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Title:
BICYCLIC COMPOUND AND USE THEREOF FOR INHIBITING HISTONE METHYLTRANSFERASE
Document Type and Number:
WIPO Patent Application WO/2018/165112
Kind Code:
A1
Abstract:
The present invention relates to a compound represented by formula (I), a method for the preparation thereof, and a pharmaceutical composition containing the compound as an active ingredient for inhibiting histone methyltransferase such as SUV39H2.

Inventors:
RAVULA SRINIVAS (IN)
SIVALENKA VIJAYASARADHI (IN)
MANTIPALLY MANOHAR (IN)
PATNAIK PRAVEEN (IN)
DUPATI PRAVEEN (IN)
CHAKRABARTI ANJAN (SG)
NAKAMURA YUSUKE (JP)
MATSUO YO (JP)
MIYAMOTO TAKASHI (JP)
OKAMOTO YASUHIDE (JP)
DUAN ZHIYONG (US)
Application Number:
PCT/US2018/021079
Publication Date:
September 13, 2018
Filing Date:
March 06, 2018
Export Citation:
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Assignee:
ONCOTHERAPY SCIENCE INC (JP)
International Classes:
A61K31/496; A61K31/497; A61P15/14
Domestic Patent References:
WO2014177458A12014-11-06
Foreign References:
US20050049277A12005-03-03
US7504501B22009-03-17
Other References:
DATABASE PubChem 12 February 2015 (2015-02-12), Database accession no. 87367073
DATABASE PubChem 25 October 2006 (2006-10-25), Database accession no. 10133248
Attorney, Agent or Firm:
BASTIAN, Kevin L. et al. (Mailstop: IP Docketing - 221100 Peachtree Street NE Suite 280, Atlanta Georgia, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R! and R2 are independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkyl, and Ci-Ce alkoxy;

R3 is independently selected from the group consisting of a halogen atom, cyano, nitro, hydroxy, carboxy, Ci-Ce alkyl, Ci-Ce alkoxy, (Ci-Ce alkoxy)carbonyl, Ci-Ce alkylthio. Ci-Ce aikylsulfinyl, and Ci-Ce alkylsuifonyl;

n is an integer selected from 0 to 3;

R'' is selected from the group consisting of a hydrogen atom, and a halogen atom; R3 is independently selected from the group consisting of a halogen atom, Ci -Ce alkyl, and Ci-Ce alkoxy;

m is an integer selected from 0 to 3;

X and Y are independently selected from a direct bond, -CH2-, and -CH2CH2-;

R6 is selected from the group consisting of Ci-Ce alkyl substituted with one or more substituents selected from Ra, C3-G0 cycloalkyl optionally substituted with one or more substituents selected from Rb, Ce-Cio aryl optionally substituted with one or more substituents selected from Rb, 5- to 10-membered heteroaryl optionaliy substituted with one or more substituents selected from Rb, 3- to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Rb, (Ci -Ce

alkoxy)carbonyl substituted with one or more substituents selected from Ra, (Ci-Ce alkyl)carbonyl optionally substituted with one or more substituents selected from Ra, (C3- C10 cycloaJkyl)carbonyl optionally substituted with one or more substituents selected from Re, (Ce-Cio aryl)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic heterocyciyl)carbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-membered heteroaryl)carbony3 optionally substituted with one or more substituents selected from Rc, ammocarbonyl, (Ci-Ce alkyl)aminocarbonyl, and di(Ci-C& aikyl}aminocarbonyi:

R7 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyi optionally substituted with one or more substituents selected from Ra;

Q is selected from Ci-Ce alkylene;

R!0 is independently selected from the group consisting of a halogen atom, and Ci-

Ce alkyl;

q is an integer selected from 0 to 4:

Ra is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkoxy, cyano, (Ci-Ce alkoxy)carbonyJ , carboxy, (Ci-Ce alkoxyjearbonyiamino, (Ci- Ce aikyi}carbonyla.nimo, amino, Ci-Ce aikylamino, di(Ci-Ce alkyijamino, aminoearbonyl, (Ci-Ce alkyl)aminocarbonyl, diiCi-Ce alkyl)aminocarbonyl, Ci-Ce alkylsulfonylamino, C3- C io cycloalkylsulfonylamino, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, C3-C 10 cycloalkenyi optionally substituted with one or more substituents selected from Rc, Ce-Cjo aryl optionally substituted with one or more substituents selected from Rd, 5- to 10-membered heteroaiyl optionally substituted with one or more substituents selected from Rc, and 4- to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Re;

Rb is independently selected from the group consisting of a halogen atom, hydroxy, C i-Ce alkyl optionally substituted with one or more substitutents selected from Ra, Ci-Gs alkoxy optionally siibstituted with one or more substitutents selected from Ra, cyano, (Ci- G> alkoxy)carbonyl, carboxy, -NR21R22, -CONR23R24, di(Ci-C6 alkyljphosphono, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10- membered heteroaryl optionally substiMed with one or more substituents selected from Rc, and 3- to 12-nienibered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Rc;

Rc is independently selected from the group consisting of nitro, hydroxy. Ci-Ce alky! optionally substituted with one or more halogen atoms, Ci-Ce alkoxy optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, di(Ci-Ce alkyijaniino, (Ci-Ce alkyl)carbonyi, (Ci-Ce alkoxy)earbonyi, Ci-Ce alkyisulfonyl, Cs-Cio eycloalkyisulfonyl, C7-C14 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, C3 -O 0 cycloalkyl optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Re, 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Re, and oxo;

Rd is independently selected from the group consisting of nitro, hydroxy, Ci-Gs alkyl optionally subsituted with one or more halogen atoms, Ci-Ce alkoxy optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, diC'Ci-Ce alkyl)amino, Ci-Ce alkylcarbonyl, (Ci-Ce alkoxy )carbonyl, Ci-Ce alkyisulfonyl, C?-Cs cycloalkyisulfonyl, C7-C14 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio and optionally substituted with one or more substituents selected from Re, Ci-Cs cycloalkyl optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Re, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Re;

Re is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, di(Ci-Ce alkyl)amino, Ci-Ce alkylcarbonyl, (Ci-Ce alkoxy)carbonyl, Ci- Ce alkyisulfonyl, and Cs-Cs cycloalkyisulfonyl; R21 is selected from the group consisting of a hydrogen atom, Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 4- to 12-nienibered heteroeyciyl optionally substituted with one or more substituents selected from Rc, 5- to 10- mernbered heteroaryl optionally substituted with one or more substituents selected from Rc, (Ci-Cf, aIkoxy)carbonyl optionally substituted with one or more substituents selected from Ra, (Ci-Ce alkyi)carbonyl optionally substituted with one or more substituents selected from Ra, (Cs-Cio cydoalkyOcarbonyL (Ce-Cio a.ryl)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membcred non-aromatic

heterocyclyljcarbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-membered heteroaryl icarbonyl optionally substituted with one or more

substituents selected from Rc, aminocarbonyi, (G-Ce aikyi)aminocarbonyl optionally substituted with one or more substituents selected from Ra, di(Ci-C6 alkyi)aminocarbonyl optionally substituted with one or more substituents selected from Ra, Ci-Ce alk isulfonyl optionally substituted with one or more halogen atoms, CTCU aralkyisulfonyl, Cii-Cio cycioalkylsiiifonyi, aminosiiifonyi, Ci-Ce alkylaminosulfonyl, di(Ci-C6 alkyi}ammosuifonyi, and di(Ci-C6 aikyl)phosphono;

R22 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra;

R23 is selected from the group consisting of a hy drogen atom, Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra, [(Ci -Ce

alky!)amino]Ci~C6 alkyl optionally substituted with one or more substituents selected from Ra, [di(Ci-Ce alkyijammoJCi-Cs alkyl optionally substituted with one or more substituents selected from Ra, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio axyl optionally substituted with one or more substituents selected from Rd, 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Rc, and 3- to 12-membered non-aromatic heteroeyciyl optionally substituted with one or more substituents selected from Rc; and R24 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R7 is a hydrogen atom.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R6 is selected from the group consisting of pyrimidyl, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, piperidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce aikoxy)carbonyl group, pyrrol idyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy)carbonyl group, C3-C7 cycloalkyl optionally substituted with a di(Ci-Ce alkyi)amino groupor a Ci-Ce alkyl group, tetrahydrofuryl, tetrahydropyranyi, phenyl optionally substituted with one substituent selected from Rb, a group -CFb-Ra, a group -CHzCHb-Ra and a group -CH2 CH2.CH.2-Ra.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, Ra is independently selected from the group consisting of hydroxy, Ci-Ce alkoxy, C3-C7 cycloalkyl optionally substituted with a di(Ci-C6 alkyI)ammo group, phenyl optionally substituted with one or more substituents selected from Rd, pyrrolidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy)carbonyl group, pipendyl optionally substituted with a Ci-Ce. alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyridyl optionally substituted with a halogen atom or a Ci-Ce. alkoxy group, thiazolyl, thienyl, pyrimidyl optinally substituted with a di(C;-Ce alkyl)amino group, and C3-C7 cycloalkenyl.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, Rb and Rd are independently selected from the group consisting of a halogen atom, methyl, cyano dimethylamino, methoxy, nit.ro, hydroxy, and trifluoromethyl ,

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound is represented by Foramula (lb):

Q is selected from the group consisting of --CH2-, -CH(CH:3)-, -CH(CH2CH3)-, - CH2CH2-, ("l i(CH : )( H - . and -C^CHiCft)-: -

R1, R2 , R3, R , R? , R6, R7, X, Y, m and n are as defined in any one of claims 1 to 5. 7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein wherein X and Y are -(GHb)-, X and Y are direct bonds, or X is a direct bond and Y is -(CH2)-.

8. The compound or a phannaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the com ound is represented by Forumula ( c):

wherein R1 and R2 are independently selected from the group consisting of Ci-Ce alkoxy,

p is an interger selected from 0 and 1 :

R3 is selected from the group consisting of a harogen atom, and

R6 and R7 are as defined in any one of claims 1 to 6.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R1 and R2 are methoxy, and R3 is a chlorine atom ,

10. The compound or a pharmaceutically acceptable salt thereof according to claim i, which is serected from the group consisting of:

l-(i -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo l ,2-ajpyridin-7-yl)piperidin-4- yl)-N-(cyclopropylrnethyi)methanarnine;

1 -( 1 ~(2-(5 -Chloro~2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidm-4- yl)- -(cyc3ope!it 'iinethyi)met3ianamine:

iert-Butyl 3-((((l-(2-(5-chloro-2,4-dimethox> henyl)imidazof l,2-a]pyridin-7- y])piperidin-4-yl)methyl) ammo)fflethyI)pyjTo!idine~I-carboxylate;

tsrt-Butyl 3-((((l -(2-(5-chIoro-2„4-dimetlioxypheny3)imidazo[ l,2-a|pyndm-7- y3)piperidin-4-yl)inethyi)(me^

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxypheny l)imidazo [ 1 ,2-a]pyridin-7-yi)piperidin-4- yl)-N-(pyirolidin-3-ylmethyl)methananiine;

l-( l-i2-(5-Chloro-2,4-dimetho ypheiiyl)imidazo[l ,2-a]pyridin-7-yl)piperidm yi)-T^-{cyc!ohexy!methy!}niei3 a.iiamine:

tert-Butyl 4-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7- yl)piperidin-4-yl)meihyl)amino)meihyl)piperidine-l-carboxylate;

1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-ajpyridin-7-yl)piperidin-4- yl)- -(piperidin-4-ylmethyl)methanamine;

-Benzyl-l-(l-(2-(5-chloro-2,4-dimethoxyphemd)iinidazo l,2-a]py'ridin-7- yl)piperidin-4-yl)met aiiara.me;

l-(l-(2-(5-CWoro-2,4-dimethox>-pbenyl)imidazo[l,2-a]pyrid}n-7-y{) piperidin-4- yl)-N-(2-methylbenzyl)methanamine;

l-(l-(2-(5-C¾loro-2,4-dimeihoxypheny3)imidazo[l,2-a]pyridin-7-yl)piperidin-4- yl)-N-(4-methylbeiizv'l)methanamine;

l-(i-(2-(5-Chloro-2,4-dimetiioxyphenyl)m^^

yl)- -(2-fluorobenzyl)methanamine;

l-(l-(2-(5-C oro-2,4-diraethoxyp^

yl)-N-{3-fluorobenzyS)fflethaiiaiiiiiiie:

l-( l -(2-(5-Chloro-2,4-dimethoxypheny

yl)-N-(4-fluorobenzy])methan amine;

l-(l -(2-(5-Chloro-2,4-dimethox>phenyl)imidazo[l ,2-a]pjxidin-7-yl)piperidm yl)-N-(4-methox}'benzyl)methanamine;

1 -( 1 -(2-( 5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridiii-7-yl)piperidin-4- yl)- -(2-chlorobe!iz\'i)methanamine:

4-i(((l -(2-(5~C1iloro-2:4-dimeihoxy

y])methyl)amino)methyl)-N,N-dimethyiani]ine

3- ((((l-(2-(5-Chloro-2.4-dimeihoxyphenyl)imidazo[ 1.2-a]pyridin-7-yl)piperidm y 1 )me thy 1) am ino )methy l)benzoni tril e

4- (({(l-(2-(5-Chioro-2,4-dimeihoxyphenyl)iinidazo[ L2-a]pyridm-7-yl)piperidin-4 yl)methyl) ainino)methyl}benzoiiitrile:

l-(l-(2~(5-Chloro-2,4-dimethoxyphenyl)^^

yl)-N -(2-nitro ben zyl )methanamine ;

l~(l -{2-(3~Chloro-2:4 iimethoxy

yl)-N-(3-(,rifluoromethyl)benzyl)methaitamine;

l-(i -(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[ ] ,2-a]pyfidin-7-yl)piperidm yl)-N-(pyridin-3-ylmethyl)methanainine;

l-(l-(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridiii-7-yl)piperidin-4- yl)-N-(pyridin-4-ylmethyi)methanamme;

1 -( 1 ~(2-(5 -Chi o ro-2,4 -dimethoxyphenyl)imidazo [ i .2-a jpy ridin -7-yi)piperidin-4- y I )-N-((3 -fluoropy ridi n -4-y I ) methy 1 )m eth anami n e ;

l-(l-(2-(5-Chloro-2>4-dimeihoxypheny3)imidazof L2-a]pyridin-7-yl)piperidin-4- y3)-N-((2-methoxypyridin-4-y3)methyl)methanamine;

1-(1 -(2-(5 -Chloro-2 ;4-dimethoxypheny l)imidazo [ i ,2-a]py ridin-7-yl) piperidin-4- yl)-N-(thiazol-2-yimethyl) methanamine;

l-(l-(2-(5-C oro-2,4-diraethoxyphenyl)imidazo[l ,2-a]pyTddin-7-yl) piperidtn-4- yl)-N-{thiazol-2-ylmethyl) methanamine;

l-(l -i2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pi yl)- , -bis(pyridin-2-ylmethyl)methanamine;

N-((l-(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[ l,2-aJpyridi

y l)methy 1) cy clob utanamine :

-{(l-(2-(5-Chloro~2.4-dimemoxyphenyl)imidazo[ 1.2-a]pyridin-7-yi)piperidin-4- yOn cthyl) cyclopcntanamme;

-({ l-(2~(5-Chloro-2,4-dimethoxyphenyl)im^

yl )me thyl) tetrah ydrofuran-3 -amine ;

-(( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)piperidin-4- yl)methyl) cyclohexanamine;

N~(( l-(2-(5~Chioro-2,4-dimetlioxyphenyl)imidazo[ l,2~a]pyridm~7-yi)pipendiii-4- yl)methyl) tetrahydro-2H-pyran-4-aniine;

N-((l -(2-(5-Chloro-2,4^imetiioxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi y 1) methyl) cycS oheptanam ine ;

N-(( 1 -(2-(5-Chloro-2,4-dime1iiiOxyphenyl)imidazo[ ,2-a]pyridin-7-yl)piperidin-4- yl)metliyl)- l-me'thylpiperidin-4-a3nine;

N-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-ajpyridin-7-yl)piperidin^ yl)metliyl}-l-isopropyipipendin-4-amine;

1 -( 1 ~(2-(5 -Chlofo-2,4-dimethoxyphenyl)imidazo [ i ,2-a]pyridin-7~yl)piperidm~4- yl)~N-((I -methylpiperidm~4~yl)raethyl)iT!ethana.fflme;

T^K(l-(2-(5-Chioro~2.4-dimethoxyph^

y 1 )methy l)-2-( 1 -me thy Ipi pen d in-4-y l)ethan amine ;

N1 -((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazof 1 ,2-a]pyridin-7-yl) piperidin-4 y])methyi)-N4,N4-dimethyl cyc]ohexane- l,4-diamine;

1 -( 1 -(2-(5 -Chloro-2 ,4-dimethoxypheny l)imidazo [ 1 ,2-a]pyridin-7-yi)pyrrolidin-3- yl)-N-(cyclopiOpylmemyl)methanamine

l-(l-(2-(5-CMoro-2,4 iiraethoxyph

yl)- -{cyclopentylmethyl)iTietlianan ine;

tert-Butyl 3-{((( I -(2-(5-chloro-2,4-dimethox>phenyl)imidazo[ l ,2-a]pyridin-7-} V} pyrrolidin-3-yl)methyl) arnino)meihyl)pyrrolidine-l -carboxy]ats;

l-(i -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazoS I ,2-a]pyridin-7-yi)pyrrolidin-3- yl)-N-(pyrfolidin-3-ylmethyl)meihan amine;

tert-Butyl 4-((((l-(2-(5-cUoro-2,4^imethoxyphen 4)imidazo[l,2-a]pyridin-7- yl)p\TToUdtn-3-yl)raeAyl)amino)raeAyl)piperidine-l-carboxylate;

1-ί ' l-(2-(5-Chloro-2,4-dimethoxypheny3)imidaz:of 1 ,2-a]pyriditi-7-yl)pyrrolidin-3- y3)-N-(pjperidm-4-ylmethyr)methanaraine;

N-Benzyl- 1 -( 1 -(2-(5 -chl oro-2 ,4-dimethoxyphenyl)imidazo [ 1 ,2-aJpyridin-7- yl)pyrrolidin-3-yl)methanamine,

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyphenyl)imida20 [ 1 ,2-a]py ridin-7-yl}pyn'olidin-3 - yl)-N-(2-fluoiObeiizyl)methanainine;

J -( 1 -(2-(5-Chloro-2.4-diraet oxyp enyl)imidazo[ 1 ,2~a]pyridin-7-vl)pyrrolidm-3- yl)-N -{ 3 -fluorobenzyi)met3ianamirie

l -(i -{2-(5-Chloro-2,4-dimethoxyphenyl)im^

yl)-N-(4"flttorobenzyl)methanarnine

4-((({ l-(2-(5-Chioro-2,4-dimet oxyph^

3-yl)meihyl)ammo}meihyl)- .N-dimethylaniline:

4-(((( 1 -(2-(5 ~Chioro-2,4-dmietlioxypheny l)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin 3-yl)metliyl)amino)raethyl)phenol:

1 -{ i ~(2~(5 -Chloro-2,4 -dimethoxypheny3)imidazo [ i .2-a]py ridin -7-y i )pyrrol idin-3 - yl)-N-(2-nitrobenzyl)methanamine;

1 -( i-(2-(5-Chloro-2,4-dimethoxy henyl)imidazof l,2-a]pyridin-7-yi)p -rrolidin-3- yl)-N-(3-(trifluoromethyl)benzyl)methanainine;

1 -( 1 -(2-(5 -CWoro-2,4-dittiethoxyphenyl)imida20 [ 1 ,2-a]py ridin-7-yl}pyn'olidin-3 yl)- -i4-(triiluoromethyl)beiizyl)methanamine;

! -( 1 -(2-(5-Chloro-2.4-diraethoxyp enyl)imida7-o[ 1 ,2-a]pyridin-7-yl)pyrrolidm-3 y 1) -N -( -methyl ben zyl )methan amine :

l-(l -{2-(5-Chloro-2,4-dimethoxyphenyl)imida

yl)- -(2-ch3orobenzyl)methanamine;

l-( I -(2-(5-ChloiO-2,4-dimethoxyphenyl)imidazo[ 1.2-a]pyridin-7-yl)pyrrolidm-3 yl)-N-(4-chlorobenzyl)methanamine;

1 -( 1 ~(2-(5 -Chlofo~2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)py rrolidm- yl)~ -(pyrRlin-3~ySn ethy!}metha«a!T5ine;

M H2-(5-Chloro-2,4-dimethoxy henyl)^^

y])-N-(pyridin-4-yimei yl)methan amine;

l-( l-(2-(5-Chloro-2,4-dimetnoxyphenyl)im

yl)-N-((3-fluoropyridin-4-yl)methyl)meihanamine,

1 ~( 1 -(2-(5-Chloro-2.4-dimetlioxyphenyl)imida2o| 1 ,2-a]pyridin-7-yl)pyrrolidin-3- yl)- -((2~fliioropyridin-4-yl)methy{)methanamine;

l-(l-(2-(5-Chloro-2,4-dira.ethoxy^ enyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- yl)- N-bis(pyridin-2-y3methyl)medianannne;

N-(( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 yl)metliyl)-2-methoxyethanamine;

N-((l-(2-(5-Chtoro-2,4-dimeihoxyphenyl)im^

yl)methy l)c> clobutanamine;

-{(l-(2-(5-Chloro-2,4^itneihoxyphenyl)imidazo[L2-ajpyridin-7-yi)pyrrolidm yl)nietbyl)-l -niethyipiperidin-4-iitnine;

l-(i-(2-(5-CWoro~2,4-dimethoxypto

y])- -((l -mei ylpiperidin-4-y])methyl)raetha3 aniine;

-({ l-(2-(5-Chloro-2,4-dimet oxy ^

N-{(l-(2-(5~Chloro-2,4~dmietlioxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pyrrolidin-3 y l)methyl)-2~phenylethan~ 1 -amine;

i -(l-i2-(5-Chloro-2,4-dimethoxyp enyl)iniidazo[l ,2-a]pyridin-7-yl)piperidio-4- yl)-N-(thiophen-2-ylmethyl)methanamiiie;

N-(( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 yl)meihyl)-2-(l -methyipiperidin-4-y3)eth an- 1 -amine;

N-Benzyl-l-(l -(2-(5-chloro-2,4-dime1iiox^heiiyl)imidazo[i ,2-a]pyridin-7- yl)azeiidin-3-yl)methanamine;

tert-Butyl 4-(2-(((l-(2-(5-chloro-2,4-dimethoxyphenyl)iimdazo L2-ajpyfidin-7- yl)piperidin-4-yl)nie† yi)a.m^

1- i l~(2-(5-Chloro~2,4-dimei oxy^^

N-(4-fluorobenzyi)mei anaraine;

tert-Butyl 3-((((l-(2-(5-chioro-2,4-dimethoxypheny3)irnidazo[ L2-a]pyridm-7- yl)azetidin-3-yl)meihyl)ammo)meihyl)pyrrolidine-l-carboxylate;

tert-Butyl 4-(((( 1 ~(2-( 5-chloro-2,4-dimethoxypheny l)-imidazo [ 1 ,2-a]py ridin-7- yl)azetidin-3-yl)meihyl)amino)-methyl)piperidme-l-carboxylate;

1 -( 1 -(2-(5 -Cliloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2~a]pyridin~7-yl)azetidin~3 -yl) N-(cyclopentylmethyl)-met anaraine;

tert-Butyl 4-{2-((( 1 -(2-(5-chloro-2,4-diraethox ,phenyl)imidazo-[ 1 ,2-a]pyridin-7- yl)pyrrolidin-3-yl)meiliyl)amino)ethyl)^iperidine-l -carboxylate;

tert-Butyl 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imida∞-[l ,2-a]pyridin-7- y l)piperidin- 3 -yl}me thy l)amino)me Ay l)-py rrolidine - 1 -carboxy late :

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 - yl)~N-(( 1 -isopropylpiperidin-4-yl)raeAyl)meAanaraine ;

2- ((((l -(2-(5-Chloro-2,4-dimethoxy^ enyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin- 3-yl)raeAyl)aniino)raeAyl)- , -dimeAy3aniline

1- (l-(2-(5-Chloro-2,4-dimei oxyphenyl)imidazo[l,2-a]pyridiii-7-yl)piperidin-4- y3)-N-(2,4-dime&oxybenzyl)-methanamine;

2- (((( 1 -(2-(5 -Chloro-2,4-dime Aoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-y i)piperidm-4 yl)methyl)amino)methyl)-N,N-dimethyiaiiiline;

1 -( 1 -(2-(5 -Cliloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2~a]pyridin~7-yl)azetidin~3 -yl) N - (cy ciohexy 1 methyl )meth anami n e ;

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- y i)-N-(4-met1ioxy~2 -ni trobenzy l)ra etb anamine ;

4- ((((l-(2-(5-Chloro-2,4-dimeAoxyphenyl)imidazo[l,2-a]pyridin-7-yl)azetidin-3- yl)meAyl)ammo)meAyl)-lS!,N-dimeihylaniline;

5 - (((( 1 -(2-(5 -Chloro-2,4-dimeAoxyphenyl)Aiidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4 yl)nietbyl}aniir!o)raethyl)~2-methoxyphenoI:

!-( i-(2-(5-Chloro-2,4-di methoxyphenyl)imidazo[1 ,2-a]pyridm-7-yl)piperidin-3- y]) T-(cyclohexylmetiiyl)methananiine;

l -( l-(2-(5-Chloro-2,4-dimet oxyphenyl)imi^^

yl)-N-(4-fluoro-3-methylbenzyl)-methanamine;

1 -( 1 -(2 -(5 ~Chloro-2,4-dimethoxypheny l)imidazo [ 1 ,2-a]py ridin-7-yl}p yrrolidin-3 - yl)-N-(4-metlioxy-3-methylbenzyl)-methanamine;

] -( i -(2-(5-Chloro-2.4-dimethoxyp^

yl)-N-{2-fluoro-4-rae1hylbenzyl)roethanamine;

3-yl)methyl)-N4,N4-dime1hylcyclohexane-l,4-diamine;

1 -( i -{2-(5-Cb.lofo-2,4-dimethoxyphenyl)imidazo[ ί ,2-a]pyridiii-7-yl)pyrrolidin-3- yl)~N-(3-fltioro-4-metliylbenzyi)methanainine:

l-(l~(2-(5-CUofo-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridiii-7-yl)pyrrolidin-3- yl)-N-(2,4-difluorobenzyl)methaoaraine;

-{( l-(2-(5-Chioro-2,4-dime†hoxyph^

y3)me"th>"l)-l -isopropylpiperidin-4-amine;

W i~(2-(5-Chloro~2,4-dimei.to

yl)-N-((l -eihylpiperidin-4-yl)methyl)propan-l-amme;

1 -(tert-Biityl)-N -(( 1 -C2~{5 -cUoro-2,4-dimethox>phenyl)-imidazo [ 1 ,2-a j pyndin-7~ yl)piperidin-4-yl)methyl)piperidin-4-aniine;

1 -( 1 -(2-(5-Chloro-2,4-diraethoxyp enyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidm-4- y 3)-N -(( 1 -ethyipiperidin -4-y 3 }raethy l)meth.anami n e ;

N-((l -(2-(5~Chloro-2,4-dimeftoxyphenyty

yl)rnet yl)-2-( l -ei3 ylpiperidin-4-yl)el1 an-l-amine

N-(( 3 -(2-(5-Chlofo-2,4-dimethoxyphen\-l)imidazo[ 3 ,2-ajpyridin-7-yl)pyrrolxdin-3 yl)methyl)cycloheptan amine;

-{( 1 ~(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2 -a]pyridin-7-y l)py rrolidin-3 yl)nietb.yl)-l-ethylpi.peridin-4-araine;

l-( l-(2-(5-Chloro-2,4<1imei oxypheny1)imidazo I,2-a pyridi

yl)-N-(2,4-ditnethoxybenzyl)methanarnine;

l -(teri-Butyl)-TSI-((

yl)pyrrolidin-3-)7l)methyl)piperidin-4-amine;

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxypheny l)imidazo [ 1 ,2-a]pyridin-7-yi)pyiTolidin-3- yl)- -((l~eihylpiperidin~4~yl)metliyi)methanainiiie;

N-(( 1 -(2-(5-Chloro-2,4-dimedioxypheny )imidazo[l ,2-a]pyridin-7-yl)piperid -4- y i) meth l ) -2 -eye! openty lethan - 1 -ami n e ;

l- i -(2-(5-Chloro-2,4-dimethoxyphenyl^^

M -(2-methylbenzy l)methanamine :

1- (i -(2- 5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)-N-(4-methoxy-3-methylbenzyl)methanamine:

-{( l-(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo [1,2-a] pyridin- 7-yi)azetidin-3- yl)metiiyl)-3 -dimethylbutan-l-amine:

2- (((( 1 -(2-(5-Chloro-2,4-dimetiio yphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidm-4 y 1 )methyl)ami n o)methyl) -5 -methoxypb enol ;

5-((((l -(2-(5~CMoro-2,4-dimetI.ox>phenyl)^

3-yl)methyl)an ino)methyl)-2-meihoxyphenol:

l-(l-(2-(5-Chloro-2,4-dinietlioxyphenyl)iniidazo[l,2-a]pyridk-7-yl)^

N-(4-methy Ibenz 1 )methanamine ;

N-((l-(2-(5-Chloro-2,4^mietlioxypheny^

y 1) methyl) -2-( 1 -p ropylp iperidi n -4-yl )eth an- 1 -am ine ;

N-(( 1 -(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[l ,2~a]pyridin~7-yl)pyirolidm-3 yl)methyl)-2-(l -e'thylpiperidin-4-yl)ethan- l-amine;

l-(l -(2-(5-Chloro-2,4-dimethox>phenyl)imidazo[l ,2-a]p>Tidin-7-yl)piperidin-4- yl)- -((l-me"thylpyTrolidin-3-yl)methyl)metiianainine;

1 -( 1 -(2-( 5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridiii-7-yl)piperidin-4- yl)-N-((l-etiiylpiperidin-3-yl)methyl)methaiiaraine;

iert-Butyl 3-((((l-(2-(5-chioro-2,4-dimethoxypheny3)imidazo-[l,2-a]pyridiii-7- yl)pyrrolidin-3-yl)methyl)ainino)methyl)piperidme-l -carboxyiate;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pyiTolidin-3- yl)-N-(cycloheptylmethyl)-methanamine;

1 ~(4-(((( 1 ~(2-( 5 -Chloro-2,4~dimethoxyphenyl)imidazo [ 1 ,2 -a]pyridin-7- yl)piperidin~4~yl)methyi)amino)methyi)pipei din-l-yl)-2,^

N-((l -(2-(5-Chloro-2,4-dime&oxy^^

y 1) methyl) -2-( 1 -p ropylp iperidi n -4-yl )eth an- 1 -am ine ;

4-((((l-(2-(5-C oro-2,4-dimethoxy h^

3-yl)methyl)ammo)methyl)-N, ,3-trimethylaniline;

1 -( 1 -(2-(5 -Chloro-2,4-dime"thoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 - yl)~N~(cyclohexylmethyl}meiliananime;

tert-Butyl 4-(((l-(2-(5-chloro-2,4-dimetlioxyphenyl)imidazo-[l,2-a]pyridin-7- yl)pyrrolidin-3-yl)raeAyl)amino)azepane- 1 -carboxylate;

4-((((l -(2-(5-Chloro-2,4-dimethoxy^ enyl)iniidazo[l ,2-a]pyridin-7-yl)pyrrolidin- 3-yl)roetbyl)amino)roethyl)-3-methoxy-N,N-dimeth.ylaniline;

l-(l~(2-(5-Chloro-2,4-dimei oxyphenyl)im

-(3 -me thy 3benzyi)methanamine ;

4-(((( 1 -(2-(5 -ChloiO-2,4-dimeihoxyphenyl)imidazo [ 1 ,2.-a]pyndin-7-y l)py rrolidin-

3-yl)methyl)amino)methyl)- , ,2-trimethylaiiiline;

4-((((l-(2-(5-Chloro-2,4-dimethoxy^

yl)methyl)amino)methyS)-N,N,2-trm ethyIaDii3ne;

4-((({l-(2-(5-Chloro-2,4-dimeihoxypheny])imidazo[l,2-a]pyridm-7-yi)piperidin-4- yl)methyl)ara ino)methyl ) -2-methoxy-N,N-diro etb ylanil ine ;

l-(i -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazoj ,2-ajpyridin-7-yl)piperidin-4- yl)- -((l-isobu piperidin-4-yl)meihyl)methanamine;

tert-Butyl 2-(((( 1 -(2-(5-c loro-2,4-dimethoxyphenyl)iinidazo-[l ,2-a]pyridin-7- yl)azetidin-3-yl)methyl)anmo)me

iert-Butyl 3-((((l-(2-(5-chioro-2,4-dimethoxypheny3)imidazo-[l,2-a]pyridiii-7- y])azetidin-3-y3)meihyl)ammo)meihyl)-piperidme-l-carboxylate;

l-( l-(tert-Butyl)pyn-olidin-3-yl)-N-((l-(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-a]pyridin-7^

1 -( 1 -(methyl)pyrrolidin-3 -yl)-N-(( 1 -(2-(5-chloro-2,4- dimeihoxyphenyljimidazo [ 1 ,2-a]pyridin-7-y l)py rrolidin-3 -yl)methyi)methanamine ;

l-(l-(2-(5-CWoro-2,4-dimethoxy^ enyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N -(( 1 -raetbylpyrrolidin-3 -yl)raethyl)methaiianiine ;

yl)methy l)-4-methylcyclohexan- 1 -amine,

6-((((M2-(5-Chloro-2,4-dimethoxypte^

yl)methjd)ainmo)methjd)-N,N-dimethylpj'ridin-3-ainme;

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)azetidin-3 -yl) N-(2-fluorobenzyl)methanaraine;

1 -(4~(2~(CC 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7- y1)piperidin-4-yl)iT3e†iyi)a.mino)et1iy1)piperidin-l-yl)

-({l-(2-(5-Chloro-2,4-dimeihoxypheny])imidazo[l,2-a]pyridm-7-yi)pyrro3idin-3 y3)meihyi)-2-ey ohepty3ethan- 1 -amine;

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxypheny l)imidazo [ 1 ,2-a]pyridin-7-yi)pyiTolidin-3- yl)- -((l-meth}dpiperidin-3-yl)meihyl)inetliaiiamine;

l-(l-(2-(5-CUoro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7-^^

y -{{1 -ethyipiperidin -3 ~y 3 }raethy I)metb anami n e ;

N-((l -(2-(5-Ch1oro-2:4-dimethoxypher!yl)ifflidazo[l ,2-a]pyridin-7-yl)pipen yl)meihyl)-4-ei ylcyclohexan- 1 -amine;

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)azetidin-3 -yi) M -(3 -fluorobenzy 3)methanamine:

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidm-4- yl)-N-(4-fluoro-3-methylbenz 'i)methanamme;

iert-Butyl 3-((((l-(2-(5-chioro-2,4-dimethoxypheny])iraidazo-[l,2-a]pyridiii-7- y])piperidin-3-yl)metbyl)amino

2-(((( l -(2-(5-Chloro-2,4-diinethoxyphenyl)imidazo[l ,2-ajpvTidin-7-yi)azetidi

l-(l-(2-(5-CUoro-2,4-dimetlioxyphenyl)imidazoi i,2-a]pyridin-^

y 1)- -(4-fluof 0-3 -methy lbenzyl}meihanamme ;

tert-Butyl 3-(((( 1 -(2-(5-chloro-2,4-dimetho7£yphenyl)imidazo-[ 1 ,2-a]pyridin-7- yl)piperidin-4-y3)methyl)amino)methyl)-piperidiiie-l -carbo ylate:

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)-N-((l-(cyclobutylmethyl)-piperidm

l-(i -(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[ ] .2-a]pyfidin-7-yl)piperidm yl)-N-(2,3-dimethylbenzyl)-methanamine;

-{ 1 -( 1 ~(2-{ 5 -Chloro-2,4-dimethoxy phen Dimidazo 11 ,2-a]py ridin~7~yl)py rrolidm 3-yl)ethy3)-l-ethy3piperidin-4-aniine

l-(].-(2-(5-Chloro~2 i-di!neihoxyphenyl)i!nidazo[L2-ajpyridin-7-yj)pyrrolidin-3- y 1 }-N-(( 1 -ethylpi pen d in-4-yl)methyl)ethan- 1 -amine ;

1 -( 1 ~(2 -(5 -Chloro-2 ,4-dimeihoxypbeny 3)imidazo f ί„2-a]pyndm -7-yl)piperidin-4- yl)-N-(2-cyclohexyletiiyl)ethan-l-amine;

l-(l-(2-(5-CUoro-2,4<limetlioxyphenyl)imidazo[ i,2-a]pyridm

y 1)- -(2-fluof 0-3 -methy ibenzyl}methanamme ;

l-(l-(2-(5-CUoro-2,4^imethoxyphenyl)imidazo[l ,2-a]pyridin- yl)-N-(2-fflethoxy-5~iT!ethyIbenz} )metbanar!ime;

l- l -(2-(5-Chloro-2,4-diniethoxyph^

yl)-N-(2-cyciopen†y"leth} 3)ethan-l -amine;

l-(i -(2-(5-ChloiO-2,4-dimethoxyphenyl)imidazoS 1.2-a]pyridin-7-yl)pyrrolidin-3- yl)- -(cycloheptylmethyl)ethan- 1 -amine;

1 -( 1 ~(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyndin-7~yl)piperidm~4- yl)-N-(2-fluoro-5-methylbenz '{)methanamme;

-((l-(2-(5-Chloro-2,4-dimeihoxypheny])imidazo[l,2-a]pyridm-7-yi)piperidin-4- yl)metby!)~2-(cycloliex~ 1 -en - 1 -y3)ethan- 1 -amine;

-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)m

5 yl)meihyI)-2-cyclopentylethan- 1 -amine;

tert-Butyl 4-(3 -((( 1 -(2-(5-chloiO-2,4-dimethoxyphenyl)imidazo [ L2-a]pyridin-7- y l)pyiToii din- 3 -y i)methyl)amino)propy l)piperidme - 1 -carboxylate ;

tert-Butyl 4-(2-(( 1 -( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7- yl)pyn-oiidin-3-yl)etiiyl)amino)ethy{)piperidine- 1 -carboxylate;

i 0 1 -( 1 -( i -(2-(5-Cbloro-2,4-dimetboxypheny1)imidazo[ 1 ,2-a]pyridin-7- yl)pyrrolidin-3-yi)ethyi)-N4^

4-(((2-( l-(2-(5-Chloro-2,4-dimetlioxyphenyl)imidazo[ l,2-a]pyridm-7-yl)pipendin- 4-yl}ethyl)amino)methyl)~benzomtrile;

tert-Butyl 4-(((2-(l-(2-(5-cUoro-2,4-dimethoxj^henjd)iimdazo[l,2-a]pj,"ridin-7- 15 yl)pj eridin-4-yl)et3iyl)ami!io)methyl)-piperidiiie-l-carboxylaie;

N-Benzyd-l-il-(2-(5-ch3oro-2,4-dimet3ioxy he!iyl)imidazo[].;,2-a]pyridin-7- y piperi din-4-yl)ethan - 1 -amine ;

tert-Butyl 3 -((( 1 -{ 1 -(2-(5 -chl oro-2,4-dimethoxyphenyl)imi dazo [ 1 , 2~a]pyridm -7- y3)pyrroiidin-3-yl)etliyl)amino)methyl)-pipefidine-l-cafboxyiate:

0 tert-Butyl 4-(3 -(( 1 -( 1 -(2-(5 -chior o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7- yl)pyn-olidin-3-yi)emyl}ainiiio)propyl}-pipendine-l-carboxyiate;

l-(l-(2-(5-Chloro-2,4-dimethoxy^henyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- yi)-N-{{ 1 -niethylpiperidin-4-yl)inethyj.)eth.an- 1 -amine;

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidb^ 5 yl)- -(2-(l-propylpiperidin-4-yl)ethyl)ethan-l-aniirie;

tert-Butyl 3-(((2-(l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| L2-a]pyridin-7- yl)piperidm-4-yl)ethyl)mnii ))methyi)-pyrfolidine- 1 -carboxylate;

tert-Butyl 4-(3-((l-(l-(2-(5-chioro-2,4-dmiethoxyphenyl)-miidazo l,2-a]pyridin-7- yl)piperidin-4-}d)ethyl)ainino)-propyl)piperidine-l-carboxylate;

2-(((( ] -(2-(5-Chloro-2,4-dimetho^

yl)methyl)amino)methyl)-4-methylphenol;

tert-Butyl 4-(((l-(l-(2-(5-cbJoro-2.4-dimethoxyphen^

yl)piperidin-4-\ )elhyl)ammo)meihyl)-piperidme-l-carboxylaie;

tert-Butyl 3-(((l-(l-(2-(5-chloro-2,4-dimetiioxyplienyl)imidazo-i L2-a]pyridm-7- yl)piperidin-4-yl)ethyl)ammo)metliyl)-pyrrolidine-l-carboxylate:

2-( {-{2-(5-Chloro-2,4~diroethoxy

yl)- -(cyclohexyi methyl )ethan- 1 -amine:

l~( ! -{2-(5-Ch!oro-2,4-dnTiethox

yl)- -((l-isopropylpyrrolidin-3-yl)metliyl)ethan-i -amine;

l-(tert-Butyl)-N-(i -(l-(2-(5-chloro-2,4-dimethoxyphenyl)imida o[ l,2-a]pyridm yl)pyrroiidin-3 -yl)ethyl)piperidin-4-amine ;

tert-Butyl 3-(((2-(l-(2-(5-chloro-2,4-dimethoxyphenyl)iinidazo-i ,2-a|pyridin-7- yl)pi eridin-4-yl)ethy])aini!io)methyl)-piperidine-l -carboxy'late;

N-Benzyl~2-{l-(2~(5-chSoro-2 4-d!methoxypheiiyl)imidaz

y piperi din-4-yl)ethan - 1 -amine ;

l-( l-(2-(5-Chloro-2,4-dimethoxypheny1)imidazo I,2-a pyridin

yl)-N-(cydopentylmetiiyl)ethan-l -amine;

tert-Butyl 3-((( l-{l-(2-(5-chloro-2,4-dimefeoxypta

l)pyi oliciiii- 3~ l)eliiyl)amiiio)metliyl)p> rrolidiiie- 1 -carboxj late;

N~(l ~(l-{2~(5~Chioro-2 ½

4~yl)ethyl}cyelohexanamme;

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pi yl)-N-pbenethylethan- i -amine;

l-( l -(2-(5-ChloxO-2,4-dimethoxypheny^

yl)- -(2-cycIopentylethyl)ethan-l-amine;

tert-Butyl 3-((( l-(l-(2-(5-cliloro-2,4-dimetlioxyphenyl)imidazo-| l,2-a]pyridm-7- yl)pj eridin-4-yl)et3iyl)a!niiio)methyl)-piperidine-l-carbox5''laie;

l-(I~(2-(5-Chloro-2,4-dimeihoxyphenyl)imid

y 1 )- -(cyc3 oh exylmethyl)e than - 1 -ami n e ; an d

l-( l-(2-(5-Chloro-2,4-dimetftoxyphenyl)m

yl)-N-((l -ethyipiperidin-4-yl)methyl)propan-2-amine; and

a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

12. A pharmaceutical composition according to claim 11 for use in treating or preventing cancer.

13. A pharmaceutical composition according to claim 12, wherein the cancer is selected from the group consisting of king cancer, cervical cancer, bladder cancer, esophageal cancer, osteosarcoma, prostate cancer and soft tissue tumor.

14. A method for treating or preventing a disease that involves overexpression of SUV39H2, which comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 to a subject in need thereof.

15. A method according to claim 14, wherein the disease is cancer.

16. Use of a compound or a pharmaceutically acceptabie salt thereof according to any one of claims 1 to lOin the manufacture of a medicament for use in treatment or prevention of a disease that involves overexpression of SUV39H2.

Description:
BICYCL1C COMPOUND AND USE THEREOF FOR I HIBi ' ITNG HISTONE

METHYLTR ANSFER A SE

CROSS-REFERENCE TO RELATED PATENT APPLICATION

The present patent application claims benefit of priority to U.S. Provisional

Application No. 62/469,319, filed March 9, 2017, the disicousre of which is incorporated by reference in its entirety for all purposes.

TECHNICAL FIELD

The present invention relates to a compound having an inhibitory activity against SUV39H21 , a method for the preparation thereof and a pharmaceutical composition containing the compound as an active ingredient. The present invention relates to a method for treatment or prevention of a disease that involves overexpression of a histone methyitransferase such as SUV39H2.

BACKGROUND ART

The nucleosome, the basic unit of D A packaging in eukaryotes that consists of a

147-bp DNA wound in sequence around a histone protein core, is a fundamental unit of chromatin structures [Non-Patent Document 1] , All four core histones (H3, H4, H2A and H2B) possess unstructured N-terminal tails and these N-termini of histones are particularly subjected to a diverse array of post-transiational modifications: acetyiation, methylation, phosphorylation, ubiquitination, SUMQyiation and ADP-ribosylation [Non-Patent Document 2]. These histone modifications cause dynamic changes to the chromatin structure and thereby impinge on transcriptional regulation, DNA replication, DNA repair, and alternative splicing [Non-Patent Documents 3 and 4]. Among these epi genetic marks on histones, the methylation process is particularly crucial for transcriptional regulation [Non-Patent Document 5] . Five lysine residues (H3K4, H3K9, H3K27, H3K36 and

H4K20) are located in the N-terminal tails and are representative lysines that can become mono-, di-, or trimethylated. Whereas H3K9, H3K27 and H4K20 methylation mainly represses transcription, methylation marks on H3K4 and H3K36 are associated with the induction of active transcription [Non-Patent Document 6]. For instance, methylation of histone H3 at lysine 9 (H3K9) is one of the most abundant and stable histone modifications, and is involved in both gene repression and heterochromatin formation. H3K9 can be mono-, di- or trimethylated on H3K9, whereas silent euchromatin regions are enriched for mono- and dimethylated H3K9 [Non-Patent Document 17]. In mammals, heterochromatic regions are highly trimethylated on H3K9, whereas silent euchromatic regions are enriched for mono- and dimethylated H3K9 [Non-Patent Document 17] . H3K9 methylation has been linked to de novo gene silencing and DNA methylation, and it is inherited after mitosis in a manner coupled to DNA methylation ,

It has previously been reported that some hi tone methyltransferases and demethylases are deeply involved in human carcinogenesis [Non-Patent Document 7, 8, 9, 10, and 11 ]. For instance, SMYD3, P MTL PRMT6, SUV420H1 and SUV420H2 have been shown to stimulate the proliferation of cells through its enzymatic activity [Patent Document L 8, 9, 12, 13, 14, and 18] .

SUV39H2, also known as KMT1B [Non-Patent Document 15], is a SET-domain containing histone methyltransferase and is known to methyiate the H3K9 lysine residue. Suv39h2, the murine homologue of human SUV39H2, has been isolated and characterized as the second murine Suv39h gene, and demonstrated to share 59% identity with Suv39hl [Non-Patent Document 16] . Hie expression of Suv39h2 is restricted to adult testis, and immunolocalization of endogenous Suv39h2 protein reveals enriched distributions at heterochromatin during the first meiotic prophase and in the early stages of sperminogenesis. During mid-pachytene, Suv39h2 specifically accumulates within the chromatin of the silenced sex chromosomes present in the XY body, hi addition, the histone

methyltransferase activity of Suv39h2 appears to play an important role in regulating higher-order chromatin dynamics during male nieiosis [Non-Patent Document 16] ,

CITATION LIST PATENT DOCUMENT 1. Strahl BD et al. Nature 2000; 403: 41-45;

2. Kouzarides T et al Cell 2007; 128: 693-705;

3. Huertas D et al. Epigenetics 2009; 4: 31-42,

4. Luco RF et al. Science 2010: 327: 996-1000;

5. Kouzandes T et ai. Curr Opin Genet Dev 2002; 12: 198-209;

6. Peterson CL et al. Curr Biol 2004; 14: R546-551 ;

7. Cho HS et al . Cancer Res 2 10;

8. Hamamoto R et al , Nat Cell Biol 2004:6: 731-40;

9. Hamamoto R et al. Cancer Sci 2006;97: 113-8;

10. Yoshimatsu M et al. in! J Cancer 201 1 ; 128: 562-573;

11. Hayaim S et al Int J Cancer 2011; 128: 574-586;

12. Kumzaki M et al. Cancer Res 2007;67: 10759-65;

13. Silva FP et al. Oncogene 2008;27:2686-92;

14. Tsuge M et al . Nat Genet 200 ;37: 1 04-7;

15. A lbs CD et al. Cell 2007; 13 1 : 633-636;

16. O'Carroll D et al. Mol Cell Biol 2000; 20; 9423-9433;

17. Martin C et al . Nat Rev Mol Cell Biol 2005;6:838-49; and

18. Schneider R et al. Trends Biochem Sci 2002;27:396-402.

SUMMARY OF INVENTION

The present inventors have endeavored to develop an effective inhibitor of a histone methy {transferase, particiilarly SUV39H2 and have found that a compound can selectively inhibit the activity of SUV39H2.

The subject specification includes the disclosure of the following inventions, [1], A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R 1 and R 2 are independently selected from the group consisting of a hal ogen atom, hydroxy, Ci-Ce alkyS, and Ci-Ce alkoxy;

R 3 is independently selected from the group consisting of a halogen atom, cyano, nitro, hydroxy, carboxy, Ci-Ce alkyl, C1-C5 alkoxy, (Ci-Ce alkoxy )carbonyl, Ci-Ce alkylthio, Ci-Ce aikylsuifmyl, and Ci -Ce alkyl sulfonyl;

n is an integer selected from 0 to 3:

R 4 is selected from the group consisting of a hydrogen atom, and a halogen atom: R 5 is independently selected from the group consisting of a halogen atom, Ci-Ce a!kyl, and Ci-Ce alkoxy;

m s an integer selected from 0 to 3;

X and Y are independently selected from a direct bond, -CH2-, and -CH2CH2-;

R 6 is selected from the group consisting of Ci-Ce aikyi substituted with one or more substituents selected from Ra, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rb, CS-CJO aryl optionally substituted with one or more substituents selected from Rb, 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Rb, 3- to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Rb, (Ci-Ce

alkoxy)carbonyl substituted with one or more substituents selected from Ra, (Ci-Ce alky3)carbonyl optionally substituted with one or more substituents selected from Ra, (C3- Cio cycloalkyl)carbonyl optionally substituted with one or more substituents selected from Rc, (C6-Cio ar}d)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic heterocyclyl)carbony{ optionally substituted with one or more substituents selected from Rc, (5- to 10-membered heteroaryljcarbonyl optionally substituted with one or more substituents selected from Rc, animocarbonyl, (Ci-Ce alkyl iaminocarbonyl, and di(Ci-C6 alkyl)aminocarbonyl;

R 7 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra:

Q is selected from Ci-Ce alkylene;

R 10 is independently selected from the group consisting of a halogen atom, and Ci-

C.6 alkyl;

q is an integer selected from 0 to 4;

Ra is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkoxy, cyano, (C i-Ce alkoxy jearbonyl, carboxy, (Ci-Ce alkoxy)carbonylamino, (Ci- Cf, alkyljcarbonylamino, amino, Ci-Ce alk lammo, di(C; -C6 alkyl)amino, aminocarbonyl, (Ci -Ce alkyl)aminocarbonyl, di(Ci-Ce alkyl)aminocarbonyl, Ci-Ce alkylsulfonylamino, C.3- Cio cyeloalkyisulfonylamino, C3-G0 cycloalkyl optionally substituted with one or more substituents selected from Rc, C3-C10 eycloalkenyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10-membered lieteroaryi optionaliy substituted with one or more substituents selected from Rc, and 4- to 12-membered non-aromatic heterocyciyi optionally substituted with one or more substituents selected from Rc;

Rb is independently selected from the group consisting of a halogen atom, hydroxy , Ci-Cr, alkyl optionally substituted with one or more substitutents selected from Ra, Ci-Ce alkoxy optionaliy substituted with one or more substitutents selected from Ra, cyano, (Ci- Ce alkoxy)carbonyl, carboxy, -NR 2 l R 22 , -CONR 23 R 24 , diiCi-Ce alkyl)phosphono, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10- membered lieteroaryi optionally substituted with one or more substituents selected from Rc, and 3- to 12-membered non-aromatic heterocyciyi optionaliy substituted with one or more substituents selected from Re;

Rc is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alky] optionally substituted with one or more halogen atoms, Ci-Ce alkoxy optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci -Ce alkylarnino, di(Ci-C6 alkyl)amino, (Ci-Ce aikyi)carbonyl, (Ci-Ce alkoxy)carbonyl, Ci-Ce alkylsulfonyl, C3-G0 cycloalkylsulfonyl, CT-CM aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Re, 3~ to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Re, 5- to iO-membered lieteroary! optionally substituted with one or more substituents selected from Re, and oxo;

Rd is independently selected from the group consisting of nitro, hydroxy, Ci-Ce. alkyi optionally subsituted with one or more halogen atoms, Ci -Ce alkoxy optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylarnino, di(Ci-Ce alkyijammo, Ci-Ce alkylearbonyl, (Ci-Ce alkoxy)carbonyl, Ci-Ce alkylsulfonyl, CJ~CS cycloalkyisulfonyl, C7-C14 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, Cs-Cs cycloalkyl optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Re, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Re;

Re is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyi optionally subsituted with one or more halogen atoms, a halogen atom, ammo, cyano, Ci-Ce alkylarnino, di{Ci-Ce alkyl)amino, Ci-Ce alkylearbonyl, (Ci-Ce alkoxyjcarbonyl, Ci- Ce alkylsulfonyl, and C3-C8 cycloalkyisulfonyl ;

R 21 is selected from the group consisting of a hydrogen atom, Ci -Ce alkyi optionally substituted with one or more substituents selected from Ra, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 4- to 12-membered heterocyciyl optionally substituted with one or more substituents selected from Rc, 5- to 10- membered lieteroaryl optionally substiMed with one or more substituents selected from Rc, (Ci-Ce alkoxy)carbonyl optionally substituted with one or more substituents selected from Ra, (Ci-Cc alkyl)carbonyl optionally substituted with one or more substituents selected from Ra, (C3-C 10 cycIoaIkyl)carbonyl, (Ce-Cio aryl)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic

heterocyclyl)carbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-nienibcred heteroaiyl)carboiiyl optionally substituted with one or more

substituents selected from Rc, aminocarbonyl , (Ci-Ce alkyl }aminocarbonyi optionally substituted with one or more substituents selected from Ra, di(Ci-C6 alkyl)aminocarbonyl optionally substituted with one or more substituents selected from Ra, Ci-Ce alkylsulfonyi optionally substituted with one or more halogen atoms, C7-C14 aralkylsultbnyl, C3-C10 cycloalkyisulfonyl, aminosulfonyl, Ci-Ce alkyiaminosuifbnyi, di(CVC6 alkyl)aminosuifonyl, and di(Ci-Cb aikyl)phosphono;

R 22 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra;

R 2 - 1 is selected from the group consisting of a hydrogen atom, Ci-Cr, alkyl optionally substituted with one or more substituents selected from Ra, [(Ci-Ce

alkyl)amino]Ci-C6 alkyl optionally substituted with one or more substituents selected from Ra, [di(Ci-C6 alkyl)amino]C] -C6 alkyl optionally substituted with one or more substituents selected from Ra, C3-O 0 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10-raembered heteroaryl optionally substituted with one or more substituents selected from Rc, and 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Rc; and

R 24 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra.

