorophenyl) piperazine, 4- (3,4-dimethoxyphenyl) piperazine, 4- (4-nitrophen I) piperazine, 4- (4-trifluoromethylphen I) piperazine, 4-hydroxy-4-phenylpiperidine, 4-hydroxypyrrolidine , 4-methylpiperazine, 4-phenylpiperazine, 4-piperidinylpiperazine, 4 - ((2-fu ranyl) carbo or I) piperazine, 4 - ((1,3-dioxolan-5-yl) methyl) piperazine, 6- fluoro-1, 2,3I4-tetrahydro-2-methylquinoline, 1,4-diazacycloheptane, 2,3-dihydroindolyl, 3,3-dimethylpiperidine, 1, 2,3,4-tetrahydroisoquinoline, 1, 2,3,4- tetrahydroquinoline, azacyclooctane, decahydroquinoline, piperazine, piperidine, pyrrolidine, thiomorpholine, triazole and the like. The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group, wherein the alkylene group is 1 to 4 carbon atoms. "Hydroxiprotective group", as used herein, refers to an easily removable group, which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and because it is selectively removable. The use of hydroxiprotective groups is well known in the art to protect groups against undesirable reactions against a synthetic process and many of these protective groups are known, cf. for example, Greene and Wuts, Protective Groups in Organic Svnthesis, 2a. edition, John Wiley &; Sons, New York (1991). Examples of hydroxy-protecting groups include methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl benzoyl, and the like. The term "ketone protecting group", as used herein, refers to an easily removable group that is known in the art to protect a ketone group against undesirable reactions during synthetic procedures and that is selectively removable. The use of protective ketone groups is well known in the art to protect groups against undesirable reactions during a synthetic process and many of these protective groups are known. See, for example, Greene and Wuts, Protective Groups in Organic Svnthesis. 2a. edition, John Wiley & Sons, New York (1991). Examples of protecting ketone groups include ketals, oximes, O-substituted oximes, for example, O-benzyloxime, O-phenylthiomethyloxime, 1-isopropoxycyclohexyl oxime, and the like. The term "protected hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example. The term "substituted aryl" as used herein refers to an aryl group as referred to herein substituted by independent replacement of one, two or three of the hydrogen atoms therein with Cl, Br, F, I, OH , CN, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted with aryl, haloalkyl, thioalkoxy, amino, aicylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy , alkoxycarbonyl and carboxamide. In addition, any substituent can be an aryl, heteroaryl, or heterocycloalkyl group. Substituted aryl groups also include tetrafluorophenyl and pentafluorophenyl. The term "substituted heteroaryl" as used herein, refers to a heteroaryl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms therein with Cl, Br, F, I , OH, CN, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde , carboxy, alkoxycarbonyl and carboxamide. In addition, any substituent can be an aryl, heteroaryl or heterocycloalkyl group. The term "substituted heterocycloalkyl", as used herein, refers to a heterocycloalkyl group as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms therein with Cl, Br, F, I, OH, CN, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any substituent can be an aryl, heteroaryl or heterocycloalkyl group. Numerous asymmetric centers may exist in the compounds of the present ntion. Except where otherwise indicated, the present ntion contemplates the various stereoisomers and mixtures thereof. Accordingly, each time a link is represented on a wavy line, it is meant that a mixture of stereo orientations or an individual isomer of assigned or unassigned orientation may be present. Preferred for the practice of the present ntion are those compounds of the formulas I, II and III, wherein X ', Y', and Z 'combine to form a group R, and R is selected from the group consisting of: - (CH2) -CsC- (5- (2-pyridyl) -2-thienyl), -pyridyl) -2-thienyl), -pyridyl) -2-thienyl), -pyrimidinyl) -2-thienyl), -pyrimidinium) -2-thienyl), -pyrazinyl) -2-thienyl), -cyano-3-pyridyl) -2-thienyl), -carboxamido-3-pyridyl) -2-thienyl), -ethoxycarbonyl-3-pyridyl) -2-thienyl), -N, N-dimethylcarboxamido-3-pyridyl) -2-thienyl), -N ', N'-dimethylhydrazidocarbonyl-3-pyridyl) -2-thienyl ), enyl) -2-thienyl), -methoxyphenyl) -2-thienyl), -fluorophenyl) -2-thienyl), -chlorophenyl) -2-thienyl),, 5-dichlorophenyl) -2-thienyl), -methylphenium ) -2-thienyl), -trifluoromethylphenyl) -2-thienyl), -acetamidophenyl) -2-thienyl), -nitrophenyl) -2-thienyl), -fluorophenyl) -2-thienyl), -furanyl) -2-thienyl ), -f ormil-2-furanyl) fenyl), -f ormil-2-furanyl) fenyl), -f ormil-2-furanyl) f enyl), - (CH 2) -C 3 C- (2,2 ' -bistienyl), - (CH2) -C -.C- (2- (5-chloro-2-thienyl) thienyl), - (CH2) -C = C- (2,3'-bis (thienyl)), - (CH2) -C = C- (5- (2-thiazolyl) -2-thienyl), - (CH2) -C-C- (5- (5-tiazolyl) -2-thienyl), - (CH2) -C3C- (5- (4-thiazolyl) -2-thienyl), - (CH2) -C = C- (5- (2-methyl-5-thiazolyl) -2-thienyl), - (CH2 ) -C_-C- (5- (1-methyl-2-imidazolyl) -2-thienyl), - (CH 2) -CsC- (5- (2-quinoxalinyl) -2-thienyl), - (CH 2) - C- C- (5- (2-benzothiophenyl) -2-thienyl) 1 - (CH 2) -C_-C- (5- (2-pyridyl) -2-thienyl), - (CH 2) -C = -C- (5- (2-benzothiophenyl) -2-thienyl), -C (H) = CH- (5- (1 H -imidazol-1-yl) -3-pyridyl), -C ( H) = CH- (3- (2-furanyl) -6-quinolinyl), -C (H) = CH- (5- (2-thienyl) -3-pyridyl), -C (H) = CH- ( 5-phenyl-3-pyridyl), -C (H) = CH- (5- (2-pyridyl) -3-pyridyl), -C (H) = CH- (5- (3-quinolinyl) -3- pyridyl), -C (H) = CH- (5- (5-pyrimidinyl) -3-pyridyl), -C (H) = CH- (5- (3-pyridyl) -3-pyridyl), -C ( H) = CH- (5- (4-isoquininoinyl) -3-pyridyl), -C (H) = CH- (5- (3-thienyl) -3-pipdyl), -C (H) = CH - (5- (2-furyl) -3-pyridyl), -C (H) = CH- (5- (1,3-thiazolyl)) - 3-pyridyl), -C (H) = CH- (5 - (2- (trimethylsilyl) -1) 3-thiazol-5-yl) -3-pyridyl), 1,3-thiazolyl) -3-pyridyl), -amino- (1,3-thiazol-5-yl) ) -2-thienyl), -amino- (1,3-thiazol-5-yl)) - 2-thienyl), -pyridyl) -2- (1,3-thiazolyl)), -pyridyl) -5- ( 1,3-thiazolyl)), -bromo-1,3-thiazol-2-yl) -5- (1,3-thiazolyl)), -bromo- (1,3-thiazol-2-yl)) - 5 - (1,3-thiazolyl)), -bromo-1,3-thiazol-2-yl) -5- (1,3-thiazoliyl)), -thienyl) -5- (1,3-thiazolyl), - pyrazinyl) -5- (1,3-thiazolyl)), -pyrimidinyl) -5- (1,3-thiazolyl)), - (1,3-thiazyl) ol-5-yl) -5- (1,3-thiazolyl)), -pyrimidinyl) -2-thienyl), -pyrazinyl) -2-thienyl), - (1,3-thiazoliI) -2-thienyl), -pyrimidinyl) -2-thienyl), -pyridyl) -2- (1,3-thiazolyl)), -pyridyl) -2- (1,3-thiazolyl)), -pyridyl) -2- (1,3- thiazolyl)), -thienyl) -2- (1,3-thiazolyl)), -pyridyl) -2-thienyl), -pyrazinyl) -2-thienyl), -pyrimidinyl) -2-thienyl),, 4-dichlorophenyl ) -2-thienyl), -f luorofenyl) -2-thienyl), -C (H) = CH- (5- (5- (1,3-thiazoyl)) - 2-thienyl), -C (H) ) = CH- (2,2'-bist.enyl). -C (H) = CH- (5- (2-? Irazinyl) -2-thienyl), -C (H) = CH- (5- (3-thienyl) -2-thienyl), and -C (H) ) = CH- (5- (2-furanyl) -2-thienyl). As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic and the like, and they agree with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of non-toxic, pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid , maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include salts of adipate, alginate. ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate, and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that are readily divided in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl portion advantageously has no more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates. The term "pharmaceutically acceptable prodrugs" as used herein, refers to those prodrugs of the compounds of the present invention, which, within the scope of medical judgment, are suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, according to a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, when possible, of the compounds of the invention. The term "prodrug" refers to compounds that are readily transformed in vivo to produce the parent compound of the above formula, for example, through hydrolysis in the blood. A full discussion is provided by T. Huiguchi and V. Stella, Pro-drugs as Novel Deliverv Svstems, Vol. 14, of the A. C. S. Symposium Series, and by Edwar E. Roche, ed. , Bioreversible Carriers in Drug Design. American Pharmaceutical Association and Pergamon Press, 1987. The representative compounds of the present invention were analyzed in vitro for antibacterial activity as follows: 20 Petri dishes containing successive aqueous dilutions of the test compound were mixed with 10 ml of Brain Infusion Agar. Sterilized Heart (BHI) (Difco 0418-01 -5), were prepared. Each plate was inoculated with dilutions of 1: 100 (or 1: 10 for slow-growing strains, such as Micrococcus and Streptococcus) of up to 32 different microorganisms, using a Steers replication block. The inoculated plates were incubated at 35-37 ° C for 20 to 24 hours. In addition, a control plate was prepared, using BHI agar without containing any test compound, and incubated at the beginning and end of each test. An additional plate containing a compound having known susceptibility standards for the organisms being tested and belonging to the same class of antibiotic as the test compound was also prepared and incubated as an additional control, as well as to provide comparison capability test to test. For this purpose, erythromycin A was used. After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug production without growth, a light turbidity, or sparsely isolated colonies in the inoculum as compared to growth control. The results of this test, shown below in Table 1, demonstrate the antibacterial activity of the compounds of the invention.

TABLE 1 Concentration M IC of Selected Compounds TABLE 1 CONT.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means an inert, semi-solid or non-toxic liquid filler, diluent, encapsulating material or formulation aid of any kind. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, etiicellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and waxes for suppositories; oils such as peanut oil, cottonseed oil, sunflower oil; Sesame oil; olive oil; corn oil and soybean oil, glycols; such as a propyl glycol; esters such as ethyl oleate and ethyl laurate; agar; pH regulating agents such as magnesium hydroxide and aluminum hydroxide, alginic acid; pyrogen-free water; Isotonic saline, Ringer's solution; ethyl alcohol; and pH-regulating solutions with phosphate, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfume-providing agents, preservatives and Antioxidants may also be present in the composition according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans or other animals, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as powders, ointments or drops), buccally, or as an oral or nasal spray. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilization agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfume-providing agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent. For example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil including synthetic mono or diglycerides can be employed. further, fatty acids such as oleic acid are used in the preparation of injectable products. Injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium. before use . In order to prolong the effect of a drug, it is generally desirable to reduce the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved through the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug is achieved by dissolving or suspending the drug in an oil vehicle. Injectable container forms are made by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the drug to polymer and the nature of the particular polymer employed, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and? Oli (anhydrides). Depot injectable or container formulations are also prepared by trapping the drug with liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquids at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dose forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate and / or (a) fillers or spreading agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose and acacia, (c) wetting agents such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) agents humectants such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium earates, sodium polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise pH regulating agents. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as milk sugar or milk sugar, as well as high molecular weight polyethylene glycols, and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shields such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Optionally these may contain opacifying agents and may also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of imbibition compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like. The active compounds may also be in a microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shields such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulating art. In such solid dose forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal in practice, additional substances other than inert diluents, for example, tablet-forming lubricants and other tablet-forming auxiliaries, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. Optionally these may contain opacifying agents and may also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of imbibition compositions that can be used include polymeric substances and waxes. Dosage dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any of the necessary preservatives or pH regulators as required. Ophthalmic formulations, eardrops, and for the eyes are also contemplated within the scope of this invention. The ointments, pastes, creams and gels may contain in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid. , talc and zinc oxide, or mixtures thereof. The powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of this substance. The sprays may also contain custom propellants such as chlorofluorocarbons. Transdermal patches have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms may be made by dissolving or supplying the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled either by providing a speed control membrane or by dispersing the compound in a polymer or gel matrix. Bacterial infections are treated or prevented in a patient, such as a human or lower mammal, by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for a time as necessary to achieve the desired result. By "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment. The therapeutically effective dose level, specific to any particular patient, will depend on a variety of factors, including the disorder that will be treated and the severity thereof.; the activity of the specific compound employed; the specific composition employed; age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or together with the specific compounds used; and similar factors well known in the medical art. The total daily dose of the compounds of this invention administered to a human or other mammal, in single or divided doses may be in amounts, for example, from 0.01 to 50 mg / kg of body weight or more usually from 0.1 to 25. mg / kg body weight. The individual dose compositions may contain such amounts or submultiples thereof to form the daily dose. In general, treatment regimens according to the present invention comprise administering to a patient, with the need for such treatment, from about 10 mg to about 2,000 mg of the compound (s) of this invention per day in single or multiple doses. . The abbreviations used in the schemes and examples include the following: Ac for acetate; dba for dibenzylidin acetone; THF for tetrahydrofuran; DME for dimethoxyethane; DMF for N, N-dimethylformamide; TFA for trifluoroacetic acid; DMSO for dimethyl sulfoxide; and TMS for trimethylsilyl. Starting materials, reagents and solvents were purchased from Aldrich Chemical Company (Milwaukee, Wl).

