CA2166320A1 - Ansamycin derivatives as antioncogene and anticancer agents - Google Patents

Abstract

A compound of formula (I) and pharmaceutically acceptable salts and prodrugs thereof wherein R1, R2, R3, R4, R5 and R6 are as defined below, methods and intermediates useful in the preparation thereof, pharmaceutical compositions thereof and methods of treatment therewith. The compounds of formula (I) are useful in inhibiting oncogene products and as antitumor and anticancer agents.

Description

~6632a 2 PCT/IP,94/00160 .

ANSAMYCIN DERIVATIVES AS ANTIONCOGENE AND ANTICANCER AGENTS
Background of the Invention This invention relates to derivatives of geldanamycin, pharmaceutically acceptable salts and prodrugs of said derivatives, processes for their preparation and antitumor and oncogene product inhibiting compositions containing said derivatives, 10 salts and prodrugs as the active i"~edier~la.
Oncogene products are proti- ,s generated by cancer genes and are involved in the transformation of normal cells into cancer cells.
Geldanamycin is an antibiotic whose preparation and uses were described in United States Patent 3,595,955 (incorporated herein by reference).
Co-pending United States Patent application serial number 07/817,235, filed January 6, 1992 and assigned to Pfizer Inc. describes fermentation processes forpreparing 4,5-dihydrogeldanamycin and its 18,21-hydroquinone.
Other derivatives of geld&namycin, and their use as antitumor agents are described in United States Patent 4,261,989.
Summary of the Invention The presenl invention relates to compounds of the formula C

~ ~ H3 1112 '.1 9 C H3_o/ 3~ \ R2 CH
el 3 35 and pharmaceutically acceptable salts and prodrugs thereof herei"a~ler, also, ~efer,ed to as the active compounds;
wherein Rt and R2 are both hydrogen or Rl and R2 together form a single bond;

WO 95/01342 PCT/lB94/00160 --21~632~

wherein Rl and R2 are both hydrogen or R' and R2 together form a single bond;
R3 is hydrogen and R4 is selected from the group consisting of -ORl, -NHR8 and halo;
wherein Rl is selected from the group consisting of hydrogen, Rl1C(=O)-, 5 Rl lSO2- and Rl2Rl3NSO2NHC(=O)-;
wherein Rll is selected from the group consisting of amino, (Cl-C8)alkyl, amino(Cl-C8)alkyl, hydroxy(Cl-C8)alkyl, protected amino(Cl-C8)alkyl, prote-,1ed hydroxy(Cl-C8)alkyl, phenyl and naphthyl; and Rl2 and Rl3 are each independently selected from the group 10 consisli"g of hydrogen, (Cl-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; or Rl2 and Rl3 together with the nitrogen to which they are attached form a heterocyclic residue scl~ied from the group consi~li"g of aziridinyl, az~lidi"yl, py"olidi.,yl, piperidinyl, thiazolidinyl, ox~oli~;rlyl, morpholino, piperæinyl, ~(Cl-C4)alkylpiperidinyl and N-(Cl-C4)piperazinyl;
and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (Cl-C8)alkyl, halo, nitro, amino, azido and (Cl-C8)alkoxyl;
or R3 and R4 together form a group of the formula = J
20 wherein J is selected from O and NOH;
R5 is NR9R9 wherein R3 and R9 are each independently selected from the group consiali"g of hydrogen, (Cl-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally suhstituted wherein said substituents are selected from the group consixli"g of halo, cyano, mercapto, (Cl-25 C8)alkylthio, optionally substituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino, acylamino, and (C2-C6)heterocycloalkyl and (Cz-C6)heterocycloaryl groups selected from the group compl isi"g imidizaloly, furyl, tetrahydrofuryl; and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R9 and R9 together with the nitrogen to which they 30 are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl;
or R5 is Rl4O wherein Rl4 is hydrogen or (Cl-C4)alkyl;
and R5 is hydrogen or a group of the formula WO 95/01342 ~16 6 3 2 ~ PCT/I~394/00160 ( R 7 ) m O
(~C-CH2-R

wherein m is 0 or an integer from 1-5 and each R7 is independently selected from halo, P7ido, nitro, (Cl-C8)alkyl, Cl-C8alkoxyl, phenyl and naphthyl, cyano and NR3R9 wherein R3 and R9 are as defined above; with the proviso that when Rl and R2 together form a 10 single bond R3 is hydrogen and R4 is ORl wherein R' is hydrogen then R5 cannot be oR14, wherein R14 is hydrogen or methyl, or NR8R9 wherein HNR8R9 is selected from the group cGIlsialill9 of &r"l"onia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, 13-hydroxyethylamine, 13-chloroethylamine, B-glycoxyethylamine, aminobutylamine, adamantylmethylamine, 15 cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylarnine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycolamine, 13-morpholinoethylamine, 13-piperidinoethylamine, picolylamine, 13-pyrrolidinoethylamine, 13-pyridinylethylamine, 13-methoxyethylamine, and 13-N-methylaminoethylamine; and when R5 is OR14 and Rl is 20 R11C(=O), R11 cannot be methyl.
Preferably, the compounds of the invention are compounds of formula I
wherein 1. R1 and R2 are each hydrogen;
a. R3 and R~ are each hydrogen and R4 is fluoro or OR10 wherein Rl 25 is selected from hydrogen, Rl lC(=O)- and Rl2Rl3NSO2NHC(o)- wherein Rll is selected frorn amino, (Cl-C8)alkyl, amino(C1-C8)alkyl, prol~cted amino(Cl-C8)alkyl phenyl and naphthyl; and Rl2 and Rl3 are each independently selected from the group consisting of hydrogen, (Cl-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; or Rl2 and Rl3 together with the nitrogen to which they 30 are attached form a heterocyclic residue selected from the group consisting of aziridinyl, a_etidinyl, pyrrolidonyl, piperidinyl, thi~oli~ yl, ox~olidinyl, morpholino, pipera_inyl, 4-(C1-C4)alkylpiperidinyl, N-(C1-C4)piperazinyl; wherein is as defined above;
and R5 is ORl4 or NR8R9 wherein WO 95/01342 . PCT/IB94/00160 --~66~

i. when R5 is R8RgN, R8 is hydrogen and R9 is sPiected from the group consiali"g of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Cl-5 C8)alkylthio, optionally s~ ~hstih~ted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8R9N, R8 and R9 together with the nitrogen to 10 which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group con5i~1i"9 of halo, cyano, mercapto, (Cl-C8)alkylthio, substituted or uns~hstituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is Rl4O, Rl4 is hydrogen or (C1-C~)alkyl; with the proviso that when R3 and R6 are hydrogen and R4 is OR10 wherein R' is hydrogen, R'4 is not methyl; or b. R3 is hydrogen and R4 is selected from the group consi~li"g of fluoro and OR10 wherein Rl is selected from hydrogen, R"C~=O)- and 20 R'2R'3NSO2NHC(O)- wherein R11 is selected from amino, (C1-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue 25 sel~_ted from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, ~ 'S'91i l'-lyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1-C4)alkylpiperidinyl, N-(C1-C4)piperazinyl; R3 is a group of the formula A wherein m is defined as above and R5 is OR14 or NR8R9 wherein i. when R5 is R8R9N, R8 is hydrogen and R9 is selected from 30 the group consi ,Li"g of (Cl-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said suhstihlents are selected from the group consisting of halo, cyano, mercapto, (C1-C8)alkylthio, optionally substituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5is R8R9N, R8 and R9 together with the nitrogen to 5 which they are attached form a heterocyclic residue selected from the group consi~li"g of optionally substituted aziridinyl, azetidinyl and py" olidii ,yl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1-C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5is Rl40, Rl4is hydrogen or (C1-C8)alkyl; or c. R6 is hydrogen, R3 and R4 together form a group of the formula =J
wherein J is O or NOH; and R5is ORl4 or R8R9N wherein i. when R5is R3R9N, R8is hydrogen and R9is selected from 15 the group consisting of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said s~hstitl~ents are s~lected from the group consi~li"g of halo, cyano, mercapto, (Ct-C8)alkylthio, oplior,ally suhstituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl and if comprising more 20 than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consi lil .g of ~ilidi,lyl, azetidinyl and pyrrolidinyl;
ii. when R5is R8R9N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consi~ling of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1-C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5is R140, Rl4is hydrogen or (Cl-C8)alkyl; or d. R3 and R4 together form a group of the formula = J
wherein J is O or NOH;

2 ~ 2 ~ `

R~is a group of the formula A wherein m and R' are as defined above;
and R5is R'40 or R8R9N wherein i. when R5is R8R9N, R8is hydrogen and R9is selected from the group consisting of (Cl-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
5 wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said s~hstih~Pnts are selected from the group consisting of halo, cyano, mercapto, (Cl-C8)alkylthio, optionally s~hstihlted amino, hydroxyl, (C,-C8)alkoxyl, carboxyl, a~"i-li"o, acylamino, (C2-C6)heterocycloalkyl and (C2-C~)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of 10 branched, cyclic and unbranched groups;
ii. when R5is R8R9N, R9 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consi j~ 9 of optionally substituted aziridinyl, azetidinyl and py"oliJi"yl wherein said substituents ue selected from the group cot,si;jli"g of halo, cyano, mercapto, (C,-C8)alkylthio, 15 s~hstitl~ted or unsubstituted amino, hydroxyl, (C,-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5is Rl40, R'4is hydrogen or (C,-C8)alkyl; or or 2. R' and R2 together form a single bond and a. R3 and R~ are each hydrogen, R4 is selected from the group 20 consi~li"g of fluoro and ORl wherein R'is selected from hydrogen, R"(C = 0)- and R'2R'3NS02NHC(0)- wherein R" is selected from amino, (C,-C8)alkyl, amino(C,-C8)alkyl, protected amino(C,-C8)alkyl, phenyl and naphthyl; and R12 and R'3 are each independently sele 1ed from the group consi~ 9 of hydrogen, (C,-C8)alkyl, amino(C,-C8)alkyl, dimethylamino(C,-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyi; or RlZ and 25 R'3 together with the nitrogen to which they are a~tached form a heterocyclic residue sol~ed from the group consisli"g of aziridinyl, ~ ,yl, pyrrolidinyl, piperidinyl, ~1 ,i~olidinyl, oxazc!iJL Iyl, morpholino, piperazinyl, ~(C, -C4)alkylpiperidinyl, N-(C,-C4)piperazinyl; and R5is oRl4 or NR8R9 wherein i. when Rs is R8R9N, R8 is hydrogen and R9is selected from 30 the group consisting of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said sl~hstihlents are selected from the group consi~lir,g of halo, cyano, mercapto, (C,-C8)alkylthio, optionally substituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino, WO 95/01342 ~16 6 3 2 ~ PCT/IB94/U11160 acylamino, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl and if comprising more - than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8R9N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally s~hstituted ~i,idi,lyl, azetidinyl and pyrrolidinyl wherein said s~hstit~ents are cele 1e~1 from the group consisting of halo, cyano, mercapto, (Cl-C8)alkylthio, optionally substituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14O, R14 is hydrogen or (C1-C8)alkyl; with the proviso that when R10 is hydrogen then R5 cannot be OR14 wherein R14 is hydrogen or mel:hyl or NR8R9 wherein HNR8R9 is selected from the group consisting of ammonia, mel:hylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, B-hydroxyethylamine, 13-chloroethylamine, 13-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, ph~nethylamine, ethyleneamine, pyrrolidine, piperidinyl, dimethylamine, aminoethylamine, diglycoamine, B-morpholinonethylamine, 13-piperidinoethylamine,picolylamine, 13-pyrrolidinoethylamine, 13-pyridinylethylamine, 13-methoxyethylamine, and 13-N-methylaminoethylamine; or b. R3 is hydrogen and R4 is selected from the group consisting of fluoro and OR10 wherein R10 is selected from hydrogen, R11C(=O)- and R12R13NSO2NHC(O)- wherein R11 is selected from amino, (C1-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each ind0pendently selected from the group consisli"g of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consi~ling of æiridinyl, ~ttidi,lyl, pyrrolidinyl, piperidinyl, tl ,i~ ~oli~ ,yl, oxP~olidinyl, morpholino, pipera_inyl, 4-(Cl-C4)alkylpiperidinyl, N-(Cl-C")piperæinyl; R~ is a group of the formula A wherein m is defined as above and R5 is OR14 or NR8R9 wherein i. when R5 is R8R9N, R8 is hydrogen and R9 is selected from the group consi jli, Ig of (C,-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said s~lhstitllPnts are sPlected from the group consi~Lir,g of halo, cyano, mercapto, (C1-C8)alkylthio, optionally substituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C~)heterocycloalkyl and (C2-C,3)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8R9N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally s~ Ihstitutecl aziridinyl, az~li.l;"yl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1-C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14O, R14 is hydrogen or (C1-C8)alkyl; or c. R5 is hydrogen, R3 and R4 together form a group of the formula =J
wherein J is O or NOH; and Rs is OR14 or NR8R9 wherein i. when R5 is R8R9N, R8 is hydrogen and R9 is selected from the group consiali. ,g of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally s~ Ihstituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1-C8)alkylthio, optionally substituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C~)heterocycloalkyl and (C2-C~)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8R9N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consi;,li"g of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are sPlectecl from the group consi~li"g of halo, cyano, mercapto, (Cl-C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14O, R14 is hydrogen or (C1-C8)alkyl; or d. R3 and R4 together form a group of the formula =O or =NOH; R~
is a group of the formula A wherein m and R7 are defined as above; and R5 is R14O or R8R9N wherein t WO 95/01342 PCT/IB94/00160 g i. when R5 is R8R9N, R8 is hydrogen and R9 is selected from the group consi~li"g of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl;
wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are Sf~lECtæCI from the group consisting of halo, cyano, mercapto, (C,-5 C8)alkylthio, optionally substituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C~)heterocycloalkyl and (C2-C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8R9N, R8 and R9 together with the nitrogen to 10 which they are attached form a heterocyclic residue selected from the group consi~li"g of optionally substituted ~i-idillyl, a_elidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercaplo, (Cl-C8)alkylthio, s~hstitllted or unsubstituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14O, R14 is hydrogen or (C1-C8)alkyl.
More pre~er,~d co",pounds of the invention are selected from the group consi~li"g of compounds of the formula I wherein 1. R1, R2, R3 and R are each hydrogen, R4 is fluoro or OR10 wherein R10 is selected from hy.llogen, RllC(=O)- and R12R13NSO2NHC(o)- wherein Rll is selected20 from amino, (Cl-C8)alkyl, amino(Cl-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hy.l, ogen, (Cl-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and na,cl,ll,yl; wherein is as defined above; or Rl2 and Rl3 together with the nitrogen to which they are attached form a heterocyclic residue selected from 25 the group consi;,li"g of a~iridinyl, a_etidinyl, pyrrolidinyl, piperidinyl, thi~oli~ yl, ox~ inyl, morpholino, pipera_inyl, 4-(Cl-C4)alkylpi,ueridinyl, and N-(Cl-C4)piper~7inyl;
and R5 is R8R9N wherein R8 is hydrogen and R9 is selected from hydrogen, (C1-C6)alkyl, - (C2 C8)alkenyl and (C2-C8)alkynyl; wherein said alkyl, alkenyl and alkynyl groups are optionally substituted and said substituents are selected from the group consisting of 30 halo, cyano, mercapto, (Cl-C8)alkylthio, optionally substituted amino, hydroxyl, (Cl-C8)alkoxyl, carboxyl, amidino, acylamino, (C2-C~)heterocycloalkyl and (C2-C~,)heterocycloaryl and if con,pri~i"g more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;

WO 95/01342 PCT/IB94/00160 ~

3 2 ~

2. R1, R2, R3 and R6 are each hydrogen, R4 is fluoro or -ORl wherein Rl is selected from hydrogen, Rl1C(=O)- and R12R13NSO2NHC(o)- wherein R11 is selected from amino, (C1-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; wherein is as defined above; or RtZ and Rl3 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group cons6li"9 of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperæinyl, 4-(Cl -C4)alkylpiperidinyl, N-(Cl -C4)piperazinyl; and R5 Ts R8R9N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (Cl-C~)alkoxyl, (C1-C~)alkylthio, (C2-C~)heterocycloalkyl and (C2-C~)heterocycloaryl;
3. R1, R2, R3 and R~ are each hydrogen, R4 is fluoro or OR10 wherein Rl is selectecl from hyd~ogen, R11C(=O)- and R12R13NSO2NHC(o)- wherein Rl1 is selectedfrom amino, (C1-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R'3 are each independently selected from the group consi~li"g of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consiali, lg of a_iridinyl, a_etidinyl, pyrrolidinyl, piperidinyl, thi~oli~ yl, oxazolidinyl, morpholino, pipera_inyl, 4-(C1-C4)alkylpiperidinyl and N-(C1-C4)piperazinyl;
and R5 is R14O wherein R14 is (C1-C8)alkyl with the proviso that when R10 is hydrogen R14 is not methyl;

4. R1 and R2 together form a single bond, R3 and R6 are each hydrogen, R4 is fluoro or OR' wherein R' is selected from hydrogen, R'1C(=O)- and R12R13NSO2NHC(O)- wherein R11 is selected from amino, (C1-C8)alkyl, amino(Cl-C8)alkyl, protected amino(C,-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently sPlected from the group consi~Lil ,9 of hydrogen, (C1-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they areattached form a heterocyclic residue selected from the group consisli"g of aziridine, azetidine, pyrrolidone, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-3 2 ~

(Cl-C4)alkylpiperidinyl and N-(C1-C4)piperazinyl; and R5 is R8R9N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (Cl-C6)alkyl, optionally s~ ~hstitl ~ted (C3-C~)cycloalkyl, optionally substituted (C2-C~)alkenyl and optionally substituted (C2-C~)alkynyl wherein the substituents of said alkyl and alkenyl and alkynyl 5 groups are selected from hydroxyl, halo, cyano, (C1-C~3)alkoxyl, (Cl-C~)alkylthio, (C2-C~)heterocycloalkyl and (C2-C~)heterocycloaryl; with the proviso that when Rl is hydrogen then Rs cannot be NR8R9 wherein HNR8R9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, 13-hydroxyethylamine, 13-10 ch'-rwtl,ylamine, 13glycoxyethylamine, aminobutylamine, benzylamine, phenethylamine, dimethylamine, aminoethylamine, diglycolamine, 13-morpholinoethylamine, 13-piperidinoethylamine, 13-pyrrolidinoethylamine, 13-pyridinylethylamine, 13-methoxyethylamine, and 13-N-methylaminoethylamine;
5. R1 and R2 together form a single bond, R3 and R8 are each hydrogen, 15 R4 is fluoro or ORl wherein Rl is selected from hydrogen, RllC(=O)- and Rl2P~l3NSO2NHC(O)- wherein Rll is selected from amino, (Cl-C8)alkyl, amino(Cl-C8)alkyl, prote~ted amino(Cl-C8)alkyl, phenyl and naphthyl; and Rl2 and Rl3 are each independer,lly s~lectæ~ from the group consi~Li"g of hydrogen, (Cl-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(C,-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; wherein 20 is as defined above; or Rl2 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, ~elidinyl, py"olidinyl, piperidinyl, this~sli~inyl, ~ sli~inyl, morpholino, piperazinyl, ~
(Cl-C4)alkylpiperidinyl and N-(Cl-C4)piperazinyl; and R5 is R8R9N wherein R8 and R9 tog0ther with the nitrogen to which they are attached form a 3 to 6 membered 25 heterocycloalkyl or heterocycloaryl ring which is optionally s~hstituted with a group selected from hydroxyl, halo, cyano, (Cl-C6)alkoxyl, (Cl-C~)alkylthio, (C3-C8)heterocycloalkyl and (C4-C8)heterocycloaryl; with the proviso that when Rl is hydrogen then NR8R9 cannot be derived from ethyleneamine, pyrrolidine or piperidine;

6. Rl and R2 together form a single bond, R3 and R~ are each hydrogen, 30 R4 is fluoro or ORl wherein Rl is selected from hydrogen, RllC(=O)- and Rl2Rl3NSO2NHC(O)- wherein Rll is selected from amino, (Cl-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (Cl-C8)alkyl, amino(Cl-WO 95/01342 PCT/IB94/00160 ~
~6~

C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and Rl3 together with the nitrogen to which they areattached form a heterocylic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, ox~oli~inyl, morpholino, piperæinyl, 4-(C1-C4)alkylpiperidinyl and N-(C,-C4)piperazinyl; and R5 is R14O wherein R14 is hydrogen or (C1-C8)alkyl; with the proviso that when R10 is hydrogen R14 cannot be hydrogen or methyl and when R10 is R11C(=O), R11 cannot be methyl;

7. Rl, R2 and R8 are each hydrogen, R3 and are R4 together form a group s~lectecl from =O and =NOH and R5 is R8R9N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (Cl-C6)alkyl or optionally s~ Ihstihlted (C3-C6)cycloalkyl (C2-C6)alkenyl and (C2-C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (Cl-C6)alkoxyl, (Cl-C~,)alkylthio, (C2-C~)heterocycloalkyl and (C2-C~)heterocycloaryl;

8. Rl, R2 and R~ are each hydrogen, R3 and R4 together form a group sEl~ecl from =O and =NOH and R5 is R8R9N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (Cl-C~)alkoxyl, (Cl-C6)alkylthio, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl;

9. R1, R2 and R6 are each hydrogen, R3 and R4 together form a group selected from =O and =NOH and R5 is R14O wherein R14 is hydrogen or (Cl-C8)alkyl;.

10. Rl and R2 together form a single bond, R6 is hydrogen, R3 and R4 together form a group selected from =O and =NOH;
and R5 is R8R9N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (Cl-C6)alkyl or optionally substituted (C3-C6)cycloalkyl, (C2-C6)alkenyl and (C2-C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (Cl-CG)alkoxyl, (Cl-C6)alkylthio, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl;

11. Rl and R2 together form a single bond, R6 is hydrogen, R3 and R4 together form a group selected from =O and =NOH and R5 is R8R9N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (Cl-C6)alkoxyl, (Cl-C6)alkylthio, ~ WO 95/01342 PCT/IB94/00160 (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl;

12. R1 and R2 together form a single bond, R6 is hydrogen, R3 and R4 together form a group selected from =O and =NOH and R5 is Rl40 wherein R14 is hydrogen or (Cl-C8)alkyl;

13. Rl, R2 and R3 are each hydrogen, R6is a group of the formula A wherein m and R7 are as defined above, R4 fluoro or OR10; wherein R10 is selected from the group consi~Ling of hydrogen, RllC(=O)-, RllSO2- and R12Rl3NSO2NHC(=O)-; whereinR11 is selected from the group consisting of amino, (C1-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independer,lly selected from the group consisting of hydrogen, (Cl-C8)alkyl, amino(Cl C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be s~hstituted with one or more residues selected from the group consi~li"g of (Cl-C8)alkyl, halo, nitro, amino, azido and (C1-C8)alkoxyl; and R5 is R8R9N wherein R8 is hydrogen and R9is selected from hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C6)cycloalkyl, optionally sl Ihstituted (C2-C6)alkenyl and optionally substituted (C2-C6)alkynyl wherein the s~hstihlents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C,-C~)alkoxyl, (Cl-C~)alkylthio, (C2-C6)heterocycloalkyl and (c2-c~)heterocycloaryl;

14. Rl, R2 and R3 are each hydrogen, R6is a group of the formula A wherein m and R7 are as defined above, R4 is fluoro or OR10; wherein R10 is selected from the group consi~li"g of hydrogen, R1lC(=O)-, RllSO2- and Rl2Rl3NSO2NHC(=O)-; whereinR1l is selected from the group consisting of amino, (Cl-C8)alkyl, amino(Cl-C8)alkyl, protected amino(Cl-C8)alkyl, phenyl and naphthyl; and Rl2 and Rl3 are each independently selected from the group consisting of hydrogen, (Cl-C8)alkyl, amino(Cl-C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; and said alkylp phenyl and naphthyl groups may be substituted with at least one residue selected from the group consisting of (Cl-C8)alkyl, halo, nitro, amino, azido and (Cl-C8)alkoxyl;
and R5 is R9R9N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with at least one group selected from hydroxyl, halo, cyano, (Cl-C6)alkoxyl, (Cl-C6)alkylthio, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl;

15. Rl, R2 and R3 are each hydrogen, R6is a group of the formula A wherein m and R7 are as defined above, R4is OR10 or fluoro; wherein Rl is selected from the group consi~li"g of hydrogen, R11C(=O)-, R11SO2- and R12R13NSO2NHC(=O)-; whereinRll is selE~,1ed from the group consisting of amino, (C1-C8)alkyl, amino(Cl-C8)alkyl, prote-,ted amino(C3-C8)alkyl, phenyl and naphthyl; Rl2 and Rl3 are each independently 5 sele_ted from the group consisting of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(Cl-C8)alkyl, cyclo(C3-C8)alkyl, morpholino, N-methylpiperazinyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (Cl-C8)alkyl, halo, nitro, amino, azido and (Cl-C8)alkoxyl; and R5is R14O wherein R14 is hydrogen or (C1-C8)alkyl;16. Rl and R2 together form a single bond, R3is hydrogen, R6is a group of the formula A wherein m and R' are as defined above, R4is OR10 or fluoro; wherein R10 is selected from the group consisting of hydrogen, Rl1C(=O)-, R11SO2- and R12R13NSO2NHC(=O)-; wherein R11 is selected from the group consisting of amino, (Cl-C8)alkyl, amino(Cl-C8)alkyl, protected amino(Cl-C8)alkyl, phenyl and naphthyl; and Rl2 and Rl3 are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl and said alkyl, phenyl and naphthyl groups may be substituted with one or more s~ ~hstituents selected from the group consi~lir,g of (C1-C8)alkyl, halo, nitro, amino, azido and (C1-C8)alkoxyl;
and R5 is R8R9N wherein R3 is hydrogen and R9 is selected from hydrogen, optionally substituted (Cl-C~)alkyl, optionally substituted (C3-C~j)cycloalkyl, optionally substituted (C2-C6)alkenyl and optionally substituted (C2-C6)alkynyl wherein thesubstituents of said alkyl and alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1-C6)alkoxyl, (C1-C6)alkylthio, (C2-C6)heterocycloalkyl and (C2-C~)heterocycloaryl;
17. R1 and R2 togetherform a single bond, R3is hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4is OR10 or fluoro; wherein R10 is selected from the group consisting of hydrogen, R11C(=O)-, R11SO2- and R12R13NSO2NHC(=O)-; wherein R11 is selected from the group consisting of amino, (C1-Cg)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consi~li"g of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or ~I WO 95/0134:~ PCT/IB94/00160 ~6~

more residues selected from the group consi~;li"g of (Cl-C8)alkyl, halo, nitro, amino, - azicio and (C1-C8)alkoxyl; and R5is R8R9N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is opliGnally substituted with at least one group selected from hydroxyl, halo, cyano, (C1-C6)alkoxyl, (C1-C6)alkylthio, (C2-C6)heterocycloalkyl and (C2- CB)heterocycloaryl;
18. R1 and R2 together form a single bond, R3 is hydrogen, R6 is a group of the formula A wherein m and R' are as defined above, R4 is OR10 or fluoro; wherein R10 is !selected from the group consisting of hydrogen, R11C(=O)-, R11SO2- and R12R13NSo2NHC(=o)-; wherein R11is selected from the group consisting of amino, (C1-C8)alkyl, amino(C1-C8)alkyl, protected amino(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consi~li"g of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naplhthyl; and said alkyl, phenyl and naphthyl groups may be sllhstitllted with one or more residues selected from the group consi~li"g of (C1-C8)alkyl, halo, nitro, amino, azido and (C1-C8)alkoxyl; and R5 is R14O wherein R14 is hydrogen or (C1-C8)alkyl;
19. R1 and R2 are each hydrogen, R~is a group of the formula A wherein m is and R7 are defined above, R3 and are R4 together form a group selected from =O
and =NOH and R5 is R8R9N wherein R8 is hydrogen and R9is selecteri from hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C6)cycloalkyl, optionally s~ ~hstihlted (C2-C6)alkenyl and optionally substituted (C2-C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cy~no, (C1-C6)alkoxyl, (C1-C~)alkylthio, (C2-C6)heterocycloalkyl and (C2- C~)heterocycloaryl;
20. R1 and R2 are each hydrogen, R~ is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group selected from =O and =NOH and R5is R8R9N wherein R8 and R9 together with the nitrogen to which they are - attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally s~ ~hstituted with one or more groups selected from hydroxyl, halo, cyano, (C1-C6)alkoxyl, (C1-C~)alkylthio, (C2-C6)heterocycloalkyl and (C2-C~)heterocycloaryl;
21. R1 and R2 are each hydrogen, R~ is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group selected from =O and =NOH and R5 is R14O wherein Rl4 is hydrogen or (Cl-C8)alkyl;