12] . The compound or a pharmaceutically acceptable salt thereof according to [ 1], wherein R? is a hydrogen atom ,

[3]. The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein R 6 is selected from the group consisting of pyrimidyl, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, piperidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyrrolidyl optionally substituted with a Ci- Ce alkyl group or a (Ci-Ce alkoxy)carbonyl group, C3-C7 cycloalkyl optionally substituted with a di(Ci-C& alkyl)amino groupor a Ci-Ce alkyl group, tetrahydrofuryl, tetrahydropyranyl, phenyl optionally substituted with one substituent selected from Rb, a group -Cft-Ra, a group -CHaCH -Ra and a group -CH2 GHbCFb-Ra.

[4] . The compound or a pharmaceutically acceptable salt thereof according to any one of [ 1 j to [3], Ra is independently selected from the group consisting of hydroxy, Ci -Ce. alkoxy, C3-C7 cycloalkyl optionally substituted with a di(G-Gs alkyl)amino group, phenyl optionally substituted with one or more substituents selected from Rd, pyrrolidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy)carbonyl group, piperidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, thiazolyi, thienyl, pyrimidyl optinally substituted with a di(Ci-Ce alkyl)amino group, and C3-C7 cycloalkenyl ,

[5] . The compound or a pharmaceutically acceptable salt thereof according to any one of [1 ] to [4], Rb and Rd are independently selected from the group consisting of a halogen atom, methyl, cyano dimethy!airiino, methoxy, nitro, hydroxy, and trifluoromethyl.

16] . The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein the com ound is represented by Forumula (lb):

Q is selected from the group consisting of -CH2-, -CH(CH3)-, -CH(Q-bCH3)-, CH2CH2-, -CH(CH3)CH2-, and -CH?.CH(CH3)-; - R 1 , R 2 , R \ R , R 5 , R 6 , R 7 , X, Y, m and n are as defined in any one of [1] to [5J .

[7] . The compound or a pharmaceutically acceptable salt thereof according to any one of [1 ] to [6], wherein wherein X and Y are -(CH2)-, or X is a direct bond and Y is -(CH2)-.

[8] . The compound or a phannaceutically acceptable salt thereof according to any one of [1 ] to j 7], wherein the com ound is represented by Forumula (Ic):

wherein R 1 and R 2 are independently selected from the group consisting of Ci-Ce alkoxy,

p is an interger selected from 0 and 1 :

R 3 is selected from the group consisting of a harogen atom, and

R 6 and 7 are as defined m any one of [1] to [6].

[9] . The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [7], wherein R ! and R 2 are methoxy. and R 3 is a chlorine atom.

[10] . The compound or a pharmaceutically acceptable salt thereof according to [1], which is serected from the group consisting of:

l-(i -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo l ,2-ajpyridin-7-yl)piperidin yl)~N~(cyclopropylmethyi)methanainine;

l-(l-(2-(5-CUoro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridm-7- yl)piperidin-4- yl)~N-(cycSopentyimethyl)niethanamine;

tert-Butyl 3-((((l-(2-(5-c oro-2,4-dimethoxypb.enyl)imidazo[l,2-a]pyridin-7- yl)piperidin-4-yl)methyl) amino)methyl)pyiTolidine-i-carboxylaie;

tert-Butyl 3-((((l-(2-(5-chioro-2,4-dimet oxypheny])imidazo[l,2-a]pyridm-7- yl)piperidin-4-yl)methyl)(metliyl)amino)metliyl)pyrrolidine- l-car^

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)piperidin-4- yl)-N-(pyrrolidin-3~ylmetliyl)methanamine; l-(l-{2-(5-Chloro-2,4-dimethoxyph

yl)-N-(cyclohexylmethyl)meAanarnine;

tert-Bulyl 4-(((( i -(2-(5-chloro-2,4-dimethox phenyl)imidazo[ 1 ,2-a]pyridin-7- yl)piperidm-4-y])methyl)amino)meihyl)piperidine-l-carboxylat e;

l-(i -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridm-7-yl)piperi yl)-N-(piperidin-4-ylinethyl)methanamine:

-Benzyl- 1 -( 1 ~(2-(5 -chloro-2,4~diineihoxyphenyl}imidazo [ 1 ,2 -a] pyridin-7- yl)piperidin-4-yl)me†haiiamme;

l-( i.-(2-(5-Chioro-2,4-dunethoxyphenyl)imidazo[l,2-aJpyrid}.o-7 -yi) piperidin-4- yl)-N-(2-methylbenzyl)methanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imida--o[ l,2-a]pyridin-7-yl)piperidin-4- yl)-N-(4-methylbenzyl)methanamine;

1 -( 1 -(2-(5-CUoro-2,4<limetlioxypheiiy l)imidazo[ 1 ,2-a]pyridin-7-y l)piperidin-4- yl)- -{2-fluorobeii2yl)methanamiiie,

] -(l-(2-(5-Chloro-2,4^iraethox>phenyl)imidazo[l ,2-a]pyridm-7-yl)piperi yl)-N-{3-fluorobenzyS)fflethaiiaiiiiiiie:

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)- -(4-fluorobenzy3)methan amine;

l -(H2-i5-Chioro-2,4 Iimethox

yl)-N-(4-methoxybenz3'l)methananiine ;

l-(l-(2-( -CWoro-2,4-dimethoxyphenyl)um

y l)~N-(2 -chlo robe iizyi)methan am ine ;

4-((((l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidiii-4- y])methyl)amino)methyl)-N,N-dimethyianiline

3-(((( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- yl)methyl) am ino)methy ])benzoniirile

4-(((( 1 -(2-(5-Chlofo-2,4-dimetlioxyphenyl)imidazo[l,2-a]p>'ridii i-7-yl)piperidin-4- y l)methy 1) ainmo)methyl}benzonitriie : l-(l-i2-(5-Chloro-2,4-dimetho ypheiiyl)imidazo[l ,2-a]pyridin-7-yl)piperi y3)-N-(2-nitrobenzy])metha.namme;

l-(l -(2-(5-Chloro-2,4-dimethox>phenyl)imidazo[l ,2-a]p>'ridin-7-yl)pi yl)- -(3-(irifluoromethyl)benzyl)methanamine;

l-(l -(2-(5-Chiofo-2,4 Iimethoxyphenyl)imidazo[1 ,2-a]pyrid!n

yl)- -(pyridin-3-ylmethyl)methanainine:

l-(l~(2-(5-Chiofo-2,4-diineihox>phenyl)imidazo[1.2-a]p ' i in-7-yl)piperidm-4- yl)-N-(}3yridm-4-yimethyi)met3ianarni!ie:

1 -( 1 -(2-(5 -Chloro-2,4 -dimethoxypbenyl)imidazo [ 1 , 2-a]pyridin ~7~yl)piperidin~4- y])- -((3-fluoropyridin-4-y])methyl)raethanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)piperidi yl)-N-((2-metlioxypyridin-4-yl)methyl)methanamine,

1 -( 1 -(2 -(5 -Cliloro-2,4<limethoxy pheny l)imidazo [ 1 ,2-a]pyridin-7-y 1) piperidin-4- yl)-N-(thiazol-2-yimethyl) methanamine;

l~(l-{2-(5-Chloro-2,4-diniethoxyphenyl)m idazo[l ,2-a]pyridm-7-yl) piperidin-4- yl)-N-(t iazol-2-ylmediyl) methanamine;

3 ~( ! -(2-(5-Chloro-2,4-dimethox}phenyl)imidazo[ 1 ,2-a]p 'ridin-7-yl)piperidin-4- yl)- , -bis(pyridin-2-y3methy])methanamine;

N-((l-(2-(5-Ch3ofo-2,4-dimethoxyphenyl)imidazo[l,2-aJpyndiR- 7

yl)methyl) cyclobutanamine:

-((l-(2-(5-Chioro-2,4-dimethoxyphenyl^

y 3 ):r:ofb !} cy clopentanami n e ;

T^K(l-(2-(5-Chloro-2,4-dimethoxy^

y 1 )methyl) te trab ydrofuran-3 -amine ;

-(il-(2-(5-Chloro-2,4-dimethoxypheny])imidazo[l,2-a]pyridin- 7-yi)piperidin-4- y3)methyl) cyclohexanamine;

N-(( l-(2-(5-Chloro-2,4-dimetiioxypheny3)iinidazo[ 1 ,2-a]pyridiri-7-yi)piperidiii-4- yl)methyl) tetrahydro-2H-pyran-4-aniine; N-((l-(2-(5-Chloro-2,4-dimetlioxyp^

yl)methyl) cycloheptanaraine;

yl)methy 1)- 1 -meihylpiperidin-4-amine;

N-((l-(2-(5-Chlofo-2,4-dimeihoxyphenyl)imidazo[l,2-a]pyridin -7-yl)piperidin-4- yl)methy 1}- 1 -i sopropylpiperidin-4-amine ;

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7~yl)piperidm~4- yl)~N-((l -methylpiperidm~4~yl)raethyl)iT!ethana.fflme;

N-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin -7-yl^

y1)methyl)-2-(l-methylpiperidin-4-yl)ethar!aiT3ine;

1-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl) piperidin-4- yl)methyi)-N 4 ,N 4 -dimethyl cyclohexane- 1 ,4-diamine:

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxypheny l)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N-(cyclopropylinethyl)methanamine

l~(l-C2~(5~Chloro-2,4~dinicthoxy

y 1)-N -(cyclopentylniethyl)ra eth anamine ;

tert-Butyl 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl) pyrrol idin -3 -y 1 )methyl) am mo)methy l)pyrro1 idi n e - 1 -carboxyl ate ;

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo j 1 ,2-a jpyridin-7-yl)pyrrolidin-3 - yl)~N~(pynOlidin-3-ylmetliyl)meihanamine;

tert-Butyl 4-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)iinidazo[l,2-a]pyri din-7- yl)p>TToliclin-3-yl)roethyl)amm^

1 -( 1 -(2-(5 -Chloro-2,4 -dimethoxyphenyl)imidazo [ 1 , 2-aJpy ridin -7-y{)pyrrolidin-3 - y])- -(piperidm-4-ylmethyi)meilianarome;

N-Benzyl-l -{l-(2-(5-ch]oro-2,4-dimethoxyphenyl)imidazo l,2-a]py

yl)pyrrolidin-3-yl)methanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pyrrolidin-3- yl)- -(2-fluorobenzyl)methanamine; I -( ί -{2-(5~Cbloro-2.4-diniethoxypher!yl)3niidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N-(3~fiuorobenzyi} ethan amine

I -( 1 -(2-(5-Chloro-2.4-dimelhoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N-(4-fliiorobenzyl)methan amine

4-((((l-(2-(5-Chloro-2,4-dime1hoxyphenyl)imidazo[l,2-a]pyrit o

3-yl)nietliyl)ainmo}meihyl)- ,N-diinethylaniline:

4-{({{ 1 -(2 -(5-€hioro-2,4-dimethoxypheny l)imidazo[ 1 ,2-a ]pyridin-7-yi)pyrrolidin- 3-yl)iOethyl)amino)raethyl)phenol;

1 -( 1 ~(2~(5 -Chloro-2,4 -dimethoxyphenyl)imidazo [ 1 , 2-aJpy ridin ~7~yi.)pyrro3idm~3 - yl)-N-(2-nitrobenzyl)methanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)im^

yl)- ^3-(1rifluofomefliyl)benzyl)methanamine;

1 -( 1 -(2-(5 ~Chloro-2.4-dimethoxypheny l)imidazo [ 1 ,2-a]py ridin-7-yl}p} IT olidin-3 - y 1)- -{4-(trifluofomethyl)benz} Ijmethanamine ;

! -(l-(2~(5-Chloro-2,4-dimethoxy^heny^

y I)-N -(4 -methyl ben zyl )methanami a e :

I -( 1 -(2-(5-Chloro-2.4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pym)lidin-3- yl)-N-(2-c1i1orobenzyl)metha.namirse;

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a jpyridin-7-yl)pyrrolidin-3 - yl)-N-(4-chlorobenzyl)methanamine;

1 -( i ~(2-(5 -Chloro-2,4-dime thoxyphenyl)imidazo [ i .2 -a ]pyridin-7~yi)pyrrolidin-3~ y])-N-(pyridin-3-yiinethyj)methanamiiie:

1 -( 1 ~(2-(5 -Chloro-2,4 -dimethoxypheny imidazo [ 1 , 2-aJpy ridin -7-y{)pyrrolidin-3 - y])-N-(pyridin-4-yimeihyl)methan amine;

l-i l~(2-(5-Chloro~2,4-dimeto

yl)-N-((3-fluoropyridin-4-yl)meth\ )meihanamine,

1 -( 1 -(2-(5-Chloro-2.4-dimethoxyphenyl)inndazo 1 ,2-a]pyridin-7-y l)pyffo3idin-3- y 1)- -( (2 -fluoropyridin-4-y l)methy l)methanamine ; l-( l-{2-(5-Chloro-2,4-dimethoxy

yl)-N,N-bis(pyridin-2-ylmethyl)methanamine:

N-(( 1 -(2-(5-Chloro-2,4-dimethox} henyl)imidazo[ 1 ,2-a]pyridin-7-yl)pynOlidin-3- y l)methy 1) -2-methoxyethanamme ;

N-(( l -(2-(5-Chlofo-2,4-dimethox>'phenyl)imidazo[l,2-aJpynd

yl)methyl}cyclobutanamine;

-(i l-(2~(5-Chloro-2,4-dimeihoxyplienyl)imidazo[l,2-a]py

yl)nietby{}- 1 - ethyipiperidm~4~amjne;

1 -( ] ~(2~(5-Chloro-2,4-dimethoxypbeny3)i3Ysidazo[ L2-a]pyridii -yi)pyrro3idin~3- y1)-N-((1 -nieihylpiperidir!-4-y1}metiiyl)metba3ia.mir!e;

N-((l-(2-(5-€hiQro-2,4-dmiethoxypheny

y3)methyi)aniliiie;

-(( l-(2-(5~Chloro-2,4~dmiethoxyp eiiyl)imidazo[ l,2-a]pyridm-7-_v l)pyrrolidin-3- yl)methyl)-2-phenyietlian-l-aniine;

] -(l-(2-(5-Chloro-2,4-diraetho >^henyl)imidazo[l ,2-a]pyridm-7-yl)pip y3)-N-{thiop en-2~yimethyl)r!iethaiiaiiiiiiie;

N-(( 1 -(2-(5-Chloro-2 : 4-dimetiioxypher!yl)ifflidazo[ 1 ,2~a]pyridm~7-yl)pyiro m-3- yl)methyl)-2-( 1 -methylpiperidin-4-yl)etban- 1 -amine;

N -Benzyl- 1 -(1 -(2-(5-chloro-2,4-dimeihoxypheRyl)imidazo[ 1 ,2-ajpyridin-7- yl)azetidin-3-yl)metlianaimne;

tert-Butyl

yl)piperidin-4-yl)methyl)ami^^^

1 -( 1 -(2-(5 -Chloro-2,4 -dimethoxypbenyl)imidazo [ 1 , 2-aJpy ridin ~7~yl)azetidm-3 -yl)- N-(4-fluorobenz 'l)methanaraine;

tert-Butyl 3-((((l-(2-(5-chloro-2,4-dimeihox> henyl)imidazof l,2-a3pyridin-7- y3)azetidin-3-yl)methyl)ammo)meih) 7 l)pyrrolidine-i-cai"boxylate:

tert-Butyl 4-((((l-(2-(5-cbloro-2„4-dimetiioxyphenyl)-imidazo[ i,2-a|pyridin-7- yl)azetidin-3-} l}meihyl)amino)-methyl)piperidme-l-carboxylate; 1 -( 1 -(2-(5 -Chloro-2,4-diraethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)azetidin-3 -yl)~ N-(cy ciopentylrn ethyl) -me Aanara ine ;

tert-Buiyl 4-{2-((( 1 -(2-(5-chloro-2,4-diraethox , phenyl)imidazo-[ 1 ,2-a]pyridin-7- yl)pyrrolidin-3-yl)meiliyl)amino)ethyl)^iperidine-l -carboxylate;

tert-But l 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imida∞-[l ,2-a]pyridin-7- y l)piperidin- 3 -yl}me thy l)amino)me Ay l)-py rrolidine - 1 -carboxy late :

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 - yl)~N-(( 1 -isopropylpiperidin-4-yl)raeAyl)meAanaraine ;

2-((((l -(2-(5-CHoro-2,4-dimeAoxy^henyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin- 3-yl)raeAyl)aniino)raeAyl)- , -dimeAy3anilme

1- ( l-(2-(5-Chloro-2,4-dimeAoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)piperidin-4- y3)-N-(2,4-dime&oxyhenzyl)-methanamine;

2- (((( 1 -(2-(5 -Chioro-2,4-dime Aoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-y i)piperidm~4- yl)methyl)amino)methyl)-N,N~dimethyiaiiiiine;

1 -( 1 -(2-(5 -Cbloro-2,4-diraethoxyphenyl)imidazo [ 1 ,2~a]pyri din-7-yl)azetidin~3 -yl)~

N~ (ey ciohexy I methyl )meth anami n e ;

l-(l -(2-(5~Chloro-2,4-dimethoxyphenyl)im^

y i)-N-(4-mei1ioxy~2 -ni trobenzy !)ra etb anamine ;

4- ((((l-(2-(5-Chloro-2,4-dimeAoxyphenyl)imi 3azo[l,2-a]pyridm-7-yl)aze " tidin-3- yl)meAyl}ainiiio)meAyl}- ,N-dimeihyianiiine;

5 - (((( 1 -(2-(5 -CUoro-2,4-dimeAoxyphenyl)Aiidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)nietbyl)amir!o)raethyl)~2-methoxyphenoI:

1 -( 1 -(2-(5 -Chioro-2,4 -di nietboxyphenyl)iraidazo[l ,2~a]pyridin-7-yl}piperidin-3- y 1 )- -(cyc3 oh exy!methyljro eA anamine ;

l-(l-(2-(5-Chloro-2 ; 4-dimeihoxypheny])imidazo[l,2-a]pyridA-7-yl)pyrro]idin -3- yl)-N-(4-fluoro-3-meAylbenz 'l)-meAanamine;

l-( l-(2-(5-Chloro-2,4-dimeAoxyphenyl)imidazo[ l,2-a]pyridm-7-yl)pyiTolidin-3- y 1)-N -(4-methoxy -3 -me thy Ibenzy 1} -me Aanamine ; l -( l -{2~(5~Chloro-2.4 imicthoxyp

yl -N-(2-fluoro-4-raethylbenzyl)raethanamine;

N i-(XM2-(5-Chloro-2 ; 4-dimethox ^

3-yl)methyl)-N4,N4-dimethylc>'clohexane-l,4-diamine;

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a jpyridin-7-yl)py rrolidin-3 - yl)~ -(3-fluoro-4-metliylbenzyl)inethanainine:

l -( l-{2-i5-Chloro-2.4-dimethoxyp

yl)-N-(2,4-difluorobenzyl)methaoaraine;

1NM(l-(2-(5-Chloro-2,4-diinethoxyphe^

y])metbyl)-l -isopropylpiperidin-4-araine;

l -( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ i,2-a]pyridin-7- l)pynOlidin-3- v3)- -(( 1 -eihylpiperidin-4-yl)methyl)propan- i -amine;

l -(tert-Butyl)-N-(( l-(2~(5-chloro-2,4-dm

yl)piperidin~4~yl)methyi)piperidin-4-amine;

l ~(l -{2-(5~Chloro-2,4-diniethoxypher!yi)m idazo[l ,2-a]pyridm-7-yl)

yI)- -({ i-efiiySpiperidin-4~yi)niethyl)methanamir!e;

N-(( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- yl)methyl)-2-(l -eihylpiperidin-4-yl)ethan-l-amine

N-((l-(2-(5-Chloro-2,4 limethoxyphenyl)imida∞[l,2-ajpyridin-7-yl)p^ yl)methy l)cycloheptanamine ;

N-{( l-(2-(5-Chioro-2,4-dimeAoxypheny^

yl)metbyl)- 1 -ethylpiperidin-4-amine ;

1 -( 1 ~(2~(5 -ChJoro-2,4 ~dimethoxyphenyl)imidaz:o [ i , 2-aJpy ridin -7-y{)pyrrolidin-3 - yl)-N-(2,4-dimeAoxybenzyl)methanamine;

l -(tert-Bulyl)-N-((] -(2-(5-cM^

yl)pyrrolidin-3-yl)methyl)piperidin-4-aniine;

1 -( 1 -(2-(5-Chloro-2.4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyjrrolidin-3- yl)- -{( 1 -eihylpiperidin~4~yl)metliyi)methanainiiie; N-(( 1 -(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- yl)methyl)-2-cyclopentylethan-l-amine;

1- (l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridm-7-yl)^

N-(2-meihylbenzyl)methanamine:

l-(l -(2-(5-Chlofo-2,4-dimethoxyphem )iinidazo[l ,2-a]pyridin-7-yl)piperi yl)-N-(4-methoxy-3-methylbenzyl)methanainine;

-((l-(2-(5-Chloro-2,4-dimeihoxyphenyl)imidazo[ L2-a]pyridm-7-yl)azetidm-3- yl)nietb.yl)-3,3-dimethylbutan-l -amine;

2- (((( 1 -(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)methyl)amino)methyl)-5-met ' hoxyphenol;

5-((((l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a|pyridin-7-yl)pyrrolidin- 3-yl)methyl)amino)meth\'l)-2-methoxyphenol;

l-(l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ I,2-a]pyridin-7-yl}azetidin-3-yl)- N-(4-methylbenzyi)methanamine;

N-(( 1 -(2-(5 -Chloro-2,4-dimetiioxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- y Ϊ) methyl) -2~( 1 -p ropy Ip ipe ridi n -4-y 3 )eth an- 1 -am ine ;

-(( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl )imidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- yl)meihyl)-2-(l -eL3i) : lpiperidin-4-yl)et ' han-l-amine:

l-(i -(2-(5-ChloiO-2,4-dimethoxyphenyl)imidazoS I ,2-a]pyridin-7-yi)piperidm-4- yl)~N~((l-methylpyrrolidiii-3~yl}inetliyl)metlianamine;

1 -( 1 ~(2-(5-Chlofo-2.4-dimethoxyphenyl)imidazoj " 1.2-a] yridin-7-yl)pi eridin-4- )- -((l -ethylpi eridi -3- yl)met ΐyi)methanarame;

test-Butyl 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)i!«idazo-[l,2-a]py ridiii-7- y3)pyrrolidin-3-yl)meth> )amino)methyl)piperidine- I -carboxylate;

l-(l-(2-(5-Chloro-2,4-dimeihoxypheny3)imidazof L2-a]pyridin-7-yl)pyrro3idin-3- yl)-N-(cycloheptylmethyl)-methanamme;

l-(4-((((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[i ,2-a]pyridin-7- y l)piperidin~4~yl)methyi )amiiio)methyi)piperidin- 1 -y l)-2, 2-dimethy Ipropan- 1 -one ; N-((l-(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)meihyl)-2-(l -propyipiperidin-4-y3)etha3 -l -amine;

4-((((l-(2-(5-Chloro-2,4-dimethox> henyl)imidazo[l,2-a]pyridin-7^

3-yl)methyl)amino)methyl)-N, ,3 rimethylaniline;

1 -( 1 -(2-i 5 -Chk)fo-2,4-dimethoxyphenyl)imidazo j 1 ,2-a jpyridin-7-yl)pyrrolidin-3 - yl)-N~(cyclohexylmethyl}meiliananime;

tert-Butyl 4-(((l-(2-(5-chloro-2,4-dimetlioxyphenyl)imidazo-[l,2-a]pyri din-7- yl)pyrrolidin-3-yl)raeAyl)amino)azepane- 1 -earboxylate;

4-((((l -(2-(5-Chloro-2,4-dimethoxyp enyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin- 3-yl)roetbyl)amino)roethyl)-3-methoxy-N,N-dimeth.ylaniline;

l-( l-(2-(5-Chloro-2.4-dimethoxypheny3)imidazo[ l,2-a]pyridin-7-yl)

-(3 -me thy 3benzyi)methanamine ;

4-(((( 1 -(2-(5 -Chloro-2,4-dimeihoxyphenyl)imidazo [ 1 ,2 -a]pyridin-7-y l)py rrolidin- 3-yl)methyl)amino)methyl)-N, ,2-trimethylaiiiline;

4-((((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyrid in-7-yl^^^ yl)!neihyj)ainmo)inethy3)-N, ; 2-triniethylao.iiine;

4-((({l-(2-(5-Chioro-2,4-dimethoxypheny])imidazo[l,2-a]pyrid m-7-yi)piperidin-4 yl)methyl)aroino)methyl)-2-methoxy-N,N-diroethylanilm^

l-(i -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo l ,2-ajpyridin-7-yl)piperi yl)-N-(( 1 -isobutyipiperidin-4-y l)methyl)methanamine;

tert-Butyl 2-(((( 1 -(2-(5-cMoro-2,4-dimethoxyphenyl)iinidazo-[l ,2-a]pyridin-7- yl)azetidin-3-yl)methyl)amino

tert-Butyl 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo-[l,2-a]pyri din-7- y])azetidin-3-y3)meihyl)amino)meihyl)-piperidme-l-carboxylat e;

1 -( 1 -(tert-Butyl)pyrro!idm-3-y!)-N-(( 1 -{2~(5-chioro-2,4- dimeihoxyphenyl)imidazo[l,2-a]pyridm^

l-( l-(methyl)pyrrolidin-3-yl)-N-((l-(2-(5-chloro-2,4- dimethoxyphenyljimidazo [ 1 ,2-a]pyridin-7-y l)py rrolidin-3 ~yl)methyi)methanamine ; l-(l-(2~(5-Chloro-2,4-dimethox>^

yl)- -((l-methylpyn-olidin-3-yl)raethyl)methanamine;

N-(( 1 -(2-(5-Ch1oro-2 : 4-dimethoxypher!yl)ifflidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)methyl)-4-methylcyclohexa«- i -amine,

6-((((l-(2-(5-ChIoro-2,4-dimetiioxypheny3)iinidazo| l,2-a]pyridin-7-yl)piperidin-4- yl)methjd)ainmo)metiiyl)->J,N-dimeihylpj'ridin-3-ainin

l-(l-(2-(5-Chlofo-2,4-dimethoxyphe¾

-(2-fluorobenzyi)methao.anime;

1 -(4-(2-((( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7- yl}piperidin-4-yl)iT3e†hyi)amino}elhy1)piperidin

N-((l-(2-(5-Chloro-2,4-dimettioxyphenyl)imidazo[ l,2-a]pyridm-7-yl)pyrrolidin-3- y])methyi)-2-eydohepiylethan- 1 -amine;

l-(l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ I,2-a]pyridin-7-yl}pynOlidin-3- yl)- -((l-methjdpiperidin-3-yl)meihyl)methai3ainine:

l~(l-{2-(5~Chloro-2.4-diniethoxypher!yl)m idazo[ l ,2-a]pyridm

yl)-N-((l-ethy{piperidin-3-yl)metl l)raeAanamine;

-(( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl )imidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)meihyl)-4-ei ylcyclohexan- 1 -amine;

l-(l -(2-(5-Chloro-2 4-dimethoxyphenyl)imidazo| I ,2-a]pyridin-7-yi)azetidm-3-Yl)- -(3-fluoiObenzyl)methanamine:

1 -( 1 ~(2-(5-Chlofo-2.4-dimethoxyphenyl)imidazoj " L2-a]pyridin-7-yl)piperidm-4- yl)-N-(4-fluoro-3 -methyl benzyi)methanam e :

test-Butyl 3-(((( i-i2-(5-diloro-2 5 4-diineihoxyphenyi)imidazo-[L2-aJpyridiii-7- y3)piperidin-3-yl)metnyI)amino)met yr)-piperidine-l-carboxy]a†.e;

2-(((( 1 -(2-(5-ChIoro-2,4-dimethoxypher!yl)imidazo 1 ,2-a]pyridin-7-yl)azetidin-3- y3)methyi)aniino)methyl)-N,N-dimethyiaiuline;

l-( l-(2-(5-Chloro-2,4-dm?ethoxypheny3)mudazo[ l,2-a]pyridin-7-yl)pipendin-4- y 1)- -(4-fluof 0-3 -methy Ibenzy l}methanamme ; tert-Butyl 3-{(((l~(2-{5-chIoro-2 -du ethoxyphenyl}miKlazo~ l ,2~a]pyridm-7- yl)piperidin-4-yl)methyl)amino)methyl)-piperidine- l -carboxylate;

j -( ! -(2-(5-Chloro-2,4-dime " thox>'phenyl)imidazo[l ,2~a]pyridin-7-yl)piperidin-4- yl)- -((l-(cyclobutylmeihyl)-piperidm^

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)-N-(2,3-dimethylbenzyl)-methanamine;

-( 1 -( 1 -(2-( 5 -Chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2 -ajpyridin- 7-yl)py rrolidin- 3 -yl)ethy I )- 1 -eth l piperidin-4-atnine

l-( i-(2-(5-ChJoro~2,4~dhnethoxypheny])H^^

yl)- -((l -eth} : lpiperidin-4-yl)methyl)ethan-l -amine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imida--o[ l,2-a]pyridin-7-yl)piperidin-4- yl)-N-(2-cyclohexylethyl)ethan-l-amine;

l-( l-i2-(5-Chloro-2,4-dimethoxypheiiy^

y 1)-N -(2 -fluoro-3 -metliy ibcnzyl)methanamme ;

] -(i-(2-( -Chloro-2,4-dimetl^

yl)-N-(2-methoxy-5-raethylbenzyl)raeAanamine;

!-(! -( 2-(5-Chloro-2,4-dimethox phenyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3 yl)- -(2-cyclopentylethy])ethan-l-amine:

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)^

yl)- -(cyclohepty neihy{)ethan- 1 -amine;

yl)-N-(2-fluoro-5-methylbenz '{)methanamine;

N-((l-(2-(5-Chloro-2,4-dimeAoxyphe^

yl)methyl)-2-(cyclohex-l -en-l-y3)eth an- 1 -amine;

-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin- 7-y

yl)methyl)-2-cyclopenty!ethan- 1 -amine;

tert-Butyl 4-(3-(((l-(2-(5-ehloro-2^-dimethoxyphenyi)imida o[ L2-a]pyridi yl)pyn'olidin-3-yi)methyl)ammo)propyl)piperidme-l-carboxyk¾ e; tert-Butyl 4-i2-((l -(l-(2-(5-chioro-2 5 4-diineihoxyphenyl)imidazo[L2-aJpyridm-7- yl)pyrrolidin-3-yi)ethyl)ainino)ei yl)piperidine-l-carboxy]ate;

1 -( 1 -( 1 -(2-(5-Chloro-2,4<1iiT3ethoxypheny])imidazo[ 1 ,2-a]pyridin-7- yl)pyrrolidin-3-yl)ethyi)-N^

4-(((2-( l-(2-(5-Chloro-2,4-dimetlioxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pipendin- 4-yl}ethyl)amino)metliyl)-benzonitrile;

tert-Butyl 4-(((2-(l-(2-(5-cUoro-2,4-dimethoxj^henjd)iinidazo[l,2-a]pj ," ridin-7- yl)pj eridin-4-yl)et3iyl)a!niiio)methyl)-piperidine-l-carbox3 ' 'laie;

N-Benzyl-l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a ]pyridi y l)piperi din-4-yl)ethan - 1 -amine ;

tert-Butyl 3-(((l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7- y3)pyrroiidin-3-yl)etliyl)amino)methyl)-piperidine-l-cafboxy iate;

tert-Butyl 4-(3 ~(( 1 -( 1 -(2-(5 -chief o-2,4-dimethoxyphenyl)irnidazo [ 1 ,2-a]pyridin-7- yl)pyn-olidin-3~yi)etliyl}ainiiio)propyl}-pipendine-l-carbox yiate;

l-(l-(2~(5-Chloro-2,4-dimethoxypheny^

yl)-N-((l-methylpiperidin-4-yl)methy{)eAan-l-aniine;

1- (l -(2-(5-Chloro-2,4-dimethox phenyl)imidazo[l ,2-a]pyridin-7-yl)pyrroli yl)- -(2-(l-propylpiperidin-4-yl)ethyl)ethan-l-aniine;

tert-Butyl 3-(((2-(l -(2-(5-cUoro-2,4-dime1iiox phenyl)imidazo[i,2-a]pyridin-7- yl)piperidiii-4-jd)ethyl)amino)niethyl)-pyrrolidine- 1 -carboxyiate ;

tert-Butyl 4-(3-{{l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)-imidazo[ l,2-a]pyridin-7- yl)piperidin-4-yl)ethyl)ainino)-propyl)piperidine-l-carboxyl ate;

2- ((((l -(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pip yl )methyl)ami n o)methyl)-4-methy3 phenol ;

tert-Butyl 4~(((l-(l-(2-(5^hloro-2,4-dimethoxyph

yl)piperidin-4-yl)ethyl)amino)meihyl)-piperidine-l-carbox ylate;

tert-Butyl 3-(((l -(l-(2-(5-chloro-2,4-dimeflioxyphenyi)imidazo- l,2-aJpyridi yl)piperidin~4~yl)ethyl)animo}methyl)-pyrrolidiiie-l-carboxy late; 2~(l-C2~(5~Chloro-2,4~dinicthoxyp

y l)- -(cyclohexylmethy3 )eth an- 1 -am ine ;

l-(l-(2-(5-Cbloro-2,4-dimethoxyphenyl)imi^

yl)-N-({ l-isopropylpyrrolidin-3-yl)medt l)ethan-l-amme;

l-{tert-Butyl)-N-(H H>-(5-chloro^

yl)pyi olidm~3-yi)ethyi)piperidm~4-anime;

tert-Butyl 3~(((2-(i-(2-(5-cliloro-2,4~dimetlioxypheiiyl)imidazo-| l,2-a]pyridin-7- yl)pj eridin-4-yl)et3iyl)ainitio)methyl)-piperidine-l-carboxy'late ;

N-Benzyl-2-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a ]pyridi y])piperidin-4-yl)ethan- ' l -amine:

l-( l-(2-(5-Chloro-2.4-dimethoxypheny3)im^

yl)-N-(cyclopentyimetiiyl)ethaii- 1 -amine;

tert-Butyl 3-((( 1 -( i -{2-(5-ehloro-2,4-dimemoxyphenyl)imidazo-[ l,2-a]pyridin-7- yl)pj r n-olidin-3-yl)ethjd)ainmo)metiijd)pyrfolidine-l-carbox ylate;

N-(l -(l-(2~(5-Cb!oro-2 l-dimethoxypl enyl)iniidazo L

4~yi)ethyl)cyelohexanamine;

l-(l -{2-(5-Cbloro-2,4-dimethox phe^

yl)-N-pheneth) leihan- ί -amine;

l-(i -(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[ ] .2-a]pyndin-7-yl)piperidm yl)-N-(2-cy ciopentyletliy l)etlian- 1 -amine ;

tert-Buty'l 3-((( l-(l-(2-(5-cliloro-2,4-dimethoxyphenyl)imidazo-| l,2-a]pyridin-7- y3)pi eridin-4-yl)et3iy3)amiiio)methyl)-piperidine-l-carboxylate'.

1 -( 1 ~(2-(5 -Chi o ro-2.4 -dimethoxyphenyl)imidazo [ 1.2-a]py ridin -7~yl)piperidin~4- yl)~N~(cyc3obexylmethyl)etlran~ 1 -amine: and

1 -( l-(2-(5-Chloro-2,4-dimethox> heny1)imidazo[ i .2-a]pyridin-7-yl)pyrro1idin-3- y3)-N-(( 1 -ethylpiperidin-4-yl methyl)propan-2-amine; and

a pharmaceutically acceptable salt thereof.

[11] . A phamiaceutical composition comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [10].

[12]. A pharmaceutical composition according to [1 1] for use in treating or preventing cancer.

[ 13]. A pharmaceutical composition accordmg to [12], wherein the cancer is selected from the group consisting of lung cancer, cervical cancer, bladder cancer, esophageal cancer, osteosarcoma, prostate cancer and soft tissue tumor.

[ 14] . A method for treating or preventing a disease that involves overexpression of SUV39H2, which comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [10] to a subject in need thereof,

[ 15] . A method according to [ 14], wherein the disease is cancer.

1 16] . Use of a compound or a pharmaceutically acceptabie salt thereof according to any one of [1] to [10] in the manufacture of a medicament for use in treatment or prevention of a disease that involves overexpression of SUV39H2.

The subject specification also includes the disclosure of the following inventions.

[].]. A compound represented by formula (I) or a pharmaceutically acceptabie salt thereof:

wherein

1 and R 2 are independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkyl, and Ci-Ce alkoxy;

R 3 is independently selected from the group consisting of a halogen atom, cyano, nitro, hydroxy, carboxy, Ci-Ce alkyl, Ci-Ce alkoxy, (Ci-Ce. alkoxy)carbonyl, Ci-Ce aikylthio, Ci-Ce aikylsuifinyl, and Ci-Ce alkylsulfonyi;

n is an integer selected from 0 to 3; R 4 is selected from the group consisting of a hydrogen atom, and a halogen atom; R 5 is independently selected from the group consisting of a hydrogen atom , a halogen atom, Ci-Ce alkyl, and Ci-Ce alkoxy;

m is an integer selected from 0 to 3;

p is an integer selected from 0 and 1 ;

R 6 is is selected from the group consisting of Ci-Ce alkyl substituted with one or more substituents selected from Ra, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rb, Ce-Cio aryl optionally substituted with one or more substituents selected from Rb, 5- to 10-membered hcteroary! optionally substituted with one or more substituents selected from Rb, 3- to 12-membered non-aromatic heterocyc optionally substituted with one or more substituents selected from Rb, (Ci -Ce

alkoxy)carbonyl substituted with one or more substituents selected from Ra, (C i-Ce alkyl)carbonyi optionally substituted with one or more substituents selected from Ra, (CV Cio cycloalkyl)carbonyl optionally substituted with one or more substituents selected from Rc, (Cs-Cio aryl)carhonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic heterocycJyl)carbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-membered heteroary])carbonyl optionally substituted w th one or more substituents selected from Rc, aminocarbony] , (Ci-Ce alkyl)aminocarbonyl, and di(Ci-Ce alkyl)aminocarbonyl;

R 7 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra; or

Ra is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkoxy, cyano, (Ci-Ce aikoxy)carbonyl, carboxy, (Ci-Gs alkoxy)carbonyl amino, (Ci- Ce alky])carbonylamino, amino, Ci-Ce aJkylamino, diiCi-Ce alky])amino, aminocarbonyl, (Ci-Ce alky])aminocarbonyl, di(Ci-C6 aIkyl)aminocarbonyl, Ci-Ce alkylsulfonylamino, C3- C10 cycloalkylsulfonyiamino, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10-membered heteroaiyl optionally substituted with one or more substituents selected from Rc, and 4- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Rc;

Rb is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkyl optionally substituted with one or more substitutents selected from Ra, Ci -Ce alkoxy optionally substituted with one or more siibstitutents selected from Ra, cyano, (Ci- Cf, alkoxy)carbonyL carboxy, -NR 21 R 22 , -CONR 23 R 24 , di(Ci-C6 alkyl)phosphono, C3-C10 cycloalkyi optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10- membered heteroaryl optionally substituted with one or more substituents selected from Rc, and 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Rc;

Rc is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally substituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, di(Ci-C ' 6 alkyi)amino, (Ci-Ce alkyljcarbonyi, (Ci-Ce alkoxy )earbonyi, Ci-Cr, alkyisulfonyl, C3-G0 cycloaikylsulfonyl, C?-C; 4 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, C3-C10 cycloalkyi optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Re, 5- to 10-mernbered heteroaryl optionally substituted with one or more substituents selected from Re, and oxo;

Rd is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, i{ ( ' :-( ' .-. alkyl)amino, Ci -Cs alkylcarbonyl, (Ci-C& aikoxy)carbonyl, Ci- Ce alkyisulfonyl, Cs-Cs cycloaikylsulfonyl, C7-C14 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, C.3-Cs cycloalkyi optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Re. and 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Re;

Re is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, C1-C5 alkylamino, di(C] -Ce alkyl)amino, Ci-Ce aikylcarbonyl, (Ci-Ce alkoxy)carbony3, Ci- Ce alkylsulfonyl, and Cs-Cs cycloalkylsulfonyl;

R 21 is selected from the group consisting of a hy drogen atom, Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra, Cs-Cio aryl optionally substituted with one or more substituents selected from Rd, 4- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from Re, 5- to 10- membered heteroaryl optionally substituted with one or more substituents selected from Rc, (Ci-Ce aIkoxy)carbonyl optionally substituted with one or more substituents selected from Ra, (Ci -Ce alkyl)carbonyl optionally substituted with one or more substitiients selected from Ra, (C. -Cso cycloalkyl)carbonyl, (Ce-Cio aryl)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic

heterocyci.yl)carbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-membered heteroaryl)carbonyi optionally substituted with one or more

substituents selected from Rc, aminocarbonyl, (C1-C0 alkyljaminocarbonyl optionally substituted with one or more substituents selected from Ra, di(Ci-Ce alkyl)aminocarbonyl optionally substituted with one or more substituents selected from Ra, Ci-Ce alkylsulfonyl optionally substituted with one or more halogen atoms, C7-C14 aralkylsulfonyl, C3-G0 cycloalkylsulfonyl, aminosulfonyl, Ci-Ce alkylaminosulfonyl, diCG-Ce alkyl)aminosuifonyl, and di(Ci-C& alkyl)phosphono;

R 22 is selected from the group consisting of a hydrogen atom, and Ci-Gs alkyl optionally substituted with one or more substituents selected from Ra;

R 23 is selected from the group consisting of a hydrogen atom, Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra, [(Ci -Ce

alkyi)amino]C] -Cb alkyl optionally substituted with one or more substituents selected from Ra, [di(C;-C6 alkyl}amino]Ci-C6 alkyl optionally substituted with one or more substituents selected from Ra, C3-C10 eycloalkyi optionally substituted with one or more substituents selected from Rc, Ce-Cio ary] optionally substituted with one or more substituents selected from Rd, 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Rc. and 3- to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Rc; and

R 24 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra.

[2] . The compound or a pharmaceutically acceptable salt thereof according to [1], wherein the compound is re resented by Forumuia (la):

wherein R 1 and R 2 are independently selected from the group consisting of Ci-Ce alkoxy,

R 3 is selected from the group consisting of a harogen atom, and

R 6 , R' and p are as defined in [1 ] .

[3] . The compound or a phamiaceutically acceptable salt thereof according to [1] or [2], wherein R ! and R 2 are methoxy, and R 3 is a chlorine atom.

[4] . The compound or a phamiaceutically acceptable salt thereof according to any one of [1] to [3], wherein p is 1.

[5] . The compound or a pharmaceutically acceptable salt thereof according to any one of [i] to [4], wherein p is 0.

[6] . The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein R is a hydrogen atom.

[7] . The compound or a pharmaceutically acceptable salt thereof according to any one of [ 1] to [6], wherein R 6 is selected from the group consisting of pyrimidyl, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, piperidyl optionally substituted with a Ci-Ce alkyi group or a (Ci-Ce alkoxy )earbonyl group, pyrrolidyl optionally substituted with a Ci-C-6 aJkyl group or a (Ci-Ce alkoxy)carbony1 group, C3-C? cycloalkyl tetrahydrofuryl, tetraliydropyranyl, phenyl optionally substituted with one substituent selected from Rb, a group --CH?.-Ra, and a group -CH2CH2- a.

[8] . The compound or a pharmaceutically acceptable salt thereof according to any one of [ 1] to [7], Ra is independently selected from the group consisting of hydroxy, Ci-Ce alkoxy, C3-C7 cycloalkyl optionally substituted with a difCi-Ce alkyl)amino group, phenyl optionally substituted with one or more substituents selected from Rd, pyrrolidyl optionally substituted with a Ci-Ce aikyl group or a (Ci-Ce alkoxy)carbonyl group, pipcridyi optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, and thiazoiyl.

[9] . The compound or a pharmaceutically acceptable salt thereof according to any one of [ 1] to [8], Rb and Rd are independently selected from the group consisting of a halogen atom, methyl, cyano dimetliylammo, metlioxy, nitro, hydroxy, and trifluoromethyl

[10] , The compound or a pharmaceutically acceptable salt thereof according to [1], which is serceted from the group consisting of:

1 -(! -{2-(3-Ch!oro-2,4-dimethoxy

yr)-N-(cyclop3 pylme†hyl)methanamine;

l-(l -(2-(5-Chioro-2,4-dimethoxyphenyl)iinidazo| " l ,2-ajpyridin-7-yl)piperidin-4- yl)~N~(cyclopentylmethyl)methanamine;

tert-Butyl 3-((((l-(2-(5-chioro-2,4-dimethoxyphenyl)iinidazo[l,2-a]pyri din-7- yl)piperidin-4-yi)mefhyi) amino)niethyl)pyrroiidine-i-earboxylate;

tert-Butyl 3~((((l-(2~(5-chioro-2,4-diinethoxyp

y])piperidin-4-yl)methyi)(methy3)a]nino)methy3)pyrro]idin

l-(l-(2-(5-Chloro-2,4-dimethoxypheny])imidazo[i,2-a]pyridin- 7-yl)piperidin-4- yl)-N-(pyrrolidin-3-ylmethyl)methanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ i,2-a]pyridin-7-yl)piperidin-4- yl)- -(cyclohexylmethyl)metlianamme; tert-Biityl 4-i(((l-(2-(5-chloro-2,4-dimethox ^ enyl)imidazo[l ,2-a]pyrid.in-7- yl)piperidin-4-yi)methyl)amino)m

j _( j -(2-(5-Chloro-2,4-dimethox} henyi)imidazo[i ,2-a]p 'ridin-7-yl)piperidin-4- yl)- -(piperidin-4-y3methyl)me " thatuimine:

N-Ben¾ j 3-l-(l -(2-(5-cUoro-2,4-diine1iioxyphenyl)imidtizo[i ,2-a]pyridin-7- yl)piperidin-4-y 3)metlianamine ;

1 -( 1 -{2-( 5 -C oro-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yi) piperidin-4- yl)-N-(2-methyl.benz\'l)methaiiaraine;

l-( J.-(2-(5-ChJoro~2,4~dimethoxypbeny^

y3)-N-(4-methylbenzyl)methanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxypheny3)imidazo[ l,2-a]pyridin-7-yl)piperidin-4- y3)-N-(2-fluorobeiizyl)methanamine;

1 -( 1 -(2-(5-CWoro-2,4<limetlioxypheiiy l)imidazo[ 1 ,2-a]pyridin-7-y l)piperidin-4- y 3)- -( 3 -il uoro beiizyl)methanamiiie ,

3 -(l-(2-(5-Cbloro-2,4-diraethox>^henyl)imidazo[l ,2-a]pyridm-7-yl)piperi y3)-N-(4-fluorobenzyS)fflethaiiaiiiiiiie:

l-(l -(2-(5-Chloro-2,4-dimethox phenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)-N-(4-methox 'benzy3 )methan amine ;

l-(l -{2-(5-Chioro-2,4-dimethoxyphen\4)imid

yl)-N-(2-chloFoben2yi)methanainine;

4-((((H .-(5-CMoro-2,4-dimethoxy

yl)meth.yl)ann.no)nietb.yl)- ; N-dimethyiani3ine

3-((((l -(2-(5-Chloro-2,4-dimedioxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pi^ y3)methyl) ainino)methy3)benzonitrile

4-(((( 1 -(2-(5-Chloro-2,4-dimethox>phenyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- yl)methyl) am ino)methy 3 Jbenzonitrils;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)piperidin-4- y 3)- -(2-nitro beiizyljmethanamine ; 1 ~( ί -{ -(5 -Ch loro-2,4-dmiethox

yl)-N-(3-(tnfiuoroniethyl)ber!zy1)mefhanamir!e;

yl)-N-(pyridin-3-ylmethyl)methanamine;

l-(l -(2- 5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi yl)- -(pyriclin-4-ylmethyl)methanainiiie:

l-( 1 ~(2-( 5-Chiofo-2,4-dimeihox>phenyl)iinidazo[l,2-a]p ' ridin-7-yl)piperidin-4- yl)- -((3-fluoropyridin-4-yl)niethyl)raethanaxnine;

1 -( 1 -(2-(5 -Chioro-2,4 -dimethoxypb.enyl)imidazo [ 1 , 2-aJpy ridin ~7~yl)piperidin~4- y])- -((2-mei oxyp\ " ridin-4-yl)methyl)raethananiine;

l-i l-(2-(5»Chloro-2.4-dm?ethoxyphenyl)inudazo[ l,2-a]pyndin-7-yl) piperidin-4- y3)-N-(thiazol-2-yInietbyl) methanamine.