The compounds and processes of the present invention will be better understood in conjunction with the following synthetic schemes, which illustrate the methods by which the compounds of the invention are prepared. The compounds of the formulas I, I I and I 1 can be prepared through a variety of synthetic routes. The representative procedures are shown below in Schemes 1-12. The groups R, Rb, L, and T, are as previously defined unless otherwise noted. It will be readily apparent to those skilled in the art that other compounds within the formulas I, II and II can be synthesized through their substitution of the appropriate reagents and agents in the syntheses shown below. It will also be apparent to those skilled in the art that selective protection and deprotection steps, as well as the order of the same steps, can be performed by varying the order, depending on the nature of the groups R, Rp, L, and T, with In order to successfully complete the synthesis of the compounds of formulas I, II and III. The conversion of erythromycin A to 1_ is described in the patents of E. U. A. Nos. 4,990,602; 4,331, 803, 4,680,368, and 4,670,549 and European Patent Application EP 260,938, the descriptions of which are hereby incorporated by reference in their entirety. In summary, the C-9-carbonyl of erythromycin A can be protected as an oxime. The preferred protecting groups on C-9-carbonyl are = NO-Rx or = NOC (Ry) (Rz) (-O-Rx), where Rx is (a) alkyl of 1 to 12 carbon atoms, (b) ) alkyl of 1 to 12 carbon atoms substituted with aryl, (c) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (d) alkyl of 1 to 12 carbon atoms substituted with heteroaryl, (e) alkyl of 1 at 12 carbon atoms substituted with substituted heteroaryl, (f) cycloalkyl of 3 to 12 carbon atoms, or (g) -Si- (Rd) (Re) (Rf), wherein Rd, Rβ and Rf are alkyl of 1 to 12 carbon atoms or -Si (aryl) 3, and wherein Ry and Rz are independently, (a) hydrogen, (b) alkyl of 1 to 12 carbon atoms, (c) alkyl of 1 to 12 carbon atoms substituted with aryl, or (d) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, or Ry and Rz taken together with the carbon to which they are attached form a cycloalkyl ring of 3 to 12 carbon atoms. A preferred protective carbonyl group is O- (1 -i or propoxy cid or hexyl) oxime. The 2'- and 4"-hydroxy groups of C-9-protected erythromycin A can be treated with a hydroxiprotective group precursor in an aprotic solvent.Precursors of the hydroxiprotective group include acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane Examples of aprotic solvents include dichloromethane, chloroform, THF, N-methyl-pyrrolidinone, DMSO, diethyl sulfoxide, DMF, N, N-dimethylacetamide, hexamethylphosphoric triamide, mixtures thereof, and mixtures thereof. one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate or acetone The aprotic solvents do not adversely affect the reaction and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidinone, or their mixtures Protection of the 2'- and 4"-hydroxy groups of erythromycin A protected with C-9 can be achieved sequentially or simultaneously. Preferred protecting groups include acetyl, benzoyl and trimethylsilyl. A particularly preferred protecting group is trimethylsilyl. A complete discussion of the protective groups and the solvents where they are very effective is provided by Greene and Wuts in Protective Groups in Organic Synthesis, 2nd. ed. , John Wiley & Son, Inc., 1991.

SCHEME 1 As shown in Scheme 1, the conversion of alcohol 1 to ether 2 can be achieved with an alkylating agent in the presence of a base. Alkylation agents include chlorides, bromides, alkyl iodides or alkylsulfonates. Specific examples of other alkylating agents are allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p- tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenylf-enylsulfone, 3-bromo-1-trimethyl eti-1-propylate, 3 -bromo-2-octino, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromotethyl quinoline, bromoacetonitrile, epichlorohydrin, bromo fluoromethane, bromo nitromethane, bromine acetate of methyl, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethylphenylsuiphone, and 1,3-dibromo-1-propene. Examples of alkylsulfonates are allyltosylate, 3-phenylpropyl trifluoromethanesulfonate, and N-butyl metal sulfonate. Examples of the solvents used are aprotic solvents such as (DMSO), diethyl sulfoxide, N, N-dimethyl formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, examethyl phosphorus triamide, and mixture thereof or mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, or acetone. Examples of the base that can be used are potassium hydroxide, cesium hydroxide, tetralkyl ammonium hydroxide, sodium hydride, potassium hydride, and alkali metal alkoxides such as potassium isopropoxide, potassium tert-butoxide, and iso- potassium butoxide. An especially preferred method for preparing 2 was the treatment of alcohol 1 with propargyl bromide in a mixture of DMSO / TH F with potassium hydroxide as the base. The conversion from 2 to 3 can be achieved as described by Greene. The preferred conditions for the deprotection of the 2'- and 4"-hydroxyl groups (acetic acid in acetonitrile and water) can result in the concomitant removal of the 1-isopropoxy-cyclohexyl group providing a non-alkylated oxime (= N-). OH) at C-9 If it is not so, then the conversion can be accomplished in a separate step The deoximation of 3 to provide intermediate 4 can be achieved as described by Greene Examples of deoxymeating agents are nitrous acid (formed in situ through the reaction of sodium nitrite with acids such as HCl, H2SO4 and TFA) and inorganic sulfur oxide compounds such as sodium acid suifite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite , sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, and potassium metabisulfite, in a protic solvent Examples of protic solvents are water, ethane, methanol, propanol, isopropanol, trime tilsilanol, or mixtures thereof. The deoximation reaction can also be achieved with an organic acid such as formic acid, acetic acid and TFA. The amount of acid used is from about 1 to about 10 equivalents per equivalent of 3. In a preferred embodiment, the deoximation is performed using sodium nitrite and an inorganic acid such as HCl in ethanol and water to provide the erythromycin 6-intermediate. O-substituted 4, wherein R is propargyl.

SCHEME 2 6 As shown in Scheme 2, the conversion of 4 to intermediate 5 can be achieved through the protection procedures of the 2'- and 4"-hydroxy group previously described.The conversion of 5 to 6 can be achieved with an excess of alkali metal hydride or bis (trimethylsilyl) amide in the presence of carbonyldiimidazole in an aprotic solvent for about 8 to about 24 hours at temperatures from about -30 ° C to about room temperature to provide 6. The alkali metal may be sodium, potassium or lithium and the aprotic solvent can be one previously defined The reaction may require cooling and heating from about -20 ° C to about 70 ° C, depending on the conditions used, and preferably from about 0 ° C to about room temperature. The reaction requires from about 0.5 hours to about 10 days, and preferably from about 10 hours to 2 days to complete The portions of this reaction sequence follow the procedure described by Baker et al., J. Org. Chem., 1988, 53, 2340, the description of which is incorporated herein by reference. The conversion of 6 to the cyclic carbamate 7, a precursor of the compounds of the formula I, was achieved through the treatment of 6 with liquid ammonia at room temperature for 20 hours.

SCHEME 3, As shown in Scheme 3, 7 can be converted to 8 through hydrolysis of the former with moderate aqueous acid or through enzymatic hydrolysis to remove the cladinose portion of the 3-hydroxy group. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or TFA. Suitable solvents for the reaction include methane, ethanol, isopropanol, butane, acetone, and mixtures thereof. Reaction times are typically from about 0.5 to about 24 hours. The preferred reaction temperature is from about -10 ° C to about 60 ° C, depending on the selected method. Alternatively, 5 can be treated with acid to remove the protected cyadinosa group from the 3-hydroxy group as described for conversion from 7 to 8 and treated with a base and carbonyldiimidazole, then ammonia as described for the conversion of 5 to 6 and the conversion from 6 to 7, respectively, to provide 8. The conversion of 8 to 9 can be achieved through oxidation of the 3-hydroxy group to a 3-oxo group using a Corey-Kim reaction with N-chlorosuccinimide sulfide dimethyl or with a modified Swern oxidation process using a carbodiimide-DMSO complex. In a preferred method, 8 is added to a complex of N-chlorosuccinimide-dimethyl sulfide in a chlorinated solvent such as dichloromethane or chloroform of about -10 to about 25 ° C. After stirring for about 0.5 to about 4 hours, a tertiary amine such as tritylamine or diisopropylethylamine was added to produce 9, a precursor for the compounds of the formula I.

SCHEME 4 n Oomo shown in Scheme 4, 4 (of Scheme 2) may alternatively be (a) treated with acid to remove the cladinose group of the 3-hydroxy group (as described for the 7 to 8 conversion) to provide 1 1 a, (b) protected (as described for the conversion of 4 to 5), to provide 1 1 b, (c) oxidized (as described for conversion from 8 to 9) to provide 12, and (d) treated with sodium hydride and carbonyldiimidazole (as described for the conversion of 5 to 6) to provide 13.

SCHEME 5 As shown in Scheme 5, 15 a precursor for compounds of formula II, was prepared through the treatment of 13 with ethylenediamine in a suitable solvent such as aqueous acetonitrile, DMF, or aqueous DMF to provide 14, which is cyclized further through intramolecular condensation with C-9-carbonyl to form 15. Preferred conditions for the formation of 15 from 14 are dilute acetic acid or hydrochloric acid in a suitable organic solvent such as ethanol or isopropanol.

SCHEME 6 As shown in Scheme 6, 16, a precursor for the compounds of formula 11, was prepared through the treatment of intermediate 13 with hydrazine in a suitable solvent such as acetonitrile, DMSO, DMF, or mixtures thereof. temperatures from about room temperature to about 100 ° C. In a preferred embodiment, 13 was treated with hydrazine in DMF at a temperature of about 58 ° C.

SCHEME 7 futa eneral 1: s (D- (pi) 15 M general route 2: 2 13 (i) - (pi) 15 M Intermediates 9, 15, and 16 can be converted to the compounds of formulas I, I I and II, respectively, through a number of general routes. In Scheme 7, 2 preferred general routes are shown. In the general route 1, the 6-O-pro-aryl group of 9, 15, or 16 was reacted with precursor groups R such as X1-Ar1-Ar2, where Ar1 and Ar2 are the same or different and are aryl groups unsubstituted or substituted, or unsubstituted or substituted heteroaryl groups, and X 1 is any of any number of covalent bond precursors, such as a halide (preferably bromide and iodide) or a sulfonate, to form compounds of the formulas I, II ylll. In general route 2, the 6-O-propargyl group was reacted with an R precursor of the bifunctionalized aryl or heteroaryl group, X1-Ar1-X2, to provide the pre-functionalized coupling precursor 18, wherein X2 is halide or sulfonate, which subsequently was coupled to the precursor group R X3-Ar2, wherein X3 is a covalent bond precursor such as halide (preferably bromide and iodide), sulfonate, trialkylstannane, boronic acid, or borate ester, to provide the compounds of the formulas I , II ylll. The coupling reactions are carried out in the presence of Pdl lo Pd (0) catalysts with promoters such as phosphines (preferably triphenylphosphine), arsines (preferably triphenylarsine), amines (preferably pyridine and triethylamine), and inorganic bases (preferably potassium carbonate or cesium fluoride), in polar, aprotic solvents such as DMF, DMSO, DME, acetonitrile, THF, or mixtures thereof, at temperatures from about room temperature to about 150 ° C, depending on the coupling method selected and the nature of X1, X2, and X3. A comprehensive investigation of the coupling, reagents and solvents procedures for transition metal catalysed couplings is provided by Larock, Comprehensive Organic Transformations. A Guide to Functional Group Preparations, VCH Publishers, New York (1989).

SCHEME 8 As shown in Scheme 8, the 6-O-propargyl groups of 9 can be derivatized with TH-borate F in aprotic solvents at temperatures from about -20 ° C to about room temperature to provide vinyl boronic acid derivatives. This chemistry is illustrated by the conversion of 9 to 19. The vinyl boronic acid is then reacted under Suzuki conditions with the reagents X1-Ar1-Ar2 or X1-Ar1-X2, catalysts and promoters described in the description for Scheme 7 for provide additional compounds of the invention. A full discussion of the Suzuki conditions is provided in Chemical Reviews, 1995, Vol. 95, No. 7, 2457-2483.

SCHEME 9 As shown in Scheme 9, the conversion from a step of 19 to the compounds of formula I can be achieved using the chemistry described for general route 1 (Scheme 7).

ESQUE MA 1 0 As shown in Scheme 10, the conversion of two steps of 19 to the compounds of formula I can be achieved using the chemistry described for general route 2 (Scheme 7) through intermediary 20.

SCHEME 11 As shown in Scheme 11, the general route 1 can also be used with the 6-O-allyl derivative 21 to prepare the compounds of the formula I. The synthesis of 21 is described in U.S. Patent No. 5,866,549, Example 1, steps 1a-g and Example 102, steps 120a-c, the description of which is incorporated herein by reference.

SCHEME 12 As shown in Scheme 12, general route 2 can also be used with the 6-O-allyl derivative 21 to prepare the compounds of formula I.

