ZA200307466B - Novel tyrosine kinase inhibitors. - Google Patents

Novel tyrosine kinase inhibitors. Download PDF

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ZA200307466B
ZA200307466B ZA200307466A ZA200307466A ZA200307466B ZA 200307466 B ZA200307466 B ZA 200307466B ZA 200307466 A ZA200307466 A ZA 200307466A ZA 200307466 A ZA200307466 A ZA 200307466A ZA 200307466 B ZA200307466 B ZA 200307466B
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methyl
ethylamino
pyridin
phenyl
hydroxy
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ZA200307466A
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Mark D Wittman
Upender Velaparthi
Mark G Saulnier
Xiaopeng Sang
Karen M Stoffan
Neelakantan Balasubramanian
Kurt Zimmermann
Peiying Liu
David B Frennesson
James G Tarrant
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Bristol Myers Squibb Co
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    • A61K31/4164—1,3-Diazoles
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Description

NOVEL TYROSINE KINASE INHIBITORS
RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. Section 119(e) of U.S.
Provisional Patent Application No. 60/279,327 filed March 28, 2001.
FIELD OF INVENTION
The present invention relates generally to the field of tyrosine kinase enzyme inhibition using novel small molecules.
BACKGROUND OF THE INVENTION
Tyrosine Kinases are a class of enzymes, which catalyze the transfer of the terminal phosphate of adenosine triphosphate to the phenolic hydroxyl group of a tyrosine residue present in the target protein. Tyrosine kinases play a critical role in signal transduction for several cellular functions including cell proliferation, carcinogenesis, apoptosis, and cell differentiation (Plowman, G. D.; Ullrich, A;
Shawver, L. K.: Receptor Tyrosine Kinases As Targets For Drug Intervention.
DN&P (1994) 7: 334-339). Therefore inhibitors of these enzymes would be useful for the treatment or prevention of proliferative diseases which are dependent on these enzymes. Strong epidemiologic evidence suggests that the overexpression or activation of receptor protein tyrosine kinases leading to constitutive mitogenic signaling is an important factor in a growing number of human malignancies.
Tyrosine kinases that have been implicated in these processes include Abl, CDK’s,
EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src, and VEGF (Traxler, P.M. Protein Tyrosine Kinase Inhibitors in Cancer Treatment.
Exp. Opin. Ther. Patents (1997) 7: 571-588; incorporated herein by reference).
Hence, there is an ongoing need to investigate novel compounds that can be used to regulate or inhibit tyrosine kinase enzymes.
SUMMARY OF THE INVENTION
’ The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using inhibitors of tyrosine kinase enzymes to treat diseases which are characterized by an overexpression or upregulation of tyrosine kinase activity such as cancer, diabetes, restenosis, arteriosclerosis, psoriasis, angiogenic diseases and immunologic disorders (Powis, G.; Workman, P. Signaling targets For The }
Development of Cancer Drugs. Anti-Cancer Drug Design (1994), 9: 263-277;
Merenmies, J.; Parada, L. F.; Henkemeyer, M. Receptor Tyrosine Kinase Signaling in Vascular Development. Cell Growth Differ (1997) 8: 3-10; Shawver, L. K ;
Lipsosn, K. E.; Fong, T. A. T.; McMahon, G.; Plowman, G. D.; Strawn, L. M.
Receptor Tyrosine Kinases As Targets For Inhibition of Angiogenesis. Drug
Discovery Today (1997) 2: 50-63; all herein incorporated by reference).
In addition to being used as single agents, it is contemplated that tyrosine kinase inhibitors can enhance the activity of cytotoxic or cytostatic treatments when used in combination with standard therapies known in the art.
The present invention is directed to compounds having formula I
R” R'y Rg
R’ N Ww
Rr N X,
RS R® AR’
I its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates thereof; wherein
X is selected from the group consisting of N, C, C;-Cs alkyl, C;-C; alkyl substituted with one or more R’ and a direct bond; .
Y is selected from the group consisting of O and S ;
W is selected from the group consisting of N, C, O, and S, provided that when .
Wis Oor S, R’ is absent;
R',R% RY, R* R’ RS R’, R® R® are each independently selected from the group consisting of H, Cy alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, OR, NO,, OH, SR%, NR®R®' , CN, CO,R*’, CONR®R®', CO,NR*R®' ’ NR®CONR®R® NR®’SO,R®' , SO,NRPR®', C(NRZ))NR®R®', aryl, heteroaryl, i 5 (CH2)WOR®, (CH,),NR®R®, (CH,),SR®, (CH), aryl, (CHa), heteroaryl, , (CHa), heterocycloalkyl, NH-Z-aryl, and NH-Z-heteroaryl; wherein n is 1 to 3; and
Z is selected from the group consisting of C; — C4 alkyl, alkenyl, and alkynyl chain; Z having one or more hydroxy, thiol, alkoxy, thioalkoxy, amino, halo,
NR¥SO,R® groups; Z optionally incorporating one or more groups selected from the group consisting of CO, CNOH, CNOR®’, CNNR® , CNNCOR® and CNNSO,R*" and
R®, R®, and R®? are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl, and alkyl-R® wherein
R® is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, -
NR¥*COOR?, -NR*C(0)R*, -NR**SO,R?, -C(O)NR*R?', heteroaryl or heterocycloalkyl; and
R*® and R* are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R? .
In preferred embodiments, R!, R’, R%and R® are H;
R? and R*are H or F;
Y is O;
X is selected from the group consisting of N and CH;
Wis N;
R’ is selected from the group consisting of H, methyl, ethyl, isopropyl, secondary butyl, cyclopropyl, F, and CF3; » RS is selected from the group consisting of H, 2-aminomethylpyridine,
NHCH(CH>OH)CH;Ph, NHCH,CH(OH)aryl, and NHCH(CH,OH)CH,aryl; and
R® is selected from the group consisting of OR®, C(NH)NHR®, C(O)NHR®° imidazole, imidazoline, tetrahydropyrimidine, piperazine, morpholine, homomorpholine, piperidine, pyrrolidine, homopiperazine and amino; wherein
R% is sclected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, and alkyl-R® wherein R” is hydrogen, alkenyl, hydroxy, thiol, . thioalkoxy, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, -NR**COOR?!, -
NRPC(O)R*, -NR*SO,R*, -C(O)NR*R™, or a heteroaryl or heterocycloalkyl; and
R30 and Rs; are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R* .
The invention also provides a pharmaceutical composition comprising a compound of formula I, as defined above, and a pharmaceutically acceptable carrier.
The invention further provides a pharmaceutical composition comprising a compound of formula I, as defined above, in combination with pharmaceutically acceptable carrier and at least one other anti-cancer agent optionally formulated as a fixed dose.
Additionally provided is a method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering to a mammalian species in need of such trcatment an effective amount of a compound of formula I, as defined above. Furthermore, the invention provides a method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering to a mammalian species at least one other anti-cancer agent in combination with a compound of formula I, as defined above.
DESCRIPTION
The present invention provides for compounds of formula I, as defined above, pharmaceutical compositions employing such compounds and methods of using such compounds.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used * throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The term "alkyl" herein alone or as part of another group refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, ) branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may . 5 be substituted with up to four substituent groups, R as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, 10 undecyl, dodecyl, and the like. Exemplary substituents may include but are not limited to one or more of the following groups: hydroxy, halo (such as F, Cl, Br, I), haloalkyl (such as CCl3 or CF3), alkoxy, alkylthio, cyano, carboxy (-COOH), alkylcarbonyl (-C(O)R), alkoxycarbonyl (-OCOR), amino, carbamoyl (-NHCOOR or -OCONHR), urea (-NHCONHR), thiol, (-SH), sulfoxy, sulfonyl, aryl, heteroaryl, and 15 heterocycloalkyl. Alkyl groups as defined may also comprise one or more carbon to carbon double bonds or one or more carbon to carbon triple bonds. Alkyl groups may also be represented by the formula alkyl-R*. In preferred embodiments, the alkyl group is a methyl, ethyl, propyl or butyl group and include substituted methyl, ethyl, propyl! or butyl groups. 20 The term “alkenyl” herein alone or as part of another group refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon double bond. An alkenyl group may be optionally substituted in the same manner as described for an alkyl group.
The term “alkynyl” herein alone or as part of another group refers to a 25 hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. An alkynyl group may be optionally substituted in the same manner as described for an alkyl group.
The term "alkoxy" as used alone or in combination herein refers to a straight v or branched chain alkyl group covalently bonded to the parent molecule through an 30 oxygen atom linkage containing from one to ten carbon atoms and the terms "C,.¢ ) alkoxy" and "lower alkoxy" refer to such groups containing from one to six carbon atoms, examples include, but are not limited to, methoxy, ethoxy, propoxy,
WG 02/079192 PCT/USG2/09402 1SOpropoxy, butoxy, t-butoxy and the like. The term "optionally substituted" when used in connection with an alkoxy substituent refers to the replacement of up to two hydrogens, preferably on different carbon atoms with a radical selected form the group of lower alkyl, phenyl, cyano, halo, trifluoromethyl, nitro, hydroxy, alkanoyl, ) amino, monoalkyl amino and dialkylamino. Alkoxy groups may be substituted in the i same manner that alkyl groups can be substituted as described above.
The term “sulfoxy” herein alone or as part of a group refers to -SO and may be substituted with, for example, alkyl or aryl groups.
The term “sulfonyl” herein alone or as part of a group refers to ~SO, and may be substituted with alkyl or aryl groups.
The term "amino" herein alone or as part of another group refers to -NH;. An "amino" may optionally be substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. Preferred substituents include alkylamino and dialkylamino, such as methylamino, ethylamino, dimethylamino, and diethylamino. These substituents may be further substituted with a carboxylic acid or any of the alkyl or aryl substituents set out herein. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1- pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 4- sulfoxymorpholine, 4-sulfonylmorpholine, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4- arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl , 1-homopiperazinyl, 4-alkyl-1- homopiperazinyl, 4-arylalkyl-1-homopiperazinyl, 4-diarylalkyl-1-homopiperazinyl; 1- pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy .
The term "aryl" herein alone or as part of another group refers to monocyclic or bicyclic aromatic rings, e.g. phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being : present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to halogen, alkyi,
alkenyl, alkynyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, alkylaminocarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O),, (m=0, 1, 2), or thiol. Aryl groups may also be substituted with heterocycloalkyl and ’ heterocycloaryl groups to form fused rings, such as dihydrobenzfuranyl, oxindolyl, . 5 indolyl, indolinyl, oxindolyl, benzoxazolidinonyl, benzoxazolinyl and benzoxazolidinone.
The term “cycloalkyl!” herein alone or as part of another group refers to fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. Further, a cycloalkyl may be substituted. A substituted cycloalkyl refers to such rings having one, two, or three substituents, preferably one, selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (=O), hydroxy, alkoxy, thioalkyl, -CO,H, -OC(=0)H, CO,-alkyl, -
OC(=0)alkyl, =N-OH, =N-O-alkyl, aryl, heteroaryl, heterocyclo, a five or six membered ketal (i.e. 1,3-dioxolane or 1,3-dioxane), -NR’R”, -C(=O)NR’'R”, —
OC(=O)NR’R”’, -NR’CO,’R”, -NR’C(=0)R”, -SO,NR’R”, and -NR’SO,’R”, wherein each of R’ and R” is independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R’ and R” together form a heterocyclo or heteroaryl ring.
Cycloalkyl groups may also be substituted with hetero atoms such as O, N, and S to form heterocycloalkyl groups. Preferred heterocycloalkyl groups include optionally substituted morpholine, homomorpholine (7 membered ring), thiomorpholine, piperazine, homopiperazine (7 membered ring), and piperidine.
The term “heteroaryl” herein alone or as part of another group refers to substituted and unsubstituted aromatic S or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. > The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and ’ sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non- aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may contain zero, one, two or three substituents selected from the group consisting of halo, alkyl, substituted alkyl, ) alkenyl, alkynyl, nitro, cyano, hydroxy, alkoxy, thioalkyl, -CO,H, -OC(=O)H, -CO»- alkyl, -OC(=0O)alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclo, heteroaryl, -NR’R”, -C(=O)NR’R”, —
OC(=O)NR’R’’, -NR’CO;’R”, -NR’C(=O)R”, -SO,NR’R”, and -NR’SO,R”, wherein each of R” and R” is independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R’ and R” together form a heterocyclo or heteroaryl ring.
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrrolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryl groups include indolyl, indolinyl, oxindolyl, benzoxazolidinone, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term "halogen" or "halo" herein alone or as part of another group refers to chlorine, bromine, fluorine or iodine selected on an independent basis.
The term "hydroxy" herein alone or as part of another group refers to -OH.
The term "thioalkoxy" herein alone or as part of another group refers to an alkyl group as defined herein attached to the parent molecular group through a sulfur atom. Examples of thioalkoxy include, but are not limited to, thiomethoxy, thioethoxy, and the like. *
Abbreviations: “Ph” represents phenyl; “Me” represents methyl; and “Et” represents ethyl.
An “anti-cancer agent” as used herein includes known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; ’ topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as . 5 CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; anti-metabolites, such as methotrexate; tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; Her1/2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2).
When a functional group is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al., Protective Groups in
Organic Synthesis, Wiley, N.Y. (1991).
When C,¢alkyl, alkenyl, alkynyl, cycloalkyl are substituted, they are preferably substituted with one or more hydroxy, cyano, carbamoyl, hydroxy, alkoxy, thiol, alkenyl, thioalkoxy, amino, alkylamino, amido, sulfonyl, sulfoxy, sulfonamido, halo, heterocycloalkyl, aryl or heteroaryl.
When aryl or heteroaryl are substituted, they are preferably substituted with one or more alkyl, alkenyl, alkynyl, cyano, carbamoyl, hydroxy, alkoxy, thioalkoxy, amino, amido, sulfonamido, halo or with R’, R>* wherein R’, R’’ form a ring that is fused to the aryl group. When CHoaryl or heteroaryl are substituted, they are preferably substituted with one or more alkyl, alkyenyl, alkynyl, cyano, carbamoyl, hydroxy, alkoxy, thioalkoxy, amino, amido, sulfonamido, or halogen.
When NH-Z-aryl or NH-Z-heteroaryl groups are substituted, they are . preferably substituted with one or more alkyl, alkenyl, alkynyl, hydroxy, alkoxy, - thioalkoxy, amino, halogen, nitro, nitrile, carboxylate, alkoxycarbonyl, carbamoyl, ester, amide, aryl, or heteroaryl ’ The numbers in the subscript after the symbol "C" define the number of carbon atoms a particular group can contain. For example "C|_g alkyl" means a straight or branched saturated carbon chain having from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t- butyl, n-pentyl, sec-pentyl, isopentyl, and n-hexyl. Depending on the context, "Cj _g alkyl” can also refer to Cj _g alkylene which bridges two groups; examples include propane-1,3-diyl, butane-1,4-diyl, 2-methyl-butane-1,4-diyl, etc. "Co _g alkenyl" . means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to six carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. Depending on the context, "Cp. alkenyl" can also refer to Cy_g alkenediyl which bridges two groups; examples include ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl, etc. "Cp.g alkynyl" means a straight or branched carbon chain having at least one carbon-carbon triple bond, and from two to six carbon atoms; examples include cthynyl, propynyl, butynyl, and hexynyl.
The term “alkyl-R® ” includes optionally substituted alkyl groups such as methyl, ethyl, propyl, and butyl, attached to an R>group. R> generally includes hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, -NHCOOH, -NHC(O)-, -NHSO;-, -C(O)NH,, heteroaryl or heterocycloalkyl groups such as morpholinyl or group having the formula: 0] Oo N
Nee EE Ee
Nay N N Rat NN p Jo i” “ ~<A, oh, CY of —Ul
The terms “imidazole” and “imidazoline” herein alone or as part of another group includes substituted imidazoles and substituted imidazolines. Similarly, the term “tetrahydropyrimidine” includes substituted tetrahydropyrimidines. Likewise, h the terms “piperazine”, “piperidine” “morpholines”, “homopiperazines”, “homomorpholines” and “pyrrolidine” include substituted piperazines, substituted piperidines, substituted morpholines, substituted homomorpholines and substituted pyrrolidines, respectively.
Compounds of the present invention have the general formula I:
R= R'y Rg
RA AN Se
Resast
LE R® WR’ its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates thereof; wherein
X is selected from the group consisting of N, C, C,-C; alkyl, C,-C; alkyl substituted with one or more R’ and a direct bond;
Y is selected from the group consisting of O and S ;
W is selected from the group consisting of N, C, O, and S, provided that when
Wis OorS,R’is absent;
R!, R% R’, RY, R® R%, R", R®, R® are each independently selected from the group consisting of H, Cj. alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, OR®, NO,, OH, SR¥®, NR¥R®', CN, CO,R®, CONR®R®, CO,NR*R®! ,
NR®2CONR®R®', NR¥SO,R®' , SO,NR®R®', C(NR®*)NR®R®' aryl, heteroaryl, (CH2).OR®’, (CH2),NR*’R®, (CH,),SR%, (CH,), aryl, (CH), heteroaryl, , (CH2)n heterocycloalkyl, NH-Z-aryl, and NH-Z-heteroaryl, wherein n is 1 to 3; and
Z is selected from the group consisting of C; — C4 alkyl, alkenyl, and alkynyl chain; Z having one or more hydroxy, thiol, alkoxy, thioalkoxy, amino, halo,
NR*’SO;R® groups; Z optionally incorporating one or more groups selected from the . group consisting of CO, CNOH, CNOR®®, CNNR®, CNNCOR® and CNNSO,R®* and i R%, and R* are independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl, and alkyl-R* wherein
R? is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, - : ’
NR¥*COOR?Y, -NR*C(O)R*, -NR¥SO,R*, -C(O)NRR*, heteroaryl or heterocycloalkyl; and
R* and R*' are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R%.
