OA12098A - Novel benzuoimidazole derivatives useful as antiproliferative agents. - Google Patents

Description

-1- 1 2098

NOVEL BENZOIMIDAZOLE DERIVATIVES USEFUL AS ANTIPROLIFERATIVE AGENTS

Background of the Invention

This invention relates to novel benzimidazole dérivatives that are useful in the treatmentof abnormal cell growth, such as cancer, in mammals. This invention also relates to a method ofusing such compounds in the treatment of abnormal cell growth in mammals, especiallyhumans, and to pharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of the transformation of a portionof its DNA into an oncogene (i.e., a gene which, on activation, leads to the formation ofmalignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Altematively, the overexpression of a normal proto-oncogenic tyrosine kinase may also resuit in proliférative disorders, sometimes resulting in amalignant phenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane and possess anextracellular binding domain for growth factors such as epidermal growth factor, atransmembrane domain, and an intracellular portion which fonctions as a kinase tophosphorylate spécifie tyrosine residues in proteins and hence to influence cell prolifération.Other receptor tyrosine kinases indude c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR. It isknown that such kinases are ffequentiy aberrantly expressed in common human cancers suchas breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, andovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factorreceptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed inmany human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head andneck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases areuseful as sélective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, atyrosine kinase inhibitor, selectively atténuâtes the growth in athymie nude mice of atransplanted human mammary carcinoma that expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of another carcinoma that does notexpress the EGF receptor. Thus, the compounds of the présent invention, which are sélectiveinhibitors of certain receptor tyrosine kinases, in particular PDGFr, are useful in the treatment ofabnormal cell growth, in particular cancer, in mammals.

Various other compounds, such as styrene dérivatives, hâve also been shown topossess tyrosine kinase inhibitory properties. More recently, five Européen patent publications,namely EP 0 566 226 A1 (published October 20,1993), EP 0 602 851 A1 (published June 22, 1994) , EP 0 635 507 A1 (published January 25,1995), EP 0 635 498 A1 (published January 25, 1995) , and EP 0 520 722 A1 (published December 30,1992), refer to certain bicyclic dérivatives. -2- 1 2098 Γ- (1994), EP 0 635 507 A1 (published January 25,1995), EP 0;635 498 A1 (published January25, 1995), and EP 0 520 722 A1 (published December 30, 1992), refer to certain bicyciicdérivatives, in particuiar quinazotine dérivatives, as possessing anti-cancer properties thatresuit from îheir tyrosine kinase inhibitory properties. Also, World Patent Application WO92/20642 (published November 26, 1992), refers to certain bis-mono and bicyciic aryl andheteroaryl cornpounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cellprolifération. World Patent Applications WO96/1696O (published June 6, 1996), WO96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO98/02434 (published January 22, 1998). WO 98/02437 (published January 22, 1998), andWO 98/02438 (published January 22,1998), also refer to substituted bicydic heteroaromaticdérivatives as tyrosine kinase inhibitors that are usefUI for the same purpose. Also seeWO 99/16755, J. Med. Chem. 1998, 41,5457-5465 and J. Med. Chem. 1999,42,2373-2382.Summary of the Invention

The présent invention relates to cornpounds of the formula 1

and to pharmaceutically acceptable salts, prodrugs and solvatés thereof, wherein:

XisCHorN; R1 is selected from -(CR4RS),C<O)OR3. -(CR4Rs)tC(O)NR3R4, -{CR^R^OR3,-(CtfR’XCiOXCa-Cw cydoalkyl). -(CR^J^OXCrC™ aryl), -{CR4Rs)1C(0)(4 to 10membered heterocydic), -(CR4R5)t(C3-C,0 cydoalkyl), -(CR*R*)t(Ce-Cw aryl), and -(CR4R5),(4to 10 membered heterocydic), wherein each t is independently an integer from 0 to 5; saidcydoalkyl, aryl and heterocydic R1 moieties are optionally fused to a benzene ring, a C5-Cscydoalkyl group, or a 4 to 10 membered heterocydic group; the -(CR4R5)r moieties of theforegoing R1 groupe optionally include a carbon-carbon double or triple bond where t is aninteger between 2 and 5; the foregoing R1 groups are each optionally substituted by 1 or 2groups independently selected from -NRSR4, -OR3, C,-C,o alkyi, Cz-C10 alkenyl. and C2-C10alkynyl, wherein said alkyi, alkenyl and alkynyl groups are substituted by 1 or 2 groupsindependently selected from -NR’R4 and -OR3: and the foregoing R’ groups are optionallysubstituted by 1 to 3 R2 groups; each R2 is independently selected from H, 0,-0« alkyi, Cz-C,0 alkenyl, C2-Cio alkynyl,C3-C10 cydoalkyl, oxo, halo, cyano, nitro. trifiuoromethyl, difluoromethoxy, trifiuoromethoxy,azidO, -OR8, -CfOJR8, -C(O)OR3, -NR*C(O)ORe. -OC(O)RS, -NR4SO2Re, -SO2NR3R4. -3- 1 2 098 -NR4(CR4R®)w(Ce-C10 aryl), -O(CR4Rs)m(4 to 10 membered heterocycle), -NR4(CR4R®)m(4 to 10membered heterocycle), -(CR4Rs)m(4 to 10 membered heterocyclic), and -(CR4R5)m(C3-C10cycloalkyl) wherein each m is independently an integer from 0 to 4; said alkyl, alkenyl andalkynyl groups optionally contain 1 or 2 hetero moieties selected from O, -S(O)j- wherein j isan integer from 0 to 2, and -N(R3)- with the proviso that two O atoms, two S atoms, or an Oand S atom are not attached directly to each other, and the proviso that an O atom, a S atomor a N atom are not attached directly to a triple bond or a non-aromatic double bond; saidcycloalkyl, aryl and heterocyclic R2 groups are optionally fused to a C6-C,0 aryl group, a C5-C8cycloalkyl group, or a 4 to 10 membered heterocyclic group; and said alkyl, cycloalkyl, aryland heterocyclic R2 groups are optionally substituted by 1 to 5 substituents independentlyselected from oxo (=0), halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,azido, -NR4SO2R®, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR®, -NR4C(O)R3,-C(O)NR3R4, -NR3R4, -OR3, C,-C10 alkyl, -(CR4R5)m(C6-C10 aryl), and -(CR4R®)m(4 to 10membered heterocyclic), wherein each m is independently an integer ranging from 0 to 4; each R3 is independently selected from H, C,-CiQ alkyl, -(CR4Rs)m(C6-CTO aryl), and-{CR4R®)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, -S(O)j-wherein j is an integer ranging from 0 to 2, and -N(R4)- with the proviso that two O atoms, twoS atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl andheterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a Cs-Ce cycloalkyl group, ora 4 to 10 membered heterocyclic group; and the foregoing R3 substituents, except H, areoptionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C(O)R4, -C(O)OR4, -OC(O)R4,-N R4 0(0) R5, -C(O)NR4R®, -NR4R®, hydroxy, C,-C6 alkyl, and C,-Ce alkoxy; each R4 and R® is independently H or C^Cg alkyl; or, where R4 and R® are attached to the same carbon or nitrogen atom, R4 and R5together with said carbon or nitrogen may be taken together to form a 4 to 10 membered ringwhich may be carbocyclic or heterocyclic; each R® is selected from the substituents provided in the définition of R3 except R® is not H; each R7, R®, R9, R10 and R11 is independently selected from the group of subsituentsprovided in the définition of R2.

In a spécifie embodiment of the présent invention R1 is C6-C10 aryl or 4 to 10membered heterocyclic wherein the foregoing R1 groups are each substituted by 1 or 2groups independently selected from -NRW, -OR3 and C,-C3 alkyl, wherein said alkyl groups 1 2098 -4- are substituted by 1 or 2 groupe independently selected from -NR3R* and -OR3; and theforegoing R1 groups are optionally substituted by 1 to 3 R2 groups; each R2 is independently selected from H, CrC10 alkyl, C3-C5O cycloalkyl, oxo(=O),-OR3, -CfOJR3, -CfOJOR3, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR4SOZR6, -SO2NR3R4,-{CR4Rs)m(4 to 10 membered heterocyclic), and (CR4R5)m(C3-Cw cycloalkyl); and said alkylgroups optionally contain 1 or 2 hetero moieties selected from O, -S(O)t- wherein j is aninteger from 0 to 2, and -N(R3)- with the proviso that two O atoms, two S atoms, or an O and Satom are not attached directly to each other; and said alkyl and cycloalkyl R2 groups areoptionally substituted by 1 to 5 substituents independently selected from oxo, cyano,trifluoromethyl, trifluoromethoxy, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -NR4C(O)OR6,-NR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, and 0,-Cw alkyl, wherein each m is independentlyan integer ranging from 0 to 4.

In another spécifie embodiment of the présent invention, R1 is piperidinyl, piperzinyl,or phenyl, wherein said R1 groups are substituted by -NR3R4, oxo (=O). -OR3 and C,-C3 alkyl,wherein said alkyl groups are substituted by 1 or 2 groups independently selected from-NR’R4 and -OR3; and the foregoing R1 groups are optionally substituted by 1 to 3 R2 groups.In a more spécifie embodiment, said R1 groups are substituted by -NR3R4, oxo (=O), OR3, orC,-C3 alkyl, wherein said alkyl group are substituted by -NR3R4.

In another spécifie embodiment of the présent invention, R1 is phenyl substituted bypyrrolidin-1 -yl which pyrrolidin-1-yl is optionally substituted by 1 to 3 substituentsindependently. selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR4SO2R6,-SO2NR3R4, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, andC^Cio c>ikyU and R11 is -OR3. More specifically, R1 is 4-pyrrolidin-1-ylmethyl-phenyl optionallysubtituted by 1 to 3 substituents independently selected from oxo, cyano, trifluoromethyl,trifluoromethoxy, -NR4SO2Re, -SO2NR3R4, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -NR*C(O)R3,-C(O)NR3R4, -Nf^R4, -OR3, and C.,-C10 alkyl; and R11 is -OR3. More specifically, R11 isconnected at the 5 position of the benzimidazole moiety of the compound of formula 1 and is -OR3. More specifically, R11 is connected at the 5 position of the benzimidazole moiety of thecompound of formula 1 and is 2-methoxyethoxy.

In another spécifie embodiment of the présent invention, R1 is pyrrolidin-1-yl orpiperidin-1-yl, said R1 being optionally substituted by 1 to 3 substituents independentlyselected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR4SO2R6, -SO2NR3R4, -C(O)R3,-C(O)OR3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, and CrC10 alkyl. Morespecifically. R1 is pyrrolidin-1-yl or piperidin-1-yl substituted by -NR3R4 and optionallysubstituted by 1 or 2 substituents independently selected from oxo, cyano, trifluoromethyl,trifluoromethoxy, -NR4SO2R®, -SO2NR3R4, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -NR4C(O)R3, -5- 1 2 098 -C(O)NR3R4, -NR3R4, -OR3, and CrC10 alkyl; and R11 is -OR3. More specifically, R11 isconnected at the 5 position of the benzimidazole moiety of the compound of formula 1 and is -OR3 and R9 and R’° are both H. More specifically, R” is connected at the S position of thebenzimidazole moiety of the compound of formula 1 and is 2-methoxyethoxy and R9 and Rw 5 are both H.

Preferred compounds include those seiected from the group consisting of:[1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-pÎperidin-4-ylamÎne,· 1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-y,]-1 H-benzoimidazol-5-ol; 1-{2-I5-(Pyridin-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 10 {1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yl}-dimethyi-amine; {4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-methyl-amine; {4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyi}-dimethyt-amine;

Cyclopropyl-{4-[2-(5-methoxy-benzoimidazol-1-yl)-quÎnolin-8-yl]-benzyl}-amine; tert-Butyl-{4-{2-(5-methoxy-benzoimidazol-1-yi)-quinolin-8-yl3-benzyl}-arnine; 15 4-[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-benzylamine; 1 -[2-{5-Ethoxy-benzoimidazol~1 -yl)-quinolin-8-yl]-piperidin-4-ylamine;{1-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-dimethylamine; 1- [2-(5-Trifluoromethoxy-benzoimidazol-1-yl)-quinolin-8-yll-pÎperidin-4-ylamine; {4-(2-( 5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yi]-benzyl}-methyl-amine; 20 Cydopropyl-{4-[2-(5-ethoxy-benzoimidazol-1-yl)-quinolin-8-yll-benzyl}-amine; tert-Butyl-{4-[2-(5-ethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-benzyl}-amine;{4-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyt}-dimethyl-amine; 1 -[2-(5-Methoxy-benzoimidazol-1 -yl>-quinolin-8-yll-piperidin-4-one; 1 -[2-(5-Ethoxy-benzoimidazol-1 -yl)-quinolin-8-ylJ-piperidin-4-one; 25 1 -[2-(5-Ethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ol; tert-ButyH'l-[2-(5-ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-amine; {1 -(2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-y,}-methyl-amine; 2- (5-Methoxy-benzoimidazoi-1-yl)-8-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-quinoline; 4-Dimethylaminomethyl-1-[2-(5-méthoxy-benzoimidazol-1-yl)-quinolin-8-yl3-piperidin- 30 4-ol; 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yll-4-methylaminomethyl-piperidin-4- ol; 4-Aminomethyl-1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-ylî-piperidin-4-ol; 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-pyrroiidin-3-yiamine; 35 1 -(2-Benzoimidazol-1 -yl-quinoÎin-8-yl)-piperidin-4-ylamine; 1-(2-lmidazol4,5-b]pyridin-3-yl-quinolin-8-yl)-piperidÎn-4-ylafnine; -6- 1 2098 1-{2-[5-(4-Methoxy-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-pipendin-4-ylamine; 1-[2-(5-Cyclopropylmethoxy-benzoimidazoi-1-yt)-quinoiin-3-yl]-piperidin-4-ylamine; 1-{2-[5-(3-Dimethylamino-propoxy)-benzoimidazoi-1-yl]-quinoiin-8-yl}-piperidin-4- yiamine; 1-{2-[5-{3-Am ino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-y lamine; 1-{2-[5-(2-Dimethylamino-ethoxy)-benzoimidazol-1-yl]-quinoiin-8-yl}-piperidin-4-ylamine; 1-{2-[5-(Pyridin-4-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 1 -t2-(5-Benzyloxy>benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 1-{2-[5-(Pyridin-3-ylmethoxy)-benzoimidazol-1-yl]-quÎnolin-8-yl}-piperidin-4-ylamine; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl}-piperidine-4-carboxyiic acid ethylester; 1-[2-(5-Methoxy-benzoimidazol-1-yi)-quinolin-8-yl]-piperidine-4-carboxylic acid; 4-Dimethylaminomethyl-1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin- 4-ol; N-{1-{2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-acetamide; N-{'l-[2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-qiiinolin-8-yl]-piperidin^4-yl}- acetamide; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-qiiinolin-8-yl}-piperidin-4-ol; {1-l2-{5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-iirea; 4-Aminomethyl-1-{2-[5-(pyridin-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}- piperidin-4-ol;

Cyclopropyl-(1-{2-[5-(2-methoxy-ethoxy)-benzoimtdazol-1-yl]-quinolin-8-yl}-piperidin- 4-yl)-amine; (1 -{2-[5-{2-Methoxy-ethoxy)-benzo»ïiidazoi-1 -yl]-quinolin-8-yl}-piperidin-4-yl)-dimethyl-amine; 1 ~{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-yl)-methyl'amine; (1-{2-[5-(3-Dimethylamino-propoxy}-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)- dimethÿl-amine; {142-(5-Cydopropyimethoxy-benzoimidazol-1-yl)-quinolin-8-ylj-piperidin-4-yl}-methyl- amine; {1 -[2-(5-Cydopropyimethoxy-benzoimidazol-1 -yi)-quinolin-8-yl]-piperidin-4ryl}-dimethyl-amine; -7- 1 2098 2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yll-quinolin-8-yI}-piperidin-4-yi)- acetamide; -(S)-2-Atnino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazoi-1-yll-quinolin-8-yi}- piperidin-4-yl)-propionamide; 5 -(R)-2-Amino-N-(1 -{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yQ-quinolin-S-yl}- piperidin-4-yl)-prop»onamide; 2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4- yl)-isobutyramide; 1 -(1 -{2-l5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-pipendin-4-ylamino)-ΐθ 2-methyl-propan-2-ol; (1-{2-[5-(2-Methoxy-ethoxy)-benzo»midazoI-1-yl]-quinolin-8-yl}-piperidin-4-yl)-pyridin- 2- ylmethyl-amine; (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-pyridin- 3- ylmethyl-amine; 1 5 4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-phenol; [2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenoxy)-ethyl]- dimethyl-amine; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline; [2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1-yl)- 2® ethyl]-dimethyl-amine; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-pyridin-2-ylmethyl-piperazin-1-yl)- quinoline; 2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-8-(4-pyridin-3-ylmethyl-piperazin-1-yl)- quinoline; 25 2-Amino-1 -{4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 - yl)-2-methyl-propan-1-one; - (S)-2-Amino-1-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1 -yl)-propan-1 -one; (S)-2-Amino-1-(4-{2-[5^{2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}- 30 piperazin-1-yl)-propan-1-one; 2-Amino-1 -(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-pÎperazin>1 -yl)-ethanone; ( 1 -Amino-cyclopropyl)-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1-yl>methanone; 35 2-(4~{2-[5-(2-Methoxy-ethoxy)-benzoimidazo)-1 -yi]-quinolin-8-yl}-piperazin-1 -yl)- ethytamine; -8" 1 2098 {R)-2-Amino-3-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazoi-1-yl]-quinolin-3-yl}-piperazin-1 -yl)-propan-1-ol; 3- {2-{5-{2-Methoxy-ethoxy)-b©nzoimkiazol-1 -yi]-quinolin-8-yl}-3-aza-bicyclo[3.1 .OJhex- 6-yiamine; 5 (S)-1-{2-[5-{2-Methoxy-ethoxy)-benzoimiclazol-1-yl]-quinolin-8-yl}-pyrroiidin-3-yIamine;(R)-1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yÎ}-pyrroliciin-3- yiamine; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-pyridin-3-yl-quinoline; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-{6-methoxy-pyridin-3-yl)-quinolÎne; 10 4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinoiin-8-yl}-benzoic acid methyiester; 1- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-4-methyl-piperidin-4-ylamine; 1 -[2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalen-1 -yl)-quinoiin-8-yl]-15 piperidin-4-ylamine; 2- {1 -[8-{4-Aminœpiperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yloxy}-ethanol; 4- Cyclopropylaminomethyl-1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinoiin-8-yl}-piperidin-4-ol; 1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazole-5-sulfonic acid dimethylamide; 1 -[2-(6-Methoxy-benzoimidazol-1 -yl)-quinoiin-8-y!]-piperidin-4-ylamine; 1 -[2-(5,6-Dimethoxy-benzoimidazo)-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 2-Dimethylamino-1 -{4-{2-[5-(2-methoxy-ethoxy}-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -yl)-ethanone; 25 1 -[2-(5-Benzyloxy-benzoimidazol-1 -yl)-quinolin-8-yl]-4-methyl-piperidin-4-ol; (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinoiin-8-yl}-benzyl)-dimethyl- amine; (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoI-1-yl]-quinolin-8-yl}-benzyl)-methyl-amine; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-morpholin-4-ylmethyl-phenyl)- 30 quinoiine; 2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yll-quino,in-8-yi}-benzylamino)- ethanol; 4-{2-i5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yi}-benzyiamine; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-8-(4-pyrrolidin-1 -ylmethyl-phenyl)- 35 quinoiine; -9- 1 2098 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-pyrrolidin-1-ylmethyl-phenyl)- quinoline; 2- l5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-pyrroiidin-1-ylmeîhyl-phenyî)-quinoline; 1 -(4-{2-[5-(2-Methoxy-ethoxy )-benzoimidazol-1 -yl]-quinoiin-8-yl}-benzyl)-cis-pyrrolidine-3,4-diol; R,R-(1-{4-{2-[5-{2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-trans- pyrrolidine-3,4-diol); 1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-pyrrolidin-3- ol; R-(1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoiniidazol-1-yl]-quinolin-8-yl}'benzyl)-pyrTolidÎn- 3- ol); S-(1-{4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoiin-8-yl}-benzyl)-pyaolidin- 3- oi); 1- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yI]-quinolin-8-yl}-benzyl)-azetidin-3-ol; 2- [5-(2-Methoxy-ethoxy)-benzoimidazol-1-yll-8-[4-(4-methyl-piperazin-1-ylmethyl)-phenylj-quinoline; 4- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester, [1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinolin-8-yl}-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester; 1- (4-{2-i5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-benzyl)-piperidin-4-ylamine; (1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-yl)-methanol; (1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-ptperidin-4-ylmethyl)-methyl-amine; 2- [5-(2-Methoxy-ethoxy)-benzoÎmidazol-1 -yl}-8-[4-(4-methyl-piperazin-1 -ylmethyl)-piperidin-1 -ylj-quinotine; (1-{2-[5-{2-Methoxy-ethoxy)-benzoimidazol-1-ylî-quinolin-8-yl}-piperidÎn-4-ylmethyl)- dimethyl-amine; 1-(1-{2-i5-(2-Methoxy-ethoxy)-benzoimîdazol-1-yl]-quinolin-8-yl}-piperidin-4-ylmethyl)- pyrrolidin-3-ol; C-{1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-pjperidin-4-yi)- methylamine; -10- 1 2098 1-{2-l5-(2-Dimethylamino-ethoxy>benzoÎmidazol-1-yl]-quinolÎn-8-yl}-4-methyl- piperidin-4-ol; 1-{2-(5-(2-Dimethylamino-etioxy)-benzoimîdazol-1-ylJ-quinolin-8-yl}-piperidin-4-ol; S,S-{1-(4-{2-[5-(2-Methoxy-ethoxy}-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-trans- 5 pyrrolidine-3,4-diot); 4-{2-[5-(3-Amino-propoxy}-benzoimidazol-1-yi]-quinolin-8-yl}-phenol; 4-{2-[5-(3-Dimethylamino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol; 1-[2-(5-Phenyl-benzoimidazol-1-yi)-quinolin-8-yl]-piperidin-4-ylarnine; 1-[2-(5-Pyridin-4-yl-benzoimidazol-1-yl)-quinolin-8-yl]-pipendin-4-ylamine·, 10 1 -{2-[5-(3-Methoxy-phenyl)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine; 1-[2-(5-Pyndin-3-yl-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine; 1-{2-[5-(6-Methoxy-pyridin-3-yl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 1- {2-[5-(4-Aminomethyl-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-p!peridin-4-ylamine; 15 4-{1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzoic acid methyl ester, 4-{1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yi}-phenoi; 2- (5-Methoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid methyl ester, 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoline-8-carboxylic acid methyl ester; 20 2-(5-Methoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid (2-dimethylamino-ethyl)-amide; 2-(5-Cyclopropylrnethoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid methylester; [2-(5-Cydopropylmethoxy-benzoimidazol-1-yl)-quinoIin-8-yl3-pyrrolidin-1-yl- 2$ methanone; [2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-morpholin-4-yl- methanone; [2-{5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-1-yl- methanone; 1 2098 -11- (3-Amino-pyrrolidin-1-yl)-[2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]- methanone; 8-Allyloxy-2-(5-methoxy-benzoimidazol-1-yl)-quinoline; {2-[2-(5-Methoxy-benzoimidazol-1-yi)-quinolin-8-yloxy]-ethyl}‘methyl-amine; 5 {2-[2-{5-Methoxy-benzoimidazoi-1-yl)-quinolin-8-yloxy]-ethyl}-dimethyI-amine; 2-[2-(5-Methoxy-benzoimidazol-1~yl)-quinolin-8-yloxy]-ethylamine; 1 -[[2-[5-(3-Morpho!inoethoxy)-1 H-benzimidazol-1 -yl]-quinolin-8-yl]]-piperidin-4-ylamine trihydrochloride; 1 -[[2-[5-(3-Morpholinoethoxy)-1 W-benzimidazol-1 -yl]-quinolin-8-yl]J-piperidin-4-10 ylamine trihydrochloride; 5-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoI-1-yiJ-quinolin-8-yl}-[1,3,4]oxadiazol-2- ylamine;

Ethyl 1 -[8-(4-aminopiperidin-1-yl)-quinolin-2-yl]-benzimidazole-5-carboxylate; 1 -[8-(4-Aminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazole-5-carboxylic acid; 15 N-(4-Morpholino)ethyl-1-[8-(4-aminopiperidin-1-yl)-quinolin-2-yl]-benzimidazole-5-carboxamide; 4-{1 -[8-(4~Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzaldehyde; 1-{2-I5-(4-Mettiylaminomethyl-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-

Si ylamine; 20 1 ~{2-[5-(4-Dimethylaminomethyl-phenyl)-benzoimidazol-1 -ylJ-quinolin-8-yl}-piperidin-4-ylamine; 1 -(2-{5-{2-(2-Methyl-imidazol-1 -yl)-ethoxy]-benzoimidazol-1 -yl}-quinolin-8-yl)-piperidin-4-ylamine and 1-{2-[5-(2-[1,2,4]TrÎazol-1-yl-ethoxy)-benzoimidazol-1-ylî-quinolin-8-yl}-piperidin-4-25 ylamine, and the pharmaceutically acceptable salts, prodrugs and solvatés of the foregoingcompounds.

In accordance with the présent invention, preferred compounds include thoseselected from the group consisting of; 30 1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 1 2098 -12- 1 -[8-(4-Amino-piperidin-1 -yl)-quïnolin-2-yl]-1 H-benzoimidazol-5-ol; 1-{2-[5-(Pyridin-2-ylmethoxy)-benzoirnidazol-1-yl]-quinolin-8-yl}-piperidin-4-yiamine;{1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinoiin-8-yl]-piperidin-4-yÎ}-dimethyl-amine;{4-[2-(5-Methoxy-benzoimidazol-1-yl>-quinolin-8-yl]-benzyl}-methyl-amine; 5 {4-[2-(5-Methoxy-benzoimidazol-1-yl)-quÎnolin-8-yl]-benzyl}-dimethyl-amine; 1 -(2-(5-Ethoxy-benzoimidazol-1 -yl)-quinotin-8-yl]-piperidin-4-ylarnine; {1-[2-{5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-dimeth ylamine; {4-[2-(5-Eüioxy-benzoimidazol-1-yl)-quinolÎn-8-yl]-benzyl}-methyl-amine; {4-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yi]-benzyl}-dirnethyl-amine; {1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yll-piperidin-4-yl}-methyl-amine; 4-Oimethyiaminomethyl-1-[2-(5-methoxy-benzoimÎdazol-1-yl)-quinoiin-8-yi]-piperidin- 4-ol; 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-4-methylaminomethyl-piperidin-4- ol; 15 4-Aminomethyl-1 -[2-(5-methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin~4-ol; 1-{2-(5-(4-Methoxy-phenyl)-benzoimÎdazol-1-yl]-quinolin-8-yl}-piperidÎn-4-ylamine; 1-[2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine; 1-{2-{5-(3-DÎmethylamino-propoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-piperidin-4-ylamine; 20 1 -{2-[5-(3-Amino-propoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine; 1-{2-[5-(2-Dimethylamino-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 1-{2-[5-(Pyridin-4-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 1 -p-(5-Benzyloxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 25 1 -{2-[5-(Pyridin-3-ylmethoxy}-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine; 1-{2-[5-{2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine;4-Dimethylaminomethyl-1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-pipendin-4-ol; 4-Aminomethyl-1-{2-[5-{pyridin-2-ylméthoxy)-benzoimidazol-1-yl]-quinolin-8-yl}- 30 piperidin-4-ol; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-dimethyl- amine; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimÎdazoI-1-yl]-quinolin-8-yl}-piperidin-4-yl)-methyl- amine; 35 ' (1 -{2-[5-(3-Dimethylamino-propoxy)-benzoimidazol-1 -ylj-quinolin-8-yi}-piperidin-4-yl)- dimethyl-amine; 1 2 09 8 -13- (1-[2-(5-Cyclopropylmethoxy-benzoimÎdazol-1-yl)-quinolin-8-yi]-piperidin-4-yl}-methyl- amine; {1-[2-(5-Cyclopropylmethoxy-benzoimidazol-1-yi)-quinoiin-8-yl]-piperidin-4-yl}- dimethyl-amine; 1 -{2-(5-(2-Methoxy-ethoxy)-benzoimidazoI-1 -yI]-quinoiin-8-yl}-piperidin-4-yl )-pyridin-2-yimethyi-amine; (1-{2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-pyridin- 3- ylmethyI-amine; 4- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol; [2-(4-{2-{5-{2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenoxy)-ethyl]- dimethyi-aminé; 2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-8-piperazin-1 -yi-quinoline; (2-(4-(2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylî-quinoiin-8-yl}-piperazin-1-yl)- ethyl]-dimethyl-amine; 2-Amino-1 -(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -yl)-2-mefliyl-propan-1 -one; (S)-2-Amino-1-(4-{2-[5-(2-methoxy-ethoxy}-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1 -yl)-propan-1 -one; (S}-2-Amino-1-(4-{2-(5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl)-piperazin-1-yl)-propan-1 -one; 2-Amino-1-(4-(2-{5-(2-methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-piperazin-1- yl)-ethanone; 2- (4-(2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -yl)-ethylamine; 3- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yi}-3-aza-bicyclo{3.1,0]hex- 6-ylamine; 1- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-4-methyl-piperidin-4-ylamine; 2- {1 -(8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yloxy}-ethanol; 1 -(2-(5,6-Dimethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 1 -(2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalen-1 -yl)-quinolin-8-yI]-piperidin-4-yiamine; (4-{2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-dimethyl- amine; (4-{2-(5-(2-Methoxy-ethoxy)-benzoirnidazol-1-yl]-quinolin-8-yl}-benzyl)-methyi-amine; -14- 1 2098 2-(4-{2-[5-{2-Methoxy-ethoxy)-benzoimiclazol-1-yj]-quinolin-8-yl}-benzylamino)- éthanol; 4- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylj-quinolin-8-yl}-benzylamirse; 2-[5-(2-Methoxy-ethoxy}-benzoimidazol-1 -yl]-8-(4-pynolidin-1 -ylmethyl-phenyl}- 5 quinoline; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-S-(4-pyrrolldin-1-ylmethyl-phenyl)- quinoline; 2- [5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-pyrrolidin-1-ylmethyl-phenyl)-quinoline; 10 1 -(4-{2-[5-(2-Methoxy-ethoxy}-benzoimidazol-1 -yl]-quinolin-8-yl}-benzyl)-cis- pyrrolidine-3,4-diol; R,R-(1-(4-{2-[5-{2’Methoxy«ethoxy)-benzoimidazol-1-yll-quinolin-8-yl}-benzyl)-trans- pyrrolidine-3,4-d»ol); 1- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-pyrrolidin-3-15 ol; R-(1-(4-{2-[i>-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-pyrrolidin- 3- ol); 5- (1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-pyrrolidin- 3-ol); 20 1 -(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-benzyl)-azetidin-3-ol 2- [5-{2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-8-[4-(4-methyl-piperazin-1 -ylmethyt)-phenyij-quinoline; 1- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylî-quinolin-8-yl}-benzyl)-pÎperidin-4-ylamine; 25 (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-methanol; (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylmethyl}- methyl-amine; 2- [5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yI]-8-[4-(4-methyl-piperazin-1 -ylmethyl}-30 piperidin-1-yl]-quinoline; (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylï-quinolin-8-yl}-piperidin-4-ylmethyl)- dimethyl-amine; C-(1 -{2-[5-{2-Methoxy-ethoxy)-benzoimidazol-1 -ylJ-quinolin-8-yl}-piperidin-4-yl)-methylamine; 1 2 09 8 -15- S,S-(1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolÎn-8-yl}-benzylKrans- pyrrolidine-3,4-diol); 4-{2-[5-(3-Dimethylamino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol; 1-[2-(5-Phenyl-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine; 5 1 -[2-(5-Pyridin-4-yl-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 1-{2-[5-(3-Methoxy-phenyl)-benzoimidazol-1-ylJ-quinolin-8-yl}-piperidin-4-ylamine; 1-[2-(5-Pyridin-3-yl-benzoimidazol-1-yl)-quinolin-8-yll-piperidin-4-ylamine; 1-{2-[5-(6-Methoxy-pyndin-3-yl)-benzoimidazol-1-yl)-quinolin-8-yl}-pipendin-4-ylamine; 1 -{2-[5-(4-Aminomethyl-phenyl)-benzoimidazol-1 -yl]-quinof in-8-yl}-piperidin-4- 1Q yiamine; 4-{1 -(8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazoI-5-yl}-benzoic acid methyl ester, 4-{1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-phenol; 1 -[[2-[5-(3-Morpholinoethoxy)-1 W-benzimidazol-1 -yl]-quinolin-8-yl]]-piperidin-4- / 15 yiamine trihydrochloride;

Ethyl 1 -[8-(4-aminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazole-5-carboxylate; N-(4-Morpholino)ethyl-1-[8-(4-aminopiperidin-1-yl)-quinolin-2-yl]-benzimidazole-5- carboxamide; 1-{2-[5>(4-Methylaminomethyl-phenyl>-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-4M yiamine; 1-{2-[5-(4-Dimethylaminomethyl-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-pipendin- 4-ylamine; 1 -(2-{5-[2-(2-Methyl-imidazol-1 -yl)-ethoxy]-benzoimidazol-1 -yl}-quinoiin-8-yl)-piperidin-4-ylamine and 25 1 -{2-l5-(2-[1,2,4)Triazol-1 -yl-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4- ylamine, and the pharmaceuticaily acceptable salts, prodrugs and solvatés of the foregoing compounds.The invention also relates to a pharmaceuticai composition for the treatment of a hyperproiiferative disorder in a mammal which comprises a therapeuticaily effective amount of a 3θ compound of formula 1, or a pharmaceuticaily acceptable sait, prodrug or hydrate thereof, and apharmaceuticaily acceptable carrier. In one embodiment, said pharmaceuticai composition is forthe treatment of cancer such as brain, lung, squamous cell, bladder, gastric, pancreatic, breast,head, neck, rénal, kidney, ovarian, prostate, colorectal, oesophageal, testicular, gynecological orthyroid cancer. In another embodiment, said pharmaceuticai composition is for the treatment of -16- 1 2098 a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g.,psoriasis), restenosis, or prostate (e.g., benign prostatic hypertropy (BPH)).

The invention also relates to a pharmaceutical composition for the treatment ofpancreatitis or kidney disease (including proliférative giomerulonephritis and diabetes-inducedrénal disease) in a mammal which comprises a therapeutically effective amount of a compoundof formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for the prévention ofbiastocyte implantation in a mammal that comprises a therapeutically effective amount of acompound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treating a disease ’datedto vasculogenesis or angiogenesis in a mammal which comprises a therapeutically edectiveamount of a compound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydratethereof, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceuticalcomposition is for treating a disease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases suchas psoriasis, excema, and sderoderma, diabètes, diabetic retinopathy, retinopathy ofprematurity, age-related macuiar degeneration, hemangioma, glioma, melanoma, Kaposi’ssarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.

The invention also relates to a method of treating a hyperproliferative disorder in amammal that comprises admïnistering to said mammal a therapeutically effective amount of thecompound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof. inone embodiment, said method relates to the treatment of cancer such as brain, squamous cell,bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, rénal,kidney, ovarian, testicular, gynecological or thyroid cancer. In another embodiment, said methodrelates to the treatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis or prostate (e.g., benign prostatic hypertropy(BPH)).

The invention also relates to a method for the treatment of a hyperproliferative disorderin a mammal which comprises admïnistering to said mammal a therapeutically effective amountof a compound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof, incombination with an anti-tumor agent selected from the group consisting of mitotic inhibitors,alkyfating agents, anti-metaboiites, intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological response modifïers, anti-hormones,angiogenesis inhibitors, and anti-androgens. -17- χ"' 1 2 098

The invention also relates to a method of treating pancreatitis or kidney disease in amammal which comprises administering to said mammal a therapeutically effective amount of acompound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof.

The invention also relates to a method of preventing blastocyte implantation in a5 mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof.

The invention also relates to a method of treating diseases related to vasculogenesis orangiogenesis in a mammal which comprises administering to said mammal an effective amountof a compound of formula 1, or a pharmaceutically acceptable sait, prodrug or hydrate thereof. 10 in one embodiment, said method is for treating a disease seiected ffom the group consisting oftumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis,skin diseases such as psoriasis, excema, and scleroderma, diabètes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma,Kaposi’s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. 15 Patients that can be treated with a compounds of formula 1, and the pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of thisinvention include, for example, patients that hâve been diagnosed as having psoriasis,resienosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skincancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, 20 ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer, breastcancer, testicular, gynécologie tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma ofthe vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer ofthe endocrine System (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of 25 soft tissues, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acuteleukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the bladder, cancer of thekidney or ureter (e.g., rénal cell carcinoma, carcinoma of tire rénal pelvis), or neoplasms of thecentral nervous System (e.g,, primary CNS lymphona, spinal axis tumors, brain stem gltomas orpituitary adenomas). 30 This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of formula 1, or apharmaceutically acceptable sait or solvaté or prodrug thereof, in combination with an amountof a chemotherapeutic, wherein the amounts of the compound, sait, solvaté, or prodrug, andof the chemotherapeutic are together effective in inhibiting abnormal cell growth. Many 35 chemotherapeutics are presently known in the art. In one embodiment, the chemotherapeuticis seiected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, -18- 1 2098 intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomeraseinhibitors, biological response modifiers, anti-hormones, e.g. anti-androgens.

This invention further relates to a method for inhibiting abnormal cell growth in amammal or treating a hyperproliferative disorder which method comprises administering to îhemammal an amount of a compound of formula 1, or a pharmaceuticaliy acceptable sait orsolvaté or prodrug thereof, in combination with radiation therapy, wherein the amount of thecompound, sait, solvaté or prodrug is in combination with the radiation therapy effective ininhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal.Techniques for administering radiation therapy are known in the art, and these techniques canbe used in the combination therapy described herein. The administration of the compound ofthe invention in this combination therapy can be determined as described herein.

It is believed that the compounds of formula 1 can render abnormal cells moresensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in amammal to treatment with radiation which comprises administering to the mammal an amountof a compound of formula 1 or pharmaceuticaliy acceptable sait, prodrug or solvaté thereof,which amount is effective in sensitizing abnormal cells to treatment with radiation. Theamount of the compound, sait, or solvaté in this method can be determined according to themeans for ascertaining effective amounts of such compounds described herein.

This invention also relates to a method of and to a pharmaceuticai composition forinhibiting abnormal cell growth in a mammal which comprises an amount of a compound offormula 1, a pharmaceuticaliy acceptable sait or solvaté thereof, a prodrug thereof, or anisotopically-labelied dérivative thereof, and an amount of one or more substances seiectedfrom anti-angiogenesis agents, signal transduction inhibitors, and antiproliférative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors,MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, canbe used in conjunction with a compound of formula 1 and pharmaceuticai compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib),valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors aredescribed in WO 96/33172 (pubiished October 24, 1996), WO 96/27583 (published March 7, 1996),. Européen Patent Application No. 97304971.1 (filed July 8, 1997), Européen PatentApplication No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26.1998), WO 98/03516 (published January 29,1998), WO 98/34918 (published August 13,1998),WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO98/30566 (published July 16, 1998), Européen Patent Publication 606,046 (published July 13,1994), European Patent Publication 931,788 (published July 28,1999), WO 90/05719 (published -19- 1 2 098

May 331,1990), WO 99/52910 (published October 21,1999), WO 99/52889 (published October21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No.PCT/IB98/01113 (filed July 21,1998), European Patent Application No. 99302232.1 (filed Mardi25,1999), Great Britain patent application number 9912961.1 (filed June 3,1999), United States 5 Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949(issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), andEuropean Patent Publication 780,386 (published June 25, 1997), ail of which are incorporatedherein in their entireties by référencé. Preferred MMP-2 and MMP-9 inhibitors are those thathâve Iittle ch* no activity inhibtting MMP-1. More preferred, are those that selectively inhibit MMP- 10 2 and/or MMP-9 relative to the other matrix-metalloproteinases (Le. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some spécifie examples of MMP inhibitors useful in the présent invention are AG-3340,RO 32-3555, RS 13-0830, and tire compounds recited in the following list: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino)-15 propionic acid; 3-exo-3-(4-(4-fluoro-phenoxy)-benzenesutfonylamino]-8-oxa-bicydo(3.2.1]octane-3-carboxylic acid hydroxyamide; (2R, 3R) 1 -i4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]~3-hydroxy-3-methyl- piperidine-2-carboxylic acid hydroxyamide; 20 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3- Q4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid; 4- [4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid25 hydroxyamide; (R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylaminoJ-tetrahydro-pyran-3-carboxyIieacid hydroxyamide; (2R, 3R) 1 -(4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonylJ-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 30 3-(l4-(4-fluoro-phenoxy)-benzenesulfûnyl]-( 1 -hydroxycarbamoyl-1 -methyl-ethyl)- aminoj-propionic acid; 3-((4-(4-fluoro-phenoxy)-benzenesulfonylJ-(4-hydroxycarbamoy,-tetrahydro-pyran-4-yl)-amino]-propionic acid; 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfdnyIaminol-8-oxa-bicyclo[3.2.1Joctane-3-35 carboxylic acid hydroxyamide; 1 2098 -20- 3-endo-3-[4-(4-fluoro-phenoxy)-ben2enesu,fonylamino]-8-oxa-bicyclo[3.2.13octane-3-carboxylic acid hydroxyamide; and (R) 3-(4-{4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acidhydroxyamide; and pharmaceuticaily acceptable salts and solvatés of said compounds.

Other anti-angiogenesis agents, including other COX-II inhibitors and other MMPinhibitors, can also be used in the présent invention.

A compound of formula 1, can also be used with signal transduction inhibitors, suchas agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molécules that are EGFR inhibitors; VEGF (vascuiar ' * endothélial growth factor) inhibitors, such as VEGF receptors and molécules that can inhibitVEGF; and erbB2 receptor inhibitors, such as organic molécules or antibodies that bind to theerbB2 receptor, for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco,California, USA). EGFR inhibitors are described in, for example in WO 95/19970 (published July 27,1995), WO 98/14451 (published April 9,1998), WO 98/02434 (published January 22,1998), andUnited States Patent 5,747,498 (issued May 5,1998), and such substances can be used in theprésent invention as described herein. EGFR-inhibiting agents include, but are not limited to, themonoclonal antibodies C225, anti-EGFR 22Mab (ImCIone Systems incorporated of New York,New York, USA), and ABX-EGF (Abgenix antibody) the compounds ZD-1839 (AstraZeneca),BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA),and OLX-103 (Merck &amp; Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (VentechResearch) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusettes). These and otherEGFR-inhibiting agents can be used in the présent invention. VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South SanFrancisco, California, USA), can also be combined with the compound of the présentinvention. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20,1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613(published August 17,1995), WO 99/61422 (published December 2,1999), United States Patent5,834,504 (issued November 10,1998), WO 98/50356 (published November 12,1998), UnitedStates Patent 5,883,113 (issued March 16,1999), United States Patent 5,886,020 (issued March23, 1999), United States Patent 5,792,783 (issued August 11, 1998), WO 99/10349 (publishedMarch 4,1999), WO 97/32856 (published September 12,1997), WO 97/22596 (published June26, 1997), WO 98/54093 (published December 3,1998), WO 98/02438 (published January 22,1998), WO 99/16755 (published April 8,1999), and WO 98/02437 (published January 22,1998),ail of which are incorporated herein in their entireties by référencé. Other examples of some 1 2 09 8 -21- spécifie VEGF inhibitors useful in the présent invention are IM862 (Cytran Inc. of Kirkland,Washington, USA); IMC-1C11 Imclone antibody, anti-VEGF monoclonal antibody ofGenentech, Inc. of South San Francisco, California; and angiozyme, a synthetic ribozymefrom Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). These and other 5 VEGF inhibitors can be used in the présent invention as described herein.

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome pic), and the monocionai antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA)and 2B-1 (Chiron), can fürthermore be combined with the compound of the invention, forexample those indicated in WO 98/02434 (published January 22, 1998), WO 99/35146 10 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (publishedJanuary 22, 1998), WO 97/13760 (published April 17, 1997). WO 95/19970 (published July 27,1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent5,877,305 (issued March 2,1999), which are ail hereby incorporated herein in their entireties byréférencé. ErbB2 receptor inhibitors useful in the présent invention are also described in United 15 States Provisional Application No. 60/117,341, filed January 27, 1999, and in United StatesProvisional Application No. 60/117,346, filed January 27,1999, both of which are incorporated intheir entireties herein by référencé. The erbB2 receptor inhibitor compounds and substancedescribed in the aforementioned PCT applications, U.S. patents, and U.S. provisionalapplications, as well as other compounds and substances that inhibit the erbB2 receptor, can be 20 used with the compound of the présent invention in accordance with the présent invention.

The. compound of the invention can also be used with other agents useful in treating abnormal cell growth or cancer, induding, but not limited to, agents capable of enhandngantitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, andother agents capable of btocking CTLA4; and anti-proliferative agents such as famesyl proteintransferase inhibitors, and ανβ3 inhibitors, such as the ανβ3 antibody Vitaxin, and ανβ5inhibitors and lhe like. Spécifie CTLA4 antibodies that can be used in the présent inventionindude those described in United States Provisional Application 60/113,647 (filed December23,1998) which is incorporated by référencé in its entirety, however other CTLA4 antibodiescan be used in the présent invention. ^0 The compounds of formula 1 and their pharmaceutically acceptable salts, prodrugs and solvatés can each independently also fürthermore be used in a palliative neo-adjuvant/adjuvant therapy in alleviating the symptoms associated with the diseases recitedherein as well as the symptoms associated with abnormal cell growth. Such therapy can be amonotherapy or can be in a combination with chemotherapy and/or immunotherapy.

The invention also relates to a method of preparing a compound of the formula 1 35 1 2098 -22-

The terms "abnormal cell growth” and “hyperproliferative disorder” are usedinterchangeably in this application. "Abnormal cell growth", as used herein, uniess otherwise indicated, refers to cell growththat is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This 5 indudes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing amutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign andmalignant cells of other proliférative diseases in which aberrant tyrosine kinase activationoccurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors thatproliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cellsof other proliférative diseases in which aberrant serine/threonine kinase activation occurs..

The term "treating", as used herein, uniess otherwise indicated, means reversing,alleviating, inhibiting the progress of, or preventing the disorder or condition to which such termapplies, or one or more symptoms of such disorder or condition. The term "treatment", as usedherein, uniess otherwise indicated, refers to the act of treating as "treating" is defined 15 immediately above.

The term “Me" means methyl, “EF means ethyl, and “Ac” means acetyl.

The term "halo", as used herein, uniess otherwise indicated, means fluoro, chloro,bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.

The term "alkyl", as used herein, uniess otherwise indicated, includes saturated20 monovalent hydrocarbon radicals having straight, branched, or cydic moieties (induding fusedand bridged bicydic and spirocyclic moieties), or a combination of the foregoing moieties. For an alkyl group to hâve cydic moieties, the group must hâve at least three carbon atoms.