EXAMPLES The compounds and processes of the present invention will be better understood in relation to the following examples, which are intended as an illustration and not as a limitation on the scope of the invention as defined in the appended claims.

Example 1 Compound of Formula I: Rb is H, L is -C (OK T is -N H-, R is - (CH1) -C3C- (5- (2-pyridin-2-thienyl) Step 1 to: compound 2 of Scheme 1 A stirred solution of compound 1 of Scheme 1 (100 g, 0.0969 moles) in 500 ml of freshly distilled THF and 200 ml of anhydrous DMSO at 0 ° C was treated with propargyl bromide ( 80% by weight in toluene, 27 ml, 0.24 mole) followed by the dropwise addition over 25 minutes of a solution / slurry of powdered KOH (13.6 g, 0.24 mole) in 300 ml of DMSO, was stirred vigorously at 0 ° C for 1 hour, sequentially treated with KOH powder (10.9 g, 0.19 mole) and propargyl bromide (80% by weight in toluene, 0.19 mole), and stirred at 0 ° C for 1.5 hours. The addition sequence of 10.9 g of KOH and 21 ml of a solution of propargyl bromide, followed by 1.5 hours of stirring at 0 ° C was repeated three times until the reaction was observed at 60-65% complete through of TLC (98: 1: 1 dichloromethane: methanol: amino hydroxide). The cold reaction mixture was diluted with 1.5 liters of ethyl acetate and 1 liter of water. It was stirred at 0 ° C for 5 minutes and stirred in a separatory funnel. The resulting organic layer was separated, washed sequentially with one liter of water and brine (2 x 500 ml), dried (MgSO4), filtered and concentrated to provide 108 g of a dark brown foam, which was used in step 1b without further purification. MS (FAB) m / z 1071 (M + H) +.

Step 1 b: compound 3 of Scheme 1 A suspension of the product from step 1 to (108 g) in 300 ml of acetonitrile was treated sequentially with 150 ml of water and 200 ml of glacial acetic acid, stirred at room temperature for 20 hours , and concentrated at 40 ° C to provide a brown foam. The foam was dissolved in 750 ml of ethyl acetate, washed sequentially with 5% aqueous sodium carbonate (2 x 250 ml) and brine (2 x 250 ml), dried (MgSO4), filtered and concentrated to a provide 74 g of the crude oxime as a brown foam, which was used in step 1 c without further purification.

Step 1 c: Compound 4 of Scheme 1 A solution of the product from step 1 b (74 g) in 50 ml of ethanol was treated sequentially with 550 ml of water and sodium nitrite (33 g, 0.48 moles), stirred at room temperature environment for 15 minutes, treated with 4M HCl (125 ml, 0.48 moles) for 15 minutes, heated at 70 ° C for 2 hours, cooled to room temperature, diluted with 1.3 liters of ethyl acetate, washed sequentially with 5% sodium carbonate (2 x 350 ml) and brine (2 x 300 ml), dried (MgSO4), filtered and concentrated. Purification of the residue by flash chromatography on silica gel with 98: 1: 1 dichloromethane: methanoi: ammonium hydroxide gave 45 g of a yellow foam. Crystallization of the foam from hot acetonitrile gave 27 g of the desired product as off-white crystals. MS (APCI) m / z 772 (M + H) +.

Step 1 d: compound 5 of Scheme 2 A solution of the product from step 1 c (18.9 g, 24.5 mmol) in 100 ml of anhydrous methylene chloride was treated sequentially with 4- (dimethylamino) pyridine (105 mg, 0.86 mmol) and triethylamine (7.16 ml, 51 mmol), cooled to 15-20 ° C in a cold water bath, treated with acetic anhydride (5.5 ml, 58 mmol) for 5 minutes, stirred at room temperature for 4.5 hours, diluted with 300 ml of ethyl acetate, washed sequentially with 5% aqueous sodium carbonate (2 x 100 ml), water (2 x 100 ml), and brine (2 x 100 ml), dried (MgSO), it was filtered and concentrated to provide 21 g of the desired product as a white foam, which was used without further purification in step 1 e.

Step 1: compound 6 of Scheme 2 A solution of the product of step 1 d (92.38 g, 0.108 moles) in 350 ml of TH F and 175 ml of DMF at room temperature was treated with 1,1 '-carbonyldiimidazole (61 .26 g, 0.378 moles), cooled to 0 ° C, treated with sodium hydride (60 ° dispersion in mineral oil, 5.4 g, 0.135 moles) for 1 hour, stirred 30 minutes at 0 ° C and room temperature for 3 hours, cooled again to 0 ° C, diluted with 800 ml of ethyl acetate, washed sequentially with 5% aqueous sodium bicarbonate (200 ml), water (2 x 500 ml) and brine (2 x 300 ml), dried (Na2SO4), filtered and concentrated to provide 104 g of the desired product as a dark yellow foam, which was used without further purification in step 1 f. MS (ESI) m / z 932 (M + H) +.

Step 1 f: compound 7 of Scheme 2 A solution of the product from step 1 e (52 g, 55.8 mmol) in 500 ml of acetonitrile at -78 ° C, was treated with 500-600 ml of liquid ammonia in a reaction vessel sealed, stirred at room temperature for 24 hours, first concentrated through evaporation of the ammonia at room temperature and atmospheric pressure, and finally concentrated to remove the acetonitrile. The crude product (52 g) was purified via flash chromatography on silica gel with a 3: 7 gradient of acetone / hexanes to 1: 1 acetone / hexanes to provide 32 g of the title compound as a foam. yellow.

Step 1 g: compound 8 of Scheme 3 A suspension of the product from step 1 f (63.92 g, 72.55 mmol) in 1: 1 ethanol / water (600 ml) at 0 ° C was treated with 4N HCl (393 ml, 1860 mmoles) for 20 minutes, stirred at room temperature for 24 hours, cooled again to 0 ° C, diluted with 200 ml of water, adjusted to a pH of 9-10 with a 4 N solution of hydroxide. sodium, diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated to provide 62.1 g of yellow foam. Crystallization of the foam from 1.5: 1 ethyl acetate / hexanes (15 ml) gave 34 g of the desired product as a white solid. MS (ESI) m / z 681 (M + H) \ Step 1 h: compound 9 of Scheme 3. A solution of N-chlorosuccinimide (10.86 g, 81.66 mmol) in 450 ml of anhydrous dichloromethane at -10 ° C was treated with methyl sulphide (6.98 ml, 95.27 mmol) for 10 minutes, stirred for a further 10 minutes, treated with a solution of the product from step 1 g (37.02 g). , 54.44 mmoles) in 450 ml of anhydrous dichloromethane for 35 minutes, stirred an additional 25 minutes at -10 ° C, treated with triethylamine (7.57 ml, 54.44 mmole), stirred at -10 ° C for a further 50 minutes, washed sequentially with a saturated solution of sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated. Purification of the residue through flash chromatography on silica gel with 3: 7 to 1: 1 acetone / hexanes gave 31.9 g of the desired product as a pale yellow foam. MS (ESI) m / z 679 (M + H) +.

Step 1i: option 1: Compound of Formula I: Rb is CHgC (O) -, L is -C.O.-. T is -NH-. R is - (CH?) - C ^ C- (5-vodo-2-thienyl) A slurry of the product from step 1h (5.02 g, 7.40 mmoles), 2,5-diiodoothiophene (5.47 g, 16.29 mmoles), dichlorobis (triphenylphosphine) palladium (II) (0.103 g, 0.148 mmole), and copper iodide I (0.014 g, 0.074 mmole) in 18 ml of triethylamine and 6 ml of acetonitrile was heated at 60 ° C for 3 hours, stirred at room temperature for 48 hours and concentrated. Purification of the residue through flash chromatography on silica gel with 40:60 to 1: 1 acetone-hexanes gave 4.54 g (69.4%) of the desired product as a yellow foam. MS (APCI) m / z 887 (M + H) +.

Step li; option 2: Compound of Formula I: Rb is CH ^ C (O) -, L is -C (QT is -NH, R is - (CH? - C = C-.5-bromo-2-t) enyl) The product from Example 1h (10.8 g) was processed as described in step 1i, option 1, (replacing 2,5-dibromothiophene with 2,5-diiodoothiophene) to provide 8.81 g of the desired product MS (APCI) m / z 841 (M + H) +.

Step 1i: Compound of Formula I: RD is CH ^ C.O.-, L is -C.O.-. T is -NH, R is - (CH?) - CsC- (5- (2-pyridyl) -2-thienyl) A solution of the product from step 1i, option 2 (300 mg, 0.34 mmoles), 2- tri-n-butylstanilpyridine (312 mg, 0.85 mmol), tetrakis (triphenylphosphine) palladium (0) (38 mg, 0.034 mmol) and copper bromide I (2.4 mg, 0.017 mmol) in degassed 1,4-dioxane (2.5 ml) ) was heated at 90 ° C for 21 hours and concentrated. Purification of the residue through flash chromatography on silica gel with 35:65 to 1: 1 acetone-hexanes gave 170 mg of a yellow foam.

Step 1k: Compound of Formula I: Rb is H. L is -C (OT is -NH.R is -.CH7.-C-C-.5-.2-pyridine-2-thienyl. The product of step 1j was dissolved in 10 ml of methanol, stirred for 6 hours at room temperature and concentrated, purification of the residue by flash chromatography on silica gel with 98: 1: 1 dichloromethane: methanol: Ammonium hydroxide produced 136 mg of the desired product as a yellow foam MS (APCI) m / z 796 (M + H) +; 13 C NMR (100 MHz, CDCl 3) 216.6, 205.1, 169.3, 157.7, 152.1, 149.5, 145.8 , 136.5, 133.4, 124.5, 124.3, 122.0, 118.9, 103.1, 90.6, 83.5, 79.4, 79.4, 77.3, 77.3, 70.2, 69.2, 65.8, 65.8, 58.2, 51.7, 51.0, 46.6, 44.7, 40.2, 38.7, 37.3, 28.3 , 22.5, 21.1, 19.7, 18.0, 14.7, 14.5, 13.6, 13.6, 10.5; High Resolution MS (FAB) cale, for (M + H) + C 2H58N3O? OS: 796.3843. It was found: 796.3826.

Example 2 Compound of Formula I: Rb is H, L is -C (O.-.T is -NH, R is - (CHy.-CsC-.dO-pyridyl.-S-thienyl) The product of step 1i , option 2 (250 mg), was processed as described in steps 1j and 1k (substituting 3-tri-n-butylstanilpyridine for 2-tri-n-butylstannyl pyridine) to provide 61 mg of the desired product. High Resolution MS (FAB) calculated (M + H) + for C 2 H58N3O? OS: 796.3843. 796.3826 was found.

Pipe 3 Compound of Formula I: Rb is H. L is -C (O) -. T is -NH, R is - (CHa.-C-.C- (5-f4-Pyridyl) -2-thienyl) The product of step 1i, option 2 (350 mg), was processed as described in the steps 1j and 1k (substituting 4-tri-n-butylstanilpyridine for 2-tri-n-butylstannyl pyridine) to provide 105 mg of the desired product. MS High Resolution MS (ESI) calculated (M + H) + for C42H58N3O? OS: 796.3843. 796.3833 was found.

Example 4 Compound of Formula I; Rb is H, L is -C (OK T is -NH, R is (CH ') -CgC- (5- (5-pyrimidinyl) -2-thienyl) Step 4a: Compound of Formula I: Rb is -C (O) CH. L is -C (OT is -NH.R is - (CH?) - C = C- (5- (5-pyrimidinyl) -2-ynyl) A solution of the product from step 1i, option 1, (250 mg, 100 mg of hexamethylditin, 16 mg of dichlorobis (triphenylphosphine) palladium (II) and 49 mg of 5-bromopyridine in 4 ml of toluene in a pressure flask was heated at 100 ° C for 18 hours, cooled and concentrated. The residue was purified on silica gel with 98: 1: 1 dichloromethane: methanol: ammonium hydroxide to provide 80 mg of the desired product.

Step 4b: Compound of Formula I: Rb is H, L is -C (QT is -NH.R is - (CH?,) - C-sC- (5- (5-pyrimidinyl-2-thienyl. The product solution from step 4a (126 mg) was stirred in 5 ml of methanol for 20 hours and concentrated to provide 118 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C42H57N4O? : 797.33790. Found 797.3793.

Example 5 Compound of Formula I: R is H, L is -C (O) -, T is -NH, R is - fCH?) - CBC- (5- (4-pyrimidinyl) -2-thienyl) The product from step 1i, option 2 (250 mg), was processed as described in steps 1j and 1k (substituting 2-tri-n-butylstanilpyrimidine for 2-tri-n-butylstannylpyridine) to provide 41 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C? H57N4O? 0S: 797.3790. 797.3795 was found.

Example 6 i Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH?) - C = C- (5- (2-pyrazinyl) -2- thienyl) The product from step 1i, option 2 (252 mg), was processed as described in steps 1j and 1k (substituting 2-tri-n-buti-stanilpyrazine for 2-tri-n-butylstannyl pyridine) to provide 93 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C41H57N4O? 0S: 797.3790. 797.3784 was found.