WO 95/01342 PCT/IB94/00160 f 2 ~

22. R' and R2 together form a bond, R~ is a group of the formula A wherein m and R' are as defined above, R3 and R4 together form a group selected from =O and =NOH and R5 is R8R9N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C,-C~)alkyl or optionally substituted (C3-C6)cycloalkyl, (C2-C~)alkenyl and (C2-C0)alkynyl wherein the substituents of said alkyl and alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (Cl-C6)alkoxyl, (C,-C")alkylthio, (C2-C~)heterocycloalkyl and (C2-CB)heterocycloaryl;
23. R1 and R2 together form a bond, R~ is a group of the formula A wherein m and R' are as defined above, R3 and R4 together form a group selected from =O and =NOH and R5 is R8R9N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (Cl-C~3)alkoxyl, (Cl-C6)alkylthio, (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl;
or 24. R' and R2 together form a bond, R~ is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group selected from =O and =NOH and R~ is R14O wherein R14 is hydrogen or (Cl-C8)alkyl.
Most prefe, - ed compounds of the invention are selected from ths group col~si~li"g of 17-Amino-4,5-dihydro-17-demethoxy-geldanamycin;
17-Methylamino-4,5-dihydro-17-demethoxygeldanamycin;
17-Cyclopropylamino~,5-dihydro-17-demethoxygeldanamycin;
17-(2'-Hydroxyethylamino)-4,5-dihydro-17-demethoxygeldanamycin;
17-(2-Methoxyethylamino)4,5-dihydro-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)4,5-dihydro-17-demethoxygeldanamycin;
17-[s-(+)-2-Hydroxypropylamino]~,5-dihydro-17-demethoxygeldanamycin;
17-Azetidin-1 -yl-4,5-dihydro-17-demethoxygeldanamycin;
17-(3-Hydroxyazetidin-1 -yl)-4,5-dihydro-17-demethoxygeldanamycin;
17-Azetidin-1 -yl-4,5-dihydro-11 -a-fluoro-17-demethoxygeldanamycin;
17-Azetidin-1 -yl-17-demethoxygeldanamycin;
17-(2'-Cyanoethylamino)-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-17-demethoxygeldanamycin;
17-Amino-22-(2'-methoxyphenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(3'-methoxyphenacyl)-17-demethoxygeldanamycin;

WO 95/0134Z ~ 3 ~ ~ PCT/Is94/00160 17-Amino-22-(4'-chlorophenacyl)-17-demethoxygeldanamycin;
- 17-Amino-22-(3',4'-dichlorophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(4'-azido-3'-iodophenacyl)-17-demethoxygeldanamycin;
17-Amino-11 -a-fluoro-17-demethoxygeldanamycin;
17-Aliylamino-11 -a-fluoro-17-demethoxygeldanamycin;
17-Propargylamino-11 -a-fluoro-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-11 -a-fluoro--17-demethoxygeldanamycin;
17-Azetidin-1 -yl-11 -(4'-~idophenyl)sulfamylcarbonyl-17-demethoxygelclan~ "ycin;
17-(2'-Fluoroethylamino)-11 -keto-17-demethoxygeldanamycin;
17-Azetidin-1 -yl-11 -keto-17-demethoxygeldanamycin; and 17-(3'-Hydroxy~lidi, l-1 -yl)-11 -keto-17-demethoxygeldanar"ycin.
This invention also relates to a pharmaceutical composition cGmprisi"g an antitumor or oncogene product inhibiting or cancer preventing or treating eflective 15 arncunt of a compound of the formula ll or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method of inhibiting an oncogene product in a l"~r"al, including a human, comprising admi"i ,leri"g to said mammal an oncogeneprocluct inhibiting effective amount of a compound of the formula I or a 20 pharmaceutically acceptable salt or prodrug thereof.
This invention also relates to a method of inhibiting an ErbB-2, src, lckl fyn or abl oncogene product in a mammall including a human, comprising administering tosaid mammal an ErbB-21 src, Ick, fyn or abl oncogene product inhibiting effective amount of a compound of the formula I or a pharmaceutically accept~ble salt or 25 prodlrug thereof.
This invention also relates to a method of treating or preventing cancer in a ma"~r"al, including a human, comprising administering to said mammal an antitumor or oncogene product inhibiting effective amount of a compound of the formula I or a phar",P~ceutic~y acceptable salt or prodrug thereof.
30 This invention also relates to a method of preventing or inhibiting the growth of a tumor in a mammall including a human, comprising administering to said mammal an antitumor effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.

WO 95/01342 f~ 63~2 ~ PCT/~B94/00160 This invention also relates to a method of inhibiting growth factors that play an important role in uncontrolled cell proliferation such as the EGF l~ceptor, the NGF
receptor, the PDGF receptor and the insulin receptor in a mammal, including a human, comprising administering to said mammal a growth factor inhibiting effective amount 5 of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
The pharmaceutically acceptable salts of the present invention are those which are non-toxic at the dosages ad",i"isteled. Since compounds of the invention maycontain basic groups, acid addition salts are possi~le. Pharmaceutically acceptable 10 acid addition salts include, for example, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate and saccharate salts.
Typical pharmAceutic~"y acceptable anions include the ~et~tP;
15 benzenesulfonate; benzocLle; bicarbonate; bitartrate; bromide; calcium edetate;
camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolD.te;
esylate; fumarate; gluceplcle; gluconate; glutamate; glycollylarsnilate; hexylresorcinate;
hydroxynaphthoate; iodide; isothionate; lactate; lactobionate; malate; maleate;
mandelate; mesylate; methylbromide; methylnitrate; methylslllf~t~; mucate; napsylate;
20 nitrate; pamoate (embonate); pantothenate; phosphate; polyg~ t~ronate; salicylate;
stearate; sub~et~te; succinate; sulfate; tannate; tartrate; and teoclate.
Unless in~ic~ted otherwise, the alkyl, alkoxy, and alkenyl moieties r~rled to herein may cor"prise linear, branched and cyclic moieties and combinations thereof and the term ~halo" includes fluoro, chloro, bromo and iodo. It will be understood, 25 however that a group comprising only 1 or 2 atoms cannot be branched or cyclic.
i xamples of alkyl groups are methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl and cyclohexyl.
Furthermore, unless otherwise indicated optionally substituted means comprising from zero to the maximum number of s~hstituents, e.g., 3 for a methyl30 group, 1 for a hexyl group and 5 for a phenyl group.
The active compounds of the invention may be administered orally, topically, parenler~lly, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

WO 95/0134~, PCT/IB94/00160 ~16~32~

The term parer,l~rdl as used herein includes subcutaneous injections, - intravenous, intramusclJ~r, i"l,~ler"al injection or infusion techniques.
Detailed Descri~lion of the Invention The following reaction schemes illustrate the preparation of the compounds of 5 the formula 1. In the reaction schemes and rliscussiQn that follow, except where otherwise indicated, R1, R2, R4, R5, R~, R7, R8, R9 and R' are defined as for formula I
above.

wo 95/0l3n ~,~ 66~ PCT/IB94/00160 --o o CH30~J~ R9R3N~J¦~

Rl ~ ~H3 ~ o~ R2 oJ;;~'`' ~ \R2 CH3 CH3 ~ CH3 CH3 , o Rs 11 ~)~1 O O

WO 95/OL342 ~16 6 3 2 0 PCT/IB94/00160 r~
O
~ Z ~""'11llo o =Ij~o ",.,. <I~
fu zI
a~ / ~ ~ ¦
~< <J~ ~
~ ~ ~ ~.. """~) 'O
C~ l ~,' ~0 1~}~

~ 1 o =~ """ ~
~ZI ~ I

- 1 o~o ~ ~""""~

`~ I ~ Y
</-""0 I
~, ZI ~--o ~ ~ ~ ~>""""'1~

~0 1~ 0 Il^) O

3~

As shown in Scheme 1 compound 2 is formed by condensation of the geldanamyacin or 4,5-dihydrogeldanamyacin 1 with an amine R8R~NH. This reaction is generally carried out by mixing the amine and the ansamycin in an inert solvent such as chloroform, methylene chloride, N,N-dimethylformamide (DMF), pyridine, acetonitrile, 5 tetrahydrofuran (THF) or a lower alcohol, preferably chloroform or methylene chloride, at a temperature from about ambient temperature to the reflux temperature of thesolvent, preferably from about ambient temperature to about 65C.
The conversion of 1 or 2 to 3 is generally carried out by oxidizing 2 with standard oxidizing reagents such as pyridinium chlorochromate in methylene chloride, 10 pyridinium dichromate in DMF, oxalyl chloride/dimethyl sulfoxide (DMSO) in methylene chloride, Dess-Martin periodinane in chloroform, and Jones reagent in acetone, preferably Dess-Martin periodinane in chloroform at reflux. Those skilled in the art will recGy"i~e that these reagents can be used with additional, inert solvents and attemperatures ranging from -60C to the reflux temperature of the solvent.
The conversion of 3 to 4 is generally carried out by reacting 3 with hydroxylamine hydrochloride in the presence of a base (e.g., sodium acetate, pyridine, sodium carbonate, sodium hydroxide, potassium carbonate, and triethylamine) in water or a lower alcohol solvent at about 0C to about 100C. Preferably, 3 is combined with hydroxylamine hydrochloride in the presence of triethylamine in ethanol at room 20 temperature.
The conversion of 3 to 5 is generally carried out under standard reductive amination conditions such as combining the amine and 3 in an inert solvent (e.g., halogenated (Cl-C6) alkanes and (C1-C6)alcohols) with a suitable reducing agent (e.g., sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and formic acid), optionally in the presence of a dehydrating agent (e.g., sodium sulfate, molecular sieves, and calcium sulfate), at temperatures ranging from about ambient temperature to the reflux temperature of the solvent. Preferably, the reaction is carried out by combining 3, the amine, sodium triacetoxyborohydride and sodium sulfate in 1,2-dichloroethane at ambient temperature.
As shown in Scheme 2 compound 1 or 2 can be selectively 22-N-alkylated to afford 6 by treatment with a base, such as a (Cl-C6) alkoxide, in a polar solvent, for instance dimethylformamide or dimethyl sulfoxide, followed by reaction with an appropriate alkylating agent, for example, an alkyl halide. Reaction temperatures are WO 95/01342 21~ 6 3 2 ~ PCT/IB94/00160 maintained between about 5 and about 65C, optimally from about 5 to about 25C.- Alternatively, the compound 1 or 2 can be reacted with anhydrous potassium carbonate and the alkyl halide in acetone at reflux.
Compound 7 can be prepared by treating compound 1 or 2 with 5 diethylaminosulfurtrifluoride (DAST). This reaction is performed in an inert solvent (e.g., methyiene chloride, chloroform and dichloroethane) at low temperature of about -78 to abolJt 0C, preferably from about -78 to about -50C. Optimally, the reaction isquenched at low temperature with dilute aqueous base, for example 5% sodium bicarbonate.
10Compound 1 or 2 can be converted to 11-O-acyl or 1 1-O-sulfonyl derivatives bytreatment with acylating or sulfonating agents in the presence of non-nucleophilic bases. The acylating agents include acid anhydrides, halides and isocyanates.
Sulfonating agents include sulfonyl halides and anhydrides.
Solvents used in these reactions include a wide variety of aprotic polar and non-15polar media, for example, acetone, chloroform, ethyl acetate, DMF, pyridine, tetrahydrofuran. Bases used include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine and 4-dimethylaminopyridine. If desired, compounds 3-7 wherein R5 is RI4O may be converted to compounds 3-7 wherein R5 is R8R9N by the method for converting 1 to 2 in Scheme 1.
20The preparation of other compounds of the formula I not specifically describedabove can be accomplished using combinations of the above reactions that will beclear to those skilled in the art in view of the foregoing r~isclos~ ~re.
The compounds of formula I and their pharmaceutically acceptable salts are useful as antitumor agents (including, but not limited to anticancer agents) and25oncogene product inhibitors. They are useful, for example, in inhibiting the ErbB-2, src, Ick, fyn and abl oncogene products. They are also useful in inhibiting certain growth factors that play an important role in uncontrolled cell proliferation such as the EGF
eceptor, the NGF receptor, the PDGF receptor and the insulin receptor.
The ability of the active compounds to inhibit the ErbB-2 oncogene product may 30be determined by the following method for determining the p185 concentrations in SKBr3 cells.
SKBr3 human breast cancer cells, obtained from the ATCC, Rockville, Maryland were seeded in 8 well tissue culture plates (9.5 cm2/well, Falcon, Becton Dickenson, ~fi~32~ ~

Lincoln Park, NJ) at 5 x 105 cells/well in 2 ml McCoys medium, supplemented with 10%
fetal calf serum and glutamine. Cells were allowed to attach overnight at 37C in a 5%
CO2 atmosphere.
The compounds are dissolved in DMSO and tested over a range of 5 conce, Ill ~lions by addition to the medium, followed by incubation at 37C for 6 hours.
At the end of the incubation, the medium is aspirated from the well, and the cells are washed twice with 2 ml of TNK buffer (50 mM tris (hydroxymethyl)aminomethane hydrochloride,140 mM NaCI, 3.3 mM KCI, 0.5 mM sodium orthovanadate, adjusted to pH 7.4). The cells are then Iysed by addition of 250,ul boiling Laemmli sample buffer 10 (140 mM tris(hydroxymethyl)aminomethane hydrochloric acid, pH 6.8, 5.7% sodium dodecyl sulfate,29% glycerol) with shaking. The cell Iysate is transferred to a tube and then placed in a boiling water bath for 5 mins. The Iysates are then sonicated with a probe sonicator and stored at -70C until analysis.
The p185 concer,l, ~lion of each sample may be determined by standard 15 immunoblotting procedures essentially as described by Harlow and Lane (Antibodies:
A Laboratory Manual. Cold Spring Harbor Laboratory, 1988). A standard portion ofeach sample is mixed with dithiothreitol (10% added of a 1M solution), and then a portion corresponding to--10 IJ9 of protein is blotted onto a nitrocellulose membrane (BA-S, Schleicher and Schuell, Keene, New Hampshire) equilibrated with rinse buffer 20 (10 mM Tris hydrochloric acid pH 7.4, 150 mM NaCI) by use of a dot blot apparatus (Mini-fold, Schleicher and Schuell, Keene, New Hampshile) with an underlayer of filter paper. The wells are rinsed with 200,ul of a rinse buffer, blocked by incubation with a blocking buffer (5% bovine serum albumin, 1% ovalbumin in rinse buffer), and then inc~hAted for 4 to 12 hours with a 1:1000 dilution of NT1, an affinity purified rabbit 25 polyclonal antibody raised by standard methods (Harlow and Lane, Antibodies, A
Labor~lo~ Manual, Cold Spring Harbor Laboratory, 1988) against a peptide representing the C-terminal domain of human p186 (sequence, TAENPEYLGLDVPV, by the standard 1 letter amino acid code). The membrane is then rinsed twice for 10minutes with rinse buffer and once for 10 minutes in rinse buffer with 0.05% Triton X-30 100, and then twice more for 10 minutes in rinse buffer. The membrane is thenincuhAtecl with a 1 :3000 dilution of horseradish peroxidase labeled donkey anti-rabbit antibody (Amersham, Arlington Heights, lllinois) in a rinse buffer with shaking for 20-45 minutes. The membrane is then again rinsed twice for 10 minutes in the rinse buffer, WO 95/01342 ~ ~ 6 6 3 2 ~ PCT/IB94/00160 once for 10 minutes in the rinse buffer with 0.05% Triton X-100, and then twice more - for 110 minutes in the rinse buffer. The pl85 is then visuAIi~ed with the ECL Detection Kit (,~mersham, Ariington I lei~l ,ls, Illinois) and recorded with Hyperfilm-ECL (Amersham, Arlington I laiyhl~a, Illinois). The pl 85 is then estimated by densitometric analysis of the 5 film. IC50 values are determined by reference to the pl 85 content of samples of cells exposed only to vehicle (DMSO) and measured as described.
The ability of the active compounds to inhibit the ErbB-2 oncogene product may be determined byfollowing the method of Kamps et al., Oncogene, 2, 305-315 (1988) for determining the phosphorylation of pl85 in SKBR3 and other ErbB-2 transformed 10 cell lines.
The ability of the active compounds to inhibit the growth of certain human carcinoma cells may be determined by the methods of Alley et al., Cancer Research 48, 589-601 (1988) using SKBr3 and MCF7 cell lines. This le~elence is incorporated herein in its entirety.
When the compounds of the formula I and their pharmAceuticAIly acceptable salts are used as antiproliferative agents, such as anticancer agents, they can be administered to a mamr"alian subject either alone or, preferably, in combination with phal",~ceutically acceplable carriers or diluents in a pharmaceutical co"~posilion according to standard phar"~aceutical practice. The compounds can be ad" ,i"ialered orally or parer,le,Glly. Parer,lelal administration includes intracenous, intramusc~ r, intraperitoneal, subcutaneous and topical.
In general, the active compounds are administered in dosages ranging from about 0.1 mg to about 20 mg per kg of body weight as needed (e.g., every 4 to 6 hours), preferably from about O.1 to about 15 mg per kg of body weight; variations will necessArily occur depending upon the condition of the subject being treated and the particular compound and dosage form being admir-ialered. It is to be noted that these compounds may be administered in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
The active compounds of the invention may be administered orally, topically, par~r,ler~lly, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
The term parer,le,cll as used herein includes subcutaneous injections, intravenous, 2 ~

intramuscular, il,l,asler"al injection or infusion techniques.
The pharmaceuticai compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or 5 syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group col~si~lil ,9 of sw,eetening agents, flavoring agents, coloring agents and preserving agents in order to provide pha",~aceutically elegant and palatable preparations. Tablets contain the 10 active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitP~Ie for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium pllosphate or sodium phosphate; granulating and di~illleylalillg agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and 15 lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl mono:,learala or glyceryl d;~tearale may be employed. They may also be coated by the techniques 20 described in, e. g., the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,266,874 to form osmotic therapeutic tablets for control release.
The hard capsules for oral use may also be presenled as gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or whereas the soft capsules may be 25 preser,led as gelatin c~ps~ ~'es wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with ex~ Jier,l~
suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-30 propylmethylcell~ ~'cse, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gumacacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with ~ WO 95/01342 PCT/IB94/00160 ~16~32~

long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for 5 example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oiiy suspensions may be formulated by suspending the active ingredient in a 10 vege.table oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for exarr ple beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
These compositions may be preserved by the addition of an anti-oxidant such as 15 ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a disper:,i"g or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already 20 mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil; a mineral oil such as liquid paraffin or mixtures of these. Suitable 25 emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides such as example soy bean and lecithin;
and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also 30 contain swet:leni"g and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulation may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical WO 95/01342 PCT/IB94/00160 ~
2~66~

compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pare"lt:rGlly-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringe~s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The active compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepaled by mixing the drug with a s~itAhle non-irritating excipient which is solid at ol di"ary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethyleneglycols.
For topical use, creams, ointments, Jellies, solutions or suspensions, etc., containing the active compounds of the invention are employed.
For administration by inhalation, the active compounds of the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer. The pr~t,r,ed composition for inhalation is a powder which may be formulated as a cartridge from which the powder composition may be inhaled with the aid of a suitable device. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.
One or more other active compounds may be added to the formulations described above to provide formulations for combination therapy. Such compounds include cytostatic, cytotoxic and antiemetic agents conventionally used in cancer chemotherapy, such as adriamycin.
The following examples illustrate the invention but are not to be construed as limiting the same. All melting points are uncorrected. In the Examples, HBOC" refers to -butoxycarbonyl .

~632~

EXAMPLES
General Methods High pressure liquid chromatography (HPLC) was performed at 1.0 mLlminute with 254 nm detection on a 250 x 4.6 mm Dupont Zorbax Sil (trademark) column eluted isocratically by a two-pump/mixer system supplying the in~ic~ted mixture of 1%
methanol in ethyl acetate and hexanes respectively. Samples to be thus analyzed are lissolved in an HPLC eluent. The HPLC retention times are reported followed by the ethyl~cet~t~/hexane ratio in parentheses. The terms ~concer,llGted in vacuo" and~coevaporated" refer to removal of solvent at water aspirator pressure on a rotary evaporator with a bath temperature of less than 40C.

17-lsopropylamino4,5-dihvdro-17-demethoxyqeldanamvcin To 4,5-dihydro-geldanamycin (75 mg, 0.13 mmol) in CHCI3 was added isopropylamine (68,uL, 0.80 mmol) and the reaction stirred at room temperature for 24 hours at which time TLC analysis indicated the reaction was not complete. The reac~ion mixture was then heated at reflux for 3 hours. The solvent was removed by rotary evaporation and the purple residue partitioned between ethyl acetate and 1 M
hydrochloric acid. The organic layer was dried, the solvent removed by rotary evaporation, and the crude material purified by column chromatography (silica gel, 9:1 CH2CI2:methanol) to give the title compound as a purple solid; Yield 56 mg (72%), mp 114-115C; 1H-NMR (300 MHz, CDCI3) ~ 0.95 (d, 3 H, J = 7 Hz), 1.00 (d, 3 H, J = 7 Hz), 1.2 (d, 3 H, J = 7 Hz), 1.35 (d, 3 H, J = 7 Hz), 1.7 (s, 3 H), 1.9 (s, 3 H), 2.2 (dd, 1 H,J=14,7),2.4(dd,1 H,J=14Hz,7Hz),2.5-2.8(m,1 H),3.3(m,1 H),3.35(s, 3 H), 3.4 (s, 3 H), 3.4-3.5 (m, 1 H), 3.6 (d, 1 H, J = 9 Hz), 3.7 (br s, 1 H), 4.1 (m, 1 H), 4.95(s,2H),5.2(d,1 H,J=7HzHz),5.75(d,1 H,J=9Hz),6.2(t,1 H,J=9Hz), 7.1 (s, 1 H), 9.3 (br s, 1 H); mass spectrum m/z 612 (M + Na).
The compounds of Examples 2-14 were prepared from 4,5-dihydro-geldanamycin and the appropriate amines using the conditions described above.

17-Amino-4.5-dihydro-17-demethoxyqeldanamvcin 1H-NMR (300 MHz, CDCI3) ~ 0.95 (m, 6 H), 1.5-1.8 (m, 8 H, contains methyl singlet), 1.85 (s, 3 H), 2.0 (m,1 H), 2.35 (m, 2 H), 2.6 (m, 1 H), 2.7 (m, 1 H), 3.2-3.5 (m, 8 H, contains 2 methyl singlets), 3.8 (m, 2 H), 5.0 (br s, 2 H), 5.1 (d, 1 H, J = 4 Hz), 5.6 WO 95/01342 PCT/IB94/00160 ~
~63~

(br s, 2 H), 5.7 (d, 1 H, J = 10 Hz), 6.2 (t, 1 H, J = 7 Hz), 7.05 (s, 1 H), 9.15 (s, 1 H);
mass spectrum m/z 547 (M+); Analysis calculated for C28H4lN3O8-0.5 H2O: C, 60.42;
H, 7.60; N, 7.55%. Found: C, 60.42; H, 7.45; N, 7.51%.

1 7-Methylamino4.5-dihvdro-1 7-demethoxvqeldanamycin Mp 181C; 'H-NMR (300 MHz, CDCI3) ~ 1.0 (m, 6 H), 1.5-1.8 (m, contains methyl singlet, 9 H), 1.9 (s, 3 H), 2.3-2.8 (m, 5 H), 3.2 (d, 3 H, J = 7 Hz), 3.3-3.45 (m, contains 2 methyl singlets, 8 H), 3.45-3.55 (m, 1 H), 3.6 (br d, 1 H, J = 7 Hz), 3.75 (br s, 1 H), 4.7 (br s, 2 H), 5.2 (d, 1 H, J = 7 Hz), 5.8 (d, 1 H, J = 10 Hz), 6.25 (t, 1 H, J
= 7 Hz), 6.4-6.55 (m, 1 H), 7.15 (s, 1 H), 9.3 (br s, 1 H); mass spectrum m/z 561 (M+);
Analysis c~lcul~ted for C29H43N3O8: C, 62.01; H, 7.72; N, 7.48%. Found: C, 61.60; H, 7.73; N, 7.16%.

1 7-Cyclo~oropylamino-4,5-dihvdro-1 7-demethoxvgeldanamycin Mp 14~147C; lH-NMR (300 MHz, CDCI3) ~ 0.6-0.9 (m, 4 H), 0.9-1.1 (m, 6 H), 1.5-1.8 (m, co"ltli"s methyl singlet, 6 H), 1.9 (s, 3 H), 2.3-2.5 (m, 2 H), 2.5-2.8 (m, 2 H), 2.8-3.0 (m, 2 H), 3.2-3.4 (m, corllai"s 2 methyl singlets, 8 H), 3.4-3.5 (m, 1 H), 3.5-3.7 (br d, 2 H), 4.9 (br s, 2 H), 5.15 (d, 1 H, J = 7 Hz), 5.75 (d, 1 H, J = 10 Hz), 6.2 (t, 1 H, J = 7 Hz), 6.35 (d, 1 H, J = 3), 7.1 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 587 (M+); Analysis c~lc~ t~d for C3l H45N3O8-0.5 H2O: C, 62.40; H, 7.77; N, 7.04%. Found:
C, 62.55; H, 7.61; N, 6.83%.

1 7-Allvlamino-4.5-dihydro-1 7-demethoxvqeldanamvcin Mp 205C; lH-NMR (300 MHz, CDCI3) ~1.0 ( m, 6 H, 2 methyl doublets), 1.5-1.8 (m, 8 H, contains methyl singlet), 1.9 (s, 3 H), 2.2-2.5 (m, 3 H), 2.5-2.8 (m, 2 H), 3.2-3.5 (m, 8 H, contains 2 methyl groups), 3.6 (d, 1 H, J = 7 Hz), 4.1 (m, 2 H), 4.8 (s, 2 H), 5.2 (d, 1 H, J = 7 Hz), 5.25 (d, 1 H, J = 10 Hz), 5.3 (s, 1 H), 5.75 (d, 1 H, J = 10 Hz), 5.9 (m, 1 H), 6.25 (t, 1 H, J = 7 Hz), 6.4 (br t, 1 H), 7.25 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 610 (M + Na); Analysis calculated for C31H45N3O8-0.5 H2O: C, 62.40; H, 30 7.77; N, 7.04%. Found: C, 62.26; H, 7.83; N, 6.75%.