The term “cycloalkyF, as used herein, uniess otherwise indicated, indudes cyciic alkylmoieties wherein alkyl is as defined above. The use of frie term “cydoalkyl” shall not be £5 construed as limiting the term “alkyl” to non-cydic moieties.

The term "alkenyl", as used herein, uniess otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon double bond wherein alkyl is as defined above and indudingE and Z isomers of said alkenyl moiety.

The term "alkynyl", as used herein, uniess otherwise indicated, indudes alkyl moieties3° having at least one carbon-carbon triple bond wherein alkyl is as defined above.

The term "alkoxy", as used herein, uniess otherwise indicated, indudes O-alkyl groupswherein alkyl is as defined above.

The term "aryF, as used herein, uniess otherwise indicated, indudes an organic radicalderived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl. ** The terni ”4 to 10 membered heterocydic", as used herein, uniess otherwise indicated, indudes aromatic and non-aromatic heterocydic groups containing one to four heteroatoms 1 2098 -23- each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ringSystem, and with the proviso that the ring of said group does not contain two adjacent O or Satoms. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ringsystem, but aromatic heterocyclic groups must hâve at least 5 atoms in their ring System. Theheterocyclic groups include benzo-fused ring Systems. An example of a 4 memberedheterocyclic group is azetidinyf (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group isquinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyi,piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazoiinyl, dithianyl, dithioianyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Examples ofaromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyi, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyt,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazoiyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties are also induded within thescope of this définition including 1-oxa-6-aza-spiro[2.5]oct-6-yl. The foregoing groups, asderived from frie groups listed above, may be C-attached or N-attached where such is possible.For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) orimidazol-3-yl (C-attached). An example of a heterocyclic group wherein 2 ring carbon atoms aresubstituted with oxo (=0) moieties is 1,1-dioxo-thiomorpholinyl.

The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwiseindicated, includes salts of acidic or basic groups which may be présent in the compounds offormula 1. The compounds of formula 1 that are basic in nature are capable of forming a widevariety of salts with various inorganic and organic acids. The acids that may be used to préparépharmaceutically acceptable acid addition salts of such basic compounds of formula 1 are thosethat form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable aniohs,such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsytate, carbonate, chloride, clavulanate, citrate, dihydrochloride,edetate, edislyate, estofate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate. 1 2098 -24- glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, todide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phospate/diphosphate, poiygalacturonate, saiicyiate, stéarate, subacetate, succinate, tannate,tartrate, teoclate, tosyiate, triethiodode, and vaierate saits. Since a single compound of theprésent invention may include more than one acidic or basic moieties, the compounds of theprésent invention may include mono, di or tri-salts in a single compound.

Those compounds of the présent invention that are acidic in nature are capable offorming base salts with various pharmacologicaliy acceptable cations. Examples of such saltsinclude the alkali métal or alkaline earth métal salts and, particularly, the calcium, magnésium,sodium and potassium salts of the compounds of the présent invention.

In the compounds of formula 1, where terms such as (CR4R6)m or (CR4RS), are used,R* and R5 may vary with each itération of m or t above 1. For instance, where m or t is 2, theterms (CR*R5)m or (CR4R5X may equal -CH2CH2-, or -CH(CH3)C(CH2CH3)(CH2CH2CH3)-. orany number of similar moieties falling within the scope of the définitions of R4 and R5.

Certain compounds of formula 1 may hâve asymmetric centers and therefore exist indifferent enantiomeric forms. Ail optical isomers and stereoisomers of the compounds of formula1, and mixtures thereof, are considered to be within the scope of the invention. With respect tothe compounds of formula 1, the invention includes the use of a racemate, one or moreenantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds offormula 1 may also exist as tautomers. This invention relates to tire use of ail such tautomersand mixtures thereof.

The subject invention also includes isotopically-labelled compounds, which areidentical to those recited in formula 1, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, ieO, 17O, 31P, “P, “S, 18F,and ^Cl, respectively. Compounds of the présent invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are within the scope of thisinvention. Certain isotopically-labelled compounds of the présent invention, for example thoseinto which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes areparticularly preferred for their ease of préparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages -25- 1 2098 resulting from greater metabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances. Isotopicallylabelled compounds of formula 1 of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the Schemes and/or in the Examplesand Préparations below, by substituting a readily avaiiabie isotopically labelled reagent for anon-isotopically labelled reagent.

This invention also encompasses pharmaceuticai compositions containing and methodsof treating proliférative disorders, or abnormal cell growth, by administering prodrugs ofcompounds of the formula 1. Compounds of formula 1 having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein anamino acid residue, or à polypeptide Chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of formula 1. The amino acid residues include but are notlimited to the 20 naturally occurring amino acids commonly designated by three letter symbolsand also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine,norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocystéine, homoserine, omithineand méthionine sulfone. Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may bederivatized using groups induding but not limited to hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced DrugDelivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are alsoincluded, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acylgroup may be an alkyl ester, optionally substituted with groups inciuding but not limited to ether,amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type are described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. Ail of these prodrug moieties may incorporate groups induding but not limitedto ether, amine and carboxylic acid functionalities. 1 2098 -26- SCHEME 1

OH

Ar = Aryl or HeteroarylX = NorC 1 2098 -27-

SCHEME 1A

2 R7

R8 6A R7 OBn OBn

OBn r^^r9

X = N or C ΡΤ6Α R7

N R 4A R7 X = N or CV = Cl, Br, OTf

x 5A -28- 1 2098 SCHEME 2

TfO

Ar-Z ai

Ar = Aryl or HeteroarylX=N,C SCHEME3

W s aryl or heterocycleX =s C or N -29- SCHEME4 12 098

Y = Cl or Br -30- 1 2098 SCHEME 6 no2

26 -31- 1 2 098 SCHEME 8

Detailed Description Of The invention

General synthetic methods which may be referred to for preparing the compounds ofthe présent invention are provided in United States patent 5,990,146 (issued November 23,1999)(Wamer-Lambert Co.) and PCT published application number WO 99/16755 (published 3 April 8, 1999)(Merck &amp; Co.). The foregoing patent and patent application are incorporatedherein by référencé in their entirety.

Scheme 1 illustrâtes the synthesis of compounds of formula 1. In step 1, the diol offormula 2 is reacted with a trialkylsiiyl chloride or trialkylsiiyl trifiuoromethanesulphonate (suchas tert-butyldimethylsilyl) with a suitabie organic base, such as imidazoie or pyridine, in an ® organic solvent, such as dichloromethane (DCM) at température ranging from -78°C to 45°C,preferably at ambient température, for 1 to 12 hours to give compound of formula 3. In step 2,compound of formula 3 is reacted with a triflating reagent and base, such as N-phenyl-bis(trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesulfonic anhydrideand 2,6-dimethylpyridine, in an anhydrous organic solvent such as tetrahydrofuran (THF) or 1 2098 -32- DCM at a température ranging from -78°C to ambient température, preferably at ambienttempérature, for 1 to 12 hours to give compound of formula 4.

In step 3, compound of formula 4 is reacted with the amine of formula 5, preferably X= C, with a palladium catalyst such as, tris(dibenzylideneacetone)dipailadium (0) or 5 palladium(ll) acetate and a base such as, césium carbonate or sodium îert-butoxide,preferably césium carbonate, and a palladium ligand such as 2,2’-bis(diphenylposphino)-1,r-binapthyl (BINAP) or 1,2-bis(diphenylphosphio)ethane (DIPHOS), in a solvent such as 1,4-dioxane or toluene, preferably toluene, at a température ranging from ambient température tobetween 80-105°C, preferably at 105°C for 1 to 48 hours. In step 4, the resulting compound of 10 formula 6 is reduced under palladium catalysis, using either 10% palladium on carbon or 20%palladium hydroxide on carbon, with a hydrogen source, such as hydrazine, ammoniumformate, or formic acid in an organic solvent such as éthanol or methanol with or without a co-solvent solvent such as THF, at a température ranging from ambient température to reflux for1 to 24 hours to give compound of the formula 7. 15 In step 5, compound of the formula 7 is reacted with formamidine acetate or formic acid in an organic solvent such as 2-methoxyethanol, 1-butanol, éthanol, or formic acid,preferably éthanol, at a température ranging from ambient température to reflux, preferably atreflux, for 1 to 48 hours to give compound of formula 8. In step 6, compound of formula 8 isreacted with a triflating reagent and base, such as N-phenyl-bis(trifiuoromethanesulfonimide) 20 and sodium hydride or triethylamine in an anhydrous organic solvent such as THF, with orwithout a co-solvent such as dimethylformamide (DMF), at a température ranging from -78°Cto ambient température, preferably at ambient température, for 1 to 24 hours to givecompound of formula 9.

In step 7, for R1 groups that include an aryl or heteroaryl group (where Ar = aryl or 25 heteroaryl), compound of formula 9 is reacted under palladium catalysis, such as withtetrakis(triphenylphosphine)palladium (0), with the appropriate organoborane (where Z =B(OH)2 or B(Alkyl)2), organostannane (where Z = Sn(aikyl)3) or organozinc (where Z =Zn(Haiogen)). When Z = B(OH)2, a base such as potassium phosphate is used in a solventsuch as 1,4-dioxane or 1,2-dimethoxyethane at a température ranging from ambient 30 température to reflux, preferably at reflux, for 1 to 48 hours to give compound of the formula 1.When Z = B(alkyl)2, a base such as sodium carbonate with or without lithium chloride is usedin a solvent System induding éthanol and water with or without toluene at a températureranging fforn ambient température to reflux, preferably around 90°C, for 1 to 48 hours to givecompound of the formula 1. When Z = Sn(alkyl)3, with or without a base such as potassium 35 phosphate, in a suitable organic solvent such as toluene or 1,4-dioxane and at a température -33- 1 2098 ranging from ambiant température to reflux, preferably between 30-100°C, for 1 to 48 hours togive compound of the formula 1. When Z = Zn(Halogen), a suitable organic solvent such asTHF, 1,4-dioxane or 1,2-dimethoxyethane is uased at a température ranging from -78°C toreflux, preferably between 20-45°C, for 1 to 48 hours to give compound of the formula 1. For 5 R1 with an NRSR6 moiety, compound of the formula 9 is reacted with an amine HNR5R6 using apalladium catalyst such as tris(dibenzylideneacetone)dipalladium (0) or palladium acetate anda base such as, césium carbonate or sodium tert-butoxide, preferably césium carbonate, anda palladium ligand such as 2,2’-bis(diphenylposphino)-1,1’-binapthyl (BINAP) or 1,2-bis(diphenylphosphio)ethane (DIPHOS) in a solvent such as 1,4-dioxane, toluene, and 10 xylenes preferably toluene, at a température ranging from ambient température to reflux,preferably at reflux for 1 to 48 hours to give compound of formula 1. Compounds of formula 1may hâve protecting groups, such as R11, R10 or R9 = OMe, that can be removed by standardconditions as discussed in “Protective Groups for Organic Synthesis". For example, R11, R’°or R9 - OMe can be transformed to Rv, RTO or Râ = OH by treating with borontribromide in anorganic solvent such as DCM at a température ranging from -78°C to 45°C, preferably atambient température for 1 to 24 hours.

Scheme 1A illustrâtes an alternative synthesis of compounds of formula 7. In step 1,the diol of formula 2 is reacted with benzyl chloride or benzyl bromide, preferably benzylbromide, with a suitable base, such as potassium carbonate, sodium carbonate or césium ‘θ carbonate, in an organic solvent, such as DMF at température ranging from -78°C to 100°C,preferably between 60-80°C for 3 to 24 hours to give compound of formula 3A. In step 2,compound of formula 3A is reacted with a triflating reagent and base, such as N-phenyl-bis(trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesulfonic anhydrideand 2,6-dimethylpyridine, in an anhydrous organic solvent such as tetrahydrofuran (THF) or 25 DCM at a température ranging from -78°C to ambient température, preferably at ambienttempérature, for 1 to 12 hours to give compound of formula 4A (where V = OTf). Alternativeiy,compound of the formula 3A is reacted with a chlorinating reagent, such as phophorusoxychloride, thionyl chloride or oxallyl chloride, in an organic solvent such as DCM, 1,2-dichlroethane (DCE) or chloroform at a température ranging from ambient température to 30 reflux, preferably at reflux, to give compound of the formula 4A (where V » Cl). Alternative^, + compound of the formula 3A is reacted with a brominating reagent, such as phophorus oxybromide, in an organic solvent such as DCM, 1,2-dichlroethane (DCE) or chloroform at atempérature ranging from ambient température to reflux, preferably at reflux, to give compound of the formula 4A (where V = Br). -34- 1 2098

In step 3, compound of formula 4A is reacted with the amine of formula 5, preferablyX = C, with a palladium catalyst such as, tris(dibenzylideneacetone)dipailadium (0) orpaliadium(ll) acetate and a base such as, césium carbonate or sodium tert-butoxide,preferably césium carbonate, and a palladium ligand such as 2,2'-bis(diphenylposphino)-1 ,Γ-binapthyl (BINAP) or 1,2-bis(diphenylphosphio)ethane (DIPHOS), in a solvent such as 1,4-dioxane or toluene, preferably toluene, at a température ranging from ambient température to105°C, preferably between 80-105°C for 1 to 48 hours. In step 4, the resulting compound offormula 6A is reduced under palladium cataiysis, using either 10% palladium on carbon or20% palladium hydroxide on carbon, with a hydrogen source, such as ammonium formate,triethylammonium formate or formic acid, preferably ammonium formate triethylammoniumformate, in an organic solvent such as éthanol (EtOH) or methanol (MeOH) with or without aco-solvent solvent such as THF, at a température ranging from ambient température to reflux,preferably between 75°C and at reflux, for 1 to 24 hours to give compound of the formula 7.

Scheme 1B illustrâtes an alternative synthesis of compounds of formula 6A. in step1, the aminoquinoline of formula 2B is reacted with benzyl chloride or benzyl bromide,preferably benzyl bromide, with a suitable base, such as sodium hydride or potassiumhydride, in an organic solvent, such as DMF, THF or 1,2-dimethoxyethane, at températureranging from -78°C to 65°C, preferably between 0-25°C, for 1 to 24 hours to give compound offormula 3B. In step 2, compound of formula 3B is reacted with bromoaromatic compound offormula 5A with a palladium catalyst such as, tris(dibenzylideneacetone)dipalladium (0) orpalladium(ll) acetate, preferably tris(dibenzylideneacetone)dipalladium (0), and a base suchas, césium carbonate or sodium tert-butoxide, preferably sodium tert-butoxide, and apalladium ligand such as 2,2’-bis(diphenylposphino)-1,r-binapthyl (BINAP) or 1,2-bis(diphenylphosphio)ethane (DIPHOS), preferably 2,2*-bis(diphenylposphino)-1,r-binapthyl(BINAP), in a solvent such as 1,4-dioxane or toluene, at a température ranging from ambienttempérature to 105°C, preferably between 80-105°C for 1 to 48 hours to give compound of theformula 6A.

Scheme 2 illustrâtes the synthesis of compounds of formula 11. In step 1, compoundof the formula 10 is reacted under standard alkylation conditions by treating with anelectrophile R3Y, where Y can be mesylate, tosylate, bromo, iodo and chloro, preferablybromo or iodo, and a base such as sodium hydride, potassium hydride, sodium carbonate,potassium carbonate or césium carbonate, preferably césium carbonate in an organic solventsuch as DMF or THF, preferably DMF, for 1 to 48 hours at a température ranging from -78°Cto 85°C. Compounds of the type formula 11 can also be obtained by starting with theappropriate amine compound of the formula 5 in step 3 of scheme 1 or step 2 of scheme 1 A. 1 2098 -35-

Altematively, compounds of the type formula 11 car» also be obtained by starting with theappropriate bromoaromatic compound of the formula 5A in step 2 of scheme 1B.

Scheme 2 also illustrâtes the synthesis of compounds of formula 13 (wherein Ar is anaryl or heteroaryl group). In step 2, compound of the formula 10 is reacted with a triflating 5 reagent and base, such as N-phenyl-bis(trifluoromethanesulfonimide) and sodium hydride ortrifluoromethanesulfonic anhydride and pyridine, in an anhydrous organic solvent such asTHF, with or without a co-solvent such as DMF, at a température ranging from -78°C toambient température, preferably at ambient température, for 1 to 24 hours to give compoundof formula 12. In step 2, compound of formula 12 is reacted under palladium catalysis, such 10 as with tefrakis(triphenylphosphine)palladium (0), with the appropriate organoborane (where Z« B(OH)2 or B(Alkyl)2), organostannane (where Z = Sn(alkyl)3) or organozinc (where Z =Zn(Halogen)). When Z = B(OH)2, a base such as potassium phosphate is used in a solventsuch as 1,4-dioxane or 1,2-dimethoxyethane at a température ranging from ambienttempérature to reflux, preferably at reflux, for 1 to 48 hours to give compound of the formula 15 13. When Z = B(alkyl)2, a base such as sodium carbonate with or without lithium chloride is used in a solvent System including éthanol and water with or without toluene at a températureranging from ambient température to reflux, preferably around 90°C, for 1 to 48 hours to givecompound of the formula 13. When Z - Sn(alkyl)3, with or without a base such as potassiumphosphate, in a suitable organic solvent such as toluene or 1,4-dioxane and at a température 20 ranging from ambient température to reflux, preferably between 80-100°C, for 1 to 48 hours togive compound of the formula 13. When Z = Zn(Haiogen), a suitable organic solvent such asTHF, 1,4-dioxane or 1,2-dimethoxyethane is uased at a température ranging from -78°C toreflux, preferably between 20-45°C, for 1 to 48 hours to give compound of the formula 13.Compounds of formula 13 may hâve protecting groups, such as R11, R10 or R® « OMe. that can 25 be removed by standard conditions as discussed in “Protective Groups for OrganicSynthesis”. For exampie, R11, R10 or R® = OMe can be transformed to R11, Rw or R® = OH bytreating with borontribromide in an organic solvent such as DCM at a température rangingfrom -78°C to 45°C, preferably at ambient température for 1 to 24 hours. Compounds of thetype formula 13 can also be obtained by starting with the appropriate amine compound of the 30 formula 5 in step 3 of scheme 1 or step 2 of scheme 1 A. Altematively, compounds of the typeformula 11 can also be obtained by starting with the appropriate bromoaromatic compound ofthe formula 5A in step 2 of scheme 1B.

Scheme 3 illustrâtes the synthesis of compounds of formula 15 (where W » aryl, orheterocycle). In step 1, compound of formula 14 is reacted with an amine HNR3R* andreducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, and -36- 1 2 098 acetic acid in an organic solvent, such as methanol or éthanol, and with or without a co-solvent such as 1,2-dichloroethane, at a température ranging from 0°C to 80°C, preferably atambient température, for 1 to 24 hours. Compounds of formula 15 may hâve protectinggroups, such as Rn, Rw or R9 = OMe, that can be removed by standard conditions as 5 discussed in “Protective Groups for Organic Synthesis”. For example, R11, R10 or R9 = OMecan be transformed to R11, Rw or R9 = OH by treating with borontribromide in an organicsolvent such as DCM at a température ranging from -78°C to 45°C, preferably at ambienttempérature for 1 to 24 hours. Compounds of the type formula 15 can also be obtained bystarting with the appropriate ArZ or amine NRSR6 in step 7 of scheme 1. 10 Scheme 4 illustrâtes the synthesis of compounds of formula 18. In step 1, compound of formula 16 is reacted with trimethylsulfonium iodide and a base, such as sodium hydride, inan organic solvent, such as dimethyisulfoxide (OMSO) or THF, at a température ranging from—78°C to 65°C, preferably at ambient température, for 1 to 24 hours. The resulting compoundof formula 17 is reacted in step 2 with an amine NR3R4 in a solvent such as THF, methanol, 15 éthanol, water, DMF, DMSO or any combination thereof at a température ranging from 0°C to100°C, preferably at 65°C in a sealed tube, for 1 to 48 hours to give compound of formula 18.Compounds of formula 18 may hâve protecting groups, such as R11, R10 or R9 - OMe, that canbe removed by standard conditions as discussed in “Protective Groups for OrganicSynthesis”. For example, R11, R10 or R9 = OMe can be transformed to R11, R10 or R9 = OH by 1 treating with borontribromide in an organic solvent such as DCM at a température rangingfrom -78°C to 45°C, preferably at ambient température for 1 to 24 hours. Compounds of thetype formula 18 can also be obtained by starting with the appropriate amine NRsRe in step 7 ofscheme 1.

Scheme 4 also illustrâtes the synthesis of compound of formula 19. In step 1,25 compound of formula 16 is reacted with an amine HNR3R4 and redudng agent, such assodium cyanoborohydride or sodium triacetoxyborohydride, and acetic acid in an organicsolvent, such as methanol, éthanol and with or without a co-solvent such as 1,2-dichloroethane (DCE), at a température ranging from 0°C to 80°C, preferably at ambienttempérature, for 1 to 24 hours. Compounds of formula 19 may hâve protecting groups, such 30 as R11, R10 or R9 s OMe, that can be removed by standard conditions as discussed in“Protective Groups for Organic Synthesis". For example, R11, R10 or R9 = OMe can betransformed to R11, R10 or R9 - OH by treating with borontribromide in an organic solvent suchas DCM at a température ranging from -78°C to 45°C, preferably at ambient température for 1to 24 hours. Compound of the type formula 19 can also be obtained by starting with the 35 appropriate amine NR5R® in step 7 of scheme 1. -37- 1 2098

Scheme 5 and 6 illustrate an alternative synthetic scheme for compound of formula 1.in step 1, bromoaniline 20 is acylated with cinnamyl chloride in an organic solvent, such asDCM or THF, preferably DCM, in the presence of an organic base, such as pyridine ortriethyiamine, preferably pyridine, at a température ranging from -78°C to 40°C, preferably 5 between 0°C and 25°C, for 1 to 24 hours to give compound of formula 21. In step 2,compound of formula 21 is reacted with a strong Lewis acid, such as aluminum trichioride, inan organic solvent, such as chlorobenzene, at a température ranging from 25°C to 120°C,preferably between 90°C and 120°C, for 1 to 24 hours to give compound of formula 22. Instep 3, compound of formula 22 is reacted with a trifiating reagent and base, such as N- 10 phenyi-bis(trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesuifonicanhydride and 2,6-dimethylpyridine, in an anhydrous organic solvent such as THF or DCM ata température ranging from -78°C to ambient température, preferably at ambient température,for 1 to 24 hours to give compound of formula 23.

In scheme 6, compound of formula 23, in step 1, is reacted with an amine of formula 15* 5, preferably X = C, with a palladium cataiyst such as, tris(dibenzyiideneacetone)dipalladium (0) or pailadium(ll) acétate and a base such as, césium carbonate or sodium tert-butoxide,preferably césium carbonate, and a palladium ligand such as 2,2’-bis(diphenylposphino)-1,T-binapthyl (BINAP) or 1,2-bis(diphenylphosphio)ethane (DIPHOS), in a solvent such as 1,2-dioxane or toluene, preferably toluene, at a température ranging from ambient température to 20 1Q5°C, preferably between 80°C-105°C for 1 to 48 hours. In step 2, the resulting compound of formula 24 is reduced with iron powder and ammonium chloride in an organic solvent, such aséthanol or methanol, with or without a co-solvent solvent, such as water, at a températureranging from ambient température to reflux, preferably at reflux, for 1 to 24 hours to givecompound of the formula 25. 25 |n step 3, compound of the formula 25 is reacted with formamidine acetate or formic acid in an organic solvent such as 2-methoxyethanol, 1-butanol, éthanol, or formic acid,preferably éthanol, at a température ranging from ambient température to reflux, preferably atreflux, for 1 to 48 hours to give compound of formula 26. In step 4, for R1 groups that includean aryl or heteroaryl group (where Ar = aryl or heteroaryl), compound of formula 26 is reacted 30 under palladium catalysis, such as with tetrakis(triphenylphosphine)palladium (0), with theappropriate organoborane (where Z = B(OH)2 or B(Alkyl)2), organostannane (where Z =Sn(alkyl)3) or organozinc (where Z = Zn(Halogen)). When Z = B(OH)2, a base such aspotassium phosphate is used in a solvent such as 1,4-dioxane or 1,2-dimethoxyethane at atempérature ranging from ambient température to reflux, preferably at reflux, for 1 to 48 hours 35 to give compound of the formula 1. When Z = B(alkyl)2, a base such as sodium carbonate with 1 2098 -38- or without lithium chloride is used in a solvent System includïng éthanol and water with orwithout toluene at a température ranging from ambient température to reflux, preferablyaround 90°C, for 1 to 48 hours to give compound of the formula 1. When Z = Sn(alkyi)3, withor without a base such as potassium phosphate, in a suitabie organic solvent such as tolueneor 1,4-dioxane and at a température ranging from ambient température to reflux, preferablybetween 80-100°C, for 1 to 48 hours to give compound of the formula 1. When Z =Zn(Halogen), a suitabie organic solvent such as THF, 1,4-dioxane or 1,2-dimethoxyethane isuased at a température ranging from -78°C to reflux, preferably between 20-45°C, for 1 to 48hours to give compound of the formula 1. For R1 with an NRSR6 moiety, compound of theformula 26 is reacted with an amine HNRSR6 using a palladium catalyst such astris(dibenzylideneacetone)dipalladium (0) or palladium acetate and a base such as, césiumcarbonate or sodium tert-butoxide, preferably césium carbonate, and a palladium ligand suchas 2,2’-bis(diphenylposphino)-1,r-binapthyl (BINAP) or 1,2-bis(diphenylphosphio)ethane(DIPHOS) in a solvent such as 1,4-dioxane, toluene, and xylenes, preferably toluene when Y= Br and preferably xylenes when Y - Cl, at a température ranging from ambient températureto reflux, preferably at reflux for 1 to 72 hours to give compound of formula 1. Compounds offormula 1 may hâve protecting groups, such as R11, R10 or R® = OMe, that can be removed bystandard conditions as discussed in “Protective Groups for Organic Synthesis”. For example,R11, R10 or R® = OMe can be transformed to R11, R10 or R® = OH by treating withborontribromide in an organic solvent such as DCM at a température ranging from -78°C to45°C, preferably at ambient température for 1 to 24 hours.

Altematively, compound of formula 26 can be prepared from compounds of formula22 in a two step sequence as outlined in scheme 7. In step 1, compound of formula 22, whereX = Cl, is reacted with either phosphorous oxychloride, thionyl chloride or oxallyl chloride,preferably oxallyl chloride, with or without an organic solvent, such as chloroform or DCE,preferably DCE, at a température ranging from ambient température to reflux, preferably atreflux, for 1 to 24 hours to give compound of the formula 27. Where X « Br, compound offormula 22 is reacted with phosphorous oxybromide with an organic solvent, such aschloroform or DCE, preferably chloroform, at a température ranging from ambient températureto reflux, preferably at reflux, for 1 to 24 hours to give compound of the formula 27. In step 2,compound of formula 27, where X = Br or Cl, is reacted with a compound of formula 28 in anorganic solvent, such as DMF or 1-methyl-2-pyrrolidinone, with or without a base, such assodium hydride or sodium bis(trimethylsilyl)amide, at a température ranging from ambienttempérature to 150°C, preferably at 60-85°C when using a base and 150°C when not, for 1 to24 hours to give compound of the formula 26. -39- 1 2 098

In stepl of scheme 8. compound of the formula 8 is reacted with an electrophile RY,where Y is a mesylate, tosylate, bromide, chloride or iodide, and a base, such as sodiumhydride, potassium hydride, potassium carbonate, sodium carbonate or césium carbonate, ina solvent, such as DMF, THF, DMSO or 1,2-dimethoxyethane, at a température ranging from-78°C to 65°C, to give compound of the the formula 29. Compounds of formula 29 may hâveprotecting groups, such as R11, R10 or R® = OMe, that can be removed by standard conditionsas discussed in “Protective Groups for Organic Synthesis”. For example, R11, Rw or R® =OMe can be transformed to R11, R10 or R® = OH by treating with borontribromide in an organicsolvent such as DCM at a température ranging from -78°C to 45°C, preferably at ambienttempérature for 1 to 24 hours.

Also outlined in scheme 1 in step 1, compound of the formula 9 is reacted with carbonmonoxide, at a pressure range of atmospheric to 50 psi, preferably 50 psi, in the presence ofan organic base, such as triethylamine, under palladium catalysis, such as palladium acetate,with a ligand, such as 1,3-bis(diphenylphosphino)propane, in a solvent, such as DMF, in thepresence of methanol to give compound of the formula 30. In step 2, compound of theformula 30 is reacted with a preformed complex of an amine HNR3R4 (or its hydrochloride sait)with trimethylaluminum in a solvent such as DCM or DCE at a température range of 0°C toreflux to give compound of the formula 31. Compounds of formula 31 may hâve protectinggroups, such as R”, R10 or R® = OMe, that can be removed by standard conditions asdiscussed in “Protective Groups for Organic Synthesis”. For example, R11, R10 or R® = OMecan be transformed to R11, R10 or R® = OH by treating with borontribromide in an organicsolvent such as DCM at a température ranging from -78°C to 45°C, preferably at ambienttempérature for 1 to 24 hours.

The compounds of the présent invention may hâve asymmetric carbon atoms.Diasteromeric mixtures can be separated into their individual diastereomers on the basis of theirphysical Chemical différences by methods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can be separated by converting theenantiomeric mixtures into a diastereomric mixture by reaction with an appropriate opticallyactive compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing)the individual diastereomers to the corresponding pure enantiomers. AH such isomers, includingdiastereomeric mixtures and pure enantiomers are considered as part of the invention.

The compounds of formulas 1, 13, 15, 18, 19, 29, 31 that are basic in nature arecapable of forming a wide variety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable for administration to animais, it is often 1 2098 -40- désirable in practice to initially isolate the compound of formula 1,13,15,18,19,29,31 from thereaction mixture as a pharmaceutically unacceptable sait and then simply convert the iatter backto the free base compound by treatment with an alkaline reagent and subsequently convert theiatter free base to a pharmaceutically acceptable acid addition sait. The acid addition salts of thebase compounds of this invention are readily prepared by treating the base compound with asubstantially équivalent amount of the chosen minerai or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or éthanol. Upon careful évaporationof the solvent, the desired solid sait is readily obtained. The desired acid sait can aiso beprecipitated from a solution of the free base in an organic solvent by adding to the solution anappropriate minerai or organic acid.

Those compounds of formula 1, 13, 15, 18, 19, 29, 31 that are acidic in nature arecapable of forming base salts with various pharmacologically acceptable cations. Examples ofsuch salts include the alkali métal or aikaline-earth métal salts and particulariy, the sodium andpotassium salts. These salts are ail prepared by conventions! techniques. The Chemical baseswhich are used as reagents to prépare the pharmaceutically acceptable base salts of thisinvention are those which form non-toxic base salts with the acidic compounds of formula 1,13,15,18,19,29,31. Such non-toxic base salts include those derived from such pharmacologicallyacceptable cations as sodium, potassium calcium and magnésium, etc. These salts can easilybe prepared by treating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternative^, they may aiso beprepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkalimétal alkoxide together, and then evaporating the resulting solution to dryness in the samemanner as before. In either case, stoichiometric quantifies of reagents are preferably employedin order to ensure compieteness of reaction and maximum yields of the desired final product.Since a single compound of the présent invention may include more than one acidic or basicmoieties, the compounds of the présent invention may include mono, di or tri-salts in a singlecompound.

The activity of the compounds of formula 1,13,15,18,19,29,31 may be determined bythe following procedure.

General PGT Kinase ELISA Method

The following reagent and stock solutions are used: adenosine triphosphate (ATP)bovine sérum albumin (BSA)Oulbecco's PBS (dPBS)

Sigma, cat. # A-2383Sigma, cat. # A-3294Gibco-BRL, cat # 14190-136

MaxiSorp plates

Nunc, cat. # 439454 -41- 1 2 098

MgClj

Poly-Glu-Tyr (PGT)TMB Micowell SubstrateTween 20 HRP-PY54 antibody

Sigma, cal. # M-1028Sigma, cat. #. P-0275

Kirkegaard &amp; Perry, cat. # 50-76-05Sigma, cat. # P-1379OSI Pharmaceuticals, Inc.

Phosphorylation Buffer (PB): 50 mM HEPES, pH 7.3,125 mM NaCI, 24 mM MgCI2;

Wash Buffer (WB): dPBS + 0.1% Tween 20 (polyoxyethylene sorbitan); and

Blocking Buffer: 3% BSA, 0.05% Tween 20 In dPBS.

Assay procedure: (a) For plate coating, fill Nunc MaxiSorp plate with 100 pl per well of Poly-Glu-Tyr (PGT)dlluted in dPBS (various concentrations). The plate is the incubated overnight at 37°C. Thesupematant PGT is then disgarded, and the plates are washed 3X with Wash Buffer. (b) The PDGF enzyme is then diluted in PB to an appropriate concentration, and 25 pl of thisstock solution is added per well. (c) ATP is then diluted (from 20 mM stock) to an appropriate concentration (0.5 nM- 2 uM)with PB. The phosphorylation reaction is commenced by addition of 25 pl ATP solution to each well ofthe assay plate. Incubation is continued for about 10 minutes, with shaking at room température. (d) The reaction is stopped by aspirating off the reaction mixture. The plate is then washed4XwithWB. (e) The HRP-PY54 antibody is diluted to an appropriate concentration in blocking buffer. 50pl of this solution is then added per well, followed by incubation for 25-35 minutes at roomtempérature. The antibpdy-containing solution is aspirated away, and the plate is again washed 4Xwith WB. (f) The extent of reaction is determined by measurement of light absorbance at 450 nm. First,color is developed by addition of TMB solution, 50 pl per well, and the reaction is permitted to run untilwells with positive signais achieve about 0.6-1.2 OD450 units. Color development is then stopped byaddition of 50 pl per well of 0.09 M K2SO4. The background Controls are wells without PGT, but withail other components included. As aforementioned, preferred signal is generally in the range of 0.6- 1.2 OD units, with esentially no background.

The in vitro activity of the compounds of the présent invention in inhibiting the PDGF βreceptor may be determined by the following procedure.

Inhibition of tyrosine kinase activity may be measured using a recombinant enzymein an assay that measures the ability of compounds to inhibit the phosphorylation of theexogenous substrate, polyGluTyr (PGT, Sigma™, 4:1 ). The cytoplasmic domain of the humanPDGFp receptor (amino acids 559-1106) (Ishikawa, F., et al. Nature 338: 557-562, 1989) isexpressed in Sf9 insect cells as a glutathione S-transferase (GST)-fusion protein using the -42- 1 2098 bacuiovirus expression System. The protein is then purified from the lysâtes of these cellsusing glutathione agarose affinity columns.

The enzyme assay is performed in 96-well plates that are coated with the PGTsubstrate (0.625 pg PGT per well). Test compounds are diluted in dimethyisulfoxide (DMSO), 5 and then added to the PGT plates so that the final concentration of DMSO in the assay is1.6% (v/v). The recombinant enzyme is diluted in phosphorylation buffer (50 mM Hepes, pH7.3, 125 mM NaCI, 24 mM MgCI2). The reaction is initiated by the addition of ATP to a finalconcentration of 10 pM. After a 10 minute incubation at room température with shaking, thereaction is aspirated, and the plates are washed with wash buffer (PBS-containing 0.1% 10 Tween-20). The amount of phosphorylated PGT is quantitated by incubation with ahorseradish peroxidase(HRP)-conjugated PY-54 antibody (Transduction Labs), developingwith TMB peroxidase (TMB is 3,3',5,5*-tetramethylbenzidine), and détection on a BioRad™Microplate reader at 450 nM. Inhibition of the kinase enzymatic activity by the test compoundis detected as a reduced absorbance, and the concentration of the compound that is required 15 to inhibit the signal by 50% (under the circumstances of the assay) is reported as the IC»value for the test compound.

To measure the ability of the compounds to inhibit PDGFRp tyrosine kinase activityfor the full length protein that exists in a cellular context, the porcine aortic endothélial (PAE)cells transfected with the human PDGFRp (Westermark, Bengt, et al., PNAS 87, pp128-132, 20 1990) may be used. Cells are plated and aliowed to attach to 96-well dishes in the same media (Ham’s F12) with 10% FBS (fêtai bovine sérum) for 6-8 hours. The celte are washed,re-fed with sérum depleted media, and aliowed to incubate over night. immediately prior todosing with compound, the cells are re-fed with the sérum depleted media. Test compounds,dissolved in DMSO, are diluted into the media (final DMSO concentration 0.5% (v/v)). At the 25 end of a 10 minutes incubation, PDGF-BB (100 ng/ml final) is added to the media for an 8minute incubation. The cells are washed with Hepes buffered saline solution (HBSS) andlysed in 50 ul of HNTG buffer (20 mM Hepes, pH 7.5, 150 mM NaCI, 0.2% Triton™ X-100,10% glycerol, plus 0.2 mM PMSF (phenymethylsuifonyl fluoride), 1 pg/ml pepstatin, 1 pg/mlleupeptin, 1 pg/ml aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate) and 30 then diluted with 50 ul of HG dilution buffer (20 mM Hepes, pH 7.5, 10% glycerol, 0.2 mMPMSF (phenymethylsuifonyl fluoride), 1 pg/ml pepstatin, 1 pg/ml leupeptin, 1 pg/ml aprotonin,2 mM sodium pyrophosphate, 2 mM sodium orthovanadate). The extent of phosphorylation ofPDGFRfi is measured using an ELISA assay. The 96-well Protein A coated plates areblocRed with Superbiock (Pierce) and coated with 0.5 pg per well anti- PDGFRfi P20 antibody 35 (Santa Cruz, catalog number SC-339). -43- . 2098

Any unbound antibody is washed off the plates prior to addition of the cell lysate.After a 2 hour room température incubation of the lysâtes (50 ul) with the PDGFRp antibody,the PDGFRp associated phosphotyrosine is quantitated by development with the I IRP-conjugated PY-54 antibody and TMB, as described above. The ability of the compounds to 5 inhibit the PDGF-BB stimulated autophosphorylation reaction by 50% under the conditionsused, relative to PDGF-BB-stimulated Controls, is reported as the IC^ value for the testcompound. The compounds of the présent invention, including the examples recited below,generally hâve IC50 values using the foregoing procedure falling within the following range: 1-1000 nM. 10 Assay *ΟΓ inhibition Activity Toward the KDR/VEGF Receptor

The in vitro activity of the compounds of the présent invention in inhibiting theKDR/VEGF receptor may be determined by the following procedure.

The ability of the compounds of the présent invention to inhibit tyrosine kinase activitymay be measured using a recombinant enzyme in an assay that measures the ability ofcompounds to Inhibit the phosphorylation of the exogenous substrate, polyGluTyr (PGT,Sigma™, 4:1). The kinase domain of the human KDR/VEGF receptor (amino acids 805-1350)is expressed in Sf9 insect cells as a glutathione S-transferase (GST)-fusion protein using thebaculovirus expression System. The protein is purified from the lysâtes of these cells usingglutathione agarose affinity columns. The enzyme assay is performed in 96-well plates that 2q are coated with the PGT substrate (0.625 pg PGT per well). Test compounds are diluted indimethylsulfoxide (DMSO), and then added to the PGT plates so that the final concentration ofDMSO in the assay is 1.6% (v/v). The recombinant enzyme is diluted in phosphorylationbuffer (50 mM Hepes, pH 7.3, 125 mM NaCI, 24 mM MgCI2). The reaction is initiated by theaddition of ATP to a final concentration of 10 μΜ. After a 30 minute incubation at roomtempérature with shaking, the reaction is aspirated, and the plates are washed with washbuffer (PBS-containing 0.1% Tween-20). The amount of phosphorylated PGT is quantitatedby incubation with a HRP-conjugated (HRP is horseradish peroxidase) PY-54 antibody(Transduction Labs), developed with TMB peroxidase (TMB is 3,3’,5,5’-tetramethylbenzidine),and the reaction is quantitated on a BioRad™ Microplate reader at 450 nM. Inhibition of thejq kinase enzymatic activity by the test compound is detected as a reduced absorbance, and theconcentration of the compound that is required to inhibit the signal by 50% is reported as the ICso value for the test compound.

To measure the ability of the compounds to inhibit KDR tyrosine kinase activity for thefull length protein that exists in a cellular context, the porcine aortic endothélial (PAE) cells 35 transfected with the human KDR (Waltenberger et al., J. Biol. Chem. 269:26988, 1994) may 1 2098 -44“ be used. Cells are plated and allowed to attach to 96-well dishes in the same media (Ham’sF12) with 10% FBS (fêtai bovine sérum). The cells are then washed. re-fed with sérumdepleted media that contains 0.1% (v/v) bovine sérum albumin (BSA), and allowed to incubatefor 24 hours. Immediately prior to dosing with compound, the cells are re-fed with the sérum 5 depleted media (without BSA). Test compounds, dissolved in DMSO, are diluted into themedia (final DMSO concentration 0.5% (v/v)). At the end of a 2 hour incubation, VEGF165 (50ng/ml final) is added to the media for an 8 minute incubation. The cells are washed and lysedin HNTG buffer (20 mM Hepes, pH 7.5,150 mM NaCI, 0.2% Triton™ X-100,10% glycerol, 0.2mM PMSF (phenymethylsulfonyl fluoride), 1 pg/ml pepstatin, 1 pg/ml leupeptin, 1 pg/ml 10 aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate). The extent ofphosphorylation of KDR is measured using an ELISA assay. The 96-well plates are coatedwith 1 pg per well of goat anti-rabbit antibody. Unbound antibody is washed off the plate andremaining sites are blocked with Superblock buffer (Pierce) prior to addition of the anti-flk-1 C-20 antibody (0.5 pg per plate, Santa Cruz). Any unbound antibody is washed off the plates 15 prior to addition of the cell lysate. Aller a 2 hour incubation of the lysâtes with the flk-1antibody, the KDR associated phosphotyrosine is quantitated by development with the HRP-conjugated PY-54 antibody and TMB, as described above. The ability of the compounds toinhibit the VEGF-stimulated autophosphorylation reaction by 50%, relative to VEGF-stimulated Controls is reported as the IC» value for the test compound. 2Q Administration of the compounds of the présent invention (hereinafter the “active compound(s)") can be effected by any method that enables delivery of the compounds to the siteof action. These methods include oral routes, intraduodenal routes, parentéral injection(including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, andrectal administration. 2^ The amount of the active compound administered wfli be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the dispositionof fiie compound and the discrétion of the prescribing physician. However, an effective dosageis in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 toabout 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels J® below the lower limit of the aforesaid range may be more than adéquate, while in other cases stilllarger doses may be employed without causing any harmfül side effect, provided that such largerdoses are first divided into several small doses for administration throughout the day.

The active compound may be applied as a sole therapy or may involve one or more 35 other anti-tumour substances, for example those selected from, for example, mitotic inhibitors, -45- 1 2088 for example Vinblastine; alkylating agents, for example cis-platin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in Européen PatentApplication No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)"N- 5 methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors;intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such as Nolvadex™ (tamoxifen) or, forexample anti-androgens such as Casodex™ (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of IG the simultaneous, séquentiel or separate dosing of the individual components of Oie treatment.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, piil, powder, sustained release formulations, solution,suspension, for parentéral injection as a stérile solution, suspension or émulsion, for topicaladministration as an ointment or cream or for rectal administration as a suppository. The 15 pharmaceutical composition may be in unit dosage forms suitable for single administration of précisé dosages. The pharmaceutical composition will indude a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as an active ingrédient. Inaddition, it may indude other médicinal or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parentéral administration forms indude solutions or suspensions of active 2ü compounds in stérile aqueous solutions, for example, aqueous propylene glycol or dextrosesolutions. Such dosage forms can be suitably butfered, if desired.

Suitable pharmaceutical carriers indude inert diluents or fillers, water and variousorganic solvents. The pharmaceutical compositions may, if desired, contain additionalingrédients such as flavorings, binders, excipients and the like. Thus for oral administration, 2$ tablets containing various exdpients, such as dtric acid may be employed together with variousdisintegrants such as starch, alginic acid and certain complex silicates and with binding agentssuch as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnésiumstéarate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solidcompositions of a similar type may also be employed in soft and hard filled gelatin capsules.jG Preferred matériels, therefor, indude lactose or milk sugar and high molecular weightpolyethylene glycols. When aqueous suspensions or élixirs are desired for oral administrationthe active compound therein may be combined with various sweetening or fiavoring agents,coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, éthanol, propylene glycol, glycerin, or combinations thereof.je; Methods of preparing various pharmaceutical compositions with a spécifie amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see 1 2 09 8 -46-

Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition(1975).

The examples and préparations provided below further illustrate and exemplify lhecompounds of the présent invention and methods of preparing such compounds. It is to be $ understood that the scope of the présent invention is not limited in any way by the scope of thefoliowing examples and préparations. In the following examples molécules with a single chiralcenter, unless otherwise noted, exist as a racemic mixture. Those molécules with two ormore chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers.Single enantiomers/diastereomers may be obtained by methods known to those skilled in the 10 art.

Where HPLC chromatography is referred to in the préparations and examples below,the general conditions used, unless otherwise indicated, are as follows. The column useri is aZORBAX™ RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6mm interior diameter. The samples are run on a Hewlett Packard-1100 System. A gradient 1j solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to100 percent acetonitrile over 10 minutes. The System then proceeds on a wash cycle with100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes.The flow rate over this period is a constant 3 ml / minute.ln the following examples andpréparations, ΈΓ means ethyl, “Ac” means acetyl, “Me** means methyl, and “Bu” means butyl. 20 Experimental Examples

Example 1

Synthesisof 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine.

Trifluoro-methanesulfonic acid 8-(tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl ester. -47- 1 2098 2,8-Quinolinediol (20.0 g, 124 mMol) was suspended in 500 mL of dichloromethane (DCM)under an atmosphère of dry nitrogen (N2). To this solution was added imidazole (20.3 g, 298mMol) followed by tert-butyldimethylsilyl chloride (20.6 g, 137 mMol) and 4-dimethylaminopyridine (1.50 g, 12.4 mMol). The reaction mixture was stirred overnight al 5 ambient température after which time it was partitioned between DCM and 1% aqueoussodium bisulfate (NaHSO4). The DCM layer was saved and washed two more times with 1%aqueous NaHSO4, then aqueous saturated sodium bicarbonate (NaHCO3) and finally brine.The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated undervacuum to give crude product (40 g) as a white solid. The solid was dissolved in 500 mL of W anhydrous tetrahydrofuran (THF) under an atmosphère of dry N2. To this solution was addedN-phenyl-bis(trifluoromethanesulfonimide) (48.7 g, 136 mMol) and the solution was cooled to0°C. To this solution was slowly added (3.2 g, 136 mMol) sodium hydride (60% in oil). Afterthe addition was complété, the reaction mixture was warmed to ambient température. Anadditional 1.00 g sodium hydride (60% in oil) was added after one hour and stirred for anadditional 30 minutes. The mixture was concentrated under vacuum and taken up in DCM.Water (1.0 mL) was slowly added dropwise to quench any unreacted sodium hydride and thenthe réaction mixture was extracted twice from 0.1 N aqueous sodium hydroxide (NaOH) andthen washed with brine. The DCM layer was dried over Na2SO4, filtered and concentratedunder vacuum to give 57 g of the crude triflate 1A as a yellow oil.