Example 7 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is fCH? .- C = C- (5- (5-pyrimidinyl-2-thienyl) Step 7a: Compound of Formula I: Rb is CH ^ CrO.-. L is -C.O) -, T is -NH. R is - (CH? _.- C = -C- (5- (5-pyrimidinyl) -2-thienyl) A solution of Pd2 (dba) 3 (96 mg, 0.105 mmol) and triphenylarsine (128 mg, 0.42 mmoles) in 6 ml of degassed acetonitrile was stirred for 30 minutes, treated sequentially with the product from step 1h (1.04 g, 1.4 moles), 2-bromo-5- (4-pyrimidinyl) thiophene (0.607 g, 2.5 mmoles ) and copper iodide I (2.7 mg, 0.014 mmol), stirred at 80 ° C for 2 hours, cooled, treated with 50 ml of ethyl acetate and 10 ml of water, filtered through seashells in Dust (Celite®) The water was removed and the organic layer was washed with brine, dried (Na 2 SO 4), filtered and concentrated The residue was chromatographed on silica gel with 98: 1: 1 dichloromethane: methanol: Ammonium hydroxide to provide 724 mg of the desired product.

Step 7b: Compound of Formula I: Rb is H, L is -C (O) -. T is -NH. R is -.CH?) - C-- C- (5 - (5-pyrimidinyl) -2-thienyl) A solution of the product from step 7a (724 mg) was stirred in 15 ml of methanol for 48 hours and He concentrated. Purification of the residue on silica gel with 98: 1: 1 dichloromethane: methanol: ammonium hydroxide gave 413 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C41 H57N4O? OS: 797.3790. 797.3787 was found.

Example 8 Compound of Formula I: R is H. L is -C (O) -, T is -N H. R is -fCH,.-C-EC- (5- (5-cyano-3-pyridyl) -2-thienyl The product of step 1 i, option 2 (250 mg), was processed as described in the steps 4a and 4b (substituting 5-bromonicotinonitrile for 5-bromopyrinidine) to provide 15 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C43H57N4O? S: 821.3795. 3766 Example 9 Compound of Formula I: Rb is H. L is -C. O .-, T is -N H. R is - (CH?) - C = C- (5- (5-carboxamido-3-pyridyl) -2-thienyl) The product of step 1 i, option 2 (250 mg), was processed as described in steps 4a and 4b (substituting 5-bromonicotinamide for 5-bromopyrimidine) to provide 15 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C43Hs9N O10S: 839.3896. 839.3895 was found.

Example 10 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH?.-C = C- (5- (5-ethoxycarbonyl-3-pyridyl) -2-thienyl) The product from step 1 i, option 2 (250 mg), was processed as described in steps 4a and 4b (substituting ethyl 5-bromonicotinate for 5-bromopyrimidine) to provide 44 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C45H62N3? 12S: 868.4049. 868.4037 was found.

Example 1 Compound of Formula I: Rb is H. L is -C (OT is -NH, R is -fCH?> C = C- (5- (5-dimethylcarboxamido-3-pyridyl) -2-thienyl) The product from step 1 i, option 1 (250 mg ), was processed as described in steps 4a and 4b (substituting 5-bromo-N, N-dimethylnicotinamide for 5-bromopyrimidine) to provide 130 mg of the desired product MS (ESI) m / z 867 (M + H) +.

Example 12 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -fCH? .C-3C- (5- (5-N ', N'-dimethylhydrazdodocarbonyl-3-pyridyl) -2-thienyl) The product from step 1 i, option 1 (250 mg), was processed as described in steps 4a and 4b (substituting 5-bromo-N ', N'-dimethylnicotinohydrazide for 5-bromopyrimidine) to provide 56 mg of the desired product. MS (ESI) m / z 882 (M + H) +.

Example 13 Compound of Formula I: Rb is H. L is -C (O) -. T is -N H. R is - (CH?) - CsC- (5- (phen-2-thienyl) Step 13a: A solution of the product from step 1 i, option 1 (195 mg, 0.22 mmol), phenylboronic acid (40.2 mg, 0.33 mmol), potassium carbonate (76 mg, 0.55 mmol), and Pd (OAc) 2 ( 0.25 mg, 0.001 mmoles) in 2 ml of acetone and 1 ml of water was heated at 60 ° C for 18 hours, cooled to room temperature, treated with ethyl acetate, washed sequentially with 5% sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated. The residue was concentrated on silica gel with 98: 1: 1 dichloromethane: methanol: ammonium hydroxide to provide 95 mg (32%) of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C43H59N2? 12S: 795.3885. 795.3870 was found.

Example 14 Compound of Formula I: Rb is H, L is -C (OT is -NH, R is - (CH? .C-C- (5- (3-methoxyphenyl) -2-thienyl) The product from step 1 i, option 1 (151 mg), was processed as described in Example 13 (substituting 3-methoxyphenylboronic acid for phenyl boronic acid) to provide 95 mg of the desired product MS High Resolution MS (FAB) calculated ( M + H) + for C44H6? N2O? S: 825.3996. 825.4023 was found.

Example 15 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH7) -C-C- (5- (3-fluorophenin-2-thienyl) The product of step 1, option 1 (195 mg), was processed as described in Example 13 (substituting 3-fluorophenylboronic acid) for phenylboronic acid) to provide 83 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C44H58N2O10SF: 813.3791. 813.3803 was found.

Example 16 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH. R is - (CH7.-C-.C- (5- (3-chlorophenyl) -2-thienyl.) The product of step 1i, option 1 (252 mg), was processed as described in Example 13 (substituting 3-chlorophenylboronic acid). for phenylboronic acid) to provide 43 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C 3H58N2O? oSCI: 829.3495. 829.3496 was found.

Example 17 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -CH7.-C3C- (5-.3,5-dichlorophenyl) -2-thienyl) Step 1i product, option 1 (266 mg), was processed as described in Example 13 (substituting 3,5-dichlorophenylboronic acid for phenylboronic acid) to provide 82 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C-J3H57N2O10SCI: 863.3105. 863.3108 was found.

Example 18 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -, CH? .- C-C-.5-.3-methylphenyl.- 2-thienyl. The product from step 1i, option 1 (159 mg), was processed as described in Example 13 (substituting 3-methylphenylboronic acid for phenylboronic acid) to provide 93 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C44H6iN2O? OS: 809.4041. It was found 809.4037.

Example 119 Compound of Formula I: Rb is H, L is -C.O) -. T is -NH. R is - (CH?) - CF * C- (5- (3-trifluoromethylphenin-2-thienyl.) The product from step 1i, option 1 (195 mg), was processed as described in Example 13 (substituting 3 - trifluoromethylphenylboronic acid for phenylboronic acid) to provide 120 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C H58N2O? oSF3: 863.3759.863.3750 was found.

Example 20 Compound of Formula I: Rb is H, L is -C (O) -, T is -N H. R is -. CH?) - C_-C- (5- (3-acetap.idofenin-2-thienyl) The product from step 1 i, option 1 (151 mg), was processed as described in Example 13 (substituting 3-acetamidophenylboronic acid) for phenylboronic acid) to provide 80 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C45H62 3O11S: 852.4100 852.4096 was found.

Example 21 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH?) - C = C- (5- (3-nitrophenyl) -2-thienyl ) The product of step 1 i, option 1 (151 mg), was processed as described in Example 13 (substituting 3-nitrophenylboronic acid for phenylboronic acid) to provide 102 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C43H58N3Oi2S: 840.3736. 840.3722 was found.

Example 22 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH?.-C-_C- (5- (4-fluorophenyl) -2-thienyl ) The product of step 1 i, option 1 (293.6 mg), was processed as described in Example 13 (substituting 4-fluorophenylboronic acid for phenylboronic acid) to provide 145 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C43Hs8N2O? OSF: 813.3796. 813.3803 was found.

Example 23 Compound of Formula I: Rb is H, L is -C (O) -. T is -N H. R is -fCH ^ -C-C-.5-.2-furanyl) -2-thienyl) The product from step 1 i, option 1 (266 mg, 0.30 mmol), was processed as described in Steps 1j and 1k (substituting 2-tri-n-butylstanthylfuran for 2-tri-n-butylstannylpyridine) to provide 74 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C41 H57N2O? ? S: 785.3683. 785.3679 was found.

Example 24 Compound of Formula I: Rb is H. L is -C (O) -. T is -N H, R is - (CH7) -C = C- (4- (5-formyl-2-furanyl) phenyl) Step 24a: Compound of Formula I: Rb is CH..C. O , L is -C (O) -, T is -N H. R is - (CH,) - C - C- (4- (5-formyl-2-furanyl) phenol) A solution of the product from step 1 h (300 mg), 6.2 mg dichlorobis (triphenylphosphine) palladium (II), 0.84 mg of copper iodide (I), and 200 mg of 5- (4-bromophenyl) -2-furaldehyde in 0.5 ml of acetonitrile and 2 ml of triethylamine was heated at 60 ° C for 18 hours, cooled to room temperature, treated with ethyl acetate, washed sequentially with 5% sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed on silica gel with 98.5: 1: 0.5 chloroform: methanol: ammonium hydroxide to provide 105 mg of the desired product.

Step 24b: Compound of Formula I: R ° is H, L is -C (OT is -NH.R is - .CH?) -C-C-.4-.5-formyl-2-furapil .phenyl . A solution of the product from step 24a (165 mg) was processed as described in step 7b, filtered through a syringe membrane filter and concentrated to provide 55 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C4 H59N2O? 2: 807.4075. It was found 807.4075.

Example 25 Compound of Formula I: Rb is H, L is -C. O) -, T is -NH, R is - (CH?) - C-_C- (5- (2,2'-bistienyl) The product of step 1 i, option 1 (1 mg), was processed as described in steps 1j and 1k (substituting 2-n-tributylstannylthiophene for 2-tri-n-butylstannylpyridine) to provide 43 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C? H57N2O ? OS2: 801.3455.801.33462 was found.

Example 26 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH, R is - (CH7?) - C = C- (2- (5-chloro-2-thien) ntienyl) The product of step 1 i, option 2 (250 mg)), was processed as described in steps 4a and 4b (substituting 2-bromo-5-chlorothiophene for 5-bromopyridine) to provide 80 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C4? H56N2O? 0S2CI: 835.3059. 835.3059 was found.

Example 27 Compound of Formula I: R is H, L is -C (O) -, T is -NH, R is - (CH,) -C-C- (2, 3'-bis, thienyl)) The product from step 1 i, option 1 (151 mg), was processed as described in Example 13 (substituting 3-thiopheneboronic acid for phenylboronic acid) to provide 78 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C4? H57N2 ?? or S2: 801.3455. 801.3462 was found.

Example 28 Compound of Formula I: R is H. L is -C (O) -, T is -NH. R is - (CH7.-C-C- (5- (2-thiazole) -2-thienyl) The product from step 1i, option 1 (250 mg), was processed as described in steps 1j and 1k (substituting 2-tri-n-butylstanilpyridine for 2-tri-n-buty-istanilpyridine) to give 110 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C40HS6 3O? OS2: 802.3402. 802.3412 was found.

Example 29 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH. R is - (CH?) - C-C-.5- (5-thiazolyl-2-thienyl) The product of step 1i, option 1 (839 mg), was processed as described in steps 1j and 1k (substituting 2-tri-n-butylstanylthiazole for 2-tri-n-butylstannylpyridine) to give 281 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C4oH56N3O? OS2: 802.3402. 802.3400 was found.

Example 30 Compound of Formula I: R is H, L is -C (O) -, T is -NH. R is - (CH? - C-C-f5- (4-thiazolyl) -2-thienyl) The product of step 1i, option 1 (1.08 mg), was processed as described in steps 1j and 1k (substituting 4-tri-n-butylstannyl pyridine for 2-tri-n-butylstannyl pyridine) to give 439 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C40H56N3O? OS2: 802.3402. 802.3402 was found.

Example 31 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH? - C-C-.5- (2-metii-5-thiazoin -2-thienyl) The product of step 1i, option 1 (100 mg), was processed as described in steps 24a and 24b (substituting 4- (5-bromo-2-thienyl) -2-methylthiazole for 5- ( 4-bromophenyl) -2-furaldehyde) to give 65 mg of the desired product: MS High Resolution MS (FAB) calculated (M + H) + for C4? H58N3 ?? or S2: 816.3582. 816.3564 was found.

Example 32 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH. R is -fCH?) - C = C- (5- (1-methy1-2-imidazolyl) -2-thienyl, The product from step 1i, option 2 (302 g), was processed as described in Steps 1j and 1k (substituting 1-methyl-2-tri-n-butylstannylimidazole for 2-tri-n-butylstanilpyridine and toluene for 1,4-dioxane) to provide 18 mg of the desired product MS High Resolution MS (FAB) ) calculated (M + H) + for C4? H59N4O10S: 799.3946. Found 799.3943.

Example 33 Compound of Formula I: R is H. L is -C (O) -. T is -NH. R is - (CH? .C-C- (5- (2-quinoxalinyl) -2-thienyl) The product from step 1 h (150 mg) was processed as described in steps 24a and 24b (substituting 2 - (5-bromo-2-thienyl) quinoxaline for 5- (4-bromophenyl) -2-furaldehyde) to provide 61 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C45H59N O ? OS: 847.3952. 847.3958 was found.

Example 34 Compound of Formula I: R is H, L is -C (OT is -NH, R is -. CH?) - C - C- (5- (2-benzothiophenyl) -2-thienyl) The product from step 1 i, option 1 (301 mg) was processed as described in Example 13 (substituting 2-benzothiophenoronic acid for phenylboronic acid) to provide 155 mg of the desired product.