~ WO 95/01342 PCT/IB94/00160 216~3~0 E)CAMPLE 6 1 7-(2'-Hydroxyethvlamino)4,5-dihydro-1 7-demethoxyqeldanamvcin Mp 129C ffoam); 1H-NMR (300 MHz, CDC13) ~ 0.9-1.1 (m, 6 H), 1.6-1.8 (m, cor,l~, 15 methyl singlet, 8 H), 1.9 (s, 3 H), 2.3-2.5 (m, 3 H), 2.7-2.8 (m, 2 H), 3.2-3.5 (m, 5 contains 2 methyi singlets, 8 H), 3.55-3.65 (d, 1 H, J = 10 Hz), 3.65-3.8 (m, 2 H), 3.8-4.0 (m, 1 H), 4.85 (br s, 2 H), 5.15 (d, 1 H, J = 4 Hz), 5.78 (d, 1 H, J = 10 Hz), 6.2 (t, 1 H, J = 7 Hz), 7.1 (s, 1 H), 9.21 (s, 1 H); mass spectrum m/z 591 (M+); Analysis c~c~ ted for C30H45N309: C, 60.90; H, 7.67; N, 7.10%. Found: C, 60.40; H, 7.89; N, 6.63%.

1 7-r2'-Methoxyethylamino)-4,5-dihydro-1 7-demethoxyqeldanamycin Mp 115C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.8-1.0 (m, 6 H), 1.5-1.8 (m, con~i"s broad methyl singlet, 7 H), 1.85 (br s, 3 H), 2.2-2.5 (m, 3 H), 2.5-2.8 (m, 2 H), 3.2-3.5 (m, contains 3 methy singlets, 12 H), 3.5-3.8 (m, 5 H), 5.0 (br s, 2 H), 5.15 (d, 15 1 H, J = 7 Hz), 5.7 (d, 1 H, J = 10 Hz), 6.2 (br t, 1 H, J = 7 Hz), 6.55 (br s, 1 H), 7.1 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 605 (M+); Analysis c~lclJl~ted forC3lH47N309: C, 61.47; H, 7.82; N, 6.94%. Found: C, 61.0; H, 7.58; N, 6.7196.
E)CAMPLE 8 1 7-(2'-FluoroethYlamino)-4,5-dihYdro-1 7-demethoxvqeldanamYcin Mp 157C ffoam); 1H-NMR (300 MHz, CDCI3) ~ 1.0 (m, 6 H), 1.6-1.8 (m, contains methyl singlet, 8 H), 1.9 (s, 3 H), 2.0-2.1 (br s, 1 H), 2.2-2.5 (m, 3 H), 2.6-2.8 (m, 2 H), 3.2-3.7 (m, contains 2 methyl singlets, 8 H), 3.7-4.0 (m, 2 H), 4.55 (t, 1 H, J
=7Hz),4.74.85(m,3H),5.2(d,1 H,J=7Hz),5.8(d,1H,J=lOHz),6.25(t,1 H, J = 7 Hz), 6.4 (t, 1 H, J = 7 Hz), 7.15 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 593 25 (M+)-E)(AMPLE 9 1 7-(2'-Methvlthioethylamino)-4.5-dihvdro-1 7-demethoxyqeldanamvcin Mp 110C ffoam); lH-NMR (300 MHz, CDCI3) ~1.0 (m, 6 H), 1.5-1.75 (m, contains methyl singlet, 8 H), 1.85 (s, 3 H), 2.1 (s, 3 H), 2.2-2.4 (m, 3 H), 2.5-2.8 (m, 4 30 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.5-3.8 (m, 4 H), 5.0 (s, 2 H), 5.15 (d, 1 H, J = 4 Hz), 5.75 (d, 1 H, J = 10 Hz), 6.2 (t, 1 H, J = 7 Hz), 6.6 (t, 1 H, J = 4 Hz), 7.1 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 644 (M + Na); Analysis c~lc~lls.tPd for WO 95/01342 PCTI~94/00160 ~

2~ -32-C31H47N308s-0.5 H20: C, 59.03; H, 7.67; N, 6.66%. Found: C, 58.87; H, 7.67; N, 6.60%

1 7-rs-(+)-2'-HvdroxyproPvlaminol4~5-dihvdro-l 7-demethoxvqeldanamycin lH-NMR (300 MHz, CDCI3) ~ 0.95 (d, 3 H, J = 7 Hz), 1.0 (d, 3 H, J = 7 Hz), 1.3 (d, 3 H, J = 7 Hz), 1.5-1.75 (m, contains methyl singlet, 6 H), 1.85 (s, 3 H), 2.25-2.45 (m, 2 H), 2.6-2.7 (m, 1 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.5-3.7 (m, 2 H), 4.05 (m, 1 H), 4.9 ts, 2 H), 5.15 (d, 1 H, J = 7 Hz), 5.8 (d, 1 H, J = 7 Hz), 6.2 (t, 1 H, J = 7 Hz), 6.7 (br s, 1 H), 7.05 (s, 1 H), 9.2 (br s, 1 H); mass spectrum m/z 605.3 (M+).

17-(2'-Cyanoethvlamino~4,5-dihvdro-17-demethoxvqeldanamycin Mp 130-140C ffoam); 1H-NMR (300 MHz, CDCI3) ~ 1.0 (m, 6 H), 1.5-1.8 (m, cor,~ni"s methyl singlet, 8 H), 1.9 (s, 3 H), 2.0-2.2 (m, 2 H), 2.4 (q, 2 H, J = 7 Hz), 2.6-2.8 (m, 4 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.6 (br d, 1 H, J = 7 Hz), 3.85 (q,2H,J=7Hz),4.75(brs,2H),5.2(d,1 H,J=7Hz),5.75(d,1 H,J=lOHz),6.2 (q, 2 H, J = 7 Hz), 7.15 (s, 1 H), 9.15 (s, 1 H); mass spectrum m/z600 (M+); Analysis c~lcl~ tecl for C3lH44N408: C, 61.98; H, 7.38; N, 9.33%. Found: C, 61.30; H, 7.31; N, 9.12%.

17-Azetidin-1 -yl4,5-dihYdro-17-demethoxvqeldanamycin Mp 110C ffoam); 1H-NMR (300 MHz, CDCI3) ~0.95 (d, 3 H, J = 7 Hz), 1.0 (d, 3 H, J = 7 Hz), 1.7 (s, 3 H), 1.6-1.8 (m, 9 H), 1.9 (s, 3 H), 2.2 (dd, 1 H, J = 14 Hz, 7 Hz), 2.3-2.55 (m, 4 H), 2.65 (d, 1 H, J = 14 Hz), 2.75 (m, 1 H), 3.35 (m, 1 H), 3.38 (s, 3 H), 3.4 (s, 3 H), 3.5 (m, 1 H), 3.6 (d, 1 H, J = 10 Hz), 4.54.8 (m, 6 H), 5.2 (d, 1 H, J = 7 Hz), 5.7 (d, 1 H, J = 10 Hz), 6.25 (t, 1 H, J = 10 Hz), 7.0 (s, 1 H), 9.3 (br s, 1 H);
mass spectrum m/z 587 (M+).

1 7-(3'-HydroxYazetidin-1 -vl)-4.5-dihydro-1 7-demethoxvqeldanamycin Mp (amorphous); 1H-NMR (300 MHz, CDCI3) ~ 1.0 (m, 6 H),1.5-1.8 (m, contains 1 methyl singlet, 8 H), 1.9 (s, 3 H), 2.2 (m, 1 H), 2.35 (m, 2 H), 2.6 (br d, 1 H, J = 14 Hz), 2.75 (m, 1 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.6 (d,1 H, J = 10 Hz), 4.34.6 (m, 2 H), 4.7 (m, 1 H), 4.75-5.0 (m, 4 H), 5.15 (d, 1 H, J = 4 Hz), 5.8 (d, 1 H, J = 10 Hz), 6.2 (brt, 1 H, J = 7 Hz), 6.95 (s, 1 H), 9.2 (s, 1 H); mass spectrum mlz 626 ~ WO 9S/01342 216 6 3 ~ O PCT/IB94/00160 (M t- Na); Analysis calcul~t~d for C3lH45N3Og: C, 61.68; H, 7.51; N, 6.96%. Found: C, 61.21; H, 7.51; N, 6.75%.

1 7-(3'-Methoxvazetidin-1 -yl)4,5-dihvdro-1 7-demethoxvqeldanamycin Mp 118C ffoam); lH-NMR (300 MHz, CDCI3) ~ 1.0 (m, 6 H, two methyl doublets), 1.5-1.8 (m, 8 H, contains methyl singlet), 1.9 (s, 3 H), 2.0-2.3 (m, 1 H), 2.4 (m, :2 H), 2.5-2.8 (m, 2 H), 3.2-3.5 (m, 11 H, contains 3 methyl singlets), 3.6 (m, 1 H), 4.0(d,1 H,J=7Hz),4.2(m,1 H),4.34.6(m,2H),4.64.9(m,4H),5.2(d,1 H,J=
4 Hz), 5.8 (d, 1 H, J = 10 Hz), 6.25 (brt, 1 H, J = 7 Hz), 7.0 (s, 1 H), 9.25 (s, 1 H);
mass spectrum m/z 640 (M+ + Na); Analysis calculated for C32H47N3Og-HzO C, 60.84;
H, 718; N, 6.65%. Found: C, 60.74; H, 7.54; N, 6.75%.

1 7-Azetidin-1 -vl4.5-dihvdro-11 -a-fluoro-1 7-demethoxyqeldanamycin A solution of diethylaminosulfurtrifluoride (DAST) (0.154 9, 0.960 mmol, 0.127 mL) in 3 mL of methylene chloride was added to a flame dried flask under nitrogen and cooled to -68 C with an external dry ice/acetone bath. 1 7-Azetidine-1 -yl4,5-dihydro-17-demethoxygeldana"~ycin (0.188 9, 0.320 mmol) dissolved in 15 mL of methylene chloride was added dropwise. After 0.5 hour 5 mL of 5% ~lueous NaHCO3 was added slowly at about -68C. After warming to room temperature the product was extracted into 100 mL of methylene chloride. The organic layer was washed with 3 x 50 mL of water and 2 x 50 mL of brine, dried with MgSO4, filtered and concentrated to a purple solid which was purified by flash column chromatography using 5:95 methanol:chloroform. Material of Rf = .42 (1:9 methanol:chloroform), the desiredproduct was disolved in a minimal amount of ethyl acetate and ple.,i~ led with hexanes; Yield 0.096 g (51%), mp 104C (dec); 1H-NMR (300 MHz, CDCI3) ~1.00(d, J = 8 Hz, 3H, 14-CH3), 1.06(d, J = 8 Hz, 3H, 10-CH3), 1.4 (br m, 2H, H-13), 1.56 (s, 3H, 8-CH3), 1.75 (m, 1H, H-14), 1.89 (s, 3H, 2-CH3), 2.20 (dd, J = 8.5 Hz, 16 Hz, 1H, H-15), 2.4 (br m, 3H, 3' azetidine CH2 and H-5), 2.66 (dd, J = 7 Hz, 16 Hz, 1 H, H-15), 2.75 (br d, J = 26 Hz, 1H, H-10), 3.25 (m, 1H, H4), 3.4 (br s, 7H, 6-OCH3, 12-OCH3 and H4), 3.60 (br m, 1 H, H-12), 4.40 (br d, J = 44 Hz, 1 H, H-11), 4.65 (br m, 7H, NH2 and 2' and 4' azetidine CH2 and H-6), 5.06 (d, J = 8 Hz, lH H-7), 5.62 ( d, J = 9 Hz, lH, H-9), 6.13 (brt, lH, H-3), 6.96 (s, lH, H-19), 9.27 (s, lH, NH-22); m/z 612. (M+ + Na); IR (KBr, WO 95/01342 ~ PCT/IB94/00160 cm-') 1735, 1695, 1650; Analysis calculated for C3lH44FN307-0.25H20: C, 62.66; H, 7.96; N, 7.07%. Found: C, 62.38; H, 7.53; N, 6.97%.

17-Allvlamino-4,5-dihydro-11 -a-fluoro-17-demethoxyqeldanamycin The title compound was made by the method of Example 15 from 1 7-allylamino-4,5-dihydro-17-demethoxygeldanamycin. Yield 0.079 g (44%), mp 84C (dec); 1H-NMR(300 MHz, CDCI3) ~ 1.02(d, 3H, J = 8Hz, 14-CH3), 1.07(d, 3H, J = 8Hz, 10-CH3), 1.45 (br m, 2H, H-13), 1.60 (s, 3H, 8-CH3), 1.7 (m, 2H, H-5), 1.83 (br m, 1 H, H-14), 1.90 (s, 3H, 2-CH3), 2.30 (dd, J = 8.5 Hz, 16 Hz, lH, H-15), 2.4 (m, 2H, H4), 2.70 (dd, J = 7 Hz, 16 Hz, lH, H-15), 2.75 (brd, J = 26 Hz, lH, H-10), 3.26 (m, lH, H-6), 3.40 and 3.43 (br s, 6H, OCH3), 3.57 (br m, 1 H, H-12), 4.08 (br t, 2H, allylic CH2), 4.35 (br d, J = 47 Hz, 1 H, H-11), 4.65 (br m, 2H, NH2), 5.07 (s, 1 H H-7), 5.25 (br d, 2H, vinylic CH2), 5.61 (d, J = 9 Hz, lH, H-9), 5.9 (m, 2H, H-5 and vinylic CH), 6.15 (brt, lH, H-3), 6.32 (brt, lH, NH), 7.15 (s, lH, H-19), 9.25 (s, lH, NH-22); m/z 612. (M+ + Na); IR (KBr, cm l) 1730, 1695, 1655; Analysis cpllc~ ted for C31H44FN307-0.25H20: C, 62.66; H, 7.96; N, 7.07%. Found: C, 62.53; H, 7.32; N, 6.97%.

17-Azetidin-1 -yl4,5-dihydro-11 -keto-17-demethoxygeldanamYcin Prepared from 17-azetidin-1-yl-4,5-dihydro-17-demethoxygeldanamycin by the method of Example 76; 1H-NMR (300 MHz, CDCI3) ~ 1.0 (d, 3 H, J = 6), 1.3 (d, 3 H, J
= 6), 1.35-1.5 (m, 2 H), 1.5-1.8 (rr~, 6 H, contains methyl singlet), 1.9 (s, 3 H), 2.15-2.3 (m, 2 H), 2.45-2.5 (m, 2 H), 2.6 (m, 1 H), 3.15 (m, 1 H), 3.35 (s, 3 H), 3.4 (s, 3 H), 3.55 (m, 1 H), 4.0 (m, 1 H), 4.65 (m, 4 H), 4.8 (br s, 2 H), 5.0 (d, 1 H, J = 6 Hz), 5.55 (d, 1 H, J = 8 Hz), 6.25 (m, 1 H), 6.92 (s, 1 H), 9.2 (s, 1H); mass spectrum m/z 608 (M
Na);

17-Azetidin-1 -Yl-17-demethoxvqeldanamycin Geldanamycin (14.0 gm, 25.0 mmol) was added to a flame dried flask under nitrogen and slurried in 350 mL of methylene chloride. Azetidine (2.85g, 49.9 mmol, 3.36 mL) in 10 mL of methylene chloride was added dropwise. The yellow suspension turned purple during the addition. A~ter 1 hour the reaction mixture was evaporated to dryness and the residue dissolved in 50 mL of chloroform and precipitated with 600 mL
of hexanes. Filtration and vacuum drying at 70C afforded pure product, yield 14.2 gm WO 9~/0134~, PCT/IB94/00160 ~6~2~

(97%); 225 C; lH-NMR (300 MHz, CDCI3) ~ 0.94 (brt, 6H,10-CH3 and 14-CH3),1.2 (m, lH, H-13), 1.65 (m, lH, H-13), 1.73 (m, lH, H-14), 1.76 (s, 3H, 8-CH3), 2.0 (s, 3H, 2-CH3), 2.17 (dd, J = 12 Hz, 16 Hz, lH, H-15), 2.40 (p, J = 8 Hz, 2H, 3' azetidine CH2), 2.56 (d, J = 16 Hz, lH, H-15), 2.67 (m, lH, H-10), 3.20(s, 3H, OCH3), 3.30 (s, 3H, 5 OCH3), 3.40 (m, lH, H-12), 3.50 (m, lH, H-11), 4.25 (d, J = 10.5 Hz, 1H, H-6), 4.5-4.9 (m, 6H, 2'and 4' azetidine CH2 and NH2), 5.13 (s, lH H-7), 5.79 (t, J = 9 Hz, lH, H-5), 5.87 (d, J = 9 Hz, lH, H-9), 6.53 (t, J = 9 Hz, lH, H4), 6.88 (d, J = 9 Hz, lH, H-3), 7.06 (s,1 H, H-19), 9.13 (s,1 H, NH-22); m/z 608. (M+ + Na); IR (KBr, cm~l) 1730,1680, 1645; Analysis calc~ t~d for C3l H43N3O8: C,63.54; H, 7.40; N, 7.17%; Found: C,63.09;
10 H, 7.33; N, 6.85%.

17-Propargylamino-17-demethoxYqeldanamycin r, oparyylamine hydrochloride (0.200 gm,2.180 mmol) and triethylamine (0.2206 gm, 2.180 mmol, 0.303 mL) were added to a flame dried flask under nitrogen and 15 slurried in 5mL chloroform. After 10 minutes geldanamycin (0.200 gm, 0.3567 mmol) was added to the mixture and the reaction was stirred at room temperature overnight.
The solution changed from a pale yellow color to a dark orange/red color. The reaction mixture was diluted with 50 mL chloroform and washed with 3 x 25 mL 1 N hydrochloric acid. The or~ic layer was then dried over magnesium sulfate, filtered and evaporated 20 to dryness to yield a crude purple residue. The crude product was then purified by flash column chl Jl"otography using 200 gm silica gel and eluting with 3:97 isopropyl alcohol:methylene chloride to afford pure purple product, 0.015 gm (7%) mp 172C;
H-NMR (300 MHz, CDCI3) ~ 0.96-1.10 (m, lH, H-13), 1.00 (d, J = 8 Hz, 3H, 10-CH3), 1.01 ~d, J = 8 Hz, 3H, 14-CH3), 1.62-1.90 (br m, 2H, H-13, H-14), 1.76 (s, 3H, 8-CH3), 25 2.04 (s, 3H, 2-CH3), 2.34-2.47 (br m, 1 H, H-15), 2.42 (s, 1 H, acetylene CH), 2.68-2.81 (br m, 2H, H-10, H-15), 3.28 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 3.49 (br m, 1H, H-12), 3.61 ~brm, 1H, H-11), 4.02 (d, J = 6 Hz, 1H, H-6), 4.31 (s, 1H, 11-OH), 4.32 (m, 2H, propargyl CH2), 4.77 (br m, 2H, NH2), 5.21 (s, 1H, H-7), 5.87 (t, J = 9 Hz, 1H, H-5), 5.90 ~d, J = 9 Hz, 1 H, H-9), 6.32 (br t, 1 H, NH), 6.60 (t, J = 9 Hz, 1H, H-4), 6.97 (d, J
30 = 9 Hz, 1H, H-3), 7.32 (s, 1H, H-19), 9.09 (s, 1H, NH-22); m/z 606.3 (M+ + Na); IR
(KBr, cm-1) 2120, 1730, 1695, 1645; Analysis calculated for C3lH4lN308-3.50H20: C, 57.55; H, 7.47; N, 6.49%. Found: C, 57.55; H, 6.14; N, 6.23%.

WO 95101342 ~ PCT/IB94/00160 17-(2'-Cyanoethylamino)-17-demethoxyqeldanamycin Geldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under nitrogen and slurried in 5 mL chloroform. 3-Aminopropionitrile 0.153 gm (2.18 mmol, 5 0.161 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture went from a pale yellow color to a dark red/orange color. An additional 0.161 mL of 3-aminopropionitrile was added and the reactionmixture was refluxed for 8 hours. The cooled reaction mixture was diluted with 75 mL
chloroform and washed with 3 x 50 mL water. The organic layer was dried over 10 magnesium sulfate, filtered and evaporated to dryness. The purple residue wasrecrystA~ ed from a minimal amount of hot ethyl acetate affording pure purple product, 0.160 gm (75%) mp 152C; lH-NMR (300 MHz, CDCI3) ~ 0.74-0.91 (br m, lH, H-13), 0.82 (d, J = 7 Hz, 3H, 10-CH3), 0.82 (d, J = 7 Hz, 3H, 14-CH3), 1.45-1.7 (br m, 2H, H-13, H-14),1.61 (s, 3H, 8-CH3),1.83 (s, 3H, 2-CH3), 1.93-2.09 (brm,1H, H-15), 2.49-2.64 15 (m, 4H"~-ethyl CH2, H-10, H15), 3.08 (s, 3H, OCH3), 3.19(s, 3H, OCH3), 3.28 (brm,1H, H-12), 3.39 (m, lH, 11-H), 3.62-3.79 (brm, 2H, a-ethyl CH2), 4.12 (d, J = 9 Hz, 1H, H-6), 4.62 (br m, 2H, NH2), 5.00 (s, 1 H, H-7), 5.62-5.72 (br m, 2H, H-5, H-9), 5.96 (br t,1 H, NH), 6.40 (t, J = 9 Hz, 1H, H4), 6.78 (d, J = 9 Hz, 1H, H-3), 7.12 (s, lH, H-19), 8.82 (s, 1H, NH-22); mtz 621.3 (M+ + Na); IR (KBr, cm-l) 1730, 1690, 1650, 1585, 1480;
20 Analysis calculated for C3lH42N4O8: C, 62.19; H, 7.07; N, 9.35%. Found: C, 62.02; H, 6.63; N, 9.09%.

17-(2'-Fluoroethvlamino~-17-demethoxvqeldanamycin 17-(2'-Fluoroethylamino)-17-demethoxygeldanamycin was prepared by the 25 method of Example 19. Pure purple product was obtained from the crude residue after flash column chro",atoy"~ hy using 200 gm silica gel eluting with 20% acetone inmethylene chloride; yield 0.060 gm (28%) mp 176C; lH-NMR (300 MHz, CDCI3) ~ 0.87 (d, J = 7 Hz, 3H, 10-CH3), 0.91 (d, J = 7 Hz, 3H, 14-CH3), 1.55-1.73 (br m, 3H, H-13, H-14), 1.70 (s, 3H, 8-CH3), 1.92 (s, 3H, 2-CH3), 2.21 (dd, J = 8 Hz, 16 Hz, lH, H-15), 30 2.62 (br m, 2H, H-10, H-15), 3.14 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.35 (br m,1 H, H-12), 3.48 (br m, 1 H, H-11), 3.59-3.91 (br m, 2H, o-ethyl CH2), 4.19 (d, J = 9 Hz, 1 H, H-6), 4.65 (two br t, J = 46 Hz, 5 Hz, 2H, ,B-ethyl CH2), 4.524.79 (br m, 2H, NH2), 5.07 (s, 1 H, H-7), 5.72 (br m, 2H, H-5,H-9), 6.29 (br t, 1 H, NH), 6.48 (t, J = 9 Hz, 1 H, H-4), WO 95/01342 ~ ~ 6 6 3 2 0 PCT/IB94/00160 6.85 (d, J = 9 Hz, 1H, H-3), 7.14 (s, 1H, H-19), 8.97 (s, 1H, NH-22); m/z 591.3. (M+);
IR (KBr, cm~') 1742,1655,1585; Analysis calculated for C30H4zN3O8: C, 60.90; H, 7.15;
N, 7.10%. Found: C, 60.65; H, 6.90; N, 6.92%.

17-tert-Butylamino-17-demethoxy-geldanamvcin Geldanamycin (0.200 gm, 0.3567 mmol) was slurried in 5 mL of tert -butylamine, in a flame dried flask under nitrogen, at reflux overnight. The reaction color went from yellow to dark purple. The reaction mixture was evaporated to dryness. The residue was dissolved into 50 mL chloroform. The chloroform solution was washed with 3 x 25 mL brine and 3 x 25 mL water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromotagraphy with 200 gm silica gel eluted with 10%
acetone/methylene chloride; yield 0.053gm (25%) mp 102C (dec); 1H-NMR (300 MHz,CDCI3) ~ 0.89 (d, J = 5 Hz, 3H, 10-CH3), 0.94 (d, J = 5 Hz, 3H, 14-CH3), 1.39 (s, 9H, t-butyl CH3), 1.49-1.80 (br m, 3H, H-13, H-14),1.74 (s, 3H, 8-CH3),1.98 (s, 3H, 2-CH3), 2.27 (br m, 1H, H-15), 2.65 (br m, 2H, H-10, H-15), 3.21 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.99 (br m, 1H, H-12), 3.45 (br m, 1H, H-11), 4.17 (br m, 1H, 11-OH), 4.23 (d, J = 7 Hz, 1H, H-6), 4.72~.91 (br m, 2H, NH2), 5.13 (s, 1H, H-7), 5.82 (br m, 3H, H-5, H-9, NH), 6.51 (t, J = 7 Hz, 1H, H-4), 6.87 (d, J = 7 Hz, 1H, H-3), 7.18 (s, 1H, H-19), 8.96 (s, 1H, NH-22); m/z 601.4 (M+); 1R (KBr, cm~') 1720, 1685, 1645, 1585, 1560;
Analysis calculated for C32H47N30e: C, 63.87; H, 7.87; N, 6.98%. Found: C, 63.91; H, 7.95; N, 6.03%.

17-(2'-Mercaploethvlamino)-17-demethoxYqeldanamvcin Geldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under nitros~en and slurried in 5 mL pyridine. Thiazolidine (0.194 gm, 2.18 mmol, 0.171 mL) was added and the reaction mixture was heated at 70C for 2 hours. The reaction mixture was evaporated to dryness in vacuo. The crude product was purified by flash column chromatography using 200 gm silica gel eluting with 4% methanol in methylene chloride to afford pure purple product, 0.041gm (20%) mp 156C; lH-NMR (300 MHz,CDCI3) ~ 0.99 (d, J = 5 Hz,6H,10-CH3,14-CH3),1.63-1.81 (br m, 3H, H-13, H-14),1.78 (s,3H, 8-CH3),2.01 (s,3H, 2-CH3),2.47(m,1 H, H-15), 2.64-2.79 (br m,2H, H-10, H-15), 2.83-3.00 (br m, 2H, 2'-CHz), 3.25 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.42 (m, lH, H-WO 95/0L342 PCTtIB94/00160 ~
3 ~ ~

12), 3.55 (m, lH, H-11), 3.87 (m, 2H, 1'-CH2), 4.10 (br m,1H, 11-OH), 4.29 (d, J = 9 Hz, lH, H-6), 4.92 (br m, 2H, NH2), 5.16 (s, 1H, H-7), 5.81-5.89 (br m, 2H, H-5, H-9), 6.48 (brt, lH, NH), 6.55 (t, J = 9 Hz, lH, H4), 6.94 (d, J = 9 Hz, lH, H-3), 7.24 (s, lH, H-19), 9.12(s,1H, NH-22); m/z 642.3(M+ +Na); IR (CHCI3, cm-l) 1730,1690,1655, 1575;
5 Analysis cz~lo~'oted for C30H44N308S-H20; C, 57.67; H,7.41; N, 6.72%. Found: C, 57.44; H, 6.37; N, 6.72%.