In some embodiments of the present invention, R?is —OR%. R® is alkyl, or — alkyl-R%, wherein R* is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, alkylsulfoxy, alkylsulfonyl, -R3*COOR*, -NR¥*C(O)R?', -
NR*SO,R? t -C(O)NRR¥, heteroaryl or heterocycloalkyl; and R3p and Rj, are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R%. In preferred embodiments,
R% is methyl, -(CH,),CH,OH, or -(CH;),CH,N(CH,CH,),0, and nis 0, 1, or 2.
In some embodiments, R® is piperazine, homopiperazine, 3-methylpiperazine, or 3,5-dimethylpiperazine being optionally substituted at the 4-N position with a compound selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkyl-R*, -C(O)-R'>, or -CO,R'® wherein R"’ is hydrogen, alkyl, aryl, alkyl-R%” , amino or aryl; and RZ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, cyano, halo, sulfoxy, sulfonyl, arylsulfonyl, -NR**COOR*, -NR*C(O)R?*!, -NR*SO,R*', -C(O)NRR*', heteroaryl or heterocycloalkyl and R* and R*' are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R%. In preferred embodiments, piperazine is substituted with Me,
CHcyclopropyl, CH,CH,NMe,, CH,CH,NEt,, CH,CH,NH,, CH,CH;NHMe,
CH,CH;NHEt, N-CH,CH,N(CH,CH,),0, (CH,),CH;-R,s wherein R® is OH, OMe,
F, CN, CF;, SOCHj or SO,CH3 whereinnis 0, 1, or 2.
In some embodiments, R* is an amino group. Preferred amino groups include
NHCH,CH,0OH, NMeCH,CH,0OH, NEtCH,CH,OH, NHCH,CH,NH,,
NMeCH,CH,NH,, NEtCH,CH,NH,, NHCH,CH,;NMe,, NMeCH,CH;NMe,,
NEtCH,CH;NMe,, NHCH,CH,NEt;, NMeCH,CH,;NEt,, NEtCH,CH,NEt,, -
NHCH,CH,N(CH,CH,),0, NMeCH,;CH,;N(CH,CH,),0, NEtCH,CH,;N(CH,CH;),0.
In some embodiments, R? is an optionally substitued piperidine. Preferred substituents are selected from the group consisting of hydroxy, thiol, amino,
alkylamino, dialkylamino, alkoxy, thioalkoxy, 1,3 dioxolane (-OCHR"),, 1,3 dioxane (-OCHR'"’CHR"CHR"0-) -NHC(O)R 3, -NHCO,R"*, wherein R" is hydrogen, alkyl or alkyl-R* wherein R% is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, alkylsulfoxy, alkylsulfonyl, -NR**COOR?', -NR*C(O)R?', - NR™SO,R*, -C(O)NR*R*, heteroaryl or heterocycloalkyl; and R* and R*' are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R%.
In some embodiments R® is an optionally substituted morpholine, homomorpholine, thiomorpholine, sulfoxymorpholine, or sulfonylmorpholine.
Preferred substituents include hydroxy, thiol, amino, alk ylamino, dialkylamino, alkoxy, thioalkoxy, alkyl-R* -NHC(O)R'?, -NHCO,R"’, wherein R"’ is hydrogen, alkyl or alkyl-R% wherein R” is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, alkylsulfoxy, alkylsulfonyl, -NR*COOR?!, -
NR*’C(O)R?*, -NR*sO,R*!, -C(O)NRR¥, heteroaryl or heterocycloalkyl; and R¥® and RY are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R”.
In some embodiments, R* is a pyrrolidine. Preferred pyrrolidines include, 3- hydroxyl pyrrolidine, 3- alkoxy pyrrolidine, and 3-alkylamino pyrrolidine.
According to one embodiment of the present invention, R? is an optionally substituted N-tetrahydropyrimidine or N-imidazoline wherein the substituents are, preferably, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanoalkyl, carboxyl, or carboxamide.
In some embodiments, R® is is selected from the group consisting of H, 2- aminomethylpyridine, NHCH,CH(OH)aryl, and NHCH(CH,OH)CHaaryl, wherein the aryl group is optionally substituted. In preferred embodiments, the aryl group is substituted with Br, Cl, F, or methoxy. In some embodiments, RS has one of the following formulae:
“nu “SNH NH
HO HO HO
Ryy Riz Ry7 ! 0 \ NRgq NRgp 0 “NH pe
FN SNH :
HO Ho
HO
OR
0 Riz R
NR NR 7 0 Riz d 0 \=N wherein R* is hydrogen or alkyl, preferably methyl, and R'7 is hydrogen or halogen, such as Br, Cl or F.
Preferred compounds of the present invention have one of the following formulae:
Biz Pi xX
Rs N ge N ) NH ro N ) NH [Sen Co
HN HN
: HOw HO" n Aur fw Fr “ Rye Pig Ryg Ris
I
Foon Qo Ae
AM N 3 NH oon lo}
CL 7 RN N NH
HN [Sen . HOw H
HOw wv . Ruy v
Ris Rig No
Ris Ryg
A n uo N o
T iQ n Q NH 0 | N NH [See In
N HN
HN
HOw HOw
Ry Riz vi of, Fi ae vi Ris Rig
Rys De:
Fis @ N 2 NH Rig 4@! N B NH
CL [Sen
HN HN
OR
HOw HOw 0 0 vill 1X
Rio Ria Rig Rs wherein
R'? and R" are, independently, hydrogen, alkyl, or alkyl-R>;
R'is hydrogen, alkyl, or alkyl-R%;
R'®is independently, hydrogen or methyl;
R", R"® and R" are, independently, hydrogen, halogen, or alkoxy,or R'® and p R" together form a heterocycloalkyl or heteroaryl group;
R¥ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, : cyano, sulfoxy, sulfonyl, -NR*®*COOR?!, -NR*C(O)R?!, -NR*’SO,R¥, -
C(O)NR*R? heteroaryl or heterocycloalkyl; and
R*® and R* are, independently, hydrogen, alkyl, cycloalkyl or alkyl-R%.
In preferred embodiments, R'? is hydrogen, methyl, hydroxymethyl, methoxymethyl, CHF, CH>CN, CO,H, or —CONR*R* wherein R* and R>' are, independently, hydrogen, or alkyl-R*>;
R "is H;
R'is Br,Clor F;
R'% is halo or methoxy; and
R" is H.
Suitable examples of salts of the compounds according to the invention include inorganic or organic acids. These include, but are not limited to, hydrochloride, hydrobromide, sulfate, methanesulfonate, maleate, fumarate, phosphate and other pharmaceutically acceptable salts. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
It should be understood that the present invention includes prodrug forms of the compounds of formula I. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: (a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); and Methods in
Enzymology, Vol. 42, pp. 309-396, edited by K. '
Widder et al., (Academic Press, 1985); (b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. )
Bundgaard, Chapter 5, "Design and
Application of Prodrugs,” by H. Bundgaard, pp. 113-191 (1991); (c) H. Bundgaard, Advanced Drug Deliver Reviews, 8, pp. 1-38 (1992); (d) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and (e) N. Kayeka et al., Chem. Phar. Bull, 32, 692 (1984). x 5 The invention also provides a pharmaceutical composition comprising a compound of formula I, as defined above, and a pharmaceutically acceptable carrier and at least one other anti-cancer agent formulated as a fixed dose. Preferred anti- cancer agents are selected from the group consisting of: tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, S-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan, an epothilone; a tyrosine kinase inhibitor such as Iressa or OSI-774; an angiogenesis inhibitor; an EGF inhibitor; a VEGF inhibitor; a CDK inhibitor; a Herl/2 inhibitor and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2).
The invention further provides a method of treating a condition via modulation of at least one tyrosine kinase enzyme comprising administering to a mammalian species in need of such treatment an effective amount of a compound of formula I, as defined above.
Additionally, the invention provides a method of treating a condition via modulation of at least one tyrosine kinase enzyme comprising administering to a mammalian species in need of such treatment an effective amount of a compound of formula I, as defined above, in combination (simultaneously or sequentially) with at least one other anti-cancer agent. : A preferred condition, treated by said methods of the instant invention, is cancer. Additionally, the tyrosine kinase enzyme may include (but is not limited to): ’ Abl, CDK’s, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET,
PDGEF, Src, and VEGF.
The invention also provides a method for treating cancer, comprising administering to a mammalian species in need of such treatment, a therapeutically effective amount of at least one of the pharmaceutical compositions defined above.
The invention further provides a method for treating proliferative diseases, comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of at least one of the pharmaceutical compositions defined above.
Certain compounds of formula I may generally be prepared according to the following schemes and the knowledge of one skilled in the art. Solvates (e.g., hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are generally known in the art. Accordingly, the compounds of the instant invention may be in the free or hydrate form, and may be obtained by methods exemplified by the following schemes below.
More specifically, Schemes I-VII illustrate the preparation of compounds claimed in this invention. The examples, which follow, illustrate the compounds that can be synthesized by these schemes. The schemes are not limited by the examples listed or by any substituents employed for illustrative purposes.
Scheme I describes the preparation of the benzimidazoles. The starting diamines 1 are readily available using literature methods or are obtained commercially. The diamine is then condensed with an aldehyde 2 to provide the benzimidazole 3. Further modification of the functional groups on the aryl group of the benzimidazole or heterocycle of 3 are then envisioned.
Scheme. rR? pg R® gp! vy PR
R® NH \ Ni R? N N
TX de - XX — a
LM I i Sg
R RE R’ R 1 2 3
Alternatively, the benzimidazole could be formed in a step-wise manner (see
Scheme II) by amide formation using the acid chloride of 5 or any of the commonly used peptide coupling reagents such as DCC (dicyclohexylcarbodiimide), EDCI (1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), etc. Once the amide 6 was formed the nitro group could be reduced using catalytic hydrogenation, transfer hydrogenation or chemical reduction such as SnCl, or iron powder or other methods known in the art for reduction of aryl nitro groups. Treatment of the aniline with acid would then form the benzimidazole.
Scheme IL
Y FR
R? gt R? BL
R? NH \ Nil R® NR' xX ou 2 rt dehydration Or RE WR’
RS ab CR RS 4 5 6
Y, R®
R? Ln R” py gr a NR? 3 x reductiog, Besse
R* NO, H R* No) x,
Rr RS R R 6 3
For example, Scheme III illustrates the use of 4-iodo-2-methoxy-pyridine-3- carbaldehyde 7 to provide the functionalized benzimidazole 8. Hydrolysis of the methoxy group using protic acid conditions, TMSI (trimethylsilyl iodide), BBr3, or other conditions known in the art for cleaving a methyl ether would provide the halopyridone 9. Addition of heteroatom nucleophiles using amines, alcohols or thiols would then provide the substituted pyridones 10. Other functionality could be . 20 incorporated into the aldehyde and the above example is included for illustrative purposes only.
Scheme 111 2 1 2 , © 8 MeO a RMeo
R NH — R = AN HCI
RY ——m 4 \ /
R* NH, o 7 R* N , }
AS Vw RS rR 1 7 8 2 1 )
R R' 0 3 7 R Q
A? N NH RH © N NH / R® 4 \ J R ge NAW , X=NHS0 R* N ,
RS cil R RS RX R 9 10
Likewise the aryl ring of the benzimidazole prepared using Schemes I or II can be modified. For example introduction of a cyano group for R® on the benzimidazole allows for the formation of heterocycles such as imidazole, imidazolines, oxazolines, thiazolines, amides, or amidines. Scheme IV illustrates such transformations. Starting from the cyano-substituted benzimidazole 11 the heterocycle can be modified as illustrated in Scheme IV to provide 12. Imidate formation preferably using ethanol and acid provides intermediate 13. Imidate 13 can be transformed using diamines to form imidazolines, amino alcohols to form oxazolines, amino acetals to form imidazoles, and amino thiols to form thiazolines 14.
Alternatively the imidate can be hydrolyzed to the acid and coupled with amines using any of the standard amide formation reagents (DCC, EDCI, etc.) to form amides 15. Imidate 13 is also a useful intermediate for the preparation of amidines 16 by reacting with amines.
Scheme IV
RRQ "Ro
NC N NH RxH NC N NH qe HCUELOH —— / —————— at NZ x-muso ge No) {. poof FR RE RXR " 12
OEt R? A! fo)
HN N NH
. an Wan
NH,RZH R 7 RNH, (% R? vo ~ RRC RN" wom ogg
U 13 +
N N NH H.N N NH
R N H,0 R N
RS RX R’ | DCC, R'R"NH RS RX. R’ 14 16 0 RR Rg 7 - Nv 7
RS RX FR’ 15
X=NH,0,S
Scheme V illustrates further transformation of benzimidazoles that bear a halogen atom using palladium catalysis using conditions developed by Suzuki [Yang et al. Acta Chem. Scand. (1993) 221; Suzuki et al. Synth. Commun. (1981) 11: 513] or Buchwald/Hartwig [Buchwald et al. J. Am. Chem. Soc. (1994) 116: 7901; Hartwig etal. J. Am. Chem. Soc. (1994) 116: 5969; Hartwig. Angew. Chem., Int. Ed. Engl. (1998) 37: 2046] and variations of these methods. Preparation of a bromide substituted benzimidazole 17 could be envisioned to provide a substrate for Suzuki coupling with aryl, vinyl, and heterocyclic boronic acids to provide benzimidazoles 18. Likewise, amines and heterocycles such as piperazine or morpholine derivatives 19 can be prepared from the same bromide using amines under conditions described by Buchwald and Hartwig or variations thereof.
Scheme V
Br N NH . ‘a Wa
Rr N
RS RX RA’
ArB(OH);, r 17 ING Pd
Y
ZY rR? R' 0 RZ glo x N NH ZYN N NH y R Re i” No? i” CN 7
RS RX WR RE RX FR
18 19
X=NH, 0,8
Alternatively amine and heterocyclic derivatives such as 19 can be prepared using intermediate 6 described in Scheme II. When the R'of6isa halogen, preferably F, the halogen can be displaced with amines, alcohols, heterocyclic amines and other nitrogen containing heterocycles such as piperazine, piperidine, 4-amino piperidine, morpholine, imidazole, etc (Scheme VI). The terminal nitrogen of piperazine or 4-amino piperidine can then be alkylated using standard alkylation conditions or reacted with aldehydes in a reductive amination reaction to provide alkylated derivatives. Alternatively the terminal nitrogen atom of piperazine or 4- amino piperidine can be acylated or carbamoylated using any number of conditions that are routine for someone skilled in the art of organic synthesis. Following the example illustrated in Scheme II compounds such as 19 could be prepared.
Scheme VL - 20
Y oO NH 2 2
FE NR' DX HNYZ ZYN N NH
R® RR’ rR
R* N : R* N X, 5 0, reduction 5 rR R’
R R
H* 6 19 N
Alternatively amines, heterocycles, and alcohols can be introduced at Rj using a nucleophilic aromatic substitution reaction started from an intermediate 20 were R3 is halogen, preferably F, the halogen can be displaced with amines, alcohols, heterocyclic amines and other nitrogen containing heterocycles such as piperazine, . 5 piperidine, 4-amino piperidine, morpholine, imidazole, etc (Scheme VII). The terminal nitrogen of piperazine or 4-amino piperidine can then be alkylated using standard alkylation conditions or reacted with aldehydes in a reductive amination reaction to provide alkylated derivatives. Alternatively the terminal nitrogen atom of piperazine or 4-amino piperidine can be acylated or carbamoylated using any number of conditions that are routine for someone skilled in the art of organic synthesis. The resulting nitro aniline could be reduced to the diamine 21 and processed as illustrated in Scheme III.
Scheme VIL 2
R* Nu I NH
F NH, Nu 1X 2 x reduction R? Rs NH;
RS
2 20
The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I are tyrosine kinase enzyme inhibitors. The novel compounds of formula I are thus useful in the therapy of a variety of proliferative diseases (including but not limited to diseases associated with tyrosine kinase enzymes) such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular disease. . More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including, but not limited to, the following: a) carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder,
ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; b) hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins } lymphoma, hairy cell lymphoma and Burkett’s lymphoma; c¢) hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; d) tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; e) tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and f) other tumors, including sacroma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Due to the key role of tyrosine kinases in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
Compounds of formula I may induce apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned herein above), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer’s disease, AIDS-related dementia, Parkinson’s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
Compounds of formula I may modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus,
Epstein-Barr virus, Sindbis virus and adenovirus).
Compounds of formula I may also be useful in the chemoprevention of cancer.
Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre- malignant cells that have already suffered an insult or inhibiting tumor relapse.
Compounds of formula I may also be useful in inhibiting tumor angiogenesis and metastasis.
The compounds of this invention may also be useful in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and 3 anti-metabolites, such as methotrexate; tyrosine kinase inhibitors such as Iressa and
OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors;
Her1/2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2).
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent or treatment within its approved dosage range.
Compounds of formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent(s).
Further subject matter of the invention also includes pharmaceuticals for use, as described above, including controlling cancer, inflammation and arthritis, which contain at least one compound of the formula I as defined above or at least one of its pharmacologically acceptable acid addition salts, and the use of a compound of the formula I as defined above for the preparation of a pharmaceutical having activity against proliferative diseases as described previously including against cancer, t5 inflammation and/or arthritis.
The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which follow have been carried out with the compounds according to the invention and their salts.
Biological Assays
A. CDK 2/cyclin E Kinase Assay
Kinase reactions consisted of 5 ng of baculovirus expressed GST-
CDK2/cyclin E complex, 0.5 pg GST-RB fusion protein (amino acids 776-928 of retinoblastoma protein), 0.2 uCi **P y-ATP, 25 uM ATP in 50 pl kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl;, 1 mM EGTA, 2 mM DTT). Reactions were incubated for 45 minutes at 30° C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15%. TCA precipitates were collected onto
GF/C unifilter plates (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester (Packard Instrument Co., Meriden, CT) and the filters were quantitated using a TopCount 96-well liquid scintillation counter (Packard Instrument
Co., Meriden, CT). Dose response curves were generated to determine the concentration required inhibiting 50% of kinase activity (ICso). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at six concentrations, each in triplicate. The final concentration of DMSO in the assay equaled 2%. ICs values were derived by non-linear regression analysis and have a coefficient of variance (SD/mean, n=6) = 14%.