Example 35 Compound of Formula I I: Rb is H, R is - (CH? - C = C- (5-. 2-pyridine-2-thienyl) Step 35a: Compound 1 1 a of Scheme 4 A suspension of compound 4 of Scheme 4 (56 g) in 180 ml of ethanol and 540 ml of water was treated slowly with 1 M HCl (130 ml) for 20 minutes, stirred for 7 hours, it was cooled to 0 ° C, treated with 1 M NaOH (130 ml), and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered and concentrated. The residue was redissolved in 300 ml of diethyl ether and extracted in 1 M HCl (300 ml). The extract was made basic (pH 10) with 1 M NaOH and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered and concentrated to provide 38 g of the desired product, which was used in the next step without further purification.

Step 35b: Compound 1 1 b of Esquema 4 The product from step 35a (37 g) was dissolved in 230 ml of dichloromethane and treated with 16.8 ml of triethylamine followed by the dropwise addition of 1.2 ml of acetic anhydride for 10 hours. minutes at room temperature, stirred for 10 hours, diluted with 200 ml of dichloromethane, washed sequentially with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to provide 40 g of the desired product, which was used in the next step without further purification.

Step 35c: Compound 12 of Scheme 4 The product of step 35b (35.73 g) was processed as described in step 1 h to provide 40.2 g of the crude product which was purified by flash chromatography on silica gel with a 98: 1: 1 gradient of dichloromethane / methanol / ammonium hydroxide to 94: 5: 1 dichloromethane / methanol / ammonium hydroxide to provide 20.5 g of the desired product.

Step 35d: Compound 13 of Scheme 4 A solution of the product from step 35c (13.57 g, 0.02 moles) in 250 ml of TH F at 0 ° C was first treated with 1,1 '-carbonyldiimidazole (16.8 g, 0.103 moles), then in portions with sodium hydride (60% dispersion in mineral oil, 831 mg) for 20 minutes, stirred at room temperature for 6 days, cooled again to 0 ° C, diluted with 500 ml of ethyl acetate , washed sequentially with 5% aqueous sodium bicarbonate (150 ml), water (2 x 150 ml) and brine (2 x 200 ml), dried (Na 2 SO 4), filtered and concentrated. The residue was purified by flash chromatography on silica gel with a 3: 7 gradient of acetone / hexanes to 4: 6 acetone / hexanes to provide 5.75 g of the desired product.

Step 35e: Compound 14 of Scheme 5 A slurry of the product from step 35d (1.5 g, 0.002 mole) in 15 ml of acetonitrile and 1 ml of water was treated with 1.4 ml of ethylene diamine, stirred at room temperature for 2 hours. hours and concentrated. The residue was treated with ethyl acetate, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 97.5: 2: 0.5 dichloromethane: methanol: ammonium hydroxide to provide 0.904 g of the desired product.

Step 35f: Compound 15 of Scheme 5 A solution of the product from step 35e (0.9 g, 1.25 mmol) in 25 ml of ethanol at room temperature was treated with 285 μl of acetic acid, heated at 78 ° C for 18 hours , treated with 150 ml of linden acetate, washed sequentially with 5% aqueous sodium bicarbonate (75 ml) and brine (2 x 75 ml), dried (Na2SO4), filtered and concentrated. The residue was purified via flash chromatography on silica gel with 8:92 methanol / dichloromethane to provide 0.572 g of the desired product.

Step 35g: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is - (CH? C - C- (5- (2-benzothiophenyl) -2-thienyl ) The product of step 35f (380 mg) was processed as described in step 7a (replacing 2-bromo-5- (4-pyrimidinyl) thiophene with 2- (5-bromo-2-thienyl) pyridine)) and purified by flash chromatography on silica gel with a gradient of 5:95 methanol / dichloromethane to 7:93 methanol / dichloromethane to provide 210 mg of the desired product. MS High Resolution MS (FAB) calculated (M + H) + for C44H6. N4O9S: 821 .4154. It was found 821 .4161.

Example 36 Compound of Formula I: Rb is H. L is -C (O) -. T is -N (W-RdK W is -NH-. Rd is H. R is - (CH?) - C = C- (5- (2-pyridyl) -2-thienyl) Step 36a: Compound 16 of Scheme 6 A solution of the product from step 35d (3 g, 4 mmol) in 22 ml of DMF was treated sequentially with 12 ml of 1 -hexene and 1.29 ml of hydrazine, heated to 58 ° C for 6 hours, treated with N H 4 Cl, saturated aqueous and extracted with ethyl acetate. The extract was washed sequentially with 5% aqueous sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated. The residue (2.2 g) was dissolved in 50 ml of methanol, stirred for 20 hours and concentrated. The residue was purified through flash chromatography on silica gel with 6: 3.5: 0.5 ethyl acetate / hexanes / ammonium hydroxide to 98.5: 2: 0.5 dichloromethane / methanol / ammonium hydroxide to provide 1.6. g of the desired product.

Step 36b: Compound of Formula I: Rb is H. L is -C (O.- .T is -N (W-Rd) - .W is -NH-. Rd is H. R is - (CH?) -C = C- (5- (2-pyridyl) -2-thienyl) A solution of the product from step 36a (350 mg) was processed as described in step 35g to provide the crude product which was purified through flash chromatography on silica gel with 2: 97.5: 0.5 methane / dichloromethane / ammonium hydroxide to provide 229 mg of the desired product MS High Resolution MS (FAB) calculated (M + H) + for C42HsgN4O? oS: 811.3946. 811.3945 was found.

Example 37 Compound of Formula I: Rb is H, L is -C (OT is -NH, R is -C (H) = CH- (5- (1H-ylazol-1-yl) -3-p ridicule) Step 37a: Compound of Formula I: Rb is CH3C (O) -, L is -C (O) -, T is -NH. R is -C.H) = CH7? The title compound was prepared as described in the patent of E. U. A. No. 5,866,549, Example 1, steps 1a-1g and Example 102, steps 120a-c.

Step 37b: 3-bromo-5- (1H-imidazol-1-yl) pyridine A solution / slurry of 3,5-dibromopyridine (474 mg, 2.0 mmol), imidazole (136 mg, 2.0 mmol), Cs2CO3 (975 mg , 30 mmol, and CuO (50 mg), was heated in a sealed vessel for 18 hours, cooled to room temperature, treated with ethyl acetate, washed with 5% NaHCO3 and brine, dried (Na2SO4), The residue was purified by flash chromatography on silica gel with a gradient of 98: 2 to 90:10 methanol / dichloromethane to provide 80 mg of the desired compound MS (DCI / NH3). m / z 224 and 226 (M + H) +.

Step 37c: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH. R is -CfH) = CH- (5- (1H-imidazol-1-yn-3-pyridyl) A solution / slurry of the product from step 37a (136 mg, 0.20 mmol), the product of step 37b (56 mg, 0.250 mmole), Pd (OAc) 2 (10 mg, 0.04 mmol), tri-o-tolylphosphine (18 mg, 0.060 mmol) and triethylamine (84 ml, 0.60 mmole) in 2 ml of degassed acetonitrile was treated at 50 ° C in a sealed container for 14 hours, treated with an additional 10 mg of Pd (OAc) 2.18 mg of tri-o-tolylphosphine, treated with acetate ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was stirred in methanol for 18 hours, concentrated and purified by flash column chromatography on silica gel with 90: 10: 0.5 dichloromethane / methanol / ammonium hydroxide to provide 48 mg of the desired compound. MS (ESI) 782 (M + H) +.

Example 38 Compound of Formula I: Rb is H. L is -C (QK T is -NH, R is -C (H) = CH- (3-bromo-6-quinolinyl) Step 38a: Compound of Formula I: Rb is CHgCfO) -, R is -C. = CH-f5-.3-bromo-6-quinolinyl) Compound 21 of Scheme 12 (136 mg) was processed as described in step 37c (substituting 3-bromo-6-iodoquinoline for the product of step 37b) and was purified by flash column chromatography on silica gel with 1: 1: 0.5 acetone / hexane / triethylamine to give 170 mg of the desired product.

Step 38b: Compound of Formula I: R is H, L is -C (O) -, T is -NH, R is -C (H) = CH- (3-bromo-6-ouinolinyl) The product of step 38a (150 mg) was stirred in 10 ml of methanol at room temperature for 48 hours, concentrated and purified by flash chromatography on silica gel with 50: 50: 0.5 methanol / dichloromethane / ammonium hydroxide provide 130 mg of the desired compound. MS (ESI) 844, 846 (M + H) +.

Example 39 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH, R is -C? "H. = CH- (3- (2-furanyl) -6-guinolinyl) Step 39a: Compound of Formula I: Rb is CHg_C (O) -. R is rC- ?. = CH- (3- (furanyl-6-quinolinyl) A solution of the product from step 38a (177 mg, 0.20 mmol), 2-tri-n-butylstanthylfuran (78 mg, 0.25 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.020 mmol) in 2 ml of dry toluene was heated at 60 ° C for 2 hours, 80 ° C for 2 hours and 90 ° C for 16 hours, cooled, treated with ethyl acetate , washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash column chromatography on silica gel with 1: 1: 0.5 acetone / hexane / triethylamine to provide the desired product.

Step 39b: Compound of Formula I: R is H, L is -C (O) -, T is -NH. R is -CH) = CH- (3- (2-furanin-6-quinolinyl) The product from step 39a was processed as described in step 38b to provide 102 mg of the desired product MS (ESI) 832 (M + H) +.

Example 40 Compound of Formula I: Rb is H, L is -C (O) -, T is -N H, R is -C (H) = CH- (5- (5-bromo-3-pyridyl) Step 40a: Compound of Formula I: Rb is CHsCÍO) -. T is -N H, R is -C. H. = CH- (5-bromo-3-pyridyl) A solution / slurry of the product from step 37a (136 mg, 0.20 mmol), 3,5-dibromopyridine (125 mg, 0.527 mmol), Pd (C2H3O2) 2 (10 mg , 0.04 mmol), tri-o-tolylphosphine (18 mg, 0.060 mmol), and triethylamine (84 ml, 0.60 mmol) in 2 ml of degassed acetonitrile was heated at 50 ° C in a sealed container for 14 hours, treated with An additional 10 mg of Pd (C2H3O2) 2, 18 mg of tri-o-tolylphosphine was treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 1: 1: 0.5 acetone / hexane / triethylamine to provide 95 mg of the desired product.

Step 40b: Compound of Formula I: Rb is H, L is -C (O) -, T is -N H. R is -C. H. = CH- (5-bromo-3-pyridyl) The product of step 38a (75 mg) was stirred in 5 ml of methanol at room temperature for 48 hours, concentrated and purified by flash column chromatography over flash. silica gel with 5: 94.5: 0.5 methanol / dichloromethane / ammonium hydroxide to provide 130 mg of the desired product. MS (ESI) 794, 796 (M + H) +.

Example 41 Compound of Formula I: Rb is H. L is -C. O.-, T is -NH, R is -C (H) = CH- (5- (2-thienyl) -3-? Iridyl) Step 41 a: Compound of Formula I: Rb is CH3C (O) -. L is -C (O) -, T is -N H. R is -C (H) = CH- (5- (2-thienyl) -3-pyridyl) To a solution of the product from step 40a, tributyl (2-thienyl) stannane (79 μL, 0.25 mmol), tetrakis (triphenylphosphine) ) palladium (0) (23 mg, 0.020 mmol) in 2 ml of dry toluene was heated at 90 ° C for 20 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3, and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 50: 50: 0.5 acetone / hexane / triethylamine to provide the desired product.

Step 41 b: Compound of Formula I: Rb is H, L is -C (O.-.T is -NH.R is -C.H. = CH-.5- (2-thienyl) -3-pyridyl ) The product from step 41 a was stirred in methanol at room temperature for 18 hours, concentrated and purified by flash column chromatography on silica gel with 5: 94.5: 0.5 methanol / dichloromethane / ammonium hydroxide. to provide 81.1 mg of the desired product. MS (ESI) 798 (M + H) +.

Example 42 Compound of Formula I: Rb is H. L is -C.O.-. T is -NH-. R is -C (H) = CH- (5-phenyl-3-pyridyl) The product of step 40a, (167 mg) was processed as described in Example 41, steps 41a-b (replacing tributyl (phenyl) stannane for tributyl (2-thienyl) stannane) to provide 91.8 mg of the desired product. MS (ESI) 792 (M + H) +.

Example 43 Compound of Formula I: Rb is H, L is -CO) -, T is -NH, R is -C (H) = CH- (5- (2-pyridyl-3-pyridyl. step 40a, (167 mg) was processed as described in Example 41, steps 41a-b (substituting 2- (tributylstannyl) pyridine for tributyl (2-thienyl) stannane) to provide 71.4 mg of the desired product MS (ESI) 793 (M + H) +.

Example 44 Compound of Formula I: Rb is H. L is -C (O.-, T is -NH.R is -C (H) = CH- (5- (3-ouinolinyl) -3-pyridyl) Step 44a: Compound of Formula I: Rb is CH ^ CfO) -, L is -C (O) -, T is -NH-. R is -C (H. = CH- (5- (3-quinolinyl-3-pyridyl) A solution of the product from step 40a (167 mg, 0.2 mmol), hexamethylditin (78 mg, 0.24 mmol), tetrakis (triphenylphosphine) ) palladium (0) (23 mg, 0.02 mmol) and 3-bromoquinoline (27 mg, 0.2 mmol), in 2 ml of toluene, heated at 90 ° for 18 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3, and brine, dried (Na2SO), filtered and concentrated The residue was purified by flash column chromatography on silica gel with 50: 50: 0.5 acetone / hexane / triethylamine to provide the desired product.