17-~2'Methvlthio)ethylaminol-17-demethoxy~eldanamycin Geldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under 10 nitrogen and slurried in 5 mL chloroform. 2-(Methylthio)ethylamine (0.199 gm, 2.18 mmol,) was added and the reaction was stirred at room ter"peralure for 36 hours. The leaction mixture was diluted with 75 mL chloroform and washed with 2 x 50 mL lN
hydrochloric acid, 2 x 50 mL brine and 3 x 50 mL water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was 15 purified by flash column chromatography using 200 gm silica gel and eluting with 3%
acetoni~,ile in ethyl etherto afford pure purple product, 0.095gm (43%) mp 157C; 'H-NMR (300 MHz, CDCI3) ~ 1.09(d, J = 7 Hz, 3H, 14-CH3), 1.14 (d, J = 7 Hz, 3H, 10-CH3), 1.71-1.89 (br m, 3H, H-13, H-14), 1.89 (s, 3H, 8-CH3), 2.13 (s, 3H, 2-CH3), 2.22 (s, 3H, SCH3), 2.46 (dd, J = 7Hz, 13Hz, 1H, H-15), 2.79 (d, J = 13 Hz, lH, H-15), 2.72-20 2.92 (br m, 3H, 2'-CH2, H-10), 3.36 (s, 3H, OCH3), 3.46 (s, 3H, OCH3), 3.54 (m, 1H, H-12), 3.68 (t, J = 7 Hz, 1H, H-11), 3.72-3.86 (br m, 1H, 1'CH2), 3.86-3.95 (br m, 1H, 1'CH2), 4.41 (d, J = 7 Hz, 2H, H-6, 11-OH), 4.93(br m, 2H, NH2), 5.28 (s,1 H, H-7), 5.91-6.04 (br m, 2H, H-5, H-9), 6.62-6.74 (br m, 2H, H-4, NH), 7.03(d, J = 7 Hz, 1 H, H-3), 7.37 (s, lH, H-19), 9.22 (s, 1H, NH-22); m/z 642.3 (M+ + Na); IR (CHCI3, cm~l) 1735, 25 1685, 1650, 1570; Analysis calculated for C3tH45N308S-1.51120: C, 57.56; H, 7.48; N, 6.49%. Found: C, 57.30; H, 6.87; N, 6.21%.
E)CAMPLE 25 1 7-r(S)-2'-Azetidinecarboxvlicacidl-1 7-demethoxyqeldanamvcin Geldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under 30 nitrogen and slurried in 5 mL chloroform. (S)-2-Azetidine carboxylic acid (0.200 gm, 1.978 mmol) in 2 mL of pyridine, and triethylamine (0.200 gm, 1.978 mmol, 0.275 mL) were added. The reaction mixture was stirred at room temperature for 36 hours, refluxed for 4 hours, cooled to room temperature, diluted with 75 mL chloroform and WO 9~;/01342 PCT/IB94/00160 ~ 1663~ d washed with 2 x 50 mL 1 N hydrochloric acid. The organic layer was extracted with 3 - x 50 mL lN NaOH. The pooled basic phases were ~Qri~lifiecl to pH = 6 with lN
hydrochloric acid and extracted with 3 x 75 mL chloroform. The combined chloroform layers were dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was d;ssolv0d in a minimal amount of ethyl acetate and precipitated withhexane to afford pure purple product, 0.056gm (25%) mp 210C (dec); 'H-NMR
(C5D5N) ~1.29-1.47 (br m, 6H, 10-CH3, 14-CH3), 1 .9~2.22(br m, 3H, H-13, H-14), 2.09 (s, 3H, 8-CH3), 2.23 (s, 3H, 2-CH3), 2.49 (br m, 1 H, H-15), 2.81 (t, J = 7 Hz, 1 H, H-10), 2.9'3 (br m, 1 H, 4'azetidine-CH), 3.28(br m, 1 H, 4'azetidine-CH), 3.42 (s, 3H, OCH3), 3.50 (s, 3H, OCH3) 3.81 (m, 1H, H-12), 4.14 (m, lH, H-11), 4.34 (br m, 1H, 3'azetidine-CH), 4.89 (br m, lH, 3'azetidine-CH), 5.01 (d, J = 7 Hz, lH, H-6), 5.79 (m, lH, 2'azetidine-CH~, 5.91 (s, lH, H-7 ), 6.21 (t, J = 7 Hz, lH, H-5), 6.47 (d, J = 7 Hz, lH, H-9), 6.60 (t, J = 7 Hz, 1 H, H4), 7.41-7.54 (br m, 2H, H-3, H-19), 9.57 (s, 1 H, NH-22); m/z 652.3 (M~- + Na); IR (CHCI3, cm-l) 1730, 1695, 1645, 1585; Analysis c-lcl~QtPd for C321143N3O,o-3H20: C, 56.21; H, 7.22; N, 6.14%. Found: C, 56.16; H, 6.13; N, 6.04%.
The compounds of Examples 26-31 were prepared from geldanamycin and the approp~ e amines by the method of Example 1 above.

17 1 lislal"i,lo-17-demethoxyqeldanamvcin Mp 150C (decomp); 'H-NMR (300 MHz, CDCI3) ~ 0.98 (overlapping d, 6 H), 1.68 (m, 1 H), 1.77 (s, 3 H)~ 2.02 (s, 3 H), 2.43 (t, 1 H, J = 7 Hz), 2.6-2.8 (m, 2 H), 2.94 (t, 2H, J = 5 Hz), 3.23 (s, 3 H), 3.39 (s, 3 H), 3.40 (m, 1 H), 3.52 (m, 1 H~, 3.7-3.9 (m, 2 H~, 4.27 (d, 1 H, J = 9 Hz), 4.88 (br exchangeable, 2 H), 5.13 (s, 1 H), 5.85 (m, 2 H), 6.56(t, 1 H,J= 12Hz),6.75(m, 1 H),6.92(m,2H),7.19(s, 1 H),7.61 (s, 1 H),9.17 (s, I H); mass spectrum m/z 640 (M+); Analysis C~QIcl~lQtP~i for C35H45N508-0.5(ethyl acetate): C, 61.48; H, 7.22; N, 10.24%. Found: C, 61.06; H, 7.35; N, 10.32%.

1 7-Furfurylamino-1 7-demethoxv~ldanar"vcin Mp 122-130C (dec); 'H-NMR (300 MHz, CDCI3) ~1.09 (overlapping d, 6 H), 1.75(m,1 H),1.79(s,3H),1.98(s,3H),2.42(dd,1 H,J=7Hz,6Hz),2.72(m,2H), 3.28 (s, 3 H), 3.37 (s, 3 H), 3.48 (m, 1 H), 3.59 (m, 1 H), 4.18 (br exchang~-~le, 1 H), 4.29 (d, 1 H, J = 9 Hz), 4.67 (dd, 1 H, J = 9 Hz, 5 Hz), 4.73 (dd, 1 H, J = 9 Hz, 5 Hz), 4.88 (br exchangeable, 2 H), 5.18 (s, 1 H), 5.89 (m, 2 H), 6.28 (m, 1 H), 6.34 (m, 1 H), WO 95/0L342 PCT/IB94/00160 ~
2~GG3~

6.42 (m, 1 H), 6.57 (t, 1 H, J = 12 Hz), 6.94 (d, 1 H, J = 12 Hz), 7.28 (s, 1 H), 7.41 (s, H), 9.11 (s, 1 H); mass spectrum m/z 626 (M+); Analysis calGu'ated for C33H43N309-0.33CHCI3: C, 62.31; H, 6.90; N, 6.54%. Found: C, 62.28; H, 6.78; N, 6.63%~

17-Tetrahvdrofurfurylamino-17-demethoxygeldanamvcin Mp 157-166C (dec); lH-NMR (300 MHz, CDCI3) ~ 1.05 (overlapping d, 6 H),1.7 (m, 2 H), 1.87 (s, 3 H), 1.9-2.1 (m, 3 H), 2.06 (s, 3 H), 2.38 (m, 1 H), 2.70 (m, 2 H), 3.27 (s, 3 H), 3.34 (s, 3 H), 3.45 (m, 1 H), 3.53 (m, 2 H), 3.82 (m, 1 H), 3.93 (m, 1 H), 4.09 (m, 1 H), 4.27 (d, 1 H, J = 8 Hz), 4.88 (br exhangeable, 2 H), 5.18 (s, 1 H), 5.7-6.0 (m, 2 H), 6.56 (m, 2 H), 6.93 (d, 1 H, J = 11 Hz), 7.26 (s, 1 H), 9.17 (s, 1 H); mass spectrum m/z 632 (M+ + 2); Analysis coic~ ot~cl for C33H4,N309: C, 62.94; H, 7.52; N, 6.69%. Found: C, 62.92; H, 7.57; N, 6.39%.

17-Tetramethylguanidino-17-demethoxvqeldanamycin Mp 140-145C (dec); lH-NMR (300 MHz, CDCI3) ~ 1.0 (overlapping d, 6 H),1.70 (m,1 H),1.77(s,3H),2.02(s,3H),2.51 (m,2H),2.76(brs,6H),2.83(s,6H),3.26 (s, 3 H), 3.38 (s, 3 H), 3.42 (m, 1 H), 3.60 (m, 1 H), 4.28 (d, 1 H, J = 9 Hz), 5.15 (s, 1 H), 5.83 (t, 1 H, J = 7 Hz), 5.95 (m, 1 H), 6.57 (t, 1 H, J = 12 Hz), 6.97 (br d, 1 H, J =
12 Hz), 7.07 (s, 1 H), 9.36 (br s, 1 H); mass spectrum m/z 646 (M + 2); Analysisc-o'cu'otPd for C33H49N5O8-0.2CHCI3: C, 60.55; H, 7.56; N, 10.64%. Found: C, 60.57;
H, 7.67; N, 10.59%.

17-beta-Alanvl-17-demethoxyqeldanamycin Mp 143-147C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.99 (overlapping d, 6 H), 1.67 (m, 1 H), 1.79 (s, 3 H), 2.03 (s, 3 H), 2.32 (m, 1 H), 2.69 (m, 3 H), 3.22 (s, 3 H), 3.32(s,3H),3.42(m,1 H),3.55(m,1 H),3.82(m,2H),4.28(d,1 H,J=9),5.08(br s,2H),5.19(s,1 H),5.83(m,2H),6.58(m,2H),6.91 (d,1 H,J=12Hz),7.25(s,1 H), 9.09 (s, 1 H); mass spectrum m/z 640 (M + Na); Analysis co~c~ ~oted for C3lH43N3Olo-H2O: C, 58.66; H, 6.99; N, 6.62%. Found: C, 58.98; H, 7.03; N, 6.60%.

17-Homohistamino-17-demethoxy~eldanamycin Mp 128-136C (dec); lH-NMR (300 MHz, CDC13) ~0.87 (d, 3 H, J = 7 Hz), 0.98 ~ WO 95tO134~, PCT/IB94/00160 ~6~3~

(d,3H,J =7Hz), 1.7(m,3H), 1.76(s,3H), 1.98(s,3H),2.12(m,4H),2.5-2.7(m, 3 H)l 3.21 (s, 3 H), 3.32 (s, 3 H), 3.4-3.55 (m, 4 H), 4.05 (m, 2 H), 4.27 (d, 1 H, J = 9 Hz), 4.85 (br exchangeabie, 2 H), 5.13 (s, 1 H), 5.85 (m, 2 H), 6.22 (m, 1 H), 6.57 (t, 1 H, J = 11 Hz), 6.88 (m, 2 H), 7.08 (s, 1 H), 7.26 (s, 1 H), 7.53 (s, 1 H), 9.09 (s, 1 H);
5 mass spectrum m/z 654 (M + 1); Analysis calculated for C34H47N508-0.1CH2CI2: C, 61.84; H, 7.18; N, 10.57%. Found: C, 61.90; H, 7.49; N, 10.29%.
E)CAMPLE 32 1 7-Amino-22-(4'-fluoroPhenacvl)-l 7-demethoxvqeldanamycin 17-Amino-17-demethoxygeldanamycin (0.254 g, 0.465 mmol) was dissolved in 10 5 ml anhydrous dimethyl sulfoxide in flame dried ~lassware. Bolassium -butoxide (0.064 9, 0.468 mmol) was added and the solution stirred at room temperature under nitro~en for 30 minutes. p-Fluorophenacyl bromide (0.102 g, 0.479 mmol) was added and the solution stirred at room temperature for 1.5 hours. This solution was diluted with ~ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered 15 and ev~ ordled in vacuo. The resulting purple residue was flash chromatographed with silica gel eluted with 2% methanol in chloroform to give a purple solid; Yield 0.270 g (66%): mp 183-185C(dec); 1H NMR (300 MHz, CDCI3) ~ 0.61 (d, J = 7 Hz, 3H, 14-CH3), 0.78 (br m, 1 H, H-13), 0.93 (d, J = 7 Hz, 3H, 10-CH3), 1.30 (s, 3H, 8-CH3), 1.49 (br m, lH, H-13), 1.82 (dd, J = 15 Hz and 4 Hz, lH, H-15), 1.92 (s, 3H, 2-CH3), 2.02 20 (brsl lH, 11-OH), 2.20 (br m, 2H, H-10 and H-14), 2.77 (dd, J = 15 Hz and 4 Hz, lH, H-15), 2.84 (br d, J = 10 Hz, lH, H-12), 3.23 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.54 (d, J = 9 Hz, lH, H-11), 4.19 (t, J = 9 Hz, lH, H-6), 4.41 (d, J = 16 Hz, lH, a-CH2), 4.95(d,J=9Hz,lH,H-7),4.97(s,2H,NH2),5.12(d,J=8Hz,lH,H-9),5.20(t,J=
9 Hzr lH, H-5), 5.40 (br s, 2H, NH2), 5.84 (s, lH, H-19), 5.96 (d, J = 17 Hz, lH, ~-CH2), 25 6.35 (t, J = 10 Hz, lH, H-4), 7.03 (d, J = 13 Hz, lH, H-3), 7.12 (m, 2H, aromatic), 7.99 (m, 2H, aromatic); m/z 704 (M+ + Na); IR (KBr, cm-1) 1722, 1691, 1675, 1659, 1580, 1504; Anal. for C36H"4N3O9F: C, 63.42; H, 6.51; N, 6.16%. Found C, 63.40; H, 6.65; N, 5.84%.
The compounds of Examples 33 to 45 were prepared by the method of Example 30 32 from the appropriately substituted phenacyl bromides.

1 7-Amino-22-(2'.4'-dimethvlPhenacvl~-1 7-demethoxyqeldanamvcin The residue obtained upon evaporation of the ethyl acetate was purified by Chromatotron (trademark) using 2% methanol in chloroform and again with 1%
methanol in chloroform to give fractions containing esser,lially pure product which were ev~porc~ed in vacuo to yield a red solid which was further purified by preparative HPLC
using aZorbax (trademark) column eluted with 54:1:45 ethyl acetate:methanol:hexanes.
Fractions containing pure material were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; Yield 0.002 gm, (0.6%) mp 154C (dec); 'H-NMR (300 MHz, CDCI3) 0.55(d, J = 6 Hz, 3H, 14-CH3), 0.89 (d, J = 6 Hz, 3H, 10-CH3), 2.76 (m, 2H, H-10, H-15), 3.04-3.19 (m, lH, H-12), 3.11 (s, 3H, OCH3), 3.17 (s, 3H, OCH3), 3.47 (m, 1H, H-11), 4.12(t, J = 7 Hz, 1H, H-6), 4.21 (d, J = 15 Hz, 1H, o-CH), 4.43(brs, 2H, NH2), 4.83 (d, J = 7 Hz, 1H, H-7), 4.89-5,07 (m, 2H, NH2), 5.04(d, J = 7 Hz, lH, H-9), 5.10(t, J =
7 Hz, 1H, H-5), 5.71 (d, J = 15 Hz, lH, o-CH), 5.80(s, lH, H-19),6.22(t, J = 7 Hz, lH, H-4), 6.81-7.03(m, 3H, H-3, Aromatic), 7.5 (d, J = 7 Hz, lH, Aromatic). m/z 714 (M+
+ Na); IR (KBr, cm 1) 1720, 1670, 1655, 1580; Analysis c~Icu'qted for C38H49N3Og-0.5H2O:C, 65.12; H, 7.19; N, 6.07%. Found C, 55.38; H, 6.89; N, 5.99%.

1 7-Amino-22-(2'-methoxyPhenacyl)-1 7-demethoxyqeldanamycin Yield 0.110 9 (34%): mp 165-168C; 'H NMR (300 MHz, CDCI3) ~ 0.72 (d, J =
7 Hz, 3H, 14-CH3), 0.84 (m, lH, H-13), 1.03 (d, J = 7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.49 (m, 1 H, H-13), 1.90 (dd, J = 12 Hz and 4 Hz, 1 H, H-15), 2.03 (s, 3H, 2-CH3), 2.24 (br m, 2H, H-10 and H-14), 2.41 (s, 1 H, 1 1-OH), 2.94 (m, 2H, H-12 and H-15), 3.30 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.62 (d, J = 8 Hz, lH, H-11), 3.97 (s, 3H, OCH3), 4.28 (t, J = 10 Hz, lH, H-6), 4.51 (d, J = 19 Hz, lH, o-CH2), 4.60 (br s, 2H, NH2), 5.02 (d, J = 10 Hz, lH, H-7), 5.10 (br s, 2H, NH2), 5.20 (d, J = 9 Hz, lH, H-9), 5.27 (t, J =
12 Hz, lH, H-5), 5.86 (d, J = 17 Hz, lH, o-CH2), 5.98 (s, lH, H-19), 6.40 (t, J = 13 Hz, lH, H-4), 7.03 (m, 2H, aromatic), 7.14(d, J = 12 Hz, lH, H-3), 7.56 (m, lH, aromatic), 7.90 (m, lH, aromatic); m/z 694 (M+); IR (KBr, cm~') 1732, 1678, 1661, 1584.

1 7-Amino-22-t3'-methoxyPhenacvl)-1 7-demethoxygeldanamvcin The residue obtained upon evaporation of the ethyl acetate was dissolved in 1 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 0.151 g (48%): mp 165-168C; 'H NMR (300 MHz, CDCI3) ~0.67 (d, J = 9 Hz, 3H, 14-CH3), 0.78 (m, 1 H, H-13), 0.98 (d, J = 9 Hz, 3H, 10-CH3), 1.32 (s, 3H, 8-CH3), 1.43 (m, WO 95/0134:~ PCT/IB94100160 2~63~0 1H, H-13), 1.83 (dd, J = 15 Hz and 5 Hz, lH, H-15), 1.92 (s, 3H, 2-CH3), 2.10-2.27 (br m, 2H, H-10 and H-14), 2.42 (s,1 H,11-OH), 2.82-2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.58 (d, J = 11 Hz,1 H, H-11), 3.81 (s, 3H, OCH3), 4.22 (t, J = 10 Hz, 1 H, H-6), 4.40 (d, J = 18 Hz, 1 H, a-CH2), 4.68 (br s, 2H, NH2), 4.99 (d, 5 J = 9 Hz, 1H, H-7), 5.15 (brs, 2H, NH2), 5.16 (d, J = 11 Hz, 1H, H-9), 5.21 (t, J = 11 Hz, IH, H-5), 5.90 ~s,1H, H-19), 5.97 (d, J = 17 Hz,1H, a-CH2), 6.35 (t, J = 12 Hz,1H, H4), 7.02 (d, J = 11 Hz, 1H, H-3), 7.12 (dd, J = 8 Hz and 5 Hz, 1H, aro",alic), 7.38 (t, J = 10 Hz, 1H, aromatic), 7.42 (d, J = 6 Hz, 1H, aromatic), 7.49 (dd, J = 8 Hz and 5 Hz, 1H, aromatic); m/z 716 (M+ + Na); IR (CH2CI2, cm-1) 1733, 1672, 1661, 1585.

17-Amino-22-(4'-methoxYphenacyl)-17-demethoxygeldanamycin The residue obtained upon evaporation of the ethyl acetate was dissolved in 1 mL chloroform and precipitated with hexanes to yield a salmon-colored solid; Yield 0.205 g (64%): mp 175-178C; lH NMR (300 MHz, CDCI3) ~ 0.65 (d, J = 9 Hz, 3H, 14-CH3,~, 0.76 (m, 1 H, H-13), 0.98 (d, J = 8 Hz, 3H,10-CH3),1.32 (s, 3H, 8-CH3),1.43 (m, 1H,1~-13), 1.82 (dd, J = 15 Hz and 5 Hz, 1H, H-15), 1.92 (s, 3H, 2-CH3), 2.10-2.28 (br m, 2H, H-10 and H-14), 2.40 (s,1 H,11-OH), 2.81-2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OCH3),3.28 (s, 3H, OCH3),3.57 (d, J = 13 Hz,1 H, H-11), 3.83 (s, 3H, -OCH3), 4.21 (t, J = 11 Hz, 1H, H-6), 4.36 (d, J = 17 Hz, 1H, o-CH2), 4.67 (br s, 2H, NH2), 4.98 (d, J = 10 Hz,1H, H-7), 5.11 (br s, 2H, NH2), 5.13 (d, J = 12 Hz, 1H, H-9), 5.21 (t, J = 12 Hz 1H, H-5), 5.89 (s,1H, H-19), 5.94 (d, J = 18 Hz,1H, a-CH2), 6.33 (t, J = 13 Hz,1H, H4), 6.91 (m, 2H, alo",hlic), 7.08 (d, J = 13 Hz,1H, H-3), 7.89 (m, 2H, aromatic); m/z 691 ~(M~) and 713 (M+ + Na); IR (CH2CI2, cm-l) 1732, 1673, 1661, 1586, 1507.

17-Amino-22-(2'-chlorophenacyl)-17-demethoxygeldanamycin The residue obtained upon evaporation of the ethyl Acet~te was purified by preparative centrifugally accelerated radial thin-layer chromatography (Chro",atol,onR) using a gradient of 24% methanol in chloroform to give fractions containing pureproduct which were evaporated in vacuo to afford a red solid; Yield 0.138 g (43%): lH
NM~ (300 MHz, CDCI3) ~ 0.72 (d, J = 7 Hz, 3H,14-CH3), 0.83 (m, 1H, H-13), 1.03 (d, J = 6 Hz, 3H,10-CH3),1.40 (s, 3H, 8-CH3),1.49 (br m,1H, H-13), 1.91 (dd, J = 13 Hz and 6 Hz,1 H, H-15),1.99 (s, 3H, 2-CH3), 2.18-2.31 (br m, 2H, H-10 and H-14), 2.43 (s, 1 H,11-OH), 2.38-2.46 (m, 2H, H-12 and H-15), 3.25 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), WO 95/01342 , PCT/IB94/00160 6~

3.63 (d, J = 8 Hz, 1H, H-11), 4.22 (t, J = 10 Hz, 1H, H-6), 4.49 (d, J = 19 Hz, 1H, o-CH2), 4.62 (br s, 2H, NH2), 5.02 (d, J = 9 Hz, 1 H, H-7), 5.19 (s, 2H, NH2), 5.21 (d, J =
12 Hz, 1H, H-9), 5.30 (t, J = 11 Hz, 1H, H-5), 5.40 (brs, 2H, NH2), 5.83 (d, J = 18 Hz, lH,a-CH2),6.15(s,1H,H-19),6.39(t,J=12Hz,lH,H4),6.96(d,J=12Hz,lH,H-5 3), 7.38-7.43 (m,1 H, aromatic), 7.48 (m, 2H, aromatic), 7.67 (m,1 H, aromatic); m/z 720 (M+ + Na); IR (KBr, cm-l) 1722, 1680, 1661, 1590; Analysis cr'~ tPd for.
C3~H44CIN309: C, 61.93; H, 6.35; N, 6.02%. Found C, 60.59; H, 6.18; N, 5.54%.

17-Amino-22-(4'-chlorophenacyl)-17-demethoxyqeldanamycin The residue obtained upon evaporation of the ethyl acetate was dissolved in 2 mL chloroform and precipit~t~d with hexanes to give a salmon-colored solid; Yield 0.087 9 (27%): mp 175-178C; lH NMR (300 MHz, CDCI3) ~ 0.66 (d, J = 7 Hz, 3H, 14-CH3), 0.76 (m, 1H, H-13), 0.98 (d, J = 6 Hz, 3H, 10-CH3), 1.33 (s, 3H, 8-CH3), 1.43 (m, lH, H-13), 1.83 (dd, J = 15 Hz and 4 Hz, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.10-2.27 (br 15 m, 2H, H-10 and H-14), 2.41 (s, 1 H, 11 -OH), 2.81 -2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.58 (d, J = 11 Hz, 1 H, H-11), 3.81 (s, 3H, OCH3), 4.21 (t, J = 10 Hz, 1H, H-6), 4.36 (d, J = 17 Hz, 1H, a-CH2), 4.54 (br s, 2H, NH2), 4.99 (d, J=10Hz,1H,H-7),5.13(brs,2H,NH2),5.15(d,J=10Hz,lH,H-9),5.22(t,J=12 Hz 1H, H-5), 5.89 (s, 1H, H-19), 5.97 (d, J = 17 Hz, 1H, a-CH2), 6.34 (t, J = 12 Hz, 1H, 20 H4),7.01 (d,J= 12Hz,1H,H-3),7.43(d,J=9Hz,2H,aromatic),7.87(d,J=9Hz, 2H, aromatic); m/z 720 (M+ + Na); IR (CH2CI2, cm-l) 1733, 1677, 1662, 1584.

1 7-Amino-22-Phenacvl-1 7-demethoxyqeldanamvcin The residue obtained upon evaporation of the ethyl acetate was purified by 25 Chrol"al~,l,on (trademark) using 2% methanol in chloroformto givefractions containing pure product which were evaporated in vacuo to yield a red solid, 0.161 gm (53%) mp 188-91 C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.68 (d, J = 5 Hz, 3H, 14-CH3), 0.80 (m, 1H, H-13), 0.98 (d, J = 5 Hz, 3H, 10-CH3), 1.35 (s, 3H, 8-CH3), 1.43 (m,1H, H-13), 1.85 (dd, J = 3 Hz, J = 10 Hz, 1H, H-15), 1.96 (s, 3H, 2-CH3), 2.11-2.29 (br m, 2H, H-10, H-30 14), 2.39 (s, 1H, 11-OH), 2.85 (m, 2H, H-12, H-15), 3.21(s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.60 (dd, J = 3 Hz, J = 7 Hz, 1H, H-11), 4.21 (t, J = 9 Hz, 1H, H-6), 4.39 (d, J = 15 Hz, 1H, a-CH), 4.61 (br s, 2H, NH2), 5.03-5.19 (m, 2H, NH2), 5.16 (d, J = 8 Hz, 1H, H-9), 5.71 (t, J = 8 Hz, 1H, H-5), 5.89 (s, 1H, H-19), 6.00 (d, J = 15 Hz, 1H, a-CH), WO 95/01342 ~16 6 3 ~ O PCT/IB94/00160 6.36 (t, J = 8 Hz, 1H, H4), 7.05 (d, J = 8 Hz, lH, H-3), 7.46 (t, J = 6 Hz, 2H, - LroI"alic), 7.60 (t, J = 6 Hz, 1H, aromatic), 7.93 (d, J = 6 Hz, 2H, aromatic); m/z 686 (M~ + Na), 664 (M+ ~H); IR (KBr, cm-l) 1720, 1670, 1655, 1580; Analysis c~Ic~IAted for C3~H45N3O0-0.5H2O: C, 64.27; H, 6.89; N, 6.27%. Found C, 64.13; H, 6.33; N, 5 6.19%.

1 7-Amino-22-(3'.4'-dichloroPhenacvl)-1 7-demethoxvqeldanamycin The residue obtained upon evaporation of the ethyl ~cetAtP was further purified by preparative HP~C using a Zorbax column eluted with 59:1:40 ethyl Acet~te methanol:hexanes. The fractions containing pure material were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; Yield 0.134 g (40%): mp 176-178C; lH NMR (300 MHz, CDCI3) ô 0.63 (d, J = 7 Hz, 3H,14-CH3), 0.74 (m,1 H, H-13), 0.98 (d, J = 8 Hz, 3H, 10-CH3~,1.31 (s, 3H, 8-CH3),1.42 (m,1 H, H-13), 1.82 (dd, J = 15 Hz and 5 Hz,1 H, H-15), 1.92 (s, 3H, 2-CH3),2.09-2.24 (br m,2H, H-10 and H-14),2.42 (s,1 H,11 -OH),2.78-2.88 (m, 2H, H-12 and H-15), 3.21 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.57 (d, J = 10 Hz, lH, H-11), 4.18 (t, J = 11 Hz, lH, H-6), 4.36 (d, J = 19 Hz, lH, o-CH2), 4.69 (brs, 2H, NHz),4.98 (d, J = 11 Hz, lH, H-7), 5.12 (d, J = 11 Hz, lH, H-9), 5.16 (brs, 2H, NH2), 5.21 (t, J = 11 Hz, lH, H-5), 5.85 (s, lH, H-19), 5.92 (d, J = 18 Hz, lH, a-CH2), 6.34 (t, J = 12 Hz, lH, H-4), 6.98 (d, J = 12 Hz, lH, H-3), 7.57 (d, J = 9 Hz, 1H, aromatic), 7.76 (dd, J = 9 Hz and 4 Hz, 1 H, aromatic), 8.01 (d, J = 4 Hz, 1 H, aromatic); m/z 732 (M+); IR (CH2CI2, cm~l) 1731, 1704, 1673, 1661, 1583.