B. EMT Kinase Assay
A filter-based kinase assay, measuring the phosphorylation of Gst-SLP76 by
Gst-Emtk, was employed to determine the compound inhibitory activity against Emit.
The kinase reaction was performed in a 96-well plate at room temperature for 15 min before being terminated by adding 100 pl of 20% trichloroacetic acid (TCA) containing 0.1 M sodium pyrophosphate. The kinase reaction mixture (60 ul ) contained 25 mM HEPES, pH 7.0, 0.1 mg/ml BSA, 5S mM MgCl,, 5 mM MnCl, 8 ng of enzyme (Gst-Emtk), 5 pg of the substrate protein (Gst-SLP76), 1 uM ATP, 0.4 nCi of [y-p¥ JATP and the tested compound (at various concentrations). After termination, the proteins were allowed to precipitate in the presence of TCA for 1 hr at 4 °C. The precipitated proteins were then harvested on a filter plate (UniFilter-96,
GF/C, Packard Instrument) and washed to remove excess [y-P* JATP. The radioactivity was determined using a TopCount NXT (Packard Instrument) after adding 35 pl of Microscint 20 (Packard Instrument).
C. FAK Tyrosine Kinase Assay
The Focal Adhesion kinase was assayed using the synthetic polymer poly(Glu/Tyr) (Sigma Chemicals) as a phosphoacceptor substrate. Each reaction mixture consisted of a total volume of 50 ul and contained 100 ng of baculovirus- expressed enzyme, 2g of poly(Glu/Tyr), 1uM of ATP, and 0.2 uCi of [y-*P]ATP.
The mixtures also contained 40 mM Tris. HCI, pH 7.4, 1 mM MnCl, 0.5 mM DTT, and 0.1 mg/ml bovine serum albumin. The reaction mixtures were incubated at 26°C for 1 hour and kinase activity was determined by quantitation of the amount of radioactive phosphate transferred to the poly(Glu/Tyr) substrate. Incorporation was measured by the addition of cold trichloroacetic acid (TCA) precipitation of the proteins which were collected onto GF/C unifilter plates (Packard Instrument Co.,
Meriden, CT) using a Filtermate universal harvester and the filters were quantitated using a TopCount 96-well liquid scintillation counter (Packard Instrument Co.,
Meriden, CT). Compounds were dissolved in dimethyl sulfoxide to a concentration of 10 mM and were evaluated at six concentrations, each in triplicate. The final concentration of DMSO added to the kinase assays was 0.5%, which has been shown to have no effect on kinase activity. IC50 values were derived non-linear regression analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
D. HER-1/HER-2 Kinase Assay
N Kinase reactions consisted of 10 ng of baculovirus expressed GST- HER, 100 ng of HER2, 100 ng/ml poly(Glu/Tyr) (Sigma), 0.2 pCi 33P y-ATP, 1 uM ATP in 50 ul kinase buffer (S50 mM Tris, pH 7.5, 10 mM MnCl2, 0.5 mM DTT). Reactions were incubated for 1h at 27 C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration 15%. TCA precipitates were collected onto GF/C unifilter plates (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester (Packard Instrument Co., Meriden, CT) and the filters were quantitated using a TopCount 96-well liquid scintillation counter (Packard Instrument Co.,
Meriden, CT). Dose response curves were generated to determine the concentration required to inhibit 50% of kinase activity (ICsp). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at six concentrations, each in triplicate. The final concentration of DMSO in the assay equaled 1%. ICs, values were derived by non-linear regression analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
E. IGF- Receptor Tyrosine Kinase Assay
The IGF-1 receptor tyrosine kinase was assayed using the synthetic polymer poly(Glu/Tyr) (Sigma Chemicals) as a phosphoacceptor substrate. Each reaction mixture consisted of a total volume of 50 ul and contained 125 ng of baculovirus expressed enzyme, 2.5ug of poly(Glu/Tyr), 25uM of ATP, and 0.1 uCi of [y- “P]ATP. The mixtures also contained 20 mM MOPS, pH 7.0, 5 mM MnCl, 0.5 mM
DDT, and 0.1mg/ml bovine serum albumin. The reaction mixtures were incubated at 30°C for 45 minutes and kinase activity was determined by quantitation of the amount of radioactive phosphate transferred to the poly(Glu/Tyr) substrate. Incorporation was measured by the addition of cold trichloroacetic acid (TCA) precipitation of the proteins which were collected onto GF/C unifilter plates (Packard Instrument Co.,
Meriden, CT) using a Filtermate universal harvester and the filters were quantitated } 5 using a TopCount 96-well liquid scintillation counter (Packard Instrument Co.,
Meriden, CT). Compounds were dissolved in dimethyl sulfoxide to a concentration of mM and were evaluated at six concentrations, each in triplicate. The final concentration of DMSO added to the kinase assays was 0.5%, which has been shown to have no effect on kinase activity. IC50 values were derived by non-linear 10 regression analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
F. Insulin Receptor Tyrosine Kinase Assay
The Insulin Receptor Tryrosine kinase was assayed using the synthetic polymer poly(Glu/Tyr) (Sigma Chemicals) as a phosphoacceptor substrate. Each reaction mixture consisted of a total volume of 50 ul and contained 90 ng of baculovirus-expressed enzyme, 2.51g of poly(Glu/Tyr), 25uM of ATP, and 0.1 uCi of [y- P]ATP. The mixtures contained also 20 mM Tris.HCI, pH 7.4, 5 mM MnCl, 0.5 mM DTT, and 0.1 mg/ml bovine serum. The reaction mixtures were incubated at 26°C for 1 hour and kinase activity was determined by quantitation of the amount of radioactive phosphate transferred to the poly(Glu/Tyr) substrate. Incorporation was measured by the addition of cold trichloroacetic acid (TCA) precipitation of the proteins which were collected onto GF/C unifilter plates (Packard Instrument Co.,
Meriden, CT) using a Filtermate universal harvester and the filters were quantitated using a TopCount 96-well liquid scintillation counter (Packard Instrument Co.,
Meriden, CT). Compounds were dissolved in dimethyl sulfoxide to a concentration of 10 mM and were evaluated at six concentrations, each in triplicate. The final concentration of DMSO added to the kinase assays was 0.5%, which has been shown to have no effect on kinase activity. IC50 values were derived non-linear regression ‘ 30 analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
G. LCK Kinase Assay
Kinase reactions consisted of 10 ng of baculovirus expressed 10ng GST-Lck, 100 ng/ml poly(Glu/Tyr) (Sigma), 0.2 uCi 33P y-ATP, 1 uM ATP in 50 ul kinase , buffer (50 mM Tris, pH 7.5, 10 mM MnCl2, 0.5 mM DTT). Reactions were incubated for 1h at 27 C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration 15%. TCA precipitates were collected onto GF/C unifilter plates (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester (Packard Instrument Co., Meriden, CT) and the filters were quantitated using a TopCount 96-well liquid scintillation counter (Packard Instrument Co.,
Meriden, CT). Dose response curves were generated to determine the concentration required to inhibit 50% of kinase activity (ICsp). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at six concentrations, each in triplicate. The final concentration of DMSO in the assay equaled 1%. ICs values were derived by non-linear regression analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
H. MET Kinase Assay
Kinase reactions consisted of 10ng of baculovirus expressed GST-Met, 2.5ug poly(Glu/Tyr) (Sigma), 0.2uCi 33P y-ATP, 10 uM ATP in 50 pl kinase buffer (40mM Tris, pH 7.5, ImM MnCI2, 0.50 mM DTT). Reactions were incubated for 1h at 27 C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration 3.5%. TCA precipitates were collected onto GF/C unifilter plates (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester (Packard Instrument Co., Meriden, CT) and the filters were quantitated using a : TopCount 96-well liquid scintillation counter (Packard Instrument Co., Meriden, CT).
Dose response curves were generated to determine the concentration required to inhibit 50% of kinase activity (ICsp). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at seven concentrations, each in triplicate. .
The final concentration of DMSO in the assay equaled 1%. ICsp values were derived by non-linear regression analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
1. PDGF Receptor Kinase Assay
Kinase reactions consisted of 70ng of baculovirus expressed GST-PDGFbR, 0.3ug biotinylated poly(Glu/Tyr) (Sigma), in 50 pl kinase buffer (20 mM Hepes, pH 7.5,0.7uM ATP, 10mM MnCI2, 0.5mM DTT, 0.15mM NaCl, 0.1mg/ml BSA). : Reactions were incubated for 30 minutes at room temperature with shaking and stopped by the addition of 10ul of 0.2M EDTA, pH8.0. 150ul of HTRF detection buffer was added and incubated for 1 hour and 30 minutes at room temperature.
Counts were quantitated on Discovery HTRF Packard Instrument.
J. VEGFR-2 (KDR) Kinase Assay
Kinase reactions consisted of 7.5ng of baculovirus expressed GST-KDR, 1.5ug poly(Glu/Tyr) (Sigma), 0.04uCi 33P y-ATP, 2.5 pM ATP in 50 pl kinase buffer (25 mM Tris, pH 7.5, 1.8 mM MnCI2, 0.0.625 mM DTT). Reactions were incubated for 1h at 27 C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration 15%. TCA precipitates were collected onto GF/C unifilter plates (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester (Packard Instrument Co., Meriden, CT) and the filters were quantitated using a TopCount 96-well liquid scintillation counter (Packard Instrument Co.,
Meriden, CT). Dose response curves were generated to determine the concentration required to inhibit 50% of kinase activity (ICsg). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at six concentrations, each in triplicate. The final concentration of DMSO in the assay equaled 1%. ICsp values were derived by non-linear regression analysis and have a coefficient of variance (SD/mean, n=6) = 16%.
K. Cytotoxicity assay (HT-29-colon; Colo205, MCF-7-breast)
Tumor cell lines are maintained in McCoy’s SA medium (GIBCO) and 10% heat inactivated fetal bovine serum (GIBCO). The in vitro cytotoxicity is assessed in tumor cells by a tetrazolium-based colorimetric assay which takes advantage of the metabolic conversion of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium, inner salt) (Promega) to a reduced form that absorbs light at 492 nm (1). Cells are seeded 24 hr prior to drug addition. Following a 72 hour incubation at 37°C with serially diluted test compound,
MTS (Riss, T.L, et al., Comparison of MTT, XTT, and a novel tetrazolium compound
MTS for in vitro proliferation and chemosensitivity assays.," Mol. Biol. Cell 3 (Suppl.):184a, 1992), in combination with the electron coupling agent phenazine methosulfate, is added to the cells. The incubation is continued for 3 hours, then the absorbency of the medium at 492 nm is measured with a spectrophotometer to obtain the number of surviving cells relative to control populations. The results are expressed as median cytotoxic concentrations (ICso values).
Table 1 - Biological Activity (uM); all compounds in the table had kinase activity of <25uM against one or more of the following kinases CDK, EMT, FAK, Herl, Her2, IGF,
IR, LCK, MET, PDGF, VEGF. HT-29 and Colo205 are human colon tumor cell lines, and
MCF-7 is a human breast tumor cell line.
HT-29 | MCF-7 | Colo205 3 Jeo | TT 399 loa | Jos 400 08 | ]09 411 Joz | 109 s17 jo3 |b] 519 03 Joe (520 [oe Jo2 [521 jos 522 lo7_ Jor [or 523 Joe 1524 Joe
ERIN
526 14 | 0 1534 loa | 1 [538 ~~ joo | [ [544 Jo3 Joe [553 09 Jo3 Jo2 555 Jo2 Joa [o2 559 Joe loz 574 Jo2 [581 jo2 Jo3 [582 for Jo2
(584 03 Joa 58s Jor fos [ 590 [08 Jo2 [02 503 Jo7 [ ) General Procedure for the Preparation of 2-Hydroxy-2-(substituted-phenyl)-
OH ci NO, or 1-(3-Chloro-phenyl)-2-nitro-ethanol: To a solution of 3-chloro-benzaldehyde (20 g, 0.142 mol) in nitromethane (100 mL) were added magnesium sulfate (37.6 g, 0.312 mol) and phosphazene base P,-t-bu-tris(tetramethylene) (4.43 g, 0.014 mol). The reaction mixture was stirred at room temperature for 2 h. After concentration in vacuo, the residue was purified by flash chromatography (25% EtOAc / hexane) to yield the title compound (26.4 g, 100%) as a green-yellow oil. '"H NMR (300 MHz,
DMSO-dg) 6 7.53 (1H, s), 7.35 —- 7.42 (3H, m), 6.23 (1H, broad s), 5.32 — 5.33 (1H, m), 4.90 (1H, dd, J =3.2, 12.4 Hz), 4.60 (1H, dd, J = 1.2, 12.4 Hz).
OTES
RO
[1-(3-Chloro-phenyl)-2-nitro-ethoxy]-triethyl-silane: To a solution of 1-(3-chloro- phenyl)-2-nitro-ethanol (26 g, 0.14 mol) in DMF (50 mL) were added imidazole (28.6 g, 0.42 mol) and chlorotriethylsilane (25.3 g, 0.17 mol). The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water - and brine, dried over Na,SO,, and filtered. After removal of solvent, the crude product was purified by flash chromatography (2% EtOAc / hexane) to yield the title compound (37 g, 91%) as a colorless oil. 'H NMR (300 MHz, CDCl) & 7.40 (1H, s), : 7.27-17.32 (3H, m), 5.40 (1H, dd, J =3.2,9.5 Hz), 4.51 (1H, dd, J = 9.5, 12.1 Hz), 4.36 (1H, dd, J =3.3,12.1 Hz), 0.85 (9H, t, J = 7.5 Hz), 0.54 (6H, q, J = 7.5 Hz).
OTES
2-(3-Chloro-phenyi)-2-triethyisilanyloxy-ethylamine: Raney nickel (1 g) was washed with distilled water five times and methanol three times. [1-(3-Chloro- : phenyl)-2-nitro-ethoxy]-triethyl-silane (10 g, 0.032 mol) and Raney nickel in methanol (100 mL) was hydrogenated (35 psi) at room temperature for 14 h. The reaction mixture was filtered through a pad of celite and rinsed with methanol.
Concentration of the filtrate to dryness gave the title compound (5.6 8, 62%) as a colorless oil which was used for the next step without purification. 'H NMR (300
MHz, CDCl3) 6 7.32 (1H, s), 7.18-7.26 (3H, m), 4.70 (1H, t, J = 5.8 Hz), 2.86 (2H, m), 0.89 (9H, t, J = 7.9 Hz), 0.56 (6H, q, J = 7.8 Hz). LRMS (M+H)* m/z 286.
General Procedure for the Preparation of 2-Hydroxy-2-(substituted-phenyl)- ethylamines: [o}
Br [+] 4-methoxy-3-bromophenyl chloroacetophenone: To a suspension of AlCl; (13.4g, 0.10 mol) in methylene chloride (40mL) was added a solution of 2-bromoanisole (12.5 mL, 0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol) at 0°C. The solution was warmed to ambient temperature for two hours and poured onto ice and extracted with methylene chloride, washed with saturated sodium bicarbonate solution, brine, and dried over MgSO. The solution was filtered, concentrated and crystalized from
EtOH to give 15.37g of white solid. LRMS [M-HJ- 260.8; IR (KBr) 1697, 1048, 1255 cm’; 'H NMR (300MHz, CDCl,) 6 8.18 (s, 1H), 7.94 (dd, J= 8.67 Hz, 1H), 6.96 (d,
J=8.67 Hz, 1H), 4.62 (s, 2H), 3.98 (s, 3H); 'C NMR (CDCl, 75.5 Hz) & 188.8, 160.3, 134.1, 129.9, 128.2, 112.4, 111.3, 56.6, 45.3.
General Procedure for chiral reduction of chleroketones and ammonolysis : ’
OH
Br ~ Cl (S)-1-[4-methoxy-3-bromophenyl] —2-chloro ethanol : To a solution of (S)-Methyl- : CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3;-THF (8mL, 8 mmol) was added at the same time a solution of BH3-THF (19mL, 19 mmol) and a solution of the chloroketone (10.03g, 37.98 mmol) in 19 mL of THF. Both solutions were added dropwise over 30 minutes. The solution was stirred for 1 hour and quenched with the slow addition of methanol (50mL). The solution was concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate) to give a quantitative yield (10.0g) of chlorohydrin as a clear oil. IR (KBr) 1053, 1258, 3406 cm’; 'H NMR (300MHz, CDCl) 6 7.59 (s, 1H), 7.30 (dd, J=2.16
Hz, 1H), 6.90 (d, J=8.46 Hz, 1H), 4.83 (dd, J= 3.57 Hz, 1H), 3.90 (s, 3H), 3.64 (ddd,
J=3.6,11.1, 8.7, 2H), 2.04 (b s, 1H). “c NMR (CDCl,, 75.5 MHz) 6 155.9, 133.5, 131.1, 126.3, 111.9, 73.1, 60.4, 56.3, 50.7.
OH
Br A NHZHCI
Beh (S) 2-Amino-1-[3-chloro-4-methoxyphenyl]ethanol Hydrochloride : To a solution of the chlorohydrin (10.0g, 37.9 mmol) in 120 mL of methanol at 40°C was added 100 grams of ammonia. The solution was sealed in a pressure bottle and warmed to ambient temperature and stirred for 48 hours. The solution was cooled and opened.