20 Example 1B ((8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-(4-methoxy-2-nitro-phenyl)-amine.

Trifluoro-methanesulfonic acid 8-(tert-butyl-dirnethyl-silanyloxy)-quinolin-2-yl ester 1A (9.81 g, 24.1 mMol) and 4-methoxy-2-nitroaniline (4.86 g, 28.9 mMol) were dissolved in 100 mL ofdioxane under an atmosphère of dry N2. To this solution was added (11.0 g, 33.7 mMol) 2j césium carbonate (Cs2CO3), (900 mg, 1.45 mMol) racemic-2,2'-bis(diphenylposphino)-1,r-binapthyl (BINAP) and tris(dibenzylideneacetone)dipalladium (0) (883 mg, 0.964 mMol) andthe reaction mixture was heated to 100°C and reacted at this température for 4 hours. Themixture was then cooled to ambient température, concentrated under vacuum, treated withDCM, filtered and concentrated under vacuum to give a red solid. The solid was 30 chromatographed on flash siiica gel eluting with hexanes/DCM (3:1) to give 7.25 g of the titlecompound 1B as a red solid.

Example 1C N1-[8-(tert-ButyI-dimethyl-silanyloxy)-quinolin-2-yl]-4-methoxy-benzene-1,2-diamine. -48- 1 2 098 ([8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-(4-methoxy-2-nitro-phenyl)-amine 1B (21.9 g, 51.3 mMol) was dissolved in a solution of 200 mL éthanol (EtOH) and 70 ml. of THF under anatmosphère of dry N2. To this solution was added 10% palladium on carbon (2.18 g) followedby the dropwise addition of 10 mL of anhydrous hydrazine. The reaction mixture was stirredat ambient température for 2 hours after which time it was filtered through Celite™ and theCelite™ was washed with OCM. The combined filtrâtes were concentrated under vacuum andthe resulting residue was partitioned between DCM and aqueous saturated NaHCO3. TheDCM layer was then washed again with saturated NaHCO3 and then brine, dried overNa2SO4, filtered and concentrated under vacuum to give 18.3 g of a tan solid as the titlecompound 1C.

Example 1D 2-(5*Methoxy-benzoimidazol~1*yl)-quinolin-8-ol. N1-[8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-4-methoxy-benzene-1,2-diamine 1C (18.3g, 46.1 mMol) was dissolved in 40 mL of 2-methoxyethanol under an atmosphère of dry N2.To this solution was added formamidine acetate (5.28 g, 50.7 mMol) and the reaction mixturewas heated to 125°C and reacted at this température for 1.5 hours. The solvent was removedunder vacuum and the resulting solid was triturated with ethyl ether (Et2O), dried undervacuum to give 13.3 g of a pink solid as the title compound 1D.

Example 1E

Trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester.

2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-ol 1D (13.9 g, 47.8 mMol) was dissolved in 100mL of anhydrous THF under an atmosphère of dry N2. To this solution was added N-phenyl-bis(trifluoromethanesulfonimide) (20.3 g, 47.8 mMol) and then the solution was subsequentlycooled to 0°C. To this solution was slowly added (1.31 g, 54.9 mMol) sodium hydride (60% inoil). After the addition was complété the reaction mixture was warmed to ambienttempérature. After 30 minutes, 500 mg more of sodium hydride (60% in oil) was addedfollowed by 3.50 g of N-phenyl-bis(trifluoromethanesulfonimide) and the reaction mixture wasstirred at ambient température for 1 hour. The solvent was then removed under vacuum andthe resulting residue was taken up in DCM. To this solution was slowly added 1.0 mL of waterto décomposé any unreacted sodium hydride. The mixture was subsequently partitionedbetween DCM and 0.1 N aqueous NaOH. The DCM layer was then washed again with 0.1 N 1 2098 -49- aqueous NaOH, followed by brine and then dried over magnésium sulfate (MgSO4), filteredand concentrated under vacuum to give 20.7 g of a pink solid as the crude title compound 1E.

Example 1F {1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl 5 ester.

Trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E (15.0g, 35.4 mMol) and piperidin-4-yl-carbamic acid tert-butyl ester (14.2 g, 70.9 mMol) weredissolved in 200 mL of dioxane under an atmosphère of dry N2. To this solution was addedCs2CO3 (16.2 g, 49.6 mMol), racemic-BINAP (1.28 g, 2.12 mMol) and 10 tris(dibenzyiideneacetone)dipalladium (0) (1.29 g, 1.41 mMol) and the reaction mixture washeated to 100°C and reacted at this température overnight. The mixture was then cooled toambient température, filtered, and concentrated under vacuum to give an orange foam. Thefoam was chromatographed on flash silica gel eluting with a gradient from ethyl acetate(EtOAc)/DCM (1:5) to EtOAc/DCM (7:3) give 12.3 g of the title compound 1F as a slightly 15 yellow solid.

Example 1G 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine. {1 -[2-(5~Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butylester 1F (8.40 g, 17.7 mMol) was dissolved in 50 mL of trifluoroacetic acid (TFA) under an 20 atmosphère of dry N2. The reaction mixture was stirred at ambient température for 15 minutes after which time it was concentrated under vacuum to give a yellow oil. The oil waspartitioned between DCM and 0.1 N aqueous NaOH. The DCM fayer was washed again with0.1 N aqueous NaOH. "The OCM layer was dried over Na2SO4, filtered and concentrated togive 5.85 g of the title compound 1 as a yellow solid. 25 C.l. m/z 374 [M+1); 1H NMR (CDCI3) δ 8.66.(s, 1 H), 8.37 (d, J = 8.9 Hz, 1 H), 8.30 (d, J = 8.7Hz, 1 H), 7.68 (d, J = 8.9 Hz, 1 H), 7.47 (m, 2 H), 7.35 (d, J = 2.3 Hz, 1 H), 7.25 (m, 1 H), 7.06(dd, J = 2.5,8.9 Hz, 1 H), 3.91 (s, 3 H), 3.88 (m, 2 H), 2.90 (m, 3 H), 2.05 (m, 2 H), 1.83 (m, 2H), 1.50 (brs, 2 H).

Example 2 1-{8-(4-Amino-piperidin-1 -yl)-quinolin-2-ylJ-1 H-benzoimidazol-5-oi. 30 1 2098 -50-

1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine 1 (500 mg, 1.10 mMol)was dissolved in 10 mL of DCM under an atmosphère of dry N2. To this solution was addedboron tribromide (300 μ1_, 3.30 mMol) and the mixture was stirred ovemight at ambienttempérature. Then an additional 200 pL of borontribromide was added and the mixture was 5 stirred for two hours. The reaction mixture was then poured over crushed ice and the pH ofthe resulting solution was adjusted to 9 with the carefui addition of sodium carbonate(Na2CO3). The slurry was filtered and the soiid was washed with water followed by Et2O andthen dried under vacuum to give the title compound 2 as a yellow soiid. C.l. m/z 360 IM+11; Ή NMR (DMSO) δ 9.07 (s, 1 H), 8.76 (d, J = 8.9 Hz, 1 H), 8.48 (d, J = 8.9 10 Hz, 1 H), 8.10 (d, J = 8.9 Hz, 1 H), 7.56 (d, J = 7.4 Hz, 1 H), 7.45 (m, 1 H), 7.26 (d, J = 7.4 Hz,1 H), 7.01 (d, J = 2.2 Hz, 1 H), 6.95 (dd, J = 2.2, 8.9 Hz, 1 H), 3.72 (m, 2 H), 2.76 (m, 3 H),1.88 (m, 2 H), 1.65 (m, 2 H).

Example 3 1-{2-[5-(Pyridin-2-ylmethoxy)-benzoimidazol-1-yl]-quÎnolin-8-yl}-piperidin-4-ylamine.

{1-[2-(5-Hydroxy-benzoimidazol-1-yl)-quinolin-8-yq-piperidin-4-yl}-carbamicacidtert-butyl ester. 1-[8-(4-Amino-piperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-ol 2 (460 mg, 1.30 mMol) wasdissolved in 5 mL of anhydrous DMF under an atmosphère of dry N2. To this solution was 20 added di-tert-butyldicarbonate (279 mg, 1.30 mMol) and the reaction mixture was stirred atambient température ovemight The reaction mixture was then concentrated under vacuumand parütioned between DCM and aqueous saturated NaHCO3. The DCM layer was driedover Na^O*, filtered and concentrated under vacuum to give a yellow soiid. The soiid was -51- 1 2098 chromatographed on flash silica gel eluting with EtOAc to give 273 mg of the title compound3A as a yellow solid.

Example 3B (1-{2-[5-(Pyridin-2-ylmethoxy)-benzoimidazol-1 -yl}-quinolin-8-yl}-piperidin-4-yl)-carbamic acidtert-butyl ester.

Z {1 -[2-{5-Hydroxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butylester 3A (73 mg, 0.16 mMol) was dissolved in 1 mL of anhydrous DMF under an atmosphèreof dry N2. To this solution was added (37 mg, 0.17 mMol) potassium bis(trimethyl)silylamide(95%) followed by 2-picolyl chloride (25 pL, 0.17 mMol). The reaction mixture was stirredovemight at ambient température after which time the reaction mixture was concentratedunder vacuum and then partitioned between DCM and aqueous saturated NaHCO3. TheDCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a yellowgel. The gel was chromatographed on flash silica gel eluting with a gradient from DCM toDCM/MeOH (98:2) to give 55 mg of the title compound 3B.

Example 3C 1-{2-[5-(Pyridln-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamÎne. (1-{2-[5-{Pyridin-2-ylmethoxy)-benzoimidazo!-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acidtert-butyl ester 3B (55 mg, 0.094 mMol) was dissolved in 1 mL of TFA under an atmosphère ofdry N2 and stirred for 15 minutes at ambient température. The reaction mixture was thenconcentrated under vacuum to give an oil which was subsequehtly partitioned between 0.1 Naqueous NaOH and DCM. The DCM layer was dried over Na2SO4, filtered and concentratedunder vacuum to give 38.9 mg of a yellow film as the title compound 3. C.l. m/z 451 [M+1 ]; 1H NMR (CDCI3) δ 8.64 (s, 1 H). 8.60 (m. 1 H), 8.42 (dd, J = 1.5, 8.9 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1 H), 7.64-7.72 (m, 2 H), 7.57 (d, J » 7.9 Hz, 1 H), 7.45 (m, 2 H), 7.40(d, J = 2.5 Hz, 1 H). 7.18-7.25 (m, 3 H), 5.29 (s, 2 H), 3.87 (m, 2 H), 2.92 (m, 3 H). 2.04 (m, 2H), 1.80 (m, 2 H), 1.60 (brs, 2 H).

Example 4 {1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-dimethyl-amine. 1 2 09 8 -52-

1-{2-(5-Methoxy-benzoimidazol-1-yi)-quinolin-8-yi]-piperidin-4-ylamine 1 (160 mg, 0.43 mMol)was dissolved in 2 mL of chioroform under an atmosphère of dry N2. To this solution wasadded 50 pL of 37% aqueous formaldéhyde and 100 pL formic acid and the reaction mixturewas subsequently heated to 65°C and reacted at this température for 4 hours. The reaction 5 mixture was then partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer wasdried over Na2SO4, filtered and concentrated under vacuum to give an orange solid as the titlecompound 4. C.l. m/z 402 [M+1]; Ή NMR (CDCI3) δ 8.65 (s, 1 H), 8.42 (d. J = 8.9 Hz, 1 H). 8.28 (d, J = 8.7Hz, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.45 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.25 (m, 1 H), 7.05 10 (dd, J = 2.5, 8.9 Hz, 1 H), 4.00 (m, 2 H). 3.89 (s, 3 H), 2.80 (m, 2 H), 2.38 (m, 1 H), 2.37 (s, 6H), 1.99 (m,4H).

Example 5 {4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-methyl-amine.

15 4-[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin*8-yl]-benzaldehyde.

Trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E (265mg, 0.630 mMol) was dissolved in 3 mL of dioxane under an atmosphère of dry N2. To thissolution was added 4-formylbenzene boronic acid (145 mg, 0.940 mMol), potassiumphosphate (267 mg, 1.26 mMol) and tetrakis(triphenylphosphine)paliadium (0) (36 mg, 0.032 20 mMol). The reaction mixture was heated to 105°C and reacted at this température ovemight.The reaction mixture was then cooled to ambient température, concentrated under vacuum -53-

I and partitioned between DCM and aqueous saturated NaHCO3. The DCM layer was thenwashed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give ayeilow solid as the title compound 5A which was pushed on without further purification.

Example 5B {4-[2-(5-Methoxy-benzoÎmidazol-1-yl)-quinolin-8-yIJ-benzyl}-methyl-amine. 4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzaldehyde 5A (120 mg, 0.32 mMol)was dissolved in 2 mL of methanol under an atmosphère of dry N2. To this solution wasadded 800 μΐ_ of a solution of 2.0 M methylamine in methanol and then acetic acid (AcOH)was added dropwise until the pH of the solution was -5. To this solution was added (42 mg,0.64 mMol) sodium cyanoborohydride (NaCNBH3) and the reaction mixture was stirred atambient température ovemight. The reaction mixture was then concentrated under vacuumand subsequently partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer waswashed again with 0.1 N aqueous NaOH, then dried over MgSO4, filtered and concentratedunder vacuum to give 220 mg of a green residue. The residue was chromatographed on flashsilica gel eluting with a gradient DCM/MeOH (5/95) to DCM/MeOH (15/85) toDCM/MeOH/NH4OH (15/84.5/0.5) to give 50 mg of a white solid of the title compound 5. C.I. m/z 395 {M+1J; 1H NMR (CDCI3) δ 8.55 (s, 1 H), 8.29 (d, J = 8.9 Hz, 1 H), 7.92 (d, J = 8.9Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.74 (m, 1 H), 7.63 (m, 3 H), 7.56 (m, 1 H), 7.44 (d, J = 8.1Hz, 2 H), 7.23 (d, J = 2.3 Hz, 1 H), 6.73 (dd, J = 2.3, 8.9,1 H), 3.88 (s, 2 H), 3.83 (s, 3 H), 2.53(s, 3 H), 2.43 (brs, 1H).

Example 6 {4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-dimethyl-amine.

The same procedure that used for Example 5 was followed with the exception that 2.0 Mdimethylamine in methanol was used in the place of 2.0 M methylamine in methanol inExample 5B to give the title compound 6 as a white solid. C.I. m/z 409 [M+1]; 1H NMR (CDCI3) δ 8.56 (s, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 9.1Hz, 1 H), 7.79 (d, J « 8.1 Hz, 1 H), 7.76 (m, 1 H), 7.63 (m, 3 H), 7.56 (m, 1 H), 7.45 (d, J = 7.9 -54- 1 2098

Hz, 2 H), 7.25 (d, J = 2.3 Hz, 1 H), 6.74 (dd, J = 2.3,8.9,1 H), 3.84 (s, 3 H), 3.57 (s, 2 H), 2.35(s, 6 H).

Example 7

Cyclopropyl-{4-[2-(5-meihoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyi}-amlne.

5 4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzaldehyde 5A (50 mg, 0.13 mMol) wasdissolved in 500 pL of dichloroethane (DCE) under an atmosphère of dry N2. To this solutionwas added 80 pL of AcOH, cyclopropylamine (50 pL, 0.65' mMol) and (42 mg, 0.20 mMol)sodium triacetoxyborohydride (NaHBfOAc^). The reaction mixture was stirred at ambienttempérature for 2 hours after which time an additional 20 pL of cyclopropylamine and 20 mg of 0 NaHB(OAc)3 were added and the resulting mixture was stirred ovemight. The reactionmixture was then partitioned between aqueous 0.1 N NaOH and DCM. The DCM layerwashed again with aqueous 0.1 N NaOH and then dried over Na2SO«, filtered andconcentrated under vacuum to give a 60 mg of the titie compound 7 as a yellow solid. C.I. m/z 421 [M+11; 1H NMR (CDCI3) δ 8.58 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 7.96 (d, J = 9.1 5 Hz, 1 H), 7.83 (d, J » 7.7 Hz, 1 H), 7.77 (d, J = 7.3 Hz, 1 H), 7.64 (m, 3 H), 7.59 (m, 1 H), 7.45 (d, J = 7.9 Hz, 2 H), 7.25 (m, 1 H), 6.75 (dd, J = 2.3,8.9,1 H), 3.97 (s, 2 H), 3.86 (s, 3 H), 2.26(m, 1 H), 1.95 (brs, 1 H), 0.49 (m, 4 H).

Example 8 tert-Butyl-{4-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-amine.

ν' -55- 1 2098

The same procedure that used for Example 7 was followed with the exception that tert-butylamine was used in the place of cyclopropylamine to give the title compound 8 as a yellowsolid. C.l. m/z 437 (M+1 ]; 1H NMR (CDCI3) δ 8.59 (s, 1 H), 8.33 (d, J = 8.9 Hz, 1 H), 7.95 (d, J = 8.95 Hz, 1 H), 7.82 (m, 1 H), 7.77 (m. 1 H), 7.65 (m, 3 H), 7.58 (m, 1 H), 7.49 (d, J = 8.1 Hz, 2 H), 7.26 (d, J = 2.3 Hz, 1 H), 6.79 (dd, J = 2.3, 8.9,1 H), 3.86 (s, 5 H), 1.24 (s, 9 H).

Example 9 4-[2-(5-Methoxy-benzoimidazol-1-yt)-quinolin-8-yl]-benzylamine.

J The same procedure that used for Example 5 was followed with the exception that ammonium 10 acetate was used in the place of 2.0 M methytamine in methanol in Example 5B to give a yellow solid. The solid was chromatographed on flash silica gel eluting with a gradient fromDCM/MeOH (5/95) to DCM/MeOH (15/85) to DCM/MeOH/NH4OH (15/94.5/0.5) to give the title compound 9 as a white solid. C.l. m/z 381 (M+1]; 1H NMR (CDCI3) δ 8.59 (s, 1 H). 8.35 (d. J - 8.9 Hz, 1 H), 7.94 (d, J « 8.9Hz, 1 H), 7.84 (m, 1 H), 7.78 (dd, J = 1.5,7.3 Hz, 1 H), 7.66 (m, 3 H), 7.60 (m, 1 H), 7.46 (d, J= 8.1 Hz, 2 H), 726 (d, J = 2.5 Hz, 1 H), 6.76 (dd, J = 2.5, 8.9,1 H), 4.00 (s, 2 H), 3.85 (s, 3H), 1.78 (brs, 2H).

Example 10 1-(2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine.

20 The same procedure that used for Example 1 was followed with the exception that 4-ethoxy-2-nitroaniline was used in the place of that 4-methoxy-2-nitroaniline in example 1B to give thetitle compound 10 as a yellow solid. -56- 1 2 098 C.l. m/z 388 [M+1]; 1H NMR (CDCI3) δ 8.63 (s, 1 H), 8.36 (d, J = 8.9 Hz. 1 H). 8.26 (d, J = 8.7Hz, 1 H), 7.64 (d. J = 8.7 Hz, 1 H), 7.44 (m, 2 H). 7.32 (d, J = 2.5 Hz, 1 H), 7.25 (m, 1 H), 7.05(dd, J = 2.5, 8.9 Hz, 1 H), 4.10 (q, J = 7.0 Hz, 2 H), 3.86 (m, 2 H), 2.90 (m, 3 H), 2.04 (m, 2 H), 1.79 (m, 2 H), 1.45 (t, J = 7.0 Hz, 3 H). 5 ' Example 11 {1-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-dimethyl-amtne.

The same procedure that used in Example 4 was followed with the exception 1-{2-(5-ethoxy-benzoimidazol-1-yl)-quinolin-8-yi]-piperidin-4-ylamine 10 was used in the place of 1-(2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine 1 to give the title compound 11as a yellow solid. C.l. m/z 416 [M+1]; ’H NMR (CDCI3) δ 8.65 (s, 1 H), 8.39 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.7Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.32 (d, J = 2.5 Hz, 1 H), 7.24 (m, 1 H), 7.05(dd, J = 2.5,8.9 Hz, 1 H), 4.10 (q, J = 7.0 Hz. 2 H), 4.00 (m, 2 H), 2.80 (m, 2 H), 2.40 (m, 1 H), 2.38 (s, 6 H), 2.00 (m, 4 H), 1.46 (t, J = 7.0 Hz. 3 H). IJ Example 12 1-[2-(5-Trifluoromethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine.

The same procedure that used in Exemple 1 was followed with the exception that 2-nitro-4-(trifluoromethoxy)aniline was used in the place of 4-methoxy-2-nitroaniline in example 1B togive the title compound 12 as a yellow solid. 1 2098 C.l. m/z 428 [M+1]; Ή NMR (CDCI3) δ 8.74 (s, 1 H), 8.50 (d, J = 8.9 Hz, 1 H), 8.33 (d, J = 8.7Hz, 1 H), 7.74 (d, J = 1.0 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.47 (m, 2 H), 7.32 (m, 1 H), 7.25(m, 1 H), 3.87 (m, 2 H), 2.90 (m, 3 H), 2.05 (m, 2 H), 1.77 (m, 2 H), 1.71 (brs, 2 H).

Example 13 5 {4-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-methyl-amine.

The same procedure that used for Example 5 was followed with the exception that 4-ethoxy-2-nitroaniline was used in the place of 4-methoxy-2-nitroaniline in example 1B to give the titlecompound 13 as a tan solid. C.l. m/z 409 [M+1]; 1H NMR (CDCI3) δ 8.54 (s, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 7.92 (d, J = 9.110 Hz, 1 H), 7.77 (d, J = 8.1 Hz, 1 H), 7.72 {d, J » 7.1 Hz, 1 H), 7.62 (m, 3 H), 7.54 (m, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.21 (d, J = 2.5 Hz, 1 H), 6.73 (dd, J = 2.5, 8.9,1 H), 4.04 (q, J = 7.0 Hz, 2H), 3.91 {s, 2 H), 2.97 (brs, 1H), 2.55 (s, 3 H), 1.41 (t, J = 7.0 Hz, 3 H).

Example 14

Cyclopropyl-{4-[2-(5-ethoxy-benzoimidazol-1-yi)-quinolin-8-yl]-benzyl}-amine.

1j The same procedure that used for Example 7 was followed with the exception that 4-ethoxy-2- nitroaniline was used in the place of 4-methoxy*2-nitroaniiine in example 1B to give thetitlecompound 14 as a yellow solid. C.l. m/z 435 [M+1]; 1H NMR (CDCl3) δ 8.57 (s, 1 H), 8.32 (d, J « 8.7 Hz, 1 H), 7.94 (d, J = 8.9Hz, 1 H), 7.83 (m, 1 H), 7.77 (m, 1 H), 7.65 (m, 3 H), 7.58 (m, 1 H), 7.45 (d, J = 8.1 Hz, 2 H), 1 2098 -58- 7.25 (m, 1 H), 6.76 (dd, J = 2.5, 9.1, 1 H), 4.06 (q, J = 7.0 Hz, 2 H), 3.97 (s, 2 H), 2.28 (m. 1H), 1.93 (brs, 1 H), 1.44 (t, J = 7.0 Hz, 3 H), 0.48 (m, 4 H).

Example 15 tert-Butyl-{4-[2-(5-ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-amine.

5 The same procedure that used for Example 8 was followed with the exception that 4-ethoxy-2-nitroaniline was used in the place of 4-methoxy-2-nitroaniline in example 1B to give thetitlecompound 15 as a yeliow solid. C.l. m/z 451 [M+1]; ’H NMR (CDCI3) δ 8.55 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 7.92 (d, J = 10.1Hz. 1 H), 7.79 (dd, J = 1.3,8.1 Hz, 1 H), 7.71 (d, J = 7.1 Hz, 1 H), 7.65 (m, 3 H), 7.55 (m, 1 H), 10 7.48 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 2.5 Hz, 1 H), 6.78 (dd, J = 2.5,8.9,1 H), 4.06 (q, J = 7.0

Hz, 2 H), 3.89 (s. 2 H), 1.43 (t, J « 7.0 Hz, 3 H), 1.28 (s, 9 H).

Example 16 {4-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinoiin-8-yl]-benzyl}-dimethyl-amine.

The same procedure that used for Example 6 was followed with the exception that 4-ethoxy-2-nitroaniline was used in the place of 4-methoxy-2-nitroaniline in example 1B to give the titlecompound 16 as a yeliow solid. C.l. m/z 423 [M+1]; Ή NMR (CDCI3) δ 8.57 (s, 1 H), 8.31 (d. J = 8.7 Hz, 1 H), 7.96 (d, J = 8.9Hz, 1 H), 7.80 (m, 1 H), 7.75 (m. 1 H), 7.64 (m, 3 H). 7.56 (m, 1 H), 7.42 (d, J = 7.9 Hz, 2 H), 15 1 2098 -59- 7.20 (d, J = 2.4 Hz, 1 H), 6.73 (dd, J = 2.4, 8.9,1 H), 4.06 (q, J = 7.0 Hz, 2 H), 3.55 (s, 2 H), 2.31 (s, 6 H), 1.41 (t, J = 7.0 Hz. 3 H).

Example 17 1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-qu‘nolin-8-yl]-piperidin-4-one.

5 The same procedure that used for Example 1 was followed with the exception that 4-piperdone was used in the place of piperidin-4-yl-carbamic acid tert-butyl ester in example 1Fto give the title compound 17 as a white solid. C.l. m/z 373 [M+1]; 1H NMR (CDCI3) δ 8.67 (s, 1 H), 8.35 (m, 2 H), 7.72 (d, J = 8.9 Hz, 1 H),

7.55 (dd, J = 1.3, 8.2,1 H), 7.50 (m, 1 H), 7.36 (d, J « 2.5 Hz, 1 H), 7.28 (m, 1 H), 7.04 (dd, J 0 = 2.5, 8.9 Hz, 1 H), 3.90 (s, 3 H), 3.71 (m, 4 H), 2.79 (m, 4 H).

Example 18 1 -[2-(5-Ethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-one.

The same procedure that was used for example 17 was followed except that 4-ethoxy-2-nitroaniline was used in the place of 4-methoxy-2-nitroaniline in example 1B to give the titlecompound 18 as a white solid. C.l. m/z 387 [M+1]; Ή NMR (CDCI3) δ 8.5? (s, 1 H), 8.30 (m, 2 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.50 (dd, J = 1.3, 8.1,1 H), 7.44 (m, 1 H), 7.30 (d, J = 2.3 Hz, 1 H), 7.23 (m, 1 H), 6.99 (dd, J= 2.5, 8.9 Hz, 1 H). 4.07 (q, J = 7.0 Hz, 2 H), 3.65 (m, 4 H), 2.74 (m, 4 H), 1.42 (t, J » 7.0 Hz, 3H). 15 X?., 1 2098

Example 19 1 -[2-(5-Ethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-ol.

1-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-pÎperidin-4-one 18 (140 mg, 0.36 mMol) wasdissolved in 1.5 mL of methanol under an atmosphère of dry N2. To this solution was added

9 sodium borohydride (NaBH4) (14 mg, 0.36 mMol) and the solution was stirred at ambienttempérature overnight The reaction mixture was then concentrated under vacuum andpartitioned between DCM and saturated aqueous NaHCO3. The OCM iayer was then washedwith brine, dried over Na2SO4, filtered and concentrated under vacuum to give a green foam.The foam was chromatographed on flash silica gel eluting with a gradient from MeOH/DCM 10 (1/99) to MeOH/DCM (4/96) to give the title compound 19 as a yellow foam. C.l. m/z 389 [M+1]; Ή NMR (COCI3) δ 8.65 (s, 1 H), 8.39 (d, J « 8.9 Hz, 1 H), 8.30 (d, J = 8.7Hz, 1 H). 7.68 (d, J = 8.9 Hz, 1 H), 7.47 (m, 2 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.25 (m, 1 H), 7.07(dd, J = 2.5,8.9 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.97 (m, 1 H), 3.75 (m, 2 H), 3.10 (m, 2 H), 2.10 (m, 2 H), 1.96 (m, 2 H), 1.46 (t, J = 7.0 Hz, 3 H). 15 Example 20

Cyciopropyl-{1*[2-(5-ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}~amine.

1-[2»(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperldin-4-one 18 (130 mg, 0.340 mMol)was dissolved in 1.5 mL of DCE under an atmosphère of dry N2. To this solution was addedcyclopropyl amine (110 pL, 1.70 mMol) and 200 pL of AcOH and the solution was stirred for 20 10 minutes. To this solution was added NaHB(OAc)3 (107 mg, 0.50 mMol) and the solution was stirred at ambient température for 5 hours. The reaction mixture was then partitionedbetween DCM and aqueous 0.1 N NaOH. The DCM Iayer was again washed with aqueous -61- 1 2098 0.1 N NaOH, dried over Na2SO4, filtered and concentrated under vacuum to give 150 mg of agreen foam. The foam was chromatographed on flash silica gel eluting with a gradient fromMeOH/DCM (2/99) to MeOH/DCM (4/96) to give the title compound 20 as a yellow solid. C.I. m/z 428 [M+1J; Ή NMR (CDCI3) δ 8.64 (s, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.75 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.32 (d, J - 2.5 Hz, 1 H), 7.25 (m, 1 H). 7.07 (dd. J = 2.5, 9.1 Hz, 1 H). 4.13 (q, J = 7.0 Hz, 2 H), 3.91 (m, 2 H), 2.90 (m, 3 H), 2.25 (m. 1 H), 2.16 (m, 2 H), 1.83 (m, 2 H), 1.46 (t, J = 7.0 Hz, 3 H), 0.43 (m, 2 H), 0.42 (m, 2 H).

Example 21 tert-Butyl-{1-(2-(5-ethoxy-benzoirnidazol-1-yl)~quinolin-8-yl]-piperidin-4-yl}-amine.

10 The same procedure that was used for example 20 was followed except tert-butylamine wasused in the place of cyclopropylamine to give the title compound 21 as a yellow solid. C.I. m/z 444 [M+1J; ’H NMR (CDCI3) δ 8.65 (s, 1 H), 8.35 (d, J = 8.9 Hz, 1 H), 8.28 (d. J « 8.9Hz. 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H). 7.32 (d, J = 2.5 Hz. 1 H), 7.24 (m, 1 H). 7.08(dd, J « 2.5, 8.91 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.90 (m, 2 H), 2.91 (m, 2 H), 2.79 (m. 1 15 H), 2.00 (m, 2 H), 1.88 (m, 2 H), 1.47 (t, J = 7.0 Hz, 3 H), 1.17 (s, 9 H).

Example 22 (1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yr|-piperidÎn-4-yl}-methyl-amine.

1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-ylî-piperidin-4-one 17 (200 mg, 0.540 mMol)was dissolved in 2 mL of MeOH under an atmosphère of dry N2. To this solution was added 20 1.34 mL of a 2.0 M solution of methylamine in methanol and AcOH was then added until the pH~5. To this solution was added 95% NaCNBH3 (93 mg, 0.540 mMol) and the reaction -62- 1 2098 mixture was stirred at ambient température for 4 hours. The reaction mixture was thenconcentrated under vacuum and subsequently partitioned between DCM and aqueous 0.1 NNaOH. The DCM layer was then washed again with aqueous 0.1 N NaOH, dried overNa2SO4, filtered and concentrated under vacuum to give a green foam. The foam waschromatographed on flash silice gel elutlng with a gradient from MeOH/DCM (5/95) toMeOH/DCM (10/90) to MeOH/DCM/NH4OH (10/89/1) give the title compound 22 as a greensolid. C.l. m/z 388 [M+1]; 1H NMR (CDCI3) δ 8.65 (s, 1 H). 8.38 (d. J « 8.9 Hz. 1 H), 8.29 (d. J = 8.7Hz. 1 H). 7.67 (d. J « 8.7 Hz. 1 H), 7.46 (m, 2 H), 7.33 (d. J = 2.3 Hz. 1 H). 7.25 (m, 1 H), 7.08(dd, J = 2.5, 8.9 Hz. 1 H), 3.93 (m, 2 H). 3.89 (s. 3 H), 2.90 (m, 2 H). 2.62 (m. 1 H). 2.51 (s. 3H). 2.14 (m. 2 H). 1.82 (m. 2 H). 1.75 (brs, 1 H).

Example 23 2-(5-Methoxy-benzoimidazol-1-yl)-8-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-quinoline.

Trimethyl sulfonium iodide (326 mg, 1.60 mMol) was dissolved in 6 mL of anhydrousdimethylsulfoxide (DMSO) under an atmosphère of dry N2. To this solution was added (67.7mg, 1.7 mMol) sodium hydride (60% in oil) and the reaction mixture was stirred for 10 minutesat ambient température. To this solution was added a solution of 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-one 17 (450 mg, 1.21 mMol) in 4 mL ofanhydrous DMSO and the réaction mixture was subsequently stirred ovemight at ambienttempérature. The reaction mixture was then partitioned between EtOAc and water. TheEtOAc layer was washed with 3 more times with water and then with brine. The EtOAc layerwas dried over Na2SO4, filtered and concentrated under vacuum to give a yellow foam as thetitle compound 23. C.l. m/z 387 [M+1]; 1H NMR (CDCI3) δ 8.64 (s, 1 H), 8.39 (d, J = 8.9 Hz, 1 H). 8.31 (d, J = 8.9Hz, 1 H), 7.68 (d, J = 8.7 Hz, 1 H), 7.48 (m, 2 H), 7.34 (d, J = 2.3 Hz. 1 H), 7.29 (m. 1 H), 7.06(dd, J = 2.5, 8.9 Hz, 1 H). 3.90 (s, 3 H), 3.68 (m, 2 H). 3.41 (m, 2 H), 2.78 (s, 2 H), 2.32 (m, 2H), 1.75 (m, 2 H). 1 2098 -63-

Example 24 4-Dimethylaminomethyl-1 -{2-(5-methoxy-benzoimidazol-1 -yl)-qt iinolin-8-yl] -piperidin-4-ol.

2-{5-Methoxy-benzoimidazol-1-yl)-8-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-quinoline 23 (250 mg,0.647 mMol) and 2 mL of 2.0 M dimethylamine in THF were suspended in 2 mL of methanol in 5 a pressure vial. The vial was capped, heated to 65°C and reacted at this température for 2hours. The reaction mixture was concentrated under vacuum to give a yellow solid. The solidwas chromatographed on flash siiica gel eluting with a gradient fforn MeOH/DCM (10/90) toMeOH/DCM/NH4OH (10/89/1) give 160 mg of the title compound 24 as a yellow solid. C.l. m/z 432 (M+1J; Ή NMR (CDCIa) 6 8.64 (s, 1 H). 8.39 (d, J = 8.9 Hz, 1 H), 8.29 (d, J = 8.7 w Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.33 (d, J = 2.5 Hz. 1 H). 7.30 (m, 1 H), 7.01(dd, J « 2.5,8.9 Hz, 1 H), 3.89 (s, 3 H), 3.68 (m, 2 H), 3.24 (m, 2 H), 2.42 (s, 8 H). 2.00 (m, 2H),1.90 (brs, 1 H), 1.79 (m. 2 H).

Example 25 1-(2-(5-Methoxy-benzoimidazol-1-y!)-quinolin-8-yl]-4-methylaminomethyl-piperidin-4-ol.

2 The same procedure that was used in example 24 was fotlowed except that 2.0 Mmethylamine in methanol was used in the place of 2.0 M dimethylamine in THF to give the titlecompound 25 C.l. m/z 418 [M+1J; 1H NMR (CDCIa) δ 8.65 (s, 1 H), 8.32 (m, 2 H), 7.67 (d, J - 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.29 (m, 1 H), 7.02 (dd, J = 2.5, 8.9 Hz, 1 H), 3.90 (s, 20 3 H), 3.70 (m, 2 H), 3.23 (m, 2 H), 2.65 (s, 2 H), 2.54 (s, 3 H), 2.04 (m, 2 H), 1.79 (m, 2 H).

Example 26 4-Aminomethyl-1-[2-{5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ol. 1 2098 -64-

The same procedure that was used in example 24 was followed except that ammoniumhydroxide was used in the place of 2.0 M dimethylamine in THF and the solvent was THFrather than methanol to give the title compound 26. C.l. m/z 404 [M+1]; Ή NMR (CDCI3) δ 8.65 (s, 1 H), 8.30 (m, 2 H), 7.66 (d, J « 8.9 Hz, 1 H),5 7.47 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.29 (m, 1 H). 7.01 (dd, J = 2.3, 8.9 Hz, 1 H), 3.89 (s, 3 H). 3.71 (m, 2 H), 3.23 (m, 2 H), 2.78 (s, 2 H), 1.96 (m, 2 H), 1.79 (m, 2 H).

Example 27 1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-pyrrolid in-3-ylamine.

The same procedure that was used in example 1 was followed except that (+/-)3-(t-jG butoxycarbonylamino)-pyrrolidine was used in the place on the piperidin-4-yl-carbamic acid tert-butyl ester in example 1F to give the title compound 27 as a yeliow solid. C.l. m/z 360 (M+1]; ’H NMR (CDCI3) δ 8.61 (s, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 8.9Hz, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.40 (m, 1 H), 7.33 (d, J = 2.3 Hz, 1 H). 7.19 (d, J - 8.5 Hz,1 H). 7.00 (dd, J = 2.5, 8.9 Hz, 1 H), 6.83 (d, J = 7.9 Hz, 1 H), 4.00 (m, 1 H), 3.90 (m, 1 H), φ 3.88 (s, 3 H), 3.75 (m, 2 H), 3.56 (m, 1 H), 2.24 (m, 1 H), 1.92 (brs, 2 H), 1.82 (m, 1 H).

Example 28 1 -(2-Benzoimidazol-1 -yl-quinolin-8-yl)-piperidin-4-ylamine. 1 2098 -65-

Example 28A 8-Benzyloxy-quinolin-2-ylamine. 2-Amino-8-hydroxyquinoline (20.0 g, 122 mMol) was dissolved in 50 mL of anhydrous DMFunder an atmosphère of dry N2. The reaction mixture was cooled to 0°C after which time (4.89 5 g, 122 mMol) sodium hydride (60% in oil) was slowly added and the reaction mixture wasstirred for 30 minutes. To this solution was added benzyl bromide (14.5 mL, 122 mMol) andthe reaction mixture was subsequently warmed to ambient température and stirred ovemight.The reaction mixture was then fiitered and the resulting solid was washed with Et2O and thendried under vacuum to give 29.4 g of the title compound 28A as a white solid.

10 Example 28B (8-Benzyloxy-quinolin-2-yl)-(2-nitro-phenyl)-amine. 8-Benzyioxy-quihoiin-2-ylamine 28A (3.50 g, 14.0 mMol) and 1-bromo-2-nitrobenzene (3.20 g, 15.4 mMol) were dissolved in 70 mL of dioxane under an atmosphère of dry N2. To thissolution was added CS2CO3 (18.3 g, 56.0 mMol), racemic-BINAP (1.00 g, 1.68 mMol) and 15 (513 mg, 0.560 mMol) tris(dibenzylideneacetone)dipalladium (0). The reaction mixture was heated to 100°C and reacted at this température ovemight. The mixture was then cooled toambient température, concentrated under vacuum, treated with DCM, fiitered andconcentrated under vacuum to give a red solid. The solid was chromatographed on flashsilica gel eluting with DCM to give 5.16 g of the title compound 28B as an orange solid.

20 Example 28C 2-(2-Amino-phenylamino)-quinolin-8-ol. (8-Benzyloxy-quinolin-2-yl)-(2-nitro-phenyl)-amine 28B (5.16 g, 13.9 mMol) was suspended in60 mL of EtOH under an atmosphère of dry N2. To this solution was added ammoniumformate (17.5 g, 278 mMol) and 550 mg of 20% palladium hydroxide on carbon. The réaction -66-

1 2 098 "I mixture was heated to 78°C and stirred at this température for 2 hours after which time it wascooied to ambient température and filtered through Celite™. The Celite™ was washed withéthanol, the filtrâtes were combined and concentrated under vacuum to give the îitlecompound 28C which was subsequently carried on crude to the next step.

5 Example 28D 1 -(2-Benzoimidazol-1-yl-quinolin-8-yl)-piperidin-4-ylamine.

The same procedure that was used in example 1 except that compound 2-(2-amino-phenylamino}-quinolin-8-ol 28C was used in the place of 2-(5-methoxy-benzoimdazol-1-yl)-quinolin-8-ol 1D in example 1E to give the title compound 28. 10 C.l. m/z 344 [M+1]; 1H NMR (CDCI3) δ 8.71 (s, 1 H), 8.43 (m, 1 H), 8.31 (d, J = 8.9 Hz, 1 H),7.89 (m, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.36-7.49 (m, 4 H), 7.24 (m, 1 H), 3.89 (m, 2 H). 2.90(m, 3 H), 2.04 (m, 2 H), 1.82 (m, 2 H), 1.28 (brs, 2 H).

Example 29 1-(2-lmidazo[4,5-b]pyridin-3-yl-quinolin-8-yl)-piperidin-4-ylamine.

15 The same procedure that was used in example 28 that 2-chloro-3-nitropyridine was used inthe place of 1-bromo-2-nitrobenzene in example 28B to give the title compound 29. C.l. m/z 345 [M+1]; 1H NMR (CDCI3) δ 9.36 (s, 1 H), 9.00 (d, J = 8.9 Hz, 1 H), 8.49 (dd, J = 1.4,4.7 Hz, 1 H), 8.34 (d, J = 8.9 Hz, 1 H), 8.15 (dd, J = 1.4, 8.1,1 H), 7.45 (m, 2 H), 7.33 (dd,J 4.8, 8.1 Hz, 1 H), 7.17 (dd, J = 1.7, 7.1 1 H), 3.93 (m, 2 H), 2.98 (m, 1 H), 2.91 (m, 2 H), 20 2.12 (m, 2 H), 1.98 (brs, 2 H), 1.88 (m, 2 H). .

Example 30 1-{2-[5-(4-Methoxy-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidtn-4-yiamine. 1 2098 -67-

Example 30A 4'-Methoxy-3-nitro-biphenyl-4-ylamine. Το a solution of 30 mL of water and 40 mL of dioxane were added 4-methoxyphenylboronicacid (1.69 g, 11.1 mMol), 4-bromo-2-nitroaniline (2.18 g, 10.0 mMol), $ tetrakis(triphenylphosphine)palladium (0) (580 mg, 0.502 mMol) and Na2CO3 (6.00 g, 56.6mMol) under an atmosphère of dry Nz. The reaction mixture was subsequently heated to80°C and stirred at this température overnight. The reaction mixture was then partitionedbetween DCM and water. The OCM iayer was then washed with brine, dried over Na2SO4,filtered and concentrated under vacuum. The resulting residue was chromatographed onflash siiica gel eluting with a gradient starting from DCM/hexanes (1 ; 1 ) to DCM to give 2.38 gof the title compound 30A.

Example 30B 1-{2-[5-(4-Methoxy-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

The same procedure that was used in example 1 was followed except that 4*-methoxy-3-nitro-biphenyl-4-ylamine was used in the place of 4-methoxy-2-nitroaniline in example 1B to givethe title compound 30. C.l. m/z 450 (M+1J; 1H NMR (CDCI3) δ 8.71 (s, 1 H), 8.43 (d, J = 8.7 Hz, 1 H), 8.28 (d, J = 8.7Hz, 1 H), 8.01 (d, J = 1.5 Hz, 1 H), 7.67 (d, J » 8.7 Hz, 1 H), 7.62 (m, 3 H), 7.45 (m, 2 H), 7.35(dd, J = 1.3, 5.8 Hz, 1 H), 6.99 (dd, J = 2.1,6.9 Hz, 2 H), 3.98 (m, 2 H), 3.83 (s, 3 H), 2.88 (m, 20 3 H), 2.04 (m, 2 H), 1.83 (m, 2 H), 1.77 (brs, 2 H).

Example 31 (442-[5-(4-Methoxy-phenyi)-benzoimidazol-1-yl]-quinoiin-8-yI}-benzyl)-methyl-amine. 1 2098 -68-

The same procedure that was used for example 5 was foliowed except that compound 4'-methoxy-3-nitro-biphenyl-4-ylamine 30A was used in the place of 4-methoxy-2-nitroaniline inexample 1B to give the title compound 31.

C.l. m/z 471 [M+1J; Ή NMR (CDCI3) δ 8.60 (s, 1 H), 8.27 (d, J = 8.9 Hz, 1 H), 8.02 (d, J = 8.75 Hz, 1 H), 7.91 (d, J = 1.5 Hz, 1 H), 7.76 (m, 2 H), 7.64 (m, 3 H), 7.47-7.57 (m, 5 H), 7.31 (dd, J = 1.7,8.5 Hz, 1 H), 6.96 (m, 2 H), 3.91 (s, 2 H), 3.82 (s, 3 H), 2.87 (brs, 1 H), 2.55 (s, 3 H).

Example 32 1-[2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine.

{1 -[2-(5-Hydroxy-benzoimidazol-1 -yl)-quinolin-8-yll-piperidin-4-yl}-carbamic acid tert-butyltO ester 3A (200 mg, 0.435 mMol) was dissolved in 1.5 mL of anhydrous DMF under anatmosphère of dry N2. To this solution was added Cs2CO3 (170 mg, 0.520 mMol) foliowed bycyclopropyl methane bromide (46 μΙ_, 0.48 mMol). The reaction mixture was subsequentiyheated to 65°C and stirred at this température for 4 hours. The reaction mixture was thencooled to ambient température and partitioned between EtOAc and water. The EtOAc layerwas washed 4 more times with water and then with brine. The EtOAc was then dried over

Na2SO4, fiitered and concentrated under vacuum and the resulting green oit was ! chromatographed on flash silica gel eluting with MeOH/DCM (2:98) to give the a green oii.The oil was dissolved in 1.5 mL of TFA undèr an atmosphère of dry N2. The reaction mixturewas stirred at ambient température for 10 minutes after which time it was concentrated under 20 vacuum and the resulting residue was partitioned between OCM and aqueous 0.1 N NaOH. 1 2098 -69-

The DCM layer was then washed with basic brine (pH = 10), dried over Na2SO4, filtered andconcentrated under vacuum to give 118 mg of the title compound as a yellow solid 32. C.l. m/z 414 [M+11; 1H NMR (CDCI3) δ 8.63 (s, 1 H), 8.37 (d. J = 8.9 Hz, 1 H), 8.27 (d, J = 8.7Hz, 1 H), 7.65 (d, J « 8.7 Hz, 1 H), 7.44 (m, 2 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.24 (m, 1 H), 7.09 5 (dd, J = 2.5, 8.9 Hz, 1 H), 3.87 (m, 4 H), 2.87 (m, 3 H), 2.03 (m, 2 H), 1.81 (m, 2 H), 1.56 (brs,2 H). 1.32 (m, 1 H), 0.66 (m, 2 H), 0.39 (m. 2 H).