1 -( 1 -(2 -(5 -Cliloro-2,4<limetlioxy pheny l)imidazo [ 1 ,2-a]pyridin-7-y i) piperidin-4- yl)-N-(thiazol-2-yimethyl) methanamine:

l-(l-(2-(5-CWoro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperidm-4- yl)-N,N-bis(pyridin-2-ylmethyl)raethanamir!e;

N-(( 1 -(2-(5-Chloro-2,4-dimethox} henyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- yi)meihyl) cyclobutanamine;

N-((l-(2^5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-ajpyridin- 7-yl)piperi yl)metliyl} cyclopentanamine;

-(( 1 ~(2-(5 -Chioro-2,4-dimethoxypbenyl)imidazo[ 1,2-a j pyridiii-7-yl)piperidin-4- yl)roethy!} tetrabydroforan~3-amme;

N-((l-(2-(5-Chloro-2,4-dimethoxypbenyl)imidazo[l,2-a]pyridin -7^

y 1 )methy 1) cyclohexan am ine ;

-(il-(2-(5-Chloro-2,4-dimeihoxypheny])imidazo[l,2-a]pyridin- 7-yi)piperidin-4- y3)meihyi) tetrahydro-2I -pyran-4-arnine;

N-(( 1 -(2-(5-Chloro-2,4-dimetiioxypheny])iinidazol 1 ,2-a]pyridin-7-yi)piperidin-4- yl)methyl) cycloheptanamine: N-((l-(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperi y l)m ethyl) - 1 -methy Ipi pen d in-4-am ine ;

-((l -(2-(5-Ch]oro-2,4-dime " thox phenyl)imidazo[l ,2-a]pyridin-7-yl)piperidin-4- ylimetliy 1)- 1 -isopropyipiperidin-4-aniine ;

l-(i -(2-(5-Chloro-2,4-dime ' thoxyphenyl)imidazoj " l ,2-ajpyridin-7-yl)piperidin-4- yl)-N-(( 1 -methy lpiperidin~4~yl)metliyi)metlianamine ;

-(( 1 -(2-(5 -ChloiO-2,4-dimeihoxyphenyl)imidazo [ 1 ,2.-ajpyridin- 7-y l)piperidm~4- yl)meth.yl)-2-(l-niethylpjperidin-4-yl)ethanarniiie:

N'-((l-(2-(5-CWoro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin -7-y{) piperidin-4- y1)methyl)-N 4 ,N 4 -dimethyl cyc3ohexane-l,4-diamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pyrfolidin-3- y3)-N-(cyclopropylniethyl)methaiiamine

1 -( 1 -(2-(5 -Chloro-2.,4-dimethoxypheny l)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- y 1)- -(cyclopentyimethyl)metlianamine ;

tert-Butyl 3-((((l-(2-(5-ehloro-2,4-dimethoxypte^

pyrrolidin-3-yl)methyl) araino)methy{)pyrrolidine- 1 -carboxylate;

l- l -(2-(5~Chloro-2,4-dimethox>phenyl)im^

yl)-N-{pyn-olidin-3-ylmeAyl)methanamine;

tert-Butyl 4-((((l-(2-(5-chlofo-2,4-dime hoxyphenyl)imidazo[l,2-a]pyndin-7- yl)pyrrolic n-3-yl)metiijd)ainino)metiijd)piperidine-l-carboxylaie:

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 - yl)-N-(piperidin-4-ylme1hyl)methanaraine;

N-Benzyl-l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a ]pyridin-7- y])pyrrolidin-3-yl)methananiine;

l-( l~(2-(5-Chloro~2,4-dimetho

yl)-N-(2-fluorobenzyl)methanamine;

l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imida--o[ l,2-a]pyridin-7-yl)pyiTolidin-3- y 1)- -(3 -fluof o benzy l)methanamine 1 ~( 1 -{ 2-(5 -Ch loro-2,4-dimetho yphen yl) imidazo [ 1 ,2-a]pyri din-7-yl)py rrolidin-3 - yl)-N-(4-fluorobenzyl)methan amine

4-((((l-(2-(5-Chloro-2,4-dimet oxyphenyl)imidazo[l,2-a]pyridin-7-yl)p

3 -y 1 )methy 1 )amino)methy 1 )-N , N-dimeihy laniline ;

4-((((l-(2-(5-Chloro-2,4-cUmeto^

3-yl}meihyl)amino)meiliyl)phenoi;

l-(l-(2-(5-Chiofo-2,4 iimetiusxvpheny^

yl)~N-(2-iiitrobenzyi}methaiiamine;

1 -( 1 -(2-(5 -Chloro-2,4 ~dimetnoxyp enyl)imidazo [ 1 , 2-aJpyridin -7-yi)pyrrolidin-3 ~ y l)- -(3 -(trifluoromethyl)benzyl)methanam ine ;

l-i l-(2-(5»Chloro-2.4-dm?ethoxyphenyl)inudazo[ l,2-a]pyndin-7-y

y3)-N-(4-(trifiuofOrtietliyl)benzyl)metlianamine;

1-(1 -(2 -(5 -Chloro-2,4-dimethox phenyl) imidazo [ 1 ,2-a]pyridin-7-yi)pyiTolidin-3- yl)-N-(4-methyibeiizyl)methanamine:

l-(l-(2-(5-Cbloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- y3)-N-{2-chlorobenz\4)nietbanamme;

j _( i -(2-(5-Chloro-2,4-dimethox}phenyl)imidazo[l ,2-a]p -ridin-7-yl)pyrrolidin-3- y l)- -(4-chl orobenzy 1 )methanamiΏ e ;

1 -( 1 -(2-(5 -Chiofo-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin-3 - yl)- -(pyridin-3 -y lmethyl)methanarnine :

1 -( 1 -{2-( 5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a ipyridiii-7-yl)py rrolidin-3 - y1)-N-(p3 ndin-4-yi!rteihyl}methanamiae;

l-(I~(2~(5-Chioro~2 4~dime^^^

y1)-N-((3-f!uoropytidin-4-y1)methyl)raetbana,fflir!e;

l-(l~(2-(5-Chloro-2,4-dimeihoxyphe^

y3)-N-((2 1uoropyr in-4-y3)methyi)methanamine:

1 -( 1 -(2-(5-Chloro-2,4-dimetlioxyphenyl)imidazo{ 1.2-a3pyridin-7-yl)pyrrolidin-3- yl)- , -bis(pyridin-2-ylniethyl)methanainiiie; -((l -(2-(5-Chloro-2,4-dimethoxyp enyl)imidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- yl)meihyl)-2-methoxyei anamine;

N-((l -(2-(5-Ch1oro-2,4-dimethoxypher!yl)ifflidazo[l ,2-a]pyridin-7-yl)pyrrolidin-3- yl)methyl)cyclobutanamine;

N-((l-(2-(5-Chlofo-2,4-dimethoxyphenyl)imidazo[l,2-aJpyridi

yl)metliyl}-l-methylpiperidm~4~ainine;

1 -( 1 ~(2-(5 -Chlofo~2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin- 7~yl)pyrrolidm~3~ yl)~N-((l -methylpiperidm~4~yl)raethyl)methana.fflme;

N-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin -7-yl)p

y])methyl)ani3ine; and

a pharmaceutically acceptable salt thereof.

11 1 ] . A phannaceutical composition comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [10].

112] . A phannaceutical composition according to [ 11] for use in treating or preventing cancer.

[13]. A pharmaceutical composition according to [12], wherein the cancer is selected from the group consisting of lung cancer, cervical cancer, bladder cancer, esophageal cancer, osteosarcoma, prostate cancer and soft tissue tumor.

[14]. A method for treating or preventing a disease that involves overexpression of SU V39H2, which comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [ 10] to a subject in need thereof.

[15]. A method according to [14], wherein the disease is cancer.

[ 16] . Use of a compound or a pharmaceutically acceptable salt thereof according to any one of [1 ] to [10] in the manufacture of a medicament for use in treatment or prevention of a disease that involves overexpression of SUV39H2.

DESCRIPTION OF EMBODIMENTS

An object of the present invention is to provide a compound having inhibitory activity against MELK. which is useful for treating proliferative diseases such as cancer, and a pharmaceutical composition comprising the compound. Another object of the present invention is to provide a method for treating and/or preventing a proliferative disease. A further object is to provide a process for preparing the compound.

Hereinafter, a compound represented by formula (I) will be referred to as compound (I). The same applies to the compounds represented by the other formula numbers. It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a "group" is a reference to one or more groups, unless otherwise noted.

In the definitions of each of the groups of formulas indicated above, the "O-Ce alkyl", and the Ci-Ce alkyl portion of "Ci-Gs alkoxy", "Ci-Ce aikylamino", "di(G-Gs alkyi)amino", "(Ci-Ce alkyl)carbonyr, "Ci-Ce aikylthio", "Ci-Ce aikylsuifinyl", "Ci-Ce alkylsulfonyl" and the like mean a straight-chain or branched-chain alkyl group having one to six carbon atoms. Specifically, examples of the "Ci-Ce alkyl" and the "Ci-Ce alkyl portion" include methyl, ethyl, propyl, isopropyS, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1 -meihylbutyl, l~ethy]propy1, 2-methylbuiyi, isopenty], tert-pentyl, 1 ,2- dimethylpropyl, neopentyl, hexyl, i-methylpentyl, l-ethylbutyl, 2-methylpentyl, 3- methyipentyl, 4-methylpentyl, isohexyi, 1 , 1-diniethylbutyi, 1 ,2-dimethylbutyl, 1 ,3- dimethylbutyl, 1-isopropylpropyl, 1 -ethyl- 1 -me thy ipropyl, 2,3-dimethyibutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 2 -ethyl butyl, and 3-ethylbutyl, but are not limited thereto.

In this specification, the Ci-Ce alkyl portion in each group has the same definition as the aforementioned "Ci-Ce alkyl portion" unless otherwise noted. In a case that a group contains plural Ci-Ce alkyl portions, the Ci-Ce alkyl portions may be same or different.

Specific examples of "Ci-Ce alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, isobutyloxy, tert-butyloxy, butoxy, pentyloxy, and hexyloxy, but are not limited thereto.

The "Ci-Ce alkoxycarbonyl" refers to a monovalent group represented by -C(=0)0-(Ci-C6 alkyl). Specific examples of "(Ci-Ce aikoxy)carbonyi" include metlioxycarbonyl, ethoxycarbonyl, propoxycaibonyl, isopropoxycarbonyl,

i sobut loxycarbonyl, tert-butoxycarbony!, butoxycarbonyl, pentyloxycarbonyl , and hexyioxyearbonyl, but are not limited thereto.

The "(Ci-Ce aikyi)carbQnyl" refers to a monovalent group represented by -C(=0)- (Ci-Cf, alkyl). Specific examples of "(Ci-Ce alkyljearbonyf include methylcarbonyl (i.e . acetyl), ethylcarbonyl, propylearbonyl, isopropylcarbonyl, isobutyicarbonyl, tert- butylcarbonyl , butylearbonyl, pentylcarbonyl, and hexylcarbonyl, but are not limited thereto.

Specific examples of "Ci-Ce alkylamino" include methylamino, ethylamino, propylamino, isopropylaroino, butyl amino, isobutylamino, sec-butylamino, and tert- butyiamino, pentylamino, but are not limited thereto.

The alkyl portions of "di(C i-Ce alkyl iamino" may be same or different. Specific examples of "di(Ci-Ce alkyl Iamino" include dimethylaniino, diethylamino, dipropylainino, diisopropylamino, dibutylammo, diisobutylammo, di(see-butyi)amino, di(tert-butyl)ammo, dipentyl amino, ethyl{methyi)ammo, propyl (methyi)amino, isopropyl(methyl)amino, butyl(methyi)a.mmo, isobutyl(methyl)amino, sec-butyl(roethyl)amino, tert- butyl(memyl)amino, and pentyl(methyl)ammo, but are not limited thereto.

Specific examples of "a halogen atom" include a fluorine, a chlorine, a bromine, and an iodine atoms.

The term "C3-O0 cyeloalkyr refers to a saturated monocyclic hydrocarbon group having three to ten carbon atoms, and a bridged cyclic hydrocarbon group having four to ten carbon atoms which is formed when two or more saturated monocyclic hydrocarbons share two or more carbon atoms. The term "C3-C10 cycloalkyl" also encompasses a cycloalkyl group condensed with an aromatic or non-aromatic carbocyclic ring to form a bi cycl c group. Specifically, examples of "C.3-C10 cycloalkyl" include saturated monocyclic hydrocarbon groups such as cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and bridged cyclic hydrocarbon groups such as adamantyl, but are not limited thereto. In the definitions of each of the groups of formulas indicated above, the Cj-Cio cycloaJkyl portion of "C3-C10 cycloalkoxy", "(C3-C10 cycloalky!)carbonyF\ "(C3-C10 cyc1oa1kyl)sulfonyl", "(Cs-Cio cycloalkyl)sulfonylamino'' and the like mean the same as described above. Specifically, examples of "C3-C10 cycloalkoxy" include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyioxy, and bridged cyclic hydrocarbon groups such as adamantyioxy, but are not limited thereto.

The term "Ce-Cio aryl" refers to an aromatic carbocyclic group having six to ten carbon atoms, and encompasses an aromatic carhoeyciic group condensed with an aromatsc or non-aromatic carbocyclic ring to form a bicyclic group. Specific examples include phenyl 1-naphthyl, 2-naphthyl, and 2,3-dihydro-l H-indenyl, but are not limited thereto.

The term "C7-C1 aralkyl" refers to an alkyl group substituted with an aryl group that has 7 to 14 carbon atoms. Specific examples include benzyl, 2-phenylethyl, 1- phenylethyl, naphtha- 1-ylmethyl, naphtha-2-ylmethyl, and 2,3-dihydro-lH-inden-4- ylmethyl, but are not limited thereto.

In the definitions of each of the groups of formulas indicated above, the C7-C 1 4 aralkyl portion of "C7-C14 araSkylsuSfonyl" and the like mean the same as described above. Specifically, examples of "C7-C14 aralkyl sulfonyl" include benzyl sulfonyl, but are not limited thereto.

The term "5- to 10-membered heteroaryl" refers to an aromatic heterocyclic group having one or more heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The term "5- to 10-membcred heteroaryl" encompasses an aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicyclic group, and also encompasses an aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bicyclic group. Specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyL thiazolyl, isothiazolyl, thiadiazolyl, triazoiyl, tetrazoiyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, bcnzothiazoiyl, isoindoiyl, indolyl, lH-indazolyl, benzimidazolyl, benzotriazolyi, oxazolopyrimidiny], thiazolopyrimidinyl, pyrrol opyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quino!inyl, isoquino!inyl, cinno!inyl, phthalazinyl, qinnazolmy] , quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, [ 1,2,4] triazolo[ i,5-a]pyridyl, and pyrrolo[2,3-b]pyridyl, but are not limited thereto. Particularly, thienyl, pyrrolyl, imidazolyl, isoxazoiyl, pyridyl, pyrimidinyl, pyrazolyi, lH-indazolyl, benzimidazolyl, j l,2,4]triazolo l,5-a]pyridyl, or pyrrolo[2,3-b]pyridyl is preferred.

The term "3- to 12-membered non-aromatic heterocyciyl" refers to a non-aromatic heterocyclic group having one or more heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Hie term "3- to 12-membered non-aromatic heterocyciyl" encompasses a non-aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicychc group, and also encompasses a non-aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bieyclic group. Specific examples include azindinyl, azetidinyS, pyrrolidinyl, piperidyl (including piperidino), azepanyl, 1 ,2,5,6-tetrahydropyridyS, 1,2,3,6- tetrahydropyridyl, miidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazmyl, pyrazohnyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5 ,6-dihydro-2H-pyranyl, oxazolidinyl, morphoiiriyi (including morphoiino), tetraliydrothiophenyl, tetrahydro-2H-thiopyra3iyl, thioxazolidinyl, tbiomoφ olinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzoimidazoiidmyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzoxazolyl, dihydrobenzothioxazoiyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyi, dihydro~2H~chromanyS, dihydro- 1 H-chroraanyl, dihydro-2H- thiochromanyl, dihydro- IH-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, oxetanyl, 1,2-dihydropyridyl, l-azabicyclo 2,2.2]octan-3-yl, 2,5- azabicyclo[2.2.1 jheptyl, 8-azabicyclo[3.2. l]octyl, piperidin-4-spiro-3 '-pyrrolidin- 1 -y 1, and isoindoiyl, but are not limited thereto. In particular, azetidinyi, pyrrolidinyl, piperidino, piperidyl, piperazmyl, morphoiino, morpholinyl, 1,2-dihydropyridyl, 1,2,5,6- tetrahydropyridyl, l-azabicyclo[2.2.2]octan-3-yl, 2,5-azabicyelo[2.2. l]hep†yl, 8- azabicyclo[3.2. l]octy], 2,3-dihydrobenzimidazolyl, or piperidin-4-spiro-3'-pyrrolidin-l-yl is preferred.

The tenn "3- to 12-membered nitrogen-containing heterocyciyi" refers to an aromatic or non-aromatic heterocyclic group having one nitrogen atom and one or more additional heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The term "3- to 12- membered nitrogen -containing heterocyciyi" encompasses a heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicycHc group. Specific examples include aziridinyl, azetidmyl, pynolyi, pyrrolidinyl, piperidyl (including piperidino), azepanvl, imidazoiyl, pyrazolyl, triazolyl, tetrazolyl, piperazinyl, and niorpholinyi.

The term ' " Ci-Ce alkylene" refers to a linear or branched divalent group having 1 to 6 carbon atoms, and includes C1-C4 alkylene and X1-C3 alkylene. Examples thereof include -CH2-, -CH(CH 3 )~, -CHiCH CHs)-, -CH2CH2-, -CH(CH 3 }CH2-, and -CH2CH(C¾)-

For examie formula (I) indicates the following structures.

(1-2)

Examples of Q mclude -CH?.-, -CH{CH:3)~, -Π ΗίΊ Κ Ή -( " 1 1 ·( " ! 1 ·-. -ί Πίί Π οΠ ! -. and

Pharmaceutically acceptable salts of compound (1) mean, for example, pharmaceutically acceptable acid-added salts, amino acid-added salts, or such. Specific examples of the pharmaceutically acceptable acid-added salts of compound (I) mclude inorganic acid salts such as hydrochloride, sulfate, and phosphate, organic acid salts such as acetate, maleate, furnarate, citrate, and such, and examples of pharmaceutically acceptable amino acid-added salts include addition salts such as of lysine, glycine, phenylalanine, asparagine acid, or glutamic acid. Particulaly, Pharmaceutically acceptable salts of compound (I) include hydrochloride salt, dihydrochloride salt, and trihydrochloride salt.

Examples of diseases involving overexpression of SUV39H2, which may be treated and/or prevented by pharraaceuticai compositions comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof of the present invention, include cancer, breast cancer, bladder cancer, cervical cancer, cholangiocellular carcmoma, chronic myeloid leukemia (CML), colorectal cancer, endometriosis, esophagus cancer, gastric cancer, liver cancer, non-small cell king cancer (NSCLC), lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma and small cell lung cancer (SCC), but are not limited thereto. Examples of the cancer which may be treated and/or prevented include breast cancer, bladder cancer, cervical cancer, cholangiocellular carcinoma, CML, colorectal cancer, endometriosis, esophagus cancer, gastric cancer, liver cancer, NSCLC, lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma and SCC, but are not limited thereto. In one embodiment, the examples of cancer includes lung cancer, cervical cancer, bladder cancer, esophageal cancer, osteosarcoma, prostate cancer and soft tissue tumor.

Compound (I) includes compounds which may have stereoisomers such as regioisomers, geometrical isomers, optical isomers, and tautomers, and ail possible isomers including them and mixtures thereof are included in the present invention.

Compound (I) also mcludes compounds having one or more minor stable isotopes or radio isotopes such as ¾, 3 H, 1 J C, 14 C, ] 3 N, !8 0 and the like, which can be preprared in line with comventional procedures for preparing a compound with one or more isotopes indicated abo ve .

Furthermore, compound (I) and pharmaceutically acceptable salts thereof may exist in a form of solvate with water (hydrate) or various other solvents, and these solvates are also included in the present invention.

Specific examples of Compound (I) of the present invention are shown in Table 1 - 1 (Examples 1 to 68), However, compounds of the presen invention are not limited thereto.

Table 1 -1

MS

Ex, Structure Name Ionization

met anamme

-

Specific examples of Compound (I) of the present invention are also shown in Table 1-2 (Examples 2-1 to 2-1 19). However, compounds of the present invention are not limited thereto.

Table 1-2

(cyclohexylmethyl)methanamine

dimethoxybenzyl)methanamme a]pyridin-7-yl)azetidin-3-yl)- - (4-met3iy1benzyl)memanarnine

N-((l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo [1,2--44 a]pyridin-7-yl)pyrroUdin-3- 540 yi)meth.yl)-2-il-propylpiperidin- 4-yl)ethan- 1 -amine

N-((l-(2-(5-Chloro-2,4- dmiethoxy pheny l)imidazo [ 1,2- a|pyridin-7-yl)pyrrolidin-3- 526-45

V-- J yi)met y3)-2-(l -ethylpj.peridin-4- yl)ethan-l -amine

l -(l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo [1,2- a]pyridm~7~y1)piperidin-4-yl)-N- 498-46

H.CO (( 1 -methyipyriOiidm-3 - yl)methyl)methanamine

l-(l -(2-(5-Chloro-2,4- dimethoxy pheny l)imidazo [ 1,2--47 a]pyridm-7-yl)piperidin~4~v3)-N- 526

(( 1 -ethyipiperidin-3 - yi)methy] )me than amine tert-Butyl 3-((((l-(2-(5-chloro- 2,4-dimeihoxypheny1)imidazo--48 [ L2-a]pyridin-7-yl)pyiTolidin-3- 584 y l)methyl)ami n o)methyl)piperi di ne- 1 -carboxylate

.— NI-I — l -(l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo [1,2--49 O X a]pyridin-7-y])pyrrolidin-3-yl)- 497

Hj O "ocH ' -(cydoheptylmethyl)- methanamine

j -(4-(((( 1 -(2-(5 -Chi oro-2,4- ' " "' v N"' ' ' ' i n dmiethoxy pheny l)imidazo [ 1,2- a]pyridin-7-yl)piperidin-4- 582-50 yi)methyl)amino)methyl)piperidi

n- 1 -yl)-2,2-dimethy lpropan- 1 - one

N-((l-(2-(5-Chloro-2,4- dimeihoxypheny1)imidazo i,2--51 a]pyridin-7-yl)piperidin~4~ 54

1 yl)methyl)-2-( 1 -propyipiperidin- 4-y 3 )eth an- 1 -am ine V H, 4-((((l-(2-(5-Chloro-2,4- dimethoxy pheny l)imidazo [ 1,2- a]pyridm-7-yl)pyrroiidin-3- 534-52

yl)methyl)ainino)methyl)-N,N,3- tri methyl aniline l-(l -(2-(5-Chloro-2,4- dimethoxy pheny l)imidazo [ 1,2-

483-53 a]pvri d in- 7- vDpvrroii din-3 -vi) - N- '

H 3 cd (cyclohexylmethyl)methanamine tert-Butyl 4-{{( I -(2-(5-chloro- 2,4-dimeihoxyphenyl)imidazo--54 [ L2-a]pyridin-7-yl)pyiTolidin-3- 584 yl)methyl)amino)azepane- 1 - earboxylate

4-((((l-(2-(5-Ch1oro-2,4- dimethoxyphenyl)imidazo [1,2--55 ajpyridin -7-y] )pyrrolidin-3 - 550

! yi)methyl}ainino)methyl) -3 - / methoxy-N,M-dimethylaniiine l-(l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo[l ,2- 477-56 a]pyridin-7-yl)azetidin-3 ~yS }-N- (3-metliylbenzyl)methaiiamine f

*"* 4-((((l-(2-(5-Chloro-2,4- dimethoxy pheny l)imidazo [ 1,2-

534-57 a]pyridm-7-yl)pyrroiidin-3- yi)methy3)amino)methy3)-N, ,2- ,cd trimethylaniline

4-((((l-(2-(5-Chloro-2,4- dimeihoxyphenyl)imidazo[l,2--58 ajpyridin-7-yl)piperidin-4- 548 yl)methyl)amino)methyl)-N,N,2- trmiethylanilme

4-((((l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo[l ,2--59 a]pyridin-7-yl)piperidin-4- 564 ΐ Ύ ' i yl)methy] )am ino)methy3 ) -2- methoxy-N ,N-dimethy laniline

- o.i - l-(l -(2-(5-Chloro-2,4- dimethoxy pheny l)imidazo [ 1,2- a]pyri d in- 7-yl)pyrroii din-3 -yi) - 526-108

N-(( 1 -isopropylpy rrolidin-3 - yi)methy] )etb an- 1 -am ine

, : : ' -( > 1 -(tert-Butvl)-N-( i -( 1 - (2-(5 - chloro-2,4- l ' 540-109 dimethoxy pheny l)imidazo [ 1,2- a]pyridin-7-yl)pyrroiidin-3- yl)ethyljpiperidin-4-amme

tert-Butyl 3-(((2-(l-(2-(5-chloro- 2,4-diniethoxyphenyl)imidazo- 11 ,2-a jpy ridm-7-yl)piperidin-4- 612-110

!-[;«)' yi)ethyl)amino)methyl)- piperidine- 1 -carboxy late

N-Benzyl-2-( 1 -(2-(5 -chloro-2,4- dimethoxyphenyl)imidazo[i,2- 505-111 a]pyridin-7-yl)piperidin~4~

yl)ethan-i -amine l-(l -(2-(5-Chloro-2,4- diniethoxyp3ienyl)iniidazo[l ,2- a]pyridin-7-yl)piperidirs-4-yl)-M- 497-112

(cycj.opentyiinethyi)ethan- 1 - amine

Λ CH " ' tert-Butyl 3 -((( 1 -( 1 -(2-{5 -chloro- 2,4-dimethoxyphenyl)imidazo- a]pyridiii-7-yl)pyrroildm-3~ 584-1 13 [l,2- yi)ethy l}amino)methy l}pyrfolidi ne-l-carboxylate

N-( 1 -( 1 -(2-(5 -Chloro-2,4- dimethoxypheny])imidazo[i,2- 497-114 ajpyridin-7-yl)piperidin-4- yl)ethyl)cyclohexanamine l -(l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo [1,2- 519-115 a]pyridin-7-y])piperidin-4-yl)-N- phenethylethan- 1 -amine l -(l-(2-(5-Chloro-2 5 4- dimethoxyphenyl)imidazo [1,2- a]pyridin-7-yl)piperidin-4-yl)-N- 511-116

(2-cyclopentylethyl)ethan- 1 - amine

tert-Buty 1 3 -((( 1 -( 1 -(2-(5 -chioro- 2,4-diniethoxyphenyl)imidazo--117 [l,2-a[pyridin-7-yl)piperidin-4- 612 yi)ethy l)ami n o)methy !)- prperidine- 1 -carboxylate

l -(l-(2-(5-Chloro-2,4- dimethoxyphenyl)imidazo [1,2--118 511 i / --% a]pyridin-7-yl)piperidm-4-yi)-N- (cyelohexyl methyl )etban- 1 - ;cd amine

l-(l -(2-(5-Chloro-2,4- dimethoxy pheny l)imidazo [ 1,2--119 a[pyridin-7-yl)pyrrolidin-3-yl)- 540 N-(( 1 -ethylpiperi din-4- yi)methyl)propan-2 -amine

Compound (1) and pharmaceutically acceptable salts thereof may be administered singly as they are: however, ordinarily, they are desirably provided as various types of pharmaceutical formulations. Such pharmaceutical formulations are used for animals or humans.

Pharmaceutical formulations of the present invention may comprise as an active ingredient compound (I) or a phannaceuticail y acceptable salt thereof alone, or a mixture with any other active ingredients for treatment. Furthermore, these pharmaceutical formulations are produced by any methods well known in the technical field of drug formulation by mixing the active ingredient together with one or more types of

pharmaceutically acceptable carriers (for example, diluents, solvents, and excipients).

Desirably, the most effective route of administration is used for the treatment, and examples include oral route, or parenteral route such as intravenous route.

The form of administration is, for example, tablets and injections.

Tablets are appropriate for oral administration and can be produced using excipients such as lactose, disintegrants such as starch, lubncants such as magnesium stearate, and binders such as hydroxypropylcellulose. Injections are appropriate for parenteral administration, and can be produced using, for example, solvents or diluents such as salt solutions, glucose solutions, or a mixture of salt water and glucose solution .

The dose of compound (1) or a pharmaceutically acceptable salt thereof, and the number of doses differs depending on tlie forrn of administration, tlie age and body weight of the patient, tlie nature of tlie symptom to be treated or severity, and such, but ordinarily for oral administration, it is 0.01 mg to 1000 nig, preferably in tlie range of 0.05 nig to 100 mg for an adult, and it is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 mg to 1000 mg, or preferably 0.01 mg to 100 mg is administered to an adult once to several times a day.

However, these doses and the number of doses vary depending on tlie various conditions mentioned above.

The intermediates and compounds of interest in the following Examples can be isolated and purified by subjecting them to separation and purification methods commonly used in synthetic organic chemistry unless otherwise specified, and examples include filtration, extraction, washing, drying, concentration, reerystaUization, and various types of chromatographies. Alternatively, intermediates can be subjected to the next reaction without purification.

Hereinbelow, the present invention will be specifically described with reference to the Examples, but tlie scope of the present invention is not to be construed as being limited thereto.

Furthermore, in the Examples shown below, unless otherwise specified, if a defined group becomes altered under the conditions of the production method or is unsuitable for carrying out the method, the compound of interest can be produced by using the methods for introducing and removing protecting groups commonly used in synthetic organic chemistry (for example, "Protective Groups in Organic Synthesis", T. W. Greene, John Wiley & Sons Inc., 1999). Furthermore, the order of the reaction processes such as substituent introduction can be changed as necessary. EXAMPLES

Abbreviations

Experimental

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE 300 spectrometer at 300 MHz, Bmker AVANCE 400 spectrometer at 400 MHz, or a Bruker AVANCE 500 spectrometer at 500 MHz. Tetramethylsilane was used as an internal standard for proton spectra. Thin-layer chromatography was performed using Merck TLC silica-gel 6OF254 plates. Visualization of TLC plates was performed using UV light (254 nm). The mass spectra were obtained on a Shimadzu LCMS-2010EV spectrometer using electrospray ionization or atmospheric-pressure chemical ionization. HPLC analyses were performed using Method I to Method 8. HPLC Met od 1

Column : Eclipse XDB CI 8 (4.6 * 150 mm, 5.0 μηι)

Column Temperature : Ambient

Detection: UV @ 220 nm

Sample Diluent: Acetonitrile: H2O (50: 50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetonitrile (with 0.05% TFA) Table 2-1. Gr:

HPLC Method 2

Column: Eclipse XDB C I 8 (4.6 150 mm, 5.0 urn)

Column Temperature: Ambient

Detection: UV @ 230 nm

Sample Diluent: Acetonitrile: H2O (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetonitrile (with 0.05% TFA) Table 2-2, Gradient Time Flow % Mobile % Mobile

(Minutes) (inL/min) Phase A Phase B

0:00 1 .0 95 5

5:00 1.0 95 5

15:00 1.0 10 90

20:00 1 .0 10 90

20: 10 1.0 95 5

25:00 1.0 95 5

HPLC Method 3

Column: Eclipse XDB C18 (4.6 150 mm,

Column Temperature: Ambient

Detection: UV @ 254 MI

Sample Diluent: Acetonitrile: H2O (50:50) Mobile Phase A: Water (with 0.05% TFA) Mobile Phase B: Acetonitrile (with 0.05% TFA)

HPLC Method 4 Column: se plus- cl8 (4.6 ¾ 100 mm, 3.

Column Temperature: Ambie t

Detection: UV @ 220 nm

Sample Diluent: Acetomtnle: I hO (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtnle (with 0.05% TFA)

Table 2-4. Gradient

HI

Column: Eclipse plus- c!8 (4.6 χ 100 mm,

Column Temperature: Ambient

Detection: UV @ 254 nm

Sample Diluent: Acetomtnle: ! I Ό (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtnle (with 0.05% TFA)

HPLC Method 6

Column: Zorbax SB-CN (4.6 1500 mm,

Column Temperature: Ambient

Detection: UV @ 254 am

Sample Diluent: Acetonitnle: H2O (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtnle (with 0.05% TFA) Table 2-6. Gradient

HPLC Method 7

Column: Xbridge-cl 8 (4.6 χ 100 mm, 3.5 μτη)

Column Temperature Ambient Detection: UV @ 220 urn Sample Diluent: Acetomtrile: H 2 0 (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtrile (with 0.05% TFA)

Table 2-7. Gradient

Column: Zodiac-cl8 (4.6 χ 100 mm, 3.0 μτη)

Column Temperate Ambient

Detection: UV @ 220 am

Sample Diluent: Acetomtrile: H2O (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtrile (with 0.05% TFA)

Table 2-8. Gradient

Time Flow % Mobile % Mobile

(Minutes) (mL/min) Ph se A Phase B

0:00 1.0 95 5 3:00 1 .0 95 5

6:00 1.0 10 90

12:00 1.0 10 90

12: 10 1 .0 95 5

15:00 1.0 95 5

HPLC Met od 9

Column : XBndge C18 (4.6 χ 100 mm, 3.5

Column Temperature: Ambient

Detection: UV @ 220 nm

Sample Diluent: Acetomtnle: I hO (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtnle (with 0.05% TFA)

HPLC Method 10

Column: Eclipse plus- cl8 (4.6 ¾ 100 mm, 3.5 μιη)

Column Temperature Ambient

Detection: UV @ 240 nm Sample Diluent: Acetonitrile: H 2 0 (50:50)

Mobile Phase A Water (with 0.05% TFA)

Mobile Phase B Acetonitrile (with 0.05% TFA)

Column: Atlantis T3 CI 8 (4.6 - 150mm, 3.0 μιη)

Column Temperature: Ambient

Detection: UV @ 220 am

Sample Diluent: Acetonitnle: H2O (50: 50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetonitnle (with 0.05% TFA) Table 2-1.1. Gradient

15:00 1 .0 10 90

20:00 1.0 10 90

20: 10 1.0 95 5

25:00 1 .0 95 5

Column: Eclipse plus- cl8 (4.6 χ 100 mm, μ,ηι)

Column Temperature: Ambient

Detection: UV @ 220 am

Sample Diluent: Acetonitnle: H2O (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetomtnle (with 0.05% TFA) Table 2-12, Gradient

HPLC Method 13

Column: Eclipse plus- cl8 (4.6 x 1 0 mm, 3.5 μηι)

Column Temperature Ambient

Detection: UV @ 254 am

Sample Diluent: Acetonitnle: i !.·(. ) (50:50) Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Acetonitrile (with 0.05%

Table 2-13, Gradient

Column: Eclipse plus- cl8 (4.6 x 100 mm, 3.5 μηι)

Column Temperature: Ambient

Detection: UV @ 254 nm

Sample Diluent: Acetonitnle: j !.·(.) (50:50)

Mobile Phase A: Water (with 0.05% TFA)

Mobile Phase B: Aeetomtrilc (with 0.05% TFA)

2-14. Gradient

Column: Eclipse plus- c l 8 (4.6 100 mm,

Column Temperature: Ambient

Detection: UV @ 215 am

Sample Diluen Acetonitriie: !¾() (50:50) Mobile Phase A: Water (with 0.05% TFA) Mobile Phase B: Acetonitriie (with 0.05% TFA)

Table 2-15. Gradient

Column: XBndge C 18 (4.6 100 mm, 3.5

Column Temperature: A mbient

Detection: UV (a) 254 nm

Sample Diluent: Acetonitriie: !¾() (50:50) Mobile Phase A: Water (with 0.05% TFA) Mobile Phase B: Acetonitriie (with 0.05% TFA)

Table 2-16. Gradient Time Flow % Mobile % Mobile (Minutes) (inL/min) Phase A Phase B

0:00 1.0 95 5

3:00 1.0 95 5

6:00 1.0 10 90

12:00 1.0 10 90

12:10 1.0 95 5

15:00 1.0 95 5

To a solution of I-(2,4-dimetlioxyphenyl)ethanone 1 (40 g, 222 mmol) m acetonitrile (500 ml.) and water (500 ml.) was added KC1 (18.2 g, 242 mmol), followed with Οχοηε™ (150 g, 242 mrnol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc (1 L) and the organic layer was separated, washed with bnne (500 ml,), dried over anhydrous Na?S04, filtered and concentrated under reduced pressure. The solid obtained was triturated with hexanes, filtered and dried under vacuum to provide l-(5-chloro-2,4-dimethoxyphenyl)ethanone 2 (30.5 g, 64%) as a white solid. f t N M R ( ) MHz, CDCb): δ 7.87 (s, 1H), 6.47 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.56 (s, 3H) . ESI+APCI-MS m/z 215 [M + H]

Preparation of 2-bromo-1 -(5-chioro-2,4-dimethoxypheRyl)ethaRone 3j,

To a solution of I-(5-chIoro-2,4-dimethoxyphenyl)ethanone 2 (30,0 g, 140 mmol) in CH2CI2 / CH3OH (700 mL/150 mL) was added tetrabutylamtnonium tribromide (TBATB, 67.6 g, 140 mmol) in a portion-wise manner over a period of 1 h, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure until the volume reduced to 20%, whereupon the product precipitated as a pale yellow solid . The solid was triturated with cold methanol, filtered and dried under vacuum to provide (37 g, 90%) of desired 2-bromo- 1 -(5-chloro-2,4-dimethoxyphenyl) ethanone 3 as an off-white solid.

rH NMR (400 MHz, CDCb): δ 7.93 (s, l i f ). 6.48 (s, 1H), 4.52 (s, 21 1 ·. 3.98 (s, 6H). ESI+APCI-MS m/z 293 | M i .

Prep r tion ^

To a solution of 2-amino-4-chloropyndine (2.50 g, 19.5 mmol) in a nirxture of isopropanol and N. jV -diisopropylethyl amine (50 mL/ 25 mL), placed in a sealed tube, was added i¾r -butyl (piperidm-4-ylraethyl)carbamate (6.30 g, 29.4 mmol). The tube was sealed and the reaction mixture was heated at 120 °C for 24 h . The reaction mixture was cooled to room temperature and concentrated under reduced pressure, whereupon the residue was partitioned between EtOAc and saturated aqueous NaHCCb solution (300 mL: 100 mL). The layers were separated and the EtOAc layer was washed with brine ( 100 mL), dried over anhydrous NazSC , filtered and concentrated under reduced pressure to provide the crade product. The product was triturated with hexanes, filtered under vacuum and dned to provide tert-bvcfyl ((l-(2-aniinopyndin-4-yl)piperidin-4-y])niet1iyl)carbamate 4 (5.5 g, 92%) as an off-white solid, which was used directly for next step without further purification. ESU-APCI-MS m/z 307 [M 1 i | . A mixture of tert-bxxtyl ((l-(2-aminopyridin-4-yl)piperidin-4-yl)methyl)carbaraate 4 (5 ,0 g, 16.3 ramol) and 2-bromo-l-(5-chloro-2,4-dimethoxyphenyl)ethanone 3 (5.3 g, 18.1 mnio!) in acetone (200 mL) was heated at 75 °C for 16 h . Tire reaction mixture was cooled to room temperature, whereupon a white precipitate formed. The precipitate was collected by filtration under vacuiim. washed with hexanes (200 mL), and dried to obtain hydrobromic salt of teri-buty 1 (( 1 -(2-( 5 -chloro-2,4-dimethoxypheny l)imidazo [ 1 ,2- ]pyridin- 7~yl)piperidm~4-yl)metliyl)carbamate 5 (7.1 g, 79%) as an off-white solid.

¾ NMR (400 MHz, DMSQ- e): δ 13.13 (br s, ΓΗ), 8.49 (d, J= 7.8 Hz, 8,23 (s, 1H), 7.91 (s, lH), 7.29 (d, J= 6.0 Hz, 1H), 6.98-6.92 (m, 2H), 6,66 (s, 1H), 4.05-3,98 (m, 8H), 3.03 (t, J= 1.2.6 Hz, 2H), 2.85 (t, J= 5.4 Hz, 2H), 1.75 (d, J = 1 1.7 Hz, 3H), i ,38 (s, 9H), 1 .23-1 , 14 (m, 2H); HPLC (Method 1) 99.2% (AUC), to = 13.78 min .;

ES1+APCI-MS m/z 501 M + H] + .

P ejrjarafioH or

yi) ii|)en^ ^

To a solution of tert-huty] (( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2- a]pyridin-7-yl)piperidin-4-yl)methyl)carbamate 5 (3,00 g, 5,98 mmol) in CH2CS2 (30 mL) was added a solution of HCI (4,0 M in 1 ,4-dioxane, 30 nil.) and the reaction mixture was stirred at room temperature for 16 h . The solid obtained in the reaction, was collected by- filtration under vacuum, and washed with CH2CI2 (100 mL). The solid was then suspended in water (70 mL) and basiiied with saturated sodium bicarbonate solution (70 mL) to pH 10, whereupon a pale yellow solid precipitated. The solid was collected by filtration under vacuum, washed with water and dried to provide ( 1 -(2-(5-chloro-2,4- dime†hoxyphenyl)imidazo[L2-a]pyridin-7-yl)piperidin-4~yl)n tetha^ 6 (2.1 g, 87%) as an off-white solid,

\ l NMR (400 MHz, DMSO-cfo): δ 8.26 (d, ./ 7.6 Hz, 1H), 8.17 is H i). 7.99 is.

H I ). 6.86 (s, l ! l !. 6.77 id. J= 6,0 Hz, 1H), 6.63 (s, 11 1 ·. 4,00 (s, 31 1 ). 3.93 (s, 3H), 3.78 id. J = 12.4 Hz, 2H), 2.87 (t, ,/= 2.0 Hz, 2H), 2.70 (t, J= 11.6 Hz, 2H), 1 .74- 1.58 (m, 3H), 1.24- 1 .16 (m, 2H); ESI+APCI-MS m/z 401 [M 4- ! ! | . vijpiperidin-4-yl)methyi)-2,2-dimethv j propan-l-amine 8aj-

To a suspension of (l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo l,2-a]pyndin-7- yl)piperidin-4-yl)methanamine 6 (150 mg, 0.37 mmol), pivalaldehyde (48 nig, 0.56 mmol) in CH3OH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium eyanoborohyd ide (118 mg, 1.87 mmol) was added thereto and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2. χ 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous aaSi filtered and concentrated under reduced pressure to obtain the crude product. The product was purified by combi-flash chromatography [silica gel; 5% NH4OH in MeOH: CH2CI2. (1 :9) |. Fractions containing the product were combined and concentrated under vacuum to obtain N-((l-(2-(5 -chloro-2,4- dimemoxyphenyl)imidazo [ L2-a]py ^

amine 8a (70 mg, 39%) as an off-white solid.

! H NMR (400 MHz, DMSO-de): δ 8.27 (d, J = 7.6 Hz, H), 8.17 (s, 1H), 7.99 (s, IH), 6.86 (s, 1 H), 6.77 (dd, J= 2.4, 7.6 Hz, IH), 6.63 (d, J= 2 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J= 12.4 Hz, 2H), 2.74-2.67 (m, 2H), 2.52-2.48 (m, 2H), 2.34-2.30 (m, 2H), 1.81 (d. ./ 11.2 Hz, 2H), 1.64 (br s, IH), 1.27-1.15 (m, 2H), 0.89 (s, 9H); HPLC (Method 1) 98.9% (AUC), === 12.15 mm.; ESI+APCLMS m/z 471 [M + Hf.

Prej3 i arat¾o i o i of i l-{

J)Bj gddii¾-4-yl^

1 -( 1 -(2-(5-CWoro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- y])-N-(cyclopropylraethyl)methanamine 8b was prepared in the same manner as N~((l -(2- (5~cbk>ro-2,4Kiimetboxyphenyl)imidazo

dimethyipropan-1 -amine 8a and was obtained as an off-white solid (18% yield).

f i NMR (400 MHz, DMSO fe): δ 8.27 (d, ,/ 7.6 Hz, IH), 8.16 (s, l i f). 7.99 is. IH), 6.86 (s, IH), 6.78 (dd, J= 2.4, 7.6 Hz, IH), 6.64 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.79 (d,■/ 12.4 Hz, 2H), 2.74-2.68 (m, 2H), 2.52-2.48 (m, 4H), 1.80 (d, J = 12.0 Hz, 2H), 1.64 (bf s, IH), 1.28-1.17 (m, 2H), 0.95-0.87 (m, l i l t. 0.45-0.40 (m, 2H), 0.14-0.10 (m, 2H); HPLC (Method 5) 95.0% (AUC), fe = 6.36 min.; ESI+APCI-MS m/z 455 [M + H] + . yJ i g^

1 -( 1 -(2-(5 -Giloro-2,4-dimethoxy pheny l)mudazo [ 1 ,2-a|pyridin-7-yl)piperidin-4- yl)-jV-(cyclopentylmeihyl)methaiiamine 8c was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimethoxyphenyl)imida^^

dimethylpropan- 1 -amine 8a and was obtained as an off-white solid (45% yield).

lH NMR (300 MHz, DMSO-a¾): δ 8.28 (d, J = 7.5 Hz, IH), 8.16 (s, IH), 8.00 (s,

IH), 6.86 (s, IH), 6.79 (d, J ------ 7.5 Hz, I H), 6.65 (s, IH), 4.00 is. 3H), 3.93 (s, 3H), 3.80 (d, J

= 12.0 Hz, 2H), 2.77-2.64 (m, 6H), 2.12- 1.98 (m, IH), 1.84-1.70 (m, 5H), 1.57-1 .49 (m,

4H), 1.31 -1.17 (m, 4H); HPLC (Method I ) 96.0% (AUC), to = 12.31 min .; EST+APCI- MS /z 483 [M · H i .

Flg iQ of fe^

gjpyridin-7-yl)piperidin-4-Yl)methvi)amino)niethv j )pYrrolidine-i-carbo.xYlate 8d_

(Example 5] _

tert-Butyl 3-((((l -(2-(5-chloro-2,4-diraethox ^henyl)imidazo[.l ,2-a]pyridin-7- yl)piperidin-4-yl)me1hyl)amino)me1hyl)pyrrolidme-l -carboxylaie Sd was prepared in the same manner as A ? -((l~(2-(5-chloro-2,4~dmiethoxyphenyl)miidazo[ l,2-a]pyridin-7- y )piperidin-4~yl)methyi)-2,2~diinethylpropaii-l-ainiiie 8a and was obtained as an off-white solid (15% yield).

! H NMR (400 MHz, DMSO- e); δ 8.27 (d, J= 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6.86 (s, IH), 6.78 (dd, ,/ 2.4, 7.6 Hz, IH), 6.62 (d, ./ 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d. ./ 12.4 Hz, 2H), 3,39-3.35 ( , IH), 3.28-3.26 (m, 2H), 3,20-3 , 1 1 (m, IH), 2.93-2.89 (m, IH), 2.73-2.67 (m, 2H), 2.52-2.48 (m, IH), 2.41 (d, J= 6.0 Hz, 2H), 2.26-2.20 (m, I H), 1.94- 1 .86 (m, IH), 1.79 (d, ./= 1 1 .6 Hz, 2H), 1.64- 1 .47 (m, 2H), 1.39 (s, 9H), 1.24- 1.18 (m, 2H); ! !PLC (Method 4) 98.3% (AUC),†. = 12.39 min.; ESI+APCI MS «z z 584 | M · H | .

Preparation of tert-bntyl 3-((((i-(2-(S-chloro-2,4-dimethosyphenvi)imidazo|l,2- a] yridin-7-yI)piperidin-4-Yl)meth^^ tert-Butyl 3-((((l-(2-(5-chloro-2,4-dimetiioxy

yl)piperidin-4-yl}meihyi)(methyl)ainino)methyl)pyrrolidme - 1 -carboxylate 9 was prepared in the same

yl)piperidin-4-yl)methyl)-2,2-diraethylpropan-l-araine 8a and was obtamed as an off-white solid (10% yield).

'H NMR (400 MHz, CD3OD): δ 8.12 (d, 7.6 Hz, 1H), 8.05 (s, lH), 7.96 (s, i l l}.

6.79 (s, H i ). 6.77 (d, ./ 2.0 Hz, 1H), 6.66 (s, 1H), 4.02 (s, 3H), 3.95 (s, 3H), 3.84 (d, ./ 14.8 Hz, 2H), 3.49-3.43 (ra, 1H), 3.44-3.36 (m, 2H), 3.06-3.02 im . 1H), 2.81 ii. ./ 12.4 Hz, 2H), 2.45-2.39 (m, 1H), 2.33-2.31 (m, 2H), 2.26-2.20 (m, 4H), 2.04-1.88 (3H), 1.78- 1 .69 (m, 1H), 1.66-1.58 (m, l i f). 1 .45 i s. 10H), 1 .34- 1.28 (m, 21 1 ·; HPLC (Method 1) 91.3% (AUC),†R = 12.32 mm.; ESI+APCI-MS m/z 598 [M + H] " .

Preparation of l-(l-(2-(S-chjoro-2 ¾ 4-dimethoxYphenYl¾imidazo l,2-a|pyridin-7- yJ piperidm-4-yl)-A-(pyrrolidin-3-ylmethyl)methanamine 8e (Example 7)L_

To a solution of fe/f -butyl 3-((((l -(2-(5-chloro-2,4<1imethoxypheny])imidazof 1 ,2- o{pyridin-7-yl)piperidin-4-yl)methyl)amino)methyl)pyTO Sd (100 mg) in 2,2,2-trifluoro ethanol (3.0 mL) was added trimethylsiiyi chloride (0.1 mL) at 0 °C and stirred at the same temperature for 30 mm. The reaction mixture was evaporated to dryness under reduced pressure and washed with hexanes to provide hydrochloric acid salt of i~(l~(2-(5~ehloro~2,4~din cthoxypheny

(pyrroiidin-3-yimei yl)metharja3nme 8e (25 mg, 30%) as an off-white solid.

¾ NMR (400 MHz, DMSO- e); δ 13.83 (hrs, ΓΗ), 9.41-9.17 (m, 4H), 8.52 (d, J =

7.6 Hz, l ! I s. 8.25 is. 1H), 8.08 is. Π Ι). 7.32 (dd, J = 2.0, 7.6 Hz, 1H), 6.97 (s, H I ). 6.78 (d, J= 2.0 Hz, 1 H), 4.05 (br s, 5H), 3.98 (s, 3H), 3.40-3.36 (m, 1 H), 3.28-3.20 (m, lH), 3.14-2.98 (m, 6H), 2.88-2.82 (m, 2H), 2.78-2.70 (m, Hi), 2.17-2.09 (m, 2H), 1 .98-1 .94 (m, 2H), 1.75-1.69 (m, 1H), 1.33-1.25 (m, 2H); HPLC (Method 1} 93.9% (AUC), ¾ = 11.07 min.; ESI+APCI-MS m/z 484 [M + H] + .

Preparation of i-(l-(2-(5-c¾l ro-2,4-dimet¾oxyp¾e8¾yI)imidazo l ¾ 2-a|pyndin-7 :

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyphenyl)imidazo j 1 ,2-a]pyridin-7-yl)piperidin-4- yl)-N-(cyclohexylmethyl)methanainine 8f was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimetiioxyphenyl)imidazo[l,2-«]pyridin-7-yl)pipe ridin-4-jd)m

diraethylpropan-l -amine 8a and was obtained as an off-white solid (38% yield).

! H NMR (300 MHz, OMSO-de) δ 8.27 (d, J= 7.5 Hz, 1H), 8.16 (s, I I I). 7.99 (s, 1H), 6.86 (s, 1H), 6.77 (d, J= 7.2 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J = 12.3 Hz, 2H), 2.71 (t, J = 10.8 Hz, 2H), 2.40 (d, J= 6,6 Hz, 2H), 1.82-1.64 (m, 9H), 1.41 -1 .09 (rsi, 7H), 0.92-0.81 (m, 2H); HPLC (Method 1) 94.8% (AUC), fe = 12.55 min.; ESI+APCI-MS m/z 497 [M + Hf.

Preparation of tert-batvl 4-ii((I-i2-iS-chIoro-2,4-dimeihoxvphenvi)imidazofi,2- ^ΙΡΥΓΜΙ.»^

(E ample 9);

tert-But l 4-((((l-(2-(5-ch1oro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyrid in-7- yl)piperidin -4-yl)methyl)aroino)methyl)piperidine-l-carboxylate Sg was prepared in the same manner as A-(( l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7- yl)piperidin-4-yl)methyl)-2,2-dimethylpropan-l-amine 8a and was obtained as an off-white solid (36% yield).

¾ NMR (400 MHz, DMSO- e): 5 8.28 (d, J= 7.6 Hz, i l l) . 8.16 (s, 1H), 7.99 (s, 1H), 6.86 is, i l l) . 6.79 (dd, J= 2.0, 7.6 Hz, 1H), 6.65 (d, J= 2.0 Hz, 1H), 4.00 is, 3H), 3.93 (br s, 5H), 3.80 (d, J= 12.4 Hz, 2H), 2.75-2.66 (m, 4H), 2.59 (br s, 3H), 1.81 (d, J= 13.2 Hz, 2H), 1.70 (d, ,/= 11 .2 Hz, 4H), 1.39 (s, 9H), 1 .29-1.22 (m, 3H), 1.04-0.97 (m, 2H); HPLC (Method 6) 95.0% (AUC), fe = 13.86 mm.: ESI+APCI-MS m/z 598 [M l i | .