The ammonia was allowed to evaporate and solution concentrated. The residue was crystalized from ethanol/ethyl acetate to give 3.83g of white solid (35%). The material was reacted with Boc,O in ethyl acetate and saturated sodium bicarbonate and analyzed by chiral HPLC using a chiralcel OJ column using 95% hexane/ethanol as elutant and determined to by 98%ee. Additional crops were collected — 2.96g and 1.41g for a total of 75% yield. LRMS [M+H]+ 246; IR (cm™, KBr) 1055, 1261, 3001, 2948, 3356; 'H NMR (500MHz, DMSO) 6 8.09 (bs, 2 H), 7.58 (s, 1H), 7.36 (dd, J=2.05, 6.45 Hz, IH), 7.11 (d, J=8.5 Hz, 1H) 6.10 (s, 1H), 4.80 (m, 1H), 3.84 (s,
3H), 3.00 (ddd, J=2.7, 12.6, 9.5 Hz, 2H); Pc NMR (DMSO, 75.5 MHz) 6 154.8, 135.4, 1304, 126.6, 112.4, 110.4, 67.9, 56.2, 45.4. oH
RO
S
(S) 2-Amino-1-[3-chlorophenyljethanol Hydrochloride : was prepared according to the general procedure outlined above. LRMS [M+H]+ 172; IR (KBr, cm-1) 3048, 3351, 2952; 'H NMR (300MHz, MeOD) 6 7.48 (5, 1H), 7.35 (m, 3H), 3.31 (ddd, J= 1.5,3.12, 9.15 Hz 2H).
OH
ROH
(S)-2-Amino-1-[3-bromophenyljethanol Hydrochloride : was prepared according to the general procedure outlined above. LRMS [MH]+ 217.9; IR (KBr, cm-1) 3025, 3443,2891; 'H NMR (S00MHz, DMSO) 8 7.93 (b s, 2H), 7.60 (s, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.35 (d, J=7.7 Hz, 1H) 6.17 (s, 1H), 4.82 (m, 1H), 3.08 (ddd, J=2.6, 12.7, 9.6 Hz, 2H); Ne NMR (DMSO, 75.5 MHz) 6 144 4, 130.5, 128.7, 125.0, 121.6, 68.3, 45.1.
OM
ROSA
MeS (S)-2-Amino-1-[3-chloro-4-methylthiophenyl]ethanol Hydrochloride : was prepared according to the general procedure outlined above. LRMS [M+H]+ 217.9;
IR (KBr, cm-1) 3007, 3358; 'H NMR (500MHz, DMSO) 6 8.12 (b s, 2H), 7.46 (s, 1H), 7.37 (s, 1H), 7.35 (d, 1H) 6.19 (d, 1H), 4.83 (m, 1H), 3.01 (ddd, J=3.2, 12.8, 9.3 3 i
Hz, 2H); C NMR (DMSO, 75.5 MHz) & 139.6, 136.5, 129.8, 126.6, 125.4, 68.0, 45.2, 14.2.
OH ct = _NHyHCI
ATT
(S)-2-Amino-1-[3-chloro-4-fluoro-phenyl]lethanol Hydrochloride : was prepared - according to the general procedure outlined above. LRMS [M+H]+ 189.9; IR (KBr, cm-1) 1509, 3008, 3359; '"H NMR (500MHz, DMSO) 6 8.21 (bs, 2H), 7.61 (d,
J=7.85 Hz, 1H), 7.42 (m, 2H), 6.29 (s, 1H), 4.88 (m, 1H), 3.03 (ddd, J=3.4, 12.8,9.2
Hz, 2H); 'C NMR (DMSO, 75.5 MHz) 8 157.5, 155.5, 139.7, 128.1, 126.7, 119.3, 116.7, 109.0, 67.8, 45.2.
OH cl A NH HCI (S)-2-Amino-1-[3-chloro-4-methoxyphenyl]lethanol Hydrochloride : was prepared according to the general procedure outlined above. LRMS [M+H]+ 202; IR (KBr, cm-1) 3354, 3003, 2949, 1288, 1064; 'H NMR (500MHz, DMSO) 6 8.18 (brs, 3H), 7.43 (d, J=2.0Hz, 1H), 7.31 (dd, J=8.5, 2.0Hz, 1H), 7.14 (d, J=5.1Hz, 1H), 6.11 (s, 1H), 4.81 (m, 1H), 3.84 (s, 3H), 2.99 (dd, J=13, 3.5Hz, 1H), 2.83 (dd, J=12.5, 9Hz, 1H); “Cc NMR (DMSO, 125MHz) § 153.9, 135.0, 127.3, 125.8, 120.8, 112.6, 68.0, 56.1, 45.5; Elemental Analysis Calcd for CoH;2CINO,-HCL: C, 45.39; H, 5.50; N, 5.88. Found: C, 45.38; H, 5.43; N, 5.70.
OH
Br ~__NHzHCI
Lr (S)-2-Amino-1-(7-bromo-2,3-dihydrobenzfuran-5-yl)-2-aminoethanol ' Hydrochloride : was prepared according to the general procedure outlined above.
LRMS [M+H]}+ 258; IR (KBr, cm-1) 3349, 3006, 2928, 1485, 1045, 983; 'H NMR (500MHz, DMSO) 6 8.13 (brs, 3H), 7.29 (s, 1H), 7.23 (s, 1H), 6.08 (d, J=4 Hz, 1H), 4.76 (m, 1H), 4.61 (t,J=9Hz, 2H), 3.29 (t, J=9Hz, 2H), 2.96 (dd, J=13, 3.5Hz, 1H),
2.82 (dd, J=13,9.5Hz, 1H); “c NMR (DMSO, 125MHz) 6 156.3, 135.9, 129.1, 128.1, 122.1, 100.9, 71.5, 68.2, 45.6, 29.9; Elemental Analysis Calcd for
CioH12BINO,-HCI: C, 40.77; H, 4.44; N, 4.75. Found: C, 40.77; H, 4.63; N, 4.63.
General Procedure for the Preparation of 2-Amine-3-(substituted-phemyl)- : propanol: “OMT
OH °o (5)-[2-(3-Bromo-phenyl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester:
To a solution of (S)-3-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-propinic acid (500 mg, 1.45 mmol) in THF (30 mL) was added borane-tetrahydrofuran complex (1.0 M solution) (4.35 mL, 4.35 mmol). The reaction mixture was stirred at room temperature for 14 h and quenched with acetic acid (1 mL). After removal of most solvent, the residue was extracted with EtOAc, washed with brine, dried over Na,SOj,.
After concentration, the crude product (400 mg, 83%) was used for the next step without purification. LCMS (M+H)" m/z 330 (t = 1.61 min
Br NH;
UL, (S)-2-Amino-3-(3-bromo-phenyl)-propan-1-ol: To a solution of (§)-[2-(3-bromo- phenyl)-1-hydroxymethyl-ethyl}-carbamic acid rerr-butyl ester (400 mg, 1.21 mmol) in methanol (30 mL) was added 4 M HCl in dioxane (2 mL, excess). The reaction mixture was stirred at room temperature for 14 h. After concentration in vacuo, the residue was used for the next step without purification. LCMS (M+H)* m/z 230 (t = 0.78 min.) [o} .
Cl (] 0
5-Chloroacetyl-7-chlorooxindole: To a suspension of AICI; (13.4g, 0.10 mol) in methylene chloride (40mL) is added a solution of 7-Chlorooxindole (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol) at 0°C. The solution is warmed to ambient temperature for two hours and poured onto ice and extracted with methylene chloride, washing with saturated bicarbonate solution, brine, and drying over MgSO,4 would provide the desired chloroketone.
OH
Cl ~ (o]]
LT o (S)-7-Chloro-5-(2-chloro-1-hydroxy-ethyl)-2-oxoindole : To a solution of (S)-
Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH;-THF (8mL, 8 mmol) is added at the same time a solution of BH3;-THF (19mL, 19 mmol) and a solution of the 5-Chloroacetyl-7-chlorooxindole (37.98 mmol) in 19 mL of
THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
OH cl A NHzHCI
WS
[0] (S)-2-Amino-1-(7-chlorooxindole-5-yl)-ethanol Hydrochloride : To a solution of the chlorohydrin (37.9 mmol) in 120 mL of methanol at 40°C is added 100 grams of ammonia. The solution is sealed in a pressure bottle and warmed to ambient temperature and stirred for 48 hours. The solution is cooled and opened. The ammonia is allowed to evaporate and solution concentrated to provide the hydrochloride salt, which can be crystallized from ethanol/ethyl acetate.
o
Cl Cl
Rea a 6-Chloroacetyl-4-chloro-2-benzooxazolinone: To a suspension of AlCl; (13.4g, 0.10 mol) in methylene chloride (40mL) is added a solution of 4-chloro-2- benzooxazolinone (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol) at 0°C. The solution is warmed to ambient temperature for two hours and poured onto ice and extracted with methylene chloride, washing with saturated bicarbonate solution, brine, and drying over MgSO4 would provide the desired chloroketone.
OH
Cl ~ Cl nS o (S)-6-(2-Chloro-1-hydroxy-ethyl)-4-chloro-2-benzooxazolinone: To a solution of (S)-Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3-
THF (8mL, 8 mmol) is added at the same time a solution of BH3-THF (19mL, 19 mmol) and a solution of the 6-Chloroacetyl-4-chloro-2-benzooxazolinone (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
OH . cl 2 _ NH HCI
J
[o) (S)-2-Amino-1-(4-chlero-2-benzooxazolinone-6-yl)-ethanol Hydrochloride : To a solution of the chlorohydrin (37.9 mmol) in 120 mL of methanol at —40°C is added 100 grams of ammonia. The solution is sealed in a pressure bottle and warmed to ambient temperature and stirred for 48 hours. The solution is cooled and opened.
The ammonia is allowed to evaporate and solution concentrated to provide the hydrochloride salt, which can be crystallized from ethanol/ethyl acetate.
Cl
N-Methyl-7-chloroindoline: To a solution of the 7-Chloroindoline (0.10 mol) in 500 mL of acetone is added K,COj; (0.15mol) and Mel (0.15mol) and refluxed until the starting material is consumed. The reaction is filtered and washed with water and saturated bicarbonate solution, drying over MgSO,4 would provide the N-Me -7- chloroindoline o
Ct Cl
MeN N-Methyl-5-chloroacetyl-7-chloro-indoline: To a suspension of AICI; (13.4g, 0.10 mol) in methylene chloride (40mL) is added a solution of N-Me-7-Chloroindoline (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol) at 0°C. The solution is warmed to ambient temperature for two hours and poured onto ice and extracted with methylene chloride, washing with saturated bicarbonate solution, brine, and drying over MgSO, provides the desired chloroketone.
OH a AC
FT
(S)-N-Methyl-5-(2-chloro-1-hydroxylethyl)-7-chloro-indoline: To a solution of (S)- : 25 Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3;-THF (8mL, 8 mmol) is added at the same time a solution of BH3;-THF (19mL, 19 mmol) ’ and a solution of N-Methyl-5S-chloroacetyl-7-chloro-indoline (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
OH cl ~__ NHyHCI wl (S)-2-Amino-1-(7-chloro-N-methyl-indoline-5-yl)-ethanol Hydrochloride : To a solution of the chlorohydrin (37.9 mmol) in 120 mL of methanol at —40°C is added 100 grams of ammonia. The solution is sealed in a pressure bottle and warmed to ambient temperature and stirred for 48 hours. The solution is cooled and opened.
The ammonia is allowed to evaporate and solution concentrated to provide the hydrochloride salt, which can be crystallized from ethanol/ethyl acetate.
OH cl Cl neh (S)-2-Chloro-1-(7-chloro-N-methyl-indol-5-yl)-ethanol: A solution (S)-N-Methyl- 5-(2-chloro-1-hydroxylethyl)-7-chloro-indoline (0.10 mmol) in 100mL of t-butyl methyl ether is treated with o-chloroanil (0.10mmol) at ambient temperature. The solution is concentrated and the residue chromatographed over silica gel (1:1 hexane/ethyl acetate) to provide the corresponding indole.
OH : cl = NH HCI wT (S)-2-Amino-1-(7-chloro-N-methyl-indol-5-yl)-ethanol Hydrochloride : Toa solution of the chlorohydrin (37.9 mmol) in 120 mL of methanol at 40°C is added 100 grams of ammonia. The solution is sealed in a pressure bottle and warmed to ambient temperature and stirred for 48 hours. The solution is cooled and opened.
The ammonia is allowed to evaporate and solution concentrated to provide the hydrochloride salt, which can be crystalized from ethanol/ethyl acetate. ’ cl
J
Jy 4-Chloro-2-methyl-benzooxazole : To a solution of the 4-chloro-2- benzooxazolinone (0.10 mol) in 200 mL ethanol is added LiOH (0.20 mol) in 100 mL of water. The solution is refluxed for 8 hr and cooled. The solution is neutralized with IN HCI and extracted with ethyl acetate followed by drying over MgSO4. The solution is concentrated and taken up in 200 mL of toluene and 0.10 mol of acetic acid. The solution is refluxed in a Dean Stark trap for 12 hours, concentrated and purified by flash chromatography. o [>] Ct
POA
Js 6-Chloroacetyl-4-chloro-2-methyl-benzooxazele: To a suspension of AICI; (13.4g, 0.10 mol) in methylene chloride (40mL) is added a solution of 2-Methyl-4-chloro- benzooxazole (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol) at 0°C. The solution is warmed to ambient temperature for two hours and poured onto ice and extracted with methylene chloride, washing with saturated bicarbonate solution, brine, and drying over MgSO, would provide the desired chloroketone.
OH
Cl ~ Cl i (S)-6-(2-chloro-1-hydroxy-ethyl)-4-chloro-2-methyl-benzooxazole: To a solution of (S)-Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and
WQ 02/079192 PCT/USO2/09402
BH3-THF (8mL, 8 mmol) is added at the same time a solution of BH3-THF (19mL., 19 mmol) and a solution of 6-Chloroacetyl-4-chloro-2-methyl-benzooxazole (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
OH cl = _NHzHCI
Tr j= (S)-2-Amino-1-(4-chloro-2-methyl-benzooxazol-6-yl)-ethanol Hydrochloride : To a solution of the chlorohydrin (37.9 mmol) in 120 mL of methanol at —40°C is added 100 grams of ammonia. The solution is sealed in a pressure bottle and warmed to ambient temperature and stirred for 48 hours. The solution is cooled and opened.
The ammonia is allowed to evaporate and solution concentrated to provide the hydrochloride salt, which can be crystallized from ethanol/ethyl acetate.
Preparation of 3-(6-Imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-iodo-1H- pyridin-2-one:
En
Qh ) 1-(3-Methyl-4-nitro-phenyl)-1H-imidazole: To a solution of 4-fluoro-2-methyl-1- nitro-benzene (300 mg, 1.84 mmol) in DMSO (2 mL) were added KOH (20 mg, 3.87 mmol) and imidazole (263 mg, 3.88 mmol). The reaction mixture was heated to 100°C for 3.5 h, cooled to room temperature, and diluted with ice-cold water. The resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum to give the title compound (310 mg, 80%) as a yellow powder. 'H NMR (300 MHz,
DMSO-d¢) 6 8.46 (1H, 5), 8.16 (1H, d, J = 8.9 Hz), 7.90 — 7.92 (2H, m), 7.78 (1H, dd,
J=125,89 Hz), 7.17 (1H, s), 2.61 (3H, s). LRMS (M+H)" m/z 204. gt : a,
S : 4-Imidazol-1-yl-2-methyl-phenylamine: To 1-(3-methyl-4-nitro-phenyl)-1H- imidazole (200 mg, 0.98 mmol) and 10% Palladium on carbon (35 mg) was added degassed methanol (3 mL). The suspension was flushed and evacuated with hydrogen / vacuum line. The suspension was allowed to stir at room temperature for 14 h under hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was filtered through a pad of celite and rinsed with methanol. Concentration of the filtrate gave the title compound (166 mg, 98%) which was used for the next step without purification. '"H NMR (300 MHz, DMSO-d) & 7.95 (1H, s), 7.48 (1H, ss), 7.16 (1H, narrow d, J = 2.5 Hz), 7.09 (1H, dd, J = 2.5, 8.4 Hz), 7.01 (1H, 5), 6.67 (1H, d, J=8.4
Hz), 5.03 (2H, broad s), 2,10 (3H, s). oy
NH
PN
N-(4-Imidazol-1-yl-2-methyl-6-nitro-phenyl)-acetamide: To a solution of 4- imidazol-1-yl-2-methyl-phenylamine (1 g, 5.78 mmol) in CH,Cl, (20 mL) was added
Acy0 (0.7 mL, 7.28 mmol) at 0°C. The reaction mixture was stir at room temperature for 14 h and diluted with water. The aqueous layer was extracted with CH,Cl, and the combined organic layers were washed with saturated NaHCOs and brine, dried over
Na;S0Os, and concentrated in vacuo to give a white solid. The white solid was : 25 suspended in H2SO4 (conc.) (15 mL). Then HNO; (conc.) (0.312 mL) was added to the suspension at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 4 h. After cooling to -10°C, the reaction mixture was neutralized with ammonium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na,SO,, and concentrated. The residue was purified by flash chromatography (1:9:5 MeOH / THF / hexane) to yield the title compound (0.61 g, 41%). '"H NMR (300 MHz, CD;0D) & 8.11 (1H, ss), 7.45 - 7.56 (2H, m), 7.38 (1H, dd, J = 2.4, 8.4 Hz), 7.14 (1H, 5), 2.33 (3H, s), 2.18 (3H, s). gi! NO,
S
4-Imidazol-1-yl-2-methyl-6-nitro-phenylamine: To a suspension of N-(4-imidazol- 1-yl-2-methyl-6-nitro-phenyl)-acetamide (279 mg, 1.07 mmol) in ethanol (3 mL) was added 2 N HCI (2 mL). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and neutralized with saturated NaHCO. The resulting bright orange solid was filtered and dried under vacuum. The title compound (179 mg, 76%) was obtained as an orange solid. 'H NMR (300 MHz, CDsOD) 6 8.78 (1H, s), 8.24 (1H, s), 7.78 (1H, s), 7.64 (1H, s), 7.46 (1H, s), 2.36 (3H, s). yg! NH, ps
S-Imidazol-1-yl-3-methyl-benzene-1,2-diamine: To 4-imidazol-1-yl-2-methyl-6- nitro-phenylamine (350 mg, 1.61 mmol) and 10% Palladium on carbon (40 mg) were added degassed methanol (5 mL) and TFA (5 drops). The reaction mixture was flushed and evacuated with hydrogen / vacuum line, stirred at room temperature for 14 h under hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was filtered through a pad of celite and rinsed with methanol. Concentration of the filtrate gave the residue, which was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCOs, brine, dried over
Na,SOs. Concentration to dryness gave the title compound (275 mg, 91%) as a solid. 'H NMR (300 MHz, CD;0D) 8 7.87 (1H, 5), 7.34 (1H, 5), 7.05 (1H, 5), 6.72 (1H, d, J
= 2.4 Hz), 6.65 (1H, d, J = 2.4 Hz) 2.21 (3H, s). LCMS (M+H)* m/z 189 (t = 0.23 min.). gd 7 4-Iodo-2-methoxy-pyridine-3-carbaldehyde (WO 95/29917): A 5-liter three-necked round bottom flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled to -78°C. To this stirred solution was added zert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78°C. The mixture was stirred for 1 h at -78°C. To the mixture was added N-formyl-N, N°, N’- trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78°C. The reaction mixture was stirred for ca. 30 min at -78°C before warming to -23°C over ca. 30 min.