Example 33 1-{2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

The same procedure that was used for example 1 was followed except that trifluoro-10 methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifiuoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)- quinolin-8-yl ester 1E in example 1F to give the title compound 33. C.l. m/z 418 [M+1]; ’H NMR (CDCI3) δ 8.65 (s. 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.7Hz, 1 H), 7.67 (d, J - 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.35 (d, 4 - 2.5 Hz, 1 H), 7.25 (m, 1 H), 7.13 15 (dd, J = 2.5, 8.7 Hz, 1 H), 4.22 (m, 2 H), 3.88 (m, 2 H), 3.81 (m, 2 H), 3.48 (s, 3 H). 2.89 (m, 3H), 2.05 (m, 2 H), 1.82 (m, 2 H), 1.57 (bre, 2 H).

Example 33A 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -y0-quinolin-8-yl}-piperidin-4-ylamine p-toluenesulphonate sait. 1 2 098 -70-

1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 (15.13 g, 36.2 mMoi) was dissolved in 93 mL of EtOH and the reaction was heated to reflux under anatmosphère of dry N2. To this solution was added p-toluenesulphonic acid mono hydrate(6.89 g, 36.2 mMol) which was then stirred at reflux ovemight. The reaction mixture was then 5 cooied to ambient température and filtered. The filtercake was washed with EtOH, driedunder vacuum to give 18.46 g of the title compound 33A as an off-white solid. ’H NMR (CD3OD) δ 8.93 (s, 1 H), 8.57 (d, J 9.1 Hz, 1 H), 8.40 (d, J = 8.7 Hz. 1 H), 7.89 (d, J= 8.7 Hz, 1 H), 7.68 (d, J = 6.2 Hz, 2 H), 7.58 (m, 1 H), 7.49 (m, 1 H), 7.33 (dd, J = 1.2,7.9 Hz,1 H), 7.25 (d, J = 2.5 Hz, 1 H), 7.17 (m, 3 H), 4.18 (m, 2 H), 3.93 (m, 2 H), 3.77 (m, 2 H), 3.43 10 (s, 3 H), 3.30 (m, 1 H), 2.86 (m, 2 H), 2.31 (s, 3 H). 2.16 (m, 2 H), 2.06 (m, 2 H).

Example 34 1-{2-[5-(Pyridin-3-ylmethoxy)-benzoimidazol-1-ylJ~quinolin-8-yl}-pÎperidin-4-ylamine.

The same procedure that was used for example 32 was followed except 3-picolyl chloridehydrochioride was used in the place of cyclopropyl methane bromide in example 32 and the 15 équivalents of Cs2CO3 was doubled to give the title compound 34. C.l. m/z 451[M+1]; 1H NMR (CDCI3) δ 8.73 (d, J = 2.3 Hz, 1 H). 8.65 (s, 1 H), 8.58 (dd, J = 1.4,5.0 Hz, 1 H), 8.42 (d, J = 8.9 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.82 (m, 1 H), 7.66 (d, J = 8.7 1 2098 -71-

Hz, 1 H), 7.46 (m, 2 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.31 (m, 1H), 7.26 (m, 1 H), 7.13 (m, 1 H), 5.17 (s, 2 H), 3.88 (m, 2 H), 2.91 (m, 3 H), 2.03 (m, 2 H), 1.80 (m, 2 H), 1.61 (brs, 2 H).

Example 35 1-[2-(5-Benzyloxy-benzoirnidazol-1-yl)-quinoliri-8-yl]-piperidin--4-ylarnine.

The same procedure that was used for example 32 was followed except benzyl bromide wasused in the place of cyclopropyl methane bromide to give the title compound 35. C.l. m/z 450[M+1J; ’H NMR (CDCI3) δ 8.65 (s, 1 H), 8.42 (d, J = 8.9 Hz, 1 H), 8.30 (d, J = 8.7Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.37-7.51 (m 7 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.26 (m, 1 H), 7.18 (dd, J = 2.5, 8.9 Hz, 1 H), 5.16 (s, 2 H), 3.88 (m, 2 H), 2.90 (m, 3 H), 2.04 (m, 2 H), 1.81 10 (m, 2 H), 1.40 (brs, 2 H).

Example 36 1-{2-[5-(Pyridin-4-ylmethoxy)-benzoimidazol-1-yl]-quÎnolin-8-yl}-piperidin-4-ylamine.

The same procedure that was used for example 32 was followed except the hydrochloride saitof 4-picofyl chloride was used h the place of cyclopropyl methane bromide and the number of 15 équivalents of Cs2CO3 was doubled to give the title compound 36. C.l. m/z 451 [M+1]; 1H NMR (CDCI3) δ 8.65 (s, 1 H), 8.63 (m, 2 H), 8.44 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 8.9 Hz, 1 H), 7.68 (d, J = 8.7 Hz, 1 H), 7.47 (m, 2 H), 7.41 (d, J = 6.0 Hz, 2 H), 1 2 098 7.37 (d, J = 2.3 Hz, 1 H), 7.26 (m, 1 H), 7.16 (dd, J = 2.3, 9.1 Hz, 1 H), 5.19 (s, 2 H), 3.90 (rn, 2 H), 2.90 (m, 3 H), 2.05 (m, 2 H), 1.80 (m, 2 H), 1.55 (brs, 2 H).

Example 37 1-{2-[5-(2-Dimethylamino-ethoxy)-benzoimÎdazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

The same procedure that was used for example 32 was followed except that the hydrochloridesait of 2-dimethylamino ethyl chloride was used in the place of cyclopropyl methane bromideand the number of équivalents of Cs2CO3 was doubled to give the title compound 37. C.I. m/z431 [M+1]; 1H NMR (CDCI3) δ 8.61 (s, 1 H), 8.45 (d, J = 8.9 Hz, 1 H), 8.27 (d, J = 8.7Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.44 (m, 2 H), 7.31 (m, 1 H), 7.24 (m, 1 H), 7.12 (m, 1 H), 4.12 (m, 2 H), 3.72-3.88 (m, 4 H), 2.90 (m, 3 H), 1.78-2.10 (m, 12 H).

Example 38 1-{2-[5-(3-Amino-propoxy)-benzoîmidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

Example 38A

[1 -(2-{5~(3-( 1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-benzoimidazol-1 -yl}-quinolin-8-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester. 15 -73- 1 2098

The same procedure that was used for example 32 was followed except N-(3-bromopropyl)-pthalimide was used in the place of cyclopropyl methane bromide and, îhe tert-butylcarbamate ester intermediate was not subjected to TFA mediated cleavage, fo give the titlecompound 38A as a yellow solid.

5 Example 38B ( 1 -{2-[5-(3-Amino-propoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-pipendin-4-yl)-carbamic acidtert-butyl ester.

[1 ~{2-{5-[3-( 1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-benzoimidazol-1 -yl}-quinolin-8-yl)-piperidin-4-yl]-carbamic acid tert*butyi ester 38A (200 mg, 0.31 mMol) was dissolved in 1 mL 10 of EtOH under an atmosphère of dry N2. To this solution was added 50 pL of hydrazine andthe resulting solution was stirred at ambrent température for 3 hours. The reaction mixturewas then filtered, concentrated under vacuum and purified via silica gel chromatographyeluting with DCM/MeOH/NH4OH (89/10/1) to give 120 mg of the title compound 38B as ayellow film.

15 Example 38C 1-{2-[5-(3-Amino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-pipendin-4-ylamine. (1-{2-[5-(3-Amino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acidtert-butyl ester 38B (175mg, 0.42 mMol) was dissolved in a solution of 0.5 mL of TFA and 0.5mL of DCM under an atmosphère of dry N2 and was stirred at ambient température for 1 hour. 20 The reaction mixture was then concentrated under vacuum and subsequently partitioned between DCM and aqueous 1 N NaOH. The DCM layer was then dried over MgSO4, filteredand concentrated to give the title compound 38 as a light green solid. C.l. m/z 417 [M+1]; 1H NMR (CDCI3) δ 8.63 (s, 1 H), 8.36 (d, J = 8.7 Hz, 1 H), 8.26 (d, J = 8.7Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H). 7.44 (m, 2 H), 7.31 (d, J = 2.5 Hz, 1 H), 7.23 (m, 1 H), 7.04 25 (m, 1 H), 4.12 (t, J = 6.2 Hz, 2 H), 3.87 (m, 2 H), 2.89 (m, 3 H), 2.03 (m, 2 H), 1.94 (m, 2 H), 1.77 (m, 2 H), 1.54 (brs, 4 H).

Example 39 1-{2-[5-(3-Dimethylamino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine. 1 2098 ts

(1 -{2-[5-(3-Amino-propoxy)-benzoimidazol-1 -yi]-quinolin-8-yl}-pipendin-4-yl)-carbamic acidtert-butyl ester 38B (120 mg, 0.288 mMol) was dissolved in a cooled (0°C) solution of 1 ml» ofacetonitrile (ACN) and 0.5 mL of formaldéhyde (37% wt in water) under an atmosphère of dryN2. To this solution was added NaCNBH3 (72 mg, 1.2 mMol) and the solution was stirred for30 minutes after which time 200 pL of AcOH was added. The reaction mixture wassubsequently warmed to ambient température and stirred ovemight. The reaction mixturewas then concentrated under vacuum and partitioned between aqueous 0.1 N NaOH andDCM. The aqueous layer was washed 3 more times with DCM. The DCM extracts werecombined, dried over Na2SO4, filtered and concentrated under vacuum to give a green film.The film was purified using flash silica gel chromatography eluting with DCM/MeOH/NH4OH(89.9/10/0.1) to give 70 mg of the tert-butylcarbonyl protected product. This residue wasdissolved in a solution of 1 mL of TFA and 1 mL of DCM under an atmosphère of dry N2. Thereaction mixture was stirred for 1 hour after which time it was concentrated under vacuum,partitioned bewteen DCM and aqueous 1 N NaOH. The aqueous layer was washed 2 moretimes with DCM. The DCM extracts were combined and dried over Na2SO4, filtered andconcentrated under vacuum to give a yellow film. The film was purified using flash silica gelchromatography eluting with DCM/MeOH/NH4OH (84.9/15/0.1) to give 30 mg of the titlecompound 39 as a yellow film. C.l. m/z 445 [M+1J; ’H NMR (CD3OD) δ 8.87 (s, 1 H), 8.58 (d, J « 8.8 Hz, 1 H), 8.31 (dd, J =2.0, 8.7 Hz, 1 H), 7.80 (dd J « 2.0, 8.7 Hz, 1 H), 7.48 (m, 1 H), 7.43 (m, 1 H), 7.25 (m, 1 H), 7.17 (d, J = 2.1 Hz, 1 H), 7.10 (m, 1 H). 4.02 (m, 2 H), 3.78 (m, 2 H), 2.71-2.84 (m. 3 H), 2.53(m, 2 H), 2.27 (s, 6 H), 2.03 (m, 2 H). 1.99 (m, 4 H), 1.79 (m, 2 H).

Example 40 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperîdine-4-carboxylic acid ethyl ester. 20 1 2098 -75-

The same procedure that was used in example 1 was followed except that ethyl isonipecotatewas used in die place on the piperidin-4-yl-carbamic acid tert-butyl ester in exampie 1F togive the titie compound 40 as a yellow solid. C.l. m/z 431 (M+1]; 1H NMR (CDCI3) δ 8.64 (s, 1 H), 8.40 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.9Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.44 (m, 2 H), 7.33 (m, 1 H), 7.23 (m, 1 H), 7.08 (dd, J =2.5, 8.9 Hz, 1 H), 4.18 <q, J « 7.5,2 H), 3.89 (s, 3 H), 3.85 (m, 2 H), 2.90 (m, 2 H), 2.52 (m, 1H), 2.14 (m, 4 H), 1.29 (t, J = 7.5 Hz, 3 H).

Example 41 1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidine-4-carboxylic acid.

10 15 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinoiin-8-yl]-pipehdine-4-carboxyiic acid ethyl ester 40(28 mg, 0.065 mMol) was dissolved in 1 mL of éthanol (EtOH). To this solution was added 1mL of 1 N aqueous NaOH and the mixture was subsequently heated to 60°C and reacted atthis température ovemight. The reaction mixture was then cooled to ambient température andpartitioned between 10% aqueous citric acid and ethyl acetate. The organic layer waswashed again with 10% aqueous citric acid then three more times with water. The ethylacetate layer was dried over Na2SO4, fîltered and concentrated to give 7 mg of the titiecompound 41 as a yellow solid. C.l. m/z 403(M+1]; 1H NMR (CD3OD) δ 8.94 (s, 1 H), 8.73 (d, J = 9.2 Hz. 1 H), 8.40 (d, J = 8.9Hz, 1 H), 7.90 (d, J = 8.9 Hz, 1 H). 7.55 (m, 1 H), 7.47 (m, 1 H), 7.31 (m, 1 H), 7.23 (d, J = 2.3Hz, 1 H), 7.07 (dd. J = 2.4, 9.0 Hz, 1 H). 3.87 (s, 3 H), 3.79 (m, 2 H), 2.85 (m, 2 H), 2.50 (m, 1H), 2.08 (m, 4 H). 20 -76- 1 2 098

Example 42 4-Dimethylaminomethyl-1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ol.

Example 42A 5-(2-Methoxy-ethoxy)-2-nitro-phenylamine. 5 4-Amino-3-nitrophenol (58.53 g, 379.7 mMol) was dissolved in 600 mL of anhydrous DMFunder an atmosphère of dry Nz and the solution was mechanically stirred. The reactionmixture was then cooled to 0°C and to this mixture was added Cs2CO3 (177.4 g, 455.7 mMol),sodium iodide (5.7 g, 37.9 mMol) and 2-bromoethyl methyl ether (39.3 mL, 417.7 mMol). Afterstirring for 15 minutes, the reaction mixture was then warmed up to ambient température and 10 then stirred overnight. The reaction mixture is then poured into 6 L of water. The precipitatewas collected via suction filtration. The wet precipitate was taken up in toluene and thenconcentrated under vacuum to remove the water. Finally, the soiid was recrystallized from 2-propanol to give 57.93 g of 5-(2-Methoxy-ethoxy)-2-nitro-phenylamine 42A as an orange soiid.A second crop of 12.5 g of compound 42A was also obtained.

15 Exemple 42B 4-Dimethylaminomethyl-1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ol.

The same procedure that was used in example 24 was followed except that 5-(2-Metho>y-ethoxy)-2-nitro-phenylamine 42A was used in the place of 4-methoxy-2-nîtroaniline inexample 1B to give the tille compound 42 as a yeliow soiid. 20 C.l. m/z 476 [M+1 ]; 1H NMR (CD3OD) δ 8.85 (s. 1 H), 8.55 (d, J = 9.1 Hz, 1 H), 8.29 (d, J = 8.7Hz, 1 H), 7.76 (d, J « 8.7 Hz, 1 H), 7.43 (m, 2 H), 7.27 (d, J = 7.5 Hz, 1 H), 7.21 (d, J = 2.5 Hz,1 H). 7.00 (dd, J = 2.5, 9.0 Hz, 1 H), 4.13 (m, 2 H), 3.77 (m, 2 H), 3.44 (s, 3 H), 3.32 (m, 2 H), 3.16 (m, 2 H), 2.42 (s, 2 H), 2.38 (s, 6 H), 1.97 (m, 2 H),1.75 (m, 2 H).

Example 43 1 2098 -77- N41-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-acetamide.

1-(2-(5-Methoxy-benzoimidazol-1-yl)-quinoIin-8-yl]-piperidin-4-ylamine 1 (100 mg, 0.268mMol) and sodium cyanate (35 mg, 0.536 mMol) were dissoived in 1 mL of AcOH under anatmosphère of dry N2. . The reaction mixture was stirred overnight at ambient température. 5 The reaction mixture was then concentrated under vacuum and partitioned between DCM andsaturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered andconcentrated to a yellow foam which was chromatographed on flash silica gei eiuting withMeOH/NH4OH/DCM (2/0.2/97.8) to give the title compound 43. C.l. m/z 416 [M+1J; ’H NMR (CDCI3) δ 8.63 (s, 1 H), 8.30 (m, 2 H), 7.66 (d, J = 8.7 Hz, 1 H), 1Ô 7.43 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.23 (dd, J « 1.7, 7.1 Hz, 1 H). 7.03 (dd, J « 2.5, 9.0Hz, 1 H), 5.64 (brd, J = 8.3 Hz, 1 H), 4.03 (m, 1 H), 3.89 (s, 3 H), 3.84 (m, 2 H), 2.93 (m, 2 H), 2.16 (m, 2 H), 2.02 (s, 3 H), 1.88 (m, 2 H).

Example 44 N-{1-[2-{5-CyClopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-acetamide.

The procedure used in example 43 was foiiowed except that 1-|2-(5-cyelopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine 32 was used in the place of 1-(2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine 1 to give the title compound 44as a yellow solid. C.l. m/z 456 (M+1); 1H NMR (CDCI3) δ 8.61 (s, 1 H), 8.33 (d, J * 8.7 Hz, 1 H), 828 (d, J = 8.720 Hz, 1 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.28 (d, J = 2.1 Hz, 1 H), 7.22 (m, 1 H), 7.07 (dd, J = 1.5,8.7 Hz, 1 H), 5.63 (brd, J « 8.3 Hz, 1 H), 4.03 (m, 1 H), 3.88 (d, J = 7.0 Hz, 2 H), -78- 1 2098 3.85 (m, 2 H), 2.92 (m, 2 H), 2.14 (m, 2 H), 2.04 (s, 3 H), 1.88 (m, 2 H), 1.33 (m, 1 H), 0.67 (m,2 H), 0.38 (m, 2 H).

Example 45 1-{2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ol.

5 The same procedure that was used for example 19 was followed except that 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A was used in the place of was used in the place of 4-methoxy-2-nitroaniline nitroaniline in example 1B to give the title compound 45 as a yellowsolid. C.l. m/z 419 [M+1J; Ή NMR (CDCI3) δ 8.62 (s, 1 H), 8.39 (d, J = 9.1 Hz, 1 H), 8.24 (d, J = 8.7 10 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.43 (m, 2 H), 7.31 (d, J = 2.1 Hz, 1 H), 7.23 (m. 1 H), 7.10(m, 1 H), 4.17 (m, 2 H), 3.93 (m, 1 H), 3.77 (m, 2 H), 3.71 (m. 2 H), 3.44 (s, 3 H), 3.04 (m, 2H), 2.47 (brd, J « 3.3 Hz, 1 H), 2.14 (m, 2 H), 1.97 (m, 2 H).

Example 46 {1 -(2-(5-Methoxy-benzoimidazoi-1 -yl>-quinolin-8-yl]-piperidin-4-yl}-urea.

12 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine 1 (150 mg, 0.402mMol) and 1,1'-carbonyldiimidazole (78 mg, 0.48 mMol) were dissolved in 1 mL of anhydrousTHF under an atmosphère of dry Nz. The reaction mixture was stirred for 2 hours at ambienttempérature. 1.0 mL of concentrated ammonium hydroxide (NH4OH) was then added to thereaction mixture that was then stirred ovemight. The reaction mixture was then partitioned _ between DCM and water. The DCM layer was dried over Na2SO4, filtered and concentrated -79- 1 2 098 under vacuum. The residue was chromatographed over flash silica gel eluting withMeOH/DCM (5/95) to give 15 mg of the title compound 46 as a white solid. C.l. m/z 417 [M+1]; 1H NMR (CD3OD) δ 8.89 (s, 1 H), 8.59 (d, J = 8.9 Hz, 1 H), 8.36 (J = 8.9Hz, 2 H), 7.85 (d, J = 8.7 Hz, 1 H), 7.74 (brs, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.45 (m, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.23 (m, 1 H), 7.05 (m, 1 H), 3.86 (s, 3 H), 3.73 (m, 2 H), 3.66 (m, 1H), 2.87 (m, 2 H), 2.08 (m, 2 H), 1.83 (m, 2 H).

Example 47 4-Aminomethyl-1-{2-[5-(pyndin-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ol.

Example 47A 2-Nitro-4-(pyridin-2-ylmethoxy)-phenylamine. 4-Amino-3-nitrophenol (5.00 g, 32.4 mMol), Cs2CO3 (22.8 g, 70 mMol), sodium iodide (476mg, 3.20 mMol) and 2-picolyi chloride hydrochloride (11.2 g, 35 mMol) were added to 20 mLof anhydrous DMF under an atmosphère of dry N2. The reaction mixture was stirred ovemightat ambient température. The reaction mixture is then poured into water. The precipitate wascoliected via suction filtration. The precipitate was partitioned between DCM and 1.0 Naqueous NaOH. The organic layer was washed 2 more times with 1 N aqueous NaOH toremove any unreacted phénol. The organic layer was then washed with brine, dried overNa2SO4, filtered and concentrated under vacuum to give 7.7 g of a dark red solid. The solidwas chromatographed on flash silica gel eluting with EtOAc/DCM (20/80) to give 3.7 g of thetitle compound 47A as an orange solid.

Example 47B 4-Aminomethyl-1-{2-[5-(pyridin-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ol.

The same procedure that was used in example 26 was followed except that 2-nitro-4-(pyridin- 2-ylmethoxy)-phenylamine 47A was used in the place of 4-methoxy-2-nitroani,ine in example1B to give the title compound 47. -80- 1 2098 C.I. m/z 481 [M+1]; Ή NMR (CDCIj) δ 8.64 (s, 1 H), 8.60 (dd, J = 0.8, 5.0 Hz, 1 H), 8.31 (d. J= 9.1 Hz, 1 H), 8.27 (d. J = 8.7 Hz, 1 H), 7.68 (m. 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.55 (d, J =7.9 Hz, 1 H), 7.44 (m, 2 H), 7.38 (d, J = 2.1 Hz, 1 H), 7.27 (m, 1 H), 7.24 (m, 1 H), 7.12 (m, 1H), 5.27 (s, 2 H), 3.67 (m, 2 H), 3.22 (m, 2 H), 2.78 (s, 2 H), 2.40 (brs, 3 H), 1.96 (m, 2 II), 1.81 (m,2H).

Example 48

Cyclopropyl-( 1 -{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin~4-yl)-amine.

The same procedure that was used in example 20 was followed except that 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A was used in the place of 4-methoxy-2-nitroaniline inexample 1B to give the title compound 48 as a yellow solid. C.I. m/z 458 [M+11; ’H NMR (CDCi3) δ 8.65 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.28 (d, J = 8.7Hz. 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.35 (d, J = 2.5 Hz, 1 H), 7.25 (m, 1 H), 7.15(m, 1 H), 4.22 (m, 2 H), 3.82 (m, 2 H), 3.80 (m, 2 H), 3.47 (s. 3 H). 2.88 (m, 3 H), 2.27 (m, 1 15 H), 2.18 (m, 2 H), 1.85 (m, 2 H), 0.50 (m, 2 H), 0.47 (m, 2 H).

Example 49 (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-dimethyl-amine.

The same procedure that was used in example 4 was followed except that 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A was used in the place of 4-methoxy-2-nitroaniline in 20 example 1B to give the title compound 49. 1 2098 -81- C.l. m/z 446 [M+1]; 1H NMR (CDCI3) δ 8.59 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.18 (d, J = 8.7Hz, 1 H). 7.57 (d, J = 8.7 Hz, 1 H), 7.38 (m, 2 H), 7.28 (d, J = 2.5 Hz, 1 H), 7.15 (d, J = 2.5, 6.2Hz, 1 H), 7.06 (m, 1 H), 4.18 (m, 2 H), 3.94 (m, 2 H), 3.75 (m, 2 H), 3.42 (s, 3 H), 2.72 (m. 2H), 2.40 (m. 1 H), 2.34 (s. 6 H), 1.95 (m. 4 H). 5 Example 50 ( 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yQ-quinolin-8-yl}-piperidin-4-yl)-methyl-amine.

The same procedure that was used in example 22 was followed except that 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A was used in the place of 4-methoxy-2-nitroaniline inexample 1B to give the title compound 50. |0 C.l. m/z 432 [M+1]; 1H NMR (CDCI3) δ 8.62 (s, 1 H), 8.37 (d, J = 9.1 Hz, 1 H), 8.23 (d, J = 8.7Hz, 1 H), 7.61 (d, J = 8.7 Hz, 1 H), 7.42 (m, 2 H), 7.31 (d, J = 2.1 Hz, 1 H), 7.20 (d, J = 3.0, 5.8Hz, 1 H), 7.11 (dd, J - 2.5,9.1 Hz, 1 H), 4.18 (m, 2 H), 3.88 (m, 2 H), 3.76 (m, 2 H), 3.45 (s. 3H), 2.85 (m, 2 H), 2.59 (m, 1 H), 2.47 (s, 3 H), 2.18 (brs, 1 H), 2.11 (m. 2 H), 1.75 (m, 2 H).

Example 51 (1-{2-[5-(3-Dimethylamino-propoxy)-benzoimidazoi-1~yl]-quinolin-8-yl}-piperidin-4-yl)-dimethyl- amine.

The same procedure that was used in example 4 was followed except that 1-{2-[5-(3-dimethylamino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylarnine 39 was used inthe place of 1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-pipendin-4-ylamine 1 to givethe title compound 51. -82- 1 2 098 C.l. m/z 473 [M+1]; ’H NMR (CD3OD) δ 8.87 (s, 1 H), 8.61 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 8.7Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.48 (d, J = 6.4 Hz, 1 H), 7.42 (m, 1 H), 7.21 (m, 2 H), 7.05(m, 1 H), 4.05 (m, 2 H), 3.82 (m, 2 H), 3.19 (m, 1 H), 2.65 (m, 5 H). 2.40 (m, 1 H), 2.34 {s, 6H), 1.95 (m, 4 H). 5 Example 52 {1-[2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yi]-piperidin-4-yl}-methyl-amine.

Example 52A 4-Cyclopropylmethoxy-2-nitro-phenylamine. 4-Amino-3-nitrophenol (13.3 g, 84.8 mMol), Cs2CO3 (33.2 g, 102 mMol) and cyclopropylmethylbromide (9.1 mL, 93.3 mMol) were added to 30 mL of anhydrous DMF under an atmosphèreof dry N2. The reaction mixture was stirred ovemight at ambient température. The reactionmixture is then poured into water. The precipitate was collected via suction filtration. Theprecipitate was partitioned between DCM and 1.0 N aqueous NaOH. The organic layer waswashed 2 more times with 1 N aqueous NaOH to remove any unreacted phénol. The organic ^5 layer was then washed with brine, dried over Na2SO4, filtered and concentrated under vacuumto give 18.6 g of the title compound 52A as an orange solid.

Example 52B {1-[2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-methyl-amine.

The same procedure that was used in example 22 was followed except that 4-cyclopropylmethoxy-2-nitro-phenylamine 52A was used in the place of 4-methoxy-2-nitroaniiine in example 1B to give the title compound 52. C.l. m/z 428 [M+1]; ’H NMR (CDCI3) δ 8.63 (s, 1 H), 8.38 (d, J = 9.1 Hz, 1 H). 8.28 (d, J = 8.7Hz, 1 H), 7.65 (d, J « 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.24 (m, 1 H), 7.06 1 2098 -83- (m, 1 H). 3.89 (m, 4 H). 2.90 (m, 2 H), 2.71 (m, 1 H), 2.S5 (s, 3 H), 2.16 (m, 2 H). 2.00 (brs, 1H), 1.89 (m, 2 H), 1.30 (m. 1 H), 0.64 (m, 2 H), 0.38 (m, 2 H).

Example 53 (1-I2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-ylJ-piperÎdin-4-yl}-d<niethyl-amine.

5 The same procedure that was used in example 4 was followed except that {1-[2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinoiin-8-yl]-piperidin-4-yl}-methyl-amine 52 wasused in the place of 1-|2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yIamine 1to give the title compound 53. C.l. m/z 442 [M+1]; 1H NMR (CDCI3) δ 8.65 (s, 1 H), 8.38 (d, J = 9.0 Hz. 1 H), 8.30 (d. J = 9.0tO Hz. 1 H). 7.69 (d. J » 8.7 Hz, 1 H), 7.48 (m, 2 H), 7.31 (d. J = 2.3 Hz. 1 H). 7.24 (m, 1 H). 7.09 (d. J = 2.3,9.0 Hz. 1 H). 4.03 (m, 2 H). 3.89 (d. J = 6.8 Hz, 2 H). 2.83 (m. 2 H), 2.55 (m, 1 H), 2.44 (s, 6 H), 2.06 (m, 4 H). 1.30 (m, 1 H), 0.68 (m, 2 H). 0.39 (m. 2 H).

Example 54 2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoÎmÎdazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-te acetamide.

N-(tert-butoxycarbonyl)glycine (105 mg, 0.600 mMol) was dissolved in 3 mL of DCM under anatmosphère of dry N2. To this mixture was added 1,1’-carbonyldiimidazole (100 mg, 0.61mMol) and the réaction mixture was stirred at ambient température for 30 minutes. To thissolution was then added 4-dimethyIaminopyridine (8.0 mg, 0.065 mMol) and 1-(2-(5-(2- 20 methoxy-ethoxy)-benzoimidazol-1-yl)-quinolin-8-yl}-piperidin-4-ylamine 33 (170 mg, 0.408 1 2098 -84- mMol). The reaction mixture was subsequently stirred ovemight at ambient température. Thereaction mixture was then partitioned between DCM and saturated aqueous NaHCO3. Theorganic iayer was saved and washed again with saturated aqueous NaHCO3, dried overNa2SO4, fiitered and concentrated under vacuum to give a yellow foam. The residue was 5 chromatographed on flash silica gei eluting with MeOH/DCM (3/97) to give 182 mg of a yeliowresidue. The residue was dissolved in 0.5 ml of TFA and stirred at ambient température for30 minutes under an atmosphère of dry N2. The reaction mixture was subsequentlyconcentrated under vacuum and then partitioned between 0.1 N aqueous NaOH. The organiciayer was saved and washed again with 0.1 N aqueous NaOH, dried over Na2SO4, fiitered andconcentrated under vacuum to give a yellow foam. The foam was chromatographed on flashsilica gel eiuting with MeOH/DCM (5/95) to give 75 mg of the title compound as 54 a yellowsolid. C.l. m/z 475 ÎM+11; Ή NMR (CDCI3) δ 8.62 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 8.27 (d, J = 8.7Hz, 1 H), 7.64 (d, J = 8.7 Hz. 1 H), 7.44 (m, 2 H), 7.38 (brd, J = 7.9 Hz, 1 H), 7.32 (d, J = 2.1 15 Hz, 1 H), 7.22 (m, 1 H), 7.06 (d, J * 2.5, 92 Hz, 1 H), 4.20 (m, 2 H), 4.02 (m, 1 H), 3.86 (m, 2H), 3.78 (m, 2 H), 3.46 (s, 3 H), 3.37 (s, 2 H), 2.94 (m, 2 H), 2.13 (m, 2 H), 1.90 (m, 2 H), 1.74(brs, 2 H).

Example 55 -(S)-2-Amino-N-( 1 -{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-yl)-

The same procedure that was used in example 54 was followed except that N-(tert-butoxycarbonyl)-L-alanine was used in the place of N-(tert-butoxycarbonÿl)glycine to give thetitle compound 55 as a yellow solid. C.l. m/z 489 (M+1J; Ή NMR (CDCI3) δ 8.61 (s, 1 H), 8.27 (d, J - 8.7 Hz, 1 H), 8.25 (d, J = 9.125 Hz, 1 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.42 (m, 3 H), 7.30 (d, J « 2.5 Hz, 1 H), 7.22 (dd, J = 2.1, 8.7 Hz, 1 H), 7.07(d, J = 2.5,8.7 Hz, 1 H), 4.17 (m, 2 H), 3.95 (m, 1 H), 3.85 (m, 2 H), 3.77 (m,2 H), 3.50 (m, 1 H), 3.43 (s, 3 H), 2.91 (m, 2 H), 2.10 (m, 2 H), 1.85 (m, 4 H). 1.34 (d, J = 6.7Hz, 3 H). 1 2098 -85-

Example 56 -<R}-2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-piperidin-4-yl)-

The same procedure that was used in example 54 was followed except that N-(tert-5 butoxycarbonyl>D-alanine was used in the place of N-(tert-butoxycarbonyl)glycine to give the titie compound 56 as a yeilow solid. C.l. m/z 489 [M+1]; Ή NMR (CDCI3) δ 8.63 (s, 1 H), 8.26 (m, 2 H), 7.65 (d, J = 8.7 Hz, 1 H),f 7.44 (m, 2 H), 7.38 (brd, J = 8.7 Hz, 1 H), 7.33 (d, J - 2.5 Hz, 1 H), 7.22 (dd, J = 2.1,7.0 Hz, 1 H), 7.10 (d, J = 2.5, 8.7 Hz, 1 H), 4.20 (m, 2 H), 3.99 (m, 1 H), 3.86 (m, 2 H), 3.79 (m, 2 H),10 3.50 (m, 1 H), 3.46 (s, 3 H), 2.96 (m, 2 H), 2.12 (m, 2 H), 1.88 (m, 2 H), 1.52 (brs, 2 H), 1.35 (d, J = 7.1 Hz, 3 H).

Example 57 ( .v 2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-

15 N-(tert-butoxycarbonyl)glycine (73 mg, 0.36 mMol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mMol) were dissolved in 1 mL of anhydrousDMF under an atmosphère of dry N2 and stirred at ambient température for 30 minutes.Triethylamine (167 pL, 1.24 mMol) and 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-piperidin-4-ylamine 33 (146 mg, 0.35 mMol) were then added to the reaction 20 mixture which was subsequently stirred ovemight. The réaction mixture was then partitioned -86- 1 2098 between DCM and saturated aqueous NaHCO3. The organic layer was saved and washedtwo more times with saturated aqueous NaHCO3, dried over Na2SO4, filtered andconcentrated under vacuum to give a yellow oil. The residue was chromatographed on flashsilica gel eluting with a gradient of DCM to MeOH/DCM (2/98) to give 30 rng of a yellow 5 residue. The residue was dissclved in 0.25 ml of TFA and stirred at ambient température for30 minutes under an atmosphère of dry N2. The reaction mixture was subsequentlyconcentrated under vacuum and then partitioned between 0.1 N aqueous NaOH. The organiclayer was saved and washed again with 0.1 N aqueous NaOH, dried over Na2SO4, filtered andconcentrated under vacuum to give the title compound 57 as a yellow residue. C.l. m/z 503 [M+1]; ’H NMR (CDCI3) δ 8.70 (s, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 8.21 (d. J = 9.1Hz, 1 H), 7.66 (m, 2 H), 7.44 (m, 2 H), 7.25 (d. J = 2.5 Hz, 1 H), 7.21 (dd, J = 2.6, 9.1 Hz, 1 H), 7.12 (m, 1 H), 4.19 (m, 2 H), 3.95 (m, 1 H), 3.88 (m, 2 H), 3.79 (m, 2 H), 3.46 (s, 3 H), 2.93 (m,2 H), 2.09 (m, 2 H), 1.90 (m, 2 H), 1.49 (s, 6 H).

Example 58 1-(1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quîr.olin-8-yl}-piperidin-4-ylamino)-2-methyl-propan-2-ol.

Example 58A (1 -{2-i5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamino)-acetic acidethyl ester. 2Q Bromo-acetic acid ethyl ester (80 pL, 0.710 mMol). diisopropylethylamine (180 pL, 1.00 mMol)and 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinol»n-8-yl}-piperidin-4-ylamine 33 (270mg, 0.647 mMol) were dissolved in 3 mL of anhydrous DCM under an atmosphère of dry N2and stirred ovemight at ambient température. The reaction mixture was then partitionedbetween DCM and 0.1 N aqueous NaOH. The organic layer was saved and washed 22 sequentiaily with 0.1 N aqueous NaOH and brine, dried over Na2SO4, filtered and -87- 1 2098 concentrated under vacuum to give a yellow residue. The residue was chromatographed onflash silica gel eluting with MeOH/DCM (2/98) to give 220 mg of the title compound 58A.

Example 58B 1 -( 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl)-piperidin-4-ylamino)-2-y methyl-propan-2-ol. (1-{2-ï5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamino)-acetic acidethyl ester (110 mg, 0.218 mMol) 58A was dissolved in 2 mL of anhydrous THF under anatmosphère of dry N2. The reaction mixture was cooled to -78°C and then 260 μΙ~ of asolution of 1.0 M méthylmagnésium bromide in THF was added. The reaction mixture wasslowly warmed up to ambient température and stirred ovemight. The reaction mixture wasthen partitioned between DCM and saturated aqueous NaHCO3. The organic layer was savedand washed again with saturated aqueous NaHCO3, dried over Na2SO4, filtered andconcentrated under vacuum to give a yellow residue. The residue was chromatographed onflash silica gel eluting with MeOH/DCM/NH4OH (2/97.9/0.1) to give 20 mg of the title ^2 compound 58 as a yellow residue. C.l. m/z 490 [M+1J; ’H NMR (CDCI3) δ 8.65 (s, 1 H), 8.35 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.44 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.22 (m, 1 H), 7.12(m, 1 H), 4.21 (m, 2 H), 3.88 (m, 2 H), 3.80 (m, 2 H), 3.47(s, 3 H), 2.88 (m, 2 H), 2.67 (m, 1 H), 2.62 (s, 2 H), 2.13 (m, 2 H), 1.78 (m, 2 H), 1.19 (s, 6 H). 20

Example 59 ( 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yIJ-quinoIin-8-yl)-piperidin-4-yl)-pyridin-2-ylmethyl-amine.

1-{2-i5-(2-methoxy-ethoxy)-benzoÎmidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 (50 mg,0.119 mMol) and pyridine-2-carbaldehyde (11 pL, 0.119 mMol) were dissolved in a solution of2 mL of EtOH and 500 pL of DCE under an atmosphère of dry N2. The reaction mixture wassubsequentfy heated to reflux and stirred at this température for 1.5 hours. The reactionmixture was then cooled to ambient température and NaBH4 (14 mg, 0.357 mMol) was added. 25 -88- 1 2 098

The réaction mixture was stirred ovemight at ambient température. The solvent was removedunder vacuum and the resulting residue was partitioned between OCM and 0.1 1 N aqueousNaOH. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum togive 47 mg of the title compound 59 as a yellow residue. C.l. m/z 509 [M+1 ]; Ή NMR (CDCI3) δ 8.63 (s, 1 H), 8.55 (m, 1 H), 8.39 (d, J = 9.1 Hz, 1 H), 8.26 (d, J * 8.7 Hz, 1 H), 7.65 (m, 2 H), 7.44 (m, 2 H), 7.36 (d, J = 8.9 Hz, 1 H), 7.32 (d, J =2.5 Hz, 1 H), 7.22 (m, 1 H). 7.12 (m, 2 H), 4.20 (m, 2 H), 4.01 (s. 2 H), 3.89 (m, 2 H), 3.79 (m,2 H), 3.46 (s, 3 H), 2.90 (m, 2 H), 2.77 (m, 1 H). 2.13 (m, 2 H), 1.88 (m, 3 H).

Example 60 ( 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-yl)-pyridin-3-ylmethyl-amine.

The same procedure that was used in example 59 was fotlowed except that pyridine-3-carbatdehyde was used in the place of pyridine-2-carbaldehyde to give the titie compound 60as a yellow residue. C.l. m/z 509 [M+1]; 1H NMR (COCI3) δ 8.65 (s, 1 H), 8.59 (d, J = 2.7 Hz, 1 H), 8.50 (dd, J = 2.7, 5.0, 1 H), 8.38 (d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.76 (m. 1 H), 7.67 (m, 1 H), 7.45 (m, 2 H), 7.34 (d. J = 2.5 Hz, 1 H), 7.27 (m, 1 H), 7.22 (m, 1 H), 7.12 (dd, J = 2.5. 8.7, 1H), 4.22 (m, 2 H), 3.91 (s, 2 H), 3.88 (m, 2 H), 3.80 (m, 2 H), 3.47 (s, 3 H), 2.90 (m, 2 H), 2.75(m, 1 H), 2.14 (m, 2 H), 1.85 (m, 2 H), 1.75 (brs, 1 H).

Example 61 4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol. 1 2098 -89-

Example 61A N-(2-Bromo-phenyl)-3-phenyl-acrylamide. 2-Bromoaniline (48.4 T g, 281.4 mMol) was dissolved in 500 mL of anhydrous DCM under anatmosphère of dry N2. Pyridine (45.5 mL, 563 mMol) was then added and the reaction was 5 subsequently cooled to 0°C after which time cinnamyl chloride (46.9 g, 281.4 mMol) wasadded. The reaction mixture was slowly warmed up to ambient température and then stirredovernight at ambient température. The reaction was diluted with 300 mL of saturatedaqueous NaHCO3 and then extracted with OCM. The DCM layer was then washed threetimes with 10% aqueous NaKSO4 followed by saturated aqueous NaHCO3 and finally brine. ^0 The DCM layer was then dried over Na2SO4, filtered and concentrated under vacuum to give85.08 g of a tan solid as the title compound 61 A.

Example 61B8-Bromo-quinolin-2-ol. N-(2-Bromo-phenyl)-3-phenyl-acrylamide 61A (85.0 g, 281.3 mMol) was dissolved in 500 mL15 of chlorobenzene under an atmosphère of dry Nz. Aluminum trichloride (187.5 g, 1.40 mMol)was then added to the solution and the reaction mixture was subsequently heated to 90°C for 3 hours after which time the température was raised to 120°C. After stirring for 1 hour at 120°C for 1 hour, an additional 40 g of aluminum trichloride was added and the reaction mixturewas stirred for an additional hour. The reaction mixture was then cooled to ambient 20 température and then slowly poured into a solution of 2 L of ice water and 1 L of DCM. TheDCM layer was washed with brine, dried over Na2SO4, filtered and concentrated undervacuum to give a volume ~100 mL. The pink precipitate was collected and washed withhexanes and then dried to give 44.1 g of the title compound 61 B.

Example 61C 25 Trifluoro-methanesulfonic acid 8-bromo-quinolin-2-yl ester. -90- 1 2 098 8-Bromo-quinolin-2-ol 61B (24.4 g, 109 mMol) and 2,6-dimethylpyridine (19 mL, 163 mMol)were dissolved in 500 mL of anhydrous DCM under an atmosphère of dry N2. The reactionmixture was then cooied to 0°C and trifluoromethanesulfonic anhydride (22.0 mL, 131 mMol)was added to the solution dropwise. After the addition was complété, the reaction was 5 warmed to ambient température and stirred for 1 hour. The reaction mixture was thenquenched with water and partitioned between DCM and aqueous NaHCO3. The DCM layerwas then washed four times with 10% aqueous cltric acid, twice with aqueous NaKCO3 andonce with brine. The DCM iayer was then dried over Na2SO4, filtered and concentrated undervacuum to give the tiüe compound 61C.

10 Example 61D (8-Bromo-quinolin-2-yl)-[4-(2-methoxy-ethoxy)-2-nitro-phenyl]-amine.

Trifluoro-methanesulfonic acid 8-bromo-quinolin-2-yl ester 61C (40.8 g, 114 mMol) and 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A (25.2 g, 119 mMol) were dissolved in 300 mL oftoluene under an atmosphère of dry N2. To this solution was added (49.3 g, 151 mMol) 15 Cs2CO3, (3.91g, 6.50 mMol) racemic-2,2-bis(diphenylposphino)-1,r-binapthyl (BINAP) and(1.98 g, 2.16 mMol) tris(dibenzylideneacetone)dipalladium (0) and the reaction mixture washeated to 80°C and reacted ovemight at this température. The mixture was then cooied toambient température, concentrated under vacuum, treated with DCM, filtered andconcentrated under vacuum to give a red solid. The solid was triturated with EtOAc and dried 20 under vacuum to give 22.0 g of the title compound 61 D.

Example 61E N1-(8-Bromo-quinolin-2-y,)-4-(2-methoxy-ethoxy)-benzene-1,2-diamine. (8-Bromo-quinolin-2-yl)-(4-(2-methoxy-ethoxy)-2-nitiO-phenyl]-amine 61D (22.0 g, 52.6 mMol)was suspended in a solution of 500 mL of EtOH and 100 mL of water under an atmosphère of 2$ dry N2. To this heterogeneous solution were added ammonium chloride (1.75 g, 63.1 mMol)and iron powder (23.5 g, 421 mMol). The réaction mixture was then heated to 100°C andreacted at this température for 6 hours. The reaction mixture was then cooied to ambienttempérature, filtered and the filtrate was concentrated under vacuum. The resulting slurrywas partitioned between DCM and water. The DCM layer was then washed two more times 30 with water and once with brine. The DCM layer was then dried over Na2SO4, filtered and 1 2098 -91- concentrated under vacuum to give 20.5 g of the title compound 61E. This matériel was usedwithout further purification.

Example 61F 8-Bromo-2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinoline. N1-(8-Bromo-quinolin-2-yl)-4-(2-methoxy-ethoxy)-benzene-1,2-diamine 61E (20.5 g, 52.7mMol) and formamidine acetate (6.03 g, 58.0 mMol) were dissolved in 150 mL of 2-methoxyethanol under an atmosphère of dry N2. The reaction mixture was heated to refluxand stirred overnight. The reaction mixture was then cooled to ambient température thatcaused the product to precipitate. The pink soiid was collected via suction filtration, washedwith 2-methoxyethanol and then dried under vacuum to give 16.1 g of the title compound 61F.The filtrate was concentrated under vacuum and the resulting residue was chromatographedon flash silica gel eluting with a gradient of DCM to MeOH/DCM (1/99) to give an additional 4.40 g of the title compound 61F.

Example 61G 4-{2-[5-(2-Methoxy-ethoxy)-benzoÎmidazol-1-yl]-quinolin-8-yl}-phenoi.8-Bromo-2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-ylî-quinoline 61F (585 mg, 1.47 mMol),was dissolved in 10 mL of dioxane under an atmosphère of dry N2. To this solution wereadded 4-hydroxyphenyl boronic acid (240 mg, 1.74 mMol), potassium phosphate (620 mg, 2.92 mMol) and tetrakis(triphenyiphosphine)palladium (0) (85 mg, 0.074 mMol). The reactionmixture was heated to 105°C and reacted at this température for 48 hours. The réactionmixture was then cooled to ambient température, concentrated under vacuum and partitionedbetween OCM and aqueous saturated NaHCO3. The OCM layer was then washed with brine,dried over Na2SO4, filtered and concentrated under vacuum to give a yellow residue. Theresidue was chromatographed on flash silica gel eluting with MeOH/DCM/NH4OH (2/97.9/0.1)to give 365 mg of a white foam as the title compound 61. C.l. m/z 412 [M+1];1H NMR (CDCI3) δ 8.64 (s, 1 H), 8.21 (d, J - 8.7 Hz, 1 H), 7.93 (d, J = 9.1Hz, 1 H), 7.68 (d, J « 7.9 Hz, 2 H), 7.56 (d, J = 9.1 Hz, 1 H), 7.49 (m, 3 H), 7.20 (d, J = 2.5 Hz,1 H), 7.07 (d, J 7.9 Hz, 2 H), 6.90 (m, 1 H), 4.02 (m, 2 H), 3.65 (m, 2 H), 3.37 (s, 3 H).