Step 44b: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH-, R is -C.H. = CH-.5-.3-ouinolinin-3-pyridyl. The product of step 44a was stirred in methanol at room temperature for 18 hours, concentrated and purified by flash column chromatography on silica gel with 5: 94.5: 0.5 methanol / dichloromethane / ammonium hydroxide to provide 62.1 mg of the desired product. MS (ESI) 843 (M + H) +.

Example 45 Compound of Formula I: Rb is H. L is -C (O) -. T is -N H. R is -C (H. = CH- (5-.5-pyrimidinyl-3-pyridyl) The product of step 40a, (167 mg) was processed as described in Example 44, steps 44a-b (substituting -bromopyrimidine for 3-bromoquinoline) to provide 71.4 mg of the desired product MS (ESI) 794 (M + H) +.

Example 46 Compound of Formula I: Rb is H, L is ~ C (OT is -N H. R is -C (H) = CH- (5- (2-pyrimidinyl-3-pyridyl) The product from step 40a, (167 mg) was processed as described in Example 44, steps 44a-b (substituting 2-bromopyrimidine for 3-bromoquinoline to provide 24.2 mg of the desired product MS (ESI 294 (M + H) +.

Example 47 Compound of Formula I: Rb is H, L is -C. O T is -N H. R is -C (H) = CH- (5- (3-pyridyl) -3-pyridyl.The product from step 40a, (417 mg) was processed as described in Example 41, steps 41 ab (substituting 3- (tributylstannyl) pyridine for tributyl (2-thienyl) stannane) to provide 202 mg of the desired product.

MS (ESI) 793 (M + H) +.

Example 48 Compound of Formula I: Rb is H, L is -C (O) -. T is -NH-, R is -C (H. = CH- (5- (4-isoguinolinyl-3-pyridyl) The product of step 40a, (167 mg) was processed as described in Example 44, steps 44a-b (substituting 4-bromoisoquinoline for 3-bromoquinoline) to provide 24.2 mg of the desired product MS (ESI) 843 (M + H) +.

Example 49 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -C (H) = CH- (5- (3-thienyl) -3-pyridyl) Step 40a product (167 mg) was processed as described in example 44, steps 44a-b (substituting 3-bromothiophene for 3-bromoquinoline) to provide 24.2 mg of the desired product. MS (ESI) 798 (M + H) \ Example 50 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -C (H) = CH- (5- (2-furyl) -3-pyridyl) Step 40a product, (167 mg) was processed as described in Example 41, steps 41a-b (substituting tri-benzyl-2-furyl) for tributyl (2-thienyl) stannane) to give 202 mg of the product wanted. MS (ESI) 782 (M + H) +.

Example 51 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH, R is -C (H) = CH- (5- (2-M.3-thiazolyl) .- 3-pyridyl) The product from step 40a, (167 mg) was processed as described in Example 41, steps 41a-b (substituting 2- (tributylstannyl) -1,3-thiazole for tributyl (2-thienyl) stannane) to provide 67.2 mg of the desired product. MS (ESI) 799 (M + H) +.

Example 52 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -C (H. = CH- (5- (5-d.3-thiazolyl) - 3-pyridyl) Step 52a: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH. R is -C (H. = CH- (5- (2- (trimethylsilyn-1,3-thiazol-5-yn-3-pyridyl) The product of step 40a, (167 mg) was processed as described in step 41a ( substituting 5- (tributylstannyl) -2- (trimethylsilyl) -1,3-thiazole for tributyl (2-thienyl) stannane) to provide the desired product.

Step 52b: Compound of Formula I: Rb is CHsC.O.-. L is -C O.-. T is -NH-, R is -C (H) = CH- (5- (1,3-thiazolyl) -3-pyridyl) A solution of the product from step 52a in THF at room temperature was treated with 5% HCl, stirred for 1 hour, treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified through flash column chromatography on silica gel with 1: 1: 0.5 acetone / hexane / triethylamine to provide the desired product.

Step 52c: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH. R is -C.H. = CH- (5-5-M.3-thiazolam-3-pyridyl) The product of step 52b was stirred in methanol at room temperature for 18 hours, concentrated and purified by column chromatography of flash on silica gel with 50: 50: 0.5 methanol / dichloromethane / ammonium hydroxide to provide 85.3 mg of the desired product. MS (ESI) 799 (M + H) +.

Example 53 Compound of Formula I: Rb is H, L is -C.O) -. T is -NH. R is -C.H. = CH- (5-.2-amino-d.3-thiazol-5-yl ..- 2-thienyl.

Step 53a: Compound of Formula I: Rb is CHaC.OK L is -C.OV-. T is -NH-. R is -C.H. = CH-B (OH)? A solution of the borane-THF complex (1M in THF, 1.8 ml, 11.8 mmol) at -10 ° C, was treated with 2-methyl-2-butene (2.7 ml, 24 mmol), stirred at 0 ° C for 2 hours, it was treated in one portion with a solution of the product from step 1h (2 g, 2.95 mmol) in 10 ml of THF, stirred at 0 ° C for one hour and room temperature for 3 hours, cooled again to 0 ° C, treated with 5% aqueous sodium carbonate, and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography on silica gel with 1: 1 acetone / hexanes to provide 3.6 g of the desired compound.

Step 53b: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH-, R is -C (H) = CH- (5- (2-amino-1,3-thiazole -5-yl ..- 2-thienyl A solution / slurry of the product of step 53a, (72 mg, 0.10 mmol), sodium carbonate (31 mg, 0.30 mmol), tetrakis (triphenylphosphine) palladium (0) (12 mg , 0.010 mmole), and 5. (5-bromo-2-thienyl) -1,3-thiazoI-2-amine (52 mg, 0.20 mmole) in 1: 1 acetone / water (2 ml) in sealed container it was heated at 60 ° C for 2 hours and at 80 ° C for 2 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in methanol (5 ml), stirred for 24 hours and concentrated The residue was purified by flash chromatography on silica gel with 5: 94.5: 0.5 methanol / dichloromethane / ammonium hydroxide, then purified again by flash chromatography on silica gel with 95: 5: 0.5 ace tone / hexane / triethylamine to provide 26.7 mg of the desired product. MS (ESI) 819 (M + H) +.

Example 54 Compound of Formula I: Rb is H, L is -C (OK T is -NH.R is -C.H. = CH- (5- (3-pyridn-2-M. -thiazolyl .. A solution / slurry of the product of step 53a, (144 mg, 0.10 mmol), sodium carbonate (62 mg, 0.60 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.020 mmol), and 3- (2-Bromo-1,3-thiazol-5-yl) pyridine (72 mg, 0.30 mmol) in toluene / water 2: 1 (3 ml) in a sealed container was heated at 80 ° C for 16 hours , it was cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO 3 and brine, dried (Na 2 SO 4), filtered and concentrated, the residue was dissolved in 5 ml of methanol, stirred at room temperature. The residue was purified by flash chromatography on silica gel with 75:24, 5: 0.5 acetone / hexane / triethylamine to give 126.5 mg of the desired product.

Example 55 Compound of Formula I: Rb is H, L is -C (O) -. T is -NH, R is -C (H) = CH- (5- (3-pyridyl) -5- (1,3-thiazolyl)) A solution / slurry of the product from step 53a, (144 mg, 0.10 mmol), sodium carbonate (62 mg, 0.60 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.020 mmol), and 3- (5-bromo-1,3-thiazol-2-yl) pyridine (72 mg, 0.30 mmoles) in 2: 1 toluene / water (3 ml) in a sealed vessel was heated at 80 ° C for 24 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in 5 ml of methanol, stirred at room temperature for 16 hours and concentrated. The residue was purified by chromatography on silica gel with 75:24, 5: 0.5 acetone / hexane / triethylamine to provide 72 mg of the desired product. MS (ESI) 799 (M + H) +.

Example 56 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH, R is -C (H. = CH- (2- (5-bromo-1,3-thiazole-2- il) -5-M .3-thiazolyl)) Step 56a: Compound of Formula I: Rb is CH-.C. OR)-. L is -C (O) -, T is -NH-. R is -C (H. = CH- (2- (5-bromo-1,3-thiazol-2-yl) -5- (1,3-thiazolyl)) A solution / slurry of the product from step 53a, (400 mg , 0.80 mmole), sodium carbonate (168 mg, 1.6 mmole), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.020 mmole), and 2- (5-bromo-1,3-thiazole-2) il) -5-bromo-1,3-thiazole (52 mg, 0.20 mmol) in 2: 1 toluene / water (6 ml) in a sealed container was heated at 50 ° C for 1 hour and at 80 ° C for 16 hours. After cooling, it was treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated, the residue was purified by flash chromatography on silica gel. with 50: 50: 0.5 acetone / hexane / triethylamine to provide 187 mg of the desired product.

Step 56b: Compound of Formula I: Rb is H, L is -C (Q) -, T is -NH-, R is -C (H) = CH- (2- (5-bromo-1 .3- thiazol-2-yl) -5- (1 .3-thiazolyl) A solution of the product from step 56a (50 mg) was stirred in methanol at room temperature for 16 hours and concentrated.The residue was purified by chromatography of flash on silica gel with 75: 24.5: 0.5 acetone / hexane / triethylamine to give 50 mg of the desired product MS (ESI) 883 (M + H) +.

Example 57 Compound of Formula I: Rb is H, L is -C (O) -. T is -NH, R is -CfH) = CH- (2- (2-thienyl) -5-thiazolyl) Step 57a: Compound of Formula I: Rb is CH3C (O) -, L is -C (O) -, T is -NH-. R is -C (H. = CH- (2- (2-thienyl) -5-thiazolyl) A solution / slurry of the product from step 53a, (470 mg, 0.650 mmol), sodium carbonate (172 mg, 1.64 mmol) ), tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.050 mmole), and 5-bromo-2- (2-thienyl) -1,3-thiazole (200 mg, 0.820 mmole) in 25: 1 of toluene / Water (52 ml) in a sealed vessel was heated at 50 ° C for 1 hour and at 80 ° C for 16 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried ( Na2SO4), filtered and concentrated The residue was purified via flash chromatography on silica gel with 50: 50: 0.5 acetone / hexane / triethylamine to give 400 mg of the desired product.

Step 57b: Compound of Formula I: Rb is H, L is -C (O) -. T is -NH-. R is -C (H) = CH- (2- (2-thienyl) -5-thiazolyl.) A solution of the product from step 56a (400 mg) was stirred in 20 ml of methanol at room temperature for 16 hours and concentrated. The residue was purified by flash chromatography on silica gel with 95: 4.5: 0.5 dichloromethane / methanol / ammonium hydroxide to provide 344 mg of the desired product. MS (ESI) 804 (M + H) +.

Example 58 Step 58a: Compound of Formula I: Rb is CH 3 C (O) -, L is -C (O) -, T is -N H-. R is -C (H. = CH- (2- (2-pyrazinyl) -5- (1,3-thiazolyl)) A solution / slurry of the product from step 53a, (158 mg, 0.332 mmol), sodium carbonate (3 equivalents), tetrakis (triphenylphosphine) palladium (0) (0.1 equivalents), and 2- (5-bromo-1,3-thiazol-2-yl) -pyrazine (1.5 equivalents) in 2: 1 toluene water (6 ml) in a sealed vessel was heated at 80 ° C for 20 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO-t), The residue was purified by flash chromatography on silica gel with 50: 50: 0.5 acetone / hexane / triethylamine to provide 103 mg of the desired product.

Step 58b: Compound of Formula I: Rb is H, L is -C (O) -, T is -NH-. R is -C (H. = CH- (2- (2-? Irazinyl-5-. 1,3-thiazolyl)) The residue was dissolved in 5 ml of methanol, stirred at room temperature for 20 hours The residue was purified by flash chromatography on silica gel with 95: 4.5: 0.5 dichloromethane / methanol / ammonium hydroxide to provide 344 mg of the desired product MS (ESI) 800 (M + H) + .

Example 59 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH-, R is -C (H) = CH- (2- (5-pyrimidinyl) -5- (1.3 -thiazolyl)) The product of step 53a (180 mg) was processed as described in Example 58, steps 58a-b, (substituting 5- (5-bromo-1,3-thiazole-2-yl) pyrimidine for 2- (5-Bromo-1,3-thiazol-2-yl) pyrazine) to provide 43 mg of the desired product. MS (ESI) 800 (M + H) +.

Example 60 Compound of Formula I: Rb is H, L is -CO) -, T is -NH-, R is -C (H) = CH- (2- (5- (1,3-thiazole-5- in-5- (1,3-thiazolyl)) The product from step 53a (247 mg) was processed as described in Example 58, steps 58a-b, (substituting 2- (1,3-thiazol-5-yl) ) -5-bromo-1,3-thiazole for 2- (5-bromo-1,3-thiazol-2-yl) pyrazine) to provide 131 mg of the desired product MS (ESI) 805 (M + H) + .

Example 61 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH-. R is -C (H) = CH- (5- (2-pyrimidinyl) -2-thienyl The product of step 53a (250 mg) was processed as described in Example 58, steps 58a-b, (substituting 2- (5-bromo-2-thienyl) pyrimidine for 2- (5-bromo-1,3-thiazol-2-yl) pyrazine and heating at 100 ° C for 48 hours) to provide 92 mg of the desired product MS (ESI) ) 799 (M + H) +.