To the mixture at -23°C was added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M solution in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled to -78°C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask at -78°C. After the addition was complete, the reaction mixture was stirred for an additional 1 h at -78°C. The cooling bath was removed and the mixture was allowed to warm to about 0°C and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2L) was added and the layers were separated. The aqueous layer was extracted with 2 x 1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na;S,04 (1.2
L), brine (1.2 L), dried over Na;SO,4. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice / water bath for ca. min. The precipitate was filtered and dried in vacuum to yield the title compound as a light yellow solid. '"H NMR (300 MHz, CDCl3) § 10.22 (s, 1H), 7.86 (1H, d, J =
5.3 Hz), 7.54 (1H, d, J = 5.3 Hz), 4.06 (3H, 5). LCMS (M+H)" m/z 364 (t = 2.26 min.). ! ns
B22 6-Imidazol-1-yl-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl-1H-benzimidazole:
To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (175 mg, 0.93 mmol) in methanol (8 mL) was added a solution of 4-iodo-2-methoxy-pyridine-3- carbaldehyde (245 mg, 0.93 mmol) in methanol (5 mL) at 0°C. The reaction mixture was stirred at 0°C for 1.5 h and then at room temperature for 2 h. After concentration, the residue was purified by flash column chromatography (10% MeOH / CH,Cl,) to give the title compound (291 mg, 60%). 'H NMR (300 MHz, CD;0D) & 8.13 (1H, s), 7.98 (1H, d,J=5.4 Hz), 7.62 (1H, d, J = 5.4 Hz), 7.59 (2H, s), 7.33 (1H, s), 7.16 (1H, s), 3.90 (3H, s), 2.67 (3H, s). LCMS (M+H)"* m/z 432 (t = 0.99 min.). gi! N 2 NH weds 3-(6-Imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-iodo-1H-pyridin-2-one:
The suspension of 6-imidazol-1-yl-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl-1H- benzimidazole in 1 N HCI (6 mL) was heated to 70°C for 3 days, cooled to room temperature, and diluted with ethyl acetate. After extraction, the combined organic layers were washed with brine, dried over Na;SO4 and concentrated. The residue was purified by flash chromatography (1% NH4OH / 10% MeOH / CH,Cl,) to yield the title compound (78 mg, 81%) as a solid. 'H NMR (300 MHz, CDs0D) 6 8.12 (1H, s), 7.58 (2H, s), 7.29 - 7.31 (2H, m), 7.16 (1H, s), 7.01 (1H, J = 6.8 Hz), 2.66 (3H, s). :
LCMS (M+H)" m/z 418 (t = 0.75 min.)
Preparation of 2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methvi-3H- benzimidazole-5-carbonitrile:
NC
CL, : 4-Amino-3-methyl-benzonitrile: To a solution of 3-methyl-4-nitro-benzonitrile (20 £0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was 10 purified by flash chromatography (40% EtOAc / hexane) to yield the title compound (15.3 g, 92%). 'H NMR (300 MHz, CDCl3) 8 7.30 — 7.34 (2H, m), 6.64 (1H, d, J = 8.7 Hz), 2.16 (3H, s). LCMS (M+H)* m/z 133 (t = 0.93 min).
NC NO, w 07 CF,
N-(4-Cyano-2-methyl-6-nitro-phenyl)-2,2,2-trifluoro-acetamide: To the ice-cold trifluoroacetic anhydride (60 mL) was added 4-amino-3-methyl-benzonitrile (14.33 g, 0.108 mol) in portion. The resulting white slurry was stirred at 0°C for 30 min. Then ammonium nitrate (17.28 g, 0.216 mol) was added. The reaction mixture was allowed to stir at 0°C for 1 h and at room temperature for 14 h. After removal of most solvent, the reaction mixture was cooled with ice and quenched with ice. The yellow precipitate was filtered, washed with cold water, and dried under vacuum. The crude product (15.5 g, 52% yield, and ca. 80% pure) was used for the next step without purification. '"H NMR (300 MHz, CD;0D) § 8.05 (1H, 5), 7.74 (1H, s), 2.30 (3H, s).
LRMS (neg. ESI, (M-H)") m/z 272.
NC NO, je
4-Amino-3-methyl-5-nitro-benzonitrile: A mixture of N-(4-cyano-2-methyl-6-nitro- phenyl)-2,2,2-trifluore-acetamide (5 g, 18.3 mmol) and 2 M ammonia in methanol (80 mL) was heated to reflux for 14 h and then cooled to room temperature. Afier concentration in vacuo, the residue was purified by flash chromatography (20%
EtOAc / hexane) to yield the title compound (3.24 g, 100%, ca 80% pure). 'H NMR (300 MHz, CDCl;3) 6 8.40 (1H, s), 7.47 (1H, s), 6.6 — 6.8 (2H, broad s), 2.89 (3H, s).
NC NH, [Ss 3,4-Diamino-5-methyi-benzonitrile: To a solution of 4-amino-3-methyl-5-nitro- benzonitrile (3.24 g, 18.3 mmol) in ethanol (80 mL) was added tin chloride dihydrate (8.67 g, 49.75 mmol). The reaction mixture was heated to reflux for 14 h, then cooled to room temperature, and concentrated in vacuum. The residue was diluted with ethyl acetate (100 mL) and treated with triethylamine (20 mL). The resulting slurry was filtered through a pad of celite and the filtercake was rinsed with three-portion ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO;, water, and brine, then dried over Na,SO4 and filtered. After removal of solvent, the residue was purified by flash chromatography on silica gel (30% - 50% EtOAc / hexane) to yield the title compound (2.17 g, 81%) as a light yellow solid. 'H NMR (300 MHz, CDCls) 36.94 (1H, s), 6.85 (1H, 5), 2.16 (3H, 5). LCMS (M+H)"* m/z 148 (t = 0.67 min.).
Ne H MeO a
Cr
I
2-(4-lIodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazole-5-carbonitrile: To a solution of 3,4-diamino-5-methyl-benzonitrile (2.00 g, 13.6 mmol) in MeOH (40 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (3.6 g, 13.6 mmol) in
MeOH (20 mL) at 0°C. The resulting slurry was stirred at 0°C for 1 h. Iodine (1.73 g, 8.8 mmol) in MeOH (10 mL) was added dropwise via a dropping funnel to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 14 h. After removal of MeOH, the residue was diluted with saturated Na;S,0; and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na;SO4. The crude product was purified by flash column chromatography (3% MeOH / CH,Cl,) to yield the title compound (1.81 g, 46%). 'H } 5 NMR (300 MHz, CDCl3) 6 7.90 (1H, s), 7.49 (1H, d, J = 5.4 Hz), 7.46 (1H, s), 7.41 (1H, d, J = 5.3 Hz), 3.78 (3H, 5), 2.68 (3H, 5). LCMS (M+H)" m/z 391 (t = 1.27 min.).
NC N ° NH
Cris [+] 2-(4-Chloro-2-0x0-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzimidazole-5- carbonitrile: A suspension of 2-(4-iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H- benzimidazole-5-carbonitrile (1.8 g, 4.63 mmol) in 4 M HCI dioxane (40 mL) was heated to 80°C for 6 h and cooled to room temperature. The precipitate was filtered and dried. The crude product (1.08 g, 82%) was used for the next step without purification. LRMS (neg. ESI, (M-H)') m/z 283.
Preparation of (5)-4-(1-Benzyl-2-trityloxy-ethylamino)-3-(6-bromo-4-methyl-1H- benzimidazol-2-yl)-1H-pyridin-2-one:
Br NH, oo 5-Bromo-3-methyl-benzene-1,2-diamine: To a suspension of 4-bromo-2-methyl-6- nitro-phenylamine (20 g, 0.086 mol) in ethanol (200 mL) was added tin chloride dihydrate (49.2 g, 0.258 mol). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with : ethyl acetate (150 mL) and treated with triethylamine (40 mL). The resulting slurry was filtered through a pad of celite, and the filtercake was rinsed with three portions ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na;SO, and filtered. After removal of the solvent, the residue
St was purified by flash chromatography on silica gel (30% EtOAc / hexane, then 5%
MeOH / CH,Cl,) to yield the title compound (10.26 g, 59%) as a yellow oil. 'H NMR (300 MHz, CDCl3) 6 6.77 (1H, d, J = 2.0 Hz), 6.74 (1H, d, J = 2.0 Hz), 2.16 (3H, s).
LCMS (M+H)" m/z 201. (t = 0.83 min.).
Be MeO =
TL
6-Bromo-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl-1H-benzimidazole: To a solution of 5-bromo-3-methyl-1,2-phenylenediamine (4 g, 19.9 mmol) in methanol (80 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (5.23 g, 19.9 mmol) in methanol (20 mL) dropwise at 0°C. The resulting slurry was stirred for 30 min at room temperature. Then iodine (2.53 g, 9.95 mmol) in methanol (20 mL) was added via a dropping funnel. After 14 h, the reaction mixture was concentrated in vacuo, diluted with 5% Na,S,03, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na;SO,. After removal of solvent, the residue was purified by careful flash chromatography (20% EtOAc / hexane) to yield the title compound (4.05 g, 46%) as a yellow foam. 'H NMR (300
MHz, CDCl;) 6 7.86 (1H, d, J = 5.31 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.26 (2H, broad s), 3.91 (3H, s), 2.63 (3H, s). LCMS (M+H)" m/z 444 (t = 1.39 min.). 8r N A NH
TL
Cl 3-(6-Bromo-4-methyl-1H-benzimidazol-2-yl)-4-chloro-1H-pyridin-2-one: The suspension of 6-bromo-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl- 1 H- benzimidazole (4 g, 9.03 mmol) and 60 mL of 4 M HCl in dioxane was heated to 80°C for 6 h and cooled to room temperature. The precipitate was filtered and dried to yield the title compound (3.0 g, 100%) as a brown powder. The crude product was used for the next step without purification. 'H NMR (300 MHz, CD;0D) 6 7.55 (1H,
s), 742 (1H, d, J = 6.0 Hz), 7.17 (1H, 5), 6.91 (1H, d, J = 6.0 Hz), 2.55 (3H, 5). LC
MS (M+H)" m/z 338 (t = 1.33 min.). :
Br N AN
Cress
HY ay (S)-4-(1-Benzyl-2-hydroxy-ethylamino)-3-(6-bromo-4-methyl-1H-benzimidazol- 2-yl)-1H-pyridin-2-one: To a solution of 3-(6-bromo-4-methyl-1H-benzimidazol-2- yl)-4-chloro-1H-pyridin-2-one (1.42 g, 3.78 mmol) in DMF (15 mL) were added (S)- (-)-2-amino-3-phenyl-1-propanol (1.43 g, 9.45 mmol) and N-methyl morpholine (1.5 mL). The reaction mixture was heated to 80°C for 6 h and cooled to room temperature. The solvent was removed with high vacuum and the residue was purified by flash chromatography (5% MeOH / CH,Cl,) to yield the title compound (1.26 g, 74%) as a yellow foam. 'H NMR (300 MHz, CDCl3) § 6.9 — 7.2 (8H, m), 5.86 (1H, d,
J=17.1Hz),3.7-3.9 (3H, m), 2.9-3.1(2H, m), 2.57 (3H, 5s). LCMS (M+H)* m/z 453 (t =2.03 min.).
Br N A NH
Tr > (S)-4-(1-Benzyl-2-trityloxy-ethylamino)-3-(6-bromo-4-methyl-1H-benzimidazol- 2-yl)-1H-pyridin-2-one: To a solution of (5)-4-(1-benzyl-2-hydroxy-ethylamino)-3- (6-bromo-4-methyl-1H-benzimidazol-2-yl)- 1H-pyridin-2-one (0.9 g, 1.98 mmol) in
THF (30 mL), was added Cs,CO3 (1.29 g, 3.96 mmol) followed by triphenylmethyl . chloride (1.10 g, 3.96 mmol). The reaction mixture was heated to reflux for 14 h under nitrogen and then cooled to room temperature. After removal of the solvent, the residue was diluted with ethyl acetate and washed with water. The aqueous fraction was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over Na,SQy4. After concentration in vacuo, the residue was purified by flash column chromatography (30% EtOAc / hexane) to yield the title compound (1 g, 73%) as a white solid. 'H NMR (300 MHz, DMSO-d) § 11.77 (1H, broads), 11.73 (1H, d, J = 5.2 Hz), 11.46 (1H, broad s), 7.13 — 7.54 (23H, m), 5.87 (IH, d, J =4.5Hz),4.09 — 4.14 (1H, m), 3.07 — 3.42 (4H, m), 2.54 (3H, 5). LCMS (M+H)" m/z 695 (t = 2.79 min.).
Preparation of 3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4- chloro-1H-pyridin-2-one:
[0]
BIN
Low NO; or 1-[4-(4-Amino-3-methyl-5-nitro-phenyl)-piperazin-1-yl]-ethanone: A mixture of 4- bromo-2-methyl-6-nitro-phenylamine (5g, 21.64 mmol), 1-acetylpiperazine (4.2g, 32.46 mmol), palladium acetate (244 mg, 1.08 mmol), tri-tert-butylphosphine (440 mg, 2.16 mmol) and sodium tert-butoxide (4.2 g, 43.29 mmol) in toluene (70 mL) was heated to 100°C for 14 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with EtOAc. After extraction, the combined organic layers were washed with water, brine, dried over Na;SO4. Concentration gave a brownish residue which was purified by flash column chromatography (10% MeOH / CH,Cl,) to yield the title compound (4.21 g, 70%). '"H NMR (400 MHz, CD;0D) § 7.42 (1H, d, J = 2.8 Hz), 7.23 (1H, d, J=2.8 Hz), 3.71 (2H,t,J=5.1 Hz), 3.67 2H, t,7=5.1 Hz), 3.04 2H, t,J=5.2
Hz), 2.98 (2H, t, J = 5.2 Hz), 2.24 (3H, s), 2.13 (3H, 5). LCMS (M+H)" nv/z 279 (t = 1.46 min). 0
BURN hn
NH,
1-[4-(3,4-Diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone: To 1-[4-(4-amino-3- methyl-5-nitro-phenyl)-piperazin-1-yl]-ethanone (4.5 g, 16.2 mmol) and 10% palladium ) on carbon (400 mg) were added methanol (50 mL) and acetic acid (5 mL) under nitrogen.
The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 14 h.
The dark solution was filtered through a pad of celite and the filtercake was washed with methanol. Concentration of the filtrate gave the title compound (4.00 g, 100%) which was used for the next step without purification. LCMS (M+H)* m/z 207 (t = 0.41 min.).
A
Ch" oP ! 1-{4-[2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazol-5-yl]-piperazin- 1-yl}-ethanone: To a solution of 1-[4-(3,4-diamino-5-methyl-phenyl)-piperazin-1-yl]- ethanone (4.00 g, 16.18 mmol) in methanol (100 mL) was added 4-iodo-2-methoxy- pyridine-3-carbaldehyde (4.25 g, 16.18 mmol). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (10% MeOH / CH,Cl,) to yield the title compound (5.25 g, 66%). 'H
NMR (400 MHz, CD;0D) 6 7.81 (1H, d, J = 5.4 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.26 (1H, s), 6.85 (1H, s), 3.85 (3H, 5), 3.78 (2H, t, J = 5.0 Hz), 3.64 (2H, t, J = 5.0 Hz), 3.16 (2H, t,
J=52Hz),3.11 (2H,t,J=5.2 Hz), 2.62 (3H, s), 2.13 (3H, 5). LCMS (M+H)* m/z 492 (t = 1.71 min.). [o]
A .
L_w N NH pete
Ci 3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl}-4-chloro-1H- pyridin-2-one: To a solution of 1-{4-[2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-methyl- 3H-benzimidazol-5-yl]-piperazin-1-yl }-ethanone (5.2 g, 10.6 mmol) in 4 M HCl in dioxane (60 mL) was added water (5 mL). The reaction mixture was stirred at room temperature for 14 h. Concentration of the reaction mixture gave the title compound (4.02 g, 100%) which was used for the next step without purification. LCMS (M+H)* m/z 486 (t = 1.55 min.). 3 .