Example 62 [2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenoxy)-ethylJ-dimethyl- amine. -92- 1 2098

4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yI]-quinolin-8-yl}-phenol 61 (100 mg, 0.243mMol) was dissolved in 600 μί. of anhydrous DMF under an atmosphère of dry N2. Cs2CO3(237 mg, 0.729 mMol) and (2-chloro-ethyl)-dimethyl-amine hydrochioride (39 mg, 267 mMol)were added to the reaction mixture. The reaction was heated to 80°C and reacted at this $ température for 3 hours. The reaction mixture was partitioned between DCM and 0.1 Naqueous NaOH. The OCM layer was washed two more times with 0.1 N aqueous NaOH,dried over Na2SO4, filtered and concentrated under vacuum to give 125 mg of a brown oïl.The oil was dissolved into 1 mL of DCM to which was added a 3.0 mL of a solution of 1 Nhydrochloric acid (HCI) in ethyl ether. The precipitate was collected, washed with ether,dissolved in methanol and finally concentrated under vacuum to give 92 mg of the bis-hydrochloride sait of the title compound 62 as a tan solid. C.l. m/z 483 (M+1J; Ή NMR (CD3OD) δ 10.2 (s, 1 H), 8.73 (d, J 9.1 Hz, 1 H), 8.21 (d, J = 9.1Hz, 1 H), 8.17 (d, J = 8.7 Hz, 1 H), 8.07 (d, J - 8.3 Hz, 1 H), 7.88 (d, J « 6.2 Hz, 1 H), 7.78 (m,1 H), 7.64 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 2.1 Hz, 1 H), 7.21 (d, J 8.3 Hz, 2 H), 7.01 (m, 1H), 4.46 (m, 2 H), 4.22 (m, 2 H). 3.80 (m, 2 H), 3.69 (m, 2 H), 3.44 (s, 3 H), 3.04 (s, 6 H).

Example 63 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-8-piperazin-1 -yl-quinoline.

The same procedure that was used in exemple 1 was followed except that 8-bromo-2-[5-(2-methoxy-ethoxy)-benzoÎmidazol-1-yl]-quinoline 61F was used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E and t-butyl-1-piperazine-carboxylate in the place of piperidin-4-yl-carbamic acid tert-butyl ester in example1F to give the title compound 63 as a tan solid.

I -93- 1 2 09 8 C.l. m/z 404 [M+1J; 1H NMR (CDCI3) δ 8.62 (s, 1 H), 8.41 (d. J = 9.1 Hz, 1 H), 8.30 (d. J * 8.7Hz, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.48 (m, 2 H), 7.34 (d, J = 2.1 Hz, 1 H), 7.23 (m, 1 H), 7.13(dd, J = 2.5, 9.1 Hz, 1 H), 4.22 (m, 2 H), 3.80 (m, 2 H), 3.46 (s. 3 H), 3.42 (m, 4 H), 3.25 (m, 4H).

Example 64 [2-(4-(2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1-yl)-ethyl]-

2-I5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-8-piperazÎn-1-yl-quinoline 63 (100 mg, 0.248mMol), 2-dimethylamino ethyl chloride hydrochloride (53 mg, 0.37 mMol) and N,N-diisopropylethylamine (130 pL, 0.743 mMol) were dissolved In 1 mL of ACN under anatmosphère of dry N2. The reaction mixture was heated to 82°C and reacted at thistempérature overnight. The reaction mixture was then concentrated under vacuum and thenpartitioned between DCM and 1 N aqueous NaOH. The DCM layer was then washed againwith 1 N aqueous NaOH, dried over Na2SOA, filtered and concentrated under vacuum to givea tan residue. The residue was chromatographed on flash silica gel eluting first withMeOH/DCM (5/95) to remove less polar impurities and then with MeOH/DCM/NH4OH(8/91.9/0.1 ) to give the title compound 64. C.l. m/z 475 [M+1J; 1H NMR (CDCI3) δ 8.63 (s, 1 H), 8.44 (d, J » 8.7,1 H), 8.27 (d, J = 8.7 Hz,1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.22 (m, 1 H), 7.12 (m,1 H), 4.22 (m, 2 H), 3.81 (m, 2 H), 3.47 (s, 3 H), 3.46 (m, 4 H), 2.83 (m, 4 H), 2.63 (m, 2 H), 2.52 (m, 2 H) 2.30 (s, 6 H).

Example 65 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-pyridin-2-ylmethyl-piperazin-1-yl)-quinoline. -94- 1 2098

The same procedure that was used in exemple 64 was used except that 2-picolyl chloridehydrochloride was used in the place of 2-dimethylamino ethyl chloride hydrochloride to givethe title compound 65 as a yellow solid. C.I. m/z 495 [M+1]; ’H NMR (CDCI3) δ 8.62 (s, 1 H), 8.43 (d, J = 9.1,1 H), 8.28 (d. J « 9.1 Hz,1 H), 7.68 (m, 2 H), 7.48 (m, 3 H), 7.33 (d, J = 2.1 Hz, 1 H), 7.23 (m, 2 H), 7.10 (m, 1 H), 4.22(m, 2 H), 3.82 (m, 4 H), 3.49 (s. 3 H), 3.47-3.49 (m, 4 H), 2.92 (m, 4 H).

Example 66 2-[5-(2-Methoxy-ethoxy)-benzoimÎdazol-1-yl]-8-(4-pyridin-3-ylmethyl-piperazin-1-yl)-quinoline.

The same procedure that was used in example 64 was used except that 3-picolyl chloride10 hydrochloride was used in the place of 2-dimethylamino ethyl chloride hydrochloride to give the title compound 66 as a yellow solid. C.l. m/z 495 [M+1]; ’H NMR (CDCI3) δ 8.63 (m, 2 H), 8.52 (dd, J = 2.6, 5.0 Hz, 1 H). 8.43 (d, J= 9.1,1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.75 (brd, J = 7.5 Hz, 1 H), 7.66 (d, J = 9.1 Hz, 1 H), 7.46(m, 2 H), 7.33 (d, J = 2.1 Hz, 1 H), 7.27 (m, 1 H), 7.22 (m. 1 H), 7.10 (m, 1 H), 4.23 (m, 2 H), 3.82 (m, 2 H), 3.67 (s, 2 H), 3.48 (s, 3 H). 3.47 (m, 4 H), 2.82 (m, 4 H).

Example 67 2-Amino-1 -(4-{2-i5-(2-methoxy-ethoxy}-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -yl)-2-methyl-propan-1 -one. 1 2098 -95-

The same procedure used in example 54 was followed except that 2-(5-(2-methoxy~ethoxy)-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline 63 was used in the place of 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 and N-t-boc-a-methylalaninewas used in the place of N-(tert-butoxycarbonyl)glycine to give the title compound 67. 5 1H NMR (CDCI3) δ 8.62 (s. 1 H), 8.42 (d, J « 8.7 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.68 (d. J= 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.34 (d, J = 2.5 Hz, 1 H), 7.21 (dd, J = 2.2, 7.5 Hz, 1 H), 7.11(dd, J = 2.5, 8.7 Hz, 1 H), 4.22 (m, 2 H), 4.17 (m, 4 H), 3.81 (m, 2 H). 3.47 (s, 3 H), 3.39 (m, 4H), 2.13 (brs, 2 H), 1.49 (s, 6 H).

Example 68 1 o (S)-2-Amino-1 -(4-{2-(5-(2-methoxy-ethoxy>benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -yl)-

The same procedure used in example 54 was followed except that 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline 63 was used in the place of 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 and N-(tert-butoxycarbonyl)-L-alanine was used in the place of N-(tert-butoxycarbonyl)glycine to give the title compound68 as a yellow solid. ’H NMR (CDCI3) δ 8.60 (s. 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 7.67 (d, J= 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.33 (d, J - 2.5 Hz, 1 H), 7.19 (dd, J « 2.3,7.5 Hz, 1 H), 7.10 (m,1 H), 4.20 (m, 2 H), 3.96 (m, 2 H), 3.88 (m, 1 H), 3.79 (m, 4 H). 3.46 (s, 3 H), 3.38 (m, 4 H), 20 2.11 (brs, 2 H), 1.30 (d, J = 7.0 Hz, 3 H). 1 2098 -96-

Example 69 (S)-2-Amino-1 -(4-{2-l5-(2-methoxy-ethoxy)-benzoÎmidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -yl)-

The same procedure used in example 54 was foilowed except that 2-[5-(2-methoxy-ethoxy)~benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline 63 was used in the place of 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 and N-(tert-butoxycarbonyl)-D-aianine was used in the place of N-(tert-butoxycarbonyi)glycine to give the title compound69 as a yellow solid. Ή NMR (COCI3) δ 8.60 (s. 1 H), 8.40 (d, J = 9.1 Hz, 1 H), 8.30 (d. J = 8.7 Hz. 1 H). 7.66 (d, J= 8.7 Hz, 1 H), 7.46 (m. 2 H), 7.33 (m, 1 H), 7.18 (m, 1 H), 7.11 (m, 1 H), 4.20 (m, 2 H). 3.96(m, 2 H), 3.88 (m, 1 H), 3.79 (m, 4 H), 3.46 (s, 3 H), 3.36 (m, 4 H). 2.10 (brs, 2 H). 1.29 (d, J = 6.2 Hz, 3 H).

Example 70 2-Amino-1 -(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperazin-1 -y I)-ethanone. NM, |

The same procedure used in example 54 was foilowed except that 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoIine 63 was used in the place of 1-{2 [5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-pipendin-4-ylamine 33 to give the title compound70.

1H NMR (CDCI3) δ 8.59 (s, 1 H), 8.40 (d, J = 8.7 Hz. 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.66 (d, J« 8.7 Hz, 1 H), 7.51 (dd, J = 2.2, 7.9,1 H), 7.45 (m, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.18 (dd, J 20 -97- 1 2 098 = 2.2, 7.5 Hz, 1 H), 7.09 (d, J = 2.5, 8.7 Hz, 1 H), 4.19 (m, 2 H), 3.96 (m, 2 H), 3.79 (m, 2 H), 3.68 (m, 2 H), 3.54 (m, 2 H), 3.46 (s, 3 H), 3.39 (m. 2 H), 3.33 (m, 2 H), 2.05 (brs, 2 H).

Example 71 (1-Amino-cyclopropyl)-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1~yll-quinolin-8-yl}- piperazin-1-yl)-methanone.

The same procedure used in example 54 was followed except that 2-[5-(2-methoxy-ethoxy>-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline 63 was used in the place of 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 and 1-tert-butoxycarbonylamino-cydopropanecarboxylic acid was used in the place of N-(tert-butoxycarbonyOglycine to give the title compound 71. C.l. m/z 487 |M+1]; <H NMR (CDCI3) δ 8.62 (s, 1 H), 8.40 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 8.7Hz, 1 H), 7.68 (d, J = 8.7 Hz, 1 H), 7.52 (dd, J = 2.2, 7.9,1 H), 7.45 (m, 1 H), 7.34 (d, J = 2.1Hz, 1 H), 7.20 (dd, J = 2.2, 7.5 Hz, 1 H), 7.10 (m, 1 H), 4.20 (m, 2 H), 4.00 (m, 4 H), 3.79 (m, 2H), 3.46 (s, 3 H), 3.39 (m, 4 H), 2.02 (brs, 2 H), 1.04 (m, 2 H). 0.84 (m, 2 H). _ Example 72 15 2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}~piperazin-1-yl)-ethylamine.

2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline 63 (100 mg, 0.248mMol), and t-butyI-N-(2-oxoethyl)-carbamate (39.5 mg, 0.248 mMol) were dissolved in 1 mL ofmethanol under an atmosphère of dry N2. To this solution was added 200 pL of AcOHfollowed by NaCNBH3 (19 mg, 0.297 mMol) and the reaction mixture was then stirred atambient température ovemight. The reaction mixture was then concentrated under vacuumand the resulting residue was partitioned between DCM and 1 N aqueous NaOH. The DCM -98- 1 2098 layer was then successively washed with 1 N aqueous NaOH and brine, dried over Na2SO4,filtered and concentrated under vacuum to give a yellowish-green film. The film was thendissolved in a solution of 1 mL of DCM and 2 mL of TFA under an atmosphère of dry N2. Thereaction mixture was stirred at ambient température for 30 minutes after which time it wasconcentrated under the vacuum. The resulting residue was partitioned between 0.1 Naqueous NaOH. The DCM layer was dried over Na2SO4, filtered and concentrated undervacuum to give a green film. The film was chromatographed on flash silica gel eluting withMeOH/DCM (5/95) to remove the less polar impurities and then MeOH/DCM/NH4OH(5/94.9/0.1) to give 71 mg of the title compound 72. C.l. m/z 447 [M+1]; ’H NMR (CDCI3) δ 8.63 (s, 1 H), 8.45 (d. J « 9.1Hz, 1 H), 8.27 (d, J = 8.7Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H). 7.22 (m, 1 H), 7.11(dd, J = 2.5 Hz, 8.7 Hz, 1 H), 4.20 (m, 2 H), 3.80 (m, 2 H), 3.47 (s, 3 H), 3.43 (m, 4 H), 2.89 (t,J ® 5.8 Hz, 2 H), 2.80 (m, 4 H), 2.59 (t, J = 5.8 Hz, 2 H), 2.17 (brs, 2 H).

Example 73 (R)-2-Amino-3-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1-yl)-

The same procedure that was used in example 72 was followed except that t-butyl-(S)-(-)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate was used in the place of t-butyl-N-(2-oxoethyl)-carbamate to give the title compound 73. C.l. m/z 477 (M+1]; ’H NMR (CDCI3) δ 8.61 (s, 1 H), 8.43 (d, J = 9.1 Hz, 1 H), 8.27 (d, J = 8.7Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.20 (dd, J = 2.6, 7.1 Hz, 1 H), 7.10 (dd, J = 2.5 Hz, 9.1* Hz, 1 H), 4.20 (m, 2 H), 3.80 (m, 2 H), 3.66 (m. 2 H), 3.46 (s, 3 H), 3.45 (m, 4 H), 3.25 (m, 1 H), 2.82 (m, 4 H), 2.65 (m, 1 H), 2.50 (m. 3 H).

Example 74 3-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-3-aza-bicyclo[3.1,0]hex-6-ylamine. -99- 12098

The same procedure that was used in example 33 was followed except that (3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester was used in the place of piperidin-4-yl-carbamic acid tert-butyl ester in example 1F to give the titie compound 74 as a yellow solid.

1H NMR (CDCI3) S 8.59 (s, 1 H), 8.22 (d, J = 8.7 Hz. 1 H). 7.99 (d, J = 9.1 Hz. 1 H). 7.59 (d, J 5 = 8.7 Hz. 1 H), 7.37 (m. 2 H). 7.35 (d. J « 2.5 Hz, 1 H). 7.09 (dd. J = 2.5, 9.1 Hz. 1 H). 6.83 (d, J = 7.9 Hz, 1 H), 4.34 (d, J = 9.6 Hz, 2 H), 4.20 (m, 2 H), 3.80 (m, 2 H), 3.46 (s, 3 H), 3.42 (d,J = 9.6 Hz, 2 H), 2.93 (brs, 2 H), 2.65 (s, 1 H). 1.73 (s, 2 H).

Example 75 (S)-1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-pyrrolÎdin-3-y,amine.

ΙΟ The same procedure that was used in example 33 was followed except that (3S)-(-)-3-(tert-butoxycarbonyl-amino)pyrrolidine was used in the place of piperidin-4-yl-carbamic acid tert-butyl ester in example 1F to give the titie compound 75 as a tan solid. 1H NMR (CD3OD) δ 8.75 (d. J = 1.7 Hz, 1 H), 8.30 (d, J * 8.7 Hz, 1 H), 8.00 (d, J = 9.1 Hz, 1H), 7.70 (dd, J = 2.1, 8.7 Hz, 1 H), 7.38 (t, J = 7.9 Hz. 1 H), 7.24 (m, 2 H), 7.04 (dd, J = 2.6, 15 9.1 Hz, 1 H), 6.90 (d, J « 7.9 Hz, 1 H), 4.16 (m, 2 H), 3.90 (m, 1 H), 3.82 (m, 1 H), 3.77 (m, 2 H), 3.66 (m, 1 H), 3.60 (m, 1 H), 3.48 (m, 1 H), 3.43 (s, 3 H), 2.21 (m, 1 H), 1.80 (m, 1 H).

Example 76 (R)-1 -{2-[5-(2-Methoxy-ethoxy )-benzoimidazol-1 -yl]-quinolin-8-yl}-pyrrolidin-3-ylamine. -100- 1 2 098

The same procedure that was used in example 33 was followed except that (3R)-(-)-3-(tert-butoxycarbonyl-amino)pyrrolidïne was used in the place of piperidin-4-yl-carbamic acid tert-butyl ester in example 1F to give the title compound 76 as a tan solid. ’H NMR (CD3OD) δ 8.80 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.05 (d. J = 8.7 Hz, 1 H), 7.76 (d,5 J = 8.7 Hz. 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.28 (m, 2 H), 7.09 (dd, J = 2.5, 9.1 Hz, 1 H), 6.93 (d, J = 7.5 Hz, 1 H), 4.18 (m, 2 H), 3.91 (m, 1 H), 3.84 (m, 1 H), 3.78 (m, 2 H), 3.66 (m, 1 H), 3.62 (m, 1 H), 3.48 (m, 1 H), 3.44 (s, 3 H), 2.23 (m, 1 H), 1.82 (m. 1 H).

Example 77 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-pyridin-3-yl-quÎnoline.

Example 77A8-Benzyloxy-quinolin-2-ol. 2,8-Quinolinediol (133.3 g, 0.827 Mol) was dissolved in 800 mL of anhydrous DMF under anatmosphère of dry N2. To this solution was added potassium carbonate (183 g, 1.32 Mol)followed by benzyl bromide (110 mL, 0.909 Mol) and the solution was then warmed up ta 65°Cand reacted at this température overnight. The reaction mixture was then poured into 9 L ofwater and the resulting solution was stirred atambient température for 5.5 hours after whichtime it was filtered. The solid was washed with water, collected and suspended in toluene andfinally the solution was concentrated under vacuum to give 142 g of the title compound 77A.

Example 77B 8-Benzyloxy-2-chloro-quinoline. 20 -101- 1 2 098 8-Benzyloxy-quinolin-2-ol 77 A (142 g, 0.565 Mol) was dissolved in 500 mL of DCE under anatmosphère of dry N2. Oxalyl chloride (99 mL, 1.13 Mol) was added dropwise to this solutionfollowed by 1 mL of DMF. After the addition was complété, the reaction was stirred at amhienttempérature for 30 minutes after which time the reaction was warmed to 84°C. The reaction 5 mixture was stirred at this température for 10 hours and then concentrated under vacuum.The resulting residue was partitioned between DCM and aqueous saturated NaHCO3. TheDCM layer was washed again with aqueous saturated NaHCO3, dried over Na2SO4, filteredand concentrated under vacuum to give a brown solid. The solid was recrystallised fromtoluene to give two crops of (68.3 g and 38.3 g) of the title compound 77B.

1Θ Example 77C (8-Benzyloxy-quinolin-2-yl)-[4-(2-methoxy-ethoxy)-2-nitro-phenyl]-amine. 8-Benzyioxy-2-chloro-quinoline 77B (25.53 g, 94.64 mMol) was added to 350 mL ofanhydrous toluene under an atmosphère of dry N2. To this solution was added 5-(2-methoxy- ) ethoxy)-2-nitro-phenylamine 42A (20.08 g, 94.64 mMol), palladium acetate (433 mg, 1.89mMol), Cs2CO3 (43.2 g, 132 mMol), phenyl boronic acid (584 mg, 4.79 mMol) and 1,2-bis(diphenylphosphino)-ethane (2.33 g, 5.68 mMol) and the mixture was then deoxygenatedby bubbling argon through for ten minutes. The réaction mixture was then heated to 95°C andreacted at this température for two hours. Then the reaction was diluted (while still hot) with .·. 350 mL of DCE and then filtered while still hot. The filter cake was washed with 100 mL of hot 20 DCE. The filtrate was concentrated to -175 mL during which time a large amount of precipitate formed. To this mixture was added 400 mL of EtOH and the reaction mixture wasstirred ovemight. The resulting red precipitate was collected via suction filtration and dried under vacuum to give 36.8g of the title compound as a red solid 77C.

Example 77D 2 j 2-[5-(2-Methoxy-ethoxy )-benzoimidazol-1 -yl]-quinolin-8-ol. (8-Benzyloxy-quinolin-2-yl)-(4-(2-methoxy-ethoxy)-2-nitro-phenyl]-amine 77C (36.8 g, 85.4mMol) was suspended in 275 mL of EtOH under an atmosphère of dry N2. The reactionmixture was then cooled to 0°C after which time 119 mL of triethylamine (NEt3) followed by 34mL of formic acid (slowly) were added. The ice bath was removed and the reaction mixtureφφ was then heated to ~80°C and reacted at this température until the nitro group has been fullyreduced to the amine and the benzyl group has been fully removed (as determined by masssprectral analysis) which, in this case, was -2 hours. To this mixture is then added -102- 1 2098 formamidine acetate (11.56 g, 111 mMol) and the reaction température was increased toreflux. After a couple of hours more formamidine acetate (3.20 g) was added and the reactionmixture was stirred at reflux for an additional 4 hours. The reaction mixture was then cooiedto ambient température and the filtered through Celite™. The Celite™ was washed withcopions amounts of a 1:1 MeOH/DCM solution and the combined filtrâtes were concentratedunder vacuum and the resulting solids were triturated with 200 ml. of EtOH. The solution wasfiltered and the precipitate was dried under vacuum to give 23.03 g of the title compound 77Dwas a white solid.

Example 77E T rifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-ylester. 20 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-ol 77D (23.0 g, 68.6 mMol) wasdissolved in a solution of 120 mL of anhydrous DMF and 250 ml. of THF under an atmosphèreof dry Nz. To this solution were added N-phenyl-bis(trifluoromethanesulfonimide) (26.95 g, 75.5 mMol) and NEt3 (6.75 mL, 137.2 mMol). The reaction mixture was stirred over night atambient température after which time an additional 2.70 g of N-phenyl-bis(trifluoromethanesulfonimide) and an 700 pL of NEt3 were added. The réaction mixturewas stirred an additional 1 hour and then was filtered and the filter cake was washed withethyl ether. The filter cake was dried under vacuum to give 6.70 g of the title compound 77Eas a white solid. A second crop was obtained by concentrating the filtrate to - 75 mL. To thissolution was added 200 mL of ethyl ether and the resulting mixture was stirred for 1 hour andthen filtered. The filter cake was washed with ethyl ether and then vacuum dried to give anadditional 19.91 g of the title compound 77E for a total of 28.61 g.

Example 77F 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylî-8-pyridin-3-yl-quinoline.

Trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester77E (1.00 g, 2.14 mMol), diethyl(3-pyridyl)-borane (620 mg, 4.36 mMol), lithium chloride (188mg, 4.36 mMol) and tetrakis(triphenylphosphine)palladium (0) (248 mg, 0.215 mMol) weredissolved in a solution of 14 mL of toluene, 4 mL of EtOH and 1.5 mL of 2 N aqueous sodiumcarbonate (Na2CO3) under an atmosphère of dry N2. The reaction mixture was heated to 90°Cand reacted at this température overnight. The reaction mixture was then cooied to ambienttempérature, concentrated under vacuum and partitioned between DCM and aqueoussaturated NaHCO3. The DCM layer was then washed with brine, dried over Na2SO4, filtered -103- 1 2098 and concentrated under vacuum. The resulting residue was chromatographed on flash silicagel eluting with a gradient from MeOH/DCM (1/99) to MeOH/DCM (2/98) to give 460 mg of thetitle compound 77. C.l. m/z 397 [M+1J; ’H NMR (CDCI3) δ 8.86 (d, J = 1.6 Hz, 1 H), 8.67 (dd, J = 1.3, 4.6 Hz, 1H), 8.56 (s. 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.08 (m, 1 H), 7.88 (m, 1 H), 7.78 (m, 2 H), 7.70 (d,J = 8.7 Hz, 1 H), 7.62 (m,1 H), 7.42 (m. 1 H), 7.25 (m, 1 H), 6.84 (dd, J = 2.5 Hz, 9.1 Hz, 1 H),4.15 (m, 2 H), 3.77 (m, 2 H), 3.45 (s, 3 H).

Example 78 2-[5-(2-Methoxy-ethoxy)-benzoimidazoH-ylJ-8-(6-methoxy-pyridin-3-yl)-quinoline. Ό

Trifluoro-methanesulfonic acid 2-(5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester77E (850 mg, 1.82 mMol), 2-methoxy-5-pyridineboronic acid (305 mg, 2.00 mMol), potassiumphosphate (K2CO3) (772 mg, 3.64 mMol) and tetrakis(triphenylphosphine)palladium (0) (208mg, 0.182 mMol) were dissolved in 5 mL of 1,4-dioxane under an atmosphère of dry N2. Thereaction mixture was heated to 100°C and reacted at this température ovemight. The réactionmixture was then coOled to ambient température, concentrated under vacuum and partitionedbetween DCM and aqueous saturated NaHCO3. The OCM layer was then washed with brine,dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue waschromatographed on flash silica gel eluting with a gradient from EtOAc/DCM (20/80) toEtOAc/DCM (75/25) to give 856 mg of the title compound 78. C.l. m/z 427 [M+1J; ’H NMR (CDCI3) δ 8.63 (s, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 8.31 (d, J = 8.7Hz, 1 H), 7.96 (m, 1 H), 7.91 (d, J = 9.1 Hz, 1 H), 7.80 (dd, J = 2.2,8.3 Hz, 1 H), 7.72 (m, 2 H), 7.56 (m, 1 H), 7.24 (m, 1 H), 6.87 (m, 1 H), 6.83 (d, J ® 8.7 Hz, 1 H), 4.14 (m, 2 H), 4.00 (s, 3H), 3.76 (m, 2 H), 3.44 (s, 3 H).

Example 79 4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}~benzoic acid methyl ester. -104- 1 2 098

The same procedure that was used in exampte 78 was fullowed except that 4-methoxycarbonylphenylboronic acid was used in the place of 2-methoxy-5-pyridineboronicacid to give the titie compound 79 as a white solid. C.I. m/z 454 [M+1J; 'H NMR (CDCI3) δ 8.77 (s, 1 H), 8.37 (d, J - 8.7 Hz, 1 H), 8.13 (d, J = 8.35 Hz, 2 H), 7.91 (d, J = 9.1 Hz, 1 H), 7.88 (dd, J = 2.2,7.9 Hz. 1 H), 7.77 (m, 4 H), 7.62 (m, 1 H), 7.26 (d, J = 2.1 Hz, 1 H), 6.82 (dd, J = 2.5, 9.1 Hz, 1 H), 4.16 (m, 2 H), 3.99 (s, 3 H), 3.77 (m,2 H), 3.46 (s, 3 H).

Example 80 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-4-methyl-piperidin-4-ylamine.

O

jO Example 80A

Piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester.

Piperidine-4-carboxylic acid ethyl ester (9.80 mL, 63.2 mMol) was dissolved in 60 ml_ oi OCMat ambient température under an atmosphère of dry N2. Di-tert-butyl dicarbonate (13.77 g, 63.16 mMol) was slowly added to the reaction mixture after which time the reaction nixturewas stirred ovemight. The reaction mixture was then partitioned between DCM and saturatedaqueous NaHCO3. The DCM layer was washed two more times with saturated aqueousNaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to give 16.13 g of thetitie compound 80A as an oil.

Example 80B

I -105- 1 2 098 4-Methyl-piperidine-1,4-dicarboxylic acid tert-butyl ester etbyJ ester.Piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester 80A (10.9 g, 42.3 mMol) wasdissolved in 44 mL anhydrous THF under an atmosphère of dry N2. The solution was thencooled to -40°C and 85 mL of a solution of 1 M lithium bis(trimethylsilyl)amide in 5 terahydrofuran was slowly added. The reaction mixture was stirred at ~40°C for 1 hour afterwhich time iodomethane (5.3 mL, 85 mMol) was added. The solution was allowed to warm upto ambient température and after 1 hour was quenched with water. The reaction mixture waspartitioned between DCM and aqueous saturated NaHCO3. The DCM layer was washed twomore times with aqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated <10 under vacuum to give 14.78 g of the title compound 80B as an orange oil. The compoundwas used without further purification.

Example 80C 4-Methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. > 4-Methyl-piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester 80B (12.8 g, 47.2 mMol) 15 was dissolved in a solution of 94 mL of EtOH and 47 ml of aqueous 2 N NaOH. The reaction mixture was heated to 60°C and reacted at this température for 6 hours. The reaction mixturewas concentrated under vacuum to remove the EtOH. The remaining aqueous solution waswashed three times with ethyl ether. The pH was then adjusted to 3 with the careful additionof 1 N HCl. The aqueous layer was then washed 4 times with EtOAc. The EtOAc extracts 20 were combined, dried over Na2SO4, filtered and concentrated under vacuum to give 9.54 g ofthe title compound 80C as white solid. The compound was used without further purification.

Example 80D 4-Carbamoyl-4-methy,-piperidine-1 -carboxylic acid tert-butyl ester. 4-Methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester 80C (9.54 g, 39.2 mMol) was 25 dissolved in 115 mL of anhydrous THF under an atmosphère of dry N2. The reaction mixturewas cooled to 0°C after which time NEt3 (4.50 mL, 47.1 mMol) followed by ethyl chloroformate(7.10 mL, 60.0 mMol) were added. The mixture was warmed to ambient température andstirred for 15 minutes after which time it was cooled back down to 0°C. To this mixture, wasadded 65 mL of NH4OH. The reaction mixture was warmed to ambient température and thejq THF was removed under vacuum. The resulting aqueous solution was washed three timeswith DCM. The DCM extracts were combined, dried over Na2SO4, filtered and concentrated -106- 1 2 098 under vacuum to give 6.19 g of the title compound 80D as an oil. The compound was usedwithout further purification.

Example 80E 4-Amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester. 5 4-Carbamoyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester 80D (6.19 g, 25.6 mMol),[Bis(trifluoroacetoxy)iodo]-benzene (16.5 g, 38.3 mMol) and pyridine (6.20 ml., 76.9 mMol)were dissolved in a solution of 40 mL of ACN and 20 mL of water under an atmosphère xrf dryN2. The reaction mixture was stirred for 2 hours at ambient température after which time itwas diluted with aqueous 1 N NaOH. The resulting solution was washed three tin,es with 10 DCM. The DCM extracts were combined, dried over Na2SO4, filtered and concentrated undervacuum to give an oil. The oil was partitioned between DCM and aqueous HCl (pH~3). Theaqueous layer was washed 2 more fîmes with DCM, and then was basified with 2 N aqueousNaOH until the pH~10. The basic aqueous layer was washed three fîmes with DCM. TheDCM extracts were combined, dried over Na2SO4, filtered and concentrated under vacuum togive 4.19 g of the title compound 80E as a yellow oil. The compound was used withoutfurther purification.

Example 80F (4-Methyl-piperidin-4-yl)-carbamic acid benzyl ester. 4-Amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester 80E (4.19 g, 19.6 mMol) was 20 dissolved in a solution of 50 mL of dioxane and 20 mL of aqueous 2 N NaOH under anatmosphère of dry N2. To this solution was siowly added benzyl chloroformate (5.6 mL, 39mMol) and the reaction was stirred for 3 hours at ambient température. The reaction mixturewas concentrated under vacuum. The réaction mixture was dissolved in DCM ardsuccessively washed three with aqueous 1 N NaOH. The DCM layer was dried over Na2SO. , 25 filtered and concentrated under vacuum to give a yellow oil. The oil was dissolved in 15 mLof TFA under an atmosphère of dry N2. The reaction mixture was concentrated under vacuuraand partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was dried overNa2SO4, filtered and concentrated under vacuum to give 3.06 g of an oil. The oil waschromatographed on flash silica gel eluting with DCM to remove less polar impurities then jq with MeOH/DCM/NH4OH (20/79.9/0.1 ) to give 2.85 g of the title compound 80F as an oil. * 1

Example 80G -107- 1 2098 1-{2-I5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-4-methyl-piperidin-4-ylamine.

The same procedure that was used in example 1 was followed except that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]~quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl>- 5 quinolin-8-yl ester 1E and (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester 80F was usedin the place of piperidin-4-yl-carbamic acid tert-butyl ester in example 1F to give the titlecompound 80 as a yellow solid. C.I. m/z 432 [M+1]; 1H NMR (CD3OD) δ 8.80 (s, 1 H), 8.49 (d, J = 9.1 Hz, 1 H), 8.24 (d, J = 9.1Hz, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.44 (m, 2 H), 7.24 (dd, J = 1.2, 8.7 Hz, 1 H), 7.18 (d, J = 10 2.5 Hz, 1 H), 7.00 (m, 1 H), 4.12 (m, 2 H), 3.76 (m, 2 H), 3.43 (s, 3 H), 3.26 (m, 2 H), 3.13 (m, 2 H), 1.75 (m, 4 H), 1.17 (s, 3 H).

Example 81 1 -[2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalen-1 -yl)-quinolin-8-ylJ-piperidin-4-

Example 81A 8-Bromo-2-chloro-quinoline. 8-Bromo-quinolin-2-ol 61B (44.11 g, 196.7 mMol) was dissolved in 450 mL of DCE under anatmosphère of dry N2. To this solution was added oxalyl chloride (65.3 mL, 749 mMol)dropwise followed by the addition of 400 pL of dimethylformamide. After the addition wascomplété, the réaction mixture was heated to reflux and reacted for 3 hours. The réactionmixture was concentrated under vacuum. The resulting residue was partitioned between DCMand saturated aqueous NaHCO3, washed again with saturated aqueous NaHCO3, dried overNa2SO4l filtered and concentrated under vacuum to give 48.40 g of the title compound 81A asan orange solid. -108- 1 2098

Example 81B 6,7-Dihydro-1 H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene. 5-6-Ethylenedioxy-2-mercaptobenzimidazole (1.27 g, 6.10 mMol) and 3.5 mL of Raney ®nickel (50% slurry in water) were suspended in 30 mL of EtOHI under an atmosphère of dry 5 N2. The reaction mixture was heated to 80°C and reacted at this température for 3 hours.The reaction mixture was then filtered through Celite™ and then the Celite™ was washed withéthanol and OCM. The filtrâtes were combined and concentrated under vacuum to give 750mg of the title compound 81B as a foam.

Example 81C 1 -(8-Bromo-quinolin-2-yl)-6,7-dihydro-1 H-5,8-dioxa-1,3-diaza-cyclopenta(b]naphthalene. 6,7-Dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene 81B (600 mg, 3.4 mMol) wasdissolved in 15 mL of 1-methyl-2-pyrrolidinone under an atmosphère of dry N2. To thissolution was added 60% sodium hydride in oil (136 mg, 3.40 mMol) and the reaction mixturewas stirred for 15 minutes. 8-Bromo-2-chloro-quinoline 81A (750 mg, 3.10 mMol) was thenadded to the reaction mixture which was subsequently heated to 65°C and reacted at thistempérature ovemight. The reaction mixture was then cooled to ambient température,partitioned between OCM and saturated aqueous NaHCO3, washed again with saturatedaqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to give 1.60 gof an orange solid. The solid was chromatographed on flash silica gel eluting with a gradient 20 from OCM to MeOH/DCM (0.5/99.5) to give 700 mg of the title compound 81C as a lightyeilow solid.

Example 81D {1 -[2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalen-1 -yl }-quinolin-8-yl]-piperidin-4-yl)-carbamic acid tert-butyl ester. 2j 1-(8-Bromo-quinolin-2-yl)-6,7-dihydro-1 H-5,8-dioxa-1,3-diaza-cyclopenta[blnaphthalene 81C(700 mg, 1.83 mMol) and piperidin-4-yl-carbamic acid tert-butyl ester (733 mg, 3.66 mMol)were dissolved in 6.0 mL of dioxane under an atmosphère of dry N2. To this solution wasadded Cs2CO3 (835 mg, 2.56 mMol), racemic-BINAP (68 mg, 0.109 mMol) andtris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.037 mMol) and the reaction mixture was _ heated to reflux and reacted at this température ovemight. The mixture was then cooled to

JW ambient température, filtered, and concentrated under vacuum to give 1.12 g of an orange -109- 1 2098 film. The film was dissolved in a solution of 5 mL of TFA and 5 mL of DCM under anatmosphère of dry N2. The reaction mixture was stirred at ambient température for 30 minutesafter which time it was concentrated under vacuum to give a yellow oil. The oïl waspartitioned between ethyl ether and 0.1 N aqueous HCl. The aqueous layer was then washed 5 with DCM. The aqueous layer was basified to pH~11 with NaOH. The resulting solution waswashed three times with DCM. The DCM extracts were combined, dried over Na2SO4. filteredand concentrated to give 500 mg of a yellow solid. The solid was chromatographed on flashsilica gel eluting with MeOH/DCM (10/90) to give 127 mg of the title compound 81 as a yellowsolid. 10 C.l. m/z 402 [M+1J; ’H NMR (CD3OD) δ 8.63 (s, 1 H), 8.19 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7.56 (d, J - 9.1 Hz, 1 H), 7.30 (m, 2 H), 7.08 (dd, J = 2.1 Hz, 6.7 Hz, 1 H), 7.06 (s, 1 H), 4.21(m, 4 H), 3.57 (m, 2 H), 2.63 (m, 3 H), 1.86 (m, 2 H), 1.73 (m, 2 H).

Example 82 4-Cyclopropylaminomethyl-1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-

The same procedure that was used in example 24 was followed except that 5-(2-Methoxy-ethoxy)-2-nitro-phenylamine 42A was used in the place of 4-methoxy-2-nitroaniline inexample 1B and cyclopropylamine was used in the place of 2.o M solution of dimethylamine inTHF to give the title compound 82 as a yellow foam 82. 20 C.l. m/z 488 (M+1 ]; Ή NMR (CDCI3) δ 8.63 (s, 1 H). 8.33 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7Hz, 1 H). 7.65 (d, J = 8.7 Hz, 1 H), 7.44 (m, 2 H), 7.33 (d, J = 2.1 Hz, 1 H), 7.27 (m, 1 H), 7.08(m, 1 H), 4.21 (m, 2 H), 3.81 (m. 2 H), 3.68 (m, 2 H), 3.47 (s, 3 H), 3.22 (m, 2 H), 2.80 (brs, 2H), 2.28 (m, 1 H), 1.99 (m, 2 H). 1.73 (m, 2 H), 0.51 (m, 2 H), 0.40 (m, 2 H).

Example 83 2-{1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yloxy}-ethanol. 25 -110- 1 2098

HO

The procedure that was used in example 2 was followed except that 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-pipendin-4-ylamine 33 was used in the place of 1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylarnine 1 to give the titlecompound 83 as a yeliow solid. 5 C.l. m/z 404(M+1); Ή NMR (CD3OD) δ 8.96 (s, 1 H), 8.69 (d, J = 8.7 Hz, 1 H), 8.42 (d, J = 8.7Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 6.5 Hz, 1 H), 7.48 (t. J · 7.9 Hz, 1 H), 7.33 (d,J « 7.5 Hz, 1 H), 7.29 (d, J = 2.5 Hz, 1 H), 7.22 (m, 1 H), 4.14 (m, 2 H). 3.92 (m, 2 H), 3.85 (m,2 H), 2.83 (m, 3 H), 2.00 (m, 2 H). 1.83 (m, 2 H).

Example 84 1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazole-5-sulfonic acid dimethylamide.

Example 84A 4-Amino-N,N-dimethyl-3-nitro-benzenesulfonamide. 6.00 g (25.0 mmol) sodium 2-nitroaniline-4-sulfonate was taken into 25.0 ml. carbontetrachioride (CCI4 ) with 13.0 g (62.4 mmol) phosphorus pentachloride (PCIS) and ailowed tobeat to reflux for five hours. The reaction was ailowed to cool to room température and waspoured into ice water. Chloroform (CHCI3) was added and normal aqueous work-up yielded abright yeliow solid. Half of the isolated material was taken into 10.0 mL H2O and caoled to 0°C. To this solution was slowly added 44.0 mL (87.5 mmol) 2.0 M dimethyl amine inmethanol. After the initial exotherm and gas discharge had subsided, reaction was heated to 20 80°C for four hours. The reaction was ailowed to cool to room température and the pH was -111- 1 2098 adjusted to 3.0 using dilute HCl. The quenched reaction was allowed to slowly stir at raomtempérature ovemight. 1.13 g (4.62 mmol, 37%) of the desired product 84A was isolated as abright yeliow solid through filtration.

Example 84B {1 -[2-(5-Dimethylsulfamoyl-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yl)-carbamic acidtert-butyl ester.

The same procedure that used for Example 1 was followed with the exception that 4-amino- N, N-dimethyl-3-nitro-benzenesulfonamide 84A was used in the place of that 4-methoxy-2-nitroaniline in example 1B to give the title compound 84B solid.

Example 84C 1-[8-(4-Amino-piperidin-1-yl)-quinolin-2-yl]-1 H-benzoimidazole-5-sulfonic acid dimethylamide. (1 -(2-(5-Dimethylsulfamoyl-benzoimidazoI-1 -yl)-quinolin-8-yl]-pipendin-4-yl}-carbamic acidtert-butyl ester 84B (129 mg, 0.234 mMol) was dissolved into 1.0 mL of 1,4-dioxane. To thissolution, was slowly added 234 pL (0.936 mmol) of a solution of 4.0 M HCl in 1,4-dioxane.Solid formation was noted and the slurry was allowed to stir at room température for twohours. Oiethyl ether was added to the reaction mixture, and the crude reaction product wasisolated through filtration (141 mg yeliow solid). This yeliow solid was taken into DCM andwashed once with 10% K2CO3. Organic layer was dried over MgSO4 and evaporated underreduced pressure. The resulting yeliow solid was purified over silica gel (94 CHCI3:6 CH3OH: O. 6 NH4OH) to give 10 mg of the title compound 84 a brownish solid. C.l. m/z 451 (M+1); ’H NMR (COCI3): δ 8.81 (s, 1 H), 8.64 (m, 1 H), 8.38 (m, 1 H), 8.34 (s, 1H),7.88 (m, 1 H), 7.71 (m, 1H), 7.52 (m, 2 H), 7.29 (m, 1 H), 3.89 (m, 1 H). 2.98 (m. 2 H), 2.74 (s,6 H), 2.09 (m, 2 H), 1.80 (m. 2 H). 1.78 (m, 2 H). .Example 85 1-[2-(8-Methoxy-benzoimidazol-1-yl)-quinoiin-8-yl]-piperidin-4-ylamine.

MeO -112- 1 2 098

The same procedure that was used in example 84 was followed except that 5-methoxy~2-nitroaniline was used in the place of 4-methoxy-2-nitroaniline in example 1B to give the titlecompound 85 as an off-white solid. C.l. m/z 374.1 (M+1J; Ή NMR (CDCI3): δ 8.60 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.90 (s, 1 H), 7.77 (d, J » 8.7 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.23 (m, 1 H), 7.02 (m, 1 H), 3.92 (s, 3 H), 3.91 (m, 2 H), 2.90 (m, 3 H), 2.10 (m, 2 H), 1.89 (m, 2 H), 1.58 (brs 2 H).

Example 86 1-(2-(5,6-Dimethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine.

MaO

Example 86A 4,5-Dimethoxy-2-nitroaniline. 4.50 g (20.0 mmol) 4,5-dimethoxy-1,2-dinitrobenzene was taken into 50.0 mL EtCH/ 8.4 mLAcOH mixture. To this was added 4.00 g powdered iron (0). The reaction was heated to anoit bath termperature of 70°C ovemight. The reaction was aliowed to cool to roomtempérature and was poured into 400 mL H2O. Aqueous layer was extracted severai timeswith diethyl ether. Organic iayers were dried over magnésium sulfate and evaporated underreduced pressure to give 4.73 g orange solid as a mixture of starting material and product.This solid was purified over silica gel (30 % DCM in hexanes) to give the title compound 86Aas an orange solid (1.15 g, 5.80 mmol).

Example 86B 1-(2-(5,6-Dimethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine.

The same procedure that was used in example 84 was followed except that 4,-5-dimethoxy-2-nitroaniline 86A was used in the place of 4-methoxy-2-nitroaniline in example 1B to give thetitle compound 86 as an off-white solid. -113- 1 2098 C.l. m/z 404 [M+1J; ’H NMR (CDCI3): δ 8.54 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.86 (s, 1 H), 7.64 (d, J = 8.7 Hz, 1H), 7.45 (m, 1 H), 7.33 (s, 1 H), 7.30 (m, 1 H), 7.20 (m, 1 H), 4.00 (s, 3H), 3.97 (s, 3H), 3.90 (m, 2 H), 2.90 (m, 3 H), 2.02 (m, 2H), 1.89 (m, 2 H).

Example 87 2-Dimethylamino-1-(4-{2>i5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin- 1-yl)-ethanone.

2-Chloro-1-(4-{2-[5-{2-methoxy-ethoxy)-benzoimidazoi-1-yl]-<]uinolin-8-yl}-piperazin~1-yl)- ethanone. 10 2-[5-{2-methoxy-ethoxy)-benzoimidazol-1-yl]-8-piperazin-1-yl-quinoline 63 (215 mg, 0.53mMol) was dissolved in 2.5 mL of anhydrous DCM under an atmosphère of dry N2. To thissolution, was sequentially added 2,6-lutidine (120 μΙ_, 1.06 mMol) and chloroacetyi chloride(630 pL, 0.800 mMol) and then reaction was then stirred overnight at ambient température.The reaction mixture was filtered and the solid was coliected and dried under vacuum to give ^5 50 mg of the title compound 87A.

Example 87B 2-Dimethylamino-1-(4-{2-[5-(2-rnethoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yi}-piperazin-1 1-yl)-ethanone. 2-Ch,oro-1-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-ylî-quinolin-8-yl}-piperazin-1-yl)- ethanone 87A (50 mg, 0.10 mMol) was dissolved in 2.0 mL of a 2.0 M solution of -114- 7 2 098 dimethylamine in methanol and the réaction mixture was subsequently stirred for 2 hours atambient température. The reaction mixture was concentrated under vacuum and the residuewas chromatographed on flash silica gel eluting with MeOH/DCM (2/98) thenMeOH/DCM/NH«OH (4/95.9/ 0.1) and finally MeOH/DCM/NH4OH (6/93.9/ 0.1 ) to give 32.5 mgof the tiüe compound 87. C.t. m/z 489 (M+1]; Ή NMR (CD3OD): δ 8.79 (s, 1H), 8.49 (d, J = 9.1 Hz, 1H), 8.24 (d, J = 8.7Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.48 (m, 1 H), 7.39 (m, 1 H), 7.17 (m, 2 H), 6.98 (dd. J = 2.5, 9.1 Hz, 1 H), 4.11 (m, 2 H), 3.76 (m, 6 H), 3.42 (s, 3 H), 3.14-3.21 (m, 6 H), 2.28 (s, 6 H). 10

Example 88 1-(2-(5-Benzyloxy-benzoimidazol-1-yl)-quinolin-8-yl]-4-methyl-piperidin-4-ol.