1 7-Amino-22-(4'-aminoPhenacyl)-l 7-demethoxyqeidanamycin From 4-aminophenacyl chloride: the product was a pink solid. Yield 0.066 g (21%): mp 188C (dec); lH-NMR (300 MHz, CDC13) ~ 0.71 (d, J = 8 Hz, 3H, 14-CH3),0.86 (br m, 1 H, H-13), 1.04 (d, J = 8 Hz, 3H, 10-CH3), 1.39 (s, 3H, 8-CH3), 1.49 (br m, lH, H-13), 1.90 (dd, J = 13 Hz, 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.22 (br m, 2H, H-10 H-14),2.48 (br s,1 H, -OH), 2.92 (m, 2H, H-12 and H-15),3.29 (s,3H, OCH3),3.33 (s, 3~-i, OCH3), 3.62 (d, J = 10 Hz, lH, H-11), 4.28 (s, 2H, NH2), 4.29 (t, J = 9 Hz, lH, H-6), 4.37 (d, J = 18 Hz, 1 H, a-CH2), 4.75 (br s, 2H, NH2), 5.03 (d, J = 9 Hz,1 H, H-7), 5.18 I(br s, 2H, NH2), 5.21 (d, J = 9 Hz, lH, H-9), 5.26 (t, J = 13 Hz, lH, H-5), 5.95 (d, J = 18 Hz, 1H, a-CH~), 5.96 ts, lH, H-19), 6.49 (t, J = 10 Hz, lH, H-4), 6.66 (d, J= 9 _ WO 95/01342 2 ~ ~ ~ 3 2 ~ PCT/lB94/00160 Hz, 2H, aromatic), 7.18 (d, J=13 Hz, lH, H-3), 7.78 (d, J = 9 Hz, 2H, aromatic); m/z 701 (M+ + Na); IR (KBr, cm-l) 1718, 1708, 1655, 1619, 1580.

1 7-Amino-22-(4'-cvanoPhenacYI)-1 7-demethoxyqeldanamvcin The residue obtained upon evaporation of the ethyl acetate was further purified by pr~ arali~/e HPLC using a Zorbax column eluted with a mixture comprising 59:1:40 ethyl ~cetP~te:methanoI:hexanes. Fractions containing pure material were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; yield 0.0296 g (8.4%): mp 186C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.71 (d, J = 6 Hz, 3H, 14-CH3), 0.83 (br m, 1 H, H-13), 1.04 (d, J = 6 Hz, 3H, 10-CH3), 1.39 (s, 3H, 8-CH3), 1.48 (m, lH, H-13), 1.90 (dd, J = 11 Hz and 5 Hz, lH, H-15), 1.99 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.41 (s, lH, -OH), 2.92 (m, 2H, H-12 and H-15), 3.27 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.64 (d, J
= 11 Hz, lH, H-ll), 4.23 (t, J = 10 Hz, lH, H-6), 4.45 (d, J = 18 Hz, lH, a-CH2), 4.61 (brs, 2H, NH2), 5.05 (d, J = 10 Hz, lH, H-7), 5.20 (brs, 2H, NH2), 5.21 (d, J = 11 Hz, lH, H9), 5.29 (t, J = 11 Hz, lH, H-5), 5.96 (s, lH, H-l9), 6.02 (d, J = 18 Hz, lH, a-CH2), 6.40 (t, J = 11 Hz, lH, H-4), 7.00 (d, J = 11 Hz, lH, H-3), 7.84 (d, J = 8 Hz, 2H, aromatic), 8.08 (d, J = 8 Hz, 2H, aromatic); m/z 712 (M+ + Na); IR (KBr, cm-l) 2220, 1721, 1701, 1672, 1655, 1580; Analysis c~Ic~ tPd for C3~H44N4Oll: C, 64.52; H, 6.44;
N, 8.13%. Found C, 58.56; H, 5.81; N, 7.33%.

1 7-Amino-22-t2'-nitrophenacYi)-l 7-demethoxvqeldal ,~mycin Yield 0.0689 g (21%): mp 165C (dec); lH NMR (300 MHz, CDCI3) ~ 0.70 (d, J
= 7 Hz, 3H, 14-CH3), 0.82 (m, lH, H-13), 1.03 (d, J = 7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.52 (m, lH, H-13), 1.90 (dd, J = 14 Hz and 4 Hz, lH, H-15), 2.00 (s, 3H, 2-CH3), 2.08 (s, lH, ll-OH), 2.26 (br m, 2H, H-10 and H-14), 2.90 (m, 2H, H-12 and H-15), 3.19 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.64 (d, J = 10 Hz, lH, H-ll), 4.15 (t, J
= 10 Hz, lH, H-6), 4.42 (d, J = 18 Hz, lH, a-CH2), 5.01 (d, J = 10 Hz, lH, H-7), 5.10 (br s, 2H, NH2), 5.20 (d, J = 9 Hz, lH, H-9), 5.23 (br s, 2H, NH2), 5.26 (t, J = 13 Hz, lH, H-5), 5.63 (d, J = 18 Hz, lH, a-CH2), 6.38 (t, J = 12 Hz, lH, H-7), 6.52 (s, lH, H-19), 6.87 (d, J = 12 Hz, 1 H, H-3), 7.63 (m, 1 H, aromatic), 7.69 (m, 1 H, aromatic), 7.80 (m, lH, aromatic), 8.20 (m, lH, aromatic); m/z 731 (M+ + Na); IR (KBr, cm~l) 1718, 1671, 1657, 1580, 1521; Analysis c~IcuI~ted for (C36H44N4Oll): C, 61.00; H, 6.26; N, ~1~632~

7.91%. Found C, 59.92; H, 6.10; N, 7.71%.

17-Amino-22-(3'-nitroPhenacvI)-17-demethoxv~eIdanamycin Yield 0.0225 g (6.9%):; 1H-NMR (300 MHz, CDCI3) ~ 0.71 (d, J = 8 Hz, 3H, 14-5 CH3), 0.88 (m, lH, H-13),1.04 (d, J = 8 Hz, 3H,10-CH3),1.34 (s, 3H, 8-CH3), 1.42 (m, 1H, H-13), 1.90 (dd, J = 13 Hz and 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.42 (br s, 1H, -OH), 2.93 (m, 2H, H-12 and H-15), 3.29 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.64 (d, J = 10 Hz, 1H, H-11), 4.23 (t, J = 9 Hz, 1H, H-6), 4.52 (d, J = 18 Hz, 1 H, o-CH2), 4.62 (br s, 2H, NH2), 5.06 (d, J = 9 Hz, 1 H, H-7), 5.15 10 (br s, 2H, NH2), 5.21 (d, J = 9 Hz, lH, H-9), 5.30 (t, J = 13 Hz, lH, H-5), 5.98 (s, 1H, H-19), 6.06 (d, J = 18 Hz, 1H, a-CH2), 6.41 (t, J = 9 Hz, lH, H-4), 7.00 (d, J = 13 Hz, 1H, H-3), 7.76 (t, J = 8 Hz, 1H, aromatic), 8.32 (d, J = 8 Hz, lH, aromatic), 8.52 (d, J
= 8 Hz,1 H, aromatic), 8.83 (s,1 H, aromatic); m/z 731 (M+ + Na); IR (KBr, cm-l) 1719, 1664, 1652, 1580, 1521.

1 7-Amino-22-(4'-nitroPhenacvl)-1 7-demethoxyqeldanamycin The residue obtained upon evaporation of the ethyl aceta~e was further purified by preparative HPLC using a Zorbax column eluted with 59: 1 :40 ethyl ~cet~te:methanoI:
hexanes. Fractions co"L"i"g pure material were evaporated in vacuo then dissolved 20 in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; Yield 0.0175 g (1.3%): mp; lH NMR (300 MHz, CDCI3) ~ 0.70 (d, J = 7Hz, 3H, 14-CH3), 0.82 (m, 1H, H-13), 1.02 (d, J = 7 Hz, 3H, 10-CH3), 1.38 (s, 3H, 8-CH3),1.50 (m,1 H, H-13),1.90 (dd, J = 16 Hz and 4 Hz,1 H, H-15), 2.00 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.50 (br s, 1 H, 11-OH), 2.89 (m, 2H, H-12 and H-15), 25 3.27 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.63 (d, J = 10 Hz, 1 H, H-11), 4.23 (t, J = 10 Hz, lH, H-6),4.50 (d, J = 18 Hz, lH, a-CH2), 4.77 (s, 2H, NH2), 5.03 (d, J = 10 Hz, lH, H-7), 5.20 (d, J = 11 Hz, lH, H-9), 5.25 (br s, 2H, NH2), 5.28 (t, J = 11 Hz, lH, H-5), 5.96 (s, lH, H-19), 6.03 (d, J = 18 Hz, lH, a-CH2), 6.40 (t, J = 12 Hz, lH, H-4), 6.99 (d, J = 12 Hz, lH, H-3), 8.15 (d, J = 9 Hz, 2H, aru",alic)~ 8.37 (d, J = 9 Hz, lH, 30 aromatic); m/z 731 (M+ + Na); IR (KBr, cm~l) 1660, 1590.

17-Amino-22-(4'-azidoPhenacyI)-17-demethoxygeldanamycin 17-Amino-17-demethoxygeldanamycin (0.500 g,0.92 mmol) was dissolved in 25 mL of acetone (stored over potassium carbonate) and 1.27 g potassium carbonate was added (9.17 mmol, 10 eq). The reaction was stirred in the dark for 24 hours, filtered, concer,l-aled in vacuo to a residue which was flash chromatographed through silica gel using 69:1:30 ethyl acetate:methanol:hexanes. The product was dissolved in 1 mL
5 chlorofor"l and precipit~ted with hexanes to give a rose-colored solid; Yield 0.095 g (15%): mp 165-167C; 1H-NMR (300 MHz, CDCI3) ~ 0.65 (d, J = 8 Hz, 3H, 14-CH3), 0.76 (m, lH, H-13), 0.97 (d, J = 8 Hz, 3H, 10-CH3), 1.32 (s, 3H, 8-CH3), 1.42 (m, lH, H-13), 1.82 (dd, J = 15 Hz and 5 Hz, lH, H-15), 1.91 (s, 3H, 2-CH3), 2.09-2.27 (br m, 2H, H-10 and H-14), 2.41 (br s, 1 H, 11 -OH), 2.79-2.90 (m, 2H, H-12 and H-15), 3.21 (s, 10 3H, OCH3), 3.27 (s, 3H, OCH3), 3.58 (d, J = 11 Hz, 1H, H-11), 4.20 (t, J = 10 Hz, 1H, H-6), 4.36 (d, J = 17 Hz, 1H, a-CH2), 4.65 (brs, 2H, NH2), 4.98 (d, J = 10 Hz, 1H, H-7), 5.11 (br s, 2H, NH2), 5.14 (d, J = 10 Hz, 1 H, H-9), 5.20 (t, J = 12 Hz, 1 H, H-5), 5.89 (s, lH, H-19), 5.95 (d, J = 17 Hz, 1H, a-CH), 6.33 (t, J = 13 Hz, 1H, H~), 7.02 (d, J = 13 Hz, 1 H, H-3), 7.08 (d, J = 9 Hz, 2H, aromatic), 7.91 (d, J = 9 Hz, 2H, aromatic); m/z 15 705 (M+ + H); Analysis calculated for C3~H44N~303-0.2H20: C, 58.37; H, 6.53; N, 11.34%; Found C, 58.37:, H, 5.85;N, 11.08%.

17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxvqeldanamycin Potassium chloride (0.022 g, 0.29 mmol) was dissolved in 1 mL water and 20 poured into iodine monochloride (0.043 g, .27 mmol). This mixture was poured into a solution of the title compound of Example 41 (0.139 g, 0.2 mmol) in 24 mL 0.1N
hydrochloric acid and 3 mL methanol. After stirring for 2 hours at room temperature the reaction was quenched with sodium bisulfite. The reaction mixture was extracted with ethyl ~cet~te The organic layer was washed with 3N hydrochloric acid, saturated 25 sodium bicarbonate, water and brine, dried over magnesium sulfate and filtered. The residue obtained upon removal of the solvent was dissolved in 1 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 0.099 g (60%): 'H NMR
(300 MHz, CDCI3) ~ 0.66 (d, J = 7 Hz, 3H, 14-CH3), 0.75 (m, lH, H-13), 0.98 (d, J =
6 Hz, 3H, 10-CH3), 1.34 (s, 3H, 8-CH3), 1.47 (m, lH, H-13), 1.91 (m, lH, H-15), 1.95 (s, 30 3H, 2-CH3), 2.10-2.29 (br m, 2H, H-10 and H-14), 2.59 (s,1 H,11 -OH), 2.78-2.92 (m, 2H, H-12 and H-15), 3.25 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.59 (d, J = 10 Hz, lH, H-11), 4.24 (t, J = 10 Hz, lH, H-6), 4.32 (d, J = 18 Hz, lH, a-CH2), 4.56 (s, 2H, NH2), 4.95 (d, J=10Hz,1H,H-7),5.04(brs,2H,NH2),5.15(d,J=11 Hz,1H,H-9),5.22(t,J=11 WO 95/OL34~, , PCT/IB94/00160 ~1663~

Hz, lH, H-5), 5.58 (br s, 2H, NH2), 5.88 (d, J = 18 Hz, lH, a-CH2), 5.89 (s, lH, H-19), - 6.37 (t, J = 12 Hz, lH, H-4), 6.60 (dd, J = 9 Hz and 3 Hz, lH, aromatic), 7.06 (d, J =
12 Hz, lH, H-3), 7.71 (dd, J = 9 Hz and 2 Hz, lH, aromatic), 8.22 (dd, J = 2 Hz and 3 Hz, lH, alolllalic) IR (KBr, cm~') 1715, 1660, 1610, 1580.
The acid washes were neutralized with sodium bicarbonate and extracted with ethyl ~cet~tP. The ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate, filtered and stripped to recover the title compound of Example 41, Yield 0.045 g (27%).

17-Amino-22-(4'-azido-3'-iodophenacyl)-17-demethoxvqeldanamycin 17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycin, from Example 47, (0.036 g,0.44 mmol) was dissolved in 89 mL methanol, cooled to 0 C and shielded from light. To this solution was added 45 mL 1 N hydrochloric acid and 45 mL
0.5N sodium nitrite. After 15 minutes of stirring, an additional 45 mL 0.5N sodium azide was added and the reaction mixture stirred another 15 minutes at 0C. The resulting solution was ~xllacted with ethyl acetate. The ethyl acetate e,.l.acts were washed with water and brine, dried over magnesium sulfate, filtered and stripped to give a red glass which was dissolved in 1 mL ethyl acetate and precipitated with hexanes. Yield 0.027 g p:2%): lH NMR (300 MHz, CDCI3) ~ 0.69 (d, J = 7 Hz, 3H, 14-CH3), 0.79 (m, lH, H-13), 1.03 (d, J = 8 Hz, 3H, 10-CH3), 1.50 (s, 3H, 8-CH3), 1.89 (m, 2H, H-13 and H-15), 1.99 (s, 3H, 2-CHJ, 2.11-2.32 (br m, 2H, H-10 and H-14), 2.53 (br s, 1 H,11-OH), 2.81-2.95 (m, 2H, H-12 and H-15), 3.28 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.62 (d, J = 9 Hz, lH, H-11), 4.22 (t, J = 12 Hz, lH, H-6), 4.41 (d, J = 17 Hz, lH, o-CH2), 4.80 (br s, 2H, NH2~, 5.02 (d, J = 9 Hz,1 H, H-7), 5.16-5.31 (br m, 4H, NH2, H-9, and H-5), 5.92 (s,1 H, H-1g), 5.99 (d, J = 18 Hz, lH, a-CH2), 6.40 (t, J = 14 Hz, lH, H-4), 7.03 (d, J = 14 Hz, lH, H-3), 7.12 (m, lH, aromatic), 8.00 (m, 2H, aromatic), 8.40 (m, lH, aromatic); IR
(KBr, cm-') 1722, 1680, 1661, 1580.
The compounds of Examples 49 and 50 were prepared according to the method of Exarnple 32.

17-Arnino-22-(4'-phenyIphenacyI)-17-demethoxy~eldanar"vcin Yield 0.119 g (35%): mp 193-195C (dec); 1H NMR (300 MHz, CDCI3) ~ 0.72 (d, J = 7 Hz, 3H,14-CH3), 0.83 (m, lH, H-13),1.04 (d, J = 7 Hz, 3H,10-CH3),1.40 (s, 3H, WO95/01342 ~ 3~ ~ PCT/~94/00160 -8-CH3), 1.49 (m, 1H, H-13), 1.90 (dd, J= 16 Hz and 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.47 (s, 1H, 11-OH), 2.91 (m, 2H, H-12 and H-15), 3.31 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.64 (d, J=10 Hz, 1H, H-11), 4.29 (t, J
= 10 Hz, 1H, H-6), 4.49 (d, J= 18 Hz, 1H, o-CH2), 4.72 (br s, 2H, NH2), 5.04 (d, J=
5 10 Hz, 1H, H-7), 5.17 (brs, 2H, NH2), 5.21 (d, J=11 Hz, 1H, H-9), 5.28 (t, J=11 Hz, 1H, H-5), 5.99 (s, lH, H-19), 6.09 (d, J = 18 Hz, 1H, a-CH2), 6.41 (t, J = 12 Hz, 1H, H-4), 7.13 (d, J = 12 Hz, 1H, H-3), 7.47 (m, 3H, aromatic), 7.12 (m, 3H, aromatic), 7.74 (d, J= 8 Hz, 2H, aromatic), 8.05 (d, J= 8 Hz, 2H, aromatic); m/z 731 (M++Na+).

1 7-Amino-22-(2-acetonaphthvl)-1 7-demethoxvqeldanamycin The crude title compound, prepared from 2-(2'-bromoacetyl)naphthalene was dissolved in 1 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 0.163 g (50%): mp 185-187C; tH NMR (300 MHz, CDCI3) ~ 0.71 (d, J=
8 Hz, 3H, 14-CH3), 0.82 (m, 1H, H-13), 1.02 (d, J= 7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.49 (m, 1 H, H-13), 1.89 (dd, J= 15 Hz and 5 Hz, 1 H, H-15), 2.00 (s, 3H, 2-CH3), 2.22 (br m, 2H, H-10 and H-14), 2.44 (s, 1 H, 11-OH), 2.91 (m, 2H, H-12 and H-15), 3.30 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.51 (d, J=11 Hz, 1H, H-11), 4.30 (t, J=11 Hz, 1H, H-6), 4.59 (d, J= 19 Hz, 1H, a-CH2), 4.68 (brs, 2H, NH2), 5.02 (d, J=10 Hz, 1H, H-7), 5.15 (br s, 2H, NH2), 5.20 (d, J= 13 Hz, 1H, H-9), 5.28 (t, J = 13 Hz, 1H, H-5), 6.00 (s, 1H, H-19), 6.20 (d, J= 17 Hz, 1H, a-CH2), 6.40 (t, J= 12 Hz, 1H, H-4), 7.13 (d, J= 13 Hz, 1H, H-3), 7.54-7.68 (m, 2H, aromatic), 7.87-8.02 (m, 2H, aromatic), 8.51 .
(s, 1H, aromatic); m/z 714 (M+) and 736 (M+ + Na); IR (CH2CI2, cm~1) 1733, 1677,1662, 1585.

1 7-Azetidin-1 -v1-1 1 -a-fluoro-1 7-demethoxvqeldanar"ycin 1 7-Azetidin-1 -yl-1 7-demethoxygeldanamycin, the title compound of Example 18, (0.200 9, 0.342 mmol) was added to a flame dried flask under nitrogen and dissolved in 15 mL of methylene chloride. The mixture was cooled to -68C with an exLer"al dry ice/acetone bath and then a solution of DAST (0.0559, 0.342 mmol, 0.045 mL) in 2.5 mL of methylene chloride was added dropwise. After 1 hour 5 mL of 596 aqueous NaHCO3 was ~ddded slowly and the product extracted into 100 mL of methylene chloride. The organic layer was washed with 3 x 50 mL of water and 2 x 50 mL of brine, dried with MgSO4, filtered and stripped of solvent to afford a purple solid. This was WO 95/0134Z, 21~ 6 3 2 ~ PCT/IB94/00160 purif3ed by flash column chromatography using 5% methanol in chloroform. Material of Rf = .42 (1 :9 methanol: chloroform), the desired product, (0.058 g 29%) was disolved in a minimal amount of ethyl acetate and precipitated with hexanes; Yield 0.042 9 (219~), mp 128C (dec); 1H-NMR (300 MHz, CDCI3) ~ 1.05(m, 6H,10-CH3 and 14-CH3),1.25 (brt, J = 15 Hz, lH, H-13), 1.55 (brt, J = 15 Hz, lH, H-13), 1.78 (s, 3H, 8-CH3), 1.96 (br m, lH, H-14), 2.03 (s, 3H, 2-CH3), 2.23 (dd, J = 8.5 Hz, 16 Hz, lH, H-15), 2.40 (br m, 2H, 3' azetidine CH2), 2.55 (dd, J = 7 Hz, 16 Hz, 1 H, H-15), 2.80 (br d, J = 26 Hz, lH, H-10), 3.35 (s, 3H, OCH3), 3.37 (s, 3H, OCH3), 3.53 (br m, lH, H-12), 4.39 (d, J = 9 Hz,1 H, H-6), 4.0 (br m, 7H, NH2 and 2' and 4' azetidine CH2 and H-11), 5.60 (d, J = 9 Hz, lH, H-9), 5.70 (s, lH, H-7), 5.88 (t, J = 9 Hz, lH, H-5), 6.55 (t, J = 9 Hz, lH, H-4), 6.96 (d, J = 9 Hz, lH, H-3), 7.05 (s, lH, H-19), 9.33 (s, lH, NH-22); m/z610. (M+
+ Na); IR (KBr, cm-l) 1735,1690, 1650; Analysis CP~Ic~ t~cl for C3lH42FN307-5H20: C, 54.93; H, 7.73; N, 6.20%. Found: C, 55.07; H, 6.23; N, 6.07%.
The compounds of Examples 52-58 were prepared by the method of Example 51 from the appru~ leIy substituted 17-amino-17-demethoxygeldanamycin derivatives.

17-Amino-11 -o-fIuoro-17-demethoxvqeIdanamvcin Yield 0.155 g (44%), mp >250C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.80 (d, 3H, J = 8Hz, 10-CH3), 0.90 (d, 3H, J = 8Hz, 14-CH3), 0.93 (br m, 1 H, H-13), 1.35 (br t, lH, H-13),1.60 (s, 3H, 8-CH3),1.85 (s, 3H,2-CH3),1.85 (brm, lH, H-14),1.85-2.1 (br m, 2H, H-15), 2.63 (brd, J = 26 Hz, lH, H-10), 3.16 (s, 6H, OCH3), 3.26 (brm, lH, H-12), ~.28 (d, J = 9 Hz, lH, H-6), 4.45 (br d, J = 47 Hz, lH, H-11), 4.60 (br m, 2H, NH2), 4.95 (s, lH H-7), 5.07 (br s, 2H, NH2), 5.45 (d, J = 9 Hz, 1 H, H-9), 5.70 (t, J = 9 Hz, lH, H-5), 6.35 (t, J = 9 Hz, lH, H~), 6.80 (d, J = 9 Hz, lH, H-3), 7.05 (s, lH, H-19), 9.0 (s, lH, NH-22); m/z 570. (M+ + Na); IR (KBr, cm~l) 1715, 1685, 1670; Analysis c~Ic~ ted for C28H38FN3O7-0.25H2O: C, 60.91; H, 7.03; N, 7.61%. Found: C, 60.78;H, 6.87; N, 7.43%.

17-lsoproPvIamino-11 -a-fluoro-17-demethoxygeldanamvcin Yield 0.035 g (16%), mp 132C; lH-NMR (300 MHz, CDCI3) ~ 0.85 (m, 6H, 10-CH3, 14-CH3), 0.85 (m, lH, H-13), 1.07 and 1.11 (br d, J = 8 Hz, 6H, isopropyl CH3), 1.38 (br m, lH, H-13), 1.60 (s, 3H, 8-CH3), 1.71 (br m, 1 H, H-14), 1.75 (s, 3H, 2-CH3), 2.15 ~dd, J = 8.5 Hz, 16 Hz, lH, H-15), 2.45 (dd, J = 7 Hz, 16 Hz, lH, H-15), 2.65 (br d, J = 26 Hz, lH, H-10), 3.19 and 3.20 (br s, 6H, OCH3), 3.35 (br m, lH, H-12), 3.95 (m, 1H, isopropyl CH), 4.22 (d, J = 9 Hz, 1 H, H-6), 4.30 (br d, J = 47 Hz, 1H, H-11), 4.65 (brm, 2H, NH2), 5.04 (s, 1H H-7), 5.46 (d, J = 9 Hz, 1H, H-9), 5.73 (t, J = 9 Hz, 1H, H-5), 5.94 (br d, J = 10.5 Hz, 1H, NH), 6.40 (t, J = 9 Hz, 1H, H4), 6.80 (d, J = 9 5 Hz, 1H, H-3), 7.05 (s, 1H, H-19), 9.15 (s, lH, NH-22); m/z 612. (M+ + Na); IR (KBr, cm-1) 1740,1705,1655;AnaIysiscaIc~ tedforC31H44FN3O7-0.5H2O: C, 62.19; H,7.57;
N, 7.01%. Found: C, 62.36; H, 7.48; N, 6.81%.

1 7-CycloproPvIamino-11 -a-fluoro-1 7-demethoxyqeIdanamycin Yield 0.056 g (25%), mp 119C (dec); 1H-NMR (300 MHz, CDCI3) ~0.70 (m, 2H, cyclopropyl CH2), 0.86 (m, 3H, cyclopropyl CH2 and H-13), 0.92 (d, 3H, J = 8Hz, 10-CH3), 1.00 (d, 3H, J = 8Hz, 14-CH3), 1.53 (br m, 1H, H-13), 1.70 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 2.00 (br m, 1 H, H-14), 2.62 (dd, J = 8.5 Hz, 16 Hz, 1 H, H-15), 2.70 (br d, J = 26 Hz, 1H, H-10), 2.80 (m, lH, cyclopropyl CH), 2.90 (dd, J = 7 Hz, 16 Hz, lH, 15 H-15), 3.33 (s, 6H, OCH3), 3.45 (br m, lH, H-12), 4.33 (d, J = 9 Hz, lH, H-6), 4.36 (br d, J = 47 Hz, lH, H-11), 4.7 (br m, 2H, NH2), 5.10 (s, lH H-7), 5.55 (d, J = 9 Hz, lH, H-9), 5.75 (t, J = 9 Hz, lH, H-5), 6.20 (brt, lH, NH), 6.46 (t, J = 9 Hz, lH, H-4), 6.90 (d, J = 9 Hz, lH, H-3), 7.15 (s, lH, H-19), 9.15 (s, lH, NH-22); m/z 610. (M+ + Na);
IR (KBr, cm-1) 1740, 1690, 1630; Analysis c~lcIII~ted forC31H42FN3O7-1 .5H2C: C, 60.57;
20 H, 7.37; N, 6.83%. Found: C, 60.43; H, 6.79; N, 6.83%.