Example 62 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH-, R is -C (H) = CH- (5- (2-pyrazinyl) -2-thienyl) The product of step 53a (880 mg) was processed as described in Example 58, steps 58a-b, (replacing 2- (5-bromo-2-thienyl) pyrazine for 2- (5-bromo-1, 3- thiazol-2-yl) pyrazine and heating at 100 ° C for 24 hours) to provide 350 mg of the desired product. MS (ESI) 799 (M + H) +.

Example 63 Compound of Formula I: Rb is H, L is -C (QK T is -NH-, R is -C (H) = CH- (5- (2- (1,3-thiazolyl) -2- thienyl) The product from step 53a (220 mg) was processed as described in Example 58, steps 58a-b, (substituting 2- (5-bromo-2-thienyl) -1,3-thiazole for 2- (5 -bromo- 1, 3-thiazol-2-yl) pyrazine and heating at 100 ° C for 24 hours) to provide 86 mg of the desired product MS (ESI) 805 (M + H) +.

Example 64 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH-, R is -C (H) = CH- (5-.4-Pyrimidinyl) -2-thienyl) The product from step 53a (250 mg) is processed as described in Example 58, steps 58a-b, (substituting 4- (5-bromo-2-thienyl) pyrimidine for 2- (5-bromo-1,3-thiazol-2-yl) pyrazine and heating to 100 ° C for 24 hours) to provide 64 mg of the desired product. MS (ESI) 799 (M + H) +.

Example 65 Compound of Formula I: Rb is H, L is -C (O) -. T is -NH-, R is -C (H) = CH- (2- (3? Ridyl) -2- (1,3-thiazolyl)) Step 65a: Compound of Formula I: Rfa is CH3_C (O) -, L is -C (O) -. T is -NH-, R is -C. H) = CH- (4-bromo-2-.l, 3-thiazolyl)) The product from step 53a (362 mg) was processed as described in Example 55 (substituting 1,4-dibromo-1, 3- thiazole for 3- (5-bromo-1,3-thiazol-2-yl) pyridine) to provide 384 mg of the desired compound.

Step 65b: Compound of Formula I: Rb; is H. L is -C (O) -. T is -NH-. R is -CH) = CH- (4- (3-pyridyl) -2-. 1,3-thiazolyl)) The product from step 65a (170) was processed as processed as described in Example 41, steps 41a-b , (substituting 3- (tributylstannyl) pyridine for tributyl (2-thienyl) stannane) to provide 25.6 mg of the desired product. MS (ESI) 799 (M + H) +.

Example 66 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH-, R is -C (H) = CH- (5- (4-pyrimidinyl) -2-thienyl) The product of step 65a (100 mg) was processed as described in Example 41, steps 41a-b, (substituting 2- (tributylstannyl) -1,3-thiazole for tributyl (2- (1,3-thiazolyl) stannane ) to provide 80 mg of the desired product MS (ESI) 805 (M + H) +.

Example 67 Compound of Formula I: Rb is H, L is -C (O) -. T is -NH-, R is -C (H) = CH- (4- (2-thienyl) -2- (1,3-thiazolyl)) The product from step 65a (100 mg) was processed as described in Example 41, steps 41a-b, (replacing 2- (tributylstannyl) -1,3-thiazole for tributyl (2- (1,3-thiazolyl) stannane and heating at 60 ° C for 2 hours and at 90 ° C for 20 hours. hours) to provide 42.7 mg of the desired product.

MS (ESI) 804 (M + H) Example 68 Compound of Formula I: R is H. R is -C (H) = CH- (5- (3-pyridyl) -2-thienyl) Step 68a: Compound of the Formula: Rb is CH3, C (O) -. L is -C (O) -, T is -N H-. R is -C (H) = CH- (5-vodo-2-thienyl) A solution / slurry of the product from step 53a (724 mg, 1.0 mmol), 2,5-diiodoothiophene (672 g, 2.0 mmol) , sodium carbonate (315 g, 3.0 moles), and tetrakis (triphenylphosphine) palladium (0) (58 g, 0.05 mmol) was heated at 90 ° C for 44 hours, cooled, treated with ethyl acetate, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 50: 50: 0.5 acetone / hexane / triethylamine to provide 340 mg of the desired product.

Step 68b: Compound of Formula I: Rb is H, L is -C. OR)-. T is -N H-, R is -C (H) = CH- (5- (3-pyridyl) -2-thienyl) The product from step 65a (100 mg) was processed as described in Example 41, steps 41 ab, (substituting 3- (tributylstannyl) pyridine for tributyl (2- (1,3-thiazolyl) stannane and heating at 80 ° C for 2 hours and at 100 ° C for 6 hours) to provide 40.9 mg of the desired product.

MS (ESI) 798 (M + H) +.

Example 69 Compound of Formula I: Rb is H, L is -C (O) -. T is -N H-. R is H, -C (H) = CH- (5- (2-pyrazinyl) -2-thienyl) Step 69a: Compound of the Formula: Rb is CH? C (O) -. L is -C (O) -, T is -N H-. R is -C. H) = CH- (5-bromo-2-thienyl) The product from step 53a was processed as described in step 68a (substituting 2,5-dibromothiophene for 2,5-diiodoothiophene) to provide 127 mg of the desired product.

Step 69b: Compound of Formula I: Rb is H, L is -C. O) -. T is -N H-. R is -C (H) = CH- (5- (2-Pyrazinyl) -2-thienyl) The product from step 69a (420 mg) was processed as described in Example 41, steps 41 ab, (substituting 2- (tributylstannyl) pyrazine for tributyl (2- (1,3-thiazolyl) stannane) to provide 127 mg of the desired product MS (ESI) 799 (M + H) +.

Example 70 Compound of Formula I: Rb is H. L is -C (O) -, T is -N H-, R is -C (H) = CH- (5-.5-pyrimidinyl) -2-thienyl The product from step 65a (250 mg) was processed as described in Example 41, steps 41 ab, (substituting 5- (tributyl) pyrimidine for tributyl (2- (1,3-thiazolyl) stannane) to provide 377 mg of the desired product MS (ESI) 799 (M + H ) *.

Example 71 Compound of Formula I: Rb is H. L is -C (O) -, T is -N H-, R is -C (H) = CH- (5- (3,4-dichlorophenyl) -2 -thienyl) The product of step 69a (120 mg) was processed as described in Example 44, steps 44a-b, (substituting 4-bromo-1,2-dichlorobenzene for 3-bromoquinoline) to provide 20 mg of the desired product . MS (ESI) 866 (M + H) +.

Example 72 Compound of Formula I: Rb is H, L is -C (OT is -NH-, R is -C (H) = CH- (5- (3-fluorophenyl) -2-thienyl) The product of step 69a (120 mg) was processed as described in Example 44, steps 44a-b, (substituting 1-bromo-3-fluorobenzene for 3-bromoquinoline) to provide 26 mg of the desired product.

Example 73 Compound of Formula I: R is H, L is -C (O) -, T is -NH-, R is -C. H? = CH-.5-.5- (1,3-thiazolyl-2-thienyl) The product of step 69a (175 mg) was processed as described in Example 52, steps 52a-c, (substituting 5- (tributylstannyl) ) -2- (trimethylsilyl) -1,3-thiazole for tributylstannyl) -2- (trimethylsilyl) -1,3-thiazole) to give 25 mg of the desired product. MS (ESI) 816 (M + H) +.

Example 74 Compound of Formula I: Rb is H, L is -C (O) -, T is -NH-, R is -C (H) = CH- (2,2'-bistienyl) The product of step 69a (175 mg) was processed as described in Example 41, steps 41 ab, to provide 9 mg of the desired product. MS (ESI) 804 (M + H) +.

Example 75 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH-, R is -C (H) = CH- (5- (2-? Iridyl) -2-thienyl) The product of step 69a (120 mg) was processed as described in Example 41, steps 41 ab, (substituting 2- (tributyl) pyridine for tributyl (2- (1,3-thiazolyl) stannane) to give 71 mg of the desired product MS (ESI) 799 (M + H) \ Example 76 Compound of Formula I: Rb is H, L is -CO) -. T is -NH-, R is -C (H) = CH- (5- (3-thienyl) -2-thienyl) The product of step 69a (150 mg) and 30 mg of thienylboronic acid were processed as described in Example 41, steps 41a-b to provide 79 mg of the desired product. MS (ESI) 804 (M + H) +.

Example 77 Compound of Formula I: Rb is H. L is -C (O) -, T is -NH-, R is -C (H) = CH- (5- (2-furanyl) -2-thienyl) The product of step 69a (120 mg) and 66 mg of 2- (tributylstannyl) furan were processed as described in Example 41, steps 41a-b, to provide 74 mg of the desired product. MS (ESI) 787 (M + H) +.

Claims (10)

1. - A compound selected from the group consisting of a compound of the formula I: or a compound of formula II: II; and a compound of the formula ll: or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein either: (a) Y and Z taken together define a group X, and X is selected from the group consisting of: d) = O (2) = N-OH, (3) = NOR \ wherein R1 is selected from the group consisting of: (a) unsubstituted 1 to 12 carbon atoms, (b) alkyl of 1 to 12 carbon atoms substituted with aryl, (c) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (d) alkyl of 1 to 12 carbon atoms substituted with heteroaryl, (e) alkyl from 1 to 12 carbon atoms substituted with substituted heteroaryl, (f) cycloalkyl of 3 to 12 carbon atoms, and (g) -Si- (R2) (R3) (R4), wherein R2, R3 and R4 each it is independently selected from alkyl and aryl of 1 to 12 carbon atoms; and (4) = NOC (R5) (R6) -O-R1, wherein R1 is as previously defined and Rs and R6 are each independently selected from the group consisting of: (a) hydrogen, (b) alkyl 1 to 12 unsubstituted carbon atoms, (c) alkyl of 1 to 12 carbon atoms substituted with aryl, (d) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (e) alkyl of 1 to 12 carbon atoms substituted with heteroaryl, and (f) alkyl of 1 to 12 carbon atoms substituted with substituted heteroaryl, or R 5 and R 6 taken together with the atom to which they are attached form a cycloalkyl ring of 3 to 12 carbon atoms; or (b) one of Y and Z is hydrogen and the other is selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) N R7R8 wherein R7 and R8 are independently select hydrogen and alkyl of 1 to 6 carbon atoms, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3 to 7 membered ring, which, when the ring is a ring of 5 to 7 members, optionally it may contain a heterogeneous function selected from the group consisting of -O-, -N H-, -N (alkyl of 1 to 6 carbon atoms) -, -N (aryl) -, -N (aryl) -alkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with aryl) -, -N (heteroaryl) -, -N (heteroarylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with heteroaryl) -, and -S- or -S (O) n-> > where n is 1 or 2; Ra is hydrogen or hydroxy; Rb is hydrogen or a protective hydroxy group; L is methylene or carbonyl, provided that L is methylene, T is -O-; T is selected from the group consisting of -O-, -N H-, and -N (W-Rd) -, where W is absent or selected from the group consisting of -O-, -N H-CO- , -N = CH- and -N H-, and Rd is selected from the group consisting of: (1) hydrogen, (2) alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of of: (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) hydroxy, (f) alkoxy of 1 to 6 carbon atoms, (g) NR7R8, wherein R7 and R8 are as previously defined, and (h) -CH2-M-R9, wherein M is selected from the group consisting of: (i) -C (O) -NH-, (ii) -NH-C (O ) -, (iii) -NH-, (v) ÍN =, (v) -N (CH3) -, (vi) -NH-C (O) -O-, (vii) -NH-C (O ) -NH- (viii) -OC (O) -NH- (ix) -OC (O) -O-, (x) -o-, (xi) -S (O) n-, where n is 0 , 1 or 2, (xii) -C (O) -O-, (xiii) -OC (O) -, and (xiv) -C (O) -; Y . wherein R9 is selected from the group consisting of: (i) alkyl of 1 to 6 carbon atoms, optionally, substituted with a substituent selected from the group consisting of: (aa) aryl, (bb) substituted aryl, (ce) heteroaryl, and (dd) substituted heteroaryl; (ii) aryl, (iii) substituted aryl, (v) heteroaryl, (v) substituted heteroaryl, and (vi) heterocycloalkyl; and (3) cycloalkyl of 3 to 7 carbon atoms, (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) substituted heteroaryl; X 'is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, and alkynyl of 3 to 10 carbon atoms; Y 'and Z' are independently selected from the group consisting of: (a) optionally substituted aryl, and (b) optionally substituted heteroaryl, provided that both Y 'and Z' are both not phenyl, and with the proviso that Y ' it is not isoxazole when Z 'is thiophenol; and A, B, D and E are independently selected from the group consisting of: (a) hydrogen; (b) alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of: (i) aryl; (ii) substituted aryl; (iii) heteroaryl; (V) substituted heteroaryl; (v) heterocycloalkyl; (vi) hydroxy; (vii) alkoxy of 1 to 6 carbon atoms; (viii) halogen consisting of Br, Cl, F or I; and (x) N R7R8, wherein R7 and R8 are as previously defined; (c) cycloalkyl of 3 to 7 carbon atoms; (d) aryl; (e) substituted aryl; (f) heteroaryl; (g) substituted heteroaryl; (h) heterocycloalkyl; and (i) a group selected from option (b) above also substituted with -M-R9, wherein M and R9 are as previously defined, provided that at least two of A, B, D, and E are hydrogen; or any pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3-7 membered ring optionally containing a hetero function selected from the group which consists of -O-, -NH-, -N (alkyl of 1 to 6 carbon atoms) -, -N (arylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms) substituted with aryl) -, -N (heteroarylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with heteroaryl) -, -S- or -S (O) n-, in where n is 1 or 2, -C (O) -NH, -C (O) -NR 12-, wherein R 12 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, -NH-C (O) -, and -NR 12 -C (O) -.