Prep u aration u of ^^Q^ ^^^^h^^^^^^^^^^^^^^^ ^^^l^^^^ vl)piperidin-4-v!)-A ? -ipiperidiii-4-vlmethvi)inethanamine 8h (Example 10); l~(i-(2~(5~Chloro-2,4-diniethoxy

yl)-N-(piperidin-4-ylraethyl)methanaraine 8h was prepared in the same manner as N-((l-(2- (5-ch]oro-2,4-dimeihoxyphenyl)imidazo l,2-a]pyridin-7-yi)pipe

dimethylpropan- -amine 8e and was obtained as an off-white solid (18% yield).

f t NMR (300 MHz, DMSO-a¾): δ 13.91 (br s H i). 9.08-8.68 (m. 4H), 8.53 (ci. J

= 7.5 Hz, i l l). 8.25 (s, 1H), 8.10 (s, IH), 7.32 (d, J = 6.3 Hz, IH), 6.97 (s, 1H), 6.79 (s, 1H), 4.05 (br s, 5H), 3.98 (s, 3H), 3.30-3.24 (m, 2H), 3.10-3.02 (m, 2H), 2.85 (br s, 6H),

2.16-2.06 (m, 2H), 1.98-1.94 (m, 4H), 1.49-1.23 (m, 4H); HPLC (Method 2} 96.8%

(AUC), tR = J 1.05 min .; ESI+APCI-MS m/z 498 [M +Hf.

Preparation of jV-benzyl-l-(l-(2-(5-chloro-2,4-dimethoxYphenyl)imidazo[l,2- a]pyridin- 7 yI)piperid -4-yl)meth m mine 8i (Example JJjj

A-BenzyI- l-(l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ I,2-ii]pyridin-7- yl)piperidin-4-yl)meihanamine 8i was prepared in the same manner as A 7 -((l -(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo[ L2^]pyridm-7-j4)piperidin-4-yi)methyl)-2,2- dimetliylpropan- 1 -amine 8a and was obtained as an off-white solid (26% yield).

! H NMR (400 MHz, DMSO-de): δ 8,26 (d, J = 7.6 Hz, IH), 8.17 (s, i l l). 7.99 is, IH), 7.34-7.28 (m, 4H), 7.22-7. 19 (m, IH), 6.86 (s, H), 6.77 (d, J = 6.4 Hz, i l l) . 6.62 (s, IH), 4.00 is, 3H), 3.93 (s, 3H), 3.77 (d, J = 12.4 Hz, 2H), 3.69 (s, 2H), 2.73-2.67 (m, 2H), 2.39 id. 6.0 Hz, 2H), 1.81 (d . ,/ 12.0 Hz, 2H), 1.61 (br s, IH), 1 .26-1. 17 (m, 2H); HPLC (Method 6) 99.3% (AUC), fo = 13.61 mm.; ESI+APCI-MS m/z 491 [M · Π | .

j^ ration ^

1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)-A-(2-methylbenzyl)meihanamine 8j was prepared in the same manner as N-((l~(2-(5- chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)piperidi

dimethylpropan-1 -amine 8a and was obtained as an off-white solid ( 12% yield).

f i NMR (400 MHz, DMSO fe): S 8.27 (d, J ------ 7.6 Hz, IH), 8.16 (s, H i ). 7.99 is.

IH), 7.34-7.32 (m, IH), 7.14-7.12 (m, 31 1 ). 6.86 (s, IH), 6.78 (dd, J = 2.4, 7.6 Hz, IH), 6.63 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.79 id. ./ 12.4 Hz, 2H), 3.71 (s, 2H), 2.75-2.69 (m, 2H), 2.45 (d, J= 6.0 Hz, 2H), 2.30 (s, 3H), 1 .83 (d, J= 12.4 Hz, 2H), 1.67 (br s, 1H), 1.28-1.20 (ra, 2H); HPLC (Method 4) 95.8% (AUC), ¾ = 12.47 ram. ; ESI+APCI-MS m z 505 [M · Π | .

yg j * .^

1 -( 1 ~(2-( 5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)~A-(4-methylbenzyl)methaiiamine 8k was prepared in the same manner as N-((l-(2-(5- ehloro-2,4-dimethoxyphenyl)imida^^

dmiethylpropan-1 -amine 8a and was obtained as an off-white solid (13% yield).

lH MR (400 MHz, C D OS) !. .·> 8.05 (d, J ------- 7.6 Hz, I H), 7.95 (s, 1H), 7.88 (s, 1H),

7.22 id. ./ 8.0 Hz, 2H), 7.13 (d, ./ 8.0 Hz, 2H), 6.70 (s, IH), 6.68 (d, J = 2.4 Hz, 1H), 6.58 (d,■/ 2.4 Hz, IH), 3.93 (s, 3H), 3.88 (s, 2H), 3.86 (s, 3H), 3.78 (d, ./ 13.2 Hz, 2H), 2.77-2.71 (m, 2H), 2.67 (d, ./ 6.4 Hz, 2H), 2.25 (s, 3H), 1.81 -1.78 (m, 3H), 1.33- 1.24 (m, 2H); HPLC (Method 6) 93.4% (AUC), & = 11 .72 mm.; ESI+APCI-MS m/z 505 [M +H] + . Preparation of l-(l-(2-(S-chjoro-2 ¾ 4-dimethoxYphenYl¾imidazo l,2-al )yridin-7- y!)piperidm-4-yI)-A T -(2-fluorobei¾zyl)methanamine 81 (E¾ample_14j _

l-(l~(2-(5-Chloro~2,4~dimei oxyphenyl)imid

y3)- J ¥-(2-tluorobenzyl)metlianamine 81 was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimeihQxyphenyl)imidazo[ L2-a]pyri

dimethylpr opan- 1 -amine 8a and was obtained as an off-white soiid (10% yield).

f t NMR (400 MHz, DMSO- e): 5 8.27 (d, ./ 7,2 Hz, IH), 8.16 (s, IH), 7,99 (s, IH), 7.50-7.46 (m, IH), 7.29-7.25 (m, IH), 7.18-7.11 (m, 2H), 6.86 (s, IH), 6.78 (dd, J ------

2.4, 8.0 Hz, IH), 6.63 is IH), 4.00 is. 3H), 3.93 is. 3H), 3.78 (d, ./ 12.8 Hz, 2H), 3.74 (s, 2H), 2.74-2.66 (m, 2H), 2.42 (d, J= 6.4 Hz, 2H), 1 .82 id, J= 12.4 Hz, 2H), 1.62 (br s, I H), 1.26- 1 .20 (m, 2H); HPLC (Method 4) 99.7% (AUC), fe = 12.16 mm. ; ESI+APCI-MS m/z 509 [M · Π | · .

Prep ration ^

l-( l-(2-(5-Chloro-2,4-dimei oxypheny1)imidazo l,2-G]pyridin- yl)-N-(3-fluorobenzyl)methanaroine 8m was prepared in the same manner as N-((l~(2-(5- chloro-2,4-dime&oxyphenyl)imida∞[l,2

dimechyipropan-1 -amine 8a and was obtained as an off-white solid (13% yield).

¾ MR (400 MHz, DMSO^fe): S 8.26 (d, ·/ 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, H I ). 7.36 -7.31 (m, 1H), 7.18-7.15 (m, 2H), 7.05-7.00 (m, 1H), 6.86 (s, 1H), 6.78 (dd, 2.0. 7.6 Hz, 1H), 6.62 (d, ./= 2.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J = 12.8 Hz, 2H), 3.71 (s, 2H), 2.73-2.67 (m, 2H), 2.38 (d. ./ 6.8 Hz, 2H), 1.82 (d, J = 11.2 Hz, 2H), 1.61 (br s, IH), 1.27-1.20 (m, 2H); HPLC (Method 5) 99.5% (AUC), fe = 6.63 mm.; ESI+APCI-MS m/z 509 [M I I I .

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)-N-(4-fluorobenzyl)methanaraine 8n was prepared in the same manner as N-((l-(2-(5- ehloro-2,4-dimethoxyphenyl)imidazo[l,^

dmiethylpropan-l -anime 8a and was obtamed as an off-white solid (8% yield).

\ \ MR (400 MHz, DMSO-ifc): S 8.26 (d, ./ 7.6 Hz, i l l). 8.16 (s, H I}. 7.99 (s, IH), 7.38-7.34 (m, 2H), 7.14-7.09 (m, 2H), 6.86 (s, i l l}. 6.78 (dd, 2.4, 8.0 Hz, IH), 6.62 (d,■/ 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.77 (d, J = 12.4 Hz, 2H), 3.67 (s, 2H), 2.73-2.66 (m, 2H), 2.38 (d, ./ 6.8 Hz, 21 1 ). 1 .81 id. ./ 12.0 Hz, 2H), 1.61 (br s, IH), 1.26-1.19 (m, 2H); HPLC (Method 5) 98.9% (AUC), ft. = 6.49 mm.; ESI+APCI-MS m/z 509 [M H j .

Preparation of 1 -(l-(2-(5-chloro-2,4-dimethox^^henyI)imidazo l,2-a| pyridiR-7- Yl)piperidii¾-4-Yl)-A ? -(4-methoxYbeRzvl)methanamine 8o (Example 17^

l-(l -(2-(5-ChlorQ-2,4-dimethoxyphenyl)i

yl)-A-(4-methoxybenzyi)methaiianiine 8o was prepared in the same manner as N-((l -(2-(5- ehloro-2,4~dimethoxyphenyl)imidazo[ l,2~a]pyridiii-7~yl)piperidin~4-yl)methyl)-2,2- dimethylpropan- 1 -amine 8a and was obtained as an off-white solid (8% yield).

! H MR {400 MHz, DMSO-ifc): δ 8.26 (d . J 7.6 Hz, i l l). 8.16 is H I). 7.99 (s. 1H), 7.24 (d, J= 8.8 Hz, 2H), 6.87-6.85 (m, 3H), 6.77 (dd, J = 2.4, 7.6 Hz, 1H), 6.62 (d, J= 2.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 31 1 ). 3.77 (d, ./ 12.8 Hz, 2H), 3.72 is. 3H), 3.63 (s, 2H), 2.73-2.67 (ni, 2H), 2.38 (d, ./= 6.8 Hz, 2H), 1 .80 (d, J= 12.0 Hz, 2H), 1.60 (br s, 1H), 1.25-1.17 (m, 2H); HPLC (Method 4) 97.2% (AUC), tv, = 12.05 mm.; ESI+APCI- MS /w/z 521 [M +H] + . vl)piperidin-4-yS)-A ; -(2-c IorobenzyS)metha«amine 8p (ExamplgJLSJj

l~(l -{2-(5~Chk>ro-2,4-dimethoxyphenylh^

yl)-N-(2-chlorobenzyi)methanamine 8p was prepared in the same manner as N~((l -(2-(5~ chloro-2,4-dimethoxyphenyl)imidazo[l,2^

dimethylpropan- 1 -amine 8a and was obtained as an off-white solid (10% yield).

¾ NMR (400 MHz, DMSOa'd): S 8.27 (d, J -- 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.55(dd, J = 1.2, 7.6 Hz, 1H), 7.40 (dd, J - 1.2, 8.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.28-7.23 (m, 1H), 6.86 (s, 1H), 6.78 (dd, J 2.4, 7.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 31 1). 3.80-3.78 (m, 4H), 2.75-2.69 (m, 2H), 2.44 (d, J= 6.4 Hz, 2H), 1.83 (d, J = 12.0 Hz, 2H), 1.64 (br s, 1H), 1 .28-1.20 (m, 2H); HPLC (Method 4) 99.1% (AUC), < ----- 12.44 mm.; ESI+APCI-MS m/z 526 [M I I I .

Preparation of 4-(((ii-(2-iS-chloro-2,4-dimethoxYphenvl)imidazo[l ,2-a[pyridm-7- iiperidin-4-yl)methyl)amino)methyl)-A V-dimethyianiiine

4~(({{i-(2~(5-Chioro-2,4-dime†hoxyphenyl)imidazo[i,2-a]pyr idin-7-yl^

yl)methyl)araino)methyl)-N,N-dimethyianiline 8q was prepared in the same manner as Λ- ((l-(2-(5-chioro-2,4-dimethoxypheny])imidazo[l,2-a]pyridin-7 -yl)piperidm-4-yl)n^ 2,2-dimethylpropan-l-amine 8a and was obtained as an off-white solid (6% yield).

i f NMR (400 MHz, DM O- ). δ 8.26 id. J -- 7.2 Hz, 11 !}. 8.16 (s, 1H), 7.99 (s, 1H), 7.14 (d, J ------- 8.8 Hz, 21 h. 6.86 (s, 1H), 6.77 (dd, J--- 2.0, 7.6 Hz, lH), 6.66 (d, J = 8.8

Hz, 2H), 6.62 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.77 (d, ./ 12.0 Hz, 2H), 3.57 (s, 2H), 2.85 (s, 6H), 2.73-2.67 (m, 2H), 2.37 (d, J = 6.8 Hz, 2H), 1.80 (d, ./ 11.6 Hz, 2H), 1.60 (br s, 1H), 1.24-1.16 (m, 2H); HPLC (Method 5) 94.75% (AUC), t& = 6.43 mm.;

EST+APCI-MS m/z 534 [M - H j \ y] p| g^

3 -(((( 1 ~(2-(5 -ChloiO-2,4-dimeihoxyphenyl)imidazo [ 1 ,2-a]py ridin-7-yl}pipendin-4~ yl)methyl)amino)methyl)benzonitriie 8r was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7-yl)piperi dm

dimethylpropan- 1 -amine 8a and was obtained as an off-white solid (9% yield).

lH NMR (400 MHz, DMSO-a¾): δ 8.26 (d, J = 7.6 Hz, 1H), 8.16 (s, III), 7.99 (s,

1H), 7.79 (s, 1 ! !}. 7.69 (dd, J ------- 1.6, 8.0 Hz, 2H), 7.52 (t, ./ 7.6 Hz, 1H), 6.86 is. 1H), 6.78

(dd, J ------ 2.4, 7.6 Hz, 1H), 6.62 (d, J -- 2.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J=

12.8 Hz, 2H), 3.75 (s, 2H), 2.74-2.66 (m, 2H), 2.38 (d, ./= 6.4 Hz, 2H), 1.82 (d, J= 1 1.2 Hz, 2H), 1.62 (br s, 1H), 1.26-1.18 (m, 2H); HPLC (Method 5) 97.1% (AUC), to = 6.59 min. : ESI+APCi-MS m/z 516 [M +H]

Preparation of 4-((( l-(2-(S-c. SorQ-2,4-dimet oxyphem f l imidazojl,2-a|pyridis¾-7 :: y!)piperidin-4-yl)methyl)amino)methyl)bei¾zonitrile 8s (Examplejlj

4-i(((l -(2-i5-C1iloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-y])p y3)methyi)amino)methyl)benzonitriie 8s was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimeihoxyphenyl)imidazo[ l,2-o]pyridin-7-yl}pipendin-4~yl)m

dimethylpropan- 1 -amine 8a and was obtained as an off-white solid (8% yield).

¾ NMR (300 MHz, DMSO- e): δ 8.27 (d, J= 7.5 Hz, i l l) . 8.16 (s, H i t. 7.99 (s, IH), 7.78 (d, J= 7.8 Hz, 2H), 7.55 (d, J= 7.8 Hz, 2H), 6.86 (s, i l l). 6.78 (d, J = 7.2 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.80-3.72 (m, 4H), 2.75-2.67 (m, 2H), 2.39 (d, J = 6.0 Hz, 2H), 1.82 (d, J= 12.0 Hz, 2H), 1.62 (br s, 1H), i .27-1.17 (m, 2H); HPLC (Method 4) 98.0% (AUC), fe - 12.14 min.: ESI +APCI-MS m/z 516 [M +H] + .

Prepjiratio¾ a of l-(l-(2~(5-Chloro-2,4-dimethoxyp3ien

yl)-N-(2-nitrobenzyl)raethanamine St was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimethoxypheny])imidazo[ l,2- ]pyridm-7-y!)pipendm-4-yl)methy]}-2,2- dimethylpropan- -amine 8a and was obtained as an off-white solid (10% yield),

¾ NM (400 MHz, DMSO-ffc): δ 8.26 (d, J -- 7.2 Hz, 1H), 8.16 (s, 1H), 7.99 (s,

1H), 7.90 (d, J ------- 8.0 ! ! ·. IH), 7.73-7.66 (m, 2H), 7.52-7.48 (i . H I ). 6.86 (s, 1H), 6.78 kid.

J ----- 2.0, 7.6 Hz, IH), 6.62 (s, IH), 4.00 (s, 3H), 3.94 (s, 2H), 3.93 (s, 3H), 3.77 (d, J ------- 12.8

Hz, 2H), 2.73-2.67 (m, 2H), 2.39 (d, J ------ 6.0 Hz, 2H), 1.79 (d, J= 12.0 Hz, 2H), 1.58 (br s,

IH), 1.24-1.15 (m, 2H); HPLC (Method 5) 96.9% (AUC),†R ------ 6.65 min.; ESI+APC1-MS

Preparation of l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazon.,2-a]pvridig 7^

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxy pheny l)imidazo [ 1 ,2-a ipyridm~7~yl)piperidin-4- yl)-jV-(3~(trifliiorometliyl)benzyl)methaiiamme 8u was prepared in tlie same manner as N- ((l-(2-(5-chloro-2,4-dimethoxypheny0

2,2-dimethylpropan- 1-amine 8a and was obtained as an off-white solid (19% yield).

lH NMR (300 MHz, DMSO~d6): δ 8.27 (d, J = 7.5 Hz, IH), 8.17 (s, I H), 7.99 (s, IH), 7.71 (s, IH), 7.66-7.52 (m, 3H), 6.86 (s, IH), 6.78 (d, J = 7.5 Hz, ΓΗ), 6.63 (s, IH), 4.00 (s, 3H), 6.93 (s, 3H), 3.79-3.76 (m, 4H), 2.75-2.67 (m, 2H), 2.42-2.39 (m, 2H), 1.85-1.80 (m, 2H), 1.69-1.58 (ni, IH), 1.28- 1.23 (m, IH), 1.17- 1 .15 (m, I H); HPLC (Method 3) 99.2% (AUC), tR = 12.81 mm.; ESI+APCI-MS m/z 559 [M + H] +

£r.e .¾tioff ol l-il-il-ig-dj o l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)im^

yl)-N-(pyridin-3-ylmethyl)methanaraine 8v was prepared in the same manner as N-((l-(2- (5-chloro-2,4-dimetiioxyphenyl)imM

dimethylpropan-i -amine 8a and was obtained as an off-white solid (15% yield).

¾ NMR (400 MHz, DMSOa'd): δ 8.52 (d, J = 1.6 Hz, IH), 8.43 (dd, J ------ 1.2, 4.4 Hz, IH), 8.26 id, J= 7.6 Hz, lH), 8.16 (s, 1H), 7.99 (s, ΓΗ), 7.74 (d, J= 8.0 Hz, 1H),

7.35-7.32 (m, 1H), 6.86 (s, 1H), 6.77 (dd, ./ 2.0, 7.6 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.77 (d, J= 12.8 Hz, .:! !}. 3.72 (s, 2H), 2.74-2.68 (ra, 2H), 2.41 (d, J= 6.4 Hz, 2H), 1.81 (d. ./ 11.2 Hz, 2H), 1,62 (b s, i l l). 1.26-1.18 (ra, 2H); HPLC (Method 6} 97.6% (AUC), tR ------ 1 1.17 mm.; ESI+APCI-MS m/z 492 [M · Π | '

l~(i-(2~(5~Chloro-2,4-diniethoxypn^

yl)-N-(pyridin-4-ylme1hyl)methan amine 8w was prepared in the same manner as N-((l-(2- (5-ch]oro~2,4~dimethox henyl)im^

dimethylpropan-I-amine 8a and was obtained as an off-white solid (19% yield),

f t NMR (400 MHz, DMSO-a¾): δ 8.50-8.47 (m, 2H), 8.26 (d, ./ 7.6 Hz, 1H), 8.16 (s, IH), 7.99 (s, IH), 7.35 L ./ 5.6 Hz, 2H), 6.86 (s, 1H), 6.78 (dd, J ------ 2.0, 7.6 Hz,

1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J ------ 12.4 Hz, 2H), 3.73 (s, 2H),

2.74-2.66 (m, 2H), 2.40 (d, J = 6.4 Hz, 2H), 1 .82 (d. ./ 11.2 Hz, 2H), 1.63 (br s, 1H),

1.27-1.19 (m, 2H); HPLC (Method 4} 91.8% (AUC), ¾ = 11.09 min.; ESI+APCI-MS m/z 492 [M I I I ' .

Preparation of l-(1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazon.,2-a]pvridiR-7-

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxyplien l)miidazo [ 1 ,2-a ipyridm~7~yl)piperidin-4- yl)-N-((3~fliioropyridin~4~yl)methyi)methanainiiie 8x was prepared in the same manner as N-((l-(2-(5-chloro-2,4-dimethoxypte^

yi)methyi)-2,2-dimethyipropan-l -amine 8a and was obtained as an off-white solid (16% yield).

] H NMR (400 MHz, DMSO-cfo): δ 8.46 (s, d, ./= 1 .6 Hz III), 8,39 (dd, J= 0.8, 4.8 Hz, 1H), 8.26 (d, J ------ 7.6 Hz, 1H), 8.17 is. 1H), 7.99 (s, 1H), 7.55 (t, J ------- 6.0 Hz, I H), 6.86 (s,

1H), 6.77 (dd, J - 2.4, 7.6 Hz, 11 1 ·. 6.63 (d, ./ 2,0 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.79 (s, 2H), 3.77 (d, J--- 12.4 Hz, 2H), 2.74-2.68 (m, 2H), 2.42 (d, ./ 6.4 Hz, 2H), 1 .82 id. ./ 11.2 Hz, 2H), 1.63 (br s, 1H), 1.28-1.18 (m, 2H); HPLC (Method 1) 95.7% (AUC), = 11.73 min.; ESI+APCI-MS m/z 510 [M +H .

Preparation of 1 -(1 2-(5-ehloro-2,4-dimethoxyphenyI)^^ l-(l -(2-(5-Chiofo-2,4-dimethoxyphenyl)imidcizon

yl)-N-((2-nle1box5φ ridin^-}4)metlayl)methanamine 8y was prepared in the same manner as 'V~(( 1 -(2.-(5 -chloro-2,4-dimethoxypheny i)imidazo[ 1 ,2~aipyridm~7-yl)piperidin-4- yl)methyl)-2,2-dimethylpropan~l -amine 8a and was obtained as an off-white solid (14% yield).

lH NMR (300 MHz, DMSO-a¾): δ 8.27 (d, J = 7.5 Hz, 1H), 8.16 (s, IH), 8.06 (d, ./

= 5.1 Hz, 1H), 7.99 (s, IH), 6.95 (d, J = 5.4 Hz, IH), 6,86 (s, 1H), 6.83-6.78 (m, 2H), 6.63 (s, IH), 4.0 (s, 3H), 3.93 (s, 3H), 3.82-3.76 (m, 6H), 3.68 (s, 2H), 2.75-2.67 (m, 3H), 2.37 (d. ./ 6 Hz, 2H), 1.82 (d, ./ 1 1.7 Hz, 2H), 1.28-1.17 (m, 2H); HPLC (Method 3) 96.9% (AUC), tR = 11.94 min.; ESHAPCl-MS m/z 522[M + H]+.

yjjpiperidin-4-yS)-A ; -(thiazol-2-ylmetS¾vj)methas¾amine 8s (Example 28);

l-(l -(2-(5-Chloro-2,4-dimethoxyp enyl)imidazo[l ,2- ]pyridin-7-y])piperidin-4- yl)-N-(1hiazol-2-ylroetbyl)methanaroine 8z was prepared in the same manner as N-((l.-(2-(5- chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]py

dimethylpropan-1 -amine 8a and was obtained as an off-white solid (13% yield).

¾ NMR (400 MHz, DMSOa'd): S 8.27 (d, J= 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 7.69 (d, J= 3.2 Hz, IH), 7.58 id, J = 3.2 Hz, IH), 6.86 (s, IH), 6.79 (dd, J = 2.0, 7.6 Hz, IH), 6.63 (d, ./ 2.0 Hz, IH), 4.00 is, 3H), 3.99 (s, 2H), 3.93 (s, 3H), 3.79 (d, J = 12.4 Hz, 2H), 2.75-2.66 (m, 2H), 2.49 (d, J = 6.4 Hz, 2H), 1.84 (d, J= 12.02 Hz, 2H), 1.63 (br s, IH), 1.29-1.20 (m, 2H); HPLC (Method 5) 97.0% (AUC), = 6.45 min .; ESI+APCI- MS m/z 498 [M ! ! j . A solution of (l-(2-(5-cWoro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyrjdin-7- yi)piperidin~4~yl)methanaininc 6 (150 mg, 0.38 mmoi), and 2~chioropyrimidine (66 rag. 0.58 nimol) in DMF (2 mL) was heated at 75 °C for 1 6 h. To the reaction mixture water was added, whereupon a white precipitate formed. The solid was collected by filtration itnder vacuum to obtain crude product. The product was purified by combi -flash

chromatography [silica gel: 5% NH OH in MeOH: CH2CI2 ( 1 :9)] . Fractions containing the product were combined and concentrated under vacuum to obtain N-((l~(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo[l,2-^

8aa (20 mg, 1 1%) as an off-white solid,

f t NMR (400 MHz, DMSQ- e): δ 8.28-8.24 (m, 3H), 8.16 (s, I H). 7,99 (s, IH),

7.24 (t, J = 6.0 Hz, IH), 6.86 (s, 1H), 6.79 (dd, ./ 2.4, 7.6 Hz, IH), 6.63 (d, J = 2.0 Hz, 1 H), 6.52 t, J~ 4.8 Hz, Hi), 4.00 (s, 3H), 3.93 (s, 3H), 3.79 (d, J= 12.8 Hz, 2H), 3.20 (t, J = 6,4 Hz, 2H), 2.74-2,67 (m, 2H), 1.78 (d, J= 10.4 Hz, 3H), 1 .30- 1.23 (m, 2H); HPLC (Method i) 98.3% (AUC), = 12.32 mm. : ES1+APCI-MS m/z 479 [M + H] + .

Flg iQ of lri

yjjpiperidin-4-yl)-^V-bis(pyridia-2-Ylmethvi)methanamine Sab (Example 30);

l~(l -(2-(5~Chloro-2,4-dimethoxyph^

yl)-N^-bis(pyridin-2-ylmethyl)methanamme Sab was prepared in the same manner as N- ((l -(2-(5-chioro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pip

2,2-dimethyipropan- l-amine Sa and was obtained as an off-white solid ( 15% yield).

¾ NMR (400 MHz, DMSOc¾): δ 8.48 l J 4.0 Hz, 2H), 8.26 (d, ./ 7.6 Hz, 1H), 8.15 (s, 1H), 7.99 (s, ΓΗ), 7.78 (t, J= 7,2 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.25 (t, J = 5 , 2 Hz, 2H), 6.86 (s, IH), 6, 76 (d, J = 6.4 Hz, 1 H), 6.59 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.76-3.70 (m, 6H), 2,69 (t J= 12.4 Hz, 2H), 2,35 (d, J = 6.0 Hz, 2H), 1 .85 (d, J= 12.0 Hz, 3H), 1.10-1.02 (m, 2H); HPLC (Method 3) 94.9% (AUC), & = 12.03 mm ,; ESI+APCI-MS

Preparation of ethyl l-(2-a8iiioopyridin-4-yj)piper¾dine-4-c.arb xYj¾t 12j^_

To a solution of 4-chloropyridin-2-a.mine 10 (2.00 g, 15,6 mmol) in N,N- diisopropylethylansine (25 mL), placed in a sealed tube, was added ethyl piperidine-4- carboxylate 11 (3.67 g, 23.4 mmol). The tube was sealed and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, whereupon the residue was partitioned between EtOAc and water (200 mL: 50 mL). The layers were separated and the EtOAc layer was washed with brine (50 mL), dried over anhydrous NaiSO,, filtered and concentrated under reduced pressure to provide the crude product. Tire product was triturated with hexanes, filtered under reduced pressure and dried to provide ethyl l-(2-aminopyridin-4- yl)piperidine-4-carboxylate 12 (2.5 g, 85%) as an off-white solid, which was used directly in the next step without further purification. ESI+APCI-MS m/z 250 [M + H} +

yj piperidine-4-carboxylate 3j.

A mixture of l-(2-aminop Tidin-4-yl)piperidine-4-carboxylate 12 (2.5 g, 1 0.0 mmol) and 2-bromo- l -(5-chIoro-2,4-dime ' ihoxyphenyl)ethatione 4 (3.2 g, 1 1.0 mmol) in acetone ( 120 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, whereupon a white precipitate formed. The precipitate was collected by filtration under vacuum, and washed with hexanes (200 mL). The crude product was suspended in water (200 mL) and saturated aqueous NaHCOs (200 mL) and stirred at room temperature for 1 h. The solid obtained was filtered under vacuum, washed with water and dried under vacuum to obtain /erf-butyl (( 1 -(2-(5-chloro-2,4-dimethoxyphenyl) imidazo[l,2^]pyridin-7-yl)piperidin-4-yl)methyl)carbamate 13 (1 .2 g, 43.7%) as an off- white solid.

i f NMR (400 MHz, CDCb): δ 8.37 (s, 1H), 7.89-7.86 (m, 21 1 ). 6.81 (s, I H), 6.58 (s, IH), 6.55 (dd, J = 2.4, 7.6 Hz, 1H), 4.16 (q, J= 7.2 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.71-3.67 (m, 2H), 2.90-2.83 (m, 2H), 2.52-2.46 (m, IH), 2.06-2.03 (m, 2H), 1.92-1.83 (m, 2H), 1 .27 (t, ,7 = 7.2 Hz, 3H); ESI+APCT MS m/z 444 [M + H] + .

Preparation of l-(2-(5-chIoro-2,4-dimethoxYphenyl)imidazo[l,2-a]pyridjn : A solution of ethyl l-(2~(5-chloro~2,4-dimethoxyphenyi)imidazo [ l,2-a|pyridin~7- yl)piperidine-4-carboxylate 13 (500 mg, 1.1 mmol) in CH2CI2 (50 mL) was cooled to -78 °C and DIBAL-H (1.1 mL, 1.6 mmol) was added thereto. The resulting mixture was stirred at -78 °C for Ih. The reaction mixture was quenched with saturated aq-NJHUCl solution and extracted with CH2CJ2 (2 χ 50 ml,). The combined organic layer was dried over anhydrous a?.S04, filtered and concentrated under reduced pressure to obtain J ~(2-{5~ chloro-2,4-dimethoxyphenyl)imidazo l,2-« pyridin-7-yl)piperidine-4-carbakte 14 (300 mg, 76%) as an off-white solid, which was used for next step without further purification.

ESI+APCl-MS m/z 400 [M + \ \ [ . Preparation of A"-{(i-(2-(5-chSoro-2,4-dimethoxypS¾es¾yI¾imickzoli,2-ajp yridin-7- Yj]piperidin-4-yS 8iiethvI)cyd bistanamj e 16a (Example '

To a suspension of l-(2-(5-chloro-2,4-dime " ihox\phenyl)imidazo[l ,2-o]pyridin-7- y3)piperidine-4-carbaldehyde 14 (80 mg, 0.20 mmol), cyclobutanamine (21 nig, 0.30 mmol) in CH3OH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred for 2 h. Sodium cyanoborohydride (62 mg, 1.00 mmol) was added thereto and the reaction mixture was stirred at room temperature for 15 mm. The reaction mixture was diluted with, aqueous NaHCCte solution and extracted with CH2C.I2 (2 χ 20 mL). The combined organic layer was dried over anhydrous aaSi filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi -flash chromatography [silica gei; 5% MH4OH in MeOH: CH2CI2 ( 1 :9)] . Fractions containing the product were combined and concentrated under reduced pressure to obtain N-((l-(2-(5- chloro-2,4~dimethoxyphenyl) imidazo[ L2-a]pyridin-7-yl)piperidin-4~

yl)methyl)cyclobutanamine 16a (17 mg, 19%) as an off-white solid.

! H NMR (400 MHz, DMSO-de): δ 8.26 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, IH), 6.86 (s, i l l ). 6.76 (dd, 2.0, 7.6 Hz, IH), 6.62 (d, ./ 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.77 (d, J= 12.4 Hz, 2H), 3, 15-3.14 ( , ΓΗ), 2.70 (t, J = 12.0 Hz, 2H), 2.33 (d, J = 6.8 Hz, 2H), 2.1 1 -2.05 (m, 2H), 1.79 (d . ./ 12.4 Hz, 2H), 1.68- 1.50 (m, 5H), 1 .24-1. 16 (m, 2H); HPLC (Method 3) 99.0% (AUC), t& = 1 1.91 min.; ES1+APC1 MS m/z 455 [M +

Η;Γ.

2-(5-Chloro-2,4-dimethox>pheny3)-7-(4-(pyrrolidm- i-ylmethy3)piperidin-l - yl)imidazo[l ,2-a]pyridine 16b was prepared in the same manner as Λ-((1 -(2-(5-chloro-2,4- dimethoxyphenyl)imidazoj T,2-i?]pyridm-7-yl)pipendin-4-yl)memyl)cyclobutanamine 16a and was obtained as an off-white solid (16% yield).

¾ NMR (400 MHz, DMSO-a'd): δ 8.27 id. ./ 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6,86 (s, H), 6.77 (dd, J= 2.4, 7.6 Hz, i l l). 6.62 (d, J= 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.76 (d, J= 13.2 Hz, 2H), 2.75-2.69 (m, 2H), 2.41 (far s, 4H), 2.28 (d, J = 6.4 Hz, 2H), 1.81 (d, ,/= 12.0 Hz, 2H), 1.68 (br s, 5H), 1.23-1 , 16 (m, 2H); HPLC (Method 5) 98.6% (AUC), te = 6.43 min.; ESI+APCI MS m/z 455 [M + H] + .

yg i t^^

N-((l~(2-(5~Chloro-2,4~diinethoxyphenyl}iinidazo| l,2-a]pyndin-7~yl)piperidm~4- yl)raethyl)cyeSopeiitaaamine 16c was prepared in the same manner as N-(( l-(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4-yl)methyl)cyclobutanaraine 16a and was obtained as an off-white solid (12% yield).

lH MR (400 MHz, C D OS.? !, δ 8.03 (d, J ------- 7.6 Hz, I H), 7.97 (s, 1H), 7.86 (s, IH),

6.96 (s, IH), 6.67 (dd, J- 2.4, 7.6 Hz, IH), 6.57 (d, ./ 2.4 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (d, J= 12.8 Hz, 2H), 3.16-3.09 (m, IH), 2.75-2.67 (m, 2H), 2.58 (d, J= 6.8 Hz, 2H), 1.94- 1.86 (m, 2H), 1.80 (d, J = 12.0 Hz, 21 1 ·. 1.70-1.62 (rn, 3H), 1 .54-1.48 (m, 2H), 1.40-1.23 (m, 4H); HPLC (Method 3) 92.5% (AUC), fa ----- 12.04 mm.; ESI+APCI MS m/z 469 [M + H] -.

Preparation of /V-((l-(2-(5-chloro-2,4-dimetho¾Yphem )imidazon s2-a pyridin-7- vl piperidii¾-4-Yl)methvl)tetrahydrofMran-3-amine 16d (Example 34)^

A-((l-(2-(5-chkiro-2,4-dmiethoxypheny3)miidazo[ l,2-a]pyridin-7-y

yl)nietliyl)tetfahydrofiiraj:!-3-amine 16d was prepared in the same manner as N-({ 1 -(2-(5- chloro-2,4~dimethoxyphenyl)imidazo[ l,2~a]pyridin-7~yl)piperidin~4- yl)methyl)cyclobutanamine 16a and was obtained as an off-white solid (26% yield).

! H NMR (400 MHz, DMSO-<sfe); δ 8.27 (d, J = 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6.86 (s, IH), 6.78 (dd, ,/ 2.0, 7.6 Hz, IH), 6.63 (d, ./ 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.80-3.68 (m, 4H), 3.65-3.60 (m, IH), 3.42-3.36 (m, IH), 3.29-3.35 (m, IH), 2.73-2.67 (m, IH), 2.50-2.40 (m, 3H), 1 .96- 1 .89 (m, IH), 1.80 (d, ,/ 1 1 .2 Hz, 2H), 1.67-1.57 (m, 2H), 1.27- 1 .15 (m, 2H); HPLC (Method 3) 98.2% (AUC), fe = 1 1.61 mm.; ESHAPCI MS m/z 471 [M + Hf.

2-(5-Chioro-2,4-dimethoxypheny])-7-(4-(piperidin-l -ylme " thyl)piperidin-l- yl)imidazo [l,2- ]pyridine 16e was prepared in the same manner as N-((l -(2-(5-chloro-2,4- dimeihoxyphenyl)imidazo[l,2-a]pyridm^ 16a and was obtained as an off-white solid (17% yield).

1 H NMR (400 MHz, DMSO-ds): δ 8.27 L ./ 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6.86 (s, H), 6.78 (dd, J= 2.4, 7.6 Hz, iH), 6.63 (s, LH), 4.00 (s, 3H), 3,93 (s, 3H), 3.77 (d, J 12.4 Hz, 2H), 2.75-2.67 (m, 2H), 2.39-2.25 (m, 4H), 2.18-2.10 (m, 2H), 1.79-1.75 (m, 3H), 1.51 (br s, 4H), 1.39 (br s, 2H), 1 .23-1.17 (m, 2H); HPLC (Method 4) 96.3% (AUC), tR = 6.50 min.; ESI+APCI MS m/z 469 [M + H] + . yJ i i| rj i djH i 4 i yJ)methyl^

jV-((l~(2-(5~chioro-2,4-dmiethoxyphenyl)mndazo l,2~ ]pyridin~7~yl)piperidin-4- yl)methyl)cyeJo.hexanamine 16f was prepared in the same manner as N-((l -(2-(5-chloro-

2,4-dimethoxypheny1)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4-yl)methy1)cyclobutanaraine

16a and was obtained as an off-white solid (20% yield),

! H MR (400 MHz, DMSO-ifc): δ 8.27 (d . ./ 7.6 Hz, IH), 8.16 is IH), 7.99 (s.

H I ). 6.86 (s, I H), 6.78 kid. ./ 2.0, 7.6 Hz, IH), 6.63 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, ./= 12.4 Hz, 2H), 2.74-2.67 (m, 2H), 2.58 (d, J= 6.8 Hz, 2H), 1.85- 1.79 (ni, 4H),

1.69- 1 .65 (m, 2H), 1.58-1.52 (m, 2H), 1 .33 -1 .21 (m, 51 1 ·. 1.19-1.02 (m, 3H); HPLC

(Method 3) 92.3% (AUC), fe = 12.24 min ,; ESI+APCI MS m/z 483 [M + H] + . y! piperidin-4-yI)methvI)tetrahydro-2//-pyran-4-amine 16g (Example 37);

A-(( l-(2-(5-chk>ro-2,4-diniethoxyphenyr)iniidazo[l ,2-a]pyridin-7-y

yl)methyl)tetrahydro-2/f-pyran-4-amine 16g was prepared in the same manner as N-((l -(2- (5-chloro-2,4-dimeflioxyphenyl)imidazo[l ,2-«Jpyridin-7-yl)piperi

yl)methyI)cyclobutanamine 16a and was obtained as an off-white solid (25% yield). ¾ NMR (400 MHz, CD3OD): δ 8,03 (d, J= 7.6 Hz, 1H), 7.97 (s, 1H), 7.86 (s, IH), 6.69 (s, IH), 6.67 (dd, ./= 2.4, 7.6 Hz, 1 H), 6.57 (d, J= 2.0 Hz, 1H), 3.92 (s, 3H), 3.87 (d, J = 4.0 Hz, .:! !}. 3,85 (s, 3H), 3.75 (d, ,/ 12.8 Hz, 2H), 3.35-3.28 (m, 2H), 2,74-2.60 (m, 3H), 2.49 (d, J= 6.8 Hz, 2H), 1.81-1.76 (m, -H i). 1.66-1.59 (m, IH), 1.38-1.20 (m, -H i) . HPLC (Method 3) 98.4% (AUC), fe - 11.66 mm.: ESI+APCI MS m/z 485 [M 4- Hf.

Pre^ r on oi

N-((l-(2~(5-chIoro~2,4~diinethoxyphenyl)n^

yl)methy{)cycloheptanamine 16h was prepared in the same manner as N-(( 1 -(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo[l,2-a]py

16a and was obtained as an off-white solid (23% yield).

lH NMR (400 MHz, DMSO-ffc): δ 8.28 (d, J -- 7.6 Hz, IH), 8.16 (s, IH), 8.00 (s, IH), 6,86 (s, IH), 6.79 (dd, ./ 2.4, 7.6 Hz, IH), 6.66 (d, J= 1.6 Hz, IH), 4,00 (s, 3H), 3.93 (s, 3H), 3.81 (d, ./ 12.4 Hz, 2H), 2.88 (bf s, IH), 2.75-2.67 (m, 4H), 1.96- 1 .80 (m, 4H), 1.75-1.60 (m, 3H), 1.56-1.32 (m, 8H), 1.30-1.22 (m, 2H); HPLC (Method 3) 98.9% (AUC), tR = 12.48 mm ,; ESI-i-APCI MS m/z 497 [M + H] ÷ .

Preparation of A-((l-(2-(5-c.hk r -2,4-dim th ¾yphenyI imida¾ n -i2-a pyridm-7- yJjpiperidin-4-yj)methyl)-l-methyIpiperidii¾-4-arn¾8¾e 1.61 (Example 39);

A-((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2-«]pyridin-7-yl)piperidin-4- yl)metliyl)-i-meth ipiperidin-4-arnine 161 was prepared in the same manner as N-((\ -(2-(5- chloro-2,4~dimethoxyphenyl)imidazo[ l,2~a]pyridin-7~yl)piperidin~4- yl)methyl)cyclobutanamine 16a and was obtained as an off-white solid ( 18% yield).

'H MMR (400 MHz, CD3OD): δ 8.04 (d, J= 7.6 Hz, IH), 7.96 (s, IH), 7.87 (s, LH), 6.70-6.67 (m, 2H), 6.58 (d, J = 2.0 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (d, J= 12.4 Hz, 2H), 2.89-2.85 (m, 2H), 2.76-2.70 (m, 2H), 2.58 (d, J= 6.8 Hz, 2H), 2.22 (s, 3H),

2.08-2.03 (m, 2H), 1.90 (d, ./= 14.0 Hz, 2H), 1.81 (d, ./= 12.0 Hz, 2H), 1 .68-1.64 (m, IH), 1.47-1.37 (m, 2H), 1.33- 1 .23 (m, 2H), 1.19-1.17 (m, IH); HPLC (Method 3) 97.7% (AUC), in ------ 10.90 mm,; ESH-APC1 MS m/z 498 M + Hf. yjjpiperidin-4-yS)met y!)-l-isopropyjpipericSin-4-amine 16; (Example 4Q)

N-((l-(2-(5-chioro-2,4<limei oxypheny1)imidazo l,2-G]pyri

yl)iT!eihyl)-l-isopropyipiperidir!-4-amir!e 16j was prepared in the same manner as N-((l -(2- (5-chloro-2,4-dimeihoxyphenyl)imida o[l,2-i?]pyridin-7-yl)piperidi

yl)methyl}cyclobutanamine 16a and was obtained as an off-white solid (34% yield).

1 H NMR(400 MHz, DMSO-ds): δ 8.27 l 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6.86 (s, H), 6.78 (dd, J= 2.0 Hz, 7,6 Hz, IH), 6.58 id, J= 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J ------ 12.8 Hz, 2H), 2.73-2.63 (m, 4H), 2.57-2.51 (m, 2H), 2.45 (d,J = 6.0 Hz, 2H), 2.11-2.05 (m, 2H), 1.81-1.77 (m, 4H), 1.58-1.49 (ra, IH), 1.25-1.15 (m, 4H), 0.93 (d, J~ 6.8 Hz, 6H); HPLC (Method 3) 97.0% (AUC), = 11.23 mm.; ESI-hAPCI MS m/z 526 [M +

Pre|)ara ioH f l- -f2-( -c|

l~(l-(2~(5~Chloro-2,4-dmiethoxy

yl)-N-((l-methylpiperidin-4-y1)methyl)raetiianamine 16k was prepared in the same manner as N-((l-(2-(5-chloro-2,4-dimeihoxyphenyl)m

yl)methyl)cyclobutanaroine 16a and was obtained as an off-white solid (18% yield).

rHNMR(400 MHz, CD3OD): δ 8.05 {ά, J ------ 7.6 Hz, IH), 7.96 (s, 111·.7.87 (s, IH), 6.70-6.67 (m, 2H), 6.58 (d, J= 2.0 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (d, J= 12.8 Hz,

2H), 2.90 (d, J--- 11.6 Hz, 2H), 2.74 (t, J -- 12.8 Hz, 2H), 2.61 (t, J 6.8 Hz, 4H), 2.28 (s,

3H), 2,09 (t,J = 11.2 Hz, 2H), 1.86-1.73 (m, 5H), 1.60-1.54 (m, IH), 1.35-1.17 (m, 4H):

HPLC (Method 4) 94.6% (AUC), ¾ = 6.28 ram.; ESI+APCI MS m/z 5\2 [M + H] + .

Preparation of A-((l-{2-(5-c.hkr -2,4-dimeth ¾yphenyI)imida¾ n-i2--a pyridm-7- Yl)piperidii¾-4-Yl)methyl)-2-(l-methylpiperidin-4-yI)ethana mine 161 (Example_42)j

A-((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-«]pyr idin-7-yl)piperidin-4- yl)metIiyl)-2-(l-methylpiperidin-4-yl)ethanamine 161 was prepared in the same manner as

N-((l-(2-(5-chloro-2,4-dimethoxyphenyl^^ yl)methyl)cyclobutanamine 16a and was obtained as an off-white sohd (11% yield).

lH NMR (400 Mliz, CD 3 OD): δ 8.03 i d. ./ 7.6 Hz, i l l ). 7.97 is M l). 7.86 (s, 1H), 6.69 (s. IH), 6.66 (dd, ./ 2.4. 7.6 HzJ H), 6.57 (d. ./ 2.0 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.75 (d, J= 12.4 Hz, 2H), 2.79-2.69 (ra, 4H), 2.58 (t, ./= 7.6 Hz, 2H), 2.49 (d, J= 6.8 Hz, 2H), 2.16 (s, 3H), 1.93 (t, J = 10.0 Hz, 2H), 1.79 (d, J = 13.6 Hz, 2H), 1.63 (d, J= 1 1.6 Hz, 3H), 1.44- 1.38 (m, 2H), 1.31 -1.17 (m, 5H); HPLC (Method 4) 98.4% (AUG), fe - 6.29 mm.; ESI+APCI MS m/z 526 [M + H] + . yj^piperidin-4-yS)met¾yI)-A r4 ^' -dimethyScycSohexane-i,4-dia^^ 16m (Example_43jj A Tl -((l-(2-(5-chloro-2,4-dimeihoxyphenyl)imidazo i,2-a]pyndin-7-yl)piperi yl)methyl)-N*^-dimethy1cyclohexane-l ,4-diamine 16m was prepared in the same manner as N-((l-(2-(5-ehloro-2,4-dimeti50xypheny

yl)methyl)cyclobutanamine 16a and was obtained as an off-white solid ( 1 1% yield).

¾ NMR (400 MHz, DMSOa'd): δ 8.27 id. ./ 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6.86 (s, IH), 6.78 (dd, ,/= 2.4, 8.0 Ηζ, ΙΗ), 6.63 (d, ./= 2.0 Hz, IH). 4.00 (s, 3H), 3.93 (s, 3H), 3.79 (d, ./ 12.0 Hz, 2H), 2.74-2.60 (m, 4H), 2.16 (s, 6H), 2.04 (br s, IH), 1.86-1 .80 (ra, 2H), 1.68- 158 (m, 5H), 1 .46-1 .34 (m, 4H), L2.7-i .19 (m, 3H); HPLC (Method i) 98.7% (AUG), tr = 10.78 mm.; ESI+APCI MS m/z 526 [M + Ιψ.

Scheme 3

To a solution of 4-chlofopyridin-2 -amine 17 (500 mg, 3.90 mmoi) in a mixture of «-BuOH: N,N-diisopropylethylaroine (10 ml,/ 5 ml,), placed in a sealed tube, was added tert-hut ] (pyrroIidm-3-yImei yl)carbamate 18 (937 mg, 4.68 mmoi). The tube was sealed and the reaction mixture was heated at 120 °C for 24 b , Tire reaction mixture was cooled to room temperature and concentrated under reduced pressure, whereupon the residue was partitioned between EtOAc and saturated aqueous NaHCCb solution (100 mL: 50 mL). The layers were separated and the EtOAc layer was washed ith bnne (50 mL), dried over anhydrous Na_S04, filtered and concentrated under reduced pressure to obtain the crude product. The product was triturated with hexanes, filtered under reduced pressure and dried to provide t ¾r -buty1 ((l-(2-aminopyridm-4-yl)pyrroiidin-3-yl)methyl) carbamate 19 (900 mg, 79%) as an off-white solid, which was used directly for next step without further purification.

ESI+APC1-MS m/z 293 [M + H] + .

Pre >arafii^

A mixture of 2-bromo~l~(5-chSoro~2,4~dimethoxyphenyl)ethanone 4 (880 mg, 3.01 mmol) and ftrf-butyl ((1 -(2-arainopyridin-4-y])pyrrolidin-3-y])methyl)carbaniaie 19 (800 mg, 2.73 mmol) in acetone ( 15 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, whereupon a white precipitate formed. The precipitate was collected by filtration under vacuum, washed with hexanes (200 mL), and dried to obtain hydrobromic salt of feri-butyl (( l-(2-(5-chioro-2,4-dimethoxyphenyi)imidazo[l,2-a]pyridin- 7-yl)pyrrolidin-3-yl)methyi)carbamate 20 (600 mg, 45%) as an off-white solid.

! H NMR (400 MHz, OMSO-de) δ 12.99 is, IH), 8.49 (d, J = 7.6 Hz, IH), 8.22 (s, IH), 7.88 (s, i l l}. 7.06 (t, ./ 5.2 Hz, H I). 6.98 is. 1H), 6.92 (d, ./ 8.0 Hz, i l l). 6.28 (s, IH), 4.05 is, 3H), 3.98 (s, 3H), 3.52-3.44 (m, 3H), 3.18-3.16 (m, H), 3,03 (t J= 6.8 Hz, 2H), 2.51-2.49 (m, IH), 2.12-2.08 (m. IH), 1.87- 1.72 (m, IH), 1.39 (s, 9H) ; HPLC (Method 1) 95.82% (AUG), = 14.25 mm.; ESI+APCI MS m/z 487 [M + H] + .

Prep ration , ^

J)Byrr in-3-

To a solution of re t-butyi ((l-(2-(5-ehloro-2,4-dimethoxyphenyl)imidazo[l ,2- a]pyridin-7-yl)pyrrolidin-3-yl)roetbyl)carbamate 20 (600 mg, 1 .23 mmol) in CH2CI2 ( 10 mL) was added a solution of HQ (4.0 M in 1 ,4-dioxane, 5 ml.) and the reaction mixture was stirred at room temperature for 16 h. The solid obtained in the reaction, was collected by filtration under vacuum, and washed with CH2CI2 (100 mL) to obtain provide hydrochloric salt oi l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| l,2-a]pyridin-7- yl)pyrrolidin-3-yl)m.ethanamine 21a (400 rag, 84%) as an off-white solid.

! H MR (300 MHz, DMSO-ifc): δ 13.55 (s, iH), 8.53 (d . J 7.5 Hz, i l l}. 8.25 is IH), 8.13 (br s, 3H), 8.03 (s, IH), 6.98 (s, IH), 6.90 (d, ./ 6.9 Hz, IH), 6.36 is M l). 4.05 (s, 3H), 3.98 (s, 3H), 3.63-3.45 (m, 4H), 2.98-2.94 (m, .:! !) . 2.69-2.65 (m, IH), 2.24-2.22 (in. 1 H), 1.94- 1 .85 (m, iH); HPLC (Method i) 90.93% (AUC), ¾ = 1 1.30 mm. ; ESI+APCI MS m .: 3H7 [M + H | .