1 7-Allvlamino-1 1 -a-fluoro-1 7-demethoxvqeIdanamvcin Yield 0.049 g (25%), mp 110-112C; 1H-NMR (300 MHz, CDCI3) ~ 0.85(d, 3H, J = 8Hz, 10-CH3), 0.88(d, 3H, J = 8Hz, 14-CH3), 1.45 (br m, 2H, H-13), 1.63 (s, 3H, 8-25 CH3), 1.86 (s, 3H, 2-CH3), 1.88 (br m, lH, H-14), 2.20 (dd, J = 8.5 Hz, 16 Hz, lH, H-15), 2.55 (dd, J = 7 Hz, 16 Hz, lH, H-15), 2.80 (br d, J = 26 Hz, lH, H-10), 3.20 (s, 6H, OCH3), 3.33 (br m, lH, H-12~, 3.95 (brt, 2H, allylic CH2), 4.23 (d, J = 9 Hz, lH, H-6), 4.26 (brd, J = 49 Hz, lH, H-11), 4.57 (brm, 2H, NH2), 5.03 (s, lH, H-7), 5.15 (brd, 2H, vinylic CH2), 5.45 (d, J = 9 Hz, 1H, H-9), 5.55 (m, 2H, H-5 and vinylic CH), 6.10 (brt, 30 1H, NH), 6.40 (t, J = 9 Hz, 1H, H-4), 6.80 (d, J = 9 Hz, 1H, H-3), 7.07 (s, 1H, H-19), 9.13 (s, 1H, NH-22); m/z 608. (M+ + Na); IR (KBr, cm-1) 1740, 1700, 1655; Analysis c~Icll~ted for C31H42FN3O7-0.75H2O: C, 61.93; H, 7.24; N, 6.98%. Found: C, 61.87;
H, 6.93; N, 7.00%.

_ WO 95/01342 2 ~ 6 6 3 2 ~ PCT/IB94/00160 17-Propar~vlamino-11 -a-fluoro-17-demethoxy~eldanamycin Yield 0.051 g (27%), mp 111 C (dec); 1H-NMR (300 MHz, CDCI3) ~ 0.83 (br m, lH, H-13), 0.95 (d, 3H, J = 8Hz, 10-CH3), 0.98 (d, 3H, J = 8Hz, 14-CH3), 1.53 (br m, 5 1H, H-13), 1.73 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 1.94 (brm, 1H, H-14), 2.35 (s, 1H, acetylene CH), 2.35 (dd, J = 8.5 Hz, 16 Hz, lH, H-15), 2.58 (dd, J = 7 Hz, 16 Hz, 1H, H-15), 2.65 (br d, J = 26 Hz,1 H, H-10), 3.3 (s, 6H, OCH3), 3.45 (br m, 1 H, H-12), 4.20 (br s 2H, propargyl CH2), 4.33 (d, J = 9 Hz, 1 H, H-6), 4.36 (br d, J = 47 Hz,1 H, H-11), 4.8(brm,2H,NH2),5.13(s,1HH-7),5.57(d,J=9Hz,lH,H-9),5.85(t,J=9Hz,lH, 10 H-5), 6.13 (brt, lH, NH), 6.50 (t, J = 9 Hz, lH, H4), 6.90 (d, J = 9 Hz, lH, H-3), 7.20 (s, 111, H-19), 9.13 (s, 1H, NH-22); m/z 608. (M+ + Na); IR (KBr, cm~l) 2120, 1735, 1695,1635; Analysis c~lc~ t~d for C37H40FN307-0.75H~O: C, 62.14; H,6.98; N,7.01%.
Found: C, 61.99; H, 6.71; N, 6.90%.

17-(2'-Cyanoethvlamino)-11 -a-fluoro-17-demethoxygeldanamvcin Yield 0.026 g (14%), mp 122-24C (dec); lH-NMR (300 MHz, CDCI3) ~ 1.15 (br m, 1H, H-13), 1.12 (d, 3H, J = 8Hz, 10-CH3), 1.17 (d, 3H, J = 8Hz, 14-CH3), 1.65 (br t, lH, H-13), 1.75 (s, 3H, 8-CH3), 1.90 (s, 3H, 2-CH3), 2.1 (br m, 1H, H-14), 2.40 (dd, J
=8.5Hz,16Hz,1H,H-15),2.65(dd,J=7Hz,16Hz,1H,H-15),2.83(t,J=8Hz,2H, 20 ~-ethyl CH2), 2.93 (br d, J = 26 Hz, 1 H, H-10), 3.46 (s, 6H, OCH3), 3.45 (br m, 1 H, H-12), 3.56 (q, J = 8 Hz, 2H, o-ethyl CH2), 4.46 (d, J = 9 Hz, 1 H, H-6), 4.55 (br d, J = 47 Hz,1 H, H-11), 4.85 (br m, 2H, NH2), 5.26 (s,1 H, H-7), 5.73 (d, J = 9 Hz,1 H, H-9), 6.00 (t, J = 9 Hz, 1H, H-5), 6.07 (br t, 1 H, NH), 6.65 (t, J = 9 Hz, 1 H, H-4), 7.07 (d, J = 9 Hz, 1H, H-3), 7.35 (s, 1H, H-19), 9.25 (s, 1H, NH-22); m/z 623. (M+ + Na); IR (KBr, 25 cm~') 2350, 1730, 1695, 1630; Analysis calculated for C3,H4lFN4O7: C, 61.99; H, 6.88;
N, 9.33%. Found: C, 61.52; H, 6.91; N, 9.25%.

17-(2'-Fluoroethvlamino)-11 -a-fluoro 17-demethoxyqeldanamvcin Yield 0.064 g (32%), mp 134C (dec); lH-NMR (300 MHz, CDCI3) ~ 1.05 (br m, 30 1H, H-13),1.03 (d, 3H, J = 8Hz,10-CH3),1.07 (d, 3H, J = 8Hz,14-CH3),1.57 (brt,1H, H-13), 1.77 (s, 3H, 8-CH3), 2.0 (br m, 1H, H-14), 2.05 (s, 3H, 2-CH3), 2.35 (dd, J = 8.5 Hz, 1 ~ Hz, 1 H, H-15), 2.63 (dd, J = 7 Hz, 16 Hz,1 H, H-15), 2.83 (br d, J = 26 Hz, 1 H, H-10), 3.4 (s, 6H, OCH3), 3.53 tbr m,1 H, H-12), 3.85 (two brd m, J = 27 Hz, 2H, a-ethyl CHz), 4.4 (d, J = 9 Hz, lH, H-6), 4.45 (br d, J = 47 Hz, 1H, H-11), 4.65 (two brd t, J =
46 Hz 7 Hz, 2H, ~-ethyl CH2), 4.75 (br m, 2H, NH2), 5.23 (s, 1 H H-7), 5.63 (d, J = 9 Hz, 1H, H-9), 5.90 (t, J = 9 Hz, 1H, H-5), 6.25 (brt, 1H, NH), 6.57 (t, J = 9 Hz, 1H, H-4), 6.97 (d, J = 9 Hz, 1H, H-3), 7.25 (s, 1H, H-19), 9.25 (s, 1H, NH-22); m/z 596. (M+ ~
5 Na); IR (KBr, cm~l) 1740, 1700, 1630; Analysis calculated for C30H4lF2N3O7: C, 60.69;
H, 6.96; N, 7.07%. Found: C, 60.23; H, 6.99; N, 7.02%.
E)CAMPLE 59 11-a-Fluoro-qeldanamvcin The title compound was prepared from geldanamycin bythe method of Example 10 51; Yield 0.064 g (32%), mp 232C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.87 (d, 3H, J
= 8Hz, 10-CH3), 1.00 (d, 3H, J = 8Hz, 14-CH3), 1.0 (br m, lH, H-13), 1.4 (br t, lH, H-13), 1.73 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 1.9 (br m, lH, H-14), 2.25 (dd, lH, J = 7 Hz, 16 Hz, lH, H-15), 2.45 (dd, J = 8.5 Hz,16 Hz, lH, H-15), 2.75 (brd, J = 26 Hz, lH, H-10), 3.3 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.4 (br m, lH, H-12), 4.05 (s, 3H, 17-15 OCH3), 4.27 (d, J = 9 Hz, lH, H-6), 4.57 (br d, J = 47 Hz, lH, H-11), 4.7 (br m, 2H, NH2), 5.05 (s, lH, H-7), 5.53 (d, J = 9 Hz, lH, H-9), 5.85 (t, J = 9 Hz, lH, H-5), 6.50 (t, J = 9 Hz, lH, H-4), 6.85 (d, J = 9 Hz, lH, H-3), 7.20 (s, lH, H-19), 8.65 (s, 1H, NH-22); m/z 585. (M+ + Na); IR (KBr, cm~l) 1740, 1705, 1655; Analysis cE~C~ tpcl for C28H39FN2O8-0.25H2O: C, 61.41; H, 7.02; N, 4.93%. Found: C, 61.03; H, 6.65;
20 N, 4.92%.

17-(S)-2'-HydroxvProPYiamino-11 -a-fluoro-17-demethoxYqeldanamycin The title compound of Example 59 (0.307 9, 0.546 mmol) was slurried in 6 mL
of chloloform and treated with (S)-2-hydroxypropylamine (0.205 g, 2.73 mmol) at 22C
25 for 16 hours. The reaction mixture was diluted with 50 mL of chloroform and washed with 3 x 50 mL of brine and 3 x 50 mL of water. The organic layer was dried withMgSO4, filtered and vacuum evaporated to a purple solid. Flash column chromatography on silica gel eluted with 3% methanol in chloroform afforded pureproduct; Yield 0.070 9 (21%), mp 119C (dec); 1H-NMR (300 MHz, CDCI3) ~ 0.95 (br30 t, 7H, H-13 and 10-CH3 and y-propyl CH3), 1.25 (d, 3H, J = 8Hz, 14-CH3), 1.50 (br t, 1 H, H-13), 1.70 (s, 3H, 8-CH3), 1.9 (br m, 1 H, H-14), 1.97 (s, 3H, 2-CH3), 2.33 (dd, J =
8.5Hz,16Hz,1H,H-15),2.53(dd,J=7Hz,16Hz,1H,H-15),2.75(brd,J=26Hz, lH, H-10), 3.30 (s, 6H, OCH3), 3.30 (m, lH, a-propyl CH), 3.45 (br m, lH, H-12), 3.57 ~ 1 6 ~

(m,1 H, a-propyl CH), 4.0 (m,1 H"6-propyl CH), 4.33 (d, J = 9 Hz, 1 H, H-6), 4.37 (br d, - J = 27 Hz, lH, H-11), 4.75 (br m, 2H, NH2), 5.15 (s, 1H H-7), 5.55 (d, J = 9 Hz, lH, H-9), 5.85 (t, J = 9 Hz, lH, H-5), 6.43 (brt, lH, NH), 6.50 (t, J = 9 Hz, lH, H4), 6.90 (d, J = 9 Hz, lH, H-3), 7.15 (s, lH, H-19), 9.23 (s, lH, NH-22); m/z 628. (M+ + Na); IR
(KBr, cm-l) 1735,1695,1655; Analysis c~lcul~tecl for C3lH44FN308-0.25H20: C, 61.01;
H, 7.35; N, 6.88%. Found: C, 60.90; H, 7.40; N, 6.74%.

17-Allvlamino-11 -aminocarbonyl-17-demethoxyqeldanamvcin 17-Allylamino-17-demethoxygeldanamycin (0.200 g,0.341 mmol) was dissolved in 5 InL of methylene chloride and cooled to 0C in a flame dried flask under nitrogen.
Sodi~lm isocyanate (0.311 9,0.4.78 mmol) and trifluoroacetic acid (0.545 g,4.78 mmol 0.368 mL) were added during 10 minutes. After stirring for 16 hours at room terllperal~re~ the reaction mixture was diluted with 200 mL of water and extracted with 3 x 150 mL of chloroform. The combined organic layers were washed with 2 x 100 mL
of water, dried with sodium sulfate, filtered and evaporated in vacuo to yield a residue, 0.236 g, which was flash chromatographed on 80 g of silica gel eluted with 69:1:30 ethyl AcetAte:methanol:hexanes. Fractions containing pure product were evaporated, taken up in 2 mL of chlGrof~r"~ and then prec;~ led with hexanes; 0.062 g (29%) mp 214-216C; 'H-NMR (300 MHz, CDCI3) ~ 0.93(d, J = 8Hz, 3H, 10-CH3), 0.98(d, J =
8Hz, 3H, 14-CH3), 1.26 (br m, 1H, H-13), 1.50 (m, 1H, H-13), 1.69 (s, 3H, 8-CH3),1.77 (br m, 1H, H-14), 1.96 (s, 3H, 2-CH3), 2.24 (dd, J = 16 Hz and 7 Hz, 1H, H-15), 2.56 (m, 1 H, H-15), 2.85 (m, 1 H, H-10), 3.31 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.46 (br m, 1H, H-12), 4.05 (br t, 2H, allylic CH2), 4.39 (br m, 2H, NH2), 4.43 (br d, J = 9 Hz, 1H, H-6), 4.71 (v br s, 2H, NH2) 4.75 (m, 1 H, H-11), 5.15-5.3 (m, 4H, vinylic CH2, H-7, H-9), 5.73-5.9 (br m, 2H, H-5, vinylic CH), 6.15 (br t, 1H, NH), 6.48 (t, J = 9 Hz, 1H, H4), 7.11 (s, 1H, H-19), 7.23 (br m, 1H, H-3), 9.20 (s, 1H, NH-22); m/z 651. (M+ + Na); IR
(KBr, - cm-l) 1740, 1725, 1705, 1680, 1645 1585, 1470; Analysis cAlc~lAted for C32H44N4O9-1.5H2O: C,58.61; H, 7.22; N, 8.54%. Found: C, 58.50; H, 6.51; N, 8.48%.

17-Azetidin-1 -yl-11 -N-BOC-~-alanvl-17-demethoxvqeldanamvcin 17-Azetidin-1 -yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g,0.341 mmol) was dissolved in 6 mL of dry methylene chloride and treated with 2 ~

N-BOC-,B-alanine (0.077 g, 0.409 mmol), dicyclohexylcarbodiimide (0.084 g, 0.409mmol) and dimethylaminopyridine (DMAP) (0.050 9, 0.409 mmol). After 24 hours themixture was filtered to remove dicyclohexylurea and concen~l~ted in vacuo to a residue which was ~;~solved in 200 mL of ethyi acetate and washed with 2 x 100 mL each of 5 lN hydrochloric acid, water and brine. The organic layer was dried with Na2SO4, filtered and evaporated in vacuo to yield a purple residue (0.240 9). This was flash chroi"~lographed on silica gel eluted with 69:1:30 ethyl acetate:methanol:hexanes.
Fractions containing pure product were evaporated to yield a residue which was dissolved in 1 mL of chloroform and precipitated with 100 mL of hexane; yield 0.098 g 10 (38%) mp 122-125C; lH-NMR (300 MHz, CDCI3) ~ 0.87 (d, J = 8 Hz, 3H, 10-CH3), 0.95 (d, J = 8 Hz, 3H, 14-CH3), 1.17 (m, 1H, H-13), 1.6 (m, lH, H-14), 1.63 (s, 3H, 8-CH3), 1.90 (m, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.35 (pent, J = 8 Hz, 2H, 3'- azetidine CH2), 2.46 (m, 2H, o-alanyl CH2), 2.6-2.8 (m, 2H, H-15, H-10), 3.25 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.35 (m, 2H"~-alanyl CH2), 3.66 (m, 1H, H-12), 4.46 (d, J = 8 Hz, lH, H-6), 4.55 15 (t, J = 8 Hz, 4H, 2'and 4' azetidine CH2), 4.4-4.9 (br s, 2H, NH2), 5.06 (d, J = 12 Hz, 1H, H-11), 5.15 (brt, lH, alanyl NH), 5.27 (d, J = 11 Hz, 1H, H-9), 5.53 (brs, 1H, H-7), 5.80 (t, J = 9, 1 H, H-5), 6.45 (t, J = 9 Hz, 1 H, H4), 6.90 (s, 1 H, H-19), 7.00 (m, J = 9 Hz, 1 H, H-3), 9.40 (s, 1 H, NH-22); m/z 759. (M+ + Na); IR (KBr, cm-l) 1732, 1645 1583, 1541, 1477; Analysis cplcul~ted for C39H5~N4Oll-2H2O: C, 59.08; H, 7.63; N, 7.07%.
20 Found: C, 59.20; H, 7.11; N, 7.16%.

1 7-Azetidin-1 -yl-1 1 -B-alanvl-1 7-demethoxygeldanamvcin The product of Example 62 (0.050 g, 0.066 mmol) was dissolved in 1 mL of trifluoroac~lic acid at 0C. After 10 minutes the reaction mixture was evaporated in 25 vacuo to a residue which was dissolved in 0.3 mL of methanol and precipitated with 20 mL of isopropylether; 0.35 9 (71%) mp 138-142C; 1H-NMR (300 MHz, CDCI3) ~ 0.84 (d, J = 8 Hz, 3H, 10-CH3), 0.96 (d, J = 8 Hz, 3H, 14-CH3), 1.24 (m, lH, H-13), 1.55 (m, 1H, H-13), 1.61 (s, 3H, 8-CH3), 1.94 (s, 3H, 2-CH3), 1.96 (m, 1H, H-15), 2.35 (pent, J =
8 Hz, 2H, 3' az~lidi.,e CH2), 2.6-2.8 (m, 4H, a-alanyl CH2 and H-15 and H-10), 3.18 (m, 30 2H"B-alanyl CH2), 3.25 (s, 6H, OCH3), 3.65 (m, 1 H, H-12), 4.43 (br s, 1 H, H-6), 4.57 (m, 4H, 2'and 4' ~lidi"e CH2), 5.0-5.5 (br s, 2H, NH2), 5.15 (d, J = 12 Hz, 1H, H-11), 5.3 (br m, lH, H-9), 5.4 (br s, lH, H-7), 5.78 (t, J = 9 Hz, 1H, H-5), 6.44 (t, J = 9 Hz, 1H, H4), 6.85-7.00 (m, J = 9 Hz, 1H, H-3), 6.93 (s, 1H, H-19), 8.16 (br s, 2H, alanyl NH2), WO 95/01342 ~ ~ o PCT/IB94/00160 9.35 (s, lH, NH-22); m/z 657. (M+ + H); IR (KBr, cm-1) 1731, 1688, 1647 1583, 1601, 1541, 1474; Analysis calc~ te~l for C34H48N409-3H20: C, 52.42; H, 6.72; N, 6.79%.
Found: C, 52.23; H, 6.22; N, 6.61%.

17-Azetidin-1 -Yl-11 -rN-(4-azidobenzovl)-~-alanvl1-17-demethoxygeldanamycin The title compound of Example 63 (0.020 9, 0.026mmol) was dissolved in 0.5 mL of anhydrous dimethylformamide and treated with 4-azidobenzoic acid N-hydroxysucc;.,i",ide ester (0.007 g, 0.025 mmol) and triethylamine (0.0025 9, 0.025 mmol, 0.0034 mL). After three hours the reaction mixture was diluted with 200 mL of ethyl acetate and washed with 2 x 100 mL of water, 1 N hydrochloric acid, and brine.
The or~an c layer was dried with sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was dissolved in 0.5 mL of chloroform and precipitated with 70 mL of hexanes, filtered and dried in vacuo; 0.012 9 (61%) mp 123-6C; 1H-NMR (300 MHz, CDCI3) ~0.85 (d, J = 8 Hz, 3H,10-CH3), 0.94 (d, J = 8 Hz, 3H, 14-CH3), 1.15 (m, 1H, H-13), 1.63 (s, 3H, 8-CH3), 1.85 (m, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.35 (pent, J =
8 Hz, 2H, 3' azetidine CH2), 2.6 (t, J = 8 Hz, 2H, o-alanyl CH2), 2.7-2.9 (m, 2H, H-15 and H-10), 3.26 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.56 (m, 1H"B-alanyl CH2), 3.70 (m, 1H, H-12), 3.82 (m, 1H,,6-alanyl CH2), 4.44.9 (m, 7H, H-6, 2' and 4' azetidine CH2, NH2), 5.10 (d, J = 12 Hz, 1H, H-11), 5.3 (brm, 1H, H-9), 5.53 (brs, 1H, H-7), 5.79 (t, J = 9, 1H, H-5), 6.45 (t, J = 9, 1H, H~), 6.91 (s, 1H, H-19), 6.9-7.0 (m, 2H, H-3, NH), 6.98 (d of ABq, J = 10 Hz, 2H, aromatic CH), 7.75 (d of ABq, J = 10 Hz, 2H, aromatic CH), 8.16 (br s, 2H, alanyl NH2), 9.38 (s, 1 H, NH-22).

17-Azetidin-1 -v1-11 -acetyl-17-demethoxyqeldanamycin 17-Azetidin-1 -yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 9, 0.341 mmol) was dissolved in 5 mL of methylene chloride in a flame dried flask under nitrogen and treated with acetic anhydride (0.070 9, 0.683 mmol, 0.064 mL), DMAP (0.042 9, 0.341 mmol) and triethylamine 0.105 g (1.04 mmol, 0.145 mL) at room temperature. After 3 hours the mixture was diluted with 200 mL of methylene chloride and washed with 100 mL of water and 2 x 100 mL of brine. The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to a residue; 0.30 9. The residue was flash chromatographed on 120 9 of silica gel with 2.5% methanol in chloroform to afford pure product, 0.120 9, which was recrystallized from 10 mL of toluene; 0.080 9 2~ 32~, , (37%) mp 195C(dec); 'H-NMR (300 MHz, CDCI3) ~ 0.93 (m, 6H, 14-CH3 and 10-CH3), 1.1-1.3 (m, 2H, H-13), 1.55 (m, 1H, H-14), 1.65 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 1.96 (s, 3H, acetyl CH3), 2.0 (m, 1 H, H-15), 2.35 (pent, J = 8 Hz, 2H, 3'-azetidine CH2), 2.6-2.85 (m, 2H, H-15, H-10), 3.29 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 3.60 (sept, J = 8 Hz, 5 1H, isopropyl CH), 3.63 (m, 1H, H-12), 4.45 (d, J = 8 Hz, 1H, H-6), 4.55 (t, J = 8 Hz, 4H, 2'and 4' azetidine CH2), 4.73 (br s, 2H, NH2), 5.0 (m, 1H, H-11), 5.75 (d, J = 11 Hz, 1H, H-9), 5.41 (br s, 1H, H-7), 5.78 (t, J = 9 Hz, 1 H, H-5), 6.46 (t, J = 9 Hz, 1 H, H4), 6.91 (s, 1H, H-19), 7.10 (m, J = 9 Hz, 1H, H-3), 9.34 (s, lH, NH-22); m/z 650. (M+ +
Na); IR (KBr, cm-1) 1735, 1685, 1645; Analysis c~lc~ ted for C33H4sN3Og: C, 63.14; H, 10 7.26; N, 6.69%. Found: C, 63.36; H, 6.94; N, 6.55%.

1 7-Azetidin-1 -v1-1 1 -aminocarbonyl-1 7-demethoxv~geldanamycin Prepared in the manner of Example 61 from 1 7-az~tidi, 1-1 -yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341 mmol);
15 yield 0.083 g (39%) mp 168-171 C; 'H-NMR (300 MHz, CDCI3) ~ 0.98(d, J = 8Hz, 3H, 10-CH3), 1.01 (d, J = 8Hz, 3H, 14-CH3), 1.3 (br m, 2H, H-13), 1.73 (s, 3H, 8-CH3), 1.75 (br m, 1 H, H-14), 2.02 (s, 3H, 2-CH3), 2.15 (m, 1 H, H-15), 2.40 (pent, J = 8 Hz, 2H, 3'-azetidine CH2), 2.67 (m, lH, H-15), 2.87 (m, lH, H-10), 3.36 (s, 6H, OCH3), 3.60 (m, 1H, H-12), 4.39 (br m, 2H, NH2), 4.5 (br d, J = 9 Hz, 3H, H-6, NH2), 4.64 (br t, J = 8 Hz, 20 6H, 2'and 4' azetidine CH2, NH2), 4.86 (m, 1H, H-11), 5.35 (d, J = 12 Hz, 1H, H-9), 5.40 (br s, 1H, H-7), 5.83 (br t, J = 9 Hz, lH, H-5), 6.54 (t, J = 9 Hz, lH, H-4), 6.97 (s, 1H, H-19), 7.21 (br m, 1H, H-3), 9.36 (s, 1H, NH-22); m/z 629. (M+); IR (KBr, cm ') 1720, 1686, 1648 1533, 1475; Analysis c~lc~ tesl for C32H44N40~-H20: C, 59.42; H, 7.61; N, 8.66%. Found: C, 59.67; H, 6.81; N, 8.38%.

1 7-Allvlamino-1 1 -isoproPylsulfamylcarbonvl-1 7-demethoxygeldanamycin 1 7-Allylamino-1 7-demethoxygeldanamycin (0.200 9, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0C in a flame dried flask under nitrogen.
Chlorosulfonylisocyanide (0.080 mg, 0.564 mmol, 0.049 mL) was added dropwise 30 during 10 minutes. After stirring for one hour in the cold, isopropyl amine (0.066 g, 1.13 mmol, 0.096 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL of chloroform and extracted with 10 mL of water. The aqueous layer was back extracted ~ WO 95/01342 PCT/IB94/00160 ~ 6B32~

with 3 x 100 mL of chlGrofc r",. The pooled organic layers were extracted with 3 x 75 mL of 1N NaOH. The combined basic layers were washed with 3 x 100 mL of chlolo~or",. The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with 3 x 100 ml of chloroform. These latter organic extracts were pooled, 5 washed with 2 x 100 mL of brine, dried with sodium sulfate, filtered and evaporated in vacuo to a solid, 0.213 9. Flash column chromatography on silica gel eluted with 5%
methanol in chloroform yielded pure title compound which was dissolved in 1 mL of chloroform and p,e..i~,ilcled with hexanes, filtered and dried in vacuo; yield 0.061 9 (25~) mp 137-139C; 1H-NMR (300 MHz, CDCI3) ~0.94 (d, 3H, J = 8 Hz,10-CH3), 0.98 (d, 3H, J = 8Hz, 14-CH3), 1.1(m, 6H, isopropyl CH3), 1.3-1.55 (brm, 2H, H-13), 1.65 (s, 3H, B-CH3), 1.70 (br m, 1 H, H-14), 1.95 (s, 3H, 2-CH3), 2.13 (m, 1 H, H-15), 2.27 (dd, J
= 7 Hz, 16 Hz, 1H, H-15), 3.00 (m, 1H, H-10), 3.25 and 3.27 (br s, 6H, OCH3), 3.5 (m, 1 H, isopropyl CH), 3.57 (br m, 1 H, H-12), 4.05 (br t, 2H, allylic CH2), 4.43 (br m, 1 H, H-6), 4.7 (br m, 2H, NH2), 4.9 (br s, 1 H, NH) 5.02 (br d, J = 11 Hz, 1 H, H-11), 5.2 (br d, 2H, ~Jinylic CH2), 5.38 (br m, 2H, H-7 and H-9), 5.75 (t, J = 9 Hz, 1 H, H-5), 5.85 (m, 1 H, vinylic CH), 6.27 (brt, lH, NH), 6.45 (t, J = 9 Hz, 1H, H4), 7.03 (br m, lH, H-3), 7.10 (s, 1H, H-19), 9.30 (s, 1H, NH-22); m/z 772. (M+ + Na); IR (KBr, cm~1) 1737, 1690, 1645; Analysis c~lc~lAt~d for C35H5lN5OllS-0.5H2O: C, 55.39; H, 6.91; N, 9.23%.
Found: C, 55.36; H, 6.95; N, 9.19%.
The compounds of Examples 68 and 69 were prepared by the method of Example 67 from the appropriate 17-demethoxy-geldanamycin.