Preparation of (5)-4-(1-Hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyi-6- piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one: x ery
HN ay (S)-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-(1- hydroxymethyl-2-phenyl-ethylamino)-1H-pyridin-2-one: To a solution of 3-[6-(4- acetyl-piperazin-1-yl)-4-methyl- 1 H-benzimidazol-2-yl]-4-chloro- 1 H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 mL) was added (S)-(-)-2-amino-3-phenyl-propanol (0.78 mg, 5.2 mmol) and N-methyl morpholine (2 mL). The reaction mixture was heated to 80°C for 12 h, cooled to room temperature and concentrated with high vacuum. The residue was purified by flash column chromatography (10% MeOH / CH,Cl,) to yield the title compound (0.90 g, 69%). 'H NMR (400 MHz, CD50D) & 7.36 (1H, s), 7.02 — 7.23 (6H, m), 6.80 (1H, s), 5.98 (IH, d, J = 7.5 Hz), 4.10 - 4.12 (3H, m), 3.67 — 3.78 (6H, m), 3.06 — 3.11 (3H, m), 2.90 (1H, dd, J = 7.8, 13.6 Hz), 2.54 (3H, 5), 2.12 (3H, 5). LCMS (M+H)" m/z 501 (t= 1.30 min.).
CL
HN,
(5)-4-(1-Hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H- benzimidazol-2-yl)-1H-pyridin-2-one: To a solution of (S)-3-[6-(4-acetyl-piperazin- 1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-(1-hydroxymethyl-2-phenyl-ethylamino)- 1H-pyridin-2-one (900 mg, 18 mmol) in 4 M HCI in dioxane (10 mL) was added water (1 mL). The reaction mixture was heated to 80°C for 14 h and cooled to room temperature. Concentration with high vacuum gave the title compound (0.83 g, 100%) which was used for the next step without purification. LCMS (M+H)* m/z 459 (t = 1.13 min.).
Preparation of 2-(4,6-Dichloro-pyrimidin-5-yl)-6-imidazol-1-yl-4-methyl-1H- benzimidazole:
H “ =N rh cl 4,6-Dichloro-pyrimidine-5-carbaldehyde: DMF (7 mL, 0.09 mol) was added to
POC]; (21 mL, 0.23 mol) at 0°C. The reaction mixture was stirred at room temperature for 0.5 h. 4,6-Dihydroxy-pyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was heated to 90°C for 6 h and cooled to room temperature. A large excess of crushed ice was added to the reaction mixture very slowly under ice-bath. The mixture was extracted with CH,Cl,. The combined organic layers were washed with water, brine, and dried over Na,SOy. After concentration, the residue was purified by column chromatography (20% EtOAc / hexane) to yield the title compound (4 g, 50%). 'H NMR (400 MHz, CDCls) 6 8.91 (1H, s), 7.87 (1H, s). LRMS (M+H)" m/z 177.
Chott Ben
CL
Cl 2-(4,6-Dichloro-pyrimidin-5-yl)-6-imidazol-1-yl-4-methyl-1H-benzimidazole: To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (180 mg, 0.96 mmol) in methanol (4 mL) was added a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde ( 183 mg, 0.96 mmol) in methanol (1 mL). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (5% methanol / CH,Cl,) to yield the title compound (180 mg, 55%).
LCMS (M+H)' m/z 344 (t = 1.31 min.).
Procedure for the Preparation of 2-Amino-4-Fluoro-6-methyl nitrobenzene:
F F
[0]
Y [o} (o] t 2-(3,5-Difluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester: To a suspension of
NaH (54.6g, 60%, 1.365 mol) in 600mL of DMF was added di-r-Butyl malonate (118g, 0.546 mol) at 0°C and stirred for 30 min. 2,4,6 trifluoronitrobenzene was added as a solution in 400 mL of DMF (75 g, 0.42mol) over 3 hours and the solution stirred at ambient temperature for 12 hours. The reaction mixture was extracted with ethyl acetate (3X’s). The ethyl acetate was washed with water (3X’s) and with brine and dried over MgSO, and concentrated to give 62 g of crude product. LCMS [M+Na] - 396; 'H NMR (500MHz, DMSO) & 7.81 (m, 1H), 7.27 (m, 1H), 5.00 (s, 1H), 1.41 (m, 18H). £ NH, ye 0
Y [o] 0 1 2-(3-Amino-5-fluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester: To the crude 2-(3,5-Difluoro-2-nitro-phenyl)-malonic acid di-ferz-butyl ester (62g, 0.42 mol) was added 700 mL of 2M ammonia in methanol in a pressure bottle. The vessel was sealed and heated to 85°C for 18 hours. The reaction mixture was cooled and the } vessel opened carefully and the methanol solution concentrated to provide 140 g of crude material. LCMS [M+Na] - 393; 'H NMR (500MHz, DMSO) 6 6.76 (dd,

Claims (71)

Co IPEA/US Re RE RRR OE TE AMENDED SHEET What is claimed is:
1. A compound according to formula I R3 R? K Y Ww yeuaadt R* N X RS R® TR’ I oe its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and oo solvates thereof: wherein X is selected from the group consisting of N, C, C,-C; alkyl, C,-C; alkyl substituted with one or more R’ and a direct bond; Y is selected from the group consisting of O and S; W is selected from the group consisting of N, C, O, and S; provided that if W is O or S, R’ is absent; R!, RL, R® RY R®, R’ R% R® are each independently selected from the group So consisting of H, Cy alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, OR%, NO,, OH, SR®, NR¥R®, CN, CO,R®’, CONR®R®', OCONR®R®, NR®CONR®R®, NR¥SO,R®' , SO,NRPR®!, CONRH)NR®*R®!, aryl, heteroaryl, k (CH,).0R®, (CH,).NR*R®, (CH,),SR¥, (CH,), aryl, (CHa), heteroaryl, , (CHz), heterocycloalkyl, NH-Z-aryl, and NH-Z-heteroaryl; whereinn is 1 to 3; RS is H, C,.s alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, OR%, NO,, OH, SR¥®, NR*R®', CN, CO,R®, CONR®R®', OCONR¥R®, NRE2CONR®R®!, NR®SO,R® , SO,NR¥R®", CONRS2NR®R', (CH,),0R®, (CH2):NR®R®, (CH,),SR®, (CH), aryl, (CHy), heteroaryl, (CHy), heterocycloalkyl, NH- Z-aryl, and NH-Z-heteroaryl provided that R® is not Hif Y is S; and 221 AMENDED SHEET
I ree IPEA/US : LER NR SR ENTE a Ed EE AMENDED SHEET R¥isH, C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, NO, OH, SR®, NR*R® , CN, CO,R®, CONR*R®', OCONR*R"", NRPCONR®RS!, NR®SO,R®! | SO;NR®R®!, C(NRHNR®R®!, (CH), OR, . (CH2).NR*R®, (CH,),SR®, (CH,), aryl, (CHa), heteroaryl, , (CHa), heterocycloalkyl, NH-Z-aryl, and NH-Z-heteroaryl; : Z is selected from the group consisting of C; — C, alkyl, alkenyl, and alkynyl chain; Z having one or more hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, NR®SO,R® groups; Z optionally incorporating one or more groups selected from the group consisting of CO, CNOH, CNOR®, CNNR® , CNNCOR® and CNNSO,R*‘ and : R®, and R¥ are independently selected from the group consisting of H, alkyl, oo alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl, and alkyl-R* wherein R* is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, NR? 'COOR?!, - NR¥C(O)R?, -NRSO,R*, -C(O)NR**R®, heteroaryl or heterocycloalkyl; and R* and R¥! are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R® . 221-1 AMENDED SHEET
To _, AMENDED SHEET IPEA/US ] : foe ELE EE TR RRR EE EE
2. "The compound according to claim 1 wherein Rr R’, R®and R® are H; R? and R*are Hor F; Y is O; ‘ X is selected from the group consisting of N and CH; Wis N; RS is selected from the group consisting of H, methyl, ethyl, isopropyl, secondary butyl, cyclopropyl, F, and CFs; R® is selected from the group consisting of H, 2-aminomethylpyrndine, NHCH,CH(OH)Ph, NHCH,CH(OH)(3-Cl-Ph), NHCH,CH(OH)(3-Br-Ph), NHCH,CH(OH)(3-Br-4-OMe-Ph), NHCH(CH,OH)CH,Ph, NHCH,CH(OH)aryl, and NHCH(CH,OH)CHaaryl; and R? is selected from the group consisting of OR®, C(NH)NHR®, C(O)NHR® imidazole, imidazoline, tetrahydropyrimidine, piperazine, morpholine, homomorpholine, piperidine, pyrrolidine, homopiperazine and amino; wherein R® is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, and alkyl-R* wherein R? is hydrogen, alkenyl, hydroxy, thiol, thioalkoxy, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, “NR¥COOR’, - NR*C(O)R? l -NR¥SO,R?, -C(O)NR® °R*' or a heteroaryl or heterocycloalkyl; and Ryo and Rs, are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R? .
3. The compound according to claim 2 wherein R? is —OR® and R% is alkyl, or ~ alkyl-R*®, wherein 222 AMENDED SHEET
R” is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR**COOR?', -NR*C(O)R*!, -NR*’SO,R*, - C(O)NR*R3! heteroaryl! or heterocycloalkyl; and Rip and Rj are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R*. 4, The compound according to claim 3 wherein R% is methyl, -(CH,),CH,OH, or -(CH2)sCH,N(CH,CH;);0, and nis 0, 1, or 2.
5. The compound according to claim 3 wherein R* is morpholine, 0 L (0) Pate AR = _ 4 3 = + 8 0 N N NR Ras Ra 4 =N 3 N-N ~N N- NEE Gy Ge Py ee 0 R o 0 Ag N\ le) —Uk 31 31 wherein R*is hydrogen, alkyl, or substituted alkyl.
6. The compound according to claim 2 wherein R? is piperazine, homopiperazine, 3-methylpiperazine, or 3,5-dimethylpiperazine being optionally substituted at the 4-N position with a compound selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkyl-R*,-C(O)-R'?, or -CO;R'® wherein R'” is hydrogen, alkyl, aryl, alkyl-R?*, amino or aryl; and RZ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, cyano, halo, sulfoxy, sulfonyl, arylsulfonyl, - NR*COOR?, -NR*C(O)R*, -NR¥*SO,R*, -C(O)NR*R?!, heteroaryl or heterocycloalkyl; and R* and RY are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R%.
TT. The compound according to claim 6 wherein said piperazine is substituted . with methyl, ethyl, CH,-cyclopropyl, hydroxyethyl, 2-dimethylaminoethyl, 2- diethylaminoethyl, 2-aminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl, methoxyethyl, ethoxyethyl, morpholine, and morpholinylethyl.
8. The compound according to claim 2 wherein R? is an amino group selected from the group consisting of hydroxyalkylamino, aminoalkylamino, dialkylaminoalkylamino, and heterocycloalkylalkylamino.
S
9. The compound according to claim 8 wherein said amino is selected from the group consisting of NHCH,CH,OH, NMeCH,CH,0H, NEtCH,CH,0H, NHCH,CH;NH;, NMeCH,CH;,NH,, NEtCH,CH,NH,;, NHCH,CH;NMe,, NMeCH,CH;NMe,, NEtCH,CH,NMe,, NHCH,CH,;NEt;, NMeCH,CH;,NEt,, NEtCH,CH,NEt,, NHCH,CH,N(CH,CH,),0, NMeCH,CH,N(CH,CH>),0, and NEtCH,CH,;N(CH,CH,)-0.
10. The compound according to claim 2 wherein R? is piperidine, optionally substituted with hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, 1,3 dioxolane, 1,3 dioxane, -NHC(O)R" , -NHCO,R", wherein R'is hydrogen, alkyl, aryl or alkyl-R® wherein R? is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR¥*COOR?!, -NR*c(O)RY, -NR¥SO,R*!, - C(O)NR RY, heteroaryl or heterocycloalkyl; and R*® and R*' are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R® .
11. The compound according to claim 2 wherein R’ is morpholine, thiomorpholine, sulfoxymorpholine, sulfonylmorpholine, or homomorpholine, or a substituted morpholine, thiomorpholine, sulfoxymorpholine, sulfonylmorpholine, or homomorpholine.
12. The compound according to claim 11 wherein said morpholine, thiomorpholine, sulfoxymorpholine, sulfonyl morpholine, or homomorpholine is substituted with hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, alkyl-R® : -NHC(O)R'’, -NHCO,R", wherein R'® is hydrogen, alkyl, aryl or alkyl-R* wherein R> is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano,
sulfoxy, sulfonyl, -NR*®*COOR? | -NR*C(O)R?*!, -NR¥SO,R?!, -C(O)NR*R?, heteroaryl or heterocycloalkyl; and R*® and RY are, independently, hydrogen, alkyl, cycloalkyl, or alkyl-R%. . 5 13. The compound according to claim 2 wherein R? is (CH,),-morpholine or (CHy),- piperazine, wherein n is 1 to 3.
14. The compound according to claim 2 wherein R? is an optionally substituted N- tetrahydropyrimidine or N-imidazoline.
15. The compound according to claim 14 wherein at least one of said substituents is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanoalkyl, carboxyl, or carboxamide.
16. The compound according to claim 2 wherein R’ is pyrrolidine.
17. The compound according to claim 2 wherein said pyrrolidine is selected from the group consisting of 3-hydroxyl pyrrolidine, 3- alkoxy pyrrolidine, and 3- alkylamino pyrrolidine, 3-dialkylamino pyrrolidine.
18. The compound according to claim 2 wherein R® is selected from the group consisting of H, 2-aminomethylpyridine, NHCH,CH(OH)aryl, and NHCH(CH,;OH)CHsaryl.
19. The compound according to claim 18 wherein said aryl is an optionally substituted phenyl.
20. The compound according to claim 19 wherein said phenyl is substituted with a Br, Cl, F, alkoxy or-NHSO,CH3.
21. The compound according to claim 19 wherein said substituent is 3-Br, 3-Cl or
3-F.
22. The compound according to claim 19 wherein said substituent is 4-F or 4- methoxy.
23. The compound according to claim 19 wherein R®is “NH “SNH “SNH HO HO HO < | Riz < | 17 Ry7
[0] \ NR4o " NR (o] AN wo NH “ HN ~~ HO
OR . Q Far Ryz7 r he NRao =r " wherein R'is H, Br, Cl, or F and R* is H or alkyl.
24. A compound having the formula: Riz o™ H ©O AN N NH Rig ) NN 7 HN HOw Riz
10 . Rig Rig wherein R'? and R" are, independently, hydrogen, alkyl, or alkyl-R* wherein R? is hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, -CO.H, -C(O)NR*R?', -NR**SO,R*', -NR*C(O)R*, - NR¥*C(O)ORY, heteroaryl or heterocycloalkyl; R'7, R'® and R" are, independently, hydrogen, halogen, or alkoxy, or R'® and R'® together form a heterocycloalkyl or heteroaryl group; and R*and R*' are, independently, hydrogen, alkyl, or alkyl-R%.
25. The compound according to claim 24 wherein R* is morpholine, 0) iN . N N N N=n 9 oo [l — J —N ey N_J — J Non TRE Tew N N NR Ras Ras ’ <N 31 N-n =N N- —N % JY 4 T % — or N EU Un Ue 31 31 5 wherein R¥is hydrogen, alkyl, or substituted alkyl.
26. The compound according to claim 24 wherein R'%is hydrogen, methyl, hydroxymethyl, methoxymethyl, CH,F, CH,CN, CO,H, or -CONR*’R*' wherein R* and R*' are, independently, hydrogen, or alkyl-R* .
27. The compound according to claim 24 incorporating the side chain “nn SNH SNH HO HO HO R Rez Ry7 " 0 NRyo [o] “NH HN ~ HO HO vo NH OR R PE 17 1 Ry7 o Ruy o “ \=N wherein R* is hydrogen or alkyl, and R™ hydrogen or halogen.
28. The compound according to claim 24 wherein R'?and R” are H; R'is Br, F, or CI; R'%is methoxy or fluoro; and RY? is H; or R'® and R" together form 4-0, 5 dihydrofuranyl. :
29. The compound according to claim 24 wherein R'?and R'3 are methyl; R" is Br, For Cl, R% is hydrogen or methoxy; and R'is H.
30. A compound having the formula fie . ew H Q CGA N HN HOw Ry7 Ryo Ris wherein R;s is hydrogen, alkyl, aryl, or -alkyl-R*, wherein R? is is-hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, -NR*COOR?, -NR*¥C(O)R?, -NR*’SO,R*, -C(O)NR*R*', heteroaryl or heterocycloalkyl; R'® is each independently hydrogen or methyl; R', R'® and R" are, independently, hydrogen, halogen, or alkoxy; or R'® and RY together form a heterocycloalkyl! or heteroaryl group; and R*® and R*' are, independently, hydrogen, alkyl or alkyl-R% .
31. The compound according to claim 30 wherein Ris morpholine, thiomorpholine, Oo 0 N N=p N N Ra Nn ; i v= ~<A, J oh, — or —l
32. The compound according to claim 30 incorporating the sidechain
NH NH NH HO HO HO = R47 \ Ry7 Riz 0 NRso NR4o 4) NH NH NH HO HO HO OR R o Rs 0 Riz NRgp i NR \=N 0 wherein R% is hydrogen or alkyl and RY hydrogen or halogen.
33. The compound according to claim 30 wherein R'” is hydrogen, methyl, ethyl, or (CH2).CH>-R® wherein R? is OH, OMe, F, CN, CF3, SOCH3 or SO,CHj3, wherein n isOor 1.
34 The compound according to claim 30 wherein RY is cyanoethyl, hydroxyethyl, CH,CH,SOCH;, CH,CH,CH,F, CH,CH,CH,CN, or CH,CH,CF;, R'® and R" are H;R" is Br, or Cl; and Rg is hydrogen or methoxy.