Example 88A 1 -[2-(5-Benzyloxy-benzoimidazoi-1 -yl)-quinoiin-8-yl]-piperidin-4-one. 15 2-{5-benzyloxy-benzoimidazol-1-yl)-8-bromo-quinoline (3.46 g, 8.05 mMol) which wasprepared using the procedure outlined in example 61 except that 4-benzyloxy-2-nitro-phenylamine was used in the place of 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A inexample 61D, and 4-piperidone hydrochloride hydrate (2.47 g, 16.1 mMol) wers dissolved in-40 mL of 1,4-dioxane under an atmosphère of dry N2. To this solution was added Cs2CO3(8.91 g, 27.4 mMol), racemic-BINAP (300 mg, 0.482 mMol) andtris(dibenzylideneacetone)dipalladium (0) (147 mg, 0.160 mMol) and the reaction mixture washeated to 100°C and reacted at this température ovemight. The mixture was then cooled toambient température, filtered, and the precipitate was washed several times with DCM/MeOH. 20 . -115- 1 2098

The combinée! filtrâtes were concentrated under vacuum and the resulting residue waspurified via flash silica gel chromatography eluting with MeOH/DCM/NH4OH (1.5/98.3/0.2) togive 1.91 g of the title compound 88A as an orange solid.

Example 88B 2 1 -[2-(5-Benzyloxy-benzoimidazol-1 -yl)-quinolin-8-yl]-4-methyl-piperidin-4-ol. 1-[2-(5-Benzyloxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-one 88A (832 mg, 1.85 mMol)was dissolved in 10 mL of anhydrous THF under an atmosphère of dry N2. The solution wasthen cooled to -78°C after which time 1.2 mL of a 3 M solution méthylmagnésium bromide inTHF was added. The reaction mixture warmed up to ambient température overnight afterwhich time it was quenched with water. The mixture was then concentrated under vacuumand subsequently partitioned between DCM and saturated aqueous NaHCO3. The organiclayer was then saved, washed again with saturated aqueous NaHCO3, then with brine, driedover Na2SO4l filtered and concentrated under vacuum to give a yellow foam. The foam waschromatographed over flash silica gel eluting with MeOH/DCM/NH4OH (1.5/98.3/0.2) to give585 mg of the title compound 88 as yellow solid. C.l. m/z 465 [M+1]; 1H NMR (CDCI3): δ 8.63 (s. 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.23 (d. J = 8.7Hz, 1H), 7.60 (d, J = 8.7 Hz. 1H), 7.24-7.48 (m. 9 H), 7.10 (dd, J = 2.5, 8.7 Hz, 1 H), 5.12 (s, 2H), 3. 58 (m, 2 H), 3.26 (m, 2 H), 2.08 (m, 2 H), 1.98 (brs, 1 H), 1.84 (m, 2 H), 1.37 (s, 3 H).

Example 89 20 (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-benzyl)-dimethyl-amine.

i The same procedure that used for Example 6 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yi]-quinolin-8-yl ester 77E -116- 1 2 098 was used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F to give the title compound 89. C.l. m/z 453 [M+1]; 1H NMR (CDCI3) δ 8.57 (s, 1 H), 8.31 (d, J « 9.1 Hz, 1 H), 7.99 (d, J = 9.1Hz, 1 H), 7.80 (m, 1 H), 7.77 (m, 1 H), 7.65 (m, 3 H), 7.57 (m, 1 H), 7.44 (d. J = 8.1 Hz, 2 H), 5 7.26 (d, J - 2.5 Hz, 1 H), 6.81 (dd, J = 2.5, 9.1, 1 H), 4.15 (m, 2 H), 3.77 (m, 2 H), 3.56 (s, 2 H), 3.45 (s, 3 H), 2.33 (s, 6 H).

Example 90 (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-methyl-amine.

The same procedure that used for Example 5 was foilowed with the exception trifiuoro-jq methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)- quinolin-8-yl ester 1E in example 1F to give the title compound 90. C.l. m/z 439 [M+1]; ’H NMR (CDCI3) δ 8.56 (s. 1 H), 8.31 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 9.1Hz, 1 H). 7.80 (m, 1 H), 7.75 (m, 1 H), 7.63 (m, 3 H), 7.56 (m, 1 H), 7.43 (d, J = 7.9 Hz, 2 H), 15 7.23 (d, J * 2.5 Hz, 1 H), 6.80 (m, 1 H), 4.14 (m, 2 H), 3.87 (s, 2 H), 3.76 (m, 2 H), 3.43 (s, 3 H), 2.53 (s, 3 H)

Example 91 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-morpholin-4-ylmethyl-phenyl)-quinofne.

I 4 1 2098

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinQlin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl>-quinolin-8-yi ester 1E in example 1F and morpholine was used in the place of methylamine inexample 5B to give the title compound 91. C.l. m/z 495 [M+1]; ’H NMR (CDCI3) δ 8.56 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 8.7Hz, 1 H), 7.81 (m, 1 H), 7.76 (m, 1 H), 7.65 (m, 3 H), 7.57 (m, 1 H), 7.43 (d, J = 7.9 Hz. 2 H), 7.25 (d, J = 2.5 Hz, 1 H), 6.80 (dd, J - 2.5, 9.1, 1 H), 4.15 (m, 2 H), 3.78 (m, 6 H), 3.62 (s, 2H), 3.46 (s, 3 H), 2.85 (m, 4 H)

Example 92 2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-f-yl]-quinolin-8-yl}-benzyiam(no)-ethanol.

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethQxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and ethanolamine was used in the place of methylaminein example 5B to give the title compound 92. C.l. m/z 469 [M+1]; ’H NMR (CD3OD) δ 8.63 (s, 1 H), 8.14 (d, J = 9.1 Hz, 1 H), 7.71 (d, J = 9.1Hz, 1 H), 7.68 (dd, J = 2.2,7.9 Hz, 1 H), 7.59 (d, J = 9.1 Hz, 1 H), 7.54 (dd, J - 2.2, 7.0 Hz, 1H), 7.43 (m, 1 H), 7.35 (d, J = 8.3 Hz, 2 H), 7.28 (d, J = 8.3 Hz, 2 H), 6.99 (d, J = 2.5 Hz, 1 H), 6.50 (m, 1 H), 4.00 (m, 2 H), 3.83 (s, 2 H), 3.70 (m, 4 H), 3.41 (s, 3 H), 3.21 (m, 2 H)

Example 93 4-{2-[5-(2-Methoxy-ethoxy)-benzoÎmidazol-1-yl]-quinolin-8-yl}-benzylamine. -118- 1 2098

The same procedure that used for Example 78 was followed with the exception that 4-aminomethylphenylboronic acid hydrochloride was used in the place 2-methoxy-5-pyridineboronic acid and the number of équivalents of potassium phosphate was doubled togive the title compound 93. C.l. m/z 425 [M+1]; 1H NMR (CD3OD) δ 8.69 (s, 1 H), 8.21 (d, J = 9.1 Hz, 1 H), 7.77 (d, J = 8.7Hz, 1 H), 7.73 (m, 1 H), 7.66 (d, J = 9.1 Hz, 1 H), 7.59 (dd, J = 1.7, 7.0 Hz, 1 H). 7.48 (m, 1 H), 7.41 (d, J = 8.3 Hz, 2 H), 7.32 (d. J = 8.3 Hz, 2 H), 7.01 (d, J = 2.5 Hz, 1 H), 6.54 (d, J = 2.5, 9.1 Hz, 1 H), 4.02 (m, 2 H), 3.86 (s, 2 H), 3.71 (m, 2 H), 3.41 (s, 3 H).

Example 94 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(4-pyrrolidin-1-ylmethyl-phenyl)-quindine.

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yI]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and pyrrotidine was used in the place of methylamine inexample 5B to give the title compound 94. C.l. m/z 479 [M+1]; 1H NMR (CD3OD) δ 8.72 (s, 1 H), 8.22 (d, J = 9.1 Hz, 1 H), 7.79 (d, J = 9.1Hz, 1 H), 7.74 (m, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.57 (dd, J = 1.7,7.0 Hz, 1 H), 7.48 (ra, 1 H), 7.36 (d, J « 8.3 Hz, 2 H), 7.27 (d, J · 8.3 Hz, 2 H), 7.03 (d, J = 2.5 Hz, 1 H), 6.50 (m, 1 H),4.02 (m, 2 H), 3.70 (m, 2 H), 3.65 (s, 2 H), 3.41 (s, 3 H), 2.55 (m, 4 H), 1.80 (m, 4 H). 15 -119- 1 2 098

Example 95 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylî-8-(4-pyrrolidin-1-ylmethyl-phenyl)-quinoline.

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-(5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolÎn-8-yl ester 77Ey was used in the place of trifiuoro-metbanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and piperidine was used in the place of methytamine h example 5B to give the title compound 95. C.l. m/z 493 [M+11; ’H NMR (CDCI3) δ 8.56 (s, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 9.1

Hz, 1 H), 7.78 (dd, J = 1.2,7.9 Hz, 1 H), 7.76 (m, 1 H), 7.64 (m, 3 H), 7.56 (m, 1 H), 7.45 (d, JtQ = 7.9 Hz, 2 H), 7.25 (d, J = 2.5 Hz, 1 H), 6.81 (d. J = 2.5,9.1 Hz, 1 H), 4.15 (m, 2 H), 3.77 (m, 2 H), 3.60 (s, 2 H), 3.46 (s, 3 H), 2.48 (m. 4 H), 1.63 (m, 4 H), 1.47 (m, 2 H).

Example 96 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-{4-pyffolidin-1-ylmethyl-phenyl)-quinoline.

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-(5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yi ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and azetidine was used in the place of methylamine inexample 5B to give the title compound 96. 1 2038 -120- C.l. m/z 465 [M+1]; ’H NMR (CD3OD) δ 8.68 (s, 1 H), 8.17 (d, J = 9.1 Hz, 1 H), 7.72 (d, J = 9.1Hz. 1 H), 7.71 (m, 1 H), 7.62 (d, J = 9.1 Hz, 1 H), 7.54 (dd, J = 1.7, 7.0 Hz, 1 H), 7.44 (m, 1 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.19 (d, J = 7.9 Hz, 2 H), 7.02 (d, J = 2.5 Hz, 1 H), 6.49 (dd, J = 2.5, 9.1 Hz, 1 H), 4.01 (m, 2 H), 3.70 (m, 2 H), 3.60 (s, 2 H), 3.41 (s, 3 H), 3.26 (m, 4 H), 2.09 (m, 2 5 H).

Example 97 1-(4-42-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-cis-pyrralidine-3,4-

The same procedure that used for Example 5 was followed with the exception that trifluoro-10 methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester -1E in example 1F and cis-pyrrolidine-3,4-diol was used in the place of methylamine in example 5B to give the title compound 97. C.l. m/z 511 [M+1]; ’H NMR (CD3OD) δ 8.68 (s, 1 H), 8.18 (d, J = 9.1 Hz, 1 H), 7.74 (d, J = 9.1Hz, 1 H), 7.71 (dd, J » 1.3, 8.3 Hz, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.54 (dd, J = 1.3, 7.0 Hz, 1H). 7.44 (m, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.00 (d, J = 2.5 Hz, 1 H), 6.50 (m, 1 H), 4.14 (m, 2 H), 4.01 (m, 2 H), 3.71 (m, 2 H), 3.66 (s, 2 H), 3.42 (s, 3 H), 2.96 (m,2 H), 2.55 (m. 2 H).

Example 98 20 R.R-0 -(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-^}-benzyl)-trans- pyrrolidine-3,4-diol). -121-

S»· 1 2098

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-{5-(2-methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in step 1F and R,R-trans-pyrrolidine-3,4-diol was used in the place of 5 methylamine in step 5B to give the title compound 98. C.l. m/z 511 (M+1J; Ή NMR (CD3OD) δ 8.87 (s, 1 H), 8.40 (d, J » 8.7 Hz, 1 H), 7.96 (d, J = 9.1Hz. 1 H), 7.88 (m, 2 H), 7.71 (dd. J = 1.2, 7.0 Hz, 1 H), 7.58 (m, 1 H), 7.54 (d. J = 8.3 Hz, 2 H),7.44 (d, J = 8.3 Hz, 2 H), 7.12 (d. J - 2.5 Hz, 1 H), 6.67 (dd, J - 2.5, 9.1 Hz, 1 H), 4.10 (m, 4H), 3.77 (m, 4 H), 3.44 (s, 3 H), 3.04 (m, 2 H), 2.60 (m, 2 H). l0 Example 99 1-(4-{2-[5-(2-Methoxy-ettioxy)~benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-pyrrolidin-3-ol.

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quînolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)- 12 quinolin-8-yl ester 1E in example 1F and racemic 3-pyrrolidinol was used in the place ofmethylamine in example 5B to give the title compound 99. C.l. m/z 495 [M+1J; 1H NMR (CD3OD) δ 8.60 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.7Hz, 1 H), 7.63 (m, 1 H), 7.53 (d, J - 9.1 Hz, 1 H), 7.49 (dd, J = 1.2, 7.1 Hz. 1 H), 7.39 (m, 1 H), 7.39 (d, J » 8.3 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H), 6.97 (d, J = 2.5 Hz, 1 H), 6.44 (dd, J ~ 2.5, -122- 1 2.098 9.1 Hz, 1 H), 4.35 (m, 1 H), 3.98 (m, 2 H), 3.69 (m, 2 H), 3.61 (d, J = 12.5 Hz, 1 H), 3.57 (d, JS 12.5 Hz, 1 H), 3.41 (s, 3 H), 2.82 (m, 1 H), 2.67 (m, 1 H), 2.48 (m, 2 H), 2.12 (m, 1 H), 1.70(m, 1 H).

Example 100 R-(1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-pynolidin-3-ol).

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and R-3-pyrrolidinol was used in the place ofmethylamine in example 5B to give the title compound 100. C.l. m/z 495 [M+1 ]; 1H NMR (CD3OD) δ 8.69 (s, 1 H), 8.19 (d, J = 9.1 Hz, 1 H), 7.76 (d, J = 9.1Hz, 1 H), 7.71 (m, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.55 (dd, J = 1.3,7.0 Hz, 1 H), 7.46 (m, 1 H), 7.34 (d, J = 8.3 Hz, 2 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.01 (d, J - 2.5 Hz, 1 H), 6.49 (dd, J - 2.5,

9.1 Hz, 1 H), 4.36 (m, 1 H), 4.01 (m. 2 H), 3.70 (m, 2 H), 3.67 (d, J = 12.5 Hz, 1 H), 3.62 (d, J <5 « 12.5 Hz, 1 H), 3.42 (s, 3 H), 2.84 (m, 1 H), 2.70 (m, 1 H), 2.55 (m, 1 H), 2.50 (m, I H), 2.15 (m, 1 H), 1.72 (m, 1 H).

Example 101 S-( 1 -{442-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-benzyl)-pyrrolidin-3-ol). -123- 1 2 098

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and S-3-pyrrolidinol was used in the place of 5 methylamine in example 5B to give the title compound 101. C.l. m/z495 [M+1J; 1H NMR (CD3OD) δ 8.84 (s, 1 H), 8.37 (d, J = 8.7 Hz, 1 H), 7.93 (d, J = 9.1Hz, 1 H), 7.86 (m, 2 H), 7.68 (dd, J = 1.7,7.1 Hz, 1 H), 7.56 (m, 1 H), 7.53 (d, J = 7.9 Hz, 2 H), 7.40 (d, J = 7.9 Hz, 2 H), 7.11 (d, J = 2.5 Hz, 1 H), 6.63 (dd, J » 2.5, 9.1 Hz, 1 H), 4.39 (m, 1H). 4.09 (m, 2 H), 3.74 (m, 4 H), 3.43 (s, 3 H), 2.90 (m, 1 H), 2.76 (m, 1 H), 2.62 (m, 1 H), 2.52 10 (m, 1 H), 2.19 (m, 1 H), 1.75 (m, 1 H).

Example 102 1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoIin-8-yl}-benzyl)-azetidin-3-ol.

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77E 15 was used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and azetidin-3-ol was used in the place of methylamine inexample 5B to give the title compound 102. C.l. m/z 481 [M+1]; Ή NMR (CD3OD) δ 8.52 (s, 1 H), 8.00 (d. J = 9.1 Hz, 1 H), 7.63 (d, J = 8.7Hz, 1 H), 7.56 (dd, J = 2.3,7.9 Hz, 1 H), 7.45 (m, 2 H), 7.33 (m, 1 H), 7.26 (d, J = 8.3 Hz, 2 H), 20 7.15 (d, J = 8.3 Hz, 2 H), 6.96 (d, J = 2.5 Hz. 1 H), 6.46 (dd, J = 2.5, 8.7 Hz, 1 H), 4.86 (brs, 1 -124· 1 2098 H), 4.37 (m, 1 H), 3.96 (m, 2 H), 3.68 (m, 2 H), 3.63 (s, 2 H), 3.59 (m, 2 H), 3.40 (s, 3 H), 2.98(m, 2 H).

Example 103 2-[5-(2-Methoxy-ethoxy)-benzoirnidazol-1-yl]-8-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]- quinoline.

The same procedure thaï used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yll-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and 1-methyfpiperazine was used in the place of 10 methylamine in example 5B to give the title compound 103. C.l. m/z 508 [M+1]; 1H NMR (CDCI3) δ 8.56 (s, 1 H). 8.30 (d, J = 9.1 Hz. 1 H). 7.98 (d, J = 8.7Hz, 1 H). 7.80 (m. 1 H), 7.75 (m, 1 H). 7.62 (m, 3 H), 7.57 (m, 1 H), 7.44 (d, J = 8.3 Hz, 2 H),7.24 (d, J = 2.1 Hz, 1 H), 6.80 (dd, J = 2.5, 8.7 Hz, 1 H), 4.15 (m, 2 H), 3.77 (m, 2 H), 3.62 (s,2 H), 3.45 (s, 3 H), 2.70 (m, 8 H), 2.30 (s, 3 H). 15 Example 104 4-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyO-piperazine-1-carboxylic acid tert-butyl ester.

-125- 1 2 09 8

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E in example 1F and 1-tert-butoxycarbonyl-piperazine was used in the 5 place of methylamine in example 5B to give the title compound 104. C.l. m/z 594 [M+1]; ’H NMR (CDCi3) δ 8.58 (s, 1 H), 8.35 (d, J = 9.1 Hz, 1 H), 8.00 (d, J = 9.1Hz, 1 H). 7.82 (m, 1 H), 7.78 (m, 1 H), 7.67 (m, 3 H), 7.60 (m, 1 H), 7.47 (d, J = 7.9 Hz, 2 H), 7.26 (d, J = 2.1 Hz, 1 H), 6.83 (dd, J = 2.5, 8.7 Hz, 1 H), 4.17 (m. 2 H), 3.79 (m, 2 H), 3.64 (s,2 H), 3.49 (m, 4 H), 3.46 (s, 3 H), 2.50 (m, 4 H), 1.45 (s, 9 H). 10 Example 105 [1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-piperidin-4-yl]-

The same procedure that used for Example 5 was followed with the exception that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77E 15 was used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl>-quinolin-8-yl ester 1E in example 1F and 4-N-tert-butoxycarbonyl-aminopiperidine was used inthe place of methylamine in example 5B to give the title compound 105. C.l. m/z 608 [M+1]; 1H NMR (CD3OD) δ 8.92 (s, 1 H), 8.48 (d, J = 9.1 Hz, 1 H), 8.04 (d, J 9.1Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 7.92 (m, 1 H), 7.75 (m, 1 H), 7.61 (m, 3 H). 7.45 (d, J « 7.9 20 Hz. 2 H), 7.16 (d, J « 2.5 Hz, 1 H), 6.65 (dd, J = 2.5,8.7 Hz, 1 H), 4.12 (m, 2 H), 3.77 (m, 2 H), 3.65 (s, 2 H), 3.44 (s, 3 H), 3.41 (m, 1 H), 3.00 (m, 2 H), 2.22 (m, 2 H), 1.88 (m, 2 H), 1.75 (m,2 H), 1.42 (s, 9 H).

Example 106 1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-piperidin-4-ylamine. -126- 1 2098

[1-{4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinolin-8-yl}-benzyi)-piperidin-4-yl]-carbamic acid tert-butyl ester 105 (110 mg, 0181 mMoI) was dissolved in a solution of 3 mL ofTFA and 3 mL of DCM under an atmosphère of dry N2. The réaction mixture was stirred for40 minutes aller which time it was concentrated under vacuum and the resulting residue was 5 partitioned between DCM and 1 N aqueous NaOH. The DCM layer was then washed withagain with 1 N aqueous NaOH, dried over Na2SO4, filtered and concentrated under vacuum togive 45 mg of the tille compound 106. C.l. m/z 508 [M+1]; Ή NMR (CDCI3) δ 8.55 (s, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 9.1Hz, 1 H), 7.78 (d, J = 8.3 Hz. 1 H), 7.76 (m, 1 H), 7.60 (m, 4 H), 7.42 (d, J = 7.9 Hz, 2 H), 7.23 10 (d, J = 2.5 Hz, 1 H), 6.80 (m, 1 H), 4.14 (m, 2 H), 3.76 (m, 2 H), 3.59 (s, 2 H), 3.44 (s, 3 H), 2.93 (m, 2 H), 2.68 (m, 1 H), 2.11 (m, 2 H), 1.94 (brs, 2 H), 1.80 (m, 2 H), 1.45 (m, 2 H).

Example 107 (142-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoiin-8-yl}-piperidin-4-yl)-methanol.

15

The same procedure that was used in example 1 was foilowed except that trïluoro-methanesuifonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77Ewas used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazoH-yl)- i quinoiin-8-yl ester 1E and 4-(hydroxymethyl)-piperidine was used in the place of piperidin-4-yl-carbamic acid tert-butyl ester in example 1F to give the title compound 107 as a yellowsolid. C.l. m/z 433 [M+1]; 1H NMR (CDCI3) δ 8.66 (s, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.29 (d, J = 9.1

Hz, 1 H), 7.67 (d, J « 8.7 Hz, 1 H), 7.47 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.28 (m, 1 H), 7.10 20 -127- 1 2 098 (dd, J = 2.5, 9.1 Hz, 1 H), 4.21 (m, 2 H). 3.95 (m, 2 H), 3.80 (m, 2 H), 3.63 (m, 2 H), 3.47 (s, 3H), 2.83 (m, 2 H), 1.95 (m, 2 H), 1.75 (m, 3 H).

Exemple 108 ( 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin~4-ylmethyl)-methyl-amine.

Example 108 A 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl)-piperidine-4-carbaldehyde. (1-{2-{5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinolin-8-yl}-piperidin-4-yl)-methanol 107(1.47 g, 3.40 mMol) was dissolved jn 15 mL of anhydrous DCM under an atmosphère of dry 10 ,N2· T° tt>is mixture was added ~2 gm of 4A molecular sieves, 4-methylmorpholine N-oxide(1.19 g, 10.2 mMol) and flnally tetrapropylammonium perruthenate (119 mg, 0.340 mMoi).The mixture was stirred at ambient température over night after which time it was filteredthrough Celite™. The Celite™ was washed with DCM and the resulting combined filtrate wasconcentrated under vacuum. The resulting residue was chromatographed on flash silica geleluting with a gradient from MeOH/DCM (1/99) to MeOH/DCM (2/98) to give 446 mg of thetitle compound 108A.

Example 108B (1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8~yl}-piperidin-4-ylmethyl)-rnethyl-amine. 2Q 1 -{2-[5-(2-Metioxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidine-4-carbaldehyde 108A(100 mg, 0.2J2 mMol) was dissolved in 1 mL of MeOH under an atmosphère of dry N2. Tothis solution vas added 580 pL of a 2.0 M solution of methylamine in MeOH. AcOH (-100 pL)was added to this solution until the pH ~ 5 after which time NaCNBH3 (30 mg, 0.46 mMol) wasadded to the mixture. The reaction mixture was stirred overnight at ambient température. 2« The reactim mixture was then concentrated under vacuum and partitioned between DCM and -128- 1 2 098 1 N aqueous NaOH. The DCM layer was saved and washed again with 1 N aqueous NaOH,dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue waschromatographed on flash silica gel eluting with a gradient from MeOH/DCM (3/97) toMeOH/DCM (5/95) and then a gradient from MeOH/DCM/NH4OH (7/92.9/0.1) to 5 MeOH/DCM/NH4OH (9/90.9/0.1 ) to give 60 mg of the title compound 108 as a yellow solid. C.l. m/z 446 [M+1]; Ή NMR (CD3OD) δ 8.96 (s, 1 H), 8.68 (d, J = 9.1 Hz, 1 H), 8.44 (d, J = 9.1Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.57 (d, J « 7.9 Hz, 1 H), 7.49 (m, 1 H), 7.34 (d, J = 7.9 Hz,1 H), 7.27 (d, J = 2.5 Hz, 1 H), 7.10 (dd, J = 2.5, 9.1 Hz, 1 H), 4.19 (m, 2 H), 3 86 (m, 2 H), 3.79 (m, 2 H), 3.45 (s, 2 H), 2.78 (m, 2 H), 2.63 (m, 2 H), 2.45 (s, 3 H). 1.92 (m, 2 H), 1.68 (m, ο 3H>·

Example 109 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-8-[4-(4-methyl-piperazin-1 -ylmethyl)-piperidin-1 -yl]-quinoline.

The same procedure that was used in example 108 was followed except that 1-t5 methylpiperazine was used in the place of methylamine in example 108B to give the title compound 109. C.l. m/z 515 [M+1]; 1H NMR (CD3OD) δ 8.79 (s, 1 H), 8.48 (d, J = 9.1 Hz, 1 H), 8.19 (d, J - 8.7Hz, 1 H), 7.67 (d, J = 9.1Hz, 1 H). 7.38 (m, 2 H), 7.16 (d, J « 2.1 Hz, 1 H), 7.12 (d, J = ?.4 Hz,1 H), 6.90 (m, 1 H). 4.11 (m, 2 H). 3.75 (m, 2 H), 3.63 (m. 2 H). 3.43 (s, 3 H), 2.20-2.60<m, 15 2Q H), 1.76 (m, 2 H), 1.55 (m. 1 H), 1.45 (m, 2 H).

Example 110 (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinolin-8-yl}-piperidin-4-ylmethyl)-dimet^yl- amine. -129- 1 2 098 /

The same procedure that was used in example 108 was followed except that dimethylaminewas used in the place of methylamine in step 108B to give the title compound 110. C.l. m/z 460(M+1]; 1H NMR (CD3OD) δ 8.85 (s, 1 H), 8.55 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7Hz, 1 H), 7.76 {d, J = 8.7 Hz, 1 H), 7.45 (d, J = 7.9 Hz, 1 H), 7.40 (m, 1 H), 7.21 (m, 2 H), 6.98 5 (dd, J = 2.1, 9.1 Hz, 1 H), 4.14 (m, 2 H), 3.75 (m, 4 H), 3.43 (s, 3 H), 2.64 (m, 2 H), 2.27 (m, 2H), 2.24 (s, 6 H), 1.83 (m, 2 H), 1.63 (m, 1 H), 1.54 (m, 2 H).

Example 111 , 1-(1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoH-yl]-quinolin-8-yl}-piperidin-4-ylmethyl)- pyrrolidin-3-ol.

, The same procedure that was used in exàmple 108 was followed except that racemic 3-pyrrolidinol was used in the place of methylamine in example 108B to give the title compound 111. C.l. m/z 502 [M+1]; 1H NMR (CD3OD) δ 8.93 (s, 1 H), 8.65 (d, J = 8.7 Hz, 1 H), 8.39 (d, J = 8.7Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.55 (m, 1 H), 7.46 (m, 1 H), 7.30 (dd, J = 1.3, 7.5 Hz, 1 H), 15 7.25 (d, J = 2.1 Hz, 1 H), 7.06 (m, 1 H), 4.35 (m, 1 H), 4.18 (m, 2 H), 3.78 (m, 4 H), 3.45 (s, 3 H), 2.86 (m, 1 H), 2.74 (m, 3 H), 2.58 (m, 1 H), 2.50 (m, 3 H), 2.12 (m, 1 H), 1.93 (m, 2 H),1,60-1-75 (m, 4 H). -130- 1 2098

Example 112 C-( 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yfJ-quinolin-8-yl}-piperidin-4-yi)-methylamine.

The same procedure that was used in example 108 was followed except that ammoniumacetate was used in the place of methylamine in example 108B to give the tiüe compound 112. C.l. m/z 432 [M+1]; 1H NMR (CD3OD) δ 8.91 (s, 1 H), 8.61 (d. J = 8.7 Hz, 1 H), 8.37 (d, J = 8.7Hz, 1 H), 7.85 (d, J = 8.7 Hz, 1 H), 7.52 (d, J = 7.1 Hz, 1 H), 7.45 (m, 1 H), 7.29 (d, J = 7.5 Hz,1 H), 7.23 (d. J = 2.1 Hz, 1 H). 7.04 (dd, J = 2.5, 9.1 Hz, 1 H), 4.17 (m, 2 H), 3.79 (m, 4 H).3.44 (s, 3 H), 2.65-2.80 (m, 4 H), 1.89 (m, 2 H), 1.60 (m, 3 H). 10 Example 113 1-{2-[5-(2-Dimethylamino-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-4-methyl-piperidin-4-ol.

1-[8-(4-Hydroxy-4-methyl-piperidin-1-yl)-quinolin-2-yi]-1H-benzoimidazol-5*ol. s 1-[2-(5-Benzyloxy-benzoimidazol-1-yl}-quinolin-8-yl]-4-methyl-piperidÎn-4-ol 88 (535 mg, 1.1515 mMol) was dissolved in 5 mL of anhydrous OCM under an atmosphère of dry N2. The solution -131- 1 2098 was then cooled to 0°C after which time 32 gL of NEt3 and 1.50 mL of a 1 M solution ofdimethylbromoborane in DCM were added. The reaction mixture was allowed to warm up toambient température and reacted at this température for - 2 hours. The mixture was thenpartitioned between iso-propanol/DCM (18/82) and saturated aqueous NaHCO3. Theaqueous layer was extracted two more times with iso-propanol/DCM. The organic extractswere combined, dried over Na2SO4, filtered and concentrated under vacuum to give a yellowsolid. The solid was chromatographed over flash silica gel eluting with MeOH/DCM/NH4OH(4/95.8/0.2) to give189 mg of the tifle compound 113A as yellow solid.

Example 113B IC . -,-{2-[5-(2-Dimethylamino-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-4-methyl-piperidin-4-ol. 1-[8-(4-Hydroxy-4-methyl-piperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-ol 113A (189 mg,0.505 mMol), CS2CO3 (592 mg, 1.81 mMol), sodium iodide (76 mg, 0.505 mMol) and (2-dimethylamino)ethyl chloride hydrochloride (87 mg, 0.61 mMol) were added to 2 mL tifanhydrous DMF and the resulting mixture was heated to 80°C under an atmosphère of dry N2. 15 The reaction was run for 48 hours after which time it was cooled to ambient température andconcentrated under vacuum. The residue was chromatographed over flash silica gel elutingwith a gradient starting from MeOH/DCM (3/97) to MeOH/DCM (8/92) then switched toMeOH/DCM/NH4OH (8/91.8/0.2) to give 67mg of the tifle compound 113 as a yellow oil. s< >1 C.l. m/z 446 (M+1 J; Ή NMR (CDCI3): δ 8.64 (s, 1 H), 8.33 (d, J » 8.7 Hz, 1 H), 8.29 (d, J « 8.7 20 Hz, 1 H). 7.66 (d, J = 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.28 (dd, J = 2.9, 5.8

Hz, 1 H), 7.08 (dd, J - 2.5,9.1 Hz, 1 H), 4.20 (m, 2 H), 3.60 (m, 2 H), 3.26 (m, 2 H), 2.86 (m, 2H), 2.41 (s, 6 H), 2.10 (m, 2 H), 1.85 (m, 2 H), 1.38 (s, 3 H). .

Example 114 1-{2-[5-(2-Dimethylamino-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-pÎperidin-4-ol.

OH -134- 1 2 098 8.3 Hz, 2 H), 7.51 (d, J = 8.3 Hz, 2 H), 7.17 (d. J = 2.5 Hz, 1 H), 6.74 (dd, J = 2.5, 9.1 Hz, 1H), 4.13 (m, 4 H), 3.88 (d J » 12.5 Hz, 1 H), 3.82 (d, J = 12.5 Hz, 1 H), 3.77 (m, 2 H), 3.44 (s,3 H), 3.11 (m, 2 H), 2.67 (m, 2 H).

Example 116 3 4-{2-[5-(3-Amino-propoxy)-benzoimidazol-1-ylJ-quinolin-8-yi}-phenol.

Trifluoro-methanesulfonic acid 2-(5-hydroxy-benzoimidazol-1-yl)-quinolin-8-yl ester.

Trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester77E (2.00 g, 4.28 mMol) was suspended in 20 mL of anydrous DCM under an atmosphère ofdry N2. To this heterogeneous solution was added 12.9 mL of a solution of 1 Mborontribromide in DCM and the resulting mixture was stirred at ambient température for 24hours. The réaction mixture was then poured into ice water. The resulting heterogeneousmixture was neutralised with the addition of NaHCO3 and then partitionea betweenisopropanol/DCM (18/82) and aqueous saturated NaHCO3. The organic layer was washed 15 again aqueous saturated NaHCO3, dried over Na2SO4, filtered, concentrated under vacuum togive 890 mg of a brownish yellow solid as the title compound 116A.

Example 116B

Trifluoro-methanesulfonic acid 2-[5-(3-tert-butoxycarbonylamino-propoxy)-benzoireidazol-1 -yij-quinolin-8-yl ester. 20 , (3-Hydroxy-propyl)-carbamic acid tert-butyl ester (180 mg, 1.03 mMol) was dissolved in 7 mLof anhydrous THF was under an atmosphère of dry N2. Trifluoro-methanesulfonic acid 2-(5-hydroxy-benzoimidazol-1-yl)-quinolin-8-yl ester 116A (420 mg, 1.03 mMol) and triphenylphosphine (538 mg, 2.05 mMol) were added to the solution resulting in a brownheterogeneous solution. A solution of 320 pL of diethyl azodicarboxylate dissolved in 3 mL of 25 anhydrous THF was then added. After - 30 minutes, the reaction mixtured was concentrated -135- 1 2098 under vacuum and the residue was chromatographed on flash siiica gel eluting withMeOH/DCM/NH4OH (1/98.8/0.2) to glve 184 mg of the title compound 116B.

Example 116C

[3-( 1 -{8-[4-(T etrahydro-pyran-2-yloxy)-phenyl]-quinolin-2-yl}-1 H-benzoimidazol-5-yloxy )-propylj-carbamic acid tert-butyl ester.

Trifluoro-methanesulfonic acid 2-[5-(3-tert-butoxycarbonylamino-propoxy)-benzoimidazol-1 -yl]-quinolin-8-yl ester 116B (144 mg, 0.254 mMol), was dissolved in 1.0 mL of 1,4-dioxaneunder an atmosphère of dry N2. To this solution were added 4-hydroxyphenyl boronic acidtertrahydropyranyl ether (67 mg, 0.31 mMol), potassium phosphate (108 mg, 0.508 mMol) andtetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mMol). The reaction mixture washeated to 100°C and reacted overnight at this température in a seal tube. The réactionmixture was then cooled to ambient température, concentrated under vacuum and the residuewas taken up in DCM. The resulting heterogeneous solution was filtered and the filter cakewas washed several times with DCM/MeOH (~1:1). The filtrâtes were combined andconcentrated under vacuum and the resulting residue was chromatographed on flash siiicagel eluting with MeOH/DCM/NH4OH (1.5/98.3/0.2) to give 128 mg of the title compound 116C.

Example 116D 4-{2-[5-(3-Amino-propoxy)-benzoimidazol-1-ylî-quinolin-8-yl}-phenol. i [3-(1-{8-(4-(Tetrahydro-pyran-2-yloxy)-phenylJ-quinolin-2-yl}-1H-benzoimidazol-5-yloxy)-propylj-carbamic acid tert-butyl ester 116C (128 mg, 0.215 mMol) was dissolved in 1 mL ofTFA under an atmosphère of dry N2 and was then stirred for 10 minutes. The réaction mixturewas concentrated under vacuum and the resulting residue was partitioned betweenisopropanol/DCM (18/82) and aqueous saturated NaHCO3. The organic layer was dried overNa2SO4, filtered and concentrated under vacuum to give a brown oil. The oil was purified viaHigh Pressure Liquid Chromatography (C-8· reverse phase; linear gradient from 0.01% HCl inwater to 0.01% HCl /acetonitrile (over 15 minutes) to give 19 mg of the title compound 116 asa white solid which was further purified by recrystallizing from EtOH to give 9 mg of the titlecompound as the bis-HCI sait. C.l. m/z 411 [M+1J; ’H NMR (CD3OD) δ 9.75 (s, 1 H), 8.61 (d, J = 8.7 Hz, 1 H), 8.19 (d, J - 9.1Hz, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 7.95 (m, 1 H), 7.80 (d, J « 6.2 Hz, 1 H), 7.70 (m, 1 H), 7.45 -136- 1 2098 (d, J = 8.3 Hz. 2 H). 7.30 (m. 1 H). 6.95 (m, 1 H). 6.94 ( d, J = 8.3 Hz, 2 H), 4.20 (m, 2 H), 3.29(m, 2 H). 2.20 (m, 2 H). !

Example 117 4-{2-[5-(3-Dimethylamino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol.

$ The same procedure that was used in example 4 was followed except that 4-{2-[5-(3-amino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol 116 was used in the place of 1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine 1 to give the title compound 117. C.l. m/z 439 [M+1]; 1H NMR (CD3OD) 8 8.82 (s. 1 H), 8.33 (d, J = 8.7 Hz. 1 H). 7.99 (d. J = 9.1 |0‘ Hz, 1 H). 7.80 (m, 2 H). 7.66 (m, 1 H). 7.52 (m. 1 H). 7.39 (d, J = 8.3 Hz, 2 H), 7.07 (d. J = 2.5

Hz, 1 H), 6.90 ( d, J = 8.3 Hz, 2 H), 6.65 (dd. J = 2.5, 9.1 Hz, 1 H), 3.99 (m, 2 H), 2.75 (m, 2H), 2.46 (s, 6 H). 2.00 (m, 2 H).

Example 118 1-[2-(5-Phenyl-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine. NHa

‘H’ 1 2 098 -137-

Example 118A T rifluoro-methanesulfonic acid 1 -[8-(4-tert-butoxycarbonylamino-piperidin-1 -yl)-quinoIin-2-yl]-1H-benzoimidazol-5-yl ester. {1 -[2-(5-Hydroxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butylester 3A (2.37 g, 5.17 mMol) was dissolved in 35 mL of anhydrous THF under an atmosphèreof dry Na. To this solution were added triethylamine (790 pL, 5.68 mMol) followed by N-phenyl-bis(trifluoromethanesulfonamide) (2.02 g, 5.68 mMol). The reaction mixture wasreacted at this température for 2 days. The yeliow precipitate was coilected via suctionfiltration, washed with isopropylether and dried under vacuum to give 1.48 g of the titlecompound as a yeliow solid.

Example 118B {1-[2-(5-Phenyl-benzoimidazol-1-yl)-quinolin-8-yll-piperidin-4-yl)-carbamic acid tert-butyl ester.

Trifluoro-methanesulfonic acid 1 -(8-(4-tert-butoxycarbonylamino-piperidin-1 -yl)-quinoiin-2-yl]-1H-benzoimidazol-5-yl ester 118A (150 mg, 0.253 mMol), was dissolved in 2.0 mL of 1,4-dioxane under an atmosphère of dry Nz. To this solution were added phenylboronic acid (46mg, 0.38 mMol), potassium phosphate (161 mg, 0.759 mMol) andtetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mMol). The reaction mixture washeated to 100°C and reacted ovemight at this température. The reaction mixture was thencooled to ambient température, concentrated under vacuum and the residue was partitionedbetween DCM and aqueous saturated NaHCO3. The OCM layer was washed again withaqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum togive a yeliow oil. The resuiting oil was chromatographed on flash siiica gel eluting withEtOAc/Hexanes (70:30) to give 121 mg of the title compound 118B.

Example 118C 1 -[2-(5-Phenyl-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidÎn-4-ylamine.

{1-[2-(5-Phenyl-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl)-carbamic acid tert-butyl ester118B (121 mg, 0.233 mMol) was dissolved in 0.50 mL of TFA under an atmosphère of dry N2and was then stirred for 45 minutes. The reaction mixture was concentrated under vacuumand the resuiting residue was partitioned between DCM and aqueous 1 N NaOH. The DCM 1 2 098 -138- layer was washed again with concentrated under vacuum and the resulting residue waspartitioned between DCM and aqueous, dried over Na2SO4, fiitered and concentrated undervacuum to give a yellow oil as the title compound 118. Compound 118 was dissolved in DCMand then 3 mL of 1 N HCl in ethyl ether was added to the mixture. The resulting precipitate 5 was collected via suction filtration and dried under vacuum to give 91 mg of the titlecompound 118 as the bis-HCI sait. C.l. m/z 420 [M+1]; 1H NMR (CD3OD) δ 10.49 (s, 1 H), 8.84 (d, J = 8.7 Hz, 1 H), 8.80 (d, J = 9.1 Hz, 1 H), 8.27 (d, J » 8.7 Hz, 1 H), 8.16 (m, 2 H). 7.91 (m, 1 H), 7.80 (m, 4 H), 7.53 (m, 2H), 7.44 (m, 1 H), 4.12 (m, 2 H), 3.50 (m. 1 H), 3.38 (m, 2 H), 2.36 (m, 4 H). 10 Example 119 1-[2-(5-Pyridin-4-yl-benzoimidazol-1-yi)-quinolin-8-yl]-piperidin-4-ylamine.

The same procedure that was used in example 118 was followed except that 4-pyridylboronicacid was used in the place of phenylboronic acid in step 118B to give the title compound 119as the free base, 15 C.l. m/z 421 [M+1 J; Ή NMR (CD3OD) δ 9.00 (s, 1 H), 8.80 (d, J a 8.5 Hz, 1 H). 8.52 (d, J = 6.0Hz, 2 H), 8.33 (d. J = 8.7 Hz, 1 H), 8.03 (s, 1 H), 7.84 (m, 2 H), 7.72 (d, J = 6.0 Hz, 2 H), 7.44(m, 2 H), 7.27 (d, J = 8.5 Hz, 1 H), 3.78 (m, 2 H), 2.84 (m, 1 H), 2.76 (m, 2 H), 1.99 (m, 2 H), 1.85 (m, 2 H). * Example 120 1-{2-[5-(3-Methoxy-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

20 1 2098 -139- - The same procedure that was used in example 118. was followed except that (3-methoxyphenyl)boronic acid was used in the place of phenylboronic acid in example 118B tagîve the title compound 120 as the free base. C.l. m/z 450 (M+1 J; Ή NMR (CDCI3) δ 8.74 (s, 1 H), 8.46 (d, J - 8.5 Hz, 1 H), 8.30 (d. J = 8.7 5 Hz, 1 H), 8.08 (d, J = 1.3 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.66 (dd, J = 1.7, 8.5 Hz, I II), 7.46 (m, 2 H), 7.38 (m, 1 H), 7.22-28 (m, 3 H), 6.90 (m, 1 H), 3.89 (m, 2 H), 3.87 (s, 3 H), 2.90(m, 3 H), 2.05 (m, 2 H), 1.83 (m, 2 H).

Example 121 1-{2-(5-Pyridin-3-yl-benzoimidazol-1-yl)-quinolin-8-yll-piperidin-4-ylamine.

^0 The same procedure that was used in example 77 was followed except that {1-[2-(5-phenyl-benzoimidazol-1-yl)-quinolin-8-ylJ-piperidin-4-yl}-carbamic acid tert-butyl ester 118B was usedin the place of trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinoiin-8-yl ester 77E in example 77F. The resulting compound was deprotected using theprocedure outlined in example 118C to give the title compound 121 as the free base. C.l. m/z 421 (M+1 J; ’H NMR (CD3OD) δ 9.32 (s, 1 H), 9.27 (s. 1 H), 8.93 (m. 1 H), 8.87 (d, J = 8.7 Hz, 1 H), 8.82 (d, J = 5.7 Hz, 1 H), 8.55 (d, J = 8.9 Hz, 1 H), 8.24 (s, 1 H), 8.13 (m, 1 H).8.03 (m, 2 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.57 (m, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 4.01 (m, 2 H), 3.38 (m, 1 H), 3.05 {m, 2 H), 2.13-2.24 (m, 4 H).

Example 122 20 1 -{2-[5-(6-Methoxy-pyridin-3-yl)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine. < MHz

MeO- -140- 1 2 098

The same procedure that was used in example 118 was followed except that 2-methoxy-5-pyridineboronic acid was used in the place of phenylboronic acid in example 118B to give thetille compound 122 as the HCl sait. C.l. m/z 451 IM+1J; Ή NMR (DMSO) S 9.27 (s, 1 H), 9.02 (d. J = 8.7 Hz, 1 H), 8.61 (d, J = 1.55 Hz. 1 H), 8.57 (d, J = 9.1 Hz, 1 H), 8.19 (d, J = 8.7 Hz, 1 H), 8.15 (m, 1 H), 8.07 (s, 1 H), 8.02. (d, J = 8.7 Hz, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.50 (m, 1 H), 7.31 (d, J » 7.5 Hz, 1 H). 6.92 (d, J = 8.3 Hz, 1 H), 3.89 (s. 3 H), 3.87 (m, 2 H), 3.22 (m, 1 H), 2.79 (m, 2 H), 2.07 (m, 4 H).

Example 123 1-{2-[5-(4-Aminomethyl-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

lû The same procedure that was used in example 118 was followed except that the HCl sait of 4-aminomethylphenylboronic acid was used in the place of phenylboronic acid in example 118Band 2.5 équivalents of N,N-diisopropylethylamine was added to the reaction mixture to givethe title compound 123 as the HCl sait. C.l. m/z 449 [M+1 ]; Ή NMR (CD3OD) δ 9.10 (s, 1 H), 8.71 (d, J = 8.7 Hz, 1 H), 8.55 M. J = 8.7 15 Hz. 1 H), 8.04 (m, 2 H), 7.87 <dd, J = 1.7, 8.7 Hz, 1 H), 7.83 (m, 2 H), 7.66 (d, J = 7.1 Hz. 1 H), 7.58 (m, 3 H), 7.40 (m, 1 H), 4.18 (s, 2 H), 4.03 (m. 2 H), 3.34 (m, 1 H), 2.95 (m, 2 H), 2.20 (m,2 H). 2.10 (m, 2 H).

Example 124 4-{1 -[8-{4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzoic acid nrwthylester.

20 -141- 1 2098

The same procedure that was used in exampie 118 was foilowed except that 4-methoxycarbonylphenylboronic acid was used in the place of phenylboronic acid in example118B to give the title compound 124 as the HCl sait. C.l. m/z 478 fM+1]; 1H NMR (CD3OD) δ 9.08 (s, 1 H), 8.79 (d, J = 8.7 Hz, 1 H), 8.52 (d, J = 8.73 Hz, 1 H), 8.11 (m, 2 H), 8.07 (d, J = 1.3 Hz, 1 H), 8.02 (d, J = 9.1 Hz, 1 H), 7.87 (m, 1 H), 7.83 (m, 2 H), 7.65 (m, 1 H), 7.55 (m, 1 H), 7.39 (m, 1 H), 4.03 (m, 2 H), 3.93 (s, 3 H), 3.33 (m. 1H), 2.93 (m, 2 H), 2.19 (m, 2 H), 2.11 (m, 2 H).