17-~-Fluoroethylamino-11 -i~opr~ ylsulfamvlcarbonyl-17-demethoxvqelda~ ,ycin Yield 0.122 g (38%) mp 142-146C (dec); 1H-NMR (300 MHz, CDCI3) ~ 0.93 (d, 3H, J = 8Hz, 10-CH3), 0.97 (d, 3H, J = 8Hz, 14-CH3), 1.07 (d, J = 8 Hz, 6H, isopropyl CH3), 1.36 (br m, 1H, H-13), 1.46 (br m, 1H, H-13), 1.63 (br s, 4H, 8-CH3 and H-14), 1.94 (s, 3H, 2-CH3), 2.1 (br m, lH, H-15), 2.82 (dd, J = 7 Hz, 16 Hz, 1 H, H-15), 2.95 (br m, lH, H-10), 3.24 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.49 (sept, J = 8 Hz, lH, isopropyl CH), 3.59 (br m, lH, H-12), 3.77 (two brd m, J = 23 Hz, 2H, o-ethyl CH2), 4.43 (br s, 1 H, H-6), 4.56 (two brd t, J = 47 Hz 7 Hz, 2H"B-ethyl CH2), 4.8 (br m, 2H, NHz), 5.02 (br d, 2H, H-11 and NH), 5.75 (t, J = 9 Hz, 1 H, H-5), 5.86 (br d, 2H, H-7 and H-9), 6.25 (br t, 1 H, NH), 6.45 (t, J = 9 Hz, 1 H, H4), 7.00 (br s, 1 H, H-3), 7.10 (s, 1 H, H-19), 7.55 (br s, lH, NH), 9.25 (s, lH, NH-22); m/z 778. (M+ ~ Na); IR (KBr, cm-1) WO 95/01342 ~ PCT/IB94/00160 1735, 1690, 1645, 1590, 1480; Analysis calculated for C34H50FN5O, l S: C, 60.69; H, 6.96;
N, 7.07%. Found: C, 60.23; H, 6.99; N, 7.02%.

1 7-~-Cyanoethylamino-11 -isoPr~,pylsulfamvlcarbonyl-1 7-demethoxvqelclal-~ "vcin Yield 0.037 9 (11%) mp 150-154C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.98 (d, 6H, J = 8 Hz, 1 0-Me and 1 4-Me), 1.08 (d, J = 8 Hz, 6H, isopropyl CH3), 1 .37 (br m, 1 H, H-13), 1.5 (brt, lH, H-13), 1.65 (s, 3H, 8-Me), 1.75 (brm, lH, H-14), 1.95 (s, 3H, 2-Me), 2.04 (m, 1 H, H-15), 2.66 (t, J = 8 Hz, 2H"~-ethyl CH2), 2.78 (m, 1 H, H-15), 3.00 (br m, lH, H-10), 3.26 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.50 (sept, J = 8 Hz, lH, isopropyl CH), 3.56 (br m, 1 H, H-12), 3.77 (br m, 2H, o-ethyl CH2), 4.40 (br d, J = 9 Hz, 1 H, H-6), 4.75 (br m, 2H, NH2), 4.93 (br s, 1 H, NH), 4.98 (br d, 1 H, H-11), 5.34 (br m, 2H, H-7 and H-9), 5.76 (t, J = 9 Hz, lH, H-5), 5.96 (brt, lH, NH), 6.45 (t, J = 9 Hz, lH, H4), 7.00 (br s, lH, H-3), 7.13 (s, lH, H-19), 7.38 (br s, lH, NH), 9.15 (s, lH, NH-22); m/z 785.
(M+ + Na); IR (KBr, cm l) 2320, 1730, 1690, 1640, 1580, 1480; Analysis c~lc~ ted for C35H50N~O11S-1.25H2O: C, 54.78; H, 6.63; N, 10.95%. Found: C, 54.75; H, 6.16; N,10.71~.

1 7-Azetidin-1 -vl-1 1 -isopropvlsulfamylcarbonvl-1 7-demethoxvqeldanamvcin 1 7-Azetidin-1 -yl-1 7-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) was added dropwise during 10 minutes. After stirring for two hours in the cold, isopropylamine (0.044 9, 0.75 mmol, 0.064 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL
of methylene chloride and extracted with 2 x 100 mL of 1 N NaOH. The combined basic layers were washed with 3 x 150 mL of methylene chloride and then acidified to pH 3 with 1 N hydrochloric acid. The acidic aqueous layer was extracted with 3 x 150 mL of methylene chloride. These latter organic extracts were pooled, dried with sodiumsulfate, filtered and evaporated in vacuo to a solid, 0.121 g which was dissolved in 1 mL of methylene chloride and precipitated with hexanes, filtered and dried in vacuo;
0.110 g (43%) mp 14548C; 'H-NMR (300 MHz, CDCI3) ~ 0.90(d, J = 8 Hz, 3H, 14-CH3), 0.96 (d, J = 8 Hz, 3H, 10-CH3), 1.14 (d, J = 8 Hz, 6H, isopropyl CH3), 1.3 (m, lH, H-13), 1.5 (m, 1 H, H-13), 1.6 (m, 1 H, H-14), 1.64 (s, 3H, 8-CH3), 1.94 (s, 3H, 2-CH3), 2.0 WO 95/0L~42 ~16 6 3 2 0 PCT/IB94/00160 (m, 1 H, H-15), 2.36 (p, J = 8 Hz, 2H, 3' æetidine CH2), 2.73 (dd, J = 8 Hz and 16 Hz, 1H, H-15), 2.9 (m, lH, H-10), 3.25 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.52 (sept, J =
8 Hz, 1H, isopropyl CH), 3.63 (m, 1H, H-12), 4.43 (m, 1H, H-6), 4.57 (t, J = 8 Hz, 4H, 2'and 4' azetidine CH2), 4.78 (br s, 2H, NH2), 5.0 (br s, 1 H, H-11), 5.86 (m, 2H H-7 and 5 H-9)~ 5.75 (t, J = 9 Hz, 1H, H-5), 6.45 (t, J = 9 Hz, lH, H-4), 6.9 (s, lH, H-19), 6.95 (m, J = 9 Hz, 1H, H-3), 7.45 (m, 1H, NH), 9.35 (s, 1H, NH-22); m/z 772. (M+ + Na); IR
(KBr, cm-') 1735, 1685, 1645; Analysis c~lc~ ted for C35H5,N5O"S-1.25H2O: C, 54.43;
H, 6~98; N, 9.07%. Found: C, 54.42; H, 6.54; N, 8.73%.

101 7-~-Cvanoethvlamino-4.5-dihydro-11 -isopropYlsulfamvlcarbonyl-17-demethoxvqeldanamvcin The title compound was prepared by the method of Example 70 from the compound of Example 11.
Yield 0.087 g (46%) mp 128-132C (dec); 'H-NMR (300 MHz, CDCI3) ~ 0.92 (d, 15 J = 8 Hz, 3H, 10-CH3), 0.93 (d, J = 8 Hz, 3H, 14-CH3), 1.07 (d, J = 8 Hz, 3H, isopropyl CH3~, 1.09 (d, J = 8 Hz, 3H, isopropyl CH3), 1.17 (brm, 1H, H-13), 1.36 (brt, 1H, H-13), 1.43 (s, 3H, 8-CH3), 1.46 (br m, 1 H, H-14), 1.58 (m, 2H, H-5), 1.75 (s, 3H, 2-CH3), 2.00 (dd, J = 14 Hz and 6 Hz, lH, H-15), 2.23 (m, 2H, H~), 2.56 (t, J = 8 Hz, 2H, ~-ethyl CH2,1, 2.77 (m, 1 H, H-15), 3.06 (br m, 1 H, H-10), 3.25 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 20 3.35 (br m, 1H, H-12), 3.47 (sept, J = 8 Hz, 1H, isopropyl CH), 3.66 (br m, 2H, a-ethyl CH2,~l, 4.5-4.63 (br m, 3H, H-6, NH2 and NH), 4.85 (d, J = 6 Hz, 1 H, H-7), 5.05 (br s, 1 H
H-7), 5.74 (d, J = 9 Hz, 1H, H-9), 5.87 (brt, 1H, NH), 6.26 (t, J = 7 Hz, 1H, H-3), 7.05 (s, 1H, H-19), 7.40 (br s, 1H, NH), 9.00 (s, 1H, NH-22); m/z 787. (M+ + Na); IR (KBr, cm-' ) 2320, 1730, 1690, 1645, 1580, 1480; Analysis c~lc~ ted for 25 C35H52N~O"S-0.25H2O: C, 54.71; H, 6.75; N, 10.93%. Found: C, 54.48; H, 6.88; N, 1 0.6B%.

1 7-Azetidin-1 -vl-1 1 -(4'-azidoPhenvl~sulfamvlcarbonyl-1 7-demethoxy~elcl~ ~amycin 1 7-Azetidin-1 -yl-1 7-demethoxygeldanamycin, the title compound of Example 18, 30 (0.260 g, 0.427 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0C
in allame dried flask under nitrogen. Chlorosulfonylisocyanide (0.099 mg, 0.704 mmol, 0.061 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, 4-azidoaniline (0.126 g, 0.938 mmol) was added and the reaction mixture allowed WO 95/0L~42 PCT/l[B94100160 to warm to room temperature during one hour. The reaction mixture was evaporatedto dryness and the residue flash chromatographed on 120 g silica gel with 3% methanol in chloroform affording pure product which was dissolved in 1 mL of chloroform and preci,uilaled with hexanes; Yield 0.059 9 (17%), mp 152-154C; 'H-NMR (300 MHz, 5 CDCI3) ~ 0.85 (d, J = 8 Hz, 3H, 14-CH3), 0.94 (d, J = 8 Hz, 3H, 10-CH3), 1.2 (m, lH, H-13), 1.36-1.7 (m, 2H, H-13 and H-14), 1.6 (s, 3H, 8-CH3), 1.94 (br s, 4H, 2-CH3 and H-15), 2.35 (pent, J = 8 Hz, 2H, 3'-azetidine CH2), 2.65-2.9 (br m, 2H, H-10 and H-15), 3.24 (br s, 6H, OCH3), 3.64 (m, 1 H, H-12), 4.46 (br s, 1 H, H-6), 4.55 (t, J = 8 Hz, 4H, 2'and 4' azetidine CH2), 4.85-5.1 (br s, 2H, NH2 and H-7), 5.85 (br s, 1 H H-11), 5.48 (br 10 s, lH, H-9), 5.77 (brt, J = 9 Hz, lH, H-5), 6.45 (t, J = 9 Hz, lH, H-4), 6.86 (s, lH, H-19), 6.8-7.15 (m, 5H, H-3 and aromatic CH), 7.8 (v brd s, lH, NH), 9.35 (s, lH, NH-22);
m/z 847. (M+ + Na); IR (KBr, cm-l 2108, 1737, 1689, 1647, 1584, 1481; Analysis ~-'.,u~oted for C38H48N8Ol1S-1.5H20: C, 53.57; H, 5.86; N, 13.15%. Found: C, 53.70;
., ~ r7. .~, ~ ., ~,.~
n, ~.~ .vc~

17-Allylamino-11 -azetidin-1 -vlsulfamylcarbonvl-17-demethoxvqeldanamycin 17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was ~issolved in 5 mL of methylene chloride and cooled to 0C in a flame dried flask under nitrogen.
Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) was added dropwise 20 during 10 minutes. A~ter stirring for one hour in the cold, azetidine (0.043 9, 0.75 mmol, 0.051 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was evaporated to a residue and flash column chromcloylaphed on 60 9 silica gel eluted with 69:1 :30 ethyl acetate:methanol:hexanes to yield pure target compound which was dissolved in 1 mL of chlonJfc,r" " prec"Jildled 25 with hexanes and dried in vacuo; Yield 0.102 g (40%) mp 134-137C; 1H-NMR (300 MHz, CDCI3) ~ 0.92 (d, 3H, J = 8Hz, 10-CH3), 1.01 (d, 3H, J = 8Hz, 14-CH3), 1.4 (br m, lH, H-13), 1.5 (br m, 2H, H-13 and H-14), 1.65 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 2.13 (m, 1 H, H-15), 2.05-2.2 (m, 3H, H-15 and azetidine 3'-CH2), 2.78 (dd, J = 6 Hz and 15 Hz, lH, H-15), 2.93 (m, lH, H-10), 3.26 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.63 (br 30 m, lH, H-12), 3.95-4.05 (br m, 6H, allylic CH2 and az~li.li.,e 2' and 4' CH2), 4.45 (br s, 1 H, H-6), 4.7 (br m, 2H, NH2), 5.02 (br d, J = 11 Hz, 1 H, H-11), 5.2 (m, 2H, vinylic CH2), 5.4 (br m, 2H, H-7 and H-9), 5.73-6.93 (m, 2H, H-5 and vinylic CH), 6.25 (br t, 1 H, NH), 6.45 (t, J = 9 Hz, lH, H~), 7.03 (br m, lH, H-3), 7.10 (s, lH, H-19), 9.32 (s, lH, NH-~ WO 95/0134~, PCT/IB94/00160 3 2 ~

22); m/z 769. (M+ + Na); iR (KBr, cm~1) 1734, 1691, 1645 1579, 1474; Analysis c~cu~ated for C35H49N5Ol1S-0.75H2O: C, 55.21; H, 6.69; N, 9.19%. Found: C, 55.19;
H, 6.18; N, 9.20%.

17-Azetidin-1 -vl-11 -piperazinYlsulfamylcarbonyl-17-demethoxyqeldanamycin 17-Azetidin-1 -yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.50 g, 0.854 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0C
in aflame dried flask under nitrogen. Chlorosulfonylisocyanide (0.133 mg, 0.939 mmol, 0.082 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, piperazine (0.162 g, 1.88 mmol) was added and the reaction mixture allowed to warrn to room temperature during one hour. The reaction mixture was evaporated to dryness and the residue flash chromatographed on 200 g silica gel with 20% methanol in chlorlJfor.n affording pure product which was dissolved in 5 mL of chloroform and precirit~ted with 150 mL of hexanes; Yield 0.161 g (24%), mp 180-182C; 1 H-NMR (300 MHz, CDCI3) ~ 0.86(m, 3H, 14-CH3), 0.9 (m, 3H, 10-CH3), 1.6 (s, 3H, 8-CH3), 1.94 (br s, 2-CH3), 2.35 (pent, J = 8 Hz, 2H, 3'-azetidine CH2), 3.25 (br s, 6H, OCH3), 3.64 (m, lH, H-12), 4.46 (br s, 1H, H-6), 4.6 (t, J = 8 Hz, 4H, 2' and 4' ~idi"e CH2), 6.43 (br t, 1 H, H4), 6.9 (s, 1 H, H-19), 9.35 (s, 1 H, NH-22), other protons observed but not well defined or assiy"able; m/z 799. (M+ + Na); IR (KBr, cm~1) 1734, 1689, 1646, 1600, 1471; Analysis c~lc~ ted for C33H52N~O11S-2H2O: C, 53.19; H, 6.94; N, 10.34%.
Found: C, 52.90; H, 6.81; N, 10.13%.

17-Azetidin-1 -yl-11 -(4'-methyl-1 '-piperazinvl)-sulfamvlcarbonyl-1 7-demethoxy-qeldanamycin 17-Azetidin-1 -yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 9, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0C
in aYlame dried flask under nitrogen. Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, N-methylpiperazine (0.075 g, 0.75 mmol, 0.083 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL of chloroform and extracted with 100 mL of water and 2 x 100 mL of brine. The organic layer was dried with sodium sulfate, filtered and evapo,aled in vacuo to a solid, 0.280 g. This was flash chromatographed on silica gel with 10%

WO 9S/0L342 ~ i 3 ~ ~ PCT/IB94/00160 ~' methanol in chloroform affording pure product: yield 0.114 g (42%) mp 14749C; 1H-NMR (300 MHz, CDC13) ~ 1.11 (d, J = 8 Hz, 3H, 14-CH3), 1.21 (d, J = 8 Hz, 3H, 10-CH3), 1.55 (m, lH, H-13), 1.72 (m, lH, H-13), 1.83 (m, lH, H-14), 1.86 (s, 3H, 8-CH3), 2.2 (br s, 4H, 2-CH3 and H-15), 2.53 (s, 3H, N-CH3), 2.60 (br t, J = 8 Hz, 2H, 3'-5 a2~tid;"e CH2), 2.70 (br s, 4H, piperazinyl CH2), 2.9-3.1 (m, 2H, H-10 and H-15), 3.53 (s, 6H, OCH3), 3.86 (m, lH, H-12), 4.69 (br s, lH, H-6), 4.82 (t, J = 8 Hz, 4H, 2'and 4' azetidine CHz), 5.15 (br s, 2H, NH2), 5.72 (br s, 1 H, H-7), 5.57 (br d, 1 H H-11), 5.66 (br s, lH, H-9), 6.00 (t, J = 9 Hz, lH, H-5), 6.68 (t, J = 9 Hz, lH, H-4), 7.15 (s, lH, H-19), 7.24 (br s, lH, H-3), 7.45 (s, lH, NH), 9.60 (s, lH, NH-22); mlz 813. (M+ + Na); IR
10 (KBr, cm l) 1738, 1688, 1646, 1583, 1471; Analysis calculated for C37H54N~OllS-H2O:
C, 54.94; H, 6.97; N, 10.39%. Found: C, 54.92; H, 6.87; N, 10.25%.

17-Allylamino-11 -keto-17-demethoxvgeldanamycin 17-Allylamino-17-demethoxygeldanamycin (90 mg, 0.15 mmol) was dissolved in 15 CHC13 (4 mL) to which was added the Dess-Martin periodinane (382 mg, 0.90 mmol) and the reaction heated to reflux. After 1 hour the reaction was complete and the reaction mixture diluted with CHCI3. The organic layer was washed with aqueous Na2S2O3, saturated aqueous sodium bicarbonate and dried over sodium sulfate. Thesolvent was removed by evaporation and the residue recrystallized from ethyl 20 AcePt~/hexanes to give 17-allylamino-11 -keto-17-demethoxygeldanamycin, yield 84 mg (96%), as light red crystals, mp 112-118~C (dec); lH-NMR (300 MHz, CDCI3) ~ 1.02 (d, 3H,J=7Hz),1.25(d,3H,J=7Hz),1.48(m,2H),1.75(m,1 H),1.80(s,3H),1.98 (s, 3 H), 2.32 (dd, 1 H, J = 14 Hz, 5 Hz), 2.58 (dd, 1 H, J = 14 Hz, 7 Hz), 3.29(overlapping s, 6 H), 3.66 (m, 1 ), 4.08 (m, 3 H), 4.28 (d, 1 H, J = 8 Hz), 4.82 (br 25 exchangeable, 2 H), 5.18-5.3 (m, 3 H), 5.55 (d, 1 H, J = 9 Hz), 5.8-6.0 (m, 3 H), 6.83 (br exchangeable, 1 H), 6.49 (t, 1 H, J = 11 Hz), 6.92 (d, 1 H, J = 11 Hz), 7.19 (s,1 H), 9.22 (s, 1 H); mass spectrum m/z 585 (M + 2); Analysis calculated for C31H4,N3O8-0.5 (ethyl acetate): C, 63.14; H, 7.23; N, 6.69%. Found: C, 63.19; H, 7.06; N, 6.92%.
The 11-keto compounds of Examples 77-87 were prepared by oxidation of the 30 appropri~le17-aminosubstituted17-demethoxygeldanamycinsaccordingtothemethod of Example 76.

WO 95/0134:~ PCT/~94/00160 2~ ~'32~

17-CycioproPvlamino-11 -keto-17-demethoxyqeldanamycin Mp 110-115C (dec); 'H-NMR (300 MHz, CDCI3) ~ 0.75-0.95 (m, 4 H), 1.03 (d, 3H,J=7Hz),1.24(d,3H,J=7Hz),1.72(m,1 H),1.79(s,3H),1.98(s,3H),2.78 5 (m,3H),3.32(s,3H),3.4-3.5(m,4H),4.08(m,2H),4.28(d,1 H,J=8Hz),4.81 (br exchangeable, 2 H), 5.15 (s, 1 H), 5.57 (d, 1 H, J = 10 Hz), 5.71 (t, 1 H, J = 7 Hz), 6.26 (bræ, 1 H), 6.51 (t, 1 H, J = 12 Hz), 6.92 (d, 1 H, J = 12 Hz), 7.15 (s, 1 H), 9.22 (s, 1 H); mass spectrum m/z 606 (M + Na) 17-lsoProPvlamino-11 -keto-17-demethoxvqeldanamycin Mp 105-111 C (dec); 1H-NMR (300 MHz, CDCI3) ~ 1.02 (d, 3 H, J = 7 Hz), 1.25 (overlapping douhletc, 9 H), 1.48 (m, 2 H), 1.75 (m, 1 H), 1.80 (s, 3 H), 1.98 (s, 3 H), 2.27 (dd, 1 H, J = 14 Hz, 5 Hz), 2.66 (dd, 1 H, J = 14 Hz, 7 Hz), 3.32 (overlapping s, 6 H), 3.67 (m, 1 H), 3.98 (m, 1 H), 4.09 (t, 1 H, J = 5 Hz), 4.38 (d, 1 H, J = 9 Hz), 4.82 15 (br ~ ;chal)ge~hlQ, 2 H), 5.17 (s, 1 H), 5.54 (d, 1 H, J = 9 Hz), 5.83 (t, 1 H, J = 7 Hz), 6.17 (d, 1 H, J = 9 Hz), 6.49 (t, 1 H, J = 11 Hz), 6.92 (d, 1 H, J = 11 Hz), 7.17 (s, 1 H), 9.27 (s, 1 H); mass spectrum m/z 587 (M + 2); Analysis c-'cu'~ted for C3lH43N3O8-0.2CHzC12: C, 62.22; H, 7.20; N,6.98%. Found: C, 62.16; H, 7.0; N, 6.75%.

17-Methylamino-11 -keto-17-demethoxvqeldanamycin Mp 108-120C (dec); 1H-NMR (300 MHz, CDCI3) ~ 1.06 (d, 3 H, J=7Hz),1.23(d,3H,J=7Hz),1.48(m,2H),1.80(s,3H),1.97(s,3H),2.43(dd, 1 H, J = 14 Hz, 5 Hz), 2.68 (dd, 1 H, J = 14 Hz, 7 Hz), 3.17 (s, 3 H), 3.30 (overlapping s, 6 H), 3.68 (m, 1 H), 4.11 (t, 1 H, J = 5 Hz), 4.32 (d, 1 H, J = 8 Hz), 4.80 (br 25 exch~~eable, 2 H), 5.21 (s, 1 H), 5.53 (d, 1 H, J = 10 Hz), 5.83 (t, 1 H, J = 7 Hz), 6.51 (t, 1 H, J = 12 Hz), 6.92 (d, 1 H, J = 10 Hz), 7.19 (s, 1 H), 9.28 (s, 1 H); mass spet:trum m/z 580 (M + Na).

17-(2'-Hydroxyethylamino)-11 -keto-17-demethoxyqeldanamvcin Mp 108-111 C (dec); 1H-NMR (300 MHz, CDCI3) ~ 1.07 (d, 3 H, J = 7 Hz), 1.25 (d,3H,J=7Hz),1.51 (m,2H),1.76(m,1 H), 1.81 (s,3H),1.98(s,3H),2.32(dd, 1 H, J = 14 Hz, 4 Hz), 2.63 (dd, 1 H, J = 14 Hz, 7 Hz), 3.34 (overlapping s, 6 H), 3.62 (m, 3 H), 3.88 (t, 2 H, J = 5 Hz), 4.09 (t, 1 H, J = 5 Hz), 4.28 (d, 1 H, J = 9 Hz), 4.8 WO 95/0L342 PCT/~B94/00160 --3~

(br exchangeable, 2 H), 5.18 (s, 1 H), 5.53 (d, 1 H, J = 13 Hz), 5.79 (d, 1 H, J = 8 Hz), 6.48 (t, 1 H, J = 14 Hz), 6.92 (d, 1 H, J = 14 Hz), 7.18 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 589 (M + 2); Analysis calculated for C30H4lN3Og: C, 61.32; H, 7.03; N, 7.15%. Found: C, 60.96; H, 7.12; N, 6.90%.

1 7-(2'-MethoxYethYlamino)-1 1 -keto-1 7-demethoxyqeldarlar"ycin Mp 130-134C (dec); lH-NMR (300 MHz, CDCI3) ~1.05 (d, 3 H, J = 7 Hz), 1.24 (d,3H,J=7Hz),1.82(m,2H),1.85(s,3H),2.00(s,3H),2.34(dd,1 H,J=14Hz, 5 Hz), 2.62 (dd, 1 H, J = 14 Hz, 7 Hz), 3.33 (overlapping s, 6 H), 3.40 (s, 3 H), 3.6-3.7 (m, 5 H), 4.10 (m, 2 H), 4.31 (d, 1 H, J = 9 Hz), 4.8 (br exchangeable, 2 H), 5.22 (s, 1 H), 5.55 (d, 1 H, J = 10 Hz), 5.82 (t, 1 H, J = 7 Hz), 6.49 (t, 1 H, J = 12 Hz), 6.92 (d, 1 H, J = 10 Hz), 7.18 (s, 1 H), 9.24 (s, 1 H); mass spectrum m/z 603 (M + 2); Analysis c~ tPd for C3lH43N3O9: C, 61.79; H, 7.20; N, 6.98%. Found: C, 61.75; H, 7.02;
N, 6.86%.

1 7-(2'-Methvlthioethylamino)-1 1 -keto-1 7-demethoxyqeldanamycin Mp 95-100C (dec); lH-NMR (300 MHz, CDCI3) ~1.05 (d, 3 H, J = 7 Hz), 1.23 (d,3H,J=7Hz), 1.48(m,2H), 1.80(m, 1 H), 1.81 (s,3H), 1.95(s,3H),2.11 (s,3 H), 2.32 (dd, 1 H, J = 14 Hz, 5 Hz), 2.63 (dd, 1 H, J = 14 Hz, 5 Hz~, 2.76 (t, 2 H, J =
20 7 Hz), 3.32 (overlapp,g s, 6 H), 3.67 (t, 2 H, J = 7 Hz), 3.67 (single proton under triplet), 4.08 (t, 1 H, J = 5 Hz), 4.37 (d, 1 H, J = 7 Hz), 4.8 (br s, 2 H), 5.18 (s, 1 H), 5.52 (d, 1 H, J = 9 Hz), 5.83 (apparent t, 1 H, J = 9 Hz), 6.50 (t, 1 H, J = 10 Hz), 6.92 (br d, 1 H, J = 12 Hz), 7.19 (s, 1 H), 9.21 (s, 1 H); mass spectrum m/z 620 (M + 2);
Analysis c~lGulAtQd for C3lH43N3O8S: C, 60.27; H, 7.02; N, 6.80%. Found: C, 60.16; H, 6.82; N, 6.67%.