The solid 21a was then suspended in water (15 niL) and the mixture was basified with saturated sodium bicarbonate solution (15 mL), to pH 9, whereupon an off-white solid precipitated. The resulting solid in the mixture was collected by filtration under vacuum, washed with water and dried to obtain provide (l~(2-(5-chloro~2,4~

dime†hoxyphenyl)imidazof l,2-a]pyridm-7-yl)pyrrolidin-3-yl)methanamine 21b which is used for further reactions without any purification.

ES1+APC1 MS m/z 387 [M + Hf.

Prep r tion ^

yDlgr oj

To a suspension of (l -(2-(5-chloro-2,4-dimeth.ox phenyi)imidazo[l ,2- ]pyridin-7- yi)pyiTo!idin~3-yl)methanamine 21b (100 mg, 0,25 mmol), pivaldehyde (67 mg, 0.77 mmol), in CH3OH (10 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred for 1 h. Sodium cyanoborohydride (39 mg, 1.32 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2 χ 20 mL). The combined organic layer was extracts were washed with brine (20 mL), dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure to obtain the crude product. Tire product was purified by combi-flash chromatography [silica gel; 5% NHiOH in MeQH: CH2G2 (1 :9)] . Fractions containing the product were combined and concentrated under vacuum to obtain N-((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2- o]pyridin-7-yl)pyrrolidin-3-yl)memyl)-2,2-dimetiiylpropan-l- amme 22a (21 mg, 17%) as an off-white solid. ¾ MR (400 MHz, DMSO- e): δ 8.26 (d, J= 7,2 Hz, IB), 8.16 (s, WD.7.94 (s, IB), 6.85 (s, 1H), 6.47 (dd, J= 2.0, 7.6 Hz, lH), 6.18 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.45-3.43 (ra, 1H), 3.30-3,26 (m, ΓΗ), 3.07 (dd,J= 6,8, 9,6 Hz, 1H), 2.64-2,55 (m, 3H),

2.47- 2,45 (m, 1H), 2.33-2.27 (m, 2H), 2,14-2.06 (m, ΓΗ), 1.78-1.69 (m, 1H), 0,89 (s, 9H); HPLC (Method 5) 98.7% (AUG), tR = 6.61 mm.; ESI+APCI-MS m/z 457 [M + Hf.

P2e|)sua|¾OH of l-(l-(2-(5-Chloro-2,4-dimethoxyp3ienyl)imidazo[l,2- ]pyridin-7-yl)pyrrolidin-3- yl)-N-(cyciopropyimethyl) methanamine 22b was prepared m the same manner as N-((l-(2- (5-ch]oro~2,4~dimethox henyl)im

dimethylpropan- -amine 22a and was obtained as an off-white solid (16% yield).

lH NMR (300 MHz, DM O- ). δ 8.26 (d, J= 7.2 Hz, lH), 8.15 (s, 1H), 7.93 (s, 1H), 6.85 (s, 1H), 6.47 (d, ./ 6.9 Hz, 1H), 6.18 is.1H), 3.99 (s, 3H), 3.92 (s, 3H),

3.48- 3.39 (m, 2H), 3.08-3.03 (rn, lif).2.61-2.56 (m, 3H), 2.46-2.41 (rn, 31 f), 2.13-2.07 (m, lilt.1.78-1.66 (m, ill).0.95-0.85 (m, lilt.0.46-0.35 (m, 2H), 0.14-0.08 (m, 2H);

HPLC (Method i) 97.46% (AUG), & = 1 i .74 mm.; ESI+APCI MS m/z 441 [M + Hf. Preparation of 1-(l-(2-(5-chloro-2,4-dimethox , phenyI)imidazo^l,2-a|pyridiR-7- yI)PYrrolidin-3-yI)- -(cvclopentylmethyl)methanamine 22c (Example 48}^

1 -( 1 -(2-(5 -Chiofo-2,4-dimethoxyphenyl)imidazo 11 ,2-o]pyridin-7-y3)pyrrolidin-3- yl)-N-(cyclopentylmethyl)methanamine 22c was prepared in the same manner as N-((l-(2- (5-chloro-2,4-dimetlioxyphenyl)im

dimethj'lpropan- 1 -amine 22a and was obtained as an off-white solid (18% yield).

! H NMR (400 MHz, DMSO- e); δ 8.28 (d, J= 7.6 Hz, 1H), 8.15 (s, ΓΗ), 7.95 (s, 1H), 6.85 (s, 1H), 6.47 (dd, J= 2, 7.2 Hz, 1H), 6.20 (d, J= 2 Hz, IB), 4.00 (s, 3H), 3.93 (s, 3H), 3.49-3.46 im. lH), 3.41-3.38 (m, 2H), 3.12-3.08 im. II li.2.82 (br s, Hi).2.69-2.60 (m, ill}.2.59-2.54 (m, 2H), 2.14-2.04 (m, 211}.1.80-1.73 (m, 3H), 1.60-1.48 (m, 5H), 1.23-1.18 (m, 2H); HPLC (Method 5) 94.60% (AUG), fe = 6.63 min.; ESI+APCI MS m/z 469 I M + ii| . ajpyridin-7-yl)pYrrolidin-3-v j )methyi amino)methYi)pyrro j idine-i-carboxy¾ate 22d_ (Example 49}^

re /'/-Butyl 3-((((l-(2-(5-chloro-2,4-dime1_ioxyphenyl)imidazo| " l ,2-«]pyridin-7- yl)pyrroIidin-3-yl)methyl)amino)methyl)pyrrolidine-l-carboxy la^ 22d was prepared in the same manner as A ? -((l~(2-(5-chloro-2,4~dimethoxyphenyl)imidazo[ l,2~a]pyndin-7~ yl)pyrfolidin-3~yi)methyl)-2,2-dimeihyipfopan-l-ainine 22a and was obtained as an off- white solid (34% yield).

! H NMR (300 MHz, DMSO-de): δ 8.26 (d, J = 7.2 Hz, IH), 8.16 (s, 1H), 7.93 (s, IH), 6.85 (s, 1H), 6.46 (d, J= 7.2 Hz, IH), 6.18 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H),

3.47-3,42 (m, 3H), 3.31 -3.25 (m, 2H), 3,20-3.17 (m, 1H), 3.08-3.02 (m, 1H), 2,95-2.90 (in. i l l}. 2.61 -2.51 <m. 3H), 2.50-2.41 (in. 2H), 2.31 -2.27 in:. 1H), 2.12-2.08 (m, 1 H), 1.91 (br s, i l l). 1.75- 1.66 (m, IH), 1.58-1.49 (in. i l l}. 1.39 is 9H); HPLC (Method 5) 99.76% (AUC), tR - 6.54 min.; ES1+APC1 MS m/z 570 [M + Hf.

Pge ar tio^^^^

A solution of tert-butyl 3-((((l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2- a]pyndin-7~yi)pym>lidm-3~yl)methy1)a^ 22d (100.0 mg) in 2,2,2-trifluoro ethanol (3.0 rnL) was charged with trimethylsilyl chloride (0.1 niL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was evaporated to diyness and washed with hexane to provide pure hydrochloric salt of l-(l-(2- (5-chSoro~2,4~dim6thoxyphenyl)imida^

3 ~y {methyl )raethanamine 22e (25 rag, 30%) as an off-white solid.

¾ NMR (400 MHz, DMSQ- e): δ 13.83 (br s, ΓΗ), 9.52-9.43 (m, 4H), 8,53 (d, J 7.6 H/ i l l). 8.24 (s. lH), 8.10 (s, IH), 6.95 (s, IH), 6.89 (d, J= 6.4 Hz, I H), 6.39 (s, J = 1.6 Hz, IH), 4.05 is 3H), 3.98 (s. 3H), 3.76-3.69 i m. IH), 3.65-3.53 (m, IH), 3.48-3.36 (m, 3H), 3.29-3.21 (in. I H), 3.19-3.01 (m, 6H), 2.92-2.85 (in. I H), 2.82-2.74 (m, IH), 2.31 -2.24 (m, IH), 2.19-2.1 1 (rn, IH), 1 .98- 1.89 (m, Hi), 1.82-1.70 (rn, IH); HPLC (Method 5) 98.12% (AUC), fe = 6.10 mm.; ESI+APCI MS m/z 470 [M + H] + .

Preparation of fcr?~bntyi 4-(((( i-(2-(S-chloro-2,4-dimethosyphenvi)imidazo|l ,2- ajpyridin-7-yI)pyrrolidin-3-yI)methyi)amino)methyI)piperidin e-l-carboxylate 22f_ tert-Butyl 4-((((l-(2-(5-c oro-2,4-dimethoxyphenyl)imidazo[ l,2-^]pyridin-7- yl)pyrrolic n-3-yl)metiijd)ainino)metiijd)piperidine-l-carboxylaie 22f was prepared in the same maimer as N~((l-(2~(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2-o]pyridin~7- yl)pyrrolidin~3-yl)niethyi)-2,2~dmiethylpropan~l -amine 22a. and was obtamed as an off- white solid (40% yield).

lH NMR (300 MHz, DMSO-a¾): δ 8.25 (d, J = 7.5 Hz, IH), 8. 15 (s, III), 7.93 (s,

IH), 6,85 (s, IH), 6.46 (d, J = 7.8 Hz, IH), 6.18 (s, i l l). 3.99 (s, 3H), 3.95-3 ,89 (m, 6H), 3.47-3.36 (m, 2H), 3.08-3.03 (m, IH), 2.68-2.51 (m, 6H), 2.17-2.08 (m, IH), 1 .78- 1 .56 (rsi, 5H), 1.38 (s, 9H), 1.02-0.91 (m, II I): HPLC (Method 1) 99.1% (AUC), fe = 12.41 mm.; ESRAPCI MS m/z 584 [M + Hf.

Plgff atjo^

yijpyrrolidin-3-yl)- -(piperidin-4-ylmethyi)methanamine 22g (Ex¾mpSe 52jj

l~(l -(2-(5~Chloro-2,4-dimethoxyphenyl)im^

yl)-A-(piperidin-4-ylmethyl)me†hanamine 22g was prepared in the same manner as 1 -(l-(2- (5-chloro-2,4-dimeflioxyphenyi)imidazo[ l,2-o |pyridin-7-yi)pym

3-ylmethyl)meihanamine 22ε and was obtained as an off-white solid 1 0 yield).

i f NMR (300 MHz, DMSO-ffc): δ 13.82 (br s, 1Η),9.40-9.28 (m, 2H), 9.06-8.82 (m, 2H), 8.53 (d, J = 7,5 Hz, IH), 8.25 (s, IH), 8.1 1 (s, IH), 6.97 (s, IH), 6.90 (d, J = 7.2 Hz, IH), 6.40 (s, IH), 4.05 (s, 3H), 3.98 (s, 3H), 3.76-3.68 (m, IH), 3.64-3.56 (m, IH), 3.49-3.38 (m, .: ! !} . 3.30-3,22 (m, 2H), 3.12-3.02 (m, 2H), 2.94-2.78 (m, 5H), 2.30-2.20 (m, IH), 2.19-1 ,85 (m, 4H), 1.51 -1 .37 (m, 2H); HPLC (Method 1) 95.52% (AUC), ¾ = 10.99 mm.; ESI+APCI MS m/z 484 | M + H] \ N-Benzyl- -(2-(5 -chloro-2,4 -dimethoxyphenyl)imidazo [ 1 , 2-a]pyri din-7- yl)pyrro{idin-3-yl)methanamine 22h was prepared m the same manner as N-((l-(2-(5- cbloro-2,4-dimetboxypheny])imidazo[ l,2- ]pyridm-7-yl)pymilidin-3-yl)methyi)-2,2- dimethylpropan- -amine 22¾ and was obtained as an off-white solid (20% yield).

¾ NM (400 MHz, DMSO-ffc): δ 8.26 (d, J= 7.6 Hz, IH), 8.15 (s, 1H), 7.94 (s,

1H), 7.37-7.30 (in, 4H), 7.24-7.21 (m, 1H), 6.85 (s, 1H), 6.46 (dd, ·/ 2.4, 7.6 Hz, IH), 6.18 id. ./ 1.6 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.75 (s, 2H), 3.48-3.44 (m, 1H), 3.30-3.25 (m, 2H), 3.09-3.05 (m, IH), 2.63-2.53 (m, 3H), 2.15-2.05 (m, IH), 1.77-1.70 (m, 1H); HPLC (Method 4) 98.67% (AUG), ft = 12.19 mm.; ESI+APCI MS m/z 477 [M + l ! | .

Preparation of l-(l-(2-(5-chioro-2,4-dimethoxyphenyl)imidazoP

1 -( 1 -(2-(5 -Chloro-2,4-dimethoxypheny i)imidazo [ 1 ,2-a]pyridm-7-yl)pyrroUdin-3- yl)-jV-(2~fluorobenzyi)metlianamine 22i was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimet oxypheny3)imidaz^

dimethyipropan- 1 -amine 22a and was obtained as an off-white solid (19% yield).

lH NMR (400 MHz, DMSO-a¾): δ 8.26 (d, J = 7.6 Hz, IH), 8.15 (s, IH), 7.93 (s, IH), 7.50-7.47 (m, ΓΗ), 7.29-7.25 (m, 7, 19-7.12 (m, 2H), 6.85 (s, IH), 6.46 (dd, J = 2.4, 7.6 Hz, 1H), 6.18 (d, ,/ 2 Hz, IH), 3.99 (s, 3H), 3.92 is 3H), 3.77 is. 2H), 3.48-3.44 (m, 1H), 3.37-3.27 (m, 2H), 3.09-3.04 (m, IH), 2.60-2.53 (m, 3H), 2.15-2.05 (m, IH),

1.76- 1 .69 (m, IH); HPLC (Method 1) 91.20% (AUG), / S ! .94 mm.; ESI+APCI MS m/z 495 [M + H | . yjjpyrrolidin-S-y -A'-CS-fluorobenzYDmethanamine 22 j (Example 55);

i-( l~(2-(5-Chloro~2,4~dimeihoxypbenyl)™^

yl)-N-(3-fluorobenzyl)methanamine 22j was prepared in the same manner as N-((l-(2-(5- chlorQ-2,4-dimeihoxyphenyl)imidazo[l,2^

dimethyipropan- i -amine 22a and was obtained as an off-white solid (20% yield). ¾ NMR (400 MHz, DMSO- e): 5 8.26 (d, J = 7,6 Hz, IH), 8. 15 (s, H), 7.94 (s, 7.38-7.32 (m, IH), 7.21-7.18 (m, 2H), 7.07-7.02 (m, IH), 6.85 (s, IH), 6.47 (dd, J = 2.4, 7.6 Hz, IH), 6.18 (d, ./= 1 .6 Hz, I H), 3.99 (s, 3H), 3.92 (s, 3H), 3.77 (s, 2H), 3 ,49-3 ,44 (m . ] | {). 3.38-3.28 (m, 2H), 3 ,09-3.05 (m, ΓΗ), 2.61 -2.53 (m, 3H), 2, 16-2.08 (in. 1 H), 1 .76- 1 .69 (m, IH); HPLC (Method 4) 97.66% (AUC), ¾ = 1 1.97 mm. ; ESI+APCI MS m/z 495 [M + Hf.

Pre¾a ^^ l-(l-(2-(5-CMoro-2,4-dime&oxypheny

yl)-N-(4-fluorobenzyl)methanaroine 22k was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)pyrfoli

dimethyipropan-1 -amine 22a and was obtained as an off -white solid ( 14% yield).

] H NMR (400 MHz, DMSO^fe): δ 8.25 (d, ./ 7.6 Hz, IH), 8.15 (s, IH), 7.93 (s, IH), 7.40-7.36 (m, 2H), 7.15-7.10 (m, 2H), 6.85 (s, IH), 6.46 (dd, ./ 2.4, 7.6 Hz, IH), 6.18 (d, ./ 1.6 Hz, IH), 3.99 (s, 3H), 3.92 (s, 3H), 3.71 (s, 2H), 3.48-3.43 (m, IH),

3.38-3.25 (m, 2H), 3.08-3.04 (m, IH), 2.60-2.44 (m, 3H), 2.14-2.08 (m, IH), 1.75-1.68 (ITS, I H); HPLC (Method 1 ) 99.41% (AUC), t& = 12.02 min .; EST+APCI MS m/z 495 [M + Hf. YS)0yrrolidiH-3-yI)metln'I)amiH )niethyl)-A r ,A r -diniethy 22S (Example 57k

4-(((( l-(2-(5 -CUoro-2,4-dimethoxyphenyl)iniidazo [ 1 ,2~a ]pyridin-7-yl)py rrolidin- 3-yl)methyl)ammo)methyl)-jVjV-dimethylaiiiline 221 was prepared in the same manner as N- ((l~(2-(5-chloro-2,4-dimethoxyphenyi)imidazo[ l ,2~ jpyridin-7~yS)py

2,2-dimethylpropan- l -amine 22a and was obtained as an off-white solid (8% yield).

! H MR (400 MHz, DMSO-cfc) δ: 8.29 (d . ./ 7.6 Hz, I H), 8.15 is IH), 7.95 (s, 1H),7.26 (d, ·/ 8.4 Hz, 2H), 6.86 (s, IH), 6.73 (d, J = 8.8 Hz, 2H), 6.47 (dd, ./ 2.4, 7.6 Hz, IH), 6.20 (s, IH), 4.10 (s, 3H), 4.0 (s, 3H), 3.93 (br s,2H), 3.49-3.47 (m, IH), 3.43- 3.38 (m, IH), 3.12-3.08 (m, IH), 2.99 (s, 6H), 2.94-2.85 (m, 2H), 2.62-2.56 (m, 2H), 2.18- 2.09 (m, IH), 1.84-1 .75 (m, 1H),; HPLC (Method 5) 97.2% (AUG), fe = 13.72 min.;

ESI+APCI MS m/z 520 [M + H i .

Preparation of 4-((((t-{2 5-ehloro-2,4-dimethoxyphefl^^ 4-((((l-(2-(5-Chloro-2,4-dimetnoxyphenyl)imida^

3-yl}meihyl)ammo}meihyl)phenoi 22m was prepared in the same manner as N-((l-(2-(5- c oro-2,4-diniethoxyphenyl)inu^

dimetliylpropan- 1 -amine 22a and was obtained as an off-white solid (15% yield).

lH MR (400 MHz, DMSQ-ife) δ: 9.34 (br s, H), 8.27 (d, J= 7.6 Hz, H), 8.15 (s, 1H), 7.94 (s, 1H), 7.1 8 (d, J= 8.4 Hz, 2H), 6.85 (s, IH), 6.72 (d, ./= 8.4 Hz, 2H), 6.47 (dd, ,/ 2.0, 7.6 Hz, 1H), 6.18 (s, 11 1 ·. 4.00 (s, 3H), 3.93 is. 3H), 3.73 (br s, 2H), 3.49-3.45 (m, IH), 3.28-3.26 (m, 2H), 3.08-3.05 (m, 1H), 2.67 (br s, 2H), 2.14-2.10 (m, I H), 1.78-1.65 (m, IH),; HPLC (Method 5) 97.2% (AUG), <¾ = 13.72 mm.; ESI+APCI MS m/z 493 [M + Hf.

yl)pyrrolidin-3-Yl)- -(2-Bitrobenzyl)methaBamine 22n (Exampjej59jj

l~(.l -{2-(5~Chloro-2,4-dimethoxyphenyl)imi^

yl)-N-(2-nitrobenzyl)raetha3 amine 22si was prepared in the same manner as N~((l -(2-(5~ chloro-2,4-dimetnoxyphenyl)imidazof 1,2-a^

dimethylpropan-1 -amine 22a and was obtained as an off-white solid (1 7% yield).

¾ NMR (400 MHz, DMSO-ifc): δ 8.29 id. ./ 7.6 Hz, IH), 8.12 (s, IH), 7.97 (s,

IH), 7.93 (d, J ------- 7.6 Hz, I H), 7.73-7.67 (m, 2H), 7.53-7.50 (m, 2H), 6.87 (s, IH), 6.51 (dd,

J ----- 2.4, 7.6 Hz, IH), 6.19 (s, IH), 4.03 (m, IH), 4.00 is. 3H), 3.93 (s, 3H), 3.37-3.42 (m,

2H), 3.29-3.27 (m, IH), 3.07-3.05 (m, IH), 2.60-2.55 (m, 3H), 2.46-2. 1 (m, 2H), 2.11-2,08 (m, I H), 1.74-1.69 (m, H); HPLC (Method 1) 97.1 % (ADC), tR = J 1.86 in in :

ESH APCi-MS m/z 522 [M 4- H] ÷ .

- i l l - l~(i-(2~(5~Chloro-2,4-dinicthoxyph^

yl)-N-(3-(trifluoromethyi)benzyl)met a!ianiine 22o was prepared in the same manner as N- ((l-(2~(5-chioro-2,4-dimethoxyphenyl)imida^^

2,2-dimethylpropan- 1-amine 22a and was obtained as an off-white solid (23% yield).

¾ NM (400 MHz, DMSO-ffc): δ 8.26 (d, J= 7.2 Hz, 1H), 8.16 (s, 1H), 7.94 (s,

1H), 7.73 (s, ll!h 7.68-7.66 (m, ill).7.60-7.53 (m, 2!!}.6.85 (s, 111·.6.46 (dd, ,/ 2, 7.2 Hz, 1H), 6.18 (s, 1H), 3.99 (s, 311·.3.93 (s, 311).3.83 (s, 2! Is.3.49-3.44 (m, 1H), 3.38-3.36 (m, 1H), 3.30-3.26 (m, 1H), 3.09(d,J = 6.8, 9.6 Hz, 1H), 2.58-2.55 (m, 3H), 2.15-2.08 (m, 1H), 1.78-1.69 (m, 1H); HPLC (Method 3) 97.4% (AUC), tR= 12.69 min.; ESI+APC1-MS m/z 545 [M + H] + .

Preparation of l-(l-(2-(5-chIoro-2,4-dimethoxyphenyl)^

1 -( 1 -(2-(5 -chloiO-2,4-dimethoxyphenyl)imidazo[ 1 ,2-o]py ridin-7-yl}pynOlidin-3 - yl)-jV-(4-(trifliioromemyl)benzyl}methaiiamme 22p was prepared in the same manner as N- ((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7 -yl)pyrrolid^

2,2-dimethylpropan- 1-amine 22a and was obtained as an off-white solid (13% yield), lH NMR (400 MHz, DMSO~d6): δ 8.27 (d, J= 7.2 Hz, IH), 8.15 (s, 1H), 7.95 (s, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 6.18 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.84 (s, 211).3.47 (dd, 7.6, 10 Hz, ill).3.37-3.36 (m, ill) 3.30-3.29 (m, 211). 3.10-3.06 (m, ill}.2.59-2.56 (m, 211;·.2.15-2.08 (m, 111).1.78-1.69 (m, 1H); HPLC (Method 5) 99.8% (AUC), tR = 6.81 mm.; ESI+APCI-MS m/z 545 [M + H]\

Prg aiog QI1-( l~(l-(2-(5~Chloro-2,4-dimethoxypheny

yl)-N-(4-raetbylbenzyl)raetbanaxnine 22q was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimetnoxyphenyl)imidazof

dimethylpropan-1 -amine 22a and was obtained as an off-white solid (26% yield).

¾ NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7,23 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.0 Hz, 2H), 6.85 (s, 1H), 6.46 (dd, ./= 2,0,7.6 Hz, 1H), 6.17 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.68 (s, 2H), 3.47-3.43 (m, 1H), 3.30-3.25 (m, H i ). 3.07-3.03 (m, IH), 2.51-2.47 (m, 4H), 2.27 (s, 3H), 2.13-2.07 (ra, 1H), 1.76-1 ,67 (m, 1H); HPLC (Method 5) 99.3% (AUC), tR - 6.70 min.; ESI+APCI-MS m/z 491 [M + Hj + . yg ri^

1 -( 1 ~(2-( 5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin- 3 - yl)-N-(2-chlorobenzyl)methanamine 22r was prepared in the same manner as N-((l-(2-(5- ehloro-2,4-dimethoxyphenyl)imidazo[l,2^

dimethylpropan-1 -amine 22a and was obtained as an off-white solid (25% yield).

: f i NMR. (400 MHz, DMSO-d6): δ 8.27 (d, J ------ 7.6 Hz, I H), 8.14 (s, IH), 7.95 is.

IH), 7.57 (dd, ,/= 1.2, 7.2 Hz, IH), 7.42 (dd, J= 1.2, 8.0 Hz, IH), 7.35-7.25 (m, 2H), 6.85 (s, IH), 6.49 (dd, J - 2.4, 7.6 Hz, IH), 6.19 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.83 (s, 2H), 3.50-3.46 (m, IH), 3.39-3.35 (rn, IH), 3.12 -3.08 ( i, IH), 2.63-2.60 (rn, 2H), 2.51-2.47 (m, 2H), 2.17-2.08 (m, IH), 1.79-1.74 (m, IH); HPLC (Method 5) 95.2% (AUC), tR - 6.66 min.; ESI+APCI-MS m/z 511 [M + H] " .

Preparation of i-(l-{2-(5-chl ro-2,4-dimethoxyphe8¾yl)imidazo l ¾ 2-a|pyridin-7- yJjPYrroMdm-3-yS}- -(4-chIor benzyS}methanami e 22s (Example 64);

l-(l -(2-(5-Chioro-2,4-dimethoxyphenyl)imidazo| l ,2-o]pyridin-7-y3)pyrrolidin-3- yl)-N-(4-chlorobenzyl)methanatnine 22s was prepared in the same manner as ,¥-(( 1 -(2-(5- chloro-2,4~dimethoxyphenyl)imidazo[ l,2~a]pyridiii-7~yl)pyrrolidin~3~yl)methyi)-2,2~ dimethj'lpropan- 1 -amine 22a and was obtained as an off-white solid (25% yield).

! H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J= 7.2 Hz, IH), 8.15 (s, IH), 7.94 (s,

IH), 7.39-7.35 (m, 4H), 6.85 (s, IH), 6.47 (dd, J= 2.0, 7.6 Hz, IH), 6.18 (s, IH), 3.99 (s, 3H), 3.92 (s, 3H), 3.72 (s, 2H), 3,48-3.43 (m, IH), 3.29-3.25 (m, H), 3,08-3.04 (m, IH),

2.51 -2.47 (m, 4H), 2.12-2.08 (m, IH), 1 .77- 1 .68 (m, IH); HPLC (Method 5) 99.1 %

(AUC), ! R 6.70 mm.; ESI+APCI-MS m/z 511 [M + I I I .

Prejjaratioo of l-I l-(l~(2-(5-Chloro-2,4-dimeihoxyphenyl)im^

y1)-N-(pyridir!-3-y]r!iet1iyl)methanamir!e 22t was prepared in the same manner as N~((1 -(2- (5-chloro-2,4-dimethoxyphenyl)imidazo| 1 ,2-«Jpyridin-7-yl)pymiiidin-3-yi)methyl)-2,2- dimethyipropan-1 -amine 22a and was obtained as an off-white solid ( 16% yield).

¾ MR (400 MHz, DMSO^fe): δ 8.54 (s, IH), 8.43 (dd, ·/ 1.6, 4.6 Hz, IH), 8.25 (cl J ------ 7.6 Hz, l i f). 8.15 (s, 1H), 7.93 (s, 1H), 7.78-7.75 (m, I H), 7.36- 7.32 (m, 1H), 6.85

(s, IH), 6.46 (dd, J = 2.4, 7.2 Hz, 1H), 6.18 (d, J = 2 Hz, IH), 3.99 (s, 3H), 3.92 (s, 3H), 3.74 (s, 2H), 3.48-3.44 (m, IH), 3.38-3.32 (m, IH), 3.32-3.28 (m, IH), 3.08-3.04 (m, IH), 2.60-2.44 (m, 3H), 2.15-2.09 (m, IH), 1.75-1 .69 (m, IH); HPLC (Method 5) 96.39% (AUG), E = 6.14 mm.; ESI+APCI MS m/z 478 [M + H | .

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin- 3 - yl)-N-(pyridin-4-y1methyl)raethanamine 22u was prepared in the same manner as N~{{ 1~(2- (5-chloro-2,4-diraethoxyphenyi)i^

dimethy!propan-1 -amine 22a and was obtained as an off-white solid ( 13% yield).

\ \ MR (400 MHz, DMSO-ifc): δ 8.48 (dd, ./ 1.6, 4.6 Hz, 2H), 8.26 (d, 7.6 Hz, IH), 8.15 (s, IH), 7.93 (s, 11 1 ·. 7.37 (d, ./ 2.0 Hz, 2H), 6.85 is. IH), 6.47 (dd, J - 2.0, 7.6 Hz, IH), 6.18 (d, ./ 1.2 Hz, IH), 3.99 is 3H), 3.92 is. 3H), 3.75 is. 2H), 3.49-3.42 (m, IH), 3.32-3.26 (m, IH), 3.10-3.06 (m, IH), 2.59-2.47 (m, 2H), 2.15-2.09 (m, I H), 1.78-1.68 (m, IH); HPLC (Method 1) 91.29% (AUG), te - 11.09 mm.: ESl+APCI MS m/z 478 [M + H] -.

Preparation of l-(l-(2-(5-c¾l ro-2,4-dimet¾oxyp¾e8¾yI)imidazo l ¾ 2-a|pyndin-7- Yl)pyrrolidin-3-yl)-A-((3-fluoropyridin-4-yl)methyl)methanam ine 22v (Example 67);

1 -( 1 -(2-(5 -(¾ioro-2,4-dimethoxyphenyl)imidazo 11 ,2 -o]pyridin-7-y3)pyrrolidin-3- yl)-A-((3-fluofopyridin-4-yl)niethyl)methananiine 22v was prepared in the same manner as N-(( 1 -(2-(5 -chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a \ py ridin-7-yl )pyrrolidin-3 - yl)metiiyl)-2,2-dimethylpropan-l -amine 22a and was obtained as an off-white solid (13% yield).

f t NMR (300 MHz, DMSO-a¾): δ 8.47 is H I). 8.39 (d. ./ 4.8 Hz, IH), 8.26 (d, ,/ = 7.5 Hz, H), 8.15 (s, IH), 7.94 (s, IH), 7.59-7.55 (m, IH), 6.85 (s, H), 6.47 (d, J= 6.3 Hz, IH), 6.19 (s, IH), 4.00 (s, 3H), 3.92 (s, 3H), 3.82 (s, 2H), 3.49-3.39 (m, 3H), 3.11 -3.07 (m, 1H), 2.59-2.47 (m, 3H), 2.15-2.09 (m, 1H), 1.79-1.69 (m, 1H); HPLC (Method 1) 99.90% (AUC), tR ------ 11.59 mm.; ESI+APC1 MS m/z 496 \ \\ + H] + . vijpyrrolidin-3-Yl)- -((2-fliioropYridin-4-v j )methyl methanamine 22w (Example Jjj, l~(l -(2-(5~Chloro-2,4-dimethoxy

yl)-A-((2-fluoropyridin-4-y3)meihyl)methanamine 22w was prepared in the same manner as A-(( l-(2-(5-chloro-2,4-dimethoxyphenyl)m^

yl)methy l)-2,2-dimethylpropan- 1 -amine 22a and was obtained as an off-white solid (17% yield).

H NMR (300 MHz, DMSO^fe): δ 8.27 (d, J ------ 7.5 Hz, IH), 8.16-8.12 (m, 21 I t.

7.94 (s, IH), 7.35 (br s, IH), 7.15 (s, IH), 6.85 (s, IH). 6.48 (d, J= 7.2 Hz, IH), 6.19 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.81 (s, 2H), 3.50-3.42 (m, 3H), 3.1 1-3.07 (m, IH), 2.59-2,47 (m, 3H), 2.14-2.08 (m, IH), 1 ,78-1.68 ( , IH); HPLC (Method 4) 98.66% (AUC), tR ----- 1 1.80 mm.; ESI+APCI MS m/z 496 [M + H] + .

Preparation of l-{l-i2-(5-chloro-2«4-diniethoxvphenvi)iniidazoil,2-alpvrid in-7- t'rroSidio-3-Yl)-AvV-bis(BYridin-2-vImeihyS

l-(l-(2-(5-Chloro-2,4-(Hm.ethoxyp3ienyl)imidazo[l ,2- ]pyridin-7-yl)pyrrolidin-3- yl)-N,N-bis(pyridin-2-ylmethyl)methanamine 22x was prepared in the same manner as N- ((l-(2~(5-chioro~2,4-dimeihoxyphenyl)im

2,2-dimethylpropan- 1-amine 22a and was obtained as an off-white solid (10% yield). lH NMR (400 MHz, DM O- ). δ 8.47 (dd, J--- 0.8, 4.8 Hz, 2H), 8.25 (d, J ------- 7.2

Hz, IH), 8.16 (s, I H), 7.94 (s, IH), 7.77-7.73 (m, 111), 7.57 (d, ,/= 7.6 Hz, 2H), 7.24-7.21 (m, 2H), 6.85 (s, IH), 6.43 (dd, J - 2.0, 7.6 Hz, IH), 6.14 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H) : 3.78 (q, ./ 14.4 Hz, 4H), 3.44-3.39 (m, 1H), 3.24-3.17 (m, 2H), 3.03-2.99 (m, 1H), 2.69-2.63 (m, 2H), 2.50-2.48 (m, 1H), 2.08-2.04 (m, 1H), 1.68-1.62 (m, 1H); HPLC (Method I) 96.8% (AUC), /R = 11 .89 min .; EST+APCI MS m/z 569 [M + i l l ' .

Scheme 4

Preparation of methyl l-{2-am½opyridi?i-4-vl)pyrro!idme-3-c¾rbosv!¾te^3L ,

To a solution of 4-chloropyridin-2-arome (0.48 g, 3.75 mmol) in N,N- diisopropyletbylamine (1.0 mL), placed in a sealed tube, was added methyl pyrrolidine-3- carboxylate (0.93 g, 5.65 mmol). The tube was sealed and the reaction mixture was heated at 120 °C for 16 h. The reaction mixture w as cooled to room temperature and

concentrated under reduced pressure, whereupon the residue was partitioned between EtOAc and saturated aqueous NaHCCb solution (300 mL: 100 mL). The layers were separated and the EtOAc layer was washed with brine (10 mL), dned over anhydrous Na?S04, filtered and concentrated under reduced pressure to obtain the crude product. The product was triturated with hexanes, filtered under reduced pressure and dried to obtain methyl l-(2-aminopyridin-4-yl)pyrrolidine-3-carboxylate 23 (700 mg, crude) as an off- white solid, which was used directly for next step without further purification.

ESI+APCI-MS m/z 222 ΓΜ + Hf. yl)pyrrolidiae-3-carboxylate_ i

A mixture of methyl l-(2-ammopyndin-4-yi)pyrrolidme-3-carboxylate 23 (0.50 g,

2.262 mraol) and 2-bromo-l-(5-chloro-2,4-diroetboxyplienyl)ethanone 4 (0.726 g, 2.48 mmol) in acetone (50 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, whereupon a white precipitate formed. Ilie precipitate was collected by filtration under vacuum, washed with hexanes (20 niL), and dried to obtain hvdrobromic salt, which was treated with Aq. NaHCC (5.0 mL) solution to obtain free base of methyl 1-

(2~(5-chloro~2,4~dimethoxyphen}d^ 24 (0.2 g, 47%) as an off-white solid.

: f i NMR (400 MHz, CDCb): δ 8.31 (s, 1 1 1 ·. 7.80 (d, ./ 7.2 Hz, l i f ). 7.74 (s, 1H),

6.50 i s. Π Ι). 6.41 (s, H I). 6.28 (dd, J ------- 2.0, 7.2 Hz, H I ). 3.92 (s, 3H), 3.88 i s. 3H), 3.68 i s.

3H), 3.56 (d, J= 7.2 Hz, 2H), 3.44-3.40 (m, 1H), 3.37-3.31 (m, III), 3.22-3.15 (m, 1 H),

2.29-2.24 (m, 2H). ESI+APCI-MS m/z 416 [M +

P¾.gJ>9j;¾^

yj)pyrrolidine-3-earboxylic acid 25;

A solution of methyl 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2~a]pyridin~

7~yl)pyrrolidine-3-carhoxylate 24 ( 1.0 g, 2.4 mmol), in THF, CH3OH and water (20 mL/ 10 mL/ 5 mL), was added LiQI H LQ (0.40 g, 9.6 mmol) and the resulting mixture was stirred at ambient temperature for 5 h. The reaction mixture was evaporated and diluted with water and extracted with ethylaeetate (2 x 10 mL). The aqueous layer was adjusted to pH 3-4 with

10% KHSO4 solution to yield precipitate. The precipitate was filtered washed and dried to afford i-(2~(5~chioro~2,4~dimethoxyphenyl)im^

carboxylic acid 25 (750 mg, 78%) as an off-white solid.

4 1 NMR (300 MHz, DMSO-ifc): δ 8.29 (d, ./ 7.5 Hz, 1 H), 8.16 (s, H I). 7.96 (s.

H I ). 6.85 (s, l i b. 6.51 i d. J -- 6.6 Hz, 1H), 6.24 (s, 1 1 1 ·. 4.00 (s, 31 1 ). 3.93 (s, 3H),

3.57-3.46 (m, 2H), 3.37-3.33 (m, 2H), 3.25-3.18(m, IH), 2.27-2.17 (m, 2H); ESI+APCI

MS m/z 4021 M + 1 11 . ^thoxY-N-metbylpvrroHdine-3-carboxamide 26;

A solution of l -{2-(5-chioro-2,4-dime† oxypheny])imidazof l,2- ]pyridin-7- yl)pyrrolidine-3-caiboxylic acid 25 (0.2g, 0.498 mmol), N,0-Dimethylhydroxylamine hydrochloride (72 nig, 0.747 mmol), Λ',Λ-diisopropylethyl amine (256 mg, 1.99), in DMF (2.0 mL), was added EDC.HC1 ( 190 mg, 0.996 mmol), and HOBt (152 mg, 0.996 mmol), and the resulting mixture was stirred at ambient temperature for 15 h. The reaction mixture was diluted with water to yield precipitate. The precipitate was extracted with ethylaeetate (2 χ 10 mL). The organic layer was dried over anhydrous NaiSC i and concentrated to afford l -(2-(5-chloro-2,4<hme†hoxypheny])imidazof l,2- ]pyridm-7-yl)-A' T - niethoxy-Y-methylpyrrolidine-S-carboxamide 26 (200 mg, crude). The crude compound used as such in the next step.

H MR (300 MHz, DMSO^fe): δ 8.29 (d, ./ 7.2 Hz, 1H), 8.16 (s, I I I). 7.95 i s. 1H), 6.85 (s, i l l ). 6.51 (d, J = 7.5 Hz, 1H), 6.23 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.72 (s, 3H), 3.59-3.55 (m, 2H), 3.42-3.37 (m, 3H), 3.15 (s, 3H), 2.26-2.08 (m, 2H): ES1+APCI MS m/z 445[M + H] + .

yrjjyrroMdine-3-c.arbaIde¾Yde ^ 27 _

A solution of l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-o]pyridm-7-yl )-N- methoxy-N-methylpyiTolidine-3-carboxamide 26 (1.0 g, 2.25 mmol), in THF (500 mL), was cooled to -78 °C. To the resultant reaction mixture at -78 °C, was added 2.0 M LAH in THF (3.37 mL, 6.75 mmol). The resultant reaction mixture was stirred at -78 °C for additional 1 h. The reaction mixture was quenched with aq. H4CI and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over anhydrous NaaSC and concentrated to afford l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7- y3)pyrrolidine-3-carbaldehyde 27 (800 mg, crude). The cuide compound used as such in the next step.

ESI+APCI MS m/z 386ΓΜ 4- Hf. yjjpyrroSidin-3-YS methyl -3,3-dimet yIbi8tai -j -¾mi?ie jga^

A suspension of l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7- yl)pyrrolidine-3-carbaldehyde 27 (100 mg, 0.25 mmo3), 3,3-dimethyibutan- -amine (34 mg, 0.38 mmol) in CITOH (5 mL) was added acetic acid (0.05 mL) and the resulting mixture was stirred for 2 h. Sodium cyanoborohydride (48 mg, 0.55 mmol) was added and the reaction mixture was stirred at room temperature for 5h. The reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with CH2CI2 (2 χ 10 ml,}. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure and the residue was purified by combi -flash companion (silica gel,

M hi)! I/C I hO! I ff ! ( ' ! -) K ? afford Λ··ί·: i•i 2H -dUoro-2.4 -dln: ii:oxv h !tvl ;ni;da oi 1.2- ojpyridin-7-yl)pyrrolidin-3-yl)methyl)-3,3-dimethylbutan- 1 -amine 28a (25 mg, 20%) as an off-white solid.

1 H NMR (400 MHz, DMSOaV,) δ: 8.25 <d. ./ 7.6 Hz, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 6.82 (s, 1H), 6.47 (dd, J= 2.4, 7.6 Hz, IH), 6.10 (s, 1H), 3.99 (s, 3H), 3.92(s, 3H), 3.38-3.34 (m, IH), 3.39-3,23 (m, 4H), 3.06-3.02 (m, IH), 2.60-2.52 (m, .:! !}. 2.46-2.37 (in. I H), 2.12-2.05 (m, IH), 1 .76-1 .67 (m, IH), 1.36-1.32 (m, 2H), 0.88 (s, 9H); HPLC (Method 3) 90.5% (AUG), tr = 12.5 mm. ; ESI+APCT MS m/z 471 [M + Hf. Ylipyrrolidin-3-Yl methvl)-2-meihoxYethanainine 28b (Example 32):

A-((l-(2-(5-CUoro-2,4-dimethoxj^henjd)imidazo[l,2- ]pyridm-7-yl)pyirolidiii-; yl)methyl)-2-methoxyethanamine 28b was prepared in the same manner as iV-((l-(2-(5- ehloro-2,4-dimethoxyphenyl)imida∞^

diniethylbutan-1 -amine 28a and was obtained as an off-white solid (21 % yield).

! H MR (400 MHz, DMSO-ife) δ: 8.26 id . ./ 7.2 Hz, IH), 8.15 is IH), 7.95 (s. IH), 6.85 (s, IH), 6.47 (dd, ./ 2.0, 7.2 Hz, IH), 6.10 (s, IH), 3.99 (s, 31 1 ·. 3.92 (s, 3H), 3.46-3.36 (m, 41 1 ). 3.32 (br s,3H), 3.06-3.02 (m, IH), 2.96 (t, ./ 5.6 Hz, 21 1). 2.62 (t, ./ 7.2 Hz, 2H), 2.57 i s. ./ 7.6 Hz, 2H), 2.17-2.06 (m, IH), 1.85-1.67 (m, IH); HPLC (Method 3) 96.7% (AUC), t& = 11.61 mm : ESI+APCI MS m/z 445 [M + H] + .

Preparation of A-((l-(2-(5-chloro-2,4-dimethoxvphenvj)imidazo[1.2-gpYridjnj ^: yl)pyrroIidin-3-yl)methyl)cyeIobiitaflai Re 28c (Example 44);

N-((l-(2-(5-Chloro-2,4-dimethQxyphenyl)im^

yl)methyl)cyclobu " ianamine 28c was prepared in the same manner as N-((l-(2-(5-chloro-2,4- dmietlioxypheiiyl)imidazo l,2^]pyridiii~7~yl)pyrrolidm~3-yl)methy

amine 28a and as obtained as an off-white solid (19% yield).

¾ MR (300 MHz, DMSO- e): 58.26 (d, J= 7.5 Hz, ill).8.15 (s, IH).7,93 (s, Hi).6.85 (s, ill).6.48 id../ 7.2 Hz, IH), 6.18 (s, Hi).3.99 (s, 3H), 3.932 (s, 3H),

3.46-3.40 (m, 2H), 3.33-3,27 (m, ΓΗ), 3.16 (br s, ill).3.06-3.01 (m, IH), 2.41-2,32 (m, 2H), 2.10-2.08(m, 3H), 1.08-1.49(m, 6H); HPLC (Method 4) 96.9% (AUC), .¾ = 6.50 nun.; ESI+APCI MS m/z 441 [M + fi| .

Pre ar tion , of ^

yljpyrroSidJo-^y

N-((l-(2-(5-Chloro-2,4-diraethoxyphe^^^

yl)!nethyj)-l-metbylpiperidiii-4-arnine 28d was prepared in the same manner as N-((l~(2~(5- chloro-2,4-dimethoxypheny])im

dimethylbutan - 1 -amine 28a and was obtained as an off-white solid (16% yield).

lH NMR (400 MHz, DMSO-ffc) δ: 8.26 (d, J= 7.2 Hz, IH), 8.15 (s, 1H), 7.93 (s, IH), 6.85 (s, IH), 6.47 (dd, ./ 2.4, 7.6 Hz, IH), 6.18 (d, J= 1.6 Hz, IH), 3.99 (s, 3H), 3.92 (s, 3H), 3.47-3.43 (m, IH), 3.42-3.27 (m, 2H), 3.07-3.03 (m, IH), 2.71-2.66 (m, 2H), 2.62-2.55 fro.2H), 2.45-2.36 (m, .:!!}.2.13-2.06 (m, 4H), i.90-1, 85 (m, 2H), 1.79-1.68 (m, 3H), 1.29-1.23 (m, 2H); HPLC (Method 3) 99.3% (AUC), to= 11.03 mm,; ESI+APCI MS m/z 484 [M + Hj

Preparation of l-(1-(2-(5-chIoro-2,4-dimethoxyphenyl)imidazon.,2-a]pvridiR- 7j: l-(l-(2-(5-Chloro-2,4-(iimetnoxyphenyl)im

yl)-N-((l-meihylpiperidiii-4~yl)metliyi)metlianainiiie 28e was prepared in the same manner as N-((l-(2-(5-cMoro-2,4-dimethoxypheny

yl)methy{)-3,3-dimethylbutan-l-amine 28a and was obtained as an off-white solid (15% yield).

: f i NMR (400 MHz, DMSO fc) δ: 8.26 (d . ,/ 7.6 Hz, i l l ). 8.15 (s, 1H), 7.93 i s. H I ). 6.85 (s, l ! l !. 6.46 kid. ./ 2.4, 7.6 Hz, 1H), 6.18 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.46-3.42 (m, IH), 3.31-3.28 (m, 2H), 3.07-3.03 (m, 1H), 2.73 (d, J - 2.4, 1 1.2 Hz, 2H), 2.55-2.51 (m, 2H), 2.40 (d, J = 6.8 Hz, 3H), 2.13-2.07 (m, 4H), 1.82- 1.77 (m, 2H), 1.72-

I .65 (m, 3H), 1.35-1 .30 (m, IH), 1.64-1.09 (m, 2H); HPLC (Method 3) 95.7% (AUC), fe =

I I .07 min.; ESi+APCl MS m/z 498 [M + \ \ V .

Yl)pYrrolidin-3-yI)methyi)aRiIine 28f (Example_68)^

N-(( 1 -(2-(5 -Chloro-2,4-dimethoxypheny l)imidazo j 1 ,2-ajpy ridin-7-yl)pyrrolidin-3- yl)metliyl)aniline 28f was prepared in the same manner as N-((l -(2-(5-chloro-2,4- dimeihoxyphenyr)imidazo[ l,2-a]pyridin-7-yl)pyffolidin-3-yl)methyl)- amme 28a and was obtained as an off-white solid ( 19% yield).

! H NMR (400 MHz, DMSO- e) δ: 8.27 (d, J = 7.6 Hz, 1H), 8.15 (s, ΓΗ), 7.95 (s, IH), 7.07 (t, ,/ 8.4 Hz, 2H), 6.85 (s. 1H), 6.60 id. ./ 7.6 Hz, 2H), 6.59 - 6.49 (m, 2H), 6.20 (s, IH), 4.01 (s, 3H), 3.93 (s, 3H), 3.54-3.51 (ra, IH), 3.49-3.41 (m, IH), 3.15-3.07 (m, 3H), 2.67-2.60 (m, 2H), 2.22-2.14 (m, IH), 1.87-1.80 (m, IH): HPLC (Metliod 5) 99.7% (AUC), /P. = 7.16 mm.; ESI+APCI MS m/z 477 M + l i |

Scheme 5

Preparation of methyl l-{2-ami pyridi -4-vI)pyrr lidine-3-c¾rboxylate 2; _

To a solution of 4-chloropyridin-2-amine 1-1 (0.48 g. 3.75 mmol) in N,N- diisopropylethyl amine (10 mL), was added methyl pyrrolidine-3-carboxylate (0.93 g, 5.65 mmol). The reaction mixture was heated in a seal tube at 120 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, The residue was partitioned between EtOAc and saturated aqueous NaHCCb solution (300 ml/ 100 mL). The layers were separated and the EtOAc layer was washed with brine (10 mL), dried over anhydrous Na?.S04, filtered and concentrated. The crude material was triturated with hexanes, filtered and dried to provide methyl l-(2-ammopyridin-4-yl)pyrroiidine-3- carboxylate 1-2 (700 nig, crude) as an off-white solid, which was used directly for next step without further purification. ESH-APC1-MS mJz 222 [M -f- Hf. vl)pyrrolidiae-3-carboxylateJ 3j__

A mixture of methyl l-(2-aminopyndin-4-yl)pyrrolidme-3-carboxylate 1-2 (0.50 g, 2.262 mmol) and 2-bromo-l-(5-chloro-2,4-dimethoxyphenyl)ethanone (0.726 g, 2.48 mmol) in acetone (50 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature. The white precipitate formed was collected by filtration, washed with hexanes (20 mL), and dried. The hydrobromic salt w r as suspended in saturated aqueous NaHCCb solution (15.0 mL) solution and stirred at room temperature for 1 h. The solid was collected by filtration, washed with water and dried to give methyl l-(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo[l.,2-a]pyri^ 1-3 (0.2 g,

47%) as an off-white solid.

i f NM (400 MHz, CDCb): δ 8.31 (s, 1H), 7.80 (d, J = 7.2 Hz, 11 1 ·. 7.74 (s, IH), 6.50 (s, IH), 6.41 (s, IH), 6.28 kk!. ./ 2.0, 7.2 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.68 (s, 3H), 3.56 id. ·/ 7.2 Hz, 2H), 3.44-3.40 (m, IH), 3.37-3.31 (rn, 1H), 3.22-3.15 (m, 1H), 2.29-2.24 (ra, 2H). ESI+APCI-MS m/z 416 [M + H] +

Preparation of l-(2- 5-chSoro-2,4-€SimethoxyphenyS)imid¾zo|l,2-a]pyridij ^

yj)pyrrolidine-3-carbo. ylic add 1 -4;

To a solution of methyl l-(2-(5-chloro-2,4-dimeihoxyphenyl)imidazof 1,2- «Jpyridin-7-yl)pyrrolidine-3-carboxylate 1-3 (1.0 g, 2.4 mmol), in THF, CH3OH and water (20 mL 10 mL/ 5 mL), was added LiOH » tbO (0.40 g, 9.6 mmol) and the resulting mixture was stirred at ambient temperature for 5 h. Hie solvents were evaporated and the residue was diluted with water and extracted with ethyl acetate (2 χ 10 mL). The aqueous layer was acidified to pH 3-4 with 10% KHSO4 solution. The precipitate formed was collected by filtration, washed with water and dried to afford l-(2-(5-chloro-2, 4- dime†hoxyphenyl)imidazof l,2-G]pyridin-7-yl)pyrrolidine-3-carboxylic acid 1-4 (750 mg, 78%) as an off-white solid.

f i NMR (300 MHz, DMSO fe): δ 8.29 (d, ,/ 7.5 Hz, IH), 8.16 (s, IH), 7.96 is. IH), 6.85 (s, IH), 6.51 (d, J = 6.6 Hz, IH), 6.24 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.57-3.46 (m, 2H), 3.37-3.33 (m, 2H), 3.25-3.18(m, 1H), 2.27-2.17 (m, 2H); ESI+APCI MS m z 402[M + H] + .