Example 125 4-{1 -[8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-phenol.

The same procedure that was used in example 118 was foilowed except that 4-hydroxyphenylboronic acid tetrahydropyranyl ether was used in the place of phenylboronicacid in exampie 118B to give the title compound 125 as the HCl sait. C.l. m/z 436 [M+1 ]; M NMR (CD3OD) δ 9.20 (s, 1 H), 8.72 (d, J = 8.3 Hz, 1 H), 8.49 (d, J = 8.7Hz, 1 H), 7.98 (d, J * 8.7 Hz, 1 H), 7.90 (s, 1 H), 7.79 (m, 1 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.53 15 (m, 3 H), 7.39 (d, J - 7.9 Hz, 1 H), 6.88 (m, 2 H), 4.03 (m, 2 H), 3.34 (m, 1 H), 2.93 (m, 2 H), 2.19 (m, 2 H), 2.10 (m, 2 H).

Example 126 2-(5-Methoxy-benzoimidazol-1-yi)-quinoline-8-carboxylic acid methyl ester.

Trifluoro-methanesuifonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E (1.0 g,g© 2.3 mMol), palladium acetate (16 mg, 0.07 mMol), 1,3-bis(diphenylphosphine)propane (30 mg, 0.07 mMol) and triethylamine (730 pL, 5.20 mMol) were dissolved in a solution of 8 mL ofDMF and 4 mL of MeOH in a Paar bottle. The reaction vessel was evacuated under vacuum -142- 1 2098 and then filled with carbon monoxide (50 psi). The reaction mixture was shaken for 24 hoursafter which time it was concentrated under vacuum. The resuiting residue was partitionedbetween DCM and aqueous saturated NaHCO3. The DCM layer was then washed again withaqueous saturated NaHCO3 and then with brine, dried over Na2SO4, fiitered and concentrated 5 under vacuum to give a iight tan foam. The foam was chromatographed on flash siiica geleluting with MeOHZDCM (1:99) to give 770 mg of the title compound 126. C.l. m/z 334 [M+1 J; 1H NMR (CDCI3) δ 8.63 (d, J = 8.9 Hz, 1 H), 8.56 (s, 1 H), 8.25 (d, J = 8.9Hz, 1 H), 8.10 (dd, J = 1.5, 7.2 Hz, 1 H), 7.90 (dd, J = 1.5, 8.1 Hz, 1 H), 7.64 (d, J · 8.9 Hz, 1H), 7.51 (m, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 7.07 (dd, J = 2.5, 9.1 Hz, 1 H), 4.04 (s, 3 H), 3.87 10. (s, 3 H).

Example 127 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoiine-8-carboxylic acid methyl ester.

The same procedure that was used in example 126 was followed except that trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester 77E 15 was used in the place of trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester 1E to give the title compound 127 as a white solid. C.l. m/z 378 [M+1 ]; ’H NMR (DMSO) δ 9.17 (s, 1 H), 8.73 (d, J = 9.1 Hz, 1 H), 8.64 (d, J = 9.1

Hz, 1 H), 8.23 (d, J 8.7 Hz, 1 H), 8.18 (m, 1 H), 8.05 (m, 1 H), 7.64 (m, 1 H), 7.29 (d, J = 2.5 ' Hz, 1 H), 7.07 (dd, J = 2.5, 9.1 Hz, 1 H), 4.14 (m, 2 H), 4.00 (s, 3 H), 3.67 (m, 2 H), 3.31 (s, 3 20 H).

Example 128 2-(5-Methoxy-benzoimidazol-1 -yl)-quinoline-8-carboxylic acid (2-dimethylamino-ethyl)-amide. -143- 1 2 098 10 15

2-(5-Methoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid methyl ester 126 (166.7 mg,0.500 mMol) was dissolved in 2 mL of anhydrous DCM under an atmosphère of dry N2. In aseparate flask, N,N-dimethylethylenediamine (2.20 mL, 20 mMol) was dissolved in 20 mL ofanhydrous DCM under an atmosphère of dry N2. To this solution was siowly added 10 mL asolution of 2.0 M trimethylaluminum in toluene. The solution was stirred for 30 minutes afterwhich time 1 mL of this solution was added to the solution containing compound 126. Thetempérature of the reaction mixture was raised to 40°C and reacted over night after which time1 mL of water was siowly added to quench the reaction. The resulting mixture was partitionedbetween DCM and aqueous 0.1 N NaOH. The DCM layer was washed again with aqueous0.1 N NaOH and then with brine. The DCM layer was then dried over Na2SO4, filtered andconcentrated under vacuum. The resulting residue was dissolved in 2 mL of DCM. To thissolution was added 1.5 mL of a solution of HCl in ethyl ether which caused an immédiateprecipitate to form. The precipitate was collected via suction filtration, washed with ethylether, and dried under vacuum to give 165 mg of the bis-HCI saltof the title compound 128 asa white solid. C.l. m/z 390 (M+1); 1H NMR (CD3OD) δ 10.22 (s, 1 H), 8.85 (d, J = 8.9 Hz, 1 H), 8.54 (d, J =9.0 Hz, 1 H), 8.49 (dd. J = 1.5, 7.2 Hz, 1 H), 8.30 (dd, J = 1.4, 8.1 Hz, 1 H), 8.18 (d, J = 8.9Hz, 1 H). 7.86 (m, 1 H), 7.42 (m, 2 H), 3.97 (s, 3 H), 3.90 (m, 2 H), 3.44 (m, 2 H), 2.96 (s, 6 H).

Example 129 2-(5-Cyclopropylmethoxy-benzoimidazol-1-yt)-quinoline-8-carboxylic acid methyl ester.

-144- 1 2098

The same procedure that was used in example 126 was followed except thaïcyclopropylmethoxy-2-nitro-phenylamine 52A was used in the place of 4-methoxy-2-nitroaniline in example 1B to give the titled compound 129. C.l. m/z 374 [M+1]; ’H NMR (CDCI3) δ 8.65 (d, J = 9.1 Hz, 1 H), 8.60 (s, 1 H), 8.34 (d, J = 8.7 5 Hz, 1 H), 8.14 (m, 1 H), 7.97 (m. 1 H), 7.72 (d, J = 9.1 Hz, 1 H), 7.57 (m, 1 H), 7.29 (d, J = 2.5

Hz. 1 H), 7.10 (m, 1 H), 4.09 (s, 3 H), 3.89 (d, J = 7.1 Hz, 2 H), 1.32 (m, 1 H), 0.66 (m, 2 H), 0.38 (m, 2 H).

Example 130 [2-(5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-pyrrolidin-1-yl-methanone.

jq The same procedure that was used in example 128 was followed except that 2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid methyl ester 129 wasused in the place of 2-(5-methoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid methylester 126 and pyrrolidine was used in the place of Ν,Ν-dimethylethylenediamine to give the ' tttle compound 130 as a white solid. W C.l. m/z 413 [M+1]; Ή NMR (CDCI3) δ 8.58 (s, 1 H), 8.51 (d, J = 9.1 Hz, 1 H), 8.26 (d, J = 9.1Hz, 1 H), 7.80 (d, J « 7.9 Hz, 1 H), 7.76 (d, J = 7.1 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.52 (m,1 H), 7.25 (d, J - 2.1 Hz, 1 H), 7.07 (m, 1 H), 3.92 (m, 1 H), 3.88 (d, J = 7.1 Hz, 2 HJ, 3.85 (m,1 H), 3.19 (m, 1 H), 3.10 (m, 1 H), 1.95 (m, 2 H), 1.75 (m, 2 H), 1.32 (m. 1 H), 0.6T (m, 2 H),0.39 (m, 2 H).

Example 131 [2-(5-Cydopropylmethoxy-benzoimidazol-1-yl)-quinorm-8-yl]-morpholin-4-yl-methanone. 20 -145- 1 2 098 ο

The same procedure that was used in example 128 was followed except that 2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinoline~8-carboxylic acid methyl ester 129 wasused in the place of 2-(5-methoxy-benzoimidazol-1-y,)-quinoiine-8-carboxylic acid methylester 126 and morpholine was used in the place of Ν,Ν-dimethylethylenediamine to give the 5 title compound 131 as a white solid. C.l. m/z429 [M+1]

Example 132 [2-(5-Cyclopropylmethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-1 -yl-methanone.

The same procedure that was used in example 128 was followed except that 2-(5-10 cyclopropylmethoxy-benzoimidazol-1-yl)-quinoline-8-carboxylÎc acid methyl ester 129 wasused in the place of 2-(5-methoxy-benzoimidazol-1-yl)-quinoline-8-carboxylic acid methylester 126 and piperdine was used in the place of Ν,Ν-dimethylethylenediamine to give the title compound 132 as a yellow solid. C.l. m/z427 [MM]; 1H NMR (CDCI3) δ 8.61 (s, 1 H), 8.49 (d, J = 9.1 Hz, 1 H), 8.31 (d. J = 9.115 Hz, 1 H), 7.85 (d, J = 7.9 Hz, 1 H), 7.72 (m, 2 H), 7.56 (m, 1 H), 7.29 (d, J = 2.5 Hz, 1 H), 7.09 (m, 1 H), 4.09 (m, 1 H), 3.88 (d, J = 6.7 Hz, 2 H), 3.78 (m, 1 H), 3.13 (m, 2 H), 1.20-1.80 (m, 7H), 0.66 (m, 2 H), 0.39 (m, 2 H).

Example 133 (3-Amino-pyrrolidin-1-yl)-[2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl] methanone. 20 -146- 1 2 098

4-Cyclopropylmethoxy-2-nitro-phenylamine. 4-Amino-3-nitrophenol (26.00 g, 165.5 mMol) was dissolved in 200 mL of anhydrous DMFunder an atmosphère of dry N2. The reaction mixture was then cooied to 0°C and to this $ mixture was added Cs2CO3 (64.7 g, 199 mMol), and cyclopropyl methane bromide (17.7 mL,182 mMol). After stirring for 15 minutes, the reaction mixture was then warmed up to ambienttempérature and then stirred ovemight. The reaction mixture is then poured into 800 mL ofwater. The precipitate was collected via suction filtration and partitioned between DCM andaqueous 0.1 N NaOH. The DCM layer was saved and washed again aqueous 0.1 N NaOH, 10 then with brine, dried over Na2SO,tl fütered and concentrated under vacuum to give 31.52 g of4-cyclopropylmethoxy-2-nitro-phenylamine 133A as an orange solid.

Example 133B {1 -[2-(5-Cyclopropylmethoxy-benzoimidazol-1 -yl)-quinoline-8-carbonyl]-pymïlidin-3-yl}-carbamic acid tert-butyl ester. 13 Trifluoro-methanesuifonic acid 2-(5-cyclopropylmethoxy-benzoimidazol-1 -yl)-quinolin-8-ylester (602 mg, 1.30 mMol), (which was prepared by following example 77E oxcept that 4-cyclopropyimethoxy-2-nitro-phenylamine 133A was used in the place of 5-(2-methoxy-ethoxy)-2-nitro-phenylamine 42A in example 77C) palladium acetate (9.0 mg, 0.04 mMol), 1,3-bis(diphenylphosphine)propane (16 mg, 0.04 mMol), (+/-)-3-(tert- 20 butoxycarbonylamino)pyrrolidine (484 mg, 2.60 mMol) and triethylamine (400 pL, 2.86 mMol)were dissolved in 6 mL of DMF and 4 mL of MeOH in a Paar bottle. The reaction vessel wasevacuated under vacuum and then filled with carbon monoxide (50 psi). The reaction mixturewas shaken for 24 hours after which lime it was concentrated under vacuum. The resultingresidue was partitioned between DCM and aqueous saturated NaHCO3. The DCM layer was 25 then washed again with aqueous saturated NaHCO3 and then with brine, dried over Na2SO4,

/V 1 2098 -147- filtered and concentrated under vacuum. The resuiting residue was chromatographed onflash silica gel eluting with MeOH/DCM (1:99) to give 139 mg of the title compound 133B.

Example 133C (3-Amino-pyrrolidin-1-yl)-[2-(5-cyclopropylmethoxy-benzoimtdazol-1-yl)-quinoliii-8-yl]-j methanone. {1-[2-(5-Cyclopropylrnethoxy-benzoimidazol-1-yl)-quinoline-8-carbonyll-pyrrolidin-3-yl}-carbamic acid tert-butyl ester 133B (130 mg, 0.246 mMol) was dissolved in a solution of 1 mlof TFA and 1 mL of DCM under an atmosphère of dry N2. The reaction mixture was stirred for30 minutes. The reaction mixture was concentrated under vacuum and the resuiting residuewas partitioned between DCM and aqueous"1 N NaOH. The DCM layer was washed againwith concentrated under vacuum and the resuiting residue was partitioned between DCM andaqueous, dried over Na2SO4, filtered and concentrated under vacuum to give the titlecompound 133. C.l. m/z428 (M+1]

Example 134 8-AHyloxy-2-(5-methoxy-benzoimidazol-1-yl)-quinoline. 2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-ol 1D (292 mg, 1.00 mMol) was dissolved in 5mL of anhydrous THF under an atmosphère of dry N2 and the reaction mixture was cooled to0°C. To this solution was slowly added 60%. sodium hydride in oil (44 mg, 1.1 mMol. After 20 reacting for 30 minutes, allyl bromide (100 pL, 1.1 mMol) was added and the reaction mixturewas then warmed to ambient température and 1 mL of DMF was added. After stirringu overnight at ambient température, the reaction mixture was partitioned between DCM andaqueous saturated NaHCO3. The DCM layer was washed again with aqueous saturatedNaHCO3, then with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 2j a red solid. The red solid was chromatographed over flash silica gel eluting with EtOAc togive 245 mg of the title compound 134 as a tan solid. •148- 1 2098 C.l. m/z 332 [M+1 ]; 1H NMR (CDCI3) Ô 8.60 (d, J = 8.9 Hz, 1 H), 8.57 (s, 1 H), 8.19 (d. J = 8.7Hz, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.37 (m, 2 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.07 (dd. J = 1.9,7.0 Hz, 1 H), 7.02 (dd, J = 2.5, 9.1 Hz, 1 H), 6.21 (m, 1 H), 5.62 (m, 1 H), 5.36 (m. 1 H), 4.76(m, 2 H), 3.87 (s, 3 H).

Example 135 {2-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yloxy]-ethyl}-methyl-amine.

Example 135A

[2-(5-Methoxy-benzoimidazol-1-yi)-quinolin-8-yloxy]-acetaldehyde. 8-Aliyloxy-2-(5-methoxy-benzoimidazol-1-yl)-quinoline 134 (245 mg, 0.74 mMol), andtrimethylamine-N-oxide dihydrate (101 mg, 0.88 mMol) were dissolved in 3 mL of anhydrousDCM under an atmosphère of dry N2. To this solution was added osmium tetroxide (245 mg,0.74 mMol) and the reaction mixture was stirred for ~ 1 hour at anrbient température. Thereaction mixture was then concentrated under vacuum and thfl resulting residue wasdissolved in 2 mL of THF. To this solution was added 2 mL of vwater followed by sodium

12 periodate (238 mg, 1.11 mMol) and the reaction mixture was stirred ovemight at ambienttempérature. The reaction mixture was partitioned between DCM and aqueous saturatedNaHCO3 causing a precipitate to form. The brown solid was coilected by suction filtration anddried under vacuum to give 214 mg of the title compound 135A

Example 135B 2o {2-[2-(5-Methoxy-benzoimidazoi-1-yl)-quinolin-8-yloxy3-ethyl}-methyl-amine.

[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yloxy]-acetaldehyde 1354 (214 mg, 064 mMol),400 pL of AcOH, 1.6 mL of a solution of 2 M methylamine in MeOH end Na(OAc)3BH (204, 1 2098 -149- 0.96 mMol) were added to 3 mL of DCE under an atmosphère of dry N2. The reaction mixturewas stirred ovemight at ambient température after which time it was partitioned between DCMand aqueous 1 N NaOH. The DCM layer was washed 2 more times with aqueous 1 N NaOH,then with brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting 5 residue was chromatographed on flash silica gel initially eluting with MeOHZEtOAc (4:96),then MeOHZEtOAcZNH4OH (8:91.9:0.1), then MeOHZEtOAcZNH4OH (10:89.9:0.1) and flnallyMeOHZEtOAcZNH4OH (15:84.9:0.1) to give 28 mg of the title compound 135 as a white solid. C.l. mZz 349 [M+1J; Ή NMR (CDCI3) δ 8.63 (d, J - 9.1 Hz, 1 H), 8.60 (s, 1 H), 8.27 (d, J « 8.7Hz, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.43 (m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.14 (dd, J = 2.1, 10 6.9 Hz, 1 H), 7.05 (dd, J = 2.5, 8.9 Hz, 1 H), 4.35 (m, 2 H), 3.89 (s, 3 H), 3.21 (m, 2 H), 2.61 (s, 3 H), 2.02 (brs, 1 H).

Example 136 {2-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yloxyî-ethyl}-dÎmethyl-amine.

{2-I2-(5-Methoxy-benzoimidazol-1-yt)-quinolin-8-yloxy]-ethyl}-rnethyl-amÎne 135 (23 mg, 0.06615 mMol), 20 pL of 37% formaldéhyde In water and 20 pL of formic acid were added to 500 pL ofchloroform under an atmosphère of dry N2. The reaction mixture was then heated to reflux for - 2 hours after which time it was concentrated under vacuum and partitioned between DCMand aqueous 1 N NaOH. The DCM layer was washed again with aqueous 1 N NaOH, thenwith brine, dried over Na2SO4, filtered and concentrated under vacuum to give 20 mg of the 20 title compound 136. C.l. mZz 363 (M+11; Ή NMR (CDCI3) δ 8.67 (d, J = 9.1 Hz, 1 H), 8.61 (s, 1 H), 8.28 (d, J = 8.7Hz, 1 H), 7.67 (d, J - 8.9 Hz, 1 H), 7.43 (m, 2 H), 7.32 (d, J = 2.3 Hz, 1 H), 7.13 (d, J = 7.3 Hz,1 H), 7.06 (dd, J = 2.5,8.9 Hz, 1 H), 4.34 (m, 2 H), 3.90 (s, 3 H), 3.00 (m, 2 H), 2.46 (s, 6 H).

Example 137 2> 2-[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yloxy)-ethylamÎne. 1 2098 -150-

10 15 20 2-(5-Methoxy-benzoimidazoi-1-yl}-quinolin-8-ol 1D (290 mg, 0.996 mMol) was dissoived in 5mL of anhydrous DMF under an atmosphère of dry N2. To this solution was slowiy added60% sodium hydride in oil (44.1 mg, 1.10 mMol. After reacting for 30 minutes, N-(2-bromoethyl)-pthalimide (280 mg, 1.10 mMol) was added and the reaction mixture was thenheated to 80°C. After stirring for 2 hours at this température, K2CO3 (360 mg, 2.61 mMol) wasadded and the reaction mixture was stirred ovemight at 80°C. The reaction mixture was thencooied to ambient température and partitioned between EtOAc and water. The EtOAc layerwas then washed 4 more times with water, then with brine, dried over MgSO4, filtered andconcentrated under vacuum. The resuiting residue was chromatographed over flash silica geleiuting with a gradient from DCM/Hex (50:50) to OCM and then to MeOHZDCM (2:98) to give awhite solid. The white solid was dissoived in 5 mL of hot (reflux) EtOH to which was added500 pL of anhydrous hydrazine. After reacting at reflux for two hours, the reaction mixturewas cooied to ambient température, filtered and the filter cake was washed with EtOH. Thecombined filtrâtes were concentrated under vacuum amd the resuiting residue waschromatographed over flash silica gel eiuting with a gradient of OCM to MeOHZDCM (8:92)then switched to MeOH//NH4OH (8:91.9: 0.1) to give 110 mg of the title compound 137 as awhite solid. 1H NMR (CDCI3) δ 8.60 (d, J = 8.9 Hz, 1 H), 8.58 (d. J = 8.9 Hz, 1 H), 8.57 (s, 1 H), 8.21 (d, J- 8.7 Hz, 1 H), 7.60 (d, J = 8.7 Hz, 1 H), 7.39 (m, 2 H), 7.29 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J =1.9, 7.1 Hz, 1 H), 7.03 (dd, J = 2.5, 8.9 Hz, 1 H), 4.21 (m, 2 H), 3.86 (s. 3 H), 3.27 (m, 2 H), 2.26 (brs, 2 H).

Example 138 1 -[{2-[5-(3-Morpholinoethoxy)-1 H-benzimidazol-1 -ylî-quinolin-8-ylîl-piperidin-4-ylaminetrihydrochloride. -151- 1 2098

Example 138A.B 8-Chloro-2-(5-methoxy-1 W-benzimidazol-1 -yl)-quinoline and 8-Chloro-2-(6-methoxy-1 H-benzimidazol-1 -yl)-quinoline, 2,8-Dichloroquinoline (11.89 g, 60 mMol), sodium hydride (60% dispersion in minerai oii, 2.88 5 g, 72 mMol) and 50 mL of toluene were combined under nitrogen, and a solution containing 5-methoxy-benzimidazole (10.67 g, 72 mMol) dissolved in 100 mL of anhydrous 1-methyl-2-pyrroiidinone was carefully added by syringe. The résultant mixture was warmed slowly to 110°C and stirred at this température for 16 hrs. After cooling, the reaction mixture was quenchedwith 650 mL of water and then extracted multiple times with EtOAc. The combined EtOAc IC extracts were dried over Na2SO4 and evaporated to leave a semi-solid residue containing thetitle product isomers 138A,B. An Ή NMR spectrum of this product mixture revealed thatformation of the 6-methoxybenzimidazol-1-yl isomer was favored over the 5-methoxybenzimidazol-1-yl isomer by about a 3:2 ratio. Fractional crystallization from EtOHprovided three eariy crystalline crops that were combined to give 7.34 g, comprised of about90% pure 6-methoxybenzimidazoI-1-yl isomer. Recrystallization from EtOH gave needle-likecrystals of the 6-methoxybenzimidazol-1-yl isomer 138A melting at 175-176° C. C.l. mZz310 [M+1]; M NMR (DMSO) 6 9.18 (s, 1 H), 8.77 (d, J = 2.5 Hz, 1 H), 8.65 (d, J - 9.0Hz, 1 H). 8.30 (d, J - 9.0 Hz, 1 H), 8.01 (m, 2 H), 7.68 (d, 8.7 Hz, 1 H). 7.58 (m, 1 H), 7.00 (dd,J - 2.5,8.7 Hz, 1 H), 3.92 (s, 3 H). 20 Additional fractional crystallization efforts ultimately yielded two crops, 2.157 g combinedweight, of the 5-methoxybenzimidazol-1-yl isomer 138B, melting at 184-185° C. 1H NMR (DMSO) δ 9.27 (s, 1 H), 8.98 (d, J = 9.0 Hz, 1 H), 8.67 (d, J = 9.0 Hz, 1 H), 8.31 (d, J= 9.0 Hz, 1 H), 8.02 (m, 2 H), 7.59 (m, 1 H), 7.35 (d, J = 2.2 Hz, 1 H), 7.12 (dd, J = 2.2,9.0 Hz,1 H), 3.87 (S, 3 H). -152- 1 2 098

Example 138C 8-Chloro-2-(5-hydroxy-1 W-benzimidazol-1 -yl)-quinoline.

To a pre-cooled (-78°C) solution containing 8-chloro-2-(5-methoxy-1 W-benzimidazol-1-yl)-quinoline 138B (2.16 g, 7.0 mMol) in anhydrous DCM (28 mL) was added a 1.0 M solution ofborontribromide in DCM (20.9 mL, 20.9 mMol). The cooling bath was removed and theréaction mixture stirred at ambient température under nitrogen for 22 hours. The reaction wasquenched by the addition of aqueous 1 N NaOH to a pH of about 8.8. After stirring for about15 minutes, the suspended solids were removed by filtration. The solids were subsequentlystirred briefly with 1 N NaOH (21 mL, 21 mMol) to hydrolyse remaining borate esters, andthen neutralized by adding 1 N HCl (21 mL, 21 mMol). The solid precipitate was filtered off,stirred briefly with a small amount of warm EtOAc to remove traces of starting material, andre-filtered to give 1.91 g, mp >250° C, of the title product 138C. C.l. m/z 296 [M+1]; ’H NMR (DMSO) δ 9.41 (br. s, 1 H). 9.20 (s, 1 H), 8.86 (d, J = 9.1 Hz, 1H), 8.65 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 7.9 Hz, 2 H), 7.57 (t. J =7.9 Hz, 1 H), 7.08 (d, J = 2.5 Hz, 1 H), 6.93 (dd, J = 2.5,8.7 Hz, 1 H).

Example 138D 8-Chioro-2-[5-(3-morpholinopropoxy)-1W-benzimidazol-1-yl]-quinoline.

I 8-Chloro-2-(5-hydroxy-1H-benzimidazol-1-yl)-quinoline 138C (0.30 g, 1 mMol) and NaH(0.047 g of 60% dispersion in minerai oil, 1.1 mMol) were combined with 3 mL of anhydrousDMF under argon, and the mixture allowed to react for 1 hr at ambient température. To thiswas added 4-(3-chloropropyi)morpholine (0.199 g, 1.22 mMol) and the reaction mixture stirredat ambient température for 4 days. Remaining sodium hydride, if any, was quenched by wateraddition and the solvents evaporated under vacuum. Water (3 mL) was added to the residue,and the mixture extracted (5 x 20 mL) with chloroform. The combined chloroform extractswere dried over Na2SO4 and evaporated to give an off-white solid. The solids were stirred witha small amount of EtOH and filtered to give 0.157 g of title product 138D. C.l. m/z 423 [M+1]; 1H NMR (DMSO) δ 9.24 (si 1 H), 8.95 (d, J = 9.1 Hz, 1 H), 8.66 (d, J = 9.1Hz, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 8.01 (d, J = 7.9 Hz, 2 H). 7.57 (t, J = 7.9 Hz, 1 H), 7.30 (d,J = 2.1 Hz, 1 H). 7.08 (dd, J = 2.5,9.1 Hz, 1 H), 4.08 (t, J = 6.4 Hz, 2 H), 3.56 (m. 4 H), 2.43(t, J « 7.3 Hz, 2 H), 2.36 (m, 4 H), 1.89 (m, 2H). i

Example 138E

I

I -153- 1 2098 {1 ~[[2-[5-(3-Morpholinopropoxy)-1 H-benzimidazol-1 -yl]-quinolÎn-8-yl]]-piperidin-4-yl}-carbarnicacid tert-butyl ester. 8-Chloro-2-[5-(3-moipholinopropoxy)-1/7-benzimidazol-1-yl]-quinoline 138D (226 mg, 0.53mMol), racemic-BINAP (50 mg, 0.08 mMol), Cs2CO3 (243 mg, 0.75 mMol), piperidin-4-yl- 5 carbamic acid tert-butyl ester (214 mg, 1.07 mMol), xylenes (1 mL), and Pd(OAc)2 (12 mg, 0.053 mMol) were combined under argon and heated at reflux for 2 days. After allowing themixture to cool, hexanes were added and decanted off, several times, to remove hexanesolubles. The residue was stirred with EtOAc and filtered, and the solids washed withadditional EtOAc. The combined EtOAc solutions were evaporated, and the residue ^0 chromatographed on silica gel with EtOAc/MeOH elution. Fractions containing the titleproduct 138E were combined and concentrated to provide 130 mg. C.l. m/z 587 [M+1J; Ή NMR (DMSO) δ 9.15 (s, 1 H), 8.88 (d, J = 9.6 Hz, 1 H), 8.51 (d, J = 8.7 Hz, 1H). 8.14 (d, J = 9.1 Hz, 1 H), 7.59 (d, J « 7.0 Hz, 1 H), 7.46 (t, .1 = 7.9 Hz, 1 H), 7.30 (m, 3 H), 7.13 (d,J = 8.3 Hz, 1 H), 4.08 (t, J - 6.2 Hz, 2 H), 3.75 (m, 2 H), 3.56 (m, 4 H), 3.42 (m, 1 H), 2.74 (t, J = 10.8Hz, 2 H), 2.44 (m, 2 H), 2.36 (m, 4 H). 1.8-1.9 (m, 6 H), 1.39 (s, 9 H).

Example 138F 1 -[[2-[5-(3-Morpholinopropoxy)-1 H-benzimidazol-1 -yl]-quinolin-8-yl]]-piperidin-4-ylaminetrihydrochloride. {1-[[2-[5-(3-Morpholinopropoxy)-1/-V-benzimidazol-1-yl]-quinolin-8-yl]]-piperidin-4-yl}-carbamiG acid tert-20 butyl ester 138E (98 mg, 0.17 mMol) was stirred at ambient température with 4N HCl in dioxane (0.5mL, 2 mMol). After 4 hr the mixture was rotoevaporated to provide the title product 138 as a pale yellow solid. C.l. m/z 487 (M+1 J; ’H NMR (DMSO) δ 9.55 (brs, 1 H), 8.94 (d, J = 8.7 Hz, 1 H), 8.65 (d, J = 9.0 Hz, 1H), 8.4 (brs, 3 H), 8.24 (d, J = 9.0 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.58 (m, 2 H). 7.42 (m, 2 H), 4.24 25 (t, J = 5.6 Hz. 2 H), 4.0 (m, 2 H), 3.9 (m, 4 H), 3.5 (m, 2 H), 3.3 (m, 3 H). 3.1 (m, 2 H), 2.88 (m, 2 H), 2.29 (m. 2 H), 2.12 (m, 4 H).

Example 139 1 -((2-[5-(3-Morpholinoethoxy)-1 H-benzimidazol-1 -yl]-quinolin-8-yl]]-piperidin~4-ylarninetrihydrochloride. 1 2098 -154-

8-Chloro-2-[5-(3-morpholinoethoxy)-1H-benzimidazol-1-yl]-quinoiine. 8-Chloro-2-(5-hydroxy-lH-benzimidazol-1-yl)-quinoline 138B (296 mg, 1 mMol) and Cs2CO3(717 mg, 2.2 mMol) and 3 ml anhydrous dioxane were combined and heated at 80° C for 1.5 $ hr under nitrogen. Morpholinoethylchloride hydrochloride (223 mg, 1.2 mMol) was added andheating continued at 80° C ovemight. Additional morpholinoethylchloride hydrochloride (112mg, 0.6 mMol) and Cs2CO3 (358 mg, 1.1 mMol) were added, and the mixture heated for anadditional 2 days. After évaporation of the solvent, water (2 mL) was added to the residue, - and the mixture extracted with EtOAc. The EtOAc extract was dried over Na2SO4 and 10 evaporated to give 200 mg of title product 139A as an off-white solid.

i Example 139B {1-I[2-[5-(3-Morpholinoethoxy)-1H-benzimidazoi-1-yl]-quinolin-8-yl]]-piperidin-4-yll-carbamic acid tert-butyl ester. 8-ckloro-2-[5-(3-morpholinoethoxy)-1H-benzimidazol-1-yl)-quinoline 139A (182 mg 0.32 15 mMol), racemic-BINAP (30 mg, 0.05 mMol), Cs2CO3 (145 mg, 0.45 mMol), piptridtt -4-yl-carbamic acid tert-butyl ester (127 mg, 0.64 mMol), xylenes (1 mL), and Pd(OAc): (7.1 mg,0.032 mMol) were combined under argon and heated at reflux for 2 days. This réaction wasworked in the same way as in example 138E, including chromatography, to provide 120 mg oftitle product 139B.

20 Example 139C 1 -[[2-[5-(3-Morpholinoethoxy)-1 H-benzimidazol-1 -yl]-quinolin-8-y,]J-piperidin-4-ylar^ne trihydrochloride. -155- 1 2 098 {1 -[[2-[5-(3-Morpholinoethoxy)-1 W-benzimidazol-1 -yl]-quinolin-8-yl]]-piperidin-4-yl}-carbamicacid tert-butyl ester 139B (121 mg, 0.21 mMol) was stirred at ambient température with 4NHCl in dioxane (0.63 mL, 2.5 mMol). After 4 hr the mixture was rotoevaporated, and theresidue stirred briefly with fresh anhydrous dioxane. Filtration provided the title product 139 as 5 a pale yellow solid. ' C.l. m/z 473 [M+1]; M NMR (DMSO) δ 9.67 (brs, 1 H), 8.92 (d. J = 9.1 Hz, 1 H), 8.62 (d, .J = 8.7 Hz, 1 H), 8.50 (brs, 3 H), 8.21 (d, J = 8.7 Hz. 1 H), 7.76 (m, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.55 (t, J = 7.9 Hz, 1 H), 7.44 (d, J 2.5 Hz, 1 H), 7.40 (m, 1H), 4.59 (m, 2 H), 3.97 (d, J =11.2 HZ, 2 H), 3.84 (m, 4 H), 3.6-3.5 (m, 4 H), 3.21-3.24 (m, 3 H), 2.86 (m, 2 H), 2.09 (m, 4 H). 10 Example 140 5-{2-[5-(2-Methoxy-ethoxy)-benzoimidazo!-1-yl]-quinolin-8-yl}-[1,3,4]oxadiazol-2-ylamine.

Example 140A 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinoline-8-carboxylic acid hydrazide. 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoline-8-carboxylic acid methyl ester 127 15 (1.00 g, 2.66 mMol) was dissolved in 10 mL of anhydrous THF under an atmosphère of dry N2. To this solution was added 400 pL of anhydrous hydrazine and the solution was thenstirred for 18 hours at ambient température. The solution was concentrated under vacuumand the resulting residue was partitioned between OCM and aqueous saturated NaHCO3.The DCM layer was washed again with aqueous saturated NaHCO3, then with brine, dried 20 over Na2SO4, flltered and concentrated under vacuum. The resulting residue waschromatographed on flash silica gel eiuting with MeOH/DCM (5/95) to give 553 mg of the titlecompound 140A as a light yellow solid.

* Example 140B 5-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-i1,3,4]oxadiazol-2-ylamine. 1 2098 -156- 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoline-8-carboxylic acid hydrazide 140A (403mg, 1.07 mMol) and NaHCO3 (275 mg, 3.28 mMol) were dissolved in a solution of 5 mL of 1,4-dioxane and 5 mL of water. To this solution was added 500 pL of a 3 M solution ofcyanogen bromide in DCM. The reaction mixture was heated to reflux and reacted at thistempérature for 48 hours. The reaction mixture was concentrated under vacuum and thenpartitioned between EtOAc and aqueous saturated NaHCO3. The DCM layer was thenwashed with brine, dried over Na2SO4 and filtered. A precipitate formed in the flltrate that wascollected via suction filtration and dried under vacuum to give 83.7 mg of the title compound140 as a yellow solid. C.l. m/z 403 [M+1]; Ή NMR (DMSO) 8 9.18 (s, 1 H), 8.75 (d, J = 8.7 Hz, 1 H), 8.68 (d, J = 9.1Hz, 1 H), 8.27 (d, J = 9.1 Hz, 1 H), 8.20 (dd, J = 1.2, 8.3 Hz, 1 H), 8.12 (m, 1 H), 7.70 (m, 1 H), 7.30 (m, 1 H), 7.28 (d, J = 2.5 Hz, 3 H), 6.97 (dd, J « 2.5,8.7 Hz, 1 H), 4.14 (m, 2 H), 3.67 (m,2 H), 3.31 (S, 3 H).

Example 141

Ethyl 1 -[8-(4-aminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazole-5-carboxylate.

EtO2C

Example 141 A,B

Ethyl 1-(8-chIoroquinolin-2-yl)-benzimidazole-5-carboxylateand Ethyl 1-(8-chloroquinolin-2-yl)-benzimidazole-6-carboxylate. 2,8-Dichloroquinoline (13.3 g, 67.2 mMol), sodium hydride (60% dispersion in minerai oil, 2.75g, 68.8 mMol), 55 mL toluene and 109 mL of 1-methyl-2-pyroiidinone were combined undernitrogen. Ethyl benzimidazole-5-carboxylate (12.81 g, 67.4 mMol) was added portionwise overa 10 minute period, and the reaction mixture heated at reflux for 20 hr. The cooied mixturewas diluted with EtOAc (-450 mL), and water (-600 mL) was added slowly to faciiitafeproduct crystallization. Filtration gave 25 g of light gray crystals, which were shown by 1HNMR analysis to contain both title regioisomers 141 A,B in a ratio of about 3 to 2 in favor of the -157- 1 2098 5-carboxylate regioisomer 141 A. Fractional crystallization from chloroform/ethanol allowedséparation of the regioisomers. 5’-Ester regioisomer 141A: C.l. m/z 352 [M+1]; ’H NMR (CDCI3) δ 8.91 (d, J = 8.7 Hz, 1 H), 8.75 (s, 1H), 8.58 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.22 (d, J = 8.7 Hz, 1 H), 7.92 (d. J = 7.9 5 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.51 {m, 1 H), 4.43 (q, J =- 7 Hz,2 H), 1.44 (t, J = 7 Hz, 3 H). 6’-Ester regioisome 141Br: C.L m/z 352 [M+1]; 1H NMR (CDCI3) δ 9.70 (s, 1H), 8.82 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.15 (d, J = 8.7 Hz, 1 H), 7.93 (d, J « 7.5 Hz, 1 H), 7.89 (d, J = 8.3Hz, 1 H), 7.80 (m, 2 H), 7.51 (t, J = 7.9 Hz, 1 H), 4.44 (q, J =- 7.2 Hz, 2 H), 1.46 (t, J « 7.1 Hz, 10 3 H).

Example 141C

Ethyl-1-[8-(4-tert-butoxycarbonylaminopiperidin-1-yl)-quinolin-2-yl]-benzimidazole-5- carboxyiate.

Ethyl 1-(8-chloroquinolin-2-yi)-benzimidazole-5-carboxylate 141A (3.00 g, 8.53 mMoi),15 racemic-BINAP (806 mg, 1.29 mMol), Cs2CO3 (4.00 g, 12.3 mMol), piperidin-4-yl-carbamicacid tert-butyl ester (3.49 g, 17.4 mMol), xylenes (26 mL), and Pd(OAc)2 (198 mg, 0.88 mMol)were combined under argon and heated at reflux for 3 days. After cooling, hexanes (25 mL) " was added and the mixture stirred overnight. Solids were removed by filtration, and repeatedlywashed with hexanes (5 X 30 mL). The solids were then extracted with EtOAc (3 X 500 mL), 20 and the EtOAc solutions combined and evaporated, leaving 4.18 g of greenish-biack foam.The title product 141C (2.06 g) was isolated as pale-yellow crystals (mp = 170-175 °C) aftersilica gel chromatography (hexanes/EtOAc) followed by brief ethyl ether trituration.

Example 141D

Ethyl 1 -[8-(4-aminopiperidin-1 -yl>quinolin-2-yl]-benzimidazole-5-carboxylate. 25 Ethyl-1 -[8-(4-tert-butoxycarbonylaminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazole-5- carboxylate 141C (125 r»g, 0.24 mMol) was stirred at ambient température with 4N HCl in • * dioxane (0.62 mL, 2.5 mNfol). After 4 hr the mixture was evaporated under reduced pressure.The solid residue was slirried biiefly in 0.5 mL ethyl ether, filtered and vacuum dried to givethe title product 141 as a kydrochloride sait. 1 2 09 8 -158- C.l. m/z 416 [M+1]; ’H NMR (DMSO) δ 9.38 (s, 1 H), 8.93 (d, J = 8.7 Hz, 2 H). 8.62 (d. J = 9.1Hz, 1 H), 8.37 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1 H), 8.16 (brs, 3 H), 7.68(d, J = 8.3 Hz, 1 H), 7.54 (m, 1 H), 7.37 (m, 1 H), 4.36 (q, J = 7 Hz, 2 H), 3.88 (m, 2 H), 3.22(m, 1 H), 2.84 (m, 2 H), 2.08 (m, 2 H), 1.97-2.00 (m, 2 H), 1.36 (t, J = 7 Hz, 3 H).

Example 142 1 -[8-(4-Aminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazole-5-carboxylic acid.

HO2C

Example 142 A 1-[8-(4-terf-Butoxycarbonylaminopiperidin-1-yl)-quinolin-2~yl]-benzimid3zole-5-carboxylic acid.

Ethyl-1 [8-(4-/ert-butoxycarbonylaminopiperidin-1 -yl)-quinolin-2-yl]-berizimidazole-5-carboxylate 141C (1.300 g, 2.52 mMol), 1,4-dioxane (5.2 mL), MeOH (1.3 mL) and aqueousIN NaOH (3.9 mL, 3.9 mMol) were combined and heated at 70 °C for 1 hr. Afler allowing themixture to cool, aqueous 1N HCl (3.9 mL, 3.9 mMol) was added slow)/ with stirring, followedby 120 mL of EtOAc. Precipitated solids were removed by filtration to give 0.916 mg of titleproduct 142A. An additional 264 mg of compound 142A was recovered upon évaporation ofthe nitrate EtOAc layer.

Example 142B 1 -[8-(4-Aminopiperidin-1 -y!)-quinolin-2-yl]-benzimidazole-5-carboxylic acid. 1 -[8-(4-tert-Butoxycarbonylaminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazi>le-5-carboxylic acid142A (51 mg, 0.105 mMol) was stirred at ambient température with 41! HCl in 1,4-dioxane 2θ (0.26 mL, 1.04 mMol). After 4 hr the mixture was evaporated under reiluced pressure. Thesolid residue was slurried briefly in 1 mL Et2O, filtered and vacuum died to give the titleproduct 142 as a hydrochloride sait. j

I C.l. m/z 388[M+1]; ’H NMR (DMSO) δ 9.36 (s, 1 H), 8.95 (d, J = 8.3 Hz, 1 H), 8.60 (d, J = 9.1Hz, 1 H), 8.34 (s, 1H), 8.28 (d, J - 9.1 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1 H} 8.08 (br, 3 H), 7.66 -159- 1 2098 (d. J = 8.3 Hz. 1 H). 7.52 (m, 1 H). 7.34 (d. J = 7.1 Hz. 1 H). 3.85-3.88 (m, 2 H). 3.20 (m, 1 H),2.81 (m, 2 H). 2.06 (m, 2 H). 1.95-1.98 (m, 2 H).

Example 143 N-(4-Morpholino)ethyl-1-[8-(4-aminopiperidin-1-yl)-quinolin~2-yl]~benzimidazole-5-$ carboxamide.

Example 143A N-(4-Morpholino)ethyl-1 -[8-(4-terf-butoxycarbonylaminopiperidin-1 -yl )-quinolin-2-yl]-benzimidazole-5-carboxamide. ♦ 1 -[8-(4-iert-Butoxycarbonylaminopiperidin-1 -yl)-quinolin-2-ylJ-benzimidazole-5-carboxylic acid 10 142A (146 mg, 0.30 mMol), DMF (1 mL) and 1,1'-carbonyldiimidazole were combined and stirred under nitrogen at ambient température for 2 hr. 4-(2-Aminoethyl)morpholine (0.050 mL.0.38 mMol) was added and tbe mixture stirred at ambient température for 16 hr. EtOAc (10mL) and saturated aqueous NaHCO3 (5 mL) were added and stirred for 30 min. The whiteprecipitate was removed by filtration and vacuum dried to give 158 mg of title compound143A.

Example 143B N-(4-Morpholino)ethyl-1-[8-(4-aminopiperidin-1-yl)-quinolin-2-yl]-benzimidazole-5~ carboxamide. N-(4-Morpholino)ethyl-1-[8-(4-tert-butoxycarbonylaminopiperidin-1-yl)-quinolin-2-yl)- 2q benzimidazole-5-carboxamide 143A (133 mg. 0.22 mMol) was stirred at ambient températurewith 4N HCl in dioxane (2.0 mL, 8 mMol). After 4 hr the mixture was evaporated underreduced pressure, 2 mL 1,4-dioxane was added and evaporated, twice, ieaving a solidresidue, which was slurried brlefly in 3 mL Et2O, filtered and vacuum dried to give the titleproduct 143 as its bis-HCI sait. 1 2098 -160- C.l. m/z 500 [M+1]; 1H NMR (DMSO) δ 9.43 (s, 1 H), 9.07-9.12 (m, 2 H), 8.61 (m, 2 H), 8.46(br, 3 H), 8.38 (s, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.68 (m, 1 H), 7.54 (m, 1 H), 7.39 (m, 1H),3.95-3.98 (m, 2 H), 3.78-3.84 (m, 4 H), 3.70-3.74 (m, 2 H), 3.57-3.68 (m. 2 H), 3.36-3.38 (m, 2H), 3.11-3.23 (m, 3 H), 2.85 (m, 2 H), 2.11 (m, 4 H). 5 Example 144 4-{1 -[8-(4-Amino-piperidin-1 -y,)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzaldehyde.

The same procedure thaï was used in example 118 was followed except that 4-formylbenzeneboronic acid was used in the place of phenylboronic acid in example 118B to ♦give the title compound 144 as the bis-HCI sait. 10 c.l. m/z 448 [M+1]; ’H NMR (DMSO) δ 10.08 (s, 1 H), 9.56 (s, 1 H), 9.08 (d, J = 8.7 Hz, 1 H), 8.64 (d, J = 8.7 Hz, 1 H), 8.40 (brs, 4 H), 8.33 (d, J = 8.7 Hz, 1 H), 8.25 (s, 1 H), 8.13 (d, J = 8.3 Hz. 2 H), 8.02 (d, J = 8.3 Hz. 1 H). 7.73 (d. J = 7.5 Hz. 1 H). 7.58 (m. 2 H), 7.44 (m. 1 H), 3.91 (m, 2 H), 3.26 (m, 1 H), 2.92 (m. 2 H). 2.14 (m. 4 H).

Example 145 15 1 -{2-[5-(4-Methylaminomethyl-phenyl)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine.

4-{ 1 -[8-(4-amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzaldehyde 144 (205mg, 0.374 mMol) was dissolved in a solution of 3 mL of MeOH and 2 mL of DCE urwler anatmosphère of dry N2. To this solution was added 935 pL of a solution of 2.0 M methytemine -161- 1 2 09 8 in MeOH and then AcOH was added dropwise until the pH of the solution was ~5. To thissolution was added (47 mg, 0.75 mMol) NaCNBH3 and the reaction mixture was stirred atambient température for 4 hours. The reaction mixture was then concentrated under vacuumand subsequently partitioned between a solution of 2-propanol/DCM (18:82) and 0.1 Naqueous NaOH. The water layer was washed 2 more times with a solution of 2-propanol/DCM (18:82). The organic extracts were combined and concentrated under vacuumto give a yellow foam. The foam was chromatographed on flash silica gel eluting with agradient DCM/MeOH/NH<OH (2/97.8/0.2) to DCM/MeOH/NH4OH (10/89.8/0.2) to give 83 mgof a yellow foam. The foam was dissolved in 2 mL of EtOH in a pressure vial. To this solutionwas added 50 pL of concentrated HCl. The reaction mixture was heated to -90°C and reactedat this température for 2 hours. The reaction mixture was then cooled to ambient températureand the resulting precipitate was coilected via suction filtration. The solid was dried undervacuum to give 82 mg of the tri-HCI sait of the title compound 145 as a white solid. C.l. m/z 463 IM+1); ’H NMR (CD3OD) δ 10.57 (s, 1 H), 8.90 (d, J = 8.7 Hz, 1 H), 8.75 (d, J * 9.5 Hz, 1 H). 8.32 (d, J « 9.1 Hz. 1 H), 8.23 (m, 2 H). 8.16 (d, J = 8.3 Hz, 1 H), 8.03 (d. J = 8.3Hz, 1 H), 7.94 (d. J = 8.3 Hz, 2 H), 7.86 (m, 1 H), 7.67 (d, J = 8.3 Hz, 2 H), 4.28 (s, 2 H), 4.18(m, 2 H), 3.73 (m, 2 H), 3.63 (m, 1 H), 2.77 (s, 3 H), 2.48 (m, 2 H), 2.41 (m, 2 H).