1 7-(2'-Fluoroethvlamino)-1 1 -keto-1 7-demethoxyqeldanamycin Mp 99-105C (dec); lH-NMR (300 MHz, CDCI3) ~1.04 (d, 3 H, J = 7 Hz), 1.25 (d, 3 H, J = 7 Hz), 1.50 (m, 2 H), 1.80 (m, 1 H), 1.81 (s, 3 H), 1.99 (s, 3 H), 2.31 (dd, 1 H, J = 14 Hz, 5 Hz), 2.62 (dd, 1 H, J = 14 Hz, 9 Hz), 3.31 (overlappi.,g s, 6 H), 3.68 (dd,1 H,J=9Hz,7Hz),3.77(m,1 H),3.84(m,1 H),4.10(t,1 H,J=6Hz),4.30(d, 1 H, J = 8 Hz), 4.54 (t, 1 H, J = 5 Hz), 4.70 (t, 1 H, J = 5 Hz), 5.19 (s, 1 H), 5.54 (d, 1 H, J = 9 Hz), 5.83 (t, 1 H, J = 9 Hz), 6.28 (t, 1 H, J = 6 Hz), 6.50 (t, 1 H, J = 12 Hz), ~ WO 95/0134Z ~ ~ ~ 6 ~ ~ ~ PCT/IB94/00160 6.93 (d, 1 H, J = 12 Hz), 7.20 (s, 1 H), 9.17 (s, 1 H); mass spectrum m/z 591 (M + 2);
Analysis calculated for C30H40N308-1/12CHCI3: C, 60.26; H, 6.84; N, 7.01%. Found: C, 60.57; H, 6.54; N, 6.87%.

17-(2'-Cyanoethvlamino)-11 -keto-17-demethoxvqeldanamycin Mp 102-107C (dec); 'H-NMR (300 MHz, CDCI3) ~ 1.07 (d, 2 H, J = 7 Hz), 1.25 (d, 3 H, J = 7 Hz), 1.53 (m, 2 H), 1.80 (m, 1 H), 1.81 (s, 3H), 2.00 (s, 3 H), 2.27 (dd, 1 H,J=14Hz,5Hz),2.58(dd,1 H,J=14Hz,6Hz),2.69(t,2H,J=8Hz),3.32(s, 3 H), 3.33 (s, 3 H), 3.71 (dd, 1 H, J = 9 Hz, 7 Hz), 3.80 (q, 2 H, J = 7 Hz), 4.07 (m, 1 H), 4.29 (d, 1 H, J = 8 Hz), 4.8 (brs, 2 H), 5.17 (s, 1 H), 5.55 (d, 1 H, J = 9 Hz), 5.84 (apparent t, 1 H, J--9 Hz), 6.02 (t, 1 H, J = 6 Hz), 6.51 (t, 1 H, J = 11 Hz), 6.94 (br d, 1 H, J = 12 Hz), 7.22 (s, 1 H), 9.09 (s, 1 H); mass spectrum m/z 619 (M + Na);
Analysis calc~ ted for C3,H40N408: C, 62.40; H, 6.76; N, 9.39%. Found: C, 61.81; H, 6.45; N, 9.06%.

17-Azetidin-1 -yl-11 -keto-17-demethoxyqeldanamvcin Mp 112-116C (dec); 'H-NMR (300 MHz, CDCI3) ~ 1.02 (d, 3 H, J=7Hz),1.37(d,3H,J=7Hz),1.48(m,2H),1.67(m,1 H),1.82(s,3H),1.97(s, 3 H), 2.22 (dd, 1 H, J = 14 Hz, 5 Hz), 2.42 (m, 2 H), 2.58 (dd, 1 H, J = 14 Hz, 7 Hz), 3.30 (overlapping s, 6 H), 3.61 (m, 1 H), 5.15 (t, 1 H, J = 5 Hz), 4.17 (d, 1 H, J = 8 Hz), 4.62(t,4H,J=7Hz),4.80(brs,2H),5.19(s,1 H),5.51 (d,1 H,J=lOHz),5.76(t, 1 H, J = 10 Hz), 6.48 (t, 1 H, J = 12 Hz), 6.90 (br d, 1 H, J = 12 Hz), 6.97 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 583 (M+); Analysis c~lcu~ted for C3,H4,N308: C,63.79; H, 7.08; N, 7.20%. Found: C, 63.83; H, 7.11; N, 6.84%.

17-(3'-Hydroxyazetidin-1 -vl)-11 -keto-17-demethoxvqeldanamycin Mp 145C ffoam); 'H-NMR (300 MHz, CDCI3) ~ 1.0 (d, 3 H, J = 4 Hz), 1.2-1.3 (m, 6 H), 1.4 (m, 2 H), 1.7 (m, 1 H), 1.8 (s, 3 H), 2.15 (s, 2 H), 2.2 (d, 1 H, J = 4 Hz), 2.5 (m, 1 H), 3.3 (2 singlets, 6 H), 3.6 (m, 1 H), 3.8 (br s, 1 H), 4.15 (m, 1 H), 4.3 (d, 1 H,J=7Hz),4.354.5(m,2H),4.5-4.9(m,3H),5.0-5.2(m,3H),5.5(d,1 H,J=7 Hz), 5.8 (m, 1 H), 6.5 (t, 1 H, J = 10 Hz), 6.9 (d, 1 H, J = 14 Hz), 7.0 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 622 (M + 2); Analysis calculated for C3lH43N30~-H20: C, 60.28; H, 7.02; N, 6.80%. Found: C, 60.76; H, 7.10; N, 6.36%.

3 2 ~

E)~AMPLE 87 17-(3'-Methoxvazetidin-1 -yl)-11 -keto-17-demethoxvqeldanamycin Mp 128C ffoam); 1H-NMR (300 MHz, CDCI3) ~ 1.0 (d, 3 H, J = 7 Hz), 1.25 (m, 6 H),1.45 (m, 2 H), 1.6-1.85 (m, 4 H, contains methyl singlet), 1.9-2.1 (m, 4 H, contains 5 methyl singlet), 2.1-2.3 (m, 1 H), 2.95-3.25 (m, 1 H), 3.3 (m, 9 H, contains 3 methyl singlets), 3.6 (m, 1 H), 4.04.3 (m, 3 H), 4.35-4.5 (m, 2 H), 4.6-4.8 (m, 2 H), 5.1 (br s, 2H),5.2(s,1H),5.5(d,1H,J=10Hz),5.8(m,1H),6.5(t,1H,J=12Hz),6.9(d, 1 H, J = 12 Hz), 7.0 (s,1 H), 9.25 (s, 1 H); mass spectrum m/z 636 (M + Na); Analysis c~lc~ ted for Cs2H43N3O9: C, 62.63; H, 7.06; N, 6.85%. Found: C, 62.23; H, 7.19; N, 10 6.70%.

17-Methvlamino-11 -12'-morPholinoethylamino)-17-demethoxygeldanamycin In a dry flask, sodium triacetoxyborohydride (152 mg, 0.72 mmol) in dichloroethane (4 mL) was sonicated until a fine suspension was formed. The mixture 15 was removed from the sonicator and treated with N-aminoethylmorpholine (47 ~L, 0.36 mmol) and a few crystals of sodium sulfate. 11 -Keto-17-methylamino-17-demethoxygeldanfi."ycin (100 mg, 0.18 mmol) was then added and the mixture stirred at room temperature for 24 hours. The reaction mixture was washed with saturatedsodium carbonate and brine and then dried over sodium sulfate. The solvent was 20 removed by rotary evaporation and the crude product purified by column chromatography (silica gel, 10% methanol in methylene chloride) to give the title compound as a purple solid; Yield 87 mg, (71%), mp 119-120C; 1H-NMR (300 MHz, CDCI3)~0.90(d,3H,J=7Hz),1.00(d,3H,J=7Hz),1.42(m,2H),1.59(m,1 H), 1.65 (s, 3 H), 1.95 (s, 3 H), 2.03 (br s 1 H), 2.25 (dd, 1 H, J = 8 Hz), 2.68 (m, 3 H), 2.81 25 (m, 2 H), 3.15 (d, 3 H, J = 7 Hz), 3.22 (s, 3 H), 3.28 (s, 3 H), 3.52 (m, 1 H), 3.62 (t, 4 H, J = 4 Hz), 4.44 (brd, 1 H, J = 10 Hz), 4.75 (brs, 1 H), 5.40 (s, 1 H), 5.55 (d, 1 H, J = 10 Hz), 5.78 (dd, 1 H, J = 8 Hz), 6.28 (d, 1 H, J = 7 Hz), 6.45 (t, 1 H, J = 13 Hz), 7.00 (m, 1 H), 7.05 (s, 1 H), 9.40 (s, 1 H); mass spectrum m/z 672 (M+).
The compounds of Examples 89-95 were prepared from 11 -keto-17-30 (methylamino)-17-demethoxygeldanamycin and the appropriate amines using the reductive amination method of Example 88.

~ WO 95/01342 PCT/IB94/00160 21~6320 11 -Benzvlamino-1 7-methvlamino-1 7-demethoxyqeldanamycin Mp 123-126C; 1H-NMR (300 MHz, CDCI3) ~ 0.91 (d, 3 H, J = 8 Hz), 0.98 (d, 3H,J=8Hz),1.35(m,1 H),1.58(m,2H),1.66(m,1 H),1.70(s,3H),1.95(s,3H), 5 2.32 (dd, 1 H, J = 8 Hz), 2.75 (dd, 1 H, J = 8 Hz, 12 Hz), 2.93 (m, 1 H), 3.08 (s, 4 H), 3.12(d,3H,J=8Hz),3.15(s,6H),3.46(d, 1 H,J=8Hz),3.61 (d,1 H,J=24Hz), 3.78 (d, 1 H, J = 24 Hz), 4.30 (d, 1 H, J = 8 Hz), 4.75 (br s, 2 H), 5.35 (s, 1 H), 5.70 (m, ~ H), 6.28 (d, 1 H, J = 8 Hz), 6.43 (t, 1 H, J = 12 Hz), 7.01 (brd, 1 H, J = 16 Hz), 7.08 (s, 1 H), 7.20 (m, 5 H), 9.42 (s, 1 H); mass spectrum m/z 649 (M + 1).

11 -Cyclopropylamino-1 7-methylamino-1 7-demethoxvqeldanamvcin Mp 120-123C; 1H-NMR (300 MHz, CDCI3) ~ 0.30 (m, 4 H), 0.93 (d, 3 H, J = 8 Hz), 1.02 (d, 3 H, J = 8 Hz), 1.40 (m, 2 H), 1.72 (s, 3 H), 1.80 (br s, 1 H), 1.99 (s, 3 H), 2.15 (s, 1 H), 2.32 (dd, 1 H, J = 8 Hz, 13 Hz), 3.00 (m, 1 H), 3.18 (d, 3 H, J = 7 Hz), 3.28(s,3H),3.30(s,3H),3.57(m,1 H),4.39(d,1 H,J=8Hz),4.84(brs,2H),5.63 (d,1 H,J=8Hz),5.80(dd,1 H,J=8Hz,8Hz),6.32(d,1 H,J=7Hz),6.51 (t,1 H, J = 13 Hz), 7.01 (br d, 1 H, J = 17 Hz), 7.09 (s, 1 H), 9.44 (s, 1 H); mass spectrum m/z 600 (M + 1).

1 1 -Isoamylamino-1 7-methylamino-1 7-demethoxyqeldanamycin Mp 108-110C; 1H-NMR (300 MHz, CDCI3) ~ 0.90 (d, 3 H, J = 8 Hz), 1.00 (d, 3 H, J = 8 Hz), 1.22-1.60 (m, 5 H), 1.63 (m, 1 H), 1.65 (s, 3 H), 1.95 (s, 3 H), 2.29 (dd, 1 H, J = 7 Hz), 2.53 (m, 1 H), 2.75 (m, 2 H), 2.90 (m, 1 H), 3.13 (d, 3 H, J = 7 Hz), 3.23 (s, 3 H), 3.28 (s, 3 H), 3.52 (m, 1 H), 4.90 (br s, 2 H), 5.35 (s, 1 H), 5.60 (br d, 1 H, J = 8), 5.75 (dd, 1 H, J = 8 Hz), 6.30 (d, 1 H, J = 7 Hz), 6.43 (t, 1 H, J = 12 Hz), 7.02 (s, 1 H), 7.09 (br s, 1 H), 9.38 (s, 1 H); mass spectrum m/z 629 (M + 1) 11 -(2'-Hvdroxyethylamino)-1 7-methvlamino-1 7-demethoxvqeldanamvcin Mp (oil); 1H-NMR (300 MHz, CDC13) ~ 0.95 (d, 3 H, J = 7 Hz), 1.09 (d, 3 H, J =
7 Hz), 1.45 (m, 1 H), 1.58 (m, 2 H), 1.72 (s, 3 H), 2.00 (s, 3 H), 2.30 (dd, 1 H, J = 8 Hz), 3.02 (m, 9 H), 3.20 (d, 3 H, J = 7 Hz), 3.28 (s, 3 H), 3.35 (s, 3 H), 3.62 (m, 3 H), 4.55 (br s, 1 H), 4.90 (br s, 2 H), 5.40 (br s, 1 H), 5.63 (d, 1 H, J = 10 Hz), 5.81 (dd, 1 H, J = 8 Hz), 6.36 (d, 1 H, J = 7 Hz), 6.50 (t, 1 H, J = 13 Hz), 7.08 (m, 1 H), 7.12 (s, WO 95/0L342 PCT/IB94/00160 1~
3 2 ~

1 H), 9.40 (s, 1 H); mass spectrum m/z 603 (M + 1).

11 -(3'-DimethYIaminoPropylamino)-1 7-methvlamino-1 7-demethoxy~eldanamYcin Mp 105-108C; 1H-NMR (300 MHz, CDCI3) ~ 0.95 (d, 3 H, J = 7 Hz), 1.03 (d, 3 H, J = 7 Hz), 1.48 (m, 1 H), 1.65 (m, 3 H), 1.70 (s, 3 H), 1.98 (s, 3 H), 2.20 (s, 6 H), 2.28 (m, 3 H), 2.65 (m, 1 H), 2.70 (m, 2 H), 2.84 (dd, 1 H, J = 7 Hz), 2.90 (m, 1 H), 3.20 (d,3H,J=7Hz),3.29(s,3H),3.33(s,3H),3.57(m,1 H),4.48(d,1 H,J=13Hz), 4.80 (br s, 2 H), 5.41 (br s, 1 H), 5.62 (br d, 1 H, J = 13 Hz), 5.81 (dd, 1 H, J = 8 Hz), 6.32 (d, 1 H, J = 7 Hz), 6.49 (t, 1 H, J = 13 Hz), 7.09 (m, 1 H), 7.10 (s, 1 H), 9.43 (s, 1 H); mass spectrum m/z 644 (M+ + 1).

1 1 -Allylamino-1 7-methylamino-1 7-demethoxYgeldanamycin Mp 123-125C; 1H-NMR (300 MHz, CDCI3) ~ 0.95 (d, 3 H, J = 7 Hz), 1.03 (d, 3 H, J = 7 Hz), 1.41 (m, 1 H), 1.52 (m, 1 H), 1.72 (s, 3 H), 1.84 (m, 2 H), 2.00 (s, 3 H), 2.36 (dd, 1 H, J = 7 Hz), 2.80 (m, 2 H), 3.00 (m, 1 H), 3.20 (d, 3 H, J = 7 Hz), 3.25 (s, 3 H), 3.32 (s, 3 H), 3.58 (m, 1 H), 4.42 (d, 1 H, J = 10 Hz), 4.80 (brs, 2 H), 5.08 (dd, 2 H, J = 16 Hz), 5.40 (s, 1 H), 5.65 (d, 1 H, J = 13 Hz), 5.83 (m, 2 H), 6.32 (d, 1 H, J
= 7 Hz), 6.50 (t, 1 H, J = 13 Hz), 7.05 (m, 1 H), 7.10 (s, 1 H), 9.45 (s, 1 H); mass spectrum m/z 599 (M+ + 1).
E3(AMPLE 95 1 7-Azetidin-1 -yl-1 1 -oximino-1 7-demethoxyqeldanamvcin To a solution of 17-azetidin-1-yl-11-keto-17-demethoxygeldanamycin (0.10 g, 0.17 mmol) in ethanol was added a solution of hydroxylamine hydrochloride (0.10 g, 1.42 mmol) and triethylamine (0.2 mL) in ethanol. The reaction mixture was stirred at room temperature for 2.5 hours and there~rler the solvent was removed by rotary evaporation and the residue dissolved in CHCI3. The chloroform solution was washed with water, dried over sodium sulfate and the solvent removed by rotary evaporation.
The residue was purified by column chromatography (silica gel, 15% acetone in CHCI3) to give 1 7-azetidino-11 -oximino-1 7-demethoxygeldanamycin (70 mg, 68 %), as a purple powder. Mp 130-145C (dec); lH-NMR (300 MHz, CDCI3) ~ 0.98 (d, 3 H, J = 7 Hz), 1.17 (d, 3 H, J = 7 Hz), 1.37 (m, 2 H), 1.54 (m, 1 H), 1.81 (s, 2 H), 1.95 (s, 3 H), 2.25 (dd, 1 H, J = 14 Hz, 4 Hz), 2.41 (m, 2 H), 2.61 (dd, 1 H, J = 14 Hz, 3 Hz), 3.20 (s, 3 H), 3.28 (s, 3 H), 4.02 (m, 2 H), 4.13 (d, 1 H, J = 8 Hz), 4.65 (t, 1 H, J = 8 Hz), 5.01 ~ WO 95/01342 PCT/IB94/00160 2~66~2~

(br exchangeable, 2 H), 5.09 (s, 1 H), 5.37 (br d, 1 H, J = 10 Hz), 5.74 (t, 1 H, J = 10 Hz)l 6.45 (t, 1 H, J = 12 Hz), 6.89 (br s, 1 H), 6.97 (s, 1 H), 9.27 (s, 1 H); mass spectrum m/z 586 (M - 2); Analysis calculated for C31H42N408: C, 62.19; H, 7.07; N, 9.36%. Found: C, 61.76; H, 6.88; N, 9.14%.
The compounds of Examples 96-99 were prepared according to the method of Example 95 from the appropriate 11-keto-17-demethoxygeldanamycin.

17-(2'-Methoxyethyiamino)-11 -oximino-17-demethoxvqeldanamvcin Mp 119-127C (dec); lH-NMR (300 MHz, CDCI3) ~ 1.03 (d, 3 H, J = 7 Hz),1.18 (d, 3 H, J = 7 Hz), 1.39 (m, 1 H), 1.84 (s, 3 H), 1.86 (m, 1 H), 1.98 (s, 3 H), 2.32 (dd, 1 H,J=14Hz,4Hz),2.68(dd,1 H,J=14Hz,7Hz),3.21 (s,3H),3.27(s,3H),3.38 (s, 3 H), 3.58 (m, 2 H), 3.62 (m, 2 H), 3.95 (m, 2 H), 4.12 (d, 1 H, J = 8 Hz), 4.90 (br s,1 H),5.11 (s,1 H),5.38(brd,1 H,J=8Hz),5.75(t,1 H,J=lOHz),6.50(m,2H), 6.9 (br s, 1 H), 7.17 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 616 (M+).

17-CycloPropylamino-11 -oximino-17-demethoxygeldanamvcin Mp (amorphous); 1H-NMR (300 MHz, CDCI3) ~ 0.7-0.9 (m, 4 H), 1.0 (d, 3 H, J
= 7 Hz), 1.2 (d, 3 H, J = 7 Hz), 1.3-1.6 (m, 3 H), 1.8 (s, 3 H), 1.95 (m, 1 H), 2.0 (s, 3 H), 2.7 (m, 1 H), 2.9 (m, 2 H), 3.2 (s, 3 H), 3.3 (s, 3 H), 4.05 (br s, 2 H), 4.15 (d, 1 H, 20 J = 7 Hz), 5.13 (d, 2 H, J = 10 Hz), 5.45 (d, 1 H, J = 10 Hz), 5.8 (t, 1 H, J = 10 Hz), 6.3 l~d, 1 H, J = 3 Hz), 6.48 (t, 1 H, J = 10 Hz), 6.9 (br d, 1 H, J = 10 Hz), 7.08 (m, 1 H), 7.15 (s, 1 H), 9.28 (br s, 1 H); mass spectrum m/z 621 (M + Na); Analysis calc~ t~d for C3lH42N408-0.5 H20: C, 61.27; H, 7.13; N, 9.22%. Found: C, 61.74; H, 7.25; N, 8.71%.

17-lsoproPvlamino-11 -oximino-17-demethoxyqeldanamycin Mp 158-160C; lH-NMR (300 MHz, CDCI3) ~ 1.0 (d, 3 H, J = 7 Hz), 1.15 (d, 3 H, J = 7 Hz), 1.2 (d, 3 H, J = 7 Hz),1.3 (d, 3 H, J = 7 Hz),1.45-1.6 (br t,1 H), 1.7-1.9 (m, 4 H), 2.0 (s, 3 H), 2.2 (br d, 1 H, J = 14), 2.75 (t, 1 H, J = 14 Hz), 3.15 (s, 3 H), 3.25 (s, 3 H), 3.84.05 (m, 3 H), 4.1 (d, 1 H, J =10), 5.1 (s, 1 H), 5.25-5.5 (br d, 3 H), 5.7(t,1 H,J=10Hz),6.2(d,1 H,J= 10Hz),6.4(t,1 H,J= 10Hz),6.75(brd,1 H), 7.1 (s,1 H), 9.25 (br s,1 H); mass spectrum m/z 623 (M + Na); Analysis c~'cl~l~tecl for C3lH44N408-1.5 H20: C, 59.32; H,7.55; N,8.93%. Found: C,59.27; H,7.07; N, 8.66%.

WO 95/01342 ~ 6 ~ 32 ~ PCT/Is94/00160 1 7-Allylamino-1 1 -oximino-1 7-demethoxvqeldanamvcin Mp 135C; mass spectrum m/z 621 (M + Na).

Claims (19)

1. A compound of the formula I

and pharmaceutically acceptable salts and prodrugs thereof;
wherein R1 and R2 are both hydrogen or R1 and R2 together form a single bond;
R3 is hydrogen and R4 is selected from the group consisting of OR10, NHR8 and halo wherein R10 is selected from the group consisting of hydrogen, R11C(=O)-, and R11SO2- and R12R13NSO2NHC(=O)-, wherein R11 is selected from the group consisting of amino, (C1-C8)alkyl, amino(C1-C8)alkyl, hydroxy(C1-C8)alkyl, protected amino(C1-C8)alkyl, protected hydroxy(C1-C8)alkyl, phenyl and naphthyl; and R12 and R13 are selected from the group consisting of hydrogen, (C1-C8)alkyl, amino(C1-C8)alkyl, dimethylamino(C1-C8)alkyl, cyclo(C3-C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1-C4)alkylpiperidinyl and N-(C1-C4)piperazinyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1-C8)alkyl, halo, nitro, amino, azido and (C1-C8)alkoxyl;
or R3 and R4 together form a group of the formula =J
wherein J is selected from O and NOH:
R5 is NR8R9 wherein R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl and (C2-C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1-C8)alkylthio, optionally substituted amino, hydroxyl, (C1-C8)alkoxyl, carboxyl, amidino, acylamino, and (C2-C6)heterocycloalkyl and (C2-C6)heterocycloaryl groups selected from the group comprising imidizaloly, furyl, tetrahydrofuryl;and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl; or R5 is R14O wherein R14 is hydrogen or (C1-C8)alkyl and R6 is hydrogen or a group of the formula A
wherein m is 0 or an integer from 1-5 and each R7 is independently selected from halo, azido, nitro, (C1-C8)alkyl, C1-C8alkoxyl, phenyl and naphthyl, cyano and NR8R9 wherein R8 and R9 are as defined above; with the proviso that when R1 and R2 together form a single bond and R3 is hydrogen and R4 OR10 and R10 is hydrogen R5 cannot be OR14, wherein R14 is hydrogen or methyl, or NR8R9 wherein HNR8R9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, .beta.-hydroxyethylamine, .beta.-chloroethylamine, .beta.-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycolamine, .beta.-morpholinoethylamine, .beta.-piperidinoethylamine, picolylamine, .beta.-pyrrolidinoethylamine, .beta.-pyridinylethylamine, .beta.-methoxyethylamine, and .beta.-N-methylaminoethylamine; and when R5 is OR14 and R10 is R11C(=O), R11 cannot be methyl.

2. The compound of claim 1 wherein R1 and R2 are each hydrogen and R3, R4, R5 and R6 are as defined in claim 1.

3. The compound of claim 1 wherein R1 and R2 together form a single bond and R3, R4, R5 and R6 are as defined in claim 1.

4. The compound of claim 2 wherein R3 is hydrogen and R4 is selected from OR10, NHR8 and halo.

5. The compound of claim 2 wherein R3 and R4 together form a group of the formula =O.

6. The compound of claim 2 wherein R3 and R4 together form a group of the formula =NOH.

7. The compound of claim 3 wherein R3 and R4 together form a group of the formula =O.

8. The compound of claim 3 wherein R3 and R4 together form a group of the formula =NOH.

9. The compound of claim 1 selected from the group consisting of 17-Amino-4,5-dihydro-17-demethoxy-geldanamycin;
17-Methylamino-4,5-dihydro-17-demethoxygeldanamycin;
17-Cyclopropylamino-4,5-dihydro-17-demethoxygeldanamycin;
17-(2'-Hydroxyethylamino)-4,5-dihydro-17-demethoxygeldanamycin;
17-(2'-Methoxyethylamino)-4,5-dihydro-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-4,5-dihydro-17-demethoxygeldanamycin;
17-[s-(+)-2-Hydroxypropylamino]-4,5-dihydro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-4,5-dihydro-17-demethoxygeldanamycin;
17-(3-Hydroxyazetidin-1-yl)-4,5-dihydro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-4,5-dihydro-11-.alpha.-fluoro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-17-demethoxygeldanamycin;
17-(2'-Cyanoethylamino)-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-17-demethoxygeldanamycin;
17-Amino-22-(2'-methoxyphenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(3'-methoxyphenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(4'-chlorophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(3',4'-dichlorophenacyl)-17-demethoxygeldanamycin;

17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(4'-azido-3'-iodophenacyl)-17-demethoxygeldanamycin;
17-Amino-11-.alpha.-fluoro-17-demethoxygeldanamycin;
17-Allylamino-11-.alpha.-fluoro-17-demethoxygeldanamycin;
17-Propargylamino-11-.alpha.-fluoro-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-11-.alpha.-fluoro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-11-(4'-azidophenyl)sulfamylcarbonyl-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-11-keto-17-demethoxygeldanamycin;
17-Azetidin-1-yl-11-keto-17-demethoxygeldanamycin; and 17-(3'-Hydroxyazetidin-1-yl)-11-keto-17-demethoxygeldanamycin.

10. A pharmaceutical composition for preventing or inhibiting the growth of a tumor in a mammal comprising an antitumor effective amount of a compound according to claim 1.

11. A pharmaceutical composition for inhibiting an oncogene product in a mammal comprising an oncogene product inhibiting effective amount of a compound according to claim 1.

12. A pharmaceutical composition for preventing cancer in a mammal comprising an oncogene product inhibiting or antitumor effective amount of a compound according to claim 1.

13. A pharmaceutical composition for inhibiting growth factors that play an important role in uncontrolled cell proliferation such as the EGF receptor, the NGF
receptor, the PDGF receptor and the insulin receptor in a mammal comprising a growth factor inhibiting effective amount of a compound of claim 1.

14. A method of preventing or inhibiting the growth of a tumor in a mammal comprising administering to said mammal an antitumor effective amount of a compound according to claim 1.

15. A method of inhibiting an oncogene product in a mammal comprising administering to said mammal an oncogene product inhibiting effective amount of a compound according to claim 1.

16. The method of claim 15 wherein said oncogene product is an an ErbB-2, src, lck, fyn or abl oncogene product.

17. The method according to claim 16 wherein said oncogene product is the ErbB-2 oncogene product.

18. A method of treating or preventing cancer in a mammal comprising administering to said mammal an oncogene product inhibiting or antitumor effective amount of a compound according to claim 1.

19. A method of inhibiting growth factors that play an important role in uncontrolled cell proliferation such as the EGF receptor, the NGF receptor, the PDGF
receptor and the insulin receptor in a mammal comprising administering to said mammal a growth factor inhibiting effective amount of a compound of claim 1.