2. A compound according to claim 1, wherein L is carbonyl.

3. A compound according to claim 1, wherein T is -NH-.

4. A compound according to claim 1, wherein Rb is a hydroxy protecting group.

5. A compound according to claim 1, wherein Rb is hydrogen.

6. A compound according to claim 1, wherein X 'is alkenyl of 3 carbon atoms.

7. A compound according to claim 1, wherein X 'is alkynyl of 3 carbon atoms.

8. A compound according to claim 1, wherein Y 'and Z' are independently selected from the group consisting of thienyl, furanyl, pyridium, pyrimidinyl, piperidinyl, phenyl, naphthyl, benzothiophenyl, benzofuranyl, thiazolyl, pyrazinyl, quinoxalinyl , imidazolyl, triazolyl, tetrazolyl, benzimidazolyl, quinolinyl, and isoquinolinyl, all of these may be optionally substituted.

9. A compound according to claim 8, wherein Y "is thienyl 10.- A compound according to claim 8, wherein Z 'is pyridyl 1 .- A compound according to claim 1, wherein -X ', Y', and Z 'combine to form a group R, and R is selected from the group consisting of: - (CH2) -C- * C- (5- (2-pyridyl) -2-thienyl), - (CH2) -C = C- (5- (3-pyridyl) -2-thienyl), - (CH2) -C = C- (5- (4-pyridyl) -2-thienyl ), - (CH2) -CsC- (5- (5-pyrimidinyl) -2-thienyl), - (CH2) -C = C- (5- (2-pyrimidinyl) -2-thienyl), - (CH2) -CSC- (5- (2-pyrazinyl) -2-thienyl), - (CH2) -CsC- (5- (5-cyano-3-pyridyl) -2-thienyl), - (CH2) -C = C - (5- (5-carboxamido-3-pyridyl) -2-thienyl), - (5-ethoxycarbonyl-3-pyridyl) -2-thienyl), - (5-N, N-dimethylcarboxamido-3-pyridyl) - 2-thienyl), - (5-N ', N'-dimethylhydrazidocarbonyl-3-pyridyl) -2-thienyl), - (enyl) -2-thienyl), - (3-methoxyphenyl) -2-thienyl), - (3-f luorofenyl) -2-thienyl), - (3-chlorophenyl) -2-thienyl), - ( 3,5-dichlorophenyl) -2-thienyl), - (3-methylphenyl) -2-thienyl), - (3-trifluoromethylphenyl) -2-thienyl), - (3-acetamidophenyl) -2-thienyl), - ( 3-nitrophenyl) -2-thieniio), - (4-fluorophenyl) -2-thienyl), - (2-furanyl) -2-thienyl), - (5-formyl-2-furanyl) f enyl), - ( 5-formyl-2-furanyl) phenyl), - (5-formyl-2-furanyl) phenyl),, 2'-bistienyl), - (5-chloro-2-thienyl) thienyl),, 3'-bis ( thienyl)), - (2-thiazolyl) -2-thienyl), - (5-thiazolyl) -2-thienyl), - (4-thiazolyl) -2-thienyl), - (2-methyl-5-) thiazolyl) -2-thienyl), - (CH 2) -CsC- (5- (1-methyl-2-imidazolyl) -2-thienyl), - (CH 2) -C-C- (5- (2-quinoxalinyl ) -2-thienyl), - (CH2) -CsC- (5- (2-benzothiophenyl) -2-thienyl), - (CH2) -C-C- (5- (2-pyridyl) -2 -thienyl), - (CH2) -CsC- (5- (2-benzothiophenyl) -2-thienyl), 1H-imidazol-1-yl) -3-pyridyl), -furanyl) -6-quinolinyl), -thienyl ) -3-pyridyl), nil-3-pyridyl), -pyridyl) -3-pyridyl), -quinolinyl) -3-pyridyl), -pyrimidinyl ) -3-pyridyl), -pyridyl) -3-pyridyl), -isoquinolinyl) -3-pyridyl), -thienyl) -3-pyridyl), -furyl) -3-pyridyl), 1,3-thiazolyl)) -3-pyridyl), - (trimethylsilyl) -1,3-thiazol-5-yl) -3-pyridyl), 1,3-thiazolyl) -3-pyridyl), -amino- (1,3-thiazole-5) -yl)) - 2-thienyl), -amino- (1,3-thiazol-5-yl)) - 2-thienyl), -pyridyl) -2- (1,3-thiazolyl)), -pyridyl) - 5- (1,3-thiazolyl)), -bromo-1,3-thiazol-2-yl) -5- (1,3-thiazolyl)), -bromo- (1,3-thiazol-2-yl) ) -5- (1,3-thiazolyl)), -C (H) = CH - (2- (5-bromo-1,3-thiazol-2-yl) -5- (1,3-thiazolyl)) , -C (H) = CH - (2- (2-thienyl) -5- (1,3-thiazolyl), -C (H) = CH - (2- (2-pyrazinyl) -5- (1, 3-thiazolyl)), -C (H) = CH "(2- (5-pyrimidinyl) -5- (1,3-thiazolyl)), -C (H) = CH - (2- (5- (1 , 3-thiazol-5-yl) -5- (1,3-thiazolyl)), -C (H) = CH - (5- (2-pyrimidinyl) -2-thienyl), -C (H) = CH - (5- (2-pyrazinyl) -2-thienyl), -C (H) = CH • (5- (2- (1,3-thiazolyl) -2-thienyl), -C (H) = CH- (5- (4-pyrimidinyl) -2-thienyl), -C (H) = CH - (4- (3-pyridyl) -2- (1,3-thiazolyl)), -C (H) = CH. (4- (3-pyridyl) -2- (1,3-thiazolyl)), -C (H) = CH - (4- (3-pyridyl) -2- (1,3-thiazolyl)), -C (H) = CH - (4- (2 -thienyl) -2- (1,3-thiazolyl)), -CiH,) = CH- - (5- (3-pyridyl) -2-thienyl), -C (H) = CH- - (5- ( 2-pyrazinyl) -2-thienyl), -C (H; > = CH- - (5- (5-pyrimidinyl) -2-thienyl), -C (H> = CH- • (5- (3,4-dichlorophenyl) -2-thienyl), -C (H; CH- (5- (3-fluorophenyl) -2-thienyl), -C (H = CH- • (5- (5- (1,3-thiazoyl)) - 2-thienyl), -C (H; CH- ((22,, 22'-bistienyl), -C (H. = CH- (5- (2-pyrazinyl) -2-thienyl), -C (H = CH- (5- (3-thienyl) -2-thienyl), and -C (H] = C H- (5- (2-furanyl) -2-thienyl) 12.- UUnna, pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the claim 1 in combination with a pharmaceutically acceptable carrier 13.- A method for treating a bacterial infection in a mammal with the need for said treatment, which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1. 14.- A process for preparing a compound selected from the group consisting of: a compound of the formula I: I; a compound of formula II: lir¬ and a compound of the formula III: or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein either: (a) Y and Z taken together define a group X, and X is selected from the group consisting of: (1) = O (2) = N-OH, (3) = NO-R1, wherein R1 is selected from the group consisting of: (a) alkyl of 1 to 12 unsubstituted carbon atoms, (b) alkyl of 1 to 12 carbon atoms. carbon substituted with aryl, (c) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (d) alkyl of 1 to 12 carbon atoms not substituted with heteroaryl, (e) alkyl of 1 to 12 carbon atoms substituted gone with substituted heteroaryl, (f) cycloalkyl of 3 to 12 carbon atoms, and (g) -Si- (R2) (R3) (R4), wherein R2, R3 and R4 are each independently selected from alkyl and aryl from 1 to 12 carbon atoms; and (4) = NOC (R5) (R6) -O-R1, wherein R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 12 unsubstituted carbon atoms, (c) alkyl of 1 to 12 carbon atoms substituted with aryl, (d) alkyl of 1 to 12 carbon atoms substituted with substituted aryl, (e) alkyl of 1 to 12 carbon atoms substituted with heteroaryl, and (f) alkyl of 1 to 12 carbon atoms substituted with substituted heteroaryl, or R5 and R6 taken together with the atom to which they are attached form a cycloalkyl ring of 3 to 12 carbon atoms; or (b) one of Y and Z is hydrogen and the other is selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) NR7R8 wherein R7 and R8 are selected independently of hydrogen and alkyl of 1 to 6 carbon atoms, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a ring of 3 to 7 members, which, when the ring is a ring of 5 to 7 members, optionally it may contain a heterogeneous function selected from the group consisting of -O-, -NH-, N- (alkyl of 1 to 6 carbon atoms) -, -N (aryl) -, -N (aryl-alkyl) from 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with aryl) -, -N (heteroaryl) -, -N (heteroarylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with heteroaryl) -, and -S- or -S (O) n-, wherein n is 1 or 2; Ra is hydrogen or hydroxy; Rb is hydrogen or a protective hydroxy group; L is methylene or carbonyl, provided that L is methylene, T is -OR-; T is selected from the group consisting of -O-, -NH-, and -N (W-Rd) -, where W is absent or is selected from the group consisting of -O-, -NH-CO-, - N = CH- and -NH-, and Rd is selected from the group consisting of: (1) hydrogen, (2) alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of: a) aryl (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) hydroxy, (f) alkoxy of 1 to 6 carbon atoms, (g) NR7R8, wherein R7 and R8 are as previously defined, and (h) -CH2-M-R9, wherein M is selected from the group consisting of: (i) -C (O) -NH-, (ii) -NH-C (O) -, ( iii) -NH-, (iv) -N =, (v) -N (CH3) -, (vi) -NH-C (O) -O-, (vii) -NH-C (O) -N H - (viii) -OC (O) -N H- (x) -OC (O) -O-, (x) -O-, (xi) -S (O) n-, where n is 0, 1 or 2, (xii) -C (O) -O-, (xiii) -OC (O) -, and (xiv) -C (O) -; and wherein R9 is selected from the group consisting of: (i) alkyl of 1 to 6 carbon atoms, optionally, substituted with a substituent selected from the group consisting of: (aa) aryl, (bb) substituted aryl, (ce) heteroaryl, and (dd) substituted heteroaryl; (ii) aryl, (iii) substituted aryl, (iv) heteroaryl, (v) substituted heteroaryl, and (vi) heterocycloalkyl; and (3) cycloalkyl of 3 to 7 carbon atoms, (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) substituted heteroaryl; X 'is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, and alkynyl of 3 to 10 carbon atoms; Y 'and Z' are independently selected from the group consisting of: (a) optionally substituted aryl, and (b) optionally substituted heteroaryl, provided that both Y 'and Z "both are not phenyl, and with the proviso that Y' is not isoxazole when Z 'is thiophenol, and A, B, D and E are independently selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected of the group consisting of: (i) aryl, (ii) substituted aryl, (iii) heteroaryl, (iv) substituted heteroaryl, (v) heterocycloalkyl, (vi) hydroxy, (vii) alkoxy of 1 to 6 carbon atoms; (viii) .alógeno consisting of Br, Cl, F or I, and (ix) N R7R8, where R7 and R8 are as previously defined, (c) cycloalkyl of 3 to 7 carbon atoms, (d) aryl (e) substituted aryl, (f) heteroaryl, (g) substituted heteroaryl, (h) heterocycloalkyl, and (i) a group selected from option (b) above. or else substituted with -M-R9, where M and R9 are as previously defined, provided that at least two of A, B, D, and E are hydrogen; or any pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3-7 membered ring optionally containing a hetero function selected from the group which consists of -O-, -N H-, -N (alkyl of 1 to 6 carbon atoms) -, -N (arylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms) carbon substituted with aryl) -, -N (heteroarylalkyl of 1 to 6 carbon atoms) -, -N (alkyl of 1 to 6 carbon atoms substituted with heteroaryl) -, -S- or -S (O) "-, wherein n is 1 or 2, -C (O) -NH, -C (O) -NR12-, wherein R12 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, -NH-C (O) -, and -NR 12-C (O) -; wherein said process comprises coupling a compound selected from the group consisting of a compound of the formula a compound of the formula l l! IIa; and a compound of the formula l l l ' III8 wherein Rb is a hydroxy protecting group, and Y, Z, X, R1, R2, R3, R4, R5, R6, R7, R8, n, Ra, L, T, Rd, W, M, R9, X ' , Y ', Z', A, B, D, E, R12 are as previously defined; with a compound selected from the group consisting of X1- Y'-Z 'X1-Y "-XJ wherein X1 X1 are independently selected from the group consisting of bromine, iodine, sulfonate, trialkylstannane, boronic acid, and borate, and Y 'and Z' are as previously defined, in the presence of a palladium catalyst, provided that when X1-Y'-X2 is used, a subsequent coupling reaction is performed with X3-Z ', wherein X3 is selected from group consisting of bromine, iodine, sulfonate, trialkylstannane, boronic acid and borate, and Z 'is as previously defined, (b) optionally deprotecting, and (c) optionally isolating the desired compound.