Preparation of 1 -(2-(5-c.hloro-2,4-dimetho. yphenyI)imidazoP ,2- ]pyr¾dm-7-yl)-A^

To a solution of l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| l ,2-«]pyridin-7- yl)pyrrolidine-3-carboxylic acid 1-4 (200 mg, 0.498 mmol), N,(9-Dimethyl hydroxylamine hydrochloride (72 mg, 0.747 mmol), N^V'-diisopropyleth i amine (256 mg, 1.99) in DMF (2.0 mL), was added EDOHC1 (190 mg, 0.996 mmol) and hyderoxybenztriazole (HOBt, 152 mg, 0,996 mmol). The resulting mixture was stirred at ambient temperature for 15 h. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate (2 χ 50 mL). The combined organic layer was washed with water (2 χ 25 mL) followed by brine, dried over anhydrous Na?.Si)4, filtered and concentrated to afford l-(2- (5-chlorQ-2,4-dimethoxyphenyl)im^

methylpyrrolidine-3-carboxamide 1-5 (200 mg, crude). The crude material was used directly in the next step without further purification,

! H NMR (300 MHz, DMSO-de): δ 8.29 (d, J = 7.2 Hz, 1H), 8.16 (s, 1H), 7.95 (s, IH), 6.85 (s, 1 H), 6.51 (d, J = 7.5 Hz, 1H), 6.23 (s, III), 4,00 (s, 3H), 3.93 (s, 3H), 3.72 (s, 3H), 3.59-3.55 (m, 2H), 3 ,42-3.37 (m, 3H), 3.15 (s, 3H), 2.26-2.08 (m, 2H); ESi+APCl

To a solution of l -(2-(5-chloro-2,4-dimethox>^henyl)imidazo[l,2-o]pyridin-7 -yl)-

N~niethoxy~A'-methylpyrrolidine-3-carboxamide 1-5 ( 1.0 g, 2.25 mmol) in anhydrous THF (500 mL) cooled to -78 °C, was added a solution of LAH in THF (2.0 M, 3.37 mL, 6.75 mmol). The resulting reaction mixture was stirred at -78 °C for additional 1 h. The reaction mixture was warmed to 0 °C and quenched with wet NazSO^ solid, and the resulting mixture was stirred at ambient temperature for 1 h. The white solid was filtered off by passing through a pad of celite, which was washed with ethyl acetate (2 χ 50 mL). The combined filtrate was concentrated to afford 1 -(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-a]pyridin-7-yl)pyrrolidine-3-cai b 1-6 (800 mg, crude), which was used in next step without purification. ESI+APCI MS m/z 386[M + H] + .

To a suspension of l-(2~(5-chlofo~2,4-dimethoxyphenyi)imidazo[l,2-a]pyridin-7- yl)pyrrolidine-3-carbaldehyde 1-6 ( 150 mg, 0.389 mmol), 2-cy clopentylethan- 1 -amine (66 mg, 0.584 mmol) in CH3OH (5.0 mL) and CH2CI2 (5.0 mL), was added acetic acid (0.05 mL) and the resulting mixture was stirred at room temperature for 2 h.

Sodiumcyanoborohydride (73 mg, 1 .168 mmol) was then added and the reaction mixture was stirred at room temperature tor another 5 h. The reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with CH2G2 (2 y 10 mL). Hie combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by eombi-flash (silica gel,

N H iOU/O LOH/i S H ;.· 1 :9:90) to afford Λ ' -U i -i 2 -i5- hioro-l -i - dime†hoxyphenyl)imidazo[ i,2-a]pyridin~7-y5)py

1 -amine ! -7a (30 mg, 1 6%) as an off-white solid.

lH NMR (400 MHz, CD3OD) δ: 8.00 i d. ./ 7.2 Hz, i l l ). 7.96 is H I). 7.80 (s, 1H), 6.68 i s. i l l). 6.41 (dd, J -- 2.4, 7.2 Hz, 1H), 6.17 (s, H i ). 3.91 (s, 3H), 3.84 (s, 3H),

3.49-3.45 (m, 1 H), 3.41 -3.35 (m, III), 3.31 (q, ./ = 8.4 Hz, IH), 3.01 (t, J = 8.0 Hz, IH), 2.63 id. ./ 7.6 Hz, 2H), 2.57 (t, J ------- 7.6 Hz, 2H), 2.49-2.43 (m, IH), 2.18-2.1 1 (m, IH),

1.74-1.45 (m, lOH), 1.10- 1 .01 (m, 2H); HPLC (Method 4) 93.0% (AUG), ;\< ----- 6.85 mm.;

ESI+APCI MS m/z 483 [M + Hf.

Preparation of i-(l-{2-(5-c¾l ro-2,4-dimet¾oxyp¾e8¾yI)imidazo L2-a|pyndin-7- yS)pyrroj¾din-3-yS -A^(cvc.lohexylmet¾yS)methanamine l-7b (Example 2-53);

1 -( 1 -(2-(5 -Chioro-2,4-dime thoxyphenyl)imidazo 11 ,2 -o]pyridin-7-yl)pyrrolidin-3- yl)-N-(cyclohexylmethyl)methanamine l-7b was prepared in the same manner as N-((l -(2- (5-diloiO-2,4-dimemoxyphenyl)imidazo[ l,2-tf jpyr^^ cyelopenty3eth.an-l -amine l-7a, using cyclohexylmetbanamine, and was obtained as an off- white solid (8% yield).

] H NM (400 MHz, CDsOD) δ: 8.00 (d, J= 7.2 Hz, lH), 7.93 (s, 1H), 7.79 (s, 1 H),

6.67 (s, H i ). 6.41 (dd, ./ 2.0, 7.2 Hz, IH), 6.16 i s. 1H), 3.91 (s, 3H), 3.84 i s. 3H), 3.49- 3.44 (m, 1H), 3.38-3.35 (m, I II), 3.31-3.26 (rn, 1H), 3.00-2.96 (m, 1H), 2.68 (d,■/ 7.6 Hz, 2H), 2.51-2.48 (m, IH), 2.46 (d. ./ 6.8 Hz, 2H), 2.19-2.12 (m, IH), 1.72- 1.46 (m, 7H), 1.30- 1.09 (m, 3H), 0.91 -0.79 (m, 2H); HPLC (Method 7) 98.6% (AUC), ,¾ = 7.39 min.; ESI+APCI MS m/z 483 [M + H] + .

Preparation of A"-((i-(2-(5-chSoro-2,4-dimethoxypS¾es¾yI¾imickg:oj ' i,2-ajpyridin-7- yl)pyrroIidin-3-yl)methyl)c.yeIoheptai¾am e l-7c (Example 2-32J^

N-(( l-(2-(5-Chloro-2,4-dimethoxyphenyl)im

yl)methyl)cycloheptanatnine l-7c was prepared in the same manner as N-((l-(2-(5-chloro-

2,4-dinietiioxyphenyl)iniidazo| l,2-«]pyri

eyclopentylethan-l -amine l-7a, using cyclokeptanamine, and was obtained as an off-white solid ( 12% yield).

'H MMR (400 MHz, (Ί) Of) } δ: 8.01 (d, J= 7.2 Hz, IH), 7.96 (s, ΓΗ), 7.80 (s, IH),

6.68 (s. IH), 6.42 (dd, ./ 2.4, 7.6 Hz, IH), 6.17 (s, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.50- 3.46 (m, I H), 3.41 -3.36 (m, IH), 3.31-3.24 (m, IH), 3.01-2.96 (m, I H), 2.67 (d, J = 6.8 Hz, IH), 2.65-2.64 (m, IH), 2.47-2.40 (m, IH), 2.19-2.12 (m, IH), 1.87-1.81 (m, 2H), 1.71- 1.60 (m, 3H), 1.54- 1.32 (m, 9H); HPLC (Method 4) 93.3% (AUC), = 6.70 mm.;

ESI+APCI MS m/z 483 [M + Hf.

l-(l -(2-(5-Chloro-2,4-dimethoxyp enyl)imidazo[l ,2- ]pyridin-7-y])pyrrolid yl)-N-(cycioheptylmethyi)mei anaraine l -7d was prepared in the same manner as N-((l-(2- (5-chloix>-2,4-dimeflioxyphenyi)imidazo[ l,2-o |pyridin-7-yi)py

cyclopentylethan-1 -amine l-7a, using cycioheptyhnethanamine, and was obtained as an off- white solid (24% yield). ¾ NMR (400 MHz, CD3OD) δ: 8 ,00 (d, ,/ 7.6 Hz, 1H), 7.96 (s, 1H), 7.79 (s, i l l). 6.68 (s, IH), 6.41 (dd, ./= 2.4, 7.6 Hz, 1 H), 6.17 (d, J= 1.6 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.48-3.44 (m, I H), 3.38-3.33 (m, IH), 3.29-3.24 (m, IH), 3.00-2.96 (m, IH), 2.62- 2.59 (m, 2H), 2.49-2.40 (m, IH), 2.39 (d, ,/ 6.4 Hz, 2H), 2.17-2.09 (m, IH), 1.72- 1.35 (m, 12H), 1.18-1.1 1 (m, 2H); HPLC (Method 4) 98.4% (AUG), fe - 6.82 mm.; ESHAPCI MS m/z 497 j \ t + H] \

Preparation oi iY {l-(2-[5-chloro-2.4-dimethoxYrf^

N-((l-(2-(5-chloro-2,4-dimetho:^^

yl)methyl)-2-cyclohept 'letban-l-amme l-7e was prepared in the same manner N-((l-(2-(5- chloro-2,4-dimetlioxyphenyl)imidazo[ l,2-a]pyridin-7-yl)py

cyclopent lethan- 1 -amine l-7a, using 2-cycloheplylethan-l -amine, and was obtained as an off-white solid (7.5% yield).

[ H NMR (400 MHz, CD3OD) δ: 8.00 (d, J= 7.6 Hz, IH), 7.95 (s, IH), 7.77 (s, IH), 6.67 (s, IH), 6.40 (dd, ./ 2.4, 7.6 Hz, IH), 6. 16 (d, ./ 1 .6 Hz, I H), 3.91 (s, 3H), 3.84 (s, 3H), 3.48-3.43 (m, IH), 3.40-3.37 (m, IH), 3.29-3 ,24 (m, I H), 2.99 (t, ,/ 7.6 Hz, IH), 2.64 (d, J= 7.2 Hz, IH), 2.58 (t, J = 8.0 Hz, 2H), 2.48-2.41 (m, I H), 2.17-2.09 (m, IH), 1.71-1.32 (m. 14H), 1.19-1.12 (m, 1 1 ). HPLC (Method 4) 98.6% (AUC), κ = 7.00 min.; ES1+ APCI MS m/z 511 [M + H] + .

Preparatiosi of A^-Cil-C -CS-dil ro-l^-dimetSnMYpl 'iSYnimsdazoiLl-al vridsn

N 1 -((l -(2-(5~ehloro-2,4-diniethoxyphenyi)imidazo[I ,2~ ]pyridm~7-y

yl)methyl)-A^,7^-diroethylcyclohexane-l,4-diamine l-7f was prepared in the same manner as N-((l -(2-(5-chloro-2,4-diniethoxyphenyi)iniidazo[ l ,2-a]pyridin-7-yl)pyrrolidin-3- y3)methyl)-2 -cyclopentylethan- 1 -amine 1 -7a, using Λ /! /] -dimethylcyclohexane- 1 ,4- diamine, and was obtained as an off-white solid (24% yield).

] H NMR (400 MHz, CDsOD) δ: 8.01 (d, J= 7.2 Hz, IH), 7.95 (s, IH), 7.80 (s, IH), 6.68 (s, IH), 6.43 (dd, J= 2.4, 7.6 Hz, 1H), 6.18 (d, J = 2.0 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.50-3.46 (m, 1H), 3.42-3.36 (m, IH), 3.32-3.26 (m, 1H), 3.05-3.01 (m, 1H), 2.71-2.60 (ra, 3H), 2.49-2.41 (m, ΓΗ), 2.25-2.14 (m, 8H), 1.78-1.45 (m, 9H); HPLC (Method 4) 99.3% (AUC), = 6.32 mm.; ESI+APCI MS m/z 512 [M + Hf.

Pre j ^atjj^ l-(l-(2~(5-Chloro-2,4-dim.ethoxy

yl)-N~((l -met yipyrroi.idin-3~yi.)m l-7g was prepared in the same manner as N-((l.-(2-(5-ehloro-2,4-dimeAoxyphenyl)im^

3-yl)methyl)-2-cyc3openlylethan-l -amine 1 -7a, using (1 -methyipyrrolidin-3- y3)niethanamine, and was obtained as an off-white solid (12% yield).

¾ NMR (400 MHz, CD 3 OD) δ: 8.06 (d, ./ 7.6 Hz, 1H), 7.86 (s, 1H), 7.82 (s, 1H),

6.70 (s, 1H), 6.50 (dd, J - 2.4, 7.6 Hz, 1H), 6.19 (d, J 2.0 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.51-3.47 (m, IH), 3.41-3.38 (m, 1H), 3.33-3.27 (m, 1H), 3.05-2.97 (m, 2H), 2.86 (t,

J 6.8 Hz, 2H), 2.75-2.64 (m, 4H), 2.61-2.55 (m, 1H), 2.55-2.41 (m, 5H), 2.00-2.02 (m,

2H), 1.77-1.60 (m, 1H), 1.61-1.52 (m, 1H); HPLC (Method 4) 95.0% (AUC), & = 6.29 min.; ESI+APCi MS m/z 484 [M + Π |

l-(l-(½rf-Butyl)pyrrolidin-3-yl)-N-((l-(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-a]pyridin-7-yl)pyrrolidin-3-yl)m eth^^ l-7h was prepared in the same manner as A-(( l-(2-(5-ch1oro-2,4-difflethoxyphenyl)imidazo[l,2- a]pyridin-7-yl)pyrrolidin-3-yl)me Ayl)-2-cyclopentylethan- 1 -amine l.-7a, using (] -(ter(- butyl)pyrrolidin-3-yl)niethanamine, and was obtained as an off-white solid ( 11% yield).

f i NMR (400 MHz, DMSO fe) δ: 8.12 (d, ./ 7.6 Hz, IH), 7.87 (s, 1H), 7.79 is. 1H), 6.73 (s, IH), 6.60 (dd, J= 2.4, 7.6 Hz, IH), 6.25 (d, ./ 2 Hz, IH), 3.95 (s, 3H), 3.87 (s, 3H), 3.55-3,28 (m, 6H), 3.11-3.07 (m, Hi).2.95-2.90 (ra, IH), 2.73-2.63 (m, 4H), 2.52- 2.45 (m.2H), 2.21-2.12 (ra, 2Π).1.80-1.63 (m, 2H), 1.29 (s, 9H); HPLC (Method 7) 97.6% (ALC). ¾ = 6.42 mm.; ESI+APCT MS m/z 526 [M + H] + . yOg goIjdjn^

N-((l-(2-(5-CMoro-2,4-dimethoxyphenyl)m

yl)methyl)-i-ethylpiperidm-4-aniine 1-71 was prepared in the same manner N-((l-(2-(5- chloro-2,4-dimethoxyphenyl)imida^^

cyclopentylethan-1 -amine l-7a, using l-ethylpiperidin-4-amine, and was obtained as an off- white solid (24% yield).

'H MR (400 MHz, CDBOD) δ: 7.99 (d, J ------- 7.6 Six. IH), 7.94 (s, lif).7.79 (s, !H).

6.67 (s, IH), 6.40 idd../ 2.4, 7.6 Hz, IH), 6.15 (d, ./ 2.0 Hz, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.48-3.43 (m, IH), 3.38-3.34 (m, IH), 3.29 (q, ./ 8.0 Hz, IH), 2.98-2.90 (m, 3H), 2.63-2.50 (m, 2H), 2.49-2.35 (m, 4H), 2.17-2.09 (m, IH), 2.00 (t, J= 12.0 Hz, 2H), 1.88 (d, J= 12.8 Hz, 2H), 1.71-1.64 (m, IH), i .40 (q, J= 11.6 Hz, 2.H), 1.03 (t, J = 7.2 Hz, 3H); HPLC (Method 4) 98.7% (AUC), .¾ = 6.29 mm.; ESI+APCI MS m/z 498 [M + H|

Preparation of A-((l-(2-(5-c.hkr -2,4-dim th ¾yphenyI imida¾ ll,2-a pyridm-7- Yl)PYrrolidin-3-yl)methyl)-l-isopropylpiperidin-4-amine 1-7; (Example 2^27}^

N-(( 1 "(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo| 1 ,2-«Jpyridin-7-yl)pyrrolidin-3- yl)methy 1)- 1 -methylpiperidin-4-amine 1-1 \ was prepared in the same manner as N-((l-(2- (5~ehloro-2,4-dimemoxyphenyl)imidazo[l,2 [pyridin~7-yi)pyrrolidm

cyclopentylethan-1 -amine l-7a, using 1 -meth lpiperidin-4-amine, and was obtained as an off-white solid (16% yield).

'HNMR (400 MHz, CD3OD) δ: 7.96 (d, J= 7.6 Hz, IH), 7.95 (s, IH), 7.77 (s, IH), 6.66 (s, IH), 6.36 (dd, ./= 2, 7.2 Hz, IH), 6.12 (d, J= 1.6 Hz, IH), 3.90 (s, 3H), 3.83 (s, 3H), 3.45-3.40 (m, IH), 3.33-3.30 (m, IH), 3.26-3.21 (m, IH), 2.94 ( J ------ 8 Hz, IH), 2.86 (d, J

------ 12.0 Hz, IH), 2.68-2.56 (m, 3H), 2.41-2.31 (m, 2H), 2.19-2.08 (m, 3H), 1.86 (d, ./ 12.0

Hz, 2H), 1.66-1.60 (m, 3H),1.36 (q, J ------- 10.8 Hz, IH), 0.99 (d, ./ 6.4 Hz, 6H): HPLC (Method 7) 98.0% (AUC), fe = 6.33 rain.; ESI+APCl MS m/z 512 [M + Hf.

Preparation of l-(ferf-butyl)-iV-((i-(2-(5-chloro-2,4-dimethoxvpheayl iniidazo ¾-.i¾: ajpyridin-7-yl)pyrrolidin-3-yl)methyl)piperidiH-4-amii¾e l-7k (Example 2-35);

l-(fm-Butyl)-N-((l-(2-(5-chlorQ-2,4-dim

yl)pyrrolidin-3-yl)methyl)piperidm-4-amine l-7k was prepared in the same manner as N- ((l-(2-(5-chioro-2,4-dimethoxyphenyl)im

2-cyclopenly leAan- 1 -aniine l-7a, using 1 -(ter -butyl)piperidin-4-aniine, and was obtained as an off-white solid (51% yield).

: H \ MR i -!OO MHz, CDsOD): δ 7.99-7.96 (m, 2H), 7.79 (s, IH), 6.67 (s, IH), 6.38 (dd, ./= 2.4, 7.6 Hz, 1H), 6.15 (d, J= 2.0 Hz, lH), 3.91 (s, 3H), 3.84 (s, 3H), 3.47-3.43

(ra, i l l). 3.38-3,33 (m, 1H), 3.29-3.21 (ra, i l l). 3.00-2,93(ra, 3H), 2.64-2.55 (m, 2H),

2.43-2.31 (m, 2H), 2.16-2.09 (m, 3H), 1 .85 (d. ./ 12.4 Hz, 2H), 1.71-1.61 (in. i l l}.

1.36-1.27 (m, 2H), 1.02 (s. 9H); HPLC (Method 4) 99.4% (AUC), .< = 6.37 mm. ;

ES1+APCI-MS m/z 526 M + H] + .

Flgff atjo^

yjjpyrrolidin-3-yl)- -((l-ethylpiperidin-4-Yi)methyl)niethanamine 1-71 Ex m iej i 36);

l-(l~(2-(5-Chloro-2,4-dimei oxyphenyl)im

y3)-A-((l-ethylpiperidin-4-yl)metliyl)methariamine 1-71 was prepared in the same manner as JV-(( 1 ~(2-(5 -chloro-2,4-dimetlioxyphenyl)imidazo [ 1 ,2-o]pyridin-7-yl)pyrrolidin-3 - y l)methyl)-2-cyclopentyletlian- 1 -amine l-7a, using ( 1 -etliylpiperidm-4-yi)methanamine, and was obtained as an off-white solid (25% yield).

'H MMR (400 MHz, CD3OD) δ: 8.01 (d, J= 7.6 Hz, 1H), 7.96 (s, ΓΗ), 7.80 (s, i l l).

6.68 (s, IH), 6.42 (dd, ./ 1.6, 7.6 Hz, 1H), 6.17 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.49 (t, J = 8.8 Hz, I H), 3.41 -3.35 (ra, IB), 3.31 (q, J= 7.6 Hz, IH), 3.02 (t, J= 8.0 Hz, I H), 2.92 (d,

J= 11.2 Hz, 2H), 2.61 (d, J = 6.0 Hz, 2H), 2.48-2.30 (m, 3H), 2.38 (q, J = 7.2 Hz, 2H),

2 15 2. 1 i ( . IH), 1.94 (t, J = 1 1.2 Hz, 2H), 1.73-1.66 (m, 3H), 1 .53- 1.43 (m, IH), 1.23-

1.13 (m, 2H), 1.03 (t, J = 7.6 Hz, 3H): HPLC (Method 4) 99.4% (AUC), & === 6.35 min.; ESI+APCI MS m/z 512 [M + Hf.

Preparation of l-(l-(2-(S-ch¾oro-2 ¾ 4-dimethoxYphenYi¾imidazo l,2-al)yridin-7- y! pyrroIidin-3-Yl)-A r -((1-isopropYlpiperidii¾-4-Yl)methyl)methanamme l-7m (Example l-(l-(2-(5 ¾ioro-2,4-dimethoxypheny

yl)-N-((l-isopropjdpiperidin-4-yl)methyl)methanainine l-7ni was prepared in the same manner as N-(( l-(2-(5 -chloro~2,4~dimethoxyphenyl)imidazo [ 1 ,2 -a]pyridin-7-y l)pyrroiidin- 3 -yl)methyl)-2-cyclopentylethan- 1 -amine l-7a, using ( 1 -isopropylpiperidin-4- yl)methanamine, and was obtained as an off-white solid (15% yield).

lH NMR (400 MHz, DMSO-a¾): δ 8.26 (d, J= 7.2 Hz, IH), 8.15 (s, 1H), 7.94 (s,

Hi).6.85 (s, ill).6.48-6,45 (m, III}.6.18-6.16 (m, LH), 3.99 (s, 3H), 3,92 (s, 3H), 3.47-3.37 (m, I I), 3.14-3.02 (m, IH), 2.86-2.72 (m, 111), 2.64-2.56 (m, 2H), 2.33-2.29 (m.2H), 2.19-2.10 (m, 4H), 1.74-1.71 (m, 4H), 1.48-1.32 (m, ill}.1.16-1.08 (m, 2H), 0.98-0.86 (m, 8H); HPLC (Method 5) 91.6% (AUG), 6.33 min.; ESI+APCI-MS m/z 526 [M + H] + .

Preparation of tert-butv\ 4-(2-( 1- 2- 5-€ΗίθΓθ-2,4-ά™6ίΗοχν ίϊ6ην1)™ϊά3ζο[1.2- ajpYridin-7-Yl)pYrrolidin-3-Yl)methvi)amino)ethYl)piperidii e-l-carbo¾:Yiate l-7n_ Example - __

ferf-Butyl 4-(2-(((l-(2-(5-Chk>ro-2,4-dimethoxyphenyl)imidazo[l,2^|p yridin-7- yl)pyTiX)lidin-3-yl)methyl)arnino)ethyl)piperidine-l-carboxy late l-7n was prepared in the same maimer as N~((l-(2~(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2-a]pyridin-7- yl)pyrrolidin-3-yl)methyl)-2-cyclopentylethan- 1 -amine l-7a, using tert-butyl 4-(2- aminoethyl)piperidine-l -carboxylate, and was obtained as an off-white (pale blue green) solid (70% yield).

lH NMR (400 MHz, CD3OD) δ: 7.98 id../ 7.6 Hz, ill).7.94 is HI).6.66 (s, 1H),

6.37 (dd, ./ 2.0, 7.2 Hz, III), 6.13 (d, J ------ 2.0 Hz, 1H), 3.96 (d, J -- 13.2 Hz, 2H) 3.91 (s,

3H), 3.84 (s, 3H), 3.45-3.41 (m, Hi), 3.37-3.32 (m. IH), 3.28-3.24 (rn, lif).2.96 id../ 7.6 Hz, IH) , 2.69-2,55 (m, 6H), 2.45-2.41 (m, IH), 2.15-2.07 (m, 1H),1.69-1.58 (m, 3H), 1.45-1.38 (m,3H), 1.35 (s, 9H), 1.04-0.94 (m, 2H); HPLC (Method 7) 99,3% (AUG),■'■> = 6.96 min.; ESI+APCI MS m/z 598 [M + Hf.

Preparation AM(1 2-|5-ehloro-2,4-dimethoxyphe^ 3J

A-((l-(2-(5-CMoro-2,4-dimethoxyphenyl)m

y l)methyl)-2-( 1 -methylpiperidin-4-yl)ethan- 1 -amine l-7o was prepared in the same manner as N-((l-(2-(5-cMoro-2,4-dime&oxypheny

yl)merayi)-2-cyciopentylethan- 1 -amine l-7a, using 2-( 1 -methy{piperidin-4-yl)e1han- 1 - amine, and was obtained as an off-white solid (9.4% yield).

: fi NMR (300 MHz, DMSO-<¾) δ: 8.27 (d, ,/ 7.6 Hz, ill).8.15 (s, 1H), 7.93 is. IH), 6.85 (s, l!l!.6.47 (d, J= 6.6 Hz, IH), 6.18 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.46- 3.41 (m, 21113.27-3.13 (m, 2H), 3.08-3.02 (m, 1H), 2.72 (d../ 11.7 Hz, 1H), 2.67-2.55 On.3H), 2.43-2.32 (m, 3H), 2.20-2.00 (m, 4H), 1.82-1.68 (m, 3H), 1.61 id../ 11.7 Hz, IH), 1.35-1,30 (m, 2H), 1.25 (s, 1H), 1.16-1.06 (m, 2H); HPLC (Method 4) 96.8% (AUG), tR = 6.29 mm.; ESI+APCI MS m/z 512 [M + Hf.

Preparation of A-((l-(2-(5-c.hkr -2,4-dimeth ¾yphenyI)imida¾ n-i2-a pYridm-7- y2)PYrrolidin-3-yl)methvl)-2-(1-ethylpiperidin-4-vl)ethaH-1- amii¾e l-7p (Example 45);

A-((l-(2-(5-cmoro-2,4-dimethoxypheny^

yl)methyl)-2~(l-ethyipiperidin-4-yl)etliaii-l-amiiie l-7p was prepared in the same manner as A^(I~(2~(5-chloro~2,4~dimethoxy^

yl)methyi)-2-cyciopentylethan- 1 -amine l-7a, using 2-( 1 -ethylpiperidin-4-yl)ethan- 1 -amine, and was obtained as an off-white solid (92% yield),

U NMR (400 MHz, CD3OD) δ: 8.01 id../ 7.2 Hz, ill).7.96 is IH), 7.81 (s, 1H),

6.69 is. IH), 6.41 (d, 7.2 Hz, IH), 6.17 (s, 1H), 3.92 is.3H), 3.85 (s, 3H), 3.49-3.451 (m, IH), 3.41-3.37 (m, Hi).3.44-3.42 (m, IH), 3.03 ii../ 8.0 Hz, lif).2.90 id../ 10.4 Hz, 2H), 2.65-2.57 (m, 4H), 2.50-2.42 (m, IH), 2.40-2.34 (m, 2H), 2.15-2.12 (m, IH), 1.96 (t, J= 10.4 Hz, 2H), 1.72-1.65 (m, 3H) 1.45-1.43 (ra, 2H), 1 .41-1.39 (ra, 1H), 1.24- 1.18 (m, 2H), 1.03 (t, ./= 7.2 Hz, 3H) ; HPLC (Method 4) 96.7% (AUC), tn = 6.34 mm .; EST+APCI MS m/z 526 [M + H] + . y])tiY.g ^

44);

jV-((l~(2-(5~Chloro-2,4~dimethoxyphenyl}iinidazo| l,2-ajpyridm-7-yl)pyriOiidm-3- yl)methyl)-2-( 1 -propylpiperidin-4-yl)ethan- 1 -amine l-7q was prepared in the same manner as N~((l ~(2-(5 :hloro-2,4-diracthoxy

yl)meAyl)-2-cyclopentyletban- 1 -amine l-7a, using 2-( 1 -propylpiperi din-4-yl)etha - 1 - amine, and was obtained as an off-white solid (28% yield).

] H NMR (400 MHz, CD3OD) 8: 7.99 (d. ./ 7.6 Hz, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 6.68 (s, IH), 6.40 (dd, J= 2.4, 7.6 Hz, 1H), 6.16 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.48- 3.44 i m. l i l t. 3.40-3.35 (m, H i ;. 3.31-3.24 (m, 1H), 3.01-2.97 (m, 1H), 2.89 (d, J = 11.6 Hz, 2H), 2.64-2.56 (ra, 4H), 2.49-2. 1 (m, 1H), 2.27-2.23 (m, 2H), 2.17-2.1 1 (m, 1H),

1.98 (t, J= 12.0 Hz, 2H), 1 ,73-1.63 (m, 3H) 1.47-1.38 (m, 4H), 1.37-1 , 18 (m, 3H), 0.83 (t, ./= 7.6 Hz, 3H); HPLC (Method 4) 98.1% (AUC), fe = 6.24 min.; ESI+APCI MS m/z 540 [Μ - ΗΓ.

tert-Butyl 4-(3-(((l-(2-(5-ehloro-2,4-dimethoxyphenyl)imidazo[3 ,2-<i]pyridin-7- yi)pyrroiidin-3-yi)methyS)amino)propyi)piperidine-i-ea l-7r was prepared in the same manner as N-((l-(2-(5-cWoro-2,4-dimetlioxyphenyl)imidazo[l,2-a]pyridin -7- yl)pyrrolidin-3-yl)methyl)-2-eyclopentylethan-l -amine l.-7a, using tert-butyl 4-(3- aniinopropyl)piperidine-l-carboxylate, and was obtained as an off-white solid (12% yield).

Ι N MR (400 MHz, CD3OD) δ: 8.01 (d, J ------- 7.2 Hz, I H), 7.95 (s, 1H), 7.80 (s, 1H),

6.68 (s, IH), 6.42 (d, J = 7.6 Hz, IH), 6.18 (s, IH), 3.97 (d, J= 19.6 Hz, 2H) 3.92 (s, 3H), 3.85 (s, 3H), 3.49 (t, J= 8,4 Hz, IH), 3.42-3.35 (m, 1H), 3,33-3.24 (m, IH), 3.02 (t, J = 1.6 Hz, 1H), 2.66-2.42 (m, 6H), 2.20-2.10 (m, IH), 1 .75-1 .65 (m, 1H), 2.39 (d, ./= 12.0 Hz, 2H), 1.55-1.45 (m, 2H), 1.40-1.25 (ra, 1 IH), 1 .25-1.13 (m, 2H), 1.00-0.93 (m, 2H); HPLC (Method 4) 92.6% (AUC), - 6.97 mm.; ESI+APCI MS m/z 612 M + Hf.

j*rg i t ^

(Example J-48^ niii

ter -Butj'i 3 -(((( I -(2-(5 -chl oro-2,4-dimetiioxyphenyl)imidazo [ 1 , 2-«]pyridin-7- yl)pyrroi.idm-3~yI)methy3)amino l-7s was prepared in the same manner as N-((l-(2-(5-cWoro-2,4-dimethoxyphenyl)imidazo[l.,2-a]pyridin -7- yl)pyrrolidin-3-yl)methyl)-2-cyclopentylethan-l -amine l -7a, using ferf-butyl 3- (aminomethyl)piperidine-l -carboxylate, and was obtained as an off-white solid (6% yield).

¾ NMR (400 MHz, CD 3 OD) δ: 8.00 (d, ./ 7.2 Hz, lH), 7.93 (s, 1H), 7.79 (s, 1H), 6.67 (s, 1H), 6.42 (dd, J = 2.0, 7.2 Hz, 1H), 6.16 (d, ./ 2 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.77-3.69 (m, 1H), 3.48-3.44 (m, 1H), 3.30-3.24(m, 2H), 3.02-2.97(m, 1H), 2.90-2.79 (m, IH), 2.63-2.54 (m, 3H), 2.49-2.39 (m, 3H), 2.18-2.09 (m, 1H), 1.82-1.54 (m, 4H), 1.40-1.39 (ra, i l l). 1.30 (s, 9H), 1.16-1.1 1 (ra, 2H); HPLC (Method 7) 99.2% (AUC), te = 7.46 rain.; ESI+APCI MS m/z 584 [M + \ \ \ .

l-(l-(2-(5-Chloro-2,4-dim.ethoxyp3ienyl)imidazo[l ,2- ]pyridin-7-yl)pyrrolidin-3- yl)-N-((l-methylpiperidin-3-yl)methyl)metiianamine l-7t was prepared in the same manner as N-((l-(2~(5-chloro~2,4~dimethoxyph

yl)methyl)-2-eyclopentylethan~ 1. -amine l-7a, using (l-methylpiperidin-3-yl)methanaroine, and was obtained as an off-white solid (11 % yield).

ΐ \ MR (400 MHz, CD3OD) δ: 8.00 (d, J ------- 7.6 Hz, I H), 7.95 (s, 1H), 7.79 (s, 1H),

6.68 (s, 1H), 6.42 (dd, J - 2.4, 7.6 Hz, 1H), 6.16 (d, ./ 2.0 Hz, IH), 3.91 (s, 3H), 3.84 (s, 3 ,48 (t, J = 8.4 Hz, I H). 3.40-3.34 (m, IH), 3.30-3.23 (ra, 2H), 3.01 (t, J = 8.0 Hz, ), 2.87 (d, J= 10 Hz, IH), 2.75 (d, J= 10.8 Hz, IH), 2.62-2.53 (m, 2H), 2.48-2.40 (ra, 3H), 2.1 8 (d, J= 2.4 Hz, 3H), 2.18-2.10 (m, IH), 1.90-1.82 (m, IH), 1.76-1.45 (m, 5H), 0.90-0.79 (m, IH), HPLC (Method 7) 97.6% (AUC), fe = 6.34 mm.: ESI+APCI MS m/z 498 [M + S i j .

Preparation of l-iI-i2-i5-ch!oro-2,4-dimethoxYphenyl)™

¾|) j£rpS¾djn^ ^ ^

1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyixoiidin-3- y])-N-((l -ethylpiperidin-3-yl)methy])me " thanamme l~7is was prepared in the same manner as N-(( l-(2-(5-chloro-2,4-dime ' thoxyphenyl)imidazo| " l ,2-o]pyridin-7-yl)pyrrolidin-3- yl)methyl)-2-cyclopentylethan- 1 -amine l-7a, using (l -elJiylpiperidin-3-yi)methanamine, and was obtained as an off-white solid (1 1% yield).

[ H NMR (400 MHz, CDsOD) δ: 8.02 (d, J= 7.2 Hz, IH), 7.92 (s, IH), 7.80 (s, IH), 6.69 (s, IH), 6.44 (dd, J= 2.0, 7.2 Hz, IH), 6. 17 (d, J = 2.0 Hz, I H), 3.92 (s, 3H), 3.85 is, 3H), 3.49 (t, J= 8,4 Hz, IH), 3.38-3.35 (m, IH), 3.29 (q, ,/= 9.2 Hz, IH), 3.08-2.95 (ra, 3H), 2.65-2.61 (m, 2H), 2.53-2.45 (m, 5H), 2.18-2.10 (m, IH), 2.07-1.99 (m, I H), 1.78- 1.67 (m, 5H), 1 .61 -1.50 (ra, IH), 1 .09-1 .04 (m, 3H), 0.99-0.90 (m, IH); HPLC (Method 4) 98.0% (AUC), fe = 6.33 min.; ESU-APCI MS 512 [M + H] + .

Preparatiosi i-{i -(2-(5-chloro-2,4-dimeihoxYphenYliimidazo[I,2-alpy

1 -( 1 -(2-(5-Chioro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N-((l-isopropylpiperidin-3-yl)methyl)tnethanarnine l-7v was prepared in the same manner as N-(( l-(2~(5-chloro-2,4-dimeihoxyphenyl)^

3-yi)methyl)-2-ey clopentyiethan- 1 -amine l-7a, using ( 1 -isopropylpiperidin-3- ylimetlianamine, and was obtained as an off-white solid ( 1 1% yield).

] H NMR (400 MHz, CDsOD) δ: 7.99 (d, J= 7.6 Hz, IH), 7.94 (s, IH), 7.78 (s, IH), 6.67 (s, IH), 6.39 (dd, J= 2,0, 7.2 Hz, 1H), 6.14 (d, J = 1.6 Hz, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.46 (I, J= 8.4 Hz, IH), 3.39-3.34 (m, IH), 3.29 (q, J= 8.0 Hz, IH), 3.02-2.96 (m, 2H), 2.89 (d, J= 11.6 Hz, lH), 2.81-2.73 (m, lH), 2.63-2.52 (m, 111), 2.49-2.39 (m, 3H), 2.12-2.09 (m, 2H), 1.91 (l. J I S .2 Hz. I H), 1.81-1.63 (rn, 4i f). 1 .59- 1.49 (m, 1H), 1.04- 1.02 (m, 6H), 0.95-0.82 (m, Hi), HPLC (Method 7) 97.6% (AUC), te = 6.39 min.;

ESI+APCI MS m/z 526 M + H] + .

Pre^a ^

54k

tert- utyl 4-(((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo l,2-a]pyridin-7- yl)pyn-olidin-3-yl)methy1)aroino)azepaiie-l -caiboxylate l-7w was prepared in the same manner as A " -(( l-(2-(5-chioro-2,4-dimethoxyphenyl)imidazo| 4 ^-aJpyridin-T-yl^yrrolidin- S-ylJmethyl^-cyclopentyleth^^ l-7a, tert-bvctyl 4-aminoazepane- 1 -carbox late, and was obtained as an off-white solid (8% yield).

¾ NMR (400 MHz, CD 3 OD) δ: 8.00 (d, J= 7.6 Hz, i l l). 7.94 (s, 1H), 7.79 (s, IH),

6.68 (s, IH), 6.41 (dd, J = 2.4, 7.6 Hz, IH), 6.16 (d, J= 1.6 Hz, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.48-3.44 (m, 2H), 3.39-3.26 (m . 4H), 3.24-3.11 (s, IH), 3.00 ii. ./ 8.4 Hz, IH), 2.64 (d, J= 6.8 Hz, 2H), 2.59-2.49 (m, IH), 2.42-2.38 (m, IH), 2.15-2.11 (m, IH), 1.96- 1.93 (m, IH), 1.87-1.71 (m, 21 1 ·. 1.70-1.65 (m, I H), 1.52-1.40 (rn, 2H), 1 .31 (s, 9H), 1.30- 1.18 (m, IH): HPLC (Method 7) 99.3% (AUC), ftt - 6.89 min.; ESI+APCI MS m/z 584 [M + H | .

N-(( 1 -(2-(5-Chloro-2,4-dirnethoxyphenyl)irnidazo[ 1 ,2-a]pyridin~7-yl)pyrrolidin-3- yl)methyl)-2-phenylethan- 1 -amine l-7x was prepared in the same manner as N-((l-(2-(5- chloro-2,4-dimetnoxyphenyl)imidazof

cyclopentylethan-1 -amine l-7a, using 2-phenylethan- 1 -amine, and was obtained as an off- white solid (15% yield). ¾ MR (400 MHz, DMSO- e) δ: 8.36 (d, J= 7,6 Hz, i l l) . 8.16 (s, 1H), 7.94 (s, 7.30-7.18 (m, 5H), 6.85 (s, 1H), 6.46 (dd, J= 2.4, 7.6 Hz, lH), 6.18 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.43-3.31 (m, H i). 3.40-3.39 (m, i l l) 3.38-3.36 {m, 1H), 3.10-3.0 (m, 1H), 2.77-2.72 (m, 4H), 2.67-2.55 (m, 2H), 2.50-2.45 (m, i l l ). 2.15-2.0 (m, 1H), 1.65- 1.60 (m, H I): HPLC (Method 4) 96.6% (AUC), te = 6.72 mm.: ES1+APCI MS m/z 491 [M + H i .

Pre$ ration oi

To a solution of l-(2-(5-ch1oro-2,4-dimetho7iyphenyl)imidazo[l,2^]pyridin-7-y {)- N-methoxy-N-methylpyn"olidine-3-carboxamide 1.-5 (500 rag, 1.12 mrool) in anhydrous THF (500 mL), was added a solution of CHjMgBr in DEE (2.0 M, 1.12 mL, 3.37 romol) at ambient temperature. The resultant reaction mixture was stirred at ambient temperature for additional 3 h. The reaction mixture was cooled to 0 °C, quenched with aqueous NH4CI solution and the aqueous layer was extracted with ethyl acetate (2 χ 50 mL). The combined organic layer was dried over anhydrous NaaSC , filtered and concentrated to afford l-(l-(2-(5-chloro-2,4-dimethoxyph^

y1)ethan-i~one 1 -8 (350 mg, crude). The crude product was used directly in next step without further purification. ESI+APCI MS m/z 400 [M 4- Hf.

rg r.^

To a suspension of 1 -( 1 -(2-(5-c oro-2,4-dimethoxyphenyl)imidazo [ 1 ,2- ]p ridin- 7-yl)pyrrolidin-3-yl)ethan-l -one 1-8 (150 mg, 0,375 mmol), 2-cyclopentylethan-l -amine (63 mg, 0,563 mmol) in CHsOH (5.0 mL) was added acetic acid (0.05 raL) and the resulting mixture was stirred at 80 °C for 12 h. To the reaction mixture was added sodium cyanoborohydride (71 mg, 1.12 mmol) and the reaction mixture was stirred at 80 °C for additional 6 h. The reaction mixture was cooled to room temperature, diluted with aqueous sodium bicarbonate solution and extracted with CH2CI2 (2 χ 10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-fiash companion (silica gel, NH4OH CH3OH CH2CI2 1 :9:90) to afford l-(l-(2-(5-ehloro-2,4-dimethoxypte

yl)~N-(2-cyclopentylethyl)ethan- 1 -amine l-9a (30 mg, 16%) as an off-white solid.

lH NMR (400 WW/.. CD3OD) δ: 8.00 id. ./ 7.2 Hz, i l l). 7.96 is IH), 7.80 (s, 1H), 6.68 (s, 1H), 6.41 id. ./ 7.2 Hz, 1H), 6.16 (s, 1 H), 3.92 (s, ill), 3.84 (s, 3H), 3.53 (t, J= 8.4 Hz, 1H), 3.45-3.35 (m, IH), 3.31-3.21 (m, IH), 3.04 (t, ./ 8.8 Hz, 1H), 2.67-2.60 (m, 2H), 2.53-2.46 (m, IH), 2.30-2.20 (m, IH), 2.10-2.03 (m, IH), 1.78-1.63 (m, 4H), 1.60- 1.41 (m, 6H), 1.06 (d, J = 6.0 Hz, 5H); HPLC (Method 4) 94.9% (AUC), t& = 6.93 min.; ES1+APCI MS m/z 497 [M + H] " .

Preparation of 1 -(l-(2-(5-chloro-2,4-dimethox^^henyI)imidazo l,2-a|pyridin-7- Yl)pyrrolidin-3-yI)-A T -(cvcloheptylmethyl)ethaii-l-amine l-9b (Example 2-88);

l-(l -(2-(5-ChIoro-2,4-dimethoxyphenyl)imidazo l ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N-(cycloheptylmethyl)ethao-l-amine l-9b was prepared in the same manner as -(2- (5~chloiO-2,4-dimemoxyphenyl)imidazo[ l,2-o]pyridm~7-}4)pyiToli cyelopentyl ethyl)ethan- 1 -amine l-9a, using cycloheptylmethanamine, and was obtained as an off- white solid (15% yield).

'H NMR (400 MHz, CD3OD) δ: 8.01 (d. 7.6 Hz, 1H), 7.96 (s, IH), 7.80 (s, i l l}. 6.68 (s, H i ). 6.41 (d. ./ 7.2 Hz, Π Ι). 6.16 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.53-3.35 (m. 2H), 3.30-3.20 (m, lH), 3.06-2.97 (m, 1H), 2.61 (q, ./ 6.4 Hz, 1H), 2.48-2.40 (m, IH), 2.36-2.05 (m, 3H), 1.70-1.35 (m, 12H), 1.18-1.10 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H); HPLC (Method 4) 99.8% (AUC), in = 6.93 mm.; ESI+APCI MS m/z 511 [M + H] + . yjjpyrroSidin-3-yS ethyS -A" 4 ,A ; -cSimethylcvdohexa«e-l,4-diamine l-9c (Example ^ 4Jx N-(l-(I~(2-(5-CMoro~2,4~dimeihoxyphenyl)imi

yl)pyrrolidm-3~yl)ethyl)-A 4 ^ l-9c was prepared in the same manner as l-( l-(2-(5-eh3oro-2,4-dimethoxyphenyi)imidazo l,2-i7|pyridin-7- yl)pyrrolidin-3-yl)-N-(2-cyclopent lethyl)ethan-l-amine l-9a, using N 1 ^- dimethylcyclohexane- 1 ,4-diamine, and was obtained as an off-white solid ( 15% yield).

'H NMR. (400 MHz, CD3OD) δ: 8.10 (d, J= 7.2 Hz, IH), 8.05 (s, H), 7.89 (s, IH),

6.78 (s, IH), 6,52 (d, J = 7.2 Hz, IH), 6.26 (s, IH), 4.01 (s, 3H), 3.94 (s, 3H), 3,52-3.45 (m, 2H), 3.40-3.32 (m, I H), 3.14 (t, J= 8.8 Hz, IH), 2.92 (s, IH), 2.75 (t, J = 6.0 Hz, IH), 2.35-2.25 (m, 9H), 1.98-1.95 (m, I H), 1.86-1.80 (m, 2H), 1 .73 (s, IH), 1.68-1 .60 (m, 4H), 1.52-1.46 (m, IH), 1.17 (d, J = 6.4 Hz, 3H); HPLC (Method 4) 99.6% (AUC), fe = 6.39 min.; ESI+APCI MS m/z 526 [M + H] + .

PrejMration of fe^

tert-Butyl 3-(((l-(l.-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2^]pyridin-7- yr)pym lidin-3-yl)ethyl)amino)methyl)pymilidine-l-carboxylat^ 1 -9d was prepared in the same manner as 1 -( 1 -(2 -(5 -chloro-2 ,4-dimetlioxyphenyi)imidazo [ 1 ,2-a]p ridin-7- yl)pyrrolidin-3-yl)-N-(2-cyclopent lethyl)ethan-l-amine l-9a, using fert-butyl 3- (aminomethyl)pyrrolidine-l-carboxylate and was obtained as an off-white solid (10% yield). ¾ NMR (400 MHz, CD3OD) δ: 7,99 (d, J= 7.6 Hz, i l l). 7.95 (s, 1H), 7.79 (s, IH), 6.68 (s, 1H), 6.40 (dd, ./= 2.4, 7.6 Hz, 1 H), 6.14 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.51- 3.31 (m, 4H), 3.27-3.23 (m, 1 H), 3.05-2.90 (m, 2H), 2.66-2.10 (m, 6H), 2.05-1.90 (m, 2H), 1.73-1.62 (m, H i ). 1.58-1.47 (m, IH), 1.36 (s, 9H), 1.04 (d, J ------- 6.0 Hz, 3H); HPLC

(Method 4) 94.8% (AUC), fe = 6.81 mm.; ESI+APCI MS m/z 584 [M 4- H | .

P ;e i aj a ¾OH i of l-(l : f2-{5-

Yl)pvrroIidin-3-yI)-iV-iil-isooropYlpyrrolidin-3-Yl}m l-9e

1 -( 1 -(2-(5-Chioro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- yl)-N-((l-isopropylpyirolidin-3-yl)methyl)e1iiian-l -amine l.-9e was prepared in the same manner as l-(l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7-yI )pyrrolidin- yl)-N-(2-cyclopentylethyl)ethan-l -amine l-9a, using (l -isopfopylpyrrolidin-3- yl)metlianamine, and was obtained as an off-white solid (7.6% yield).

[ H NMR (400 MHz, CD3OD) δ: 8.00 (d, J= 7.6 Hz, IH), 7.95 (s, IH), 7.80 (s, IH), 6.68 (s, IH), 6.41 (dd, J= 1.6, 7.2 Hz, IH), 6.16 (s, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.51-

3.35 (HI, 2H), 3.30-3.23 (n , IH), 3,06-2.89 (m, 2H), 2.76-2.69 (m, IH), 2.66-2.52 (m, 3H), 2.50-2.36 (ra, 2H), 2.31-2.14 (m, 4H), 2.05-1.92 (m, IH), 1.73-1.62 (m, I H), 1.50-1.40 (m, IH), 1.08-1.03 (m, 9H); HPLC (Method 4) 93.4% (AUC), R = 6.39 mm .; EST+APCI MS m/z 526 [M + H] + .

Preparation of A-(I-{l-i2-(5-chloro-2«4-diniethoxvphenvi)imidazoil.2-alpyr idin-7- rroIidin-3-Yi)ethYi)-l-eihvipiperidin-4-aiiiine l-9f (Example 2-82)

N-( 1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)py rrolidin- 3~yl)ethyl)-i-ethylp3peridiii-4-aiiiiiiie l-9f was prepared in the same manner as ί~(1~(2-(5~ chloro-2,4-diiT3ethoxypheny])imidazof l ,2-a]pyridin-7-yl)pyrrolidm-3-yl)-N-(2- cyclopentylethy])eth an- 1 -amine l-9a, using 1 -ethylpiperidin-4-amine, and was obtained as an off-white solid (15% yield).

¾ NMR (400 MHz, CD3OD) δ: 8.00 (d, J ------- 7.6 Hz, I H), 7.96 (s, IH), 7.80 (s, IH),

6.68 (s, IH), 6.42 (dd, J - 2.4, 7.6 Hz, IH), 6.16 (s, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.54 (t, J = 8,8 Hz, i l l). 3,43-3.37 (m, 2H), 3 ,30-3,20 (m, H), 3.05-3.00 (m, H i ). 2.89 id. ./ 10.4 Hz, 2H), 2.74-2,67 (m, i l l}. 2.60-2.52 (m . IH), 2.39 (q, ./ 7.2 Hz, 2H), 2.25-2, 14 (m, IH), 2.14-1 ,85 (m, 3H), 1.82-1.65 (m, 2H), 1 .45-1 .35 (m, 1H), 1 ,30-1.20 (m, IH), 1.04- 0.99 m, 6H); HPLC (Method 4) 99.5% (AUC), fe - 6.35 mm.; ESI-hAPCI MS m/z 512 [M

l-(rer^Bi3tyl)-A-(l-(l-(2-(5-chSoro~2,4~dimethoxypheiiy

yl)pyrroj.idm-3-yI)etb.yl)piperidm-4-a!niiie l-9g was prepared in the same manner as i-(l- (2-(5-chloro-2,4-dimethox phenyi)imidazo[l ,2-a]pyridin-7-y])pyrrolidi

cyclopentylethy])eth an- 1 -amine l-9¾, using l -(rt'r -butyl)pipendin-4-amine, and was obtained as an off-white solid (10% yield).

'H NM (400 MHz, CD 3 OD) δ: 7.99 (d, ./ 7,6 Hz, IH), 7.96 (s, IH), 7.79 (s, IH),

6,68 (s, IH), 6.40 (dd, J = 2.0, 7.6 Hz, IH), 6.15 (s, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3,52- 3.37 ( :r:. .:! !}. 3,28-3,23 (m, IH), 3.03-2.97 (m, 3H), 2,74-2,66 (m, IH), 2.53-2.47 (m . IH).

2,23-2,02 (m, 4H), 1 ,93-1 ,77 (m, 2H), 1.73-1.65 (ra, IH), 1 .40-1.30 (m, IH), 1 ,29-1 , 15

(m, I H), 1.17 (d, J= 4,8 Hz, 3H), 1.02 (s, 9H); HPLC (Method 4) 96.9% (AUC), R = 6.40 mm.; ESI+APCi MS m/z 540 [M + Π |

l-(l-(2-(5-Chloro-2,4-(hmethoxyphenyl)imidazo[l ,2- ]pyridin-7-yl)pyrrolidin-3- yl)-N-(( 1 -me1hylpiperidin-4-y{)methyl)ethan- 1 -amine l-9h was prepared in the same manner as l-( l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2~a]pyridm-7~yl)pyrrolidm~3~ γΓ)-Λ-(2-ονο1 openl lethyl)ethar!-l -amine l~9a, using (i-methylpipendin-4-yl)meihar!amme, and was obtained as an off-white solid (15% yield).

ΐ N MR (400 MHz, CD3OD) δ: 7.99 (d, J ------- 7.2 Hz, I H), 7.96 (s, IH), 7.79 (s, IH),

6,68 (s, IH), 6.40 (dd, J - 2.0, 7.2 Hz, IH), 6.15 (s, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3,52 (t, J = 8,0 Hz, 1H), 3,40 (t, J= 9.6 Hz, IH), 3,28 (q, ,/= 9,6 Hz, 1H), 3.05 (t, ./= 9,2 Hz, 1H), 2.82 (d, ./= 11.6 Hz, 2H), 2.57-2.46 (m, 2H), 2.39-2.34 (m, IH), 2.25-2.19 (m, IH), 2,19 (s, 3H), 2,07-2,01 (m, IH), 1.97-1.91 (m, 2H), 1.75-1.61 (m, 3H), 1.42-1.32 (m, IH), 1.23-1.13 (m, 2H), 1.05 (d, J~ 6.4 Hz, 3H); HPLC (Method 7) 95,9% (AUG), ΐκ = 6.29 nun.; ESI+APCI MS m/z 512 [M + fi| .

P e^ar tion , ^

1 -( 1 -(2-(5-Chioro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyrrolidin-3- y])-N-((l-ethylpiperidiii-4-yl)methy])ethan-l-amme l-9i was prepared in the same manner as l-(l-(2-(5-chlorQ-2,4-dimeihoxyphenyl)im^

(2-cyclopentylethyl)ethan-l -amine l-9a, using (l-ethylpiperidin-4-yl)rnethanamine, and was obtained as an off-white solid (25% yield).

[ H NMR (400 MHz, CDsOD) δ: 8.01 (d, J= 7.6 Hz, IH), 7.96 (s, IH), 7.80 (s, IH), 6.68 (s, IH), 6.42 (dd, ./ 2.4, 7.6 Hz, IH), 6.16 (d, ./ 2.0 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.53 (t, J=8,0 Hz, IH), 3.42-3.36 (m, IH), 3.29-3,23 (m, IH), 3.07 (t, J = 9.2 Hz, IH), 2.94 (d, J= I 1.6 Hz, 2H), 2.61-2.48 (m, 2H), 2.40-2.34 (m, 3H), 2.28-2.18 (m, IH), 2.08-2.02 (m. IH), 1.95-1.89 (m, 2H), 1.77-1.63 (m, 3H), 1.44-1.39 (m, IH), 1.24-1.14 (m, 2H), 1.05 id../ 6.4 Hz, 3H), 1.02 ix.J 7.2 Hz, 3H); HPLC (Method 8) 99.5% (AUG),

= 6.40 mm.; ESI+APCI MS m/z 526 M + H] + .

ferf-Butyl 4-(2-(( -(2-(5-chloro-2,4-diroethoxyplienyl)imidazo[l ,2-o]pyridin-7- yl)pyrrolidin-3-yI)ethyl)ainino)eihyl)piperidine-l-carboxyla te l~9j was prepared in the same manner as 1 -( 1 -(2 -(5 -chloro-2 ,4-dimetlioxyphenyl)imidazo [ 1 ,2-o]py ridin-7- yl)pyrrolidin-3-yl N-(2^yclopent iethyl)ethan-l-ainine l-9a, e7-butyl 4-(2- aininoetiiyl)piperidine- 1 -carbox late, and was obtained as an off-white solid (13% yield). ¾ MR (400 MHz, CD3OD) δ: 8.1 1 (d, J = 7.6 Hz, i l l). 8.05 d, J = 0.8 Hz, 1H), 7.90 (s, IH), 6.78 (s, 1 H), 6.52 (dd, ,/ = 2.0, 7.6 Hz, IH), 6.26 (d, J = 2.0 Hz, IH), 4.06 (d, J = 17.6 Hz, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.62-3.45 (m, 2H), 3.40-3.32 (m, IH), 3. 16-3.08 (m, IH), 2.82-2.60 (m, 5H), 2.40-2.32 (m, IH), 2.30-2.15 (m, IH), 1.86- 1 .76 (m, IH), 1 .72 id. ./ 12.4 Hz, 2H), 1.60- 1 .42 (ni, 12H), 1.17 (d, ./ 6.4 Hz, 3H), 1 .08 id. ./ 12.8 Hz, 2H); HPLC (Method 4) 91.9% (AUG), ftt = 6.93 mm.; ESI+APCI MS m/z 612. [M + H] + Preparation J n - ^

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2- ]pyridin-7-y])pyn " olidi yl)-N-(2-(l -propylpiperidin-4-y])ethyi)ethan-.l -amine -9k was prepared in the same manner as l-( l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-y

yl)-N-(2-cyclopentylethyI)etlian- -amine l-9a, using 2-( 1 -propylpiperidm-4-yi)ethan- 1 - amine, and was obtained as an off-white solid (12% yield).

H NMR (300 MHz, DMSG- e) δ: 8.00 (d, ./ 7,2 Hz, IH), 7.96 (s, IH), 7,79 (s,

IH). 6.81 (s, IH), 6.40 (dd, J= 2.4, 5.2 Hz, IH), 6.15 (s, I H), 3.91 (s, 3H), 3.84 (s, 3H), 3.50-3.34 (m, 2H), 3.26 (d, J = 7.2 Hz, I H), 3.01-2.97 (m, I H), 2.84 (d, J= 1 1.6 Hz, 2H), 2.68-2.52 (m, 2H), 2.48-2.42 (m, I H), 2.30-2.14 (m, 4H), 1 .92-1 .80 (m, 2H), 1.77-1.66 (m, I H), 1 .62 i d. ./ 10.8 Hz, 2H), 1.47- 1 .32 (m, 4H), 1.26-1.13 (m, 3H), 1.04 i d. ./ 6.4 Hz, 3H) 0.82. (q, J ===8.0 Hz, 3H); HPLC (Method 7) 97.9% (AUC), t& === 6.36 min.;

ESHAPCI MS m/z 554 [M + Hf.

(Example 2-99}

tert-Butyl 4-(3-(( l -(l-(2-(5-ch]oro-2,4-dimeihoxyphenyl)imidazo l,2-a]pyndin-7- yl)pyrroIidin-3-yl)etiiyl)ammo)propyl)pipendine- l-carboxylate 1-91 was prepared in the same manner as 1-(1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| 1 ,2-«Jpyridin-7- yl)pyn-olidin-3~yi)-jV~(2-cyelopentylethyl)ethaii~l-ainine l-9a, using i ' gri-biityl 4~(3- aminopropyl)piperidine~l -carboxyiate, and was obtained as an off-white solid (12% yield).

! H NMR {400 MHz, CDsOD) δ: 8.01 id ./ 7.6 Hz, i l l). 7.95 (d, 1.6 Hz, IH), 7.80 (s, IH), 6.69 is. IH), 6.42 (dd, 2.0, 5.6 Hz, IH), 6.17 (d, ./ 1.6 Hz, IH), 3.97 id. J ------ 18.8 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.52-3.36 (m, 2H), 3.31-3.23 (m, IH), 3.06-2.98 (m, IH), 2.72-2.60 (m, 3H), 2.55-2.49 (m, IH), 2.35-2.02 (m, 21 1 . 1.77-1.64 (m, I H), 1.63 (d.■/ 12.4 Hz, 2H), 1.57-1.42 (m, 2H), 1.40- 1.30 (m, 11H), 1.24- 1.16 (m, 2H), 1.08 (d,■/ 6.0 Hz, 3H), 1.01-0.92 (m, 2H); HPLC (Method 4) 96.9% (AUC), t& = 7.00 min.; ESI+APCI MS m/z 626 [M + H] + .

Preparation of tert-butv\ 3-(({l-(i-(2-{5-c !oro-2,4-dimet oxvphenyS)imidazoji.2- a pyridin-7-yI)pyrrolidin-3-yl)ethyI)ammo)methYl)piperidii¾e- l-carbo¾:Yiate

Example 2-98^

/iTi-Buryi 3-(((l-(l-(2-(5-chloro-2,4-dimethoxypheny

yl)pyrrolidin-3-yi)ethyl)amino)methyl)piperidine-l-carbox y l-9m was prepared in the same maimer as l~(l-(2-(5~ehloro-2,4-dimetlioxyphenyl)imidazo[ l,2-i7]pyridm-7- yl)pyrrolidin-3-yl)-N-(2-cyclopentylethyl)ethan-l-araine l-9a, using tot-butyl 3-

(aniinomethyS)piperidine-i~carboxylate, and was obtained as an off-white solid (13% yield), 'H NMR (400 MHz, CD3OD) δ: 7.98 (d, J= 12 Hz, IH), 8.94 (s, IH), 7.78 (s, I H),

6.67 (s, IH), 6.40 (d, J= 5.6 Hz, IH), 6.14 (s, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.80-3.73 (m,

IH), 3.55-3.32 (m, 2H), 3.28-3.20 (m, IH), 3.06-2.94 (m, IH), 2.59-2.47 (m, 3H), 2.39- 2.13 (m, 3H), 2.08-2.00 (m, IH), 1.82- 1.63 (m, 2H), 1.60-1.50 (m, 2H), 1.40-20 (m, 11H),

1.17- 1.10 (m, IH), 1.03 (d, J ------ 4.0 Hz, 3H); HPLC (Method 4) 98.1% (AUC), to ----- 6.92 min.; ES1+APCI MS m/z 598 [M +

Scheme 7

2-6f 2-<5g 2-<5h 2-6j :-6k

Preparation of 1 -(2 5-ehloro-2,4-dimetho¾yphenyI)imidazoP ,2-a]pyridin-7- yS|jjiperidine-4-carb ¾YSic arid 2^

To a solution of ethyl i -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-

7-yl)piperidine-4-carboxylate 2-1 ( 1.00 g, 2.25 rnmol) in THF, CH3OH and water (20 mL/10 mL/5 mL), was added LiOH*H?.Q ( 140 mg, 3.37 nimol) and the resulting mixture was stirred at ambient temperature for 5 h . The solvents were evaporated and the residue was diluted with water, extracted with ethyl acetate (2 χ 10 ml,). The aqueous layer was acidified to pH 3-4 with 1.0% KHSO solution. Tire precipitate formed was collected by filtration, washed with water and dried to afford l-(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-i?]pyridm-7-yl)pipendine-4-carbo xytic acid 2-2 (750 mg, 80%) as an off-white solid. ESI+APCI-MS m/z 416[M + H] + .

To a suspension of 1 -(2-(5-chloro-2,4-diraemoxyphenyl)imidazo[l ,2-<?]pyridin-7- yl)piperidine-4-carboxylic acid 2-2 {700 mg, 1.68 mmol), N,i9-dimethymydroxylamme hydrochloride (327mg, 3.37 rnmol), and NN'-diisopropylethyl amine (1.55 g, 8.4 mrnol) in DMF (10 mL), was added HATU (1.6 g, 4.2 mmol). The resulting mixture was stirred at ambient temperature for 15 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with ethylacetate (2 χ 100 mL). The combined organic layer was washed with water and brined, dried over NaiSCH, filtered and concentrated to afford 1 - (2~(5-chioro~2,4~dimethoxypheny

metbylpiperidme-4-carhoxamide 2-3 (600 mg, 83%) as an off-white solid , ESI+APCI MS m/z 459ΓΜ + H | . yl| jl gll ig„-^

To a solution of l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| l,2-a]pyndin-7-yl)- A L methoxy-iV-metliylpipei"idine-4-carboxamide 2-3 (1.00 g, 2.17 mmol) in THF (50 mL) cooled to 0 °C, was added a solution of QHbMgBr in diethyl ether (3.0M, 2.9 mL, 6.51 mmol) dropwise. Tire reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with aqueous NH4CI solution, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water and brine, dried over NaaS04, filtered and concentrated. The residue was purified by combi-fiash chromatography [silica gel; 5% NH4OH in MeOH: CH2CI2 (1:9)] to give 1- (l-(2~(5-chIoro~2,4-dimet oxypheny3

one 2-4 (800 nig, 89%) as a light yellow solid.

] H NM (400 MHz, CDsOD): δ 8.02 (d, J= 7.6 Hz, IH), 7.95 (s, 1H), 7.85 (s, 1H), 6.67 (d,■/ 3.6 Hz, I H), 6.65 id. ./ 2.4 Hz, 1H), 6.56 (d,■/ 2.0 Hz, I H), 3.91 (s, 3H), 3.84 (s, 3H), 3.75-3.72 (m, 2H), 2.80-2.73 (m, 2H), 2.57-2.50 (m, IH), 2.12 (s, 3H), 1 .91 (d, J = 13.2 Hz, 2H), 1.63-1.53 (m, 2H), I . Si AFC! MS m/z 414 [M + Hf.

Pre¾a ^^

To a suspension of l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin- 7-yl)piperidin-4-yI)ethan-l -one 2-4 ( ISOmg, 0.36 mmol), cyc!opentylmethanamme 2~5a (35 mg, 0.36 mmol) in CH3OH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium eyanoborohydride (114 mg, 1.81 mmol) w r as added in one portion and the reaction mixture was stirred at room temperature for 15 nun. The reaction mixture was diluted with aqueous sodium bicarbonate solution (20 niL) and the aqueous layer was extracted with CH2CI2 (2 χ 20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaaSCfo, filtered and concentrated . The residue was purified by combi-flash chromatography [silica gel; 5% NH4OH in MeOH: CH2CI2. (1 :9)] to give I-(l-(2-(5-chloro-2,4-dimethox pher!yI)imidazo[l ,2- ]pyridin-7- yl)piperidin-4-yl)-N-(cyclopentylmethyl)ethan- 1 -amine 2-6a (60 mg, 36%yeild) as an off- white solid.

] H NMR (400 MHz, CD3OD): δ 8.00 (d, J= 7.2 Hz, IH), 7.97 (s, IH), 7.84 (s, IH), 6.67 (s, IH), 6.64 (dd, J= 2.4, 7.6 Hz, IH), 6.55 (s, IH), 3.91(s, 3.H), 3.84 (s, 3H), 3.77 (d, J ----- 12.4Hz, 2.H), 2.68-2.61 (m, 2H), 2.55-2.38 (m, 3H), 1.98-1.90 (m, IH), 1.72-1.69 (m, 4H), 1.57-1.46 (ra, 5H) 1.39-1.30 (ra, 2.H), 1.14-1.06 (m, 2H), 0.96 (d, J= 6.8 Hz, 3H); HPLC (Method 11) 98.9% (AUG), ¾ = 7.35 mm. ; ESI+APCT-MS m/z 497 [M + H] + . te/f-Butyl 3-((( 1 -( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-«]pyridin-7- yl)piperidin-4-y3)ethyl)aniino)methyi)pyrroiidme-l -carboxyiate 2-6b was prepared in the same manner as l-(l-(2-(5-ch3oro-2,4-dimelhoxyphenyl)imida o[l,2-«]pyridm-7- yl)piperidin-4-yl)-N-(cyclopentj'lmethy1)ethan- 1 -amine 2-6a, using tert-huty] 3- (aminomeihyl)pyrrolidme-l-carboxylate 2-Sb, and was obtained as an off-white solid (45% yield).

[ H NMR (400 MHz, CDsOD): δ 8.00 (d, J= 7.6 Hz, IH), 7.96 (s, IH), 7.84 (s, IH),

6.67 (s, IH), 6.64 (dd, J= 2.0, 7.6 Hz, IH), 6.55 (s, IH), 3.9i(s, 3H), 3.84 (s, 3H), 3.77 (d, J ----- 12.8 Hz, 2H), 3.45-3.30 (m, 2H), 2.92-2.86 (m, IH), 2.67-2.44 (m, 5H), 2.24-2.23(d, J = 5.2 Hz, IH), I.95-L9i(ni, IH) 1.75-1 .68 (m, 2H), 1.51-1.49 (m, 2H) 1.36 (s, 1 1H), 0.95 (d, J= 6.4 Hz, 3H), 0,81-0.73 (m, IH); HPLC (Method 4) 94.9% (ADC), fe = 6.83 mm.; ES1+APCI-MS m/z 598 M + H] + .

Preparation ^

N~( 1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidia-

4~yl)ethyl)cyelohexananime 2-6c was prepared in the same manner as l-(I~(2~(5-chloro~ 2,4-dimethoxyphenyl)imidazo[1.,2-a]pyri^

(cyclopentylmetbyl)ethan~l -amine 2-6a, using cyclohexanamine 2-5c, and was obtained as an off-wbite solid (52% yield).

¾ NMR (400 MHz, CD 3 OD): δ 8.02 (d, J ------ 7.6 Hz, IH), 7.97 (s, IH), 7.85 (s, IH),

6.68 (s, IH), 6.65 (dd, J - 2.4, 7.6 Hz, IH), 6.56 (d, ./ 1.6 Hz, IH), 3.91(s, 3H), 3.84 (s, 3H), 3.79 (d, J ------- 12 Hz, 21 1 ). 2.79-2.57 (m, 4H), 1.91-1.67(m, 6H), 1.58-1.51 (m, 2H),

1.40-1.13 (m, 7H), 1.17-1.13(m, 3H) ; HPLC (Method 4) 98.1% (AUC), ft. = 6.73 mm.; EST+APCI-MS m/z 497 [M + Hf.

Preparation of j-(1 -(2-(5-chIoro-2,4-dimethoxyphenyl)imidazon.,2-a]pyridin-7j: l-( l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ I,2-«lpyridin-7-yl)piperidm-4- yl)-jV-(2~cyclohexy lethyl)ethan-l -amine 2-6d was prepared in the same manner asl-(l-(2- (5-chloro~2,4~dimethoxyphenyl)inhd^

(cyclopenlylmethyl)ethan-l -amine 2-6a, using 2-cycl ohexylethan- 1 -amine 2-5d, and was obtained as an off-white solid (40% yield).

lH MR (400 MHz, C D OS)!, δ 8.03 (d, J ------- 7.6 !!z. iii.s.7.97 (s, lif).7.86 (s, !H). 6.68 (d,J ---- : 2.8, Hz, IH), 6.66 (d, J -- 2.0, Hz, lH),6.57(s, 1H), 3.92 (s, 3H), 3.85 (s, 3H),

3.80 (d,■/ 12.0 Hz, 2H), 2.71-2.60 (m, 3H), 2.56-2.48 (rn, 2H), 1.72-1.56 (m, 8H), 1.39-1.16 (m, 8H), 0.98 (d, J ------ 6.4 Hz, 3H), 0.90- 0.80 (ni, 211·; HPLC (Method 4) 98.6%

(AUC), tR = 6.95 ram.; ESI+APCI-MS m/z 525 [M +

Preparation of tert-butv\ 4-(((I -(i-(2-(5-c !oro-2,4-dimet oxvphenyS)imidazoji.2- a pyridin-7-yI)piperidin-4-Yl)ethYl)ammo)methyl)piperidine-l-c arboxylate 2-6e

(Example 2-105^

/irf-Butyi 4-(((l-(l-(2-(5-chlofo-2,4-dimethoxyphenyl)imidazo l,2-i?]pyridin-7- yl)piperidin-4-yl)e1hyl)amino)methyl)piperidine-l-carboxylat e 2-6e was prepared in the same maimer as l~(l-(2-(5~chloro-2,4-dimetlioxyphenyl)imidazo[ l,2-i7]pyridm~7- yl)piperidin-4-yl)-N-(cyclopentylraeAyl)ethan- 1 -amine 2-6a , using reri-butyl 4- (aminomethyS)piperidine-l~earboxylate 2-5e, and was obtained as an off-white solid (32% yield).

U NMR (400 MHz, CD3OD): δ 8.01 id../ 7.6 Hz, ill).7.97 is HI).7.85 (s, IH), 6.68 (s, IH), 6.65 (dd, J -- 2.4, 7.6 Hz, IH), 6.56 (s, IH), 3.98 (d, ./ 13.2 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.78 (d, J= 12.0 Hz, 2H), 2.68-2.63 (m, 4H), 2.47-2.43 (m, 2H), 2.38-2.33 (m, IH), 1.75-1.64 (rn, 4H), 1.59-1.48 (ni, 211·.1.35 (s, 11H), 1.03-0.99 (rn, 2H), 0.96 (d, J= 6.4 Hz, 3H); HPLC (Method 10) 98.9% (AUC), to = 6.85 min.;

ESI+APCI-MS m/z 612 [M + H] + .

Preparation of tert-hv l 4-(3-((l-(l-(2-(5-c.hloro-2,4-dimeth ¾yp¾enyI)imida¾ ns2^ a]p_yridin-7-Yl)piperidin-4-Yl)ethYl)ammo)propyl)piperidine- 1-carboxylate 2J> teri- uty 14-(3 -(( 1 -( 1 -(2-(5 -chloro-2 ,4-dimemoxyphenyl)imidazo [ 1 ,2-a]pyridin-7- l)piperidin-4-yl)eth l)ammo)prop l)piperidine- 1 -carboxylate 2-61 " was prepared in the same manner as 1 -( 1 -(2-(5 -chl oro-2,4-dimetiioxyphenyl)imidazo [ 1 ,2-«]pyridin-7- yl)piperidin-4-yl)-N-(cyclopent\'jmet y3)et a!i-l-araine 2-6a, uisng tert-buty] 4-(3- aminopropyl)piperidine-l -carboxylate 2-5f, and was obtained as an off-white solid {32% yield).

]H NMR (400 MHz, CDsOD): δ 8.02 (d, J= 7.6 Hz, 1H), 7.97 (s, 1H), 7.85 (s, IH),

6.69 (s, IH), 6.66 (dd,■/ 2.4, 7.6 Hz, i l l). 6.56 (s, 1H), 3.97(s, 3H), 3.92 (br s, 2H), 3.85 s, 3H) 3.79 (d, J = 11.6 Hz, 2H), 2.70-2.43 (m. 7H), 1.72- 1 .44 (m, 8H), 1.42-1.34 (m, 11H), 1.22-1.16 (m, 2H), 0.97(d, ./ 6.4 Hz, 5H); HPLC (Method 4) 92.3% (AUG), to = 6.96 min.; ESI+APCI-MS m/z 640 [M + H] + .

Preparation of A~berc¾yB-l-(l~(2~(5-chBoro~2,4~dm^

^)piperidm~4-yl)ethan-l~amme 2-6g (Example 2~9Ί)χ_

A-BenzyI-l-(l-(2-(5-chloro-2,4-dimetboxyphenyl)imidazo[ l,2-ii]pyridin-7- yl)piperidin-4-yl)ethan-l -amine 2-6g was prepared in the same manner as l-( l-(2-(5- chloro-2,4~dimethoxyphenyl)imidazo[ ,2-«]pyridin-7-yl)piperidin-4-_yl)-N- (cyclopentylmethyl)ethaii- 1-amine 2-6a , using benzyl amine 2-5g, and was obtained as an off-white solid (28% yield).

'H NMR (400 MHz, CD3OD): δ 8.00 (d, 7.6 Hz, i l l) 7.96 (s, IH), 7.84 (s, i l l}. 7.27-7, 13 (m, 5H), 6.67 (s, H), 6.64 (dd, J = 2.4, 7.6 Hz, IH), 6.54 (d, J = 2.0 Hz, IH). 3.91 (s, 3H), 3.84 (s, 3H), 3.76 (ra, J= 12.8 Hz, 3H), 3.63 (d, J= 13.2 Hz, IH), 2.67-2.61 (m, 2H), 2.49-2.46 (m, 1 H), 1.70 (d, ./ 12.4 Hz, 2H), 1.53-1.47 (ra, I I I ). I .36-1.27 (m, 2H), 0.98 (d, J= 6.4 Hz, 3H); HPLC (Method 4) 98.1% (AUC), to = 6.73 mm.; ESI+APCI- MS m/z 497 [M + H | . yjjpiperidm-4-yS)-A / -phenetbySei¾a -l-amine 2-6¾ (Example 2-115)^

l-(l-(2-(5-Chloro-2 ; 4-dimeihoxypheny])imidazo[I,2-G]pyridm-7-yl)piperidin- 4- yl)-N-phenethylethan- 1-amine 2-6h was prepared in the same manner as l -(l-(2-(5-ehioro- 2,4-dimethoxypheny l)imidazo j 1 ,2-a ]pyridin-7-yI)piperidm-4-yl)-N- (eyciopentylmethyl)ethan-l-aimne 2-6a, using 2-phenylethan- 1-amine 2-5h, and was obtained as an off-white solid (41 % yield) ,

lH NMR (400 MHz, CD 3 OD): δ 7.99 i d. ./ 7.6 Hz, i l l ). 7.97 is IH), 7.83 (s, 1H), 7.21 -7.08 (ra, 5H), 6.66 (s, IH), 6.62 (dd, J = 2 A, 7.6 Hz, ΓΗ), 6.53 (s, IH), 3.90 (s, 3H), 3.83 (s, 3H), 3,72 (311, 2H), 2.84-2.80 (m, IH), 2.73-2.57 (m, 5H), 2.49-2.42 (m, IH), 1 .64- 1 .42 i n:. 3H), L30 -1 .12 (ni, 2H), 0.97(d, ./ 6.4 Hz, 3H); HPLC (Method 9) 98.2% (AUG), to ----- 7.40 mm.; ESI+APCI-MS m/z 519 [M + H] \

1 -( 1 -(2-(5-Chioro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- y])-N-(2-cyclopentylethyl)ethan-l -amine 2-6i was prepared in the same manner as I~( i~(2- (5-chloro-2,4-dimethoxyphenyl)imidazo| 1 ,2-«]pyridin-7-yl)piperidin-4-yl)-N- (cyclopenlylmethyl)ethan-l -amine 2~6a, using 2-cyclopentylethan- 1-amine 2-51, and was obtamed as an off-white solid (38% yield).

[ H NMR (400 MHz, CD3OD): δ 8.01 (d, J= 7.6 Hz, IH), 7.97 (s, IH), 7.85 (s, IH), 6.68 (s, IH), 6.65 (dd, J= 2.4, 7.6 Hz, LH), 6.56 (s, IH), 3.9 i(s, 3H), 3.84 (s, 3H), 3.77 (d, J ----- 12.8 Hz, 2H), 2.70-2.49 (m, 5H), 1.72-1.69 (m, 5H), 1.57-1.35 (m, 9H), 1.10-1.03 (m, 2H), 0.99 (d, J= 6.4 Hz, 3H); HPLC (Method 5) 98.3% (AUG), ¾ = 6.85 mm. ; ESI+APCT - MS m z 51 1 [M + Hf. %LY£ kll:^^

(Exam i )Ie ii 2 : l ii i2) i

te/f-Butyl 3-((( 1 -( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-«]pyridin-7- yl)piperidin-4-y3)ethyl)aniino)met yI)piperidine- l -carboxyj.ate 2-6j was prepared in the same manner as l -(i-(2-(5-chloro-2,4-dimeihoxyphenyl)imidazo l,2-a]pyndin-7- yl)piperidin-4-y1)-A r -(cyc1openiylmethy1)ethan- i -amine 2-6¾, using tert-butyl 3-

(aminomethyl)piperidme- 1 -carboxylate 2-5 j , and was obtained as an off-white solid (47% yield).

] H NMR (400 MHz, CD3OD): δ 8.01 (d, J= 7.6 Hz, IH), 7.97 (s, IH), 7.85 (s, IH), 6.68 (s, 1H), 6.65 (dd, J= 2,0, 7.6 Hz, 1H), 6.55 (s, 1H), 3.91{s, 3H), 3.84 (s, 3H), 3,77 (d, J ----- 12.8 Hz, 3H), 2.69-2.56 (m, 3H), 2.48-2.33 (m, 3H), 1.78-1.70 (m, 3H), 1.58-1.51 (m, 3H), 1.36 (s, 11H), 1.18-1.11 (m.4H), 0.95 (d../ 6.4 Hz, 3H); HPLC (Method 5) 99.5% (AUG), E = 6.89 mm.; ESI+APCI- MS /w/z 612 [M 4- lij .

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4- yl)~A'~(cyeIohexylmethyi)cthan~I -amine 2-6k was prepared m the same manner as 1 ~( .1 -(:2~

(5~chloro-2,4-dimethoxyphenyl)iniidazo[l,2 ,']pyridin~7-yl)pipe

(cyclopent>'lmethyl)ethan-l-amine 2-6a, using cyclohexylroethanamine 2-5k, and was obtained as an off-white solid (32% yield).

] HNMR(400 MHz, CD3OD): δ 8.00 {ά, J ------ 7.6 Hz, 1H), 7.97 (s, 111·.7.84 (s, 1H),

6.67 (s, Ml).6.64 (dd, J= 2.0, 7.6 Hz, lilt.6.54 (brs, Hit.3.91(s, 3H), 3.84 (s, 3H), 3.77 (d,

J -- 12.8 Hz, 2H), 2.67-2.61 (m.2H), 2.45-2.37 (m, 2H), 2.31-2.27 (m. III).1.70-1.58 (m, 7H), 1.38-1.15 (m, 7H), 0.95 (d, J= 6.4 Hz, 3H), 0.85-0.82 (m, 2H): HPLC (Method 4)

98.7% (AUC),fe = 6.81 min.; ES1+APCI- MSm/z511 |\i lij ' .

Scheme 8

To a suspension of 4-c oropyrichn-2-amine (20 mg, 0.156 mniol) in N f- diisopropylethyl amine (2.0 mL), was added methyl 2-( l-(2-ammop}'ridin-4-yl)pyrrolidin- 3-yl)acetate hydrochloride (30 mg, 0.171 ramol) and the reaction mixture was heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature and 7v',A ; '~ diisopropylethyl amine was decanted, and the residue was partitioned between 15%

[(5% ¾ in CHsOH) and CH2.CI2)] and saturated aqueous NaHCCh solution (10 mL: 5 ml,). The layers were separated and the organic layer was washed with brine (2.0 mL), dried over anhydrous NaiSC , filtered and concentrated under reduced pressure. The residue was triturated with hexanes and dned to provide methyl 2-( l-(2-aniinopyridm-4-yl)pyiTolidin-3- yl)acetate 3-2 (20 mg, erode) as a brown solid, which was used directly for next step without further purification. EST+APCI-MS m/z 236 [M + H j

Preparation methyl 2-(l-(2-(5-chloro-2,4-dimethoxypheHyI)imidazo l,2-a pyridiR-7-

A mixture of 2-bromo-l-(5-chloro-2,4-dimethoxyphenyl ethanone 3-1 (0.80 g,

2.73 mmol) and methyl 2-(l-(2-aininopyridin-4-yl)pyrrolidin-3-yl)acetate 3-2 (0.63 g, 2.73 mmol) in acetone (20 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, the precipitate formed was collected by filtration, washed with hexanes (20 mL), and dried. The hydrobromide salt was basified using aqueous NaHCCb solution (15.0 ml.) by stirring at ambient temperature for 1 h. The solid was collected by filtration, washed with water and dried to give methyl 2-( 1 -(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-i?]pyridm-7-yl)pyrrolidin-3-yl)a cetate 3-3 (0.45 g, 41%) as an off-white solid. ESI+APCI-MS m/z 430 [M + U | \

Prerjaratioo oi^

yDpy ro^

To a solution of methyl 2-( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2- a]pyridin-7-yl)pyrrolidin-3-yl)acetate 3-3 (0.5 g, 1.16 mmol) in THF, CH3OH and water (10 niL/10 raL/2 ml.) was added LiOT-MrfcO (0.14 g, 3,49 mmol) and the resulting mixture was stirred at ambient temperature for 5 h. The solvents were evaporated and the residue was diluted with water and extracted with ethylacetate (2 x 10 mL). The aqueous layer was adjusted to pH 3-4 with 10% KHSO4 aqueous solution. The precipitate formed was collected by filtration, washed with water and dried to afford 2-(l -(2-(5-chloro-2,4- dimemoxyphenyl)imidazo[l,2-a]p\Tidin-7-yl)pyrrolidin-3-yl)ac «tic acid 3-4 (270 mg, crude) as an off-white solid, which was used in the next step without further purification. ESI+APCI MS m/z 416[M + i l l ' .

To a solution of 2-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo l,2-aipyridin-7- yl)pyrrolidin~3-yl)acetic acid 3-4 (0.25 g, 0.602 ramol), N,0-dimethylhydroxylamine hydrochloride (1 16 mg, 1 .20 mmol), and N,N-diisopropylethy] amine (466 mg, 3.61 mmol) in DMF (5.0 mL) was added EDOHC1 (345 rag, 1.80 mmol) and HOBt (243 mg, 1 .80 mmol). The resulting mixture was stirred at ambient temperature for 15 h. Hie reaction mixture was diluted with water and extracted with ethylacetate (2 χ 10 mL). The combined organic layer was dried over anhydrous Na?.SG4. filtered and concentrated to afford 2-(l-(2- (5-chloro-2,4-dimemoxyphenyl)im

methylacetaniide 3-5 (200 n g, crude). The crude compound was used directly in the next step without further purification . ESi+APCi MS m/z 459[M + H] " .

Preparation of 1 -(l-(2-(5-chloro-2,4-dimethox^^henyI)imidazo l,2-a|pyridiR-7^ yJjjyrroMdin-3-yS pr pan-2-one^6

To a solution of 2-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ I,2-a]pyridin-7- yl)pyrrolidin-3-yl)-N-methoxy-A-methylaceiamide 3-5 (0.2 g, 0.436 mmol) in THF (10 mL) was added a solution of CtbMgBr in diethviether (3M, 0.43 mL, 1.31 mmol) at ambi nt temperature. The reaction mixture was stirred at ambient temperature for 3 h.

The reaction mixture was cooled to 0 °C and quenched with aqueous NH Q solution. The aqueous layer was extracted with ethyl acetate (2 χ 20 mL). The combined organic layerwas were dried over anhydrous Na-SCh, filtered and concentrated to afford 1 -(I~(2~(5- chloro-2,4^me1hoxyphenyi)imidazo[l,2-alpyridin-7-yl)pyrrolid in 3-6 ( 160 mg, crude), which was used directly in the next step without futher purification.

ESHAPCI MS m/z 414 [M + Hf.

119);

To a suspension of 1 -(l -(2-(5-chloro-2,4-dimeihoxyphenyl)imidazo[ l,2-a]pyridin-

7-yI)pyrrolidin-3-yl)propan-2-one 6 ( 100 mg, 0.242 mmol) and (l -ethylpiperidin-4- ylimetlianainine 3-7 (51 mg, 0.3631 mmol) in CH3OH (5.0 rnL) was added acetic acid (0.05 mL) and the reaction mixture was stirred at 80 °C for 12 h. Sodium cyanoborohydride (45 mg, 0.72 mmoi) was added in one portion and the reaction mixture was stirred at the same temperature for additional 6 h. The reaction mixture was cooled to ambient temperature, diluted with aqueous sodium bicarbonate solution and extracted with CH2CI2 (2 * 10 ml,). Hie combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combi-flash companion (silica gel,

N¾OH/CH30H/CH2Cl2, 1 :9:90} to afford l-(l-(2-(5-chloro-2,4- dimeAoxyphenyl)imidazo[l,2-tf]pyri

yl)methyl)propan-2-amine 3-8 (20 mg, 15%) as an. off-white solid.

'H MMR (400 MHz, CD3OD) δ: 7.99 (d, J= 7.6 Hz, IH), 7.96 (s, ΓΗ), 7.79 (s, IH), 6.68 (s. i l l). 6.41 (dd, ./ 2.0, 7.2 Hz, IH), 6.15 (s, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.50 (q, ./ 9.2 Hz, IH) , 3.39-3.34 (m, IH), 3.30 (q, ./ 8,8 Hz, IH), 2.91 id . ./ 9.6 Hz, 3H), 2.68-2.60 (m, IH), 2.49-2.30 (m, 5H), 2.17-2.09 (m, IH), 1.92-1.86 (m, 2H), 1 .72 (q, J= 12.8 Hz, 2H), 1 .65 -1.57 (m, 2H), 1.46-1.37 (m, 2H), 1 .23-1.18 (m, IH), 1.16-1.12 (m, IH), 1.06 (q, J= 4.0 Hz, 3H), 1.02 (dt, J= 1.6, 7.2 Hz, 3H); HPLC (Method 4) 94.8% (AUC), tR = 6.38 mm. ; ESI+APCI MS m/z 540 [M + H | .

Scheme 9

Preparation of ethyl l-(2-aminopyridifl-4-yl)piperidine-4-carboxylate 4-3L_

To a solution of 4~chloropyridin~2-aniine 4-1 (2.00 g, 15.6 rnmol) in NN'- diisopropyletbyl amine (25 mL) was added ethyl piperidine-4-caiboxylate 4-2 (3.67 g, 23.4 mmol). The reaction mixture was heated in a seal tube at 110 °C for 16 h. Hie reaction mixture was cooled to room temperature and solvent was removed under reduced pressure, the residue was partitioned between EtOAc and water (200 niL/50 mL). The layers were separated and the EtOAc layer was washed with brine (50 mL), dried over anhydrous NaiSCU, filtered and concentrated. The crude material was triturated with hexanes, filtered and dried to provide ethyl l-(2-aniinopyridm-4-yi)piperidine-4-carboxy3ate 4-3 (2.5 g, 85%) as an off-white solid. ESI+APCI-MS m/z 250 [M + H] + . ihie-4-carboxvlate 4-5:

A mixture of l-(2-aminopyridin-4-yl)piperidine-4-carboxylate 4-3 ( mmol) and 2-bromo-l-i5-chloro-2,4-dimetb.oxyp3ienyi)ethanone 4-4 (3.2 g, 1 1.0 mmoi) in acetone (120 mL) was heated at 75 °C for 16 h . The reaction mixture was cooled to room temperature, the white precipitate formed was collected by filtration, washed with hexanes (200 mL) and dried. The crude product was suspended in water (200 rnL) and saturated aqueous NaHCCb solution (200 rnL), stirred at room temperature for 1 h. The solid obtained was collected by filtration, washed with water and dried to give ft?rf-butyl ((l-(2- (5-chloro-2,4-dimethoxyphenyl) imidazoj l,2-a]pyndin-7-yl)piperidm-4- yl)methyl)carbaniate 4-5 (1.2 g, 43%) as an off-white solid.

1 H MR (400 MHz, CDCb): δ 8.37 i s. 1H), 7.89-7.86 (m, 21 1 ). 6.81 (s, H i). 6.58 (s, 1H), 6.55 (dd, ./= 2.4, 7.6 Hz, 1H), 4.16 (q, J= 7.2 Hz, 111), 3.99 (s, 3H), 3.95 (s, 3H), 3.71-3.67 (m, 2H), 2.90-2.83 (m, 2H), 2.52-2.46 (m, 1H), 2.06-2.03 (m, 2H), 1.92-1.83 (m, 2H), 1.27 (t, ./ 7.2 Hz, 3H); ESI+APCI MS m/z 444 M + Hf.

Pre|)ara ioH f l-(2 : f5-c l^

y n i) i )eridine 4 : carb

To a solution of ethyl l-(2-(5-chloro-2.4-dimethoxj-'phenyl)imidazo [l ,2~ ]pyridin~

7~yl)piperidine-4~earboxyIa†e 4-5 (500 nig, 1.1 mmol) in CH2CI2 (50 mL) cooled to -78 °C was added DIBAL-H (1.1 mL. 1.6 mmol) fropwise. The resulting mixture was stirred at -78 °C for lb . The reaction mixture was quenched with saturated aq.NH.4Ci solution and extracted with CH2CI2 (2 χ 50 rnL). The combined organic extracts were dried over anhydrous Ma 2 S04, filtered and concentrated under reduced pressure to get l-(2- (5-cMoro-2,4-dimethoxypkenyl)im^ 4-6 (300 mg, 76%) as an off-white solid. ESI+APCI-MS m/z 400 [M + H] + . y!)piperidin-4-yl)-A-(thiophei¾-2-Ylmethyl)methanamine 4-8a (Example 2^2)

To a suspension of l.-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7- yl)piperidine-4-carbaldehyde 4-6 (80 mg, 0.20 mmol), thiophen-2-ylmethanamine 4-7a (44 mg, 0.30 mmol) in CH3OH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred for 2 h. Sodium cyanoborohydride (62 mg, 1.00 mmol) was added and the reaction mixture was stirred at room temperature for 15 rain. The reaction mixture was diluted with aqueous NaHCCte solution and extracted with CH2G2 {2 χ 20 ml). The combined organic extracts were dried over anhydrous aiSOi, filtered and concentrated. Hie crude material was purified by combi -flash chromatography [silica gel: 5% NH4OH in MeOH: CH2CI2 (1 :9)] to afford l -(l-(2-(5-chloro-2,4-dimethoxyphenyl)m^

]pyridin-7-yl)piperidin-4-yl)-N-(tWophen-2-ylnie1iiyl)m 4-8a (18 nig, 19%) as an off-white solid.

¾ MR (400 MHz, DMSQ- e): δ 8.26 (d, J= 7,6 Hz, i l l) . 8.16 (s, I H). 7,99 (s, lH), 7.36 (t, J= 3,6 Hz, IH), 6,94 (d, J = 3.6 Hz, 2H), 6.86 (s, IH), 6.78 (dd. J= 2.4, 7.6 Hz, IH), 6.62(d, ./ 1.6 Hz, i l l). 4.00 is 3H), 3.93 (s, 3H), 3.88 is. 21 1} 3.77 id ./ 12.4 Hz, 2H), 2.74-2.66 (m, 2H), 2.44 (d, J= 6.4 Hz, 2H), 1 .8 i(d, J= 11.6 Hz, 2H), 1 .61-1.58 (m, IH), 1.27- 1.17 (m, 2H); HPLC (Method 13) 97.7% (AUC), hi = 6.59 rain. ; ESI+APCI MS m/z 497 \ \\ + H] ÷ .

Prej3arat¾oojf iV i ((l

A-((l~(2-(5-Chloro~2,4~d3mefhoxyphenyl)imidazo[i,2-a]pyrid

y1)niethyl)-2-cyclopenty1ethan- .l -amine 4-8h was prepared in the same manner as 1 -( 1 -(2- (5-chk)ro-2,4Hiiraetboxyphenyl)imidazo[l

ylmethyl)methanamine 4-8a, using 2-cyclopentylethan- 1 -amine 4-7b, and was obtained as an off-white solid (70%),

¾ NMR (400 MHz, DMSO^fe): δ 8,27 (d, J = 7.6 Hz, IH), 8, 16 (s, IH), 7.99 (s, IH), 6.86 (s, IH), 6.78 (dd, J= 2.4, 7.6 Hz, ΓΗ), 6.64 (d, J= 1.6 Hz, I H), 4.00 (s, 3H), 3,93 (s, 3H), 3.79 (d. ./ 12.4 Hz, 2H), 2,74-2.67 (m, 2H), 2.63-2.59 (m, 2H), 2.55-2.52 (m, 2H), 1.82-1.66 (ra, 6H), 1 ,58-1 ,53 (m, 2H), 1.51-1.43 (m, 4H), 1.28-1 .20 (m, 2H), 1.09-1.02 (ra, 2H); HPLC (Method 12) 99,6% (AUC), t& = 6,81 mm, ; ESI+APCl-MS m/z 497 I M + H j . N-((l-(2~(5-Chloro-2.4-dimethoxyphem^

yl)methyi)-4-raeAylcyclohexan-l-amine 4-8c was prepared in the same manner asl-(l-(2- (5-ch]oro~2,4~dimethoxyphenyl)im^

ylmethyl)methanamine 4-8a, using 4-methylcyclohexan- 1 -amine 4-7c, and was obtained as an off-white solid (21 % yield).

¾ MR (400 MHz, DMSO^fe): δ 8.27 (d, ·/ 7.2 Hz, lH), 8.16 (s, 1H), 7.99 (s, 1H), 6.86 (s, lH), 6.76 (d, J 7.6 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J ------ 11.6 Hz, 2H), 2.73-2.67 (m, 2H), 2.59-2.58 (m, 2H), 2.43(s, 1H), 1.84-1.81 (m, 3H),

1.65-1.45 (m, 51 11. 1.34-1.21 (m, 5H), 1.03-0.91 (m, 1H), 0.88-0.84 (m, 3H); HPLC (Method 9) 96.1% (AUC), t& = 6.85 min.; ESI+APCI MS m/z 497 [M + H .

Preparation of A^(i-(2-(5-ehIoro-2,4-dimethoxypheny^

N-(( l-(2-(5-CMoro-2,4-dimethoxyphenyl)m

yl)methyl)-4-ethylcyclohexan-l -amine 4-8d was prepared in the same manner as l-(l-(2-(5- chloro-2,4-dimethoxyphenyl)imi

ylme†hyl)methaiiamine 4-Sa, using 4-ethylcyclohexan-l -amine 4-7d, and was obtained as an off-white solid (21% yield).

1 1 N MR (400 MHz, CD3OD): δ 8.04 id. ./ 7.2 Hz, i l l). 7.96 is H i). 7.87 (s, 1H),

6.69-6.66 (m, 2H), 6.71 (d, ./= 2.0 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (d, ,/= 12.8 Hz, 2H), 2.93-2.91 (m, IH), 2.78-2.71 (m, 4H), 1.83- 1.70 (m, 5H), 1.54-1.51 (m, 7H),

1.32- 1 .27 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); HPLC (Method 12) 94.3% (AUC), to ----- 6.83 min.; ESI+APCI MS m/z 511 [M + H] + . ajpyridin-7-yI)piperidin-4-Yl)methyl)piperidin-4-amine 4-8e (Example 2 = 29 i

l-(im~Butyl)-N-((l-(2-(5-chloro-2,4-dim

yl)piperidin-4-yl)rnethyi)piperidin-4-amine 4-8e was prepared in the same manner as as 1- (l-(2-(5-chloro-2,4-dimethoxyphenyl)im^

(tliiophen~2-ylmethyi)metlianamine 4-8a, using l-(tert-butyl)piperidin-4-amine 4-7e, and was obtained as an off-white solid (19% yield).

lH NMR (400 MHz, CD 3 OD): δ 8.01 id. ./ 8.4 Hz, i l l). 7.97 is IH), 7.84 (s, 1H), 6.68 is. IH), 6.64 (dd, ./ 2.4, 7.6 Hz, 1H), 6.56 (d, ,/ 2.0 Hz, i l l}. 3.91 (s. 3H), 3.84 is. 3H), 3.73 (d, J= 12.4 Hz, 2H), 3.01 (d, J = 12.0 Hz, 2H), 2.72-2.67 (m, 2H), 2.43 (d, J = 6.8 Hz, 2H), 2.39-2.33 (m, !H), 2.20 (t, ./ ! i .6 Hz, 21 ! }. 1.87- 1 .76 (m, 4H), 1.61-1.56 (m, IH), 1.37-1.14 (m, 4H), 1.03 (s, 9H); HPLC (Method 9) 98.8 % (AUG), / = 6.42 min.; ESHAPCI MS m/z 540 [M + Hi " . yjjpiperidin-4-yS)-A ; -((l-methylpyrroIidis¾-3-Yl)methvj)metS¾anamine 4-8f (Ex mpIeJ 46);

l-( l-(2-(5-Chloro-2,4-dimetlioxyphenyl)imidazo[ l,2-«lpyridin-7-yl)piperidin-4- yl)-N-((l-methylpyrrolidin-3-yl)methyl)methanatnine 4-8f was prepared in the same manner as l-(l~(2-(5-chioro-2,4-dimetlioxyphenyl)imidazo[ l,2~a]pyridin-7~yl)piperidm~4- yl)-jV-(tliioplien~2~ylmetliyi)nietlianamine 4-8a, usmg (l-methylpyrrolidm-S- yl)raethanamine 7 and was obtained as an off-white solid (22% yield).

! H NMR (400 MHz, CD3OD): δ 8.20 (d, J= 7.6 Hz, IH), 8.00 (d, J= 4.4 Hz, 2H), 6.88 (dd, J= 2.4, 5.2 Hz, IH), 6.83 (s, IH), 6.71 (d, ./= 2.0 Hz, I H ), 4.05 (s, 3H), 3.98 (s, 3H), 3.95 (br s, 2H), 3, 16-3.12 (m, IH), 3.02-2.97 (m, 2H), 2.94-2.89 (m, 3H), 2.80-2.71 (in. 3H), 2.66-2.59 (m, 4H), 2.28-2.19 (m, I H), 1.95- 1 .88 (m, 3H), 1.77-1.68 (m, I H), 1.47-1.30 (m, 3H); HPLC (Method 9) 94.8% (AUC), = 6.35 min.; ESI+APCI MS m/z 498 [M + H | .

£re r iog ol lril-il-ig-djjfi

l-(l -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l ,2- ]pyridin-7-y])piperidm yl)-N-((l.-ethylpiperidin-3-yl)roethyl)methanamine 4-8g was prepared in the same manner as l-(!-(2-(5-chlQro-2,4-dimetiTOxypheny3

(thiophen-2-y3niethyl)methaiianiine 4-8a, using (l-ethylpiperidin-3-y3)methanamine 4-7g, and was obtained as an off-white solid (28% yield). ¾ NMR (400 MHz, CD3OD): δ 8,15 (d, ,/ 7.6 Hz, 1H), 8.08 (s, 1H), 7.98 (s, III}. 6.80 (dd, J= 3.2, 2.4 Hz, 2H), 6.70 (d, J= 2.0 Hz, 1H ), 4.04 (s, 3H), 3.97 (s, 3H), 3.92 (d, J = 12.4 Hz, 2H), 3.13 (d,,/= 12.0 Hz, ill ).3.02 (d, J= 12.0 Hz, 1H }, 2.86-2.81 (m, 2H), 2.60-2,56 (m, 5H), 2.10-1.98 (m, 1H), 1,93-1,77 (m, 7H), 1.70-1.63 (m, !H), 1,43-1,30 (m,3H), 1.18 (t, 7=7.2 Hz, 3H), 1.04-0.98 (m, 1H); HPLC (Method 9) 97.4% (AUC), fe = 6.37 mm.; ESI+APCI MS m/z 52.6 [M + H] +

1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperidin-4- y])-N-((l-ethylpiperidin-4-yi)methy])me " thanamme 4~8 was prepared in the same manner as l-(l-(2-(5-chioro-2,4-diniethoxyphenyl^

(thiophen-2-ylmethyl)methanamine 4-8a, using (1 -ethylpiperidin-4-yl)methanamine 4-7h, and was obtained as an off-white solid (35% yield)

¾ NMR (400 MHz, DMSOc¾): δ 8.27 (d, J= 7.6 Hz, 1H),8.16 (s, 1H),7.99 (s, 1H), 6,86 (s,lH), 6.78 (dd, ./ 2.0, 7.6 Hz, ill}.6.64 (s, ill }, 4.00 (s, 3H), 3.93 (s, 3H), 3.80 (d, J 12.0 Hz, 2H ), 2.90 (s, 2H), 2.74-2.66 (m, 2H), 2.63-2.55 (m, 3H), 2.47-2.39 (HI, 2H), 2.08-1.73 (ra, 5H), 1.70 (d, J= 12.8 Hz, 3H), 1.52-1.44 (m, ill). 1.28-1.13 (m, 4H), 1.01 (t, ./ 6.8 Hz, 3H ); HPLC (Method 12) 95.3% (AUC), κ = 6.22 min.; EST+APCI MS m/z 526 [M 4- Hf.

Preparatiosi of Λ-(( i-{2-(S-chloro-2,4-dimeihoxYpheiivI)imidazoii,2-al vridin-7- yljpi^eridm-^- Jm^

A'-((i-(2~(5-Chloro-2,4-diiT!ethoxypheny{)imidazo[i,2 ,']pyri

yl)methy{)-2-( 1 -ethylpiperidin-4-yl)ethan- 1 -amine 4-8i was prepared in the same manner as i-(l-(2-(5-chloro~2,4~dimeihoxypbe

(thiopher!-2-y1methyl)metha.namir!e 4-Sa, using 2-( 1 -ethylpiperidin-4-yl)ethan - 1 -amine 4-7i, and was obtained as an off-white solid (35% yield).

fi NMR (400 MHz, CD3OD): δ 8.17 (d, J = 7.6 Hz, 1H),7.97 (s, 1H),7.85 (s, 1H), 6.86 (s,lH), 6.65 (dd, /= 2.4, 7.6 Hz, 1H), 6.56 (d, J :::: 1.6 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.74 (d, J = 12.8 Hz, 2H ), 2.86 (d, J = 11.6 Hz, 2H), 2.73-2.67 (m, 2H), 2.55 ( t, J 8.0 Hz, 2H), 2.43 (d, J -- 6.8 Hz, 2H), 2.35-2.29 (m, 2H), 1.90 (t, ./ 10.4 Hz, 2H), 1.77 (d, ./= 11.6 Hz, 2H), 1.63 (d, J= 11.2 Hz, 3H),1.42-1.36 (m, 2H), 1.29-1.33 (m, 5H), 1.01 (t, J ------ 7.2 Hz, 3H ); HPLC (Method 12) 93.3% (AUC), to - 6.23 mm.; LSI - APC ' f MS m/z 540

[M + S i j .

P2 e|)aratiofl nii ^

N-((l-(2-(5-Chloro-2,4-dimethoxyph^

yl)methyl)-2-( 1 -propylpiperidin-4-yl)ethan - 1 -amine 4-8j was prepared in the same manner as l-( l-(2-(5-chioro-2,4-diniethoxyphen^

(thiophen-2-ylmethyl)niethananiine 4-8a, using 2 -( 1 -prop lpiperidin-4-yl)ethan- 1 -amine 4-

7j, and was obtained as an off-white solid (13% yield).

¾ NMR (400 MHz, CDsOD): δ 8.01 (d, J= 7.6 Hz, 1H),7.97 (s, Π 0.7.85 (s, 1H), 6.86 (s, 1H), 6.65 (dd, J= 2.0, 7.6 Hz, IH), 6.56 (d, J = 2.0 Hz, IH), 3.92 (s, 3H), 3.84 (s, 3H), 3.74 (d, J--- 12.8 Hz, 2H ), 2.85 (d, ./ 12.0 Hz, 2H), 2.72-2.67 (m, 2H), 2.54 ( t, ./ 7.6 Hz, 2H), 2.42 (d, J= 6.8 Hz, 2H), 2.22-2.18 (m, 2H), 1.90 (t, J = 10.4 Hz, 2H), 1.77 (d, J = 12.4 Hz, 2H), 1.62 (d, ,/= 11.2 Hz, 2H), 1.46-1.36 (m, -H i). 1.29-1.15 (m, 6H), 0.83 (t, J -- 7.2 Hz, 3H ): HPLC (Method 9) 98.6% (AUC), te - 6.45 mm.; ESI+APCI MS m/z 554 [M + H | .

re$arati^

N-((l~(2-(5-Chloro~2,4~dmiethoxyphenyl)imidazo[ i,2-a]pyndm^

yl)methyl)-2-(4-methoxycyclohexyl)ethan-l-amine 4-8k was prepared in the same manner as l-(l-(2-(5-chloro-2,4-dimeftoxyphenyl)imida∞

(tihophen-2-ylrnethyi)methanamine 4-8a, using 2-(4-methoxycyclohexyl)ethan-l -amine 4- 7k, and was obtained as an off-white solid (18% yield).

¾ NMR (400 MHz, CD3OD): δ 8.05 (d, J= 7.6 Hz, 1H),7.96 (s, 1H),7.87 (s, IH), 6.70-6.67 (m, 2H), 6.58 (d, J ------- 2.0 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (d, J= 12.4 Hz,

2H ), 3.38-3.26 (m, 1H), 3.24 (s, 3H), 2.84-2.70 (m, 6H), 1.81-1.72 (m, 5H), 1.50-1.18 (m, 10H), 1 , 12-0.92 (m, IH); HPLC (Method 12) 98.2% (AUC), fe = 6.71 min.; ES1+APCI MS m z 541 [M + H] + .

j^g j * ^

yjl j ridm-^

A-(( l-(2-(5-CUoro-2,4-dimethoxj^henjd)imidazo[ l,2- ]pyridin-7-yi)piperidin-4- yl)methyl)-2-(cyclohex- 1 -en- 1 -yl)ethan- 1 -amine 4-81 was prepared in the same manner as l~( l -(2-(5~eliloi -2,4-diiT!ethoxyphenyl)iniidazo[l ,2- ]pyrid

(†hiopben-2-ybnetbyi)methanamme 4-8a, using 2-(cy ohex~l~en-l~y])etban-i-arome 4-71, and was obtained as an off-white solid (14%).

lH NM (400 MHz, DM O- ). δ 8.27 (d, J -- 7.6 Hz, 1H),8.16 (s, 1H),7.99 (s, IH), 6.86 (s, IH), 6.78 (d, ./ 7.6 Hz, IH), 6.63 (s, IH), 5.39 i s. IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, ./ 12,4 Hz, 2H ), 2.74-2.67 (m, 2H), 2.61-2.58 (m, 21 1 ·. 2.05-1.93 (m, 2H), 1.89-1.79 (m, 4H),1.78-1.72 (m, 2H), 1.56-1.48 (m, 6H), 1.23-1.20 (m, 3H); HPLC (Method 9) 98,7% (AUC), ft = 6.86 mm.; ESI+APCI MS m z 509 [M + H | .

Preparation of tof-Butyl 4-(2-(((l-(2-(5-chloro-2,4-dimetho¾>' , phei¾yl)imid8zo l,2- a|gYridin-7-Yl)piperidin-4-yl)methvl)amino)ethYl)piperidii¾ e-l-carbowiate ^8m_ fert-Buty 1 4-(2-((( l-(2-( 5 -ehioro-2,4-dmiethoxypheny l)imidazo [ 1 ,2~ ]pyridin~7~ yl)piperidin~4~yl)methyi)amino)etliyl)piperidine-l-carboxyla te 4-8m was prepared in the same manner as 1 -( 1 -(2-(5 -chl oro-2,4-dimetiioxyphenyl)itnidazo [ 1 ,2-«]pyridin-7- yl)piperidin-4-yl)-N-(1hiophen-2-ylraethyl)methaiiaraine 4-8a, using tert-bntyl 4-(2- aminoethyl)piperidine- 1 -carboxylate 4~7m, and was obtained as an off-white solid (18% yield).

i f NMR (400 MHz, CD3OD): δ 8.03 (d, J = 7.6 Hz, 1H),7.97 (s, 1H),7.86 (s, IH), 6.67 (dd, J ----- 5.2, 8.0 Hz, 2H), 6.57 (s, IH), 3.98 (d, J ----- 8.4 Hz, 2H), 3.92 (s, 3H), 3.85 (s,3H), 3.76 (d,■/ 12.8 Hz, 2H ), 2.74-2.59 (m, 6H), 2.48 ( d, J ------- 6.8 Hz, 2H), 1.79 (d, J ------- 12.8 Hz, 2H), 1.60 {0. 12.8 Hz, 3H), 1.43-1.39 (m, 2H), 1.35 (s, 9H), 1.28-1.21 (m, 3H), 1.03-0.98 (m, 2H): HPLC (Meiliod 9) 98.7% (AUG), ,¾ - 6.99 min.; ESI+APCI MS m/z 612 i M H |

Scheme 10

Preparation of methyl l-(2-ami pyridi -4-vI)pyrr lidine--3-c¾rboxylat S 2 _

To a solution of 4-chloropyridin-2-amine 5-1 (0.48 g, 3.75 mmol) in N,N- diisopropylethyl amine (10 mL) was added methyl pyrrolidme-3-carboxylate hydrochloride salt (0.93 g, 5.65 mmol). The reaction mixture was heated at 120 °C in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCCh solution (300 ml,: 100 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over anhydrous NaiSCh, filtered and concentrated. The residue was triturated with hexanes, and dried to provide methyl 1 -(2- animopyridm-4-yl)pyrrolidine-3-carboxylate 5-2 (700 mg, crude) as an off-white solid, which was used directly for next step without further purification. ESI+APCI-MS m/z 222 [M + Hf.

Preparation of methyl l-(2-(5-c Ioro-2,4-dimethoxyp envj)imMazojl.2-a pyridi«^7 yj)pyrroSidine-3-carb ¾yL¾tg_5^4

A mixture of methyl l-(2-aminopyridin-4-yl)pyirolidine-3-earboxylate 5-2 (0.50 g, 2.262 mmol) and 2 )romo-l-(5-chtoro-2,4-dimethoxyphenyi)ethanone 5-3 (0.726 g, 2.48 mmol) in acetone (50 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, the white precipitate formed was collected by filtration, washed with hexanes (20 mL), and dried. The hydrobromic salt was basified with aqueous NaHCCh satureated solution (5.0 mL), by stirring at room temperature for 1 h. The solid was collected by filtration, washed with water and dried to give methyl l~(2-(5-chloro~2,4~ dime†hoxyphenyl)imidazof i,2-G]pyridin-7-yl)pyrrolidine-3-carboxylate 5-4 (0.2 g, 47%) as an off-white solid.

H MR (400 MHz, CDCb): δ 8.31 (s, 1H), 7.80 (d, ./ 7.2 Hz, 1H), 7.74 (s, 1H),

6.50 (s, lH), 6.41 (s, 1H), 6.28 (dd, J ----- 2.0, 7.2 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.68 (s, 3H), 3.56 { ./ 7.2 Hz, 2H), 3.44-3.40 (m, 1H), 3.37-3.31 (m, 1H), 3.22-3.15 (m, I H), 2.29-2.24 (m, 2H). ESI+APCI-MS m/z 416 [M + H] ÷ .

yl)pyrrolidine-3-c.arboxYlic acid 5-5^

To a solution of methyl l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2- o|pyridin-7-yi)pyrrolidine-3-carboxyiate 5-4 (1.0 g, 2.4 mmol) in THF, CH3OH and water (20 niL/10 mL/5 mL), was added LiCM fcO (0.40 g, 9.6 mmol) and the resulting mixture was stirred at ambient temperature for 5 h . The solvents were evaporated and the residue was diluted with water and extracted with ethyl acetate (2 χ 10 mL). The aqueous layer was acidified to pH 3-4 with 10% KHSO4 solution, and the precipitate formed was collected by filtration, washed with water and dried to afford l -(2-(5-chloro-2, 4- dimeihoxyphenyl)imidazo[l,2-i?]pyridin-7-yl)pyiTolidine-3-ca rboxylic acid 5-5 (750 mg, 78%) as an off-white solid.

' i NMR (300 MHz, DMSO-ds): δ 8.29 <d. ./ 7.5 Hz, IH), 8.16 (s, IH), 7.96 (s, IH), 6.85 (s, IH), 6.51 (d, J= 6.6 Hz, i l l). 6.24 (s, !H), 4,00 (s, 3H), 3.93 (s, 3H), 3.57-3.46 (m, 2H), 3.37-3.33 (m, 2H), 3.25-3.18(m, 1H), 2.27-2.17 (m, 2H): ESI+APC1 MS m/z 402[M + H] + .

Preparation of l-(2-(5-chIoro-2,4-dimethoxYphenYl)imidazo[l,2-a]pyridin-7-y I)-A-

To a solution of l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ L2-i7 [pyridm-7- yl)pyrrolidine-3-carboxylic acid 5-5 (200 mg, 0.498 mmol), N,0-dimeihyl hydroxylamine hydrochloride (72 mg, 0,747 mmol), N.N-diisopropylethyl amine (256 mg, 1.99 mmol) in DMF (2.0 mL), was added EDOHC1 (190 mg, 0,996 mmol), and HOBt (152 mg, 0,996 mmol). The reaction mixture was stirred at ambient temperature for 15 h. The reaction mixture was diluted with water, and extracted with ethyl acetate (2 χ 30 mL). The combined organic layer was washed with water followed by brine, dried over anhydrous NaaSCk, filtered and concentrated to afford l-(2-(5-chloro-2,4- dimeAoxyphenyl)imidazo[l,2-tf]pyridin^

carboxamide 5-6 (200 mg, crude). The crude material was used directly in the next step without further purification.

Ti NMR (300 MHz, DMSO~a¾): δ 8.29 (d, J= 7.2 Hz, 1H), 8.16 (s, IH), 7.95 (s, IH), 6.85 (s, 1H), 6.51 (d, J= 7.5 Hz, I H), 6.23 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.72 (s, 3H), 3.59-3.55 (m, 2H), 3.42-3.37 (m, 3H), 3.15 (s, 3H), 2.26-2.08 (m, 2H); ESI+APCT MS m/z 445[M + Hf.

Prejjaratioo f l-ll- To a solution of l-(2-(5-ch1oro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7-y l)- N-methoxy-N-methylpyrrolidine-3-caiboxamide 5-6 (1 .0 g, 2.25 mmol) in THF (500 mL) was added a solution of Q-LCHjMgBf in THF (2.0 M, 3.35 mL, 6.70 mmol) at ambient temperature. Hie reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with aqueous NH4CI saturated solution at 0 °C and extracted with ethyl acetate (2 χ 100 mL). The combined organic layer was dried over anhydrous NaaSCfe, filtered and concentrated to afford l -(l-(2-(5-chIoro-2,4- dimethoxyphenyl)imidazo[l,2-a]py^ 5-7 (700 mg, crude), which was used directly in the next step without further purification. ESI+APCT MS m/z 414 | M · H | .

28);

To a suspension of l-(l-(2-(5-chloro-2,4-dimethox , phenyl)imidazo[l ,2-a]pyridin-

7-yi)pyrrolidin-3-y3)propan-l-0!ie 5-7 (100 mg, 0.242 mmol), (l -ethylpiperidin-4- y])methanamine (51 mg, 0,36 mmol) in CH3OH (5.0 mL) was added acetic acid (0.05 mL) and the resulting mixture was stirred for 12 h at 80 °C. Sodium cyanoborohydride (45 mg, 0.72 mmol) was added and the reaction mixture was stirred at 80 °C for additional 6 h. The reaction mixture was cooled to ambient temperature, diluted with aqueous sodium bicarbonate solution and extracted with CH2CI2 (2 χ 20 mL). The combined organic layer was dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure. The residue was purified by combi-fiash companion (silica gel, NH4OH/CH3OH/CH2CI2, 1 :9:90) to afford 1-(1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-o]pyridin-7- yl)pyrrolidin-3-yl)-N-((l -etty 5-8 (20 mg, 15%) as an off-white solid.

'H NM (400 MHz, CD3OD) δ: 8.00 (d, J ------- 7.6 Hz, I H), 7.95 (s, 1H), 7.80 (s, 1H),

6,69 (s, IH), 6.42 idd. ./ 2.4, 7.6 Hz, IH), 6.16 (s, IH), 3.92 (s, 3H), 3.85 (s, 3H), 3,49- 3.24 (ra, ·!! !}. 3.07-2.91 (m, 3H), 2.50-2.34 (ra, 6H), 2.17-2.04 (m, 1H), 2.01-1.93 (m, 2H), 1.79-1.67 (m, 3H), 1.67-1.50 (m, 1 H), 1.44-1.37 (ra, 2H), 1 .22-1 .16 (m, 1H), 1.05 (t, J = 6.8 Hz, 3H), 0.90 (t, ./= 7.2 Hz, 3H); HPLC (Method 4) 93.6% (AUC), fe = 6.35 ram.; ESI+APCI MS M z 540 M + I I .

Scheme 11

-animopvridm-^-YUpipermm-^-yljmet-iYijcarPamate To a solution of 4-diloropyridin-2 -amine 6-1 (2.50 g, 19.5 mmol) in a mixture of isopropanol and N, N'-diisopropylcthyl amine (50 mL/ 25 mL), was added ferf-butyl (piperidm-4~y]methy1)carbamate 6-2 (6.30 g, 29.4 mmol). The e reaction mixture was heated in a sealed tube at 120 C C tor 24 h. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCt solution (300 mL/iOO mL). The layers were separated and the EtOAc layer was washed with brine ( 100 mL), dried over NazSCfe, filtered and concentrated. The residue was triturated with hexanes, filtered and dried to provide tert-butyl ({ l~(2-aminopyridin-4~yS)piperidin~4-yl)niethyl}carba.raate 6-3 (5.50 g, 92%) as an off-white solid, which was used directly for next step without further purification. ESI+APCI-MS m/z 307 [M + H] \

7-y])]3i|3er^

A mixture of tert-butyl ((1 -(2-aminopyndin-4- i)piperidin~4~yl)metliy i)carbamate 6-3 (5.00 g, 16.3 mmol) and 2-bronio-l~(5-chloro-2 4-dimethoxyphenyl)ethanone 6-4 (5.30 g, 1 8.1 mmol) in acetone (200 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature. The precipitate formed was collected by filtration, washed with hexanes (200 mL), and dried. The hydrobromide salt was taken up in saturated sodium bicarbonate solution (200 mL) and stirred at room temperature for 1 h. The solid was collected by filtration, washed with water and dried to afford tert-butyl (( 1- (2-(5 -chloro-2,4-climethoxyphenyi)imidazo [ 1 ,2 -a]pyridin-7-y l)piperidin-4- yl)methyi)carbaniate 6-5 (7.1 g, 79%) as an off-white solid.

! H NMR (400 MHz, DMSO-de): δ 13.13 (br s, 1H), 8,49 (d, J = 7.8 Hz, ΓΗ), 8.23 (s, 1H), 7.91 (s, 1H), 7.29 (d, J= 6.0 Hz, IH), 6.98-6,92 (m, 2H), 6.66 (s, ΓΗ), 4.05-3.98 (ni, 8H), 3.03 (t, J = 12.6 Hz, 111), 2.85 (t, J= 5.4 Hz, 2H), 1.75 (d, J = 1 1.7 Hz, 3H), 1 .38 (s, 9H), 1.23- 1.14 i . 2H); LIPLC (Method 9) 99.2% (AUG), ¾ = 13.78 rain.;

ESI-i-APCl-MS m/z 501 [M + H] + .

To a sijspention of tert-butyl ((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2- a]pyridin-7-yl)piperidin-4-yl)iT3ethyi)carbaraate 6-5 (3.00 g, 5.98 mmol) in CH2Q2 (30 mL) was added a solution of HCl (4.0 M in ,4-dioxane, 30 mL) and the reaction mixture was stirred at room temperature for 16 h. The solid obtained was collected by filtration, washed with CH2CI2 (100 mL) and dried. The solid was then suspended in water (70 mL) and basiiied with saturated sodium bicarbonate solution (70 mL), by stirring at room temperature for 1 hour. The pale yellow solid formed was collected by filtration, washed with water and dried to provide (l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo l,2- a]pyridin-7-yl)piperidin-4-yl)methanamine 6-6 (2.1 g, 87%) as an off-white solid.

: fi NMR (400 MHz, DMSO fc): δ 8.26 (d, ,/ 7.6 Hz, ill).8.17 (s, lif).7.99 is. HI).6.86 (s, l!l!.6.77 id. J -- 6.0 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 id. J ------ 12.4 Hz, 2H), 2.87 (t, ./ 2.0 Hz, 2H), 2.70 (t, J -- 11.6 Hz, 2H), 1.74-1.58 (m, 3H),

1.24-1.16 (m, 2H); LSI · APCI-ViS m/z 401 [M 4- lij . yijpiperidin-4-yl)-.V-(2 < S-dimethoxybeazvl)niethanamine 6-8a (Example 2-14);

To a suspension of (l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo l,2-a]pyndin-7- yl)piperidin-4-y])methanarnme 6-6 (150 mg, 0.37 mmol), 2,5-dimethoxybenzaldehyde 6-7a (68 mg, 0.41 mmol) in CifcOH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (118 mg, 1.87 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2 χ 20 mL). The combined organic extracts were washed with brine (20 nil,), dried over anhydrous a?S04, filtered and concentrated. The residue was purified by combi-flash chromatography [silica gel; 5% NH-tOH in MeOH: CH2CI2 (1:9)] to givel-(l-(2-(5-chloro-2,4-dimeihoxyphenyl)imidazo[l,2-£?]py ridin-7- yl)piperidin-4-yl)-A L (2,5-dimethoxybenzyl)metlianamine 6-8a (70 mg, 39%) as an off- white solid.

¾ NMR (400 MHz, DMSQ- e): δ 8.26 (d, J= 7.6 Hz, ill).8.16 (s, 1H), 7.99 (s, 1H), 7.19 (d, J= 8.4 Hz, 1H), 6.86 (s, H), 6.77 (dd, J = 2.4, 7.6 Hz, 1H), 6.62 (s,lH), 6.58 (d, ./= 2.4 Hz, 1H), 6.47(dd, ./= 2.0, 7.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.80 (d, J= 10.0 Hz, 3H), 3.76 (s, 3H), 3.73(s, 3H), 3.60 (s, 2H), 2.74-2.67 (m, 2. H), 2.40 (d, J= 6.4 Hz, 2H), 1.80 (d, ./ 12.0 Hz, 2H), 1.66-1.53 (m, HI). 1.23-1.17 (m, 1H); HPLC (Method 10) 91.0% (AUG), > ----- 6.76 mm.; ESI+APCI-MS m/z 551[M + III .

Prej3 i arat¾o i o i of i l-{

l-(l-(2-(5-Chloro-2,4-dimei oxypheny])imidazo[l,2-a]pyridin-7-yl)piperidin-4 yl)-N-(4-methoxy-2-nitrobenzyl)methanamine 6-8b was prepared in the same manner as 1- ( l-(2-(5-chlorQ-2,4-dimeihoxyphenyl)imid

dimethoxybenzyl)methanamine 6~8a, using 4-methoxy-2-nitrobenzaldehyde 6-7h, and was obtained as an off-white solid (39% yield).

1 H NMR (400 MHz, DMSO-ds): δ 8.25 id. ./ 7.2 Hz, IH), 8.16 (s, IH), 7.98 (s, IH), 7.59 (d, J= 8.8 Hz, 1H), 7.40 (d, J= 2.8 Hz, IH), 7.25 (dd, J = 2.8, 11.2 Hz, i l l). 6.86 (s, IH), 6,76 (dd, J = 2.0, 7.6 Hz, H), 6.61 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.85 (s, 2H), 3.82 (s, 3H), 3.74 (d, J= 12.8 Hz, 2H), 2.73-2.66 (m, 2 H), 2.44-2.36 (m, 3 H), 1 .78 (d, J= 12.0 Hz, 2H), 1.20-1 , 15 (m, 2H); HPLC (Method 10) 95.1% (AUC), te = 6.76 min.; ESl+APCI-MS m/z 566[M 4- Hj + .

Preparatiosi of S-{{{ii-(2-iS-chloro-2,4-dimeihoxYphenvl)imidazo[l ,2-a

siperidin-

5~((((i-(2~(5-C.hioro-2,4-dime†hoxyphenyl)irflidazo[i,2 -a]pyridin-7-} ^ yl)methyl)araino)methyl)-2-raeAoxyphenol 6-8c was prepared in the same manner as (2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2^]pyridin-7-yl)piperidin^

dimethoxybenzyl)roetbanamine 6-8a, using 3-hydroxy-4-methoxybenzaldehyde 6- 7c, and was obtained as an off-white solid 140"·.. yield).

H MR (400 MHz, DMSO-t/i): δ 8.8 l(s, IH), 8.26 (d, J = 7.2 Hz, IH), 8.16 (s, IH), 7.99 (s, I H), 6.86 (s, IH), 6.82 id. ./ 8.0 Hz, I I ! ·. 6.79-6.76 (rn, 2H), 6.68 (dd, ./ 2.0, 8.4 Hz, IH), 6.62 (d, ,/= 1.6 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.77(d, J= 12 Hz, 2H), 3.72 is. 3H), 3.33 (s, 2H), 2.73-2.67 (m, 2H), 2.38 (d, J= 6.4 Hz, 2H), 1.80 (d, J === 12.0 Hz, 2H), 1.60-1.54 (m, IH), 1.25-1.17 (m, 2H); HPLC (Method 10) 97,6% (AUC), f R = 6.55 min.; ESI÷APCi-MS m/z 537[M + H] + . ySi0ipersdiri-4-yl)m thvl)ainssio)meihvl)-5-niet!i xvp!ien l 6-8d (Example 2-41):

2 ·-(((( l-(2-(5 -CUoro-2,4-dimethoxyphenyl)iniidazo [ 1 ,2- ]pyridin-7~yl)piperidin~4- yl)metb.yl)ainino)niethyl)-5-met oxyphenol 6-8d was prepared in the same manner as 1 - ~ (2~(5-chloro~2,4~dimeihoxyphenyl)imida^

dimethoxybenzyl)methanarnine 6-8a, using 2-hydroxy-4-methoxybenzaldehyde 6-7d, and was obtained as an off-white solid (45% yield).

]H NMR (400 MHz, CD3OD): δ 8.02 (d, ./ 7.6 Hz, iH), 7.97 (s, IH), 7.85 (s, 1H),

6.87 (d,■/ 8.8 Hz, i l l). 6.68 (m, IH), 6.65 (dd, ./ 2.4, 7.6 Hz, IH), 6.55 (d, J= 2.4 Hz, H I ). 6.25-6.22 (m, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.74 {ά, J ------ 15.6 Hz, 4H), 3.62 (s, 3H),

2.73-2.70 (m, 2H), 2.48(d, ./ 6.8 Hz, 2H), 1.78 (d, J = 1 1.6 Hz, 2H), 1.70-1.63 (m, lHU .30-1.18 (m, 2H); HPLC (Method 10) 96.1% (AUC), te = 6.65 mm.: ESI+APCI-MS m/z 537[M + H] + .

Preparation of 4-((((i-(2-(5-chloro-2,4-dimetho¾ hem )imidazon ^-a pYridm-7 iEx tin ¾le ii 2 59 i ; i

4-(((( l-(2-(5 -CUoro-2,4-dimethoxyphenyl)iniidazo [ 1 ,2-a ]pyridin-7-yl)piperidin-4- yl)rae&yl)amino)methyl)-2-methoxy-N,N-dimethylaniline 6-8e was prepared in the same manner asl-(l-(2-(5-chloro-2,4-dimethoxyph^

y1)-A / -(2,5-dimethoxybenzy])met1ianamine 6-8a, using 4-(dimethylamino)-3- niethoxybenzaldehyde 6-7e, and was obtained as an off-white solid (70 mg,33%).

lH NMR (400 MHz, DMSO-ffc): δ 8.26 (d, J -- 7.6 Hz, IH), 8.16 (s, IH), 7.99 (s, IH), 6.91(s, I H), 6.86 (s, IH), 6.79-6.77 (m, 3H), 6.62 (d, J= 2.0 Hz, IH), 4.00 (s, 3H),

3.93 (s, 3H), 3.78 id. ./ 8.8 Hz, 21 1 ). 3.62 (s, 2H), 2.73-2.67 (m, 2H), 2.64 (s, 6H), 2.40 (d, ,/ 6.4 Hz, 2H), 1.82 id. ./ 11.2 Hz, 2H), 1.61-1.59 (m, l H), 1.26-i . l 7 (m, 2H): HPLC (Method 9) 98,3% (AUC), m = 6.41 mm. ; ESI+APCI-MS m/z 564[M + Hf.

Preparation of l-(l-{2-(5-c¾l ro-2,4-dimet¾oxyp¾e8¾yl)imidazo l ¾ 2-a|pyridin-7- Yl)piperidii¾-4-Yl)-A ? -(4-methoxY-3-methylbeHzyl)methanamine 6-8f (Example 2^3 } 1 -( 1 -(2-(5 -Chioro-2,4-dimethoxyphenyl)imidazo 11 ,2 -o]pyridin-7-y3)piperidin-4- yl)-N-(4-methox -3-methylbenzyl)methananiine 6-Sf was prepared in the same manner as 1-(1 -(2.-(5-chloro-2 ,4-dimethoxyphenyl)imidazo [ 1 ,2-a ipyridm~7-yl)piperidin-4-yl)-A ? -(2, 5 - dimetiioxybenz 'l)methanamine 6-8a, using 4-methoxy-3-roethylbenzaldehyde 6-81 and was obtained as an off-white solid (30%, yield).

lH NMR (400 MHz, DMSO-a¾): δ 8.26 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.10 (d, J ------- 8.0 Hz, 2H), 6.85 (d, J --- 9.2 Hz, 2H), 6.77 (dd, J ------- 2.0, 7.6 Hz, 1H), 6.62 (d,■/ 2.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.79 (s, 2H), 3.75 (s, 3H), 3.61(s, 2H), 2.73-2.67 (m, 2H), 2.40 id. ./ 6.4 Hz, 2H), 2.12 (s, 3H), 1.80 (d, ./ 11.6 Hz, 2H), 1.62- 1 .57 (m, 1H), 1.26-1.19 (m, 2H); HPLC (Method 9) 99.5% (AUC), > ----- 6.89 mm.;

ESI+APCI-MS m/z 535 [M + H] + .

Preparation of 4-(((U-(2-(S-c. SorQ-2,4-dimet oxyphem f l imidazojl,2-a^pyridis¾-7 :: yl)piperidin-4-yl)methyl)amino)methyl)-A r ^ , ,2-trimethylaniline 6-§g (Example 2-58);

4-((((l-(2-(5-Chk>fo-2,4-dimethoxyphenyl)imidazo[l,2-a]py ri

yl)methyl)aniino)methyl)-A i ,A^2 rimethylaniline 6-8g was prepared in the same manner as 1 -( 1 -(2~(5-chloro-2,4~dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-y l)piperidin~4~yl)-N~(2,5~ dimeihoxybenzyl}methanamme 6- 8a, using 4-(dimeihylammo}-3-methylbenzaldehyde 6-7g, and was obtained as a off-white solid (44% yield).

! H NMR (400 MHz, DMSO-i¾); δ 8.27 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, IH), 7.08 (d, ,/ 8.4 Hz, IH), 6.86 (s, 1H), 6.74 (dd, ./ 2.4, 7.6 Hz, i l l). 6.62 (d, ,/ 2.0 Hz, IH), 6.54 (d, ,/ 2.4 Hz, IH), 6.51-6.48 (m, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J= 8.8 Hz, 21 1). 3.60 (s, 21 1}. 2.84 (s. 6H), 2.74-2.66 (m, 2H), 2.52-2.48 (m, 2H), 2.26 (s, 31 1} 1.81 (d, J= 1 1.2 Hz, 2H), 1.65-1.59 (m, 1 H), 1.27-1.19 (m, 2H); HPLC (Method 9) 98.3% (AUC),†R ------ 6.41 min.; ESI+APCI-MS m/z 548[M + H] + .

l¾:g aj:a iQB i 2-^

2-((((l-(2-(5-Chioro-2,4-dime†hoxypheny1)imidazofl,2-a] pyridm-7-yl)pipendin-4 yr)methyl)amino)methyl)-4-methylphenol 6-8h was prepared in the same manner as 1-(1 - (2-(5-chloro-2,4-dimethoxyphenyi)imidazo| l ,2-o]pyridin-7-y3)piperidin-4-yl)-A i -(2,5- dimethoxybenzyl)methanamine 6-8a, using 2-hydroxy-5-methylbenzaldehyde 6-7h, and was obtained as an off-white solid (32% yield). f t NMR (400 MHz, DMSO- e): 5 8.27 (d, ./ 10.0 Hz, IH), 8.17 is, i l l) . 7.99 (s, IH), 6.86 (s, 3H), 6.77 (d, J = 2.0, Hz, IH), 6.63 (s, IH), 6.57(d, J = 1 1.6 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.80 (d, J= 1 1.6 Hz, 4H), 2.75 (t, J= 15.2 Hz, 2H), 2.42 (d, J= 8.4 Hz, 2H), 2.16(s 5 3H), 1.79 (d, J= 15.2 Hz, 2H), 1.65-1.59 (m, 1H), 1.29-1.18 (ra, 2H); HPLC (Method 9) 99.5% (AUC), fe = 6.69 mm.; ESI+APCI-MS m/z 521 [M + H | .

Preparation ,, ^

¾|) pjger¾dj^^^

l~(i -(2~(5~Giloro-2,4-diniethoxyphe

yl)-N-(2-raethox '-5-methylbenzyl)methanaraine 6-Si was prepared in the same manner as l -{ l-(2-(5-chloro-2,4~dimethoxyph^

dimethoxybenzyljroetbanaitnne 6-8a, using 2 -raethoxy- -methyl benzaldehyde 6~7i, and was obtained as an off-white solid (27% yield).

¾ NMR (400 MHz, CD 3 OD): δ 8.01 (d, ./ 7.6 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 6.97 id. ./ 8.4 Hz, 2H), 6.77 (d, ./ 8.0 Hz, 1H), 6.86 --6.63 (m, 2H), 6.55 (s, H i ). 3.91 (s, 3H), 3.84 (s, 3H), 3.72 (d, J = 10.0 Hz, 5H), 3.65 (s, 2H), 2.72-2.66 (m, 2H), 2.41 (d, / === 6.8 Hz, 2H), 2.17 (s, 3H), 1.75 i d . ./ 12.8 Hz, 2H), 1.65-1.64 (m, 1H), 1.25-1.17 (m, 2H); HPLC (Method 10) 97.3% (AUC), fe = 6.85 min.; ESI+APCI-MS m/z 536 [M + l ! i .

Preparation of l-(1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazon.,2-a]pvridiR-7- 1 -( 1 -(2-(5 -Chloro-2,4-dimethoxy pheny l)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4- l). J V-(2,3-dimethylbenzyl)meihanamine 6-8j was prepared in the same manner as l-(l-(2- (5-ch3oro~2,4~dimethoxy heiiyl)m^

dime†hoxybenzyl)methanarnine 6-8a, using 2,3-dimethylbenzaldehyde 6-7j, and was obtained as an off-white solid (36% yield) .

¾ NMR (400 MHz, CDC ): δ 8.36 (d, J = 1 .6 Hz, I H), 7.87-7.84 (m, 2H), 7. 13

(d,■/ 2.4 Hz, 1H), 7.07 id. ./ 1.6 Hz, 2H), 6.81 (s, I H), 6.57 (d, ./ 6.4 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3! 3.78 (s, 2H), 3.74 (d. ./ 12.8 Hz, 2H), 2.8 ! (L ./ 12.0 Hz, 21 1 ·. 2.61 (d, J = 6.4 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.89 (d, J= 12.4 Hz, 2H), 1.60-1.53 (m, IH), 1.42-1.34 (m, 2H); HPLC (Method 9) 99.5% (AUG), ft. ----- 6.84 mm.; ESI+APCI-MS m/z 519 j \l · \ \ [ .

Preparation ofl~(l-(2-{5~ChK¾ro~2,4~dimetho¾vp¾envI)i^ l-(l -(2-(5-Chioro-2,4-dimethoxyphe

yl)-N-(4-fluoro-3-methylbenzyl)methanamine 6-8k was prepared in the same manner as 1- (l~(2-(5-chloro-2,4~dimethoxyphenyl)imidazo[ ,2-«]pyridin-7-yl)piperidin-4-yl)-A- 2,5- dimethoxybenzyS)methanamiiie 6-8a, using 4-fluoro~3~methylbenzaldehyde 6- 7k, and was obtained as an off-white solid (16% yield).

!H NMR. (400 MHz, CD3OD): δ 7.99 (d. 7.6 Hz, IH), 7.96 (s, IH), 7.83 (s, 1 H),

7.22-7.18 (m, 1H), 6.83-6.75 (m, 2H), 6.66 (s, 1H), 6.63 (dd, J= 2.4, 7.6 Hz, IH), 6.54 (d, J -- 2.0 Hz, IH), 3.90 (s, 3H), 3.83 (s, 3H), 3.72 (d, J= 12.4 Hz, 2H), 3.64 (s, 2H),

2.72-2.65 (m, 2H), 2.46 (d. ./ 6.8 Hz, 2H), 2.26 (s, 3H), 1.83-1.77 (m, 2H), 1 .67-1.60 (m, IH) 1.28-1.18 (m, 2H); HPLC (Method 10) 95.7% (AUC), fe = 6.77 mm.: ESI+APCI- MS m/z 523 [M + H] ÷ .

Preparation of i-(l-(2-{ ' S-chjoro-2 ¾ 4-dimetho.xYphenYl¾imidazon- < 2-al )yridin-7- y!)piperidm-4-yI)-A-(2-fluoro-3-methYlbenzyl)methanamine 6-81 (Example 2-85)^

l-(l-(2-(5-Chloro-2,4-dimeihoxypheny])imidazo[l,2-a]pyridm-7 -yl)piperidin-4- yl)-N-(2-fluoro-3-methylbenzyl)methanamine 6-81 was prepared in the same manner as 1 - ( l-(2-(5-chioro-2,4-dimeihoxyphenyl)imidazo[ L2-o]pyridin

dimethoxybenzyl)methanamme 6-8a, using 2-fluoro-3-methylbenzaldehyde 6-71, and was obtained as an. off-white solid (31 % yield),

¾ NMR (400 MHz, CD3OD): δ 8.11-8.05 (m, 2H), 7.94 (br s, IH), 7.20-7.14(m, 2H), 7.02 (br s, IH), 6.77 (br s, 2H), 6.64 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.81 (br s, 4H), 2.81 (t, J= 1 1.6 Hz, 2H), 2,5 i (s, 2H), 2.25 (s, 3H), 1.87 (d, J= 3.2 Hz, 2H), 1.78-1.73

(m, I H), 1.33- 1 .30 (rsi, 2H); HPLC (Method 9) 96.3% (AUC), fe = 6.76 min.; ESI+APCI-

MS m/z 523 [M + H | .

Pj^ ration ^

l-(l~(2-(5-Chloro-2,4-dimeihoxyphenyl)im

yl)-N-(2-fluoro-5-methylbenzyl)methanamine 6-8m was prepared in the same manner as 1 - ( l-(2-(5-ehioro-2,4-dimetl ' K>xv

dimethoxybenzyl)methanamine 6-8a. using 2-tluoro-5-methylbenzaldehyde 6-7m, and was obtamed as an off-white solid (42% yield).

1 H NMR (400 MHz, DMSO-ds): δ 8.27 id. 7.6 Hz, IH), 8.16 (s, 1H), 7.99 (s, 1H), 7.26 (d, J ------ 6.8 Hz, IH), 7.05-6.95 (m, 2H), 6.86 (s, 1H), 6.78 (d, ./ 7.2 Hz, 1H),

6.63 (s, IH), 4,00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J= 12.4 Hz, 2H), 3.69 (s, 2H), 2.74 (t, J = 12.0 Hz, 2.H), 2.42 (d, J= 6.4 Hz, 2.H), 2.27 (s, 3H), 1 ,81(d, J= 12.4 Hz, 2H), 1.62-1.58 (m, IH), 1.26-1.18 Cm, 2H); HPLC (Method 9) 96.6% (AUG), fe = 6.76 rain.; ES1+APCI-MS m/z 523 [M + ! ! | ' .

Pre|)ara ioH f 6-(({{J.-{2 : ^5 67)i

6-((((l-(2-(5-Chloro-2,4-dimetiioxyphenyl)imidazo[l ,2^]pyridin-7-y1)pi^ yl)methyl)amino)methyl)-N,N-dime1hylp>Tidin-3-amine 6-8n was prepared in the same manner as 1 -( l -{2-(5-chioro-2,4-dime†hoxypheny])iinidazof l,2- ]pyridin-7-yl)pipendin-4- yl)-N-(2,5-dimethoxybenzyl)methanamine 6-8a, using 5-(dimethylamino)picolinaldehyde, and was obtamed as an off-white solid (24% yield).

¾ NMR (400 MHz, DMSO-a'd): δ 8.26 (d, J ----- 7.6 Hz, IH), 8.16 (s, IH), 8.02 (d, J = 2.8 Hz, IH), 7.99 (s, IH), 7.21(d, J= 8.8 Hz, IH), 7.09 (dd, J = 3.2, 8.8 Hz, IH), 6.86 (s, IH), 6.77 (dd, J= 2.4, 8.0 Hz, H), 6,63 (d, J = 2.4 Hz, ΓΗ), 4.00 (s, 3H), 3.93 (s, 3H), 3.80 (d, J = 9.6 Hz, 2H), 3.70 (s, 2H), 2.89 (s, 6H), 2.74-2.66 (m, 2.H), 2.44 (d, J= 6,4 Hz, .:! !}. 1.80 (d, J = 10.8 Hz, 2H), 1.64-1.61 (m, 1H), 1.27-1.17 (m, 2H); HPLC (Method 9) 95.8% (AUG), f R === 6.53 mm.; ESI+APCI-MS m/z 535[M + i f | tert-Butyl 3-((((l -(2-(5-chloro-2,4-diraethox ^henyl)imidazo[l ,2-a]pyridin-7- y])piperidin-4-yl)meihyi)amino)methyi)piperidine-l-carboxy3a te 6~8 was prepared in the same manner as 1-(1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| 1 ,2-«]pyridin-7- y3)piperidin-4-yl)-A'-(2,5-dirnethoxybenzyi)methananiine 6-8a, using cert-butyl 3- fonnylpiperidine- 1-carboxylate 7o, and was obtained as an off-white solid (23% yield).

: H WiR (400 MHz, DMSO-ds): δ 8.27 id. ./ 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H) 6.86 (s, i l l). 6.78 (dd, J= 2.4, 7.6 Hz, 1H), 6.62 (s, 1 H), 4.00 (s, 3H), 3.93 (s, -H i). 3.79 (t, J ------ 12.8 Hz, 3H), 2.76-2.67 (m, 2H), 2.44-2.32 (m, 4H), 1.87-1.72 (m, 3H), 1.58-1.54 (m, 4H), 1.38 (s, 9H), 1.30-1.21 (m, 4H), 1.18-1.10 (m, i l l) . HPLC (Method 10) 99,2% (AUC), E = 6.85 mm.; ESHAPCI-MS m/z 598[M + f i | .

2 ·-(((( l-(2-(5 -CUoro-2,4-dimethoxyphenyl)iniidazo [ 1 ,2- ]pyridin-7-yl)piperidin-4- yl)raethyl)aniino)raethyl)-A^A'-diraethylaniiine 6-8p was prepared in the same manner as 1- (l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin-7- y{)piperid

dmiethoxybenzy])metha,namine 6-8a, using 2-(dimethylamino)benzaldehyde 6-7p, and was obtained as an off-white solid (23% yield).

lH NM (400 MHz, DMSO-ffc): δ 8.28 (d, J -- 7.6 Hz, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.44 (d, J= 6.8 Hz, 1H), 7.29 (d, J= 7.6 Hz, 1H), 7.18 (d, J= 7.6 Hz, 1H),7.10-7.06 (m, 1H), 6.86 (s, 1H), 6.79 (dd, J = 5.6, 7.6 Hz, 1H), 6.66 (s, 1H), 4.00 (s, 5H), 3.93 (s, 3H), 3.81 [ύ. . I 12.8 Hz, 2H), 2.77-2.71 (m, 4H), 2.66 (s, 6H), 1.85- 1.76 (m, 3H), 1.37- 1.23 (m, 2H); HPLC (Method 10) 95.5% (AUC), t& = 6.85 mm.; ES1+APCI-MS m/z 534[M + H i . Scheme 2

To a solution of 4-chloropyridm-2-arame 7-1 (500 mg, 3.90 mmol) in a mixture of n-BuOI-i: N,A p -diisopropylethyl amine (10 mL/5 ml,), was added ferf-butyi (pyrrolidm-3- y3methyi)carbamate 7-2 (937 mg, 4.68 mmol). The reaction mixture was heated in a seal tube at 120 °C for 24 h. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCCb solution (100 mL/50 n L). The layers were separated and the EtOAc layer was washed with brine (50 ml..), dried over anhydrous Na 2 S04, filtered and concentrated. The residue was triturated with hexaues, filtered and dried to provide tert- buty! (( l-(2-aminopyridin-4-yi)pyrro3idin-3-yl)methy]) carbamate 7-3 (900 mg, 79%) as an off-white solid, which was used directly in next step without further purification.

ESI+APCI-MS m/z 293 [M + H] + .

Prep r tion , ^ A mixture of ¾rt-butyl iil-(2-aniinopyridin-4-yi)pyrro3idiri-3-yl)methy])carbamate 7-3 (800 mg, 2.73 mmol) and 2-brorno-l-(5-chioro-2,4-dimei oxyphenyl)ethanone 7-4 (880 mg, 3.01 rnmol) in acetone ( 15 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature. The precipitate formed was collected by filtration, washed with hexanes (200 mL), and dried to give tert -butyl (( 1 -(2-(5-chlor o-2,4- dimemoxyphenyl)imidazo[L2-a]pyridin-7-yl)pyrrohdin-3-yl)me

hydrobromide 7-5 (600 mg, 45%) as an off-white solid.

! H NMR (400 MHz, OMSO-de) δ 12.99 is, i l l). 8.49 (d, J = 7.6 Hz, H), 8.22 (s, IH), 7.88 (s, i l l}. 7.06 (t, ./ 5.2 Hz, H I). 6.98 is. 1H), 6.92 (d, ./ 8.0 Hz, i l l). 6.28 (s, IH), 4.05 is, 3H), 3.98 (s, 3H), 3.52-3.44 (m, 3H), 3.18-3.16 (ni, IH), 3,03 (t, J= 6.8 Hz, 2H), 2.51-2.49 (m, IH), 2.12-2.08 (m, IH), 1.87- 1.72 (m, IH), 1.39 (s, 9H); ESI+APCT MS m/z 487 [M + H | .

Pr¾ ratii^

To a suspension of tert-bntyl ((l -(2-(5~chloi -2,4-diniethoxyphenyJ)imidazo[l ,2- a]pyridin-7-yl)pyrrolidin-3-yl)roetbyl)carbamate hydrobromide 7-5 (600 mg, 1 ,23 mmol) in CH2CI2 (1 mL) was added a solution of HQ (4,0 M in 1,4-dioxane, 5 mL) and the reaction mixture was stirred at room temperature for 16 h. The solid obtained was collected by filtration and washed with CH2CI2. The solid was then suspended in water (15 mL) and basified with saturated sodium bicarbonate solution ( 15 mL), by stirring at room temperature for 1 hour. The solid was collected by filtration, washed with water and dried to provide {l ~(2-i5~ehloro-2,4-diniethoxyphenyi)ini^

yl)niethanamine 7-6, which is used in next reaciton without further purification. EST+APCT MS m/z 387 [M + H] ÷ .

Yl)PYrrolidm-3-Yl meihvi)ammo ' imeihy^ 7-Sa (Example 2-52);

To a solution of ( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2~a]pyridin- yl)pyrrolidin~3-yI)metbanamme 7-6 (150 rag, 0,38 mmol), 4-(dimethylamino)-2- raethylbenzaldehyde 7-7a (76 mg, 0.46 mmol) in CHfaOH (10 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (60 nig, 0.97 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 15 min. Hie reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2 χ 20 mL). Hie combined organic extracts were washed with brine (20 mL), dried over anhydrous NazSCfe, filtered and concentrated. The residue was purified by combi-flash

chromatography [silica gel ; 5% Xi hOH in MeOH; CH2CS2 (1 :9)J to give 4~((((i-(2~(5~ chloro-2,4-dimethoxypheny3)imidazo[l,2-a]pyridin-7-yl)pymili din-3- yl)methyl)aromo)methyl)-N /,3-trimethylaniline 7-8a (25 mg, 12%) as an off-white solid , i f NM (400 MHz, CDCI3): δ 8.38 (s, l i f). 7.83 (d, J = 7.2 Hz, Hi), 7.80 (s, H I ). 7.13 (d, ./= 8.0 Hz, 1 H), 6.58-6.54 (ni, 3H), 6.42 (s, IH), 6.32 (dd, ./= 2.4, 7.6 Hz, IH), 3.99 is. 3H), 3.95 (s, 3H), 3.72 (s, 2H), 3.53-3. 1 (m, I H), 3.45-3.32 (m, 2H), 3.13-3.09 (m, IH), 2.92 (s, 6H), 2.79-2.69 (m, 2H), 2.58-2.49 (m, IH), 2.35 (s, 3H), 2.22-2.15 (m, IH), 1.83-1.74 (m, IH); HPLC (Method 7) 91.7% (AUC),†R = 6.45 min.; ESI+APC1-MS m/z 534 [M + H i ' .

Preparation of 4-((((1-(2-(5-chloro-2,4-dimetho¾ hem )imidazon ^-a pYridin- 4~(((( 1~(2~(5 -ChloiO-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]py ridin-7-yl)pyriOlidin-

3-yl)methyl)mimo)methyl)-N^,2-trmiethylaniline 7-8b was prepared in the same manner as 4-(((( i ~(2~( -chl oro~2.,4~dimethoxyphenyl)imidazo [ 1 ,2-a]pyndin-7-yi)pyrroS idi -3 - yi)methyl)amino)methyS)-AViV,3 rimethylanih 7~8a, using 4-(dimethylamino)-3- methylbenzaldehyde 7- 7b, and was obtained as an off-white solid (12% yield).

]H NMR (400 Ml !/. CDCh): δ 8.39 (s, IH), 7.83 (d, J = 7.2 Hz, IH), 7.80 (s, IH),

7.12 (d, J = 8.0 Hz, IH), 6.58-6.54 (m, 3H), 6,40 (s, IH), 6.31 (dd, J = 2.0, 7.2 Hz, IH), 3.99 (s, 3H), 3.94 (s, 3H), 3.72 (s, 2H), 3.52 (t, J = 9.2 Hz, IH), 3 ,45-3.31 (m, 2H), 3.13-3.09 (m, I H), 2.92 (s, 6H), 2.79-2.69 (m, 2H), 2.58-2.50 (m, IH), 2.35 (s, 3H), 2.22-2.11 (m, 1H), 1.83-1.74 (m, 1H); HPLC (Method 7) 93.5% (AUG), tn = 6.45 mm.;

ESI+APCI-MS m/z 534 [M + H] + .

Preparation of 4-((((l-(2-(5-ehIoro-2,4-dimethoxy^ (Exam le 2-55)

4-(((( 1 ~(2-(5 -Chioro-2,4-dimemoxyphenyl)imidazo [ 1 ,2-a]py ridin-7-yl}pynOlidin- 3~yl)inethyr)amino)inethyr)~3~memoxy-A A'-dimetliylaiiiline 7-8c was prepared in the same manner as 4~(((( l -(2-(5~diloi -2,4-diniethoxy

3~yl)niethyl)amino)niethyl)-A r ,N,3-tnmethylanilme 7-8a, using 4-(dimethySamino)-2- methoxybenzaldehyde 7c, and was obtained as an off-white sohd (14% yield).

! H NMR (300 MHz, CDCb): δ 8.38 (s, H), 7.84-7.80 (m, 2H), 7.06 (d, J= 9.0 Hz, IH), 6.56 (s, IH), 6.39 (s, 1H), 6.32-6.26 (m, 3H), 3.99 (s, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.73 (s, 2H), 3.52 (i. 7.8 Hz, !H), 3.44-3.29 (m . 2H), 3.10-3.04 {m, IH), 2.95 (s, 6H), 2.72-2.61 (m, 2H), 2.56-2.46 (m, IH), 2.20-2.15 (m, IH), 1.80-1.70 (m, I H); HPLC (Method 7) 97.3% (AUC), = 6.65 min.; ESI+APCI-MS m/z 550 [M + H | .

Preparation of 2-((((i-(2-(S-chloro-2,4-dimethosvphenvi)imidazo|l,2-a^pyrid ia-7 :: yj)pyrroIidin-3-Yl)methyl)amino)methyl)-AyV-dimethylaniline 7-8d (Example 2-15)^

2-((((l -(2-(5~Chloro-2,4-diniethoxypheny^

3-yi)methyl)aniino)methyl)-A r ,A-dimethylani3ine 7-8d was prepared in the same manner as 4-(((( 1 ~(2-( 5 -chioro-2,4~dimethoxy pheny l)imidazo [ 1 ,2- ]pyridin-7-yl)py rrolidm-3 - yl)methyl)amino)methyl)-A V,3-trimethylaniline 7-8a, using 2-

(dimethylamino)benzaldehyde 7-7d, and was obtained as an off-white solid (12% yield).

! H NMR (300 MHz, DMSO-<sfe); δ 8.26 (d, J = 7.2 Hz, IH), 8.15 (s, IH), 7.93 (s, IH), 7.43 (d, J= 7.5 Hz, IH), 7.18 (t, J= 7.2 Hz, H), 7.09-6.98 (m, 2H), 6.85 (s, IH), 6.46 (d, J= 7.5 Hz, IH), 6.18 (s, IH), 3.99 (s, 3H), 3.92 (s, 3H), 3.79 (s, 2H), 3.46 (t, J= 9.0 Hz, IH), 3.40-3.36 (m, IH), 3.30-3.25 (m, IH), 3.08 (! . ,/ 6.3 Hz, I H), 2.64-2.58 (m, 9H), 2.16-2.08 (m, I H), 1.77-1 .68 (m, IH); HPLC (Method 14) 98.2% (AUC), t\\ = 6.72 mm.; ESI+APCI-MS m/z 520 M + H] + . yl)pyrrolidin-3-Yl)methvi)amino)niethvj)-2-methoxyphenoj 7-8e (Example 2-42);.

5 -(((( 1 -(2 -(5 -Chioro-2,4-dimethoxypheny] )imidazo f 1 ,2-ajpyridm- 7-yl)pyrrolidin- 3-yl)methy1)aiT3ino)methy1)-2-methoxypheno] 7-8e was prepared in the same manner as 4- ((((l-(2-(5-chloro-2,4-dimethoxyphenyi)in?idazo[ l,2-o |pyrid

yl)metliyl)ainiiio)metliyl)-Av¥,3 -trimethylaniline 7-8a, using 3 -hydfoxy-4- methoxybenzakiehyde 7-7ε, and was obtained as an off-white solid (14% yield).

¾ NMR (400 MHz, CD 3 OD): δ 8.98 (d, J= 7.2 Hz, IH). 7.92 (s, H), 7.78 (s, I H), 6.79-6.75 (m, 2H), 6.71-6.67 (m, 2H), 6.38 (dd, J = 2.0, 7.2 Hz, IH), 6.14 (s, IH), 3.91 (s, 3H), 3.84 (s, 3H), 3.73 (s, 3H), 3.61 (s, 2H), 3.46-3.42 (m, IH), 