35. A compound having the formula: pil Rie Ris JQ! H (0) Rig N NH / HN HOw Riz Rg Ris wherein RY is hydrogen, alkyl, aryl or alkyl-R*” :
R% is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR**COOR?', -NR*C(O)R*', -NR*’SO,R?!, - C(O)NR*R*, heteroaryl or heterocycloalkyl; R'® is each independently hydrogen or methyl; R' R'®and R' are, independently, hydrogen, halogen, or alkoxy, or R'® and rR" together form a heterocycloalkylor heteroaryl group; and R* and R* are, independently, hydrogen, alkyl, cycloalkyl or alkyl-R%.
36. The compound according to claim 35 wherein R* is morpholine, thiomorpholine, (o] L N N N Nan — O _ 3 —N —_J | : vs N_ NJ Non Ne \=N N N No _R Ra Raq SSN 31 N-n nN N- —N <I —~« J a a or N NT 0 Rj, [0] 0g, \_-0 —\Nh wherein R* is hydrogen, alkyl, or substituted alkyl.
37. The compound according to claim 35 incorporating the sidechain “am SNH “SNH ) ) HO R R R J 17 \ NA 17 Neo 17
[0] “aH HN” . HO HO NH HO OR fo} Riz Rey a : NR r 0 NR i v wherein R* is hydrogen or alkyl and R'7 hydrogen or halo.
38. The compound according to claim 35 wherein R"® is hydrogen or methyl; R" } 5 is bromo, chloro or fluoro; R'® is hydrogen or methoxy; and Ris hydrogen .
39. A compound having the formula O Ry EEN H O R, AN N NH 4 CL «J HN How { Ry7 : Rig Rig wherein Ris is hydrogen, alkyl, or, -alkyl-R% R R” is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR*COOR?, -NR*C(0)R*, -NR¥SO,R* | -C(O)NR*’R*, heteroaryl or heterocycloalkyl; R' is each independently hydrogen or methyl; R", R'® and R" are, independently, hydrogen, halogen, or alkoxy; or R'®and R'’ together form a heterocyclo or heteroaryl group; and R¥ and R* are, independently, hydrogen, alkyl, cycloalkyl or alkyl-R%® .
40. The compound according to claim 39 incorporating the sidechain
“im “NH NH HO | | HO Ry7 R R 7 \ NRgg i NRgo o “NH HN" HO HO TNH HO x OR C Riz Riz R ye NRe o_T 17 wherein R* is hydrogen or alkyl and RY hydrogen or halo.
41. The compound according to claim 39 wherein R" is hydrogen, methyl, ethyl, or -(CHy),CH,-R® wherein nis 0, 1, or 2; and R” is OH, OMe, F, CN, CF;, SOCH; or SO,CHj3, -NR*COR?', -NR*COOR? -NR¥S0,RY, -C(O)NR*R?, or has the formula: 0 * . N N N N=nN NO NT —N —N_J —N N N NL _R Rai Ra , =N 31 N-n =N N-n —N C1. —~ 71 7 1 or n N= 8 Ry © A Ra wherein R*® is hydrogen, alkyl, or substituted alkyl.
42. The compound according to claim 39 wherein R" is ethyl, methoxyethyl, CH,CH,F, or CH,CH,CN; R'7 is bromo or chloro; R'is methoxy or hydrogen; and R"is hydrogen.
43. A compound having the formula: H H _ Rison AN I. I TO H OQ o N N NH : o N N NH > ay jo \_/ N HN HN OR HO!" HOM Rs Riz Rie Ria Rip Rig wherein Ris is hydrogen, alkyl, aryl, or -alkyl-R%>; R? is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR*COOR?, -NR¥C(O)R?!, -NR*SO,R’ '- C(O)NR*R®!, heteroaryl or heterocycloalkyl; R',R"® and R" are, independently, hydrogen, halogen, or alkoxy; or R'® and R' together form a heterocyclo or heteroaryl group; and R* and R¥ are, independently, hydrogen, alkyl, cycloalkyl or alkyl-R%.
44. The compound according to claim 43 wherein RY is «(CH)nCH,R® nis 0, 1, 2 or 3 and R% is OH, OMe, F, CN, CFs, SOCH3 or SO,CHs , -NR*COOR?, - NR¥C(O)R*, -NR*SO,R*, -C(O)NR’'R* or has the formula: (0) L N N N Nzn NO gS —N —N_] —N Ng NI NJ Neon Ne \=N Ra, Ra Ney — 0 Ast a eS N-n —N _ J} T 4 ( [} or i N= 0g, © 0p, Wa ) 20 wherein R*is hydrogen, alkyl, or substituted alkyl.
45. The compound according to claim 43 wherein R'® is methyl, ethyl, CH,F, methoxyethyl, CH,CH,F, or CH,CH,CH,SOCH3; R'” is bromo; R'® is hydrogen, methoxy, or fluoro; and R'? is H.
46. The compound according to claim 45 incorporating the sidechain “ni NH SNH HO HO HO R47 Ry7 Ry7 o \ NRg4o NRyo oO “nH ~~ HO ml NH HO HO OR 0 Ry7 R )r~NRa in 7 lo) Riz pd 40 \=N wherein R*® is hydrogen or alkyl, and R'is hydrogen or halo.
47. A compound having the formula: Rys Ris Rs a Th 1) 4H R Res 1) H O N N NH N N NH CHS a oc HN HN HOw . or HO Ry? Rez Rio Ris Rig Rig wherein each R'? is independently hydrogen, alkyl, aryl, or -alkyl-R* ; )
R® is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR®COOR?', -NR¥C(O)R*!, -NR*SO,R?, - C(O)NR*R¥ heteroaryl or heterocycloalkyl; R',R'® and R" are, independently, hydrogen, halogen, or alkoxy; or R'® and i 5s R'" together form a heterocyclo or heteroaryl group; and R*® and R* are, independently, hydrogen, alkyl, cycloalkyl or alkyl-R%.
48. The compound according to claim 1 selected from the group consisting of : A compound according to claim 1 having the formula: (S)-4-(2-Hydroxy-1-phenyl-ethylamino)-3-(6-imidazol- 1-yl-4-methyl-1H- benzimidazol-2-yl)-1H-pyridin-2-one; ()-4-[2-Hydroxy-2-(3-iodo-phenyl)-ethylamino]-3-(6-imidazol-1-yl-4-methyl- 1H- benzimidazol-2-yl)- 1H-pyridin-2-one; (+)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-(6-imidazol-1-yl-4-methyl-1H- benzimidazol-2-yl)-1H-pyridin-2-one; (£)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3-(6-imidazol-1-yl-4-methyl-1H- benzimidazol-2-yl)-1H-pyridin-2-one; (5)-4-[2-(2-Chloro-phenyl)-1-hydroxymethyl-ethylamino]-3-(6-imidazol-1-yl-4- methyl- 1 H-benzimidazol-2-yl)-1H-pyridin-2-one; (S)-4-[2-(3-Chloro-phenyl)- 1-hydroxymethyl-ethylamino]-3-(6-imidazol-1-yl-4- methyl- 1H-benzimidazol-2-yl)-1H-pyridin-2-one; (S)-4-[2-(4-Chloro-phenyl)-1-hydroxymethyl-ethylamino]-3-(6-imidazol- 1-yl-4- methyl- 1H-benzimidazol-2-yl)- 1H-pyridin-2-one; (S)-4-[2-(2-Bromo-phenyl)-1-hydroxymethyl-ethylamino]-3-(6-imidazol-1-yl-4- methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (8)-4-[2-(3-Bromo-phenyl)-1-hydroxymethyl-ethylamino]-3-(6-imidazol-1-yl-4- methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (+)-4-(1-Hydrox ymethyl-2-pentafluorophenyl-ethylamino)-3-(6-imidazol-1-yl-4- methyl- 1 H-benzimidazol-2-yl)-1H-pyridin-2-one; (S)-4-(1-Hydroxymethyl-2-pyridin4-yl-ethylamino)-3-(6-imidazol-1-yl-4-methyl-1H- benzimidazol-2-yl)- 1H-pyridin-2-one;
(5)-4-[1-Hydroxymethyl-2-(2-naphthalenyl)-ethylamino]-3-(6-imidazol-1-yl-4- methyl-1H-benzimidazol-2-yl)- 1 H-pyridin-2-one; 3-(6-Imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-(pyridin-2-ylmethoxy)- 1H- pyridin-2-one; ($)-4-[2-(3-Bromo-phenyl)-2-fluoro-ethylamino}-3-(6-imidazol-1-yl-4-methyl- 1 H- benzimidazol-2-yl)- 1H-pyridin-2-one; (8)-2-[4-(1-Hydroxymethyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7- methyl-3H-benzimidazole-5-carbonitrile; (£)-2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino)-2-oxo-1,2-dihydro-pyridin-3- yl}-7-methyl-3H-benzimidazole-5-carbonitrile; (S5)-2-{4-[2-(3-Chloro-phenyl)- 1-hydroxymethyl-ethylamino]-2-oxo-1,2-dihydro- pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile; (2)-2-{4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydrox y-ethylamino]-2-oxo-1,2-dihydro- pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile; (%)-2-{4-[2-(3-Fluoro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3- yl}-7-methyl-3H-benzimidazole-5-carbonitrile; ()-2-{4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-2-oxo- 1,2-dihydro-pyridin-3- yl}-7-methyl-3H-benzimidazole-5-carbonitrile; ($)-2-[4-(2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7- methyl-3H-benzimidazole-5-carbonitrile; (+)-3-(1H-Benzimidazol-2-yl)-4-[2-(3-bromo-phenyl)-2-hydrox y-ethylamino]- 1 H- pyridin-2-one; (8)-3-(1H-Benzimidazol-2-yl)-4-(1-hydrox ymethyl-2-phenyl-ethylamino)- 1 H- pyridin-2-one;
. 25 (})-3-(1H-Benzimidazol-2-yl)-4-[2-(3-bromo-4-methoxy-phenyl)-2-hydroxy- } ethylamino]-1H-pyridin-2-one; (5)-4-{2-[4-(1-hydroxymethyl-2-phenyl-ethylamino)-2-oxo- 1,2-dihydro-pyridin-3- yl]-7-methyl-3H-benzimidazol-5-yl }-piperazine- 1-carboxylic acid isopropylamide; (8)-4-{2-[4-(1-hydroxymethyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-y1]-7- methyl-3H-benzimidazol-5-yl}-piperazine-1-carboxylic acid ethylamide; ) (5)-4-(1-Hydroxymethyl-2-phenyl-ethylamino)-3- {4-methyl-6-[4-(1-phenyl-methanoyl)- piperazin-1-yl]- 1H-benzimidazol-2-yl }- 1H-pyridin-2-one;
(5)-4-(1-Hydroxymethyl-2-phenyl-ethylamino)-3-[6-(4-isopropyl-piperazin-1-yl)-4- methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one;
(S)-3-[6-(4-Benzyl-piperazine- 1-yl)-4-methyl- 1H-benzimidazoi-2-yl]-4-(1- hydroxymethyl-2-phenyl-ethylamino)-1H-pyridin-2-one;
()-3-[6-(4-Acetyl-piperazine-1-yl)-4-methyl- 1H-benzimidazol-2-yl]-4-{2-(3-chloro- phenyl)-2-hydroxy-ethylamino]- 1 H-pyridin-2-one; (£)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-piperazin-1-yl- 1H- benzimidazol-2-yl) -1H-pyridin-2-one; (+)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-[6-(4-isopropyl-piperazine- 1-yl)-4-
methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one; (5)-6-(1-Hydroxymethyl-2-phenyl-ethylamino)-5-(6-imidazol-1-yl-4-methyl-1H- benzimidazol-2-yl)-3H-pyrimidin-4-one;
(85)-2-{6-Chioro-5-(6-imidazol- 1-yl-4-methyl- 1 H-benzimidazol-2-yl)-pyrimidin-4- ylamino]-3-phenyl-propan-1-ol;
(8)-4-(2-Hydroxy-2-phenyl-ethylamino)-3-(6- imidazol-1-yl-4-methyl-1H- benzimidazol-2-yl)-1H- pyridin-2-one; (R)-4-(2-Hydroxy-2-phenyl-ethylamino)-3-(6-imidazol- 1-yl-4-methyl-1H- benzimidazol-2-yl)- 1 H-pyridin-2-one; (1S,2R)-4-(1-Hydroxy-indan-2-ylamino)-3-(6-imidazol-1-yl-4-methyl-1H-
benzimidazol-2-yl)- 1H-pyridin-2-one; (1)-4-[2-Hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-3-(6-imidazol- 1-yl-4-methyl- 1H-benzimidazol-2-yl)- 1H-pyridin-2-one; (8)-4-(2-Hydroxy-2-pyridin-2-yl-ethylamino)-3-(6-imidazol-1-yl-4-methyl-1H- benzimidazol-2-yl)- 1H-pyridin-2-one;
(¥)-N-(3-{1-Hydroxy-2-[3-(6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl)-2-0xo0- 1,2-dihydro-pyridin-4-ylamino]-ethyl } -phenyl)-methanesulfonamide; (+)-4-[2-(3-Fluoro-phenyl)-2-hydroxy-ethylamino]-3-(6-imidazol- 1-yl-4-methyl- 1 H- benzimidazol-2-yl)-1H-pyridin-2-one;
oo (2)-4-[2-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-3-(6-imidazol-1-yl-4- methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (S)-4-[2-(3-Fluoro-phenyl)-1-hydroxymethyl-ethylamino]-3-(6-imidazol- 1 -yl-4- methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one;
(+)-4-[2-(3-Chloro-phenyl)-2-hydrox y-ethylamino]-3-(6-imidazol-1-yl- 1 H- benzimidazol-2-yl)-1H-pyridin-2-one; (£)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino}-3-(6-imidazol- 1-yl-4- methyl-1H-benzimidazol-2-yl)- | H-pyridin-2-one;
(8)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3-(6-imidazol-1-yl-4-methyl- 1 H- benzimidazol-2-yl)-1H-pyridin-2-one;
(S)-4-[2-(3-Chloro-phenyl)-2-hydrox y-ethylamino]-3-(6-imidazol- 1-yl-4-methyl-1 H- benzimidazol-2-yl)-1H-pyridin-2-one; (R)-4-[2-(3-Chloro-phenyl)-2-hydrox y-ethylamino]-3-(6-imidazol- 1-yl-4-methyl- 1 H-
benzimidazol-2-yl)-1H-pyridin-2-one; (#)-4-[2-(3-Chloro-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(6-imidazol-1-yl-4- methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one;
(+)-(2-Chloro-4-{ 1-hydroxy-2-[3-(6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl)- 2-0x0-1,2-dihydro-pyridin-4-ylamino]-ethyl } -phenyl)-carbamic acid methyl ester;
(S)-4-(1-Hydroxymethyl-2-phenyl-ethylamino)-3-[4-methyl-6-(4-methyl-piperazin-1- yl)-1H-benzimidazol-2-yl]- 1H-pyridin-2-one;
(5)-4-(1-Hydrox ymethyl-2-phenyl-ethylamino)-3-[4-methyl-6-(4-n-butyl-piperazin-1-yl)- 1H-benzimidazol-2-yl}-1H-pyridin-2-one; (5)-3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-4-methyl- 1H-benzimidazol-2-yl } -4-(1-
hydroxymethyl-2-phenyl-ethylamino)- IH-pyridin-2-one;
($)-4-{2-[4-(1-Hydrox ymethyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3- yl]-7-methyl-3H-benzimidazol-5-yl } -piperazine-1-carboxylic acid amide; (£)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-piperazin-1-yl-1H- benzimidazol-2-yl)-1H-pyridin-2-one;
(%)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-[6-(4-ethyl-piperazin-1-yl)-4- _.. methyl- 1H-benzimidazol-2-yl]- 1H-pyridin-2-one;
()-4-[2-(3-Chloro-phenyl)-2-hydroxy-eth ylamino]-3- {6-[4-(2-hydroxy- ethyl)piperazin-1-yl]-4-methyl-1H-benzimidazol-2-yl }- 1Hpyridin-2-one, (+)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-(4-methyl-6-morpholin-4-yl-
1H-benzimidazol-2-yl)-1H-pyridin-2-one; ; (+)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin- 4-yl-1H-benzimidazol-2-yl)- 1H-;
(¥)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6- morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (3)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3- { 6-[4-(2-hydroxy-ethyl)- piperazin- 1-yl]-4-methyl-1H-benzimidazol-2-yl }- 1H-pyridin-2-one;
. S (3)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-piperazin- 1-yl-1H-benzimidazol-2-yl }-1H-pyridin-2-one; (1)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-piperazin- 1-yl-1H-benzimidazol-2-yl }- 1H-pyridin-2-one; (3)-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl}-4-[2-(3-bromo- phenyl)-2-hydroxy-ethylamino]-1H-pyridin-2-one; (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-[4-methy}-6-(2-morpholin-4-yl- ethylamino)- 1 H-benzimidazol-2-yl]-1H-pyridin-2-one; (#)-6-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-5-(6-imidazol- 1-yl-4-methyl- 1 H- benzimidazol-2-yl)-3H-pyrimidin-4-one; (£)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-[6-(1-hydroxy- 1-methyl-ethyl)- 4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one; (+)-3-(6-Aminomethyl-4-methyl-1H-benzimidazol-2-yl)-4-[2-(3-chloro-phenyl)-2- hydroxy-ethylamino]-1H-pyridin-2-one; (#)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(6-hydrox ymethyl-4-methyl- 1H-benzimidazol-2-yl)-1H-pyridin-2-one; (S)-4-(1-Benzyl-2-hydroxy-ethylamino)-3-(4-methyl-6-morpholin-4-yl- 1H- benzimidazol-2-yl)- 1H-pyridin-2-one; and (8)-4-(1-Benzyl-2-hydroxy-ethylamino)-3-(4-methyl-6-piperidin-1-yl-1H- benzimidazol-2-yl)- 1H-pyridin-2-one;
49. The compound according to claim 1 selected from the group consisting of: (S)-4-(1-Benzyl-2-hydroxy-ethylamino)-3-(4-methyl-6-piperidin-1-yl-1H- benzimidazol-2-yl)- 1H-pyridin-2-one; 4-[2-(3-Chloro-4-methylsulfanyl-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6- : 30 piperazin-1-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one; 4-[2-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-piperazin-1- yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one;
3-[4-(2-{4-[2-(3-Chloro-phenyl)-2-hydrox y-ethylamino]-2-0xo- 1,2-dihydro-pyridin- 3-yl}-7-methyl-3H-benzoimidazol-5-yl)-piperazin- 1-yl]-propionitrile; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{6-[4-(2-methanesulfonyl-ethyl)- piperazin-1-yl]-4-methyl- 1 H-benzoimidazol-2-yl }- 1 H-pyridin-2-one; 3-[4-(2-{4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydrox y-ethylamino]-2-oxo-1,2- } dihydro-pyridin-3-yl}-3H-benzoimidazol-5-yl)-7-methyl-piperazin-1-yl]- propionitrile; 4-(2-{4-[2-(3-Chloro-phenyl)-2-hydrox y-ethylamino]-2-oxo-1,2-dihydro-pyridin-3- yl }-7-methyl-3H-benzoimidazol-5-yl)-piperazine- 1 -carboxylic acid 2-fluoro-ethyl ester, 4-(2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3- yl }-7-methyl-3H-benzoimidazol-5-yl)-piperazine- | -carboxylic acid 2-methoxy-ethyl ester; 4-(2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-
yl}-7-methyl-3H-benzoimidazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester; 4-(2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3- yl }-7-methyl-3H-benzoimidazol-5-yl)-piperazine-1-carboxylic acid prop-2-ynyl ester; 4-(2-{4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro- pyridin-3-yl}-7-methyl-3H-benzoimidazol-5-yl)-piperazine- 1-carboxylic acid tert-
butyl ester;
(S)-4-(2-{4-[2-(3-Bromo-4-methox y-phenyl)-2-hydrox y-ethylamino}-2-oxo-1,2- dihydro-pyridin-3-yl }-7-methyl-3H-benzimidazol-5-yl)-piperazine- 1-carboxylic acid ethyl ester;
4-[2-(3-Chloro-4-methox y-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(3-fluoro-propyl)-
piperazin-1-yl]-4-methyl- 1H-benzoimidazol-2-yl }-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3- 6-[4-(2-fluoro-ethyl)-piperazin- 1- yl]-4-methyl- 1H-benzoimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino}-3-{6-[4-(3-fluoro-propyl)- piperazin-1-yl]-4-methyl- 1 H-benzoimidazol-2-yl } - |H-pyridin-2-one;
4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(3-fluoro-propyl)- piperazin-1-yl]-4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one;
4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-{4-methyl-6-[4-(3,3,3-trifluoro- propyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl }-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{6-[4-(3-fluoro-propyl)-piperazin- 1-yl]-4-methyl-1H-benzoimidazol-2-yl }-1H-pyridin-2-one;
. 5 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{4-methyl-6-[4-(3.4,4-trifluoro-but- 3-enyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl }- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(3-fluoro-2-hydroxy-propyl)- piperazin-1-yl]-4-methyl-1H-benzoimidazol-2-yl }-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2-hydroxy-2-methyl- propyl)-piperazin-1-yl]-4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; (8)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2-hydroxy-ethyl)- piperazin-1-yl}-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one; (S)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydrox y-ethylamino}-3-{6-[4-(2-hydroxy- ethyl)-piperazin-1-yl]-4-methyl- 1 H-benzimidazol-2-yl } -1H-pyridin-2-one; [4-(2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo- 1,2-dihydro-pyridin-3- yl}-7-methyl-3H-benzoimidazol-5-yl)-piperazin-1-yl]-acetonitrile; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(4-fluoro-butyryl)-piperazin- 1-yl]-4-methyl- 1 H-benzoimidazol-2-yl }- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2,2-difluoro-acetyl)- piperazin-1-yl]-4-methyl-1H-benzoimidazol-2-yl }- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2-methanesulfonyl-acetyl)- piperazin- 1-yl]-4-methyl-1H-benzoimidazol-2-yl }- 1H-pyridin-2-one; 3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl- 1 H-benzoimidazol-2-yl]-4-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino}-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-{4-[2-(1-ox0-114- thiomorpholin-4-yl)-acetyl]-piperazin-1-yl }-1H-benzoimidazol-2-yl)- 1H-pyridin-2- one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-(6-{4-[2-(1,1-dioxo-116- thiomorpholin-4-yl)-acetyl]-piperazin-1-yl }-4-methyl- 1 H-benzoimidazol-2-yl)- 1H- pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3- { 4-methyl-6-[4-(2-thiomorpholin- 4-yl-acetyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl }- 1H-pyridin-2-one; 241 _ _ _ _ LC
4-[2-(3-Chloro-phenyl)-2-hydrox y-ethylamino}-3-{6-[4-(2-methanesulfinyl-acety!)- piperazin-1-yl]-4-methyl-1H-benzoimidazol-2-yl}- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-{6-[4-(2-methoxy-acetyl)- piperazin-1-yl]-4-methyl-1H-benzoimidazol-2-yl}-1H -pyridin-2-one;
4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-{4-methyl-6-{4-(2-methylsulfanyl- acetyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-1 H-pyridin-2-one; 3-{6-[4-(2-Chloro-acetyl)-piperazin- 1 -yl]-4-methyl- 1H-benzoimidazol-2-yl } -4-[2-(3- chloro-phenyl)-2-hydroxy-ethylamino]- 1H-pyridin-2-one;
(S)-4-(2-{ 4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydrox y-ethylamino]-2-oxo-1,2-
dihydro-pyridin-3-yl }-7-methyl-3H-benzimidazol-5-yl)-piperazine-1-carbaldehyde; ($)-4-(2-{4-[2-(3-Chloro-phen yl)-2-hydroxy-ethylamino]-2-oxo-1 ,2-dihydro-pyridin- 3-yl}-7-methyl-3H-benzimidazol-5-yl)-piperazine-1 -carbaldehyde; (§)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino)-3-(4-methyl-6-morpholin-4-yl- 1H-benzoimidazol-2-yl)-1 H-pyridin-2-one;
4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin- 4-yl-1H-benzoimidazol-2-yl)- IH-pyridin-2-one; 4-[2-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin-4- yl-1H-benzoimidazol-2-yl)- 1H-pyridin-2-one; 4-[2-(3-Chloro-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin-
4-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one; 4-[2-(7-Bromo-2,3-dihydro-benzofuran-5-yl)-2-hydrox y-ethylamino]-3-(4-methyl-6- morpholin-4-yl-1H-benzoimidazol-2-yl)- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2(S)-hydroxy-ethylamino}-3-[4-methyl-6-[2(S),6(R)- dimethyl-morpholine-4-yl]-1H-benzoimidazol-2-yl]- 1 H-pyridine-2-one;
4-[2-(3-Bromo-4-methoxy-phenyl)-2(S)-hydroxy-ethylamino]-3-[4-methyl-6- [2(S).6(R)-dimethyl-morpholine-4-yl}-1H-benzoimidazol-2-yl]- 1H-pyridine-2-one; 4-[2-(3-Chloro-phen y1)-(S)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2-fluoromethyl- morpholin-4-yl]-4-methyl- 1H-benzimidazol-2-yl }- 1H-pyridin-2-one and 4-[2-(3- chloro-phenyl)-(S )-2-hydroxy-ethylamino}-3-{6-[(S )-2-fluoromethyl-morpholin-4-yl]-
4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(5)-2-h ydroxy-ethylamino]-3-{6-[(R )-2- fluoromethyl-morpholin-4-yl]-4-methyl-1 H-benzimidazol-2-yl }-1H-pyridin-2-one and 4-[2-(3-bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-{(S)-2- fluoromethyl-morpholin-4-yl1]-4-methyl- 1 H-benzimidazol-2-yl } - 1H-pyridin-2-one; 4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2-
fluoromethyl-morpholin-4-yl}-4-methyl- 1 H-benzimidazol-2-yl } - | H-pyridin-2-one . 5 and 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydrox y-ethylamino]-3-{ 6-[(S)-2-
fluoromethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl } -1H-pyridin-2-one; 4-[2-(7-Bromo-2,3-dihydro-benzofuran-4-yl)-(5)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2- fluoromethyl-morpholin-4-yl]-4-methyl- 1 H-benzimidazol-2-yl } - 1H-pyridin-2-one and 4-[2-(7-bromo-2,3-dihydro-benzofuran-4-yl)-(§)-2-hydrox y-ethylamino}-3-{ 6-
[(S)-2-fluoromethyl-morpholin-4-yl]-4-methyl- 1 H-benzimidazol-2-yl }- 1H-pyridin-2- one; 4-[2-(3-Chloro-phenyl)-(S)-2-hydroxy-ethylamino}-3-{6-[(R)-2-hydroxymethyl- morpholin-4-yl]-4-methyl- 1H-benzimidazol-2-yl }- 1H-pyridin-2-one and 4-[2-(3- chloro -phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-hydroxy-methyl-morpholin-4-
yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2- hydroxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl } -1H-pyridin-2-one and 4-[2-(3-bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3- {6-[( S)-2- hydroxy-methyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one;
4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2- hydroxymethyl-morpholin-4-yl}-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one and 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2- hydroxy-methyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2-methyl-morpholin-4-
yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one and 4-[2-(3-chloro-phenyl)- (8)-2-hydroxy-ethylamino]-3-{ 6-[(S)-2-methyl-morpholin-4-yl]-4-methyl-1H- benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-methyl-
: morpholin-4-yl]-4-methyl- 1H-benzimidazol-2-yl}-1H-pyridin-2-one and 4-[2-(3- bromo-4-methoxy-phenyl)-($)-2-hydroxy-ethylamino]-3-{6-[(S)-2-methyl-morpholin- 4-yl]-4-methyl-1H-benzimidazol-2-yl }- 1 H-pyridin-2-one;
4-[2-(3-Chloro-4-methoxy-phenyl)-(5)-2-hydrox y-ethylamino]-3-{6-[(R)-2-methyl- morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl }- 1H-pyridin-2-one and 4-[2-(3- chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino}-3-{6-[(S )-2-methyl-morpholin- 4-yl]-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one;
4-[2-(3-Chloro-phenyl)-(5)-2-hydroxy-ethylamino]-3-{ 6-[(R)-2-methox ymethyl- morpholin-4-yl}-4-methyl- 1H-benzimidazol-2-yl }- 1H-pyridin-2-one and 4-{2-(3- chloro -phenyl)-(5)-2-hydroxy-ethylamino}-3-{6-[(S)-2-methoxy-methyl-morpholin- 4-yl]-4-methyl-1H-benzimidazol-2-yl }- 1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-
methoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one and 4-[2-(3-bromo-4-methoxy-phenyl)-(5)-2-hydrox y-ethylamino]-3-{ 6-[(S)-2- methoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl } - 1H-pyridin-2-one; 4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2- methoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl }-1H-pyridin-2-one and 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydrox y-ethylamino]-3-{ 6-[(S)-2- methoxymethyl-morpholin-4-yl]-4-methyl- 1 H-benzimidazol-2-yl }- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2(S)-hydroxy-ethylamino)-3-[4-methyl-6-(4-methyl-
piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-pyridine-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-2(S)-hydroxy-ethylamino}-3-[4-methyl-6-(4-
methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-pyridine-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{6-[4-(acetamido)- piperidin-1-yl]- 4-methyl-1H-benzoimidazol-2-yl }-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{6-[4-(2-hydroxyacetamido)- piperidin- 1-yl]-4-methyl- 1H-benzoimidazol-2-yl }- | H-pyridin-2-one;
4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{6-[4-(2-fluoroacetamido)-
piperidin-1-yl]-4-methyl-1H-benzoimidazol-2-yl }-1H-pyridin-2-one; oo 4-[2-(3-Bromo-4-methox y-phenyl)-2-hydroxy-ethylamino}-3- { 6-[4-(acetamido)- piperidin-1-yl]-4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4-[2-(3-Bromo -phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2-hydroxyacetamido)-
piperidin-1-yl]-4-methyl-1H-benzoimidazol-2-yl }- 1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3- {6-[4-(2-fluoroacetamido)- piperidin-1-yl}-4-methyl- 1 H-benzoimidazol-2-yl } -1H-pyridin-2-one;
D 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2- methoxyethoxycarbamoyl)- piperidin -1-yl]-4-methyl-1H-benzoimidazo!-2-yl}-1H- pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(methox ycarbamoy!)- : 5 piperidin -1-yl]-4-methyl- 1H-benzoimidazol-2-yl }-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{ 6-[4-(2-fluoroethox y carbamoyl)- piperidin -1-yl]-4-methyl-1H-benzoimidazol-2-yl }-1H-pyridin-2-one; (8)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino}-3-{4-methyl-6-(2-morpholin-4-yl- ethoxy)-1H-benzimidazol-2-yl}- 1H-pyridin-2-one; (5)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-[4-methyl-6-(2- morpholin-4-yl-ethoxy)- 1H-benzimidazol-2-yl]-1H-pyridin-2-one; (8)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-[4-methyl-6-(2-methox y- ethoxy)-1H-benzimidazol-2-yl]- 1H-pyridin-2-one; (8)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{4-methyl-6-(2-hydroxy- ethoxy)-1H-benzimidazol-2-yl}-1H-pyridin-2-one; (8)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydrox y-ethylamino]-3-[4-methyl-6-(2- morpholin-4-yl-propoxy)-1H-benzimidazol-2-yl]-1H-pyridin-2-one; (8)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{4-methyl-6-(2-morpholin-4-yl- propoxy)-1H-benzimidazol-2-yl]- 1 H-pyridin-2-one; (5)-3-(4-Bromo-6-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-4-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino]- 1 H-pyridin-2-one; (S)-3-[4-Bromo-6-(4-methyl-piperazin- 1-ylmethyl- 1 H-benzimidazol-2-yl)-4-[2-(3- chloro-phenyl)-2-hydroxy-ethylamino]-1H-pyridin-2-one; (8)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-[{4-methyl-6-(4-methyl- : piperazin-1-ylmethyl)-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2(S)-hydroxy-ethylamino]-3-[4-methyl-6-(1,4,5,6- tetrahydropyrimidine-1-yl)-1H-benzoimidazol-2-yl]-1H-pyridine-2-one; and 4-[2-(4-Methoxy-3-Chloro-phenyl)-2(S)-hydrox y-ethylamino]-3-[4-methyl-6- : (1,4,5,6-tetrahydropyrimidine-1-yl)- 1 H-benzoimidazol-2-yl]- 1H-pyridine-2-one.
50. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
51. The pharmaceutical composition according to claim 50 further comprising at least one other anti-cancer agent formulated as a fixed dose.
52. The pharmaceutical composition according to claim 51, wherein said anti- cancer agent is selected from the group consisting of: tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan, an epothilone, Iressa, OSI1-774, angiogenesis inhibitors, EGF inhibitors, VEGF inhibitors, CDK inhibitors, Herl and Her?2 inhibitors and monoclonal antibodies.
53. A method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering to a mammalian species in need of such treatment an effective amount of a compound according to claim 1.
54. The method according to claim 53 wherein said tyrosine kinase enzyme is Abl, CDK’s, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src, or VEGF.
55. The method according to claim 53 further comprising administering to said mammalian species at least one other anti-cancer agent in combination with said compound.
56. The method according to claim 53 wherein the condition is cancer. .
‘ ‘e " PCT/US02/09402
57. Use according to claim 53 wherein the condition is cancer.
58. Use of a compound according to claim 50 or a composition according to claim 51 or 52 in the manufacture of a medicament for treating cancer.
59. Use of a compound according to claim 50 or a composition according to claim 51 or 52 in the manufacture of a medicament for treating proliferative diseases.
60. A substance or composition for use in a method for treating a condition associated with at least one tyrosine kinase enzyme, said substance or composition comprising a compound according to claim 1, and said method comprising : administering to a mammalian species in need of such treatment an effective amount of said substance or composition.
61. A substance or composition for use in a method of treatment according to claim 60 wherein said tyrosine kinase enzyme is Abl, CDK’s, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src, or VEGF.
62. A substance or composition for use in a method for treating a condition associated with at least one tyrosine kinase enzyme, said substance or composition comprising a compound according to claim 1 and at least one other anti-cancer agent, and said method comprising administering said substance or composition to a mammalian species.
63. A substance or composition for use with at least one other anti-cancer agent in a method for treating a condition associated with at least one tyrosine kinase enzyme, said substance or composition comprising a compound according to claim 1, and said method comprising administering said substance or composition and said other agent to a mammalian species. 247 AMENDED SHEET
“ Se ) PCT/US02/09402
64. A substance or composition for use in a method of treatment according to claim 60 wherein the condition is cancer.
65. A substance or composition for use in a method for treating cancer, said substance or composition comprising a compound according to claim 50 or a composition according to claim 51 or 52, and said method comprising administering to a mammalian species in need of such treatment, a therapeutically effective amount of said substance or composition. :
66. A substance or composition for use in a method for treating proliferative diseases, said substance or composition comprising a compound according to claim : 50 or a composition according to claim 51 or 52, and said method comprising administering to a mammalian species in need of such treatment a therapeutically effective amount of said substance or composition.
67. A compound according to any one of claims 1 to 49, substantially as herein described and illustrated.
68. A composition according to claim 50, substantially as herein described and illustrated.
69. Use according to any one of claims 53 to 59, substantially as herein described and illustrated.
70. A substance or composition for use in a method of treatment according to any one of claims 60 to 66, substantially as herein described and illustrated. 248 AMENDED SHEET
) PCT/US02/09402
71. A new compound, a new composition, a new use of a compound as claimed in claim 1 or a composition as claimed in claim 50, or a substance or composition for a new use in a method of treatment, substantially as herein described.
5 . 249 AMENDED SHEET
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