Example 146 1-{2-[5-(4-Dimethylaminomethyl-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-

The same procedure that was used in example 145 was followed exceptthat a solution of 2.0M dimethylamine in MeOH was used in the place of a solution of 2.0 M methylamine in MeOHto give the tri-HCI sait of the title compound 146 as a white solid. C.l. m/z 477 [M+1Î; ’H NMR (CD3OD) δ 10.74 (s. 1 H), 8.97 (d, J = 9.1 Hz, 1 H), 8.70 (d, J - 8.7 Hz, 1 H), 8.39 (d, J = 9.1 Hz, 1 H), 8.28 (m. 4 H), 7.97 (d, J = 8.3 Hz, 2 H), 7.93 (m, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 4.43 (s, 2 H), 4.22 (m, 2 H), 3.97 (m, 2 H), 3.73 (m, 1 H), 2.91 (s, 6H), 2.61 (m, 2 H), 2.49 (m, 2 H). ?098 -162-

Example 147 1 -(2-{5-(2-(2-Methyl-imidazol-1 -yl)-ethoxy]-benzoimidazol-1 -yl)-quinolin-8-yl)-piperidin-4-

Example 147 A

Methanesulfonic acid 2-{1-[8-(4-tert-butoxycarbonylamino-piperidin-1-yl)-quiriolin-2-yl]-1 H-5> benzoimidazol-5-yloxy}-ethyl ester. 2-{1-[8-(4-Amino-pïperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-yioxy}-ethanûl 83 (1.89 g 4.68 mMol) and di-tert-butyldicarbonate (1.02 g, 4.68 mMol) were added to a solution of 40mL of anhydrous DCM and 20 mL of anhydrous THF under an atmosphère of dry N2. Theheterogeneous reaction mixture was stirred at ambient température for 3 hours after which «0 time 1.2 mL of N Eta foliowed by 2.10 mL of methanesulphonyl chloride were added. Theréaction mixture was stirred at ambient température for 48 hours and then partitwned betweenDCM and aqueous saturated NaHCO3. The DCM layer was saved and washed 2 more timeswith aqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated under vacuumto give a yellow foam as the title compound 147A and was used without further purification.

15 Example 147B 1 -(2-{5-[2-(2-Methyl-Îmidazol-1 -yl)-ethoxy]-benzoimidazol-1 -yl}-quinolin-8-yl)-piperidin-4- yiamine.

Methanesulfonic acid 2-{1-[8-(4-tert-butoxycarbonylamino-piperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-yloxy)-ethyl ester 147A (344 mg, 0.591 mMol) was slurried in 2.0 mL of 20 anhydrous DMF under an atmosphère of dry N2. To thls heterogeneous solution was added2-methylimidazole (53 mg, 0.65 mMol) foliowed by sodium hydride (60% in oil> (16 mg, 0.65mMol). The reaction mixture was then heated to 60°C. After 1 hour, the reaction mixture wascooied to ambient température and 26 mg more of sodium hydride (60% in oï) was added. 1 2 098 -163-

The reaction mixture was reheated to 60°C and reacted at this température overnight. Thereaction mixture was cooled to ambient température and then quenched with water. Thereaction mixture was concentrated under vacuum and the resulting brown oii was partitionedbetween DCM and aqueous 1.0 M NaOH. The DCM layer was saved and washed 2 more 5 times with aqueous 1.0 M NaOH, dried over Na2SO4, filtered and concentrated under vacuum.The resulting residue was chromatographed on flash silica gel eiuting with a gradient fromDCM/MeOH/NH4OH (2/97,8/0.2) to DCM/MeOH/NH4OH (10/89.8/0.2) to give 158 mg of ayeltow foam. The foam was dissolved in 1 mL of TFA under an atmosphère of dry N2 andstirred at ambient température for 1 hour. The reaction mixture was fconcentrated undervacuum, and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH.The water layer was washed 2 more times with DCM. The DCM extracts were combined,dried over Na2SQ4, filtered and concentrated under vacuum to give 128 mg of the titlecompound 147. C.l. m/z 468 [M+1]; Ή NMR (CDCI3) δ 8.63 (s, 1 H), 8.37 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7Hz. 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.46 (m, 2 H), 7.26 (d, J = 2.5 Hz, 1 H), 7.22 (m, 1 H), 6.97(m, 2 H), 6.91 (d, J = 1.3 Hz, 1 H), 4.28 (s, 4 H), 3.88 (m, 2 H), 2.88 (m, 3 H), 2.46 (s, 3 H),2.05 (m, 2 H), 1.86 (brs, 2 H), 1.80 (m, 2 H).

Example 148 1 -{2-[5-(2-[1,2,4]T riazol-1 -yl-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine.

2q Methanesulfonic acid 2-{1-[8-(4-tert-butoxycarbonylamino-piperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-yloxy)-ethyl ester 147A (500 mg, 0.860 mMol) was slurried in 2.0 mL ofanhydrous DMF under an atmosphère of dry N2. To this heterogeneous solution was added 1,2,4-triazole (65 mg, 0.95 mMol) followed by sodium hydride (60% in oil) (23 mg, 095 mMol).The reaction mixture was then heated to 60°C and reacted at this température for 3 hours.

The reaction mixture was cooled to ambient température and then quenched with water. The «5 reaction mixture was concentrated under vacuum and the resulting brown oil was partitionedbetween a solution of 2-propanol/DCM (18:82) and aqueous 0.1 M NaOH. The organic layer -164- ί 2098 was saved and washed 2 more times with aqueous 0.1 M NaOH, dried over Na2SO4, filteredand concentrated under vacuum to a yellow oit. The yellow oit was chromatographed on flashsilica gel eluting with DCM/MeOH/NH4OH (1.5/98.4/0.1) to give 126 mg of a yellow foam Thefoam was dissolved in 2 mL of EtOH in a pressure vial. To this solution was added 75 pL of 5 concentrated HCl. The reaction mixture was heated to ~90°C and reacted at this températurefor 2 hours. The reaction mixture was then cooled to ambient température and the resuitingprecipitate was coflected via suction filtration. The solid was dried under vacuum to give 86mg of the bis-HCI sait of the tille compound 148 as a yellow solid. C.l. m/z 455 [M+1]; Ή NMR (CD3OD) δ 10.46 (s, 1 H), 9.71 (s, 1 H), 8.84 (d, J = 9.7 Hz, 1 H),i0 8.73 (s, 1 H). 8.60 (d, J = 9.1 Hz. 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H). 7.83 (m, 1 H), 7.54 (dd, J = 2.5, 9.1 Hz, 1 H), 7.50 (d, J = 2.1 Hz, 1 H), 4.93 (m, 2 H), 4.67 (m, 2 H), 4.12 (m, 2 H), 3.60 (m, 3 H), 2.37 (m, 4 H). i

Claims (20)

1. A compound of the formula

or a pharmaceutically acceptable sait, prodrug or solvaté thereof, wherein:wherein X is CH or N; R1 is selected from -(CR4R5)lC(O)OR3, -(CR4R5),C(O)NR3R4, -(CR4RS)IOR3,-{CR4R5)«C(O){C3-C10 cydoalkyl), -ÎCR4R5),C{O)(C6-C10 aryl), -(CR4R5XC(O)(4 to 10 memberedheterocydic), -(CR4Rs),(C3-C10 cydoalkyl), -(CR4R5),(C6-C,0 aryl), and -(CR*R5),(4 to 10membered heterocydic), wherein each t is independently an integer from 0 to 5; saidcydoalkyl, aryl and heterocydic R1 moieties are optionally fused to a benzene ring, a C5-Cecydoalkyl group, or a 4 to 10 membered heterocydic group; the -(CR4Rs)t- moieties of theforegoing R1 groups optionally indude a carbon-carbon double or triple bond where t is aninteger between 2 and 5; the foregoing R1 groups are each optionally substituted by 1 or 2groups independently selected from ~NR3R4, -OR3, 0^0« alkyl, C2«C10 alkenyl, and C2-C10alkynyl, wherein said alkyl, alkenyl and alkynyl groups are substituted by 1 or 2 groupsindependently selected from -N R3R4 and -OR3; and the foregoing R1 groups are optionallysubstituted by 1 to 3 R2 groups; each R2 is independently selected from H, Cn-Cw alkyl, C2-Cw alkenyl, Ca-Cw alkynyl,C3-C10 cydoalkyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,azido, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR®, -OC(O)R3, -NR4SOZR6, -SO2NR3R4,-NR4C(O)R3, -C(O)NR3R4, -NRSC(O)NR3R4, -NR3R4, -S(O),(CR4R6)m(C6-C10 aryl),alkyl), wherein j is an integer from 0 to 2, -{CR4R5)m(C6-C10 aryl), -O(CR4R5)m(Cs-C10 aryl),-NR4(CR4R5)m(C6-C10 aryl), -O(CR4R5)m(4 to 10 membered heterocycle), -NR4(CR4R5)m(4 to 10membered heterocycle), -(CR4Rs)m(4 to 10 membered heterocydic), and -{CR4R5)m(C3-C10cydoalkyl) wherein each m is independently an integer from 0 to 4; said alkyl, alkenyl andalkynyl groups optionally contain 1 or 2 hetero moieties selected from O, -S(O)j- wherein j isan integer from 0 to 2, and -N(R3)- with the proviso that two O atoms, two S atoms, or an Oand S atom are not attached diredly to each other, and the proviso that an O atom, a S atomor a N atom are not attached diredly to a triple bond or a non-aromatic double bond; saidcydoalkyl, aryl and heterocydic R2 groups are optionally fused to a C6-C10 aryl group, a Cs-C„cydoalkyl group, ch* a 4 to 10 membered heterocydic group; and said alkyl, cydoalkyl, aryl 1 2 098 -166- and heterocycllc R2 groupe are optionaHy substituted by 1 to 5 substituants independentlyseiected from oxo (=O), halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,azido, -NR4SO2R®, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C{O)OR8, -NR4C(O)R3,-C(O)NR3R4, -NR3R\ -OR3, Ο,-Ο1ο alkyl, -(CR4R5)m(Ce-Cw aryl), and -{CR4R5)m(4 to 10membered heterocyclic), wherein each m is independently an integer ranging from 0 to 4; each R3 is independently seiected from H, C,-C10 alkyl, -(CR4R5)m(Ce-C,0 aryl), and-{CR4Rs)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0to 4; said alkyl group optionally includes 1 or 2 hetero moieties seiected from O, -S(O)rwherein j is an integer ranging from 0 to 2, and -N(R4)- with the proviso that two O atoms, twoS atoms, or an O and S atom are not attached directly to each other; said cydoalkyl, aryl andheterocyclic R3 groupe are optionally fused to a C6-C,0 aryl group, a Cs-C8 cydoalkyl group, ora 4 to 10 membered heterocyclic group; and the foregoing R3 substituents, except H, areoptionally substituted by 1 to 5 substituents independently seiected from oxo, halo, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C(O)R4, -CfOJOR4, -OC(O)R4,-NR4C(O)R5, -C(O)NR4R5, -NR4R8, hydroxy, CrC8 alkyl, and CrC8 alkoxy; each R4 and Rs is independently H or CrC8 alkyl; or, where R4 and R5 are attached to the same carbon or nitrogen atom, R4 and R5together with said carbon or nitrogen may be taken together to form a 4 to 10 membered ringwhich may be carbocydic or heterocyclic; each R* is seiected from the substituents provided in the définition of R3 except R6 is not H; each R7, R8, R®, R’° and R11 is independently seiected from the group of subsituentsprovided in the définition of R2.

1 2 098 -165- CLAIMS

2-Amino-1-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1- yl)-ethanone; 2- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1-yl)- ethylamine; 3- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-3-aza-bicyclo[3.1 .OJhex- 6-y!amine; 1- {2-I5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinoljn-8-yl}-4-fTiethyl-piperidin-4-ylamine; 2- {1-[8-{4-Amino-piperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-yloxy}-eîhanor, 1 -[2-(5,6-Dimethoxy-benzoimidazol-1 -yl)-quinoiin-8-ylJ-piperid in-4-ylamine; 1 -[2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta{b]naphthalen-1 -yl)-quinolin-8-yl]-ptperidin-4-ylamine; -177- t 2 098 ! (4-{2-{5-{2-Methoxy-ethoxy)-benzoimidazol-1-yll-quinolin-8"yl}-benzyl)-dimethyl- amine; (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl)-methyl-amine; 2-{4-{2-[5-(2-Methoxy-ethoxy)-benz0imidazol-1-ylî-quin0lin~8-yl}-benzylamino>- 3 éthanol; 4- {2-[5-(2-Methoxy-ethoxy)-benzoimidazoH-yl}-quinolin-8-yl}-benzylamine;2-[5-(2-Methoxy-ethoxy)-benzoimidazd-1-yll-8-(4-pyrrol»din-1-ylmeUiyl-phenyl)-quinoline; 2-(5-(2-Methoxy-ethoxy)-benzoimtdazol-1-yl]-8-(4-pynOlidin-1-ylinethyl-phenyi)-|0 quinoiine; 2- [5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-8-(4-pyrrolidÎn-1-ylmethyl-phenyl)-quindine; 1 -{4-{2-[5-{2-Methoxy-ethoxy)-benzoimidazol"1 -yQ-quirwlin-8-yl}-benzyl)-cis-pyrroIidine-3,4-di0b R,R-(1 -(4-{2-[5-{2-Methoxy-ethoxy}-benzoirnidazol-1 -yl]-quinoiin-8-yl}~benzyl)-trans-pyrrdidine-3,4-diol); 1- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazo!-1-yl]-quinolin-8-yl}-benzyi)-pyrrolidin-3-ol; R-(1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-3-yl}-benzyl)-pyrraltdin-20 3-d); 5- (1-{4-{2-[5-{2-Methoxy-ethoxy)-benzoimidazoi-l-yl]~quînoiin-8-yl}-benzyl)-pyrrolidin- 3- ol); 1 -(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -ylJ-quinolin-8-yl}-benzyl)-azetidin-3-ol 2- [5-(2-Methoxy-ethoxy)-benzoimidazoI-1-yll-8-[4-(4-methyl-piperazin-1-ylmethyl)- 25 phenylj-quinoline; 1- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-benzyl)-piperidin-4-ylamine; (1-{2-[5-{2-Methoxy-ethoxy)-benzoitnidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)- methanol; 30 (1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinoiin-8-yl}-piperidin-4-ylrnethyi)- methyl-amine; 2- [5-{2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-[4-(4-methyl-piperazin-1-ylmethyl)-piperidin-1 -ylj-quinoline; -178- 1 2098 (1-{2-[5-(2-Methoxy-ethoxy)-benzoimldazol-1-yl]-quinolin-8-yl}-piperidin-4-ylmeiliyf>- dimethyl-amine; C-(1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quÎnolin-8-yi}-piperidin-4-yl)- methylamine; 5 S,S-(1-(4-{2-i5-(2-Methoxy-ethoxy)-benzoimïdazoi-1-ylJ-quinolin-8-yl}-benzyl)-trans-pyrrolidine-3,4"diol); 4-{2-i5-(3-Dimethylamino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenol; 1~[2-{5-Phenyl-benzolmidazol"1-yl)-quinolin-8-yIl~piperidin-4-ylamine; 1-[2-(5-Pyridin-4-yl-benzoimidazol-1-yl)-quinolin-8~yl]-piperidin-4-ylamine; 10 1 -{2-[5-(3-Methoxy-phenyl)-benzoimidazol-1 -yl]-quindin-8-yl}-piperidin-4-ylamine; 1 -[2-(5-Pyridin-3-yl-benzoimidazol-1 -yl )-quinolin-8-yl]-piperidin-4-ylamine; 1-{2-[5-(6-Methoxy-pyridin-3-yl)-benzoimidazol-1-yi]-quinolin-8-yl}-piperidin-4-ylamine; 142-(5-(4-Aminomethyl-phenyl)-benzoimidazol-1-yll-quinolin-8-yl}-piperidin-4-ylamine; 15 4-{1-{8-(4-Amino-piperidin-1-yl>quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzoic acidmethyl ester; 4-{1 -[8-(4-Arnino-piperidin-1 -yl)-quinolin-2-yl]-1 H-henzolmidazol-5-yi}-phenol; 1 -[(2-(5-(3-Morpholinoethoxy)-1 H-benzimidazol-1 -yl]-quinolin-8-yl]l-piperidin-4-ylamine trihydrochloride; 20 Ethyl 1 -[8-(4-aminopiperidin-1 -yl)-quinolin-2-yi]-benzimidazole-5-carboxylate; N-(4-Morpholino)ethyl-1-[8-(4-amÎnopiperidin-1-yl)-quinolin-2-ylJ-benzimidazole-5- carboxamide; 1-{2-[5-(4-Methylaminomethyl-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4- ytamine; 2J 1 -{2-(5-(4-Dimethylaminomethyl-phenyl)-benzoimidazol-1 -yl]-quinolln-8-yl}-plperidin- 4-ylamine; 1 -(2-{5-[2-(2-Methyl-imidazol-1 -yl)-ethoxy]-benzoimidazol-1 -yi}-quinolin-8-yl)-piperidin-4-yiamine and 1-{2-[5-(2-[1,2,4ÎTnazol-1-yl-ethoxy)-benzoirnidazol-1-yl]-quinolin-8-yl}-pipertdin-4-30 ylamine, and the pharmaceuticallv acceptable salts, prodrugs and solvatés of the foregoing compounds.

2-Amino-1-(4-{2-(5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1-yl)-2-methyl-propan-1 -one; (S)-2-Amino-1-(442-[5-(2-methoxy-ethoxy)-benzoimÎdazol-1-yl]-quinolin-8-yl}-piperazin-1-yl)-propan-1 -one; (S)-2-Amino-1-(4~{2~[5-{2-methoxy-ethoxy)-benzoimidazQl-1-yl]-quinolin-8-yl}-piperazin-1 -yl)-propan-1 -one;

2-Dimethylamino-1 -{4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}- piperazin-1 -yl)-ethanone; 1 -{2-(5-Benzyloxy-benzoimidazol-1 -yl)-quinolin-8-yl]-4-methyl-piperidin-4-ol; (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolÎn-8-yi}-benzyl)-dimethyl- amirte; JO (4-{2-[5-(2-Methoxy-ethoxy)-benzoÎmidazol-1 -yl]-quinolin-8-yl}-benzyl)-methyl-arn!ne; 2- (5-(2-Methoxy-ettioxy)-benzoimidazol-1-yl]-8-(4-morphoitn-4-ylrnethyl-phenyl)-quinoline; 2-{4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yi}-benzylamino)- ethanol; 35 4-{2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yi]-quinolin-8-y!}-benzyiamine; -172- 10Γ 15 20 · 25 30 1 2098 2-(5-(2-Methoxy-ethoxy)-benzoinnidazol-1-yl]-8-(4-pyrrolidÎn-1-ylmethyl-phenyl)- quinoline; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yll-8-(4-pyrrol»din-1-ylmethyl-phenyl)- quinoline; 2- [5-(2-Methoxy-ettioxy)-benzoimidazol-1-yl]-8-(4-pyrrolidin-1-ylmethyl-phenyl)-quinoline; 1-(4-{2-[5-(2-Methoxy-eflKîxy)-benzoimidazol-1-ylJ-quinoiÎn-8-yl}-benzyl)-cis- pyrrolidine-3,4-diol; R.R-(1"(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl3-quinolin-8-yl}-benzyl)-trans- pyrrolidine-3,4-diol); 1-(4-{2-i5-(2-Mèthoxy-ethoxy)-benzoimÎdézol-1-yl]-quinolin-8-yl}-benzyl)-pynOlidin-3- ol; R-{1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazd-1-ylJ-quinolin-8-yl}-benzyl)-pyrrolidin~ 3- ol); S-(1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yl]-quinolin-8-yl}-benzyl)-pyrrolidin- 3- ol); 1- (4-{2-(5-{2-Methoxy-ethoxy)-benzoimidazol-1-yi]-quinolin-8-yl}-benzyl)-azeticfin-3-ol; 2- [5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-8-[4-(4-methyl~piperazin-1 -ylmethyl)-phenyQ-quinoline; 4- (4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl}-piperazine-1-carboxylic acid tert-butyl ester; [1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyi)-piperidin-4-yl]-carbamic acid tert-butyl ester, 1- (4-{2-[5-(2-Metboxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-benzyl>-piperidin-4-ylamine; (1 -{2-{5-(2-Methoxy-ethoxy)-benzoimidazol-1 -ylj-quinoltn-8-yl}-piperidin-4-yl)-methanol; (1-{2-[5-(2-Methoxy-ethoxy)-benzoirnidazol-1-yl]-quinolin-8-yl}-piperidÎn-4-ylrTiethyl)- methyl-amine; 2- [5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-I4~{4-iTiethyl-piperazin-1-ylmethyl)-piperidin-1-yl]-quinoline; (1-{2-l5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quino,in-8-yl}-piperidin-4-ylmethyl)- dimethyl-amine; 1-(1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-piperidin-4-ylmethyl)- pyrrolidin-3-ol; 35 -173- 1 2 09 8 C-( 1 -{2-î5-(2-Methoxy-ethoxy)-benzoimidazo!-1 -yi]-quinoiin-8-yi}-piperidin-4-y!)-methylamine; 1-{2-[5-(2-Dimethyiamino-ethoxy)-benzoimidazoi-1-yO-quinoiïn-8-yS}-4-methyl- piperidin-4-ol; 1 -{2-[5-(2-Dimethylamino-ethoxy)-benzoimidazol-1 -y0-quinolin-8-yl}-piperid»n-4-of : S,S-(1-(4-{2-[5-(2-Methoxy-ethoxy)-benzoinnidazol-1-ylJ-quinolin-8-yl}-benzyl)-trans- pyrroIidine-3,4-diol); 4-{2-[5-{3-Amino-prapoxy)-benzoimidazoÎ-1-yl]-quinolin-8-yl}-phenol; 4-{2-i5-(3-Dimethylamino-propoxy)-benzoimidazol-1-yl]-quinoiin-8-yi}-phenoi; 1 -I2-{5-Phenyl-benzoimidazol-1 -yl)-quinoÎin-8-yiJ-piperidin-4-ylamine; 1-[2-(5-Pyridin-4-yl-benzoimidazol-1-yl)-quinolin-8-yl]-pîperidin-4-ylamine; 142-[5-(3-Methoxy-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; 1-[2-{5-Pyridin-3-yl-benzoimidazoi-1-yl)-quinoiin-8-yi]-piperidin-4-yÎamine; 1-{2-[5-(6-Methoxy-pyridÎn-3-yi)-benzoimidazol-1-yi3-quinolin-8-yl}-piperidin-4-ylamine; 1- {2-i5-(4-Aminomethyl-phenyl)-benzoimidazoM-ylJ-quinolin-8-yl}-piperidin-4-ylamirte; 4-{1 -l8-(4-Amîno-piperidln-1 -yl)-quinolin-2-ylî-1 H-benzoimidazol-5-yl}-benzoic acid methyl ester; 4414844-Amino-piperidin-l -yî)-quinoiin-2-yl]-1 H-benzoimidazol-5-yl}-phenoi; 2- (5-Methoxy-benzoimidazol-1-yl)-quinoline-8-carboxylie acid methyl ester, 2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yt]-quinoiine-8-carboxylic acid methy! ester;

245-Methoxy-benzoimidazol-l -yl)-quinoline-8-carboxylic acid (2-dimethylamino-ethyl)-amide;

245-Cyciopropylmethoxy-benzoimidazol-1-yl}-quinoline-8-carboxylic acid methylester, [245-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinoIin-8-yll-pyrrolidin-1-yi- methanone; [2-(5-Cydopropylmethoxy-benzoÎmidazol-1-yl)-quinolin-8-yll-morpholin-4-yl- methanone; -174- 1 2098 ï2-(5-Cydopropylmethoxy-benzoimidazol-1-yl)~quinolin-8-yi]-piperidin-1-yl- methanone; (3-Am»K>-pyrrolidln-1-yl)-[2-(5-cydopropylmethoxy-benzoimidazol-1-yl)-quinoiin-8-yl]- methanone;

2-Amino-1-{4-{2-[5-{2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperazin-1· yi)-ethanone; 35 (1 -Amino-cyclopropyl)-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1 -ylJ-quinoiin-8-yl}- piperazin-1 -yl)-methanone; -171- 1 2 098 2-(442-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yiJ-quinolin-8-yl}-piperazin-1-yl>· ethyiamine; (R)-2-Amino-3-(4-{2-{5-(2-methoxy-eihoxy)-benzoimÎdazol-1-yi]-quinoiin-8-yl}-piperazin-1 -yl)-propan-1 -oi; 5 3-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinoiin-8-yl}-3-aza-bicyclo[3.1.0]hex- 6-ylamine; (S>1-{2-i5-(2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinolin-8-yl}-pyTOlidin-3-ylamine; (R)-1-{2-[5-(2-Methoxy-ethoxy>benzoimidazol-1-yl]-quinolin-8-yl}-pyrralidin-3- yiamine; 10 2-[5-(2-Methoxy-ethûxy)-benzoimidazol-1-yl]-8-pyridin-3-yi-quinoline; 2-{5-{2-Methoxy-ethoxy)-benzoimidazol-1-yl]-8-(6-methoxy-pyridin-3-yl)-quincHne;442-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yiJ-quinolin-8-yl}-benzo«c acid methylester; 142-l5-(2-Methoxy-ethoxy)-benZQimidazol-1-ylJ-quÎnolïn-8-yl}-4-methyi-piperidin-4- 15 ylamine; 1 -(2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyc!openta[bjnaphthalen-1 -yl)-quinolin-8-yl]-piperidin-4-ylamine; 2-{1 -[8-(4-Arnino-piperidin-1 -yl)-quinolin-2-yl]-1 H-beraoimidazol-5-yloxy}-ethanol;4-Cydopropylaminomethyl-1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yi]-quinolin-8- 20 ylJ-piperidin-4-ol; 1 -[8-(4-Amino-piperidin-1 -yl)-quinoiin-2”ylj-1 H-benzdmidazole-5-sulfonic acid dimethylamide; 1 -[2-(6-Methoxy-benzoimidazol-1 -yl)-quinoiin-8-yl]-piperidin-4-ylamine; 1- [2-(5,6-Dimethoxy-benzoirr>idazol-1-yl}-quinolin-8-yl]-piperidïn-4-ylamine;

2-Amino-1-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yi}-piperazin-1- yl)-2-methyl-propan-1-one; (S)-2-Amino-1-(4-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yi}- 30 piperazin-1-yl)-propan-1-one; (S)-2-Amino-1-(4-{2-[5-(2-methoxy-ethoxy)-benzotmidazol-1-yi]-quinolin-&amp;yl}-piperazin-1 -yl>propan-1 -one;

2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazQl-1-ylJ-quinolin-8-yl}-piperidin-4- ΙΟ yl)-isobutyramide; 1 -{1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1 -yl]-quinoiin-8-yi}-piperidin-4-ylamino)- 2-methyl-propan-2-ol; (1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1 -yl]-quinQlin-8-y!}-piperidin-4-yî)-py ridin- 2- yimethyl-amine; 15 (1 -{2-l5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yi>piperidin-4-yi)-pyridin- 3- ylmethyl-amine; 4- {2-[5-(2-Methoxy-ethoxy)-benzoirnidazQl-1-yl]-quinolin-8-yi}-phenoi;j2-(4-{2-i5-{2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-phenoxy)-ethy!3~dimethyi-amine; 20 2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1 -yl]-8-piperazin-1 -yi-quinoline; [2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yIJ-quinQiin-8-yi}-piperazh-1-yl}- ethylj-dimethyl-amine; 2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yfl-8-(4-pyridin-2-yimethyl-piperazin-1-yl)- quinoline; 25 2-[5-(2-Methoxy-ethoxy)-benzoimÎdazol-1 -ylJ-8-(4-pyiidin-3-ylmethyÎ-piperazin-1 -yl)-quinoline;

2-Amino-N-( 1 -{2-[5-(2-methoxy-ethoxy}-benzoimidazol-1 -^}-ρυίηοϋη-8-νΙ}-ρίρβπάΐη-4-yl)- acetamide; 5 -(S)-2-Amino-N-(1 -{2-{5-(2-methoxy-ethoxy)-ben2oimidazoi-1 -yl]-quinolin-8-y!}- piperidin-4-yl)-propionamide; -(R)-2-Amino-N-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yO-quinQiin-3-yi}- piperidin-4-yl)-prQpionamide;

2. A compound according to daim 1 wherein R1 is C8-C10 aryl or 4 to 10 memberedheterocyclic wherein the foregoing R1 groups are each substituted by 1 or 2 groupsindependently seiected from -NR3R4, -OR3 and C,-C3 alkyl, wherein said alkyl groups aresubstituted by 1 or 2 groups independently seiected from -NR3R4 and -OR3; and the foregoingR1 groups are optionally substituted by 1 to 3 R2 groups; each R2 is independently seiected from H, C,-C10 alkyl, C3-C10 cydoalkyl, oxo(=0),-OR3, -C(O)R3, -C(O)OR3, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR4SO2Re, -3O2NR3R4,-(CR4Rs)m(4 to 10 membered heterocyclic), and (CR4R5)m(C3-C10 cydoalkyl); and said alkylgroups optionally contain 1 or 2 hetero moieties seiected from O, -S(O),- wherein j is aninteger from 0 to 2, and -N(R3)- with the proviso that two O atoms, two S atoms, or an O and Satom are not attached directly to each other; and said alkyl and cydoalkyl R2 groups areoptionally substituted by 1 to 5 substituents independently seiected from oxo, cyano,trifluoromethyl, trifluoromethoxy, -NR4SO2R®, -SO2NR3R4, -C(O)R3, -C(O)OR3, -NR4C(O)OR®, -167- ι 2 098 -MR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, and 0,-0,0 alkyl, wherein each m is independentlyan integer ranging from 0 to 4.

3. A compound according to daim 1 wherein R1 is piperidinyl, piperzinyl, or phenyl,wherein said R’ groups are substituted by -NR3R4, oxo (=0), -OR3 and C<C3 alkyl, wherein 5 said alkyl group is optionally substituted by 1 or 2 groups independently selected from -NR3R4and -OR3; and the foregoing R’ groups are optionally substituted by 1 to 3 R2 groups.

4-Aminomethy!-1 -{2-[5-(pyridin-2-ylmethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}- piperidin-4-ol; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl3-quinolin-8-yl}-piperidin-4-y!)-dimethyl- amine; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yf}-piperidin-4-yi)-methyl- 35 amine; -176- 1 2 Ü9 8 (1-{2-[5-{3-Dimethylannino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl}- dimethyi-amine; {1 -i2-(5-Cyclopropylmethoxy-benzoimidazol-1 -yl)-quinolin-8-yiJ-piperidin-4-yl}-methyl-arnine; {1 -[2-{5-Cydopropylme1îioxy-benzoimidazol-1 -yI)-quinolin-8-yl]-piperidin-4-yf}-dimethyl-amine; 1 -{2-[5-{2-Methoxy-ethoxy)-benzoimidazoi-î -yiJ-quinoiin-8-yi}-piperidin-4-yi)-pyridin-2-ylmeihyl-amine; (H2-[5-(2-Methoxy-ethoxy>benzoimÎdazol-1-ylî-quinolin-8-yl}-piperidin-4-yt)-pyridin- 3- ylmethyl-amine; 4- {2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolÎn-8-yl}-phenot; i2-(4-{2-[5-(2-Methoxy-ethoxy)-benzoimidazoi-1-yiî-quinolin-8-yi}-phenoxy)-ethyiJ- dimethyl-amine; 2-[5-(2-Methoxy-ethoxy)-benzoirnidazol-1 -yl]-8-piperazin-1 -yî-quinoline; [2-(4-{2-(5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperaz5n-1-yl}- ethylj-dimethyl-amine;

4-Aminomethyl-1>{2>(5-me1hoxy-benzoimidazol-1-yl)-quinolin-8-^l-piperidin-4-oi; 1-{2-î5-(4-Methoxy-phenyl)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-j4amine; 1-(2-{5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-ylJ-piperidin-4-yiamine; 1-{2-{5-(3-Dimethylam»no-propoxy)-benzoimidazol-1-yl}-quinolin-8-yî}-piperidin-4- 20 yiamine; 1-{2-i5-(3-AmÎno-propoxy)-benzoimidazol-1-ylî-quinoiin-8-yi}-pÎperidin-4-yianiine; 142-[5-(2-Dimettiylamino-ethoxy)-benzojmidazoi-1-ylî-quinoîin-8>yl}-piperidin-4- yiamine; 1-{2-[5-(Pyridin-4-ylmethoxy)-benzoimidazol-1-yl]-quinoiin-8-yi}-piperidin-4-ytamine·, 25 1 -[2-(5-8enzyloxy-benzoimidazol-1 -yl)-quinolin-8-yi]-piperidin-4-ylamine; 1 -{2-[5-(Pyridin-3-ylmethoxy)-benzoimidazol-1 -yl]-quinoiin-8-yi}-piperid!n-4-yiamin6;1-{2-[5-{2-Methoxy-ethoxy)-benzoimidazol-1-ylJ-quinoiin-8-yl}-piperidin-4-ylamine;4-Dimethylaminomethyl-1-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperïdin-4-ol;

4-Dimethylaminomethyl-1-[2-(5-meeioxy-benzoimida2oi-1-yi)-quinoiin-8-yO-piperidin- 4-ol; 1-|2-(5-MeÜioxy-benzoimidazol-1-yl)-quinoiin-8-yl]-4-meihyÎaminomethyi-pipendin-4- 15 oi;

4-Aminomethyi-1-{2-[5-(pyridÎn-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yi}- piperidin-4-ol; Cyclopropyl-(1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinoiin-8-yl}-piperidin- 4-yl)-amine; (1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quÎnolin-8-yl}-piperidÎn-4-yl}- dimethyl-amine; 1-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yÎ}-piperidin-4-yl)-methyl- amine; ( 1-(2-(5-(3-0 imethyiamino-propoxy)-benzoimÎdazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-dimethyl-amine; {1-[2-{5-Cyclopropylmethoxy-benzoimidazol-1-yl)-quinoiin-8-yl3-piperidin-4-yl}-methyi- arnine; -170- 1 2098 {1-[2-(5-Cyclopropylmethoxy-benzoimida2Ol-1-yl)-quinolin-8-yf]-pipericlin-4-yl}- dimethyl-amine;

4-DimethyIaminomethyl-1-(2-(5-methoxy-benzoinriidazol-1-yl)-qdinolÎn-8-yQ-piperidin- 4-ol; N-{1-[2-(5-Methoxy-benzoimidazoi-1-yi)-quinoIin-8-yi]-piperidin-4-yi}-acetamide; N41-[2-(5-Cyclopropylmethoxy~benzoimidazol-1-yl)-quinolin-8-yll-piperidin-4-yi}~ acetamide; 1 -{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ol; {1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yf}-urea;

4-Aminomethyl-1 -[2-{5-methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-pipendin-4-ol; -169- 1 2098 1-(2-(5-Methoxy-benzoimidazoH-yl>-quinolÎn-8-ylJ-pyrrol«din-3-ylamine; 1-(2-Benzoimidazoi-1-yl-quinolin-8-yf)-piperidin-4-ylamine; 1-{2-Ιηΐά3ζο[4,5-6^πάΐη-3^ςυΐηοΙΐη-8-γΙ)-ρΐρβΓίάϊη-4-γΐ3ΐηίηβ; H2-(5-(4-Methoxy-phenyl)-benzQimidazol-1-yQ-qu»noiin-8-ylbpiperidin-4-ylamine; 1-{2-{5-Cyclopropylmethoxy-benzoimidazol-1-yt)-quinolin-8-yiJ-piperidin-4-ylamine; 142'[5-(3-Dimethylamino-propoxy)-benzoimidazol-1 -yl]-quinolin-8-yl}-piperidin-4-ylamine; 1-{2-i5-(3-Amino-propoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine;l42-[5-(2-Dimethylamino-ethoxy)-benzoimidazoi-1-yll-quinoiin-8-ylbpiperidin-4-ylamine; i 1-{2-[5-(Pyridin-4-ylmethoxy)-benzoimidazol-1-yll-quinolin-8-ylî-piperidin-4-ylamine; 1-[2-(5-Benzyloxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperid»n-4-ylamine; 1"{2-{5-(Pyridin-3-ylmethoxy)-benzoimidazol-1-yl]-quinoiin-8-yi}-pipeiidin-4-ylamine; 1-{2-{5-(2-Metfioxy-ethoxy)-benzoirnidazd-1-yl]-quinolin-8~yi}-piperidtn-4-y(arnine; I -(2-{5-Methoxy-benzûimidazoi-1-yl)-quindin-8-yq-piperidtne-4-carboxylic acid ethylester, 1 -{2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidine-4-carboxyÎic acid ;

4-Dimethylaminomethyl-1 -[2-(5-methoxy-benzoimidazoi-1 -yl)-quinolh-8-y!]-piperidin- 4-ol; 1-[2-(5-Methoxy-benzoimidazd-1-yl)-quinolin-8-yQ-4-methylaminomethyl-piperidin-4-15 ΐ 0,;

4. A compound according to daim 2 wherein said R1 groups are substituted by-NR3R\ oxo (=0), OR3, or C,-C3 alkyl, wherein. said alkyl group is optionally substituted by-NR3R4. 10

5. A compound according to claim 1 wherein R1 is phenyl substituted by pyrrolidin-1 - yl which pyrrolidin-1 -yl is optionally substituted by 1 to 3 substituents independently selectedfrom oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR4SO2R6, -SO2NR3R4, -C(0)R3,-C(O)OR3, -NR4C(O)OR6, -NR4C{O)R3, -C(O>NR3R4, -NR3R4, -OR3, and CrC10 alkyl; and Rnis -OR3. 15

6. A compound according to daim 5 wherein R’ is 4-pyrrolidin-1-ylmethyl-phenyl optionally subtituted by 1 to 3 substituents independently selected from oxo, cyano,trifluoromethyl, trifluoromethoxy, -NR4SO2R6, -SO2Np3R4, -C(O)R3, -C<O)OR3, -NR4C(O)OR6,-NR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, and CrC10 alkyl; and R11 is -OR3.

7. A compound according to daim 6 wherein R11 is connected at the 5 position of the 20 benzimidazole moiety of the compound of formula 1 and is -OR3.

8-Allyloxy-2-<5-methoxy-benzoimidazol-1-yl)-quinoline; {2-p-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yloxy]-ethyl}-methyl-amine; {2-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yloxy|-ethyl}-dimethyl-amine; 2-i2-(5-Methoxy-benzoimidazol-1 -yl)-qulnolin-8-yloxyJ-ethylamine; 1 -[[2-[5-(3-Morpholinoethoxy)-1 H-benzimidazol-1 -yl]-quinolin-8-yl]]-piperidin-4-ylamine trihydrochloride; 1 -{[2-[5-(3-Morphoiinoethoxy)~1 H-benzirnidazol-1 -yl]-quinolin-8-yl]]-piperidin-4-ylamine trihydrochloride; 5-{2-[5-(2-Methoxy-ethoxy)-benzoimidazol-1~yl]-quinolin-8-yl}-[1,3,4]oxadiazol-2- ylamine; Ethyl 1 -[8-{4-aminopiperidin-1 -yi)-quinoiin-2-yl]-henzimidazole-5-carhoxyJate; 1 -t8-(4-Aminopiperidin-1 -yl)-quinolin-2-yl]-benzimidazole-5-carboxylic acid; N-(4~Morpholino)ethyH-[8-(4-aminopiperidin-1-yl)-quinotin-2-yiJ-benz!midazoi8-5- carboxamide; 4-{148-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-yl}-benzaldehyde; 1-{2-[5-(4-Methylaminomethyl-phenyl)-benzoimÎdazol-1-yl]-quinolin-8-yl}-piperidin-4- ylamine; 1-{2-[5-(4-Dimethylaminomethyl-phenyl)-benzolmidazol-1-yl]-quinolin-8-yl}-piperidin- 4-ylamine; 1 -(2-{5-I2-(2-Methyl-imidazol-1 -ÿl)-ethoxy]-benzoimidazol-1 -yl}-quinoiin-8-yl)-piperidin-4-ylamine and 1-{2-[5-(2-(1,2.4]Triazol-1-yl-ethoxy)-benzolmidazol-1-yl]-quinolin-8-yl}-piperidÎn-4- ylamine, and the pharmaceutically acceptable salts, prodrugs and solvatés of the foregoingcompounds.

8. A compound according to ciaim 7 wherein R11 is connected at the 5 position of thebenzimidazole moiety of the compound of formula 1 and is 2-methoxyethoxy.

9. A compound according to claim 1 wherein R1 is pyrrolidin-1-yl or piperidin-1-yl,said R1 being optionally substituted by 1 to 3 substituents independently selected from oxo, 25 cyano, trifluoromethyl, trifluoromethoxy, -NR4SO2R®, -SO2NR3R4, -C(O)R3, -C(O)OR3,-NR4C(O)OR®, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, and C,-C,o alkyl.

10. A compound according to ciaim 9 wherein R’ is pyrrolidin-1-yl or piperidin-1-ylsubstituted by -NR3R4 and optionally substituted by 1 or 2 substituents independently selectedfrom oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR4SO2R6, -SO2NR3R4, -C(0)R3, JO -C(0)OR3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -OR3, and C,-C10 alkyl; and R11is -OR3.

11. A compound according to claim 10 or claim 9 wherein R11 is connected at the 5position of the benzimidazole moiety of the compound of formula 1 and is -OR3 and R9 andR'° are both H. 1 2 098 -168-

12. A compound according to daim 10 or daim 9 wherein R11 is connected ai the 5position of the benzimidazole moiety of the compound of formula 1 and is 2-methaxyethoxyand R9 and R10 are both H.

13. A compound according to daim 1 wherein R9 is -C(O)R3 wherein R3 is pyrrolidin-5 i-yl or azeOdin-1-yi wherein said R3 groups are optionaily substituted by 1 to 3 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, -C(Q)R\ -C(O)OR4, -OC(O)R4, -NR4C(O)R5, -C(O)NR4RS, -NR4R5,hydroxy, C<-Ce alkyl, and CrCB alkoxy.

14. A compound according to claim 1 selected from the group consisting of: 10 11 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8~yl]-piperidin-4-ylamine; c 1 -{8-(4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-oi; 1-{2-[5-(Pyridin-2-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine; {1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-dimeihyl-amine; {4-[2-(5-Methoxy-benzoimidazol-1-yi)-quinofin-8-yi]-benzyi}-methyl-amine; 15 {4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-dimethyl-amÎne; Cydopropyi-{4-[2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyi}-amine; terî-Butyl-{4-[2-(5-methoxy-benzoimidazal-1-yl)-quinolin-8-yl]-benzyl}-amine; 4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzylamine; 1-[2-(5-Ethoxy-benzoimidazoM-yl)-quinolin-8-ylI-piperidin-4-ylamine; 20 {1 -(2-(5-Ethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yi}-dimethylamine; 1 -[2-(5-T rifluoromethoxy-benzoimidazol-1 -yl)-quinolin-8-yll-piperidin-4-yiamine; {4-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinoiin-8-yl]-benzyl}-methyl-amine; Cyclopropy!-{4-[2-(5-ethoxy-benzoimidazol-1-yl)-quinolin~8-yl]-benzy!]-anr»ine; tert-Butyl-{4-[2-(5-ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzyl}-ainine; 2>' {4-[2-(5-Ethoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-benzyi}-dimethyl-arnine; 1 -(2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-one; 1 -{2-(5-Ethoxy-benzoimidazoS-1 -yl)-quinolin-8-yl]-pipendin-4-one; 1- l2-(5-Ethoxy-benzoimWazol-1-yl)-quinolin-8-yl]-piperidin-4-ol;tert-Butyl-{1-[2-(5-ethoxy-benzôimidazol-1-yl)-quinolin-8-yl]-piperidin4-yl}-amine; 30 {1 -[2-(5-Methoxy-benzoimidazol-1 -yl)-quinolin-8-yl]-piperidin-4-yl}-methyl-amine; 2- (5-Methoxy-benzoimidazol-1-y I )-8-(1-oxa-6-aza-spiro[2.5]oct-6-yl>quinoline;

15. A compound according to claim 1 selected from the group consisting of: -175- 1 2098 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yIÏ-piperidin-4-yiamine; 1 -[8-{4-Amino-piperidin-1 -yl)-quinolin-2-yl]-1 H-benzoimidazol-5-ol; 1-{2-[5-{Pyridin-2-ylmethoxy)-benzoiniÎdazol-1-yl]-quinoîin-S-yi}-piperidin-4-yiamine; {1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yf]-piperidin-4-yl}-dimethyi-amine; 5 {4-i2-(5-Methoxy-benzoimidazoi-1-yl)-quinolin-8-y0-benzy!}-methyi-arnine; {4-[2-{5-Meihoxy-benzoimidazol-1-yl)-quinolîn-8-yi3-benzyî}-dimeihyi-amine; 1-[2-(5-Ethoxy-benzoimidazol-1-yi)-quinoiin-8-yl]-pipendin-4-y!amine; {1-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-dimethyiamins; {4-[2-(5-Ethoxy-benzoimidazol-1-yl)-quinolin-8-yi]-benzy!}-methy!-amine; 10 {4-(2-(5-Ethoxy-benzoimidazol-1-yl}-quinolin-8-yI]-benzyi}-dimethyl-amine; {1-ï2-(5-MethoXy-benzoimÎdazol-1-yl)-quinolin-8-yI3iîiperidin-4-yl}-meibyi-amjne;

16. Use of a compound of claim 1 that is effective in treating abnormal cellgrowth, in the manufacture of a médicament for the treatment of abnormal cell growthin a mammal.

17. Use according to daim 16 wherein said abnormal cell growth Is cancer. 35 -179- 1 2098

18. Use ' according to claim 17 wherein said cancer is selected from iung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma. uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région,stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the faiiopian tubes, 5 carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma ofthe vulva, Hodgkin's Oisease, cancer of the esophagus, cancer of the small intestine, cancer ofthe endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of theadrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer,chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney 10 or ureter, rénal cell carcinoma, carcinoma of the renai pelvis, neoplasms of the central nervousSystem (CNS), primary CNS iymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, or a combination of one or more of the foregoing cancers.

19. A pharmaceutical composition for the treatment of abnormal ceil growth in arnammal comprising an amount of a compound of claim 1 that is effective in treating abnormal 15 ce» growth, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of daim 19 wherein said abnormal cell growth is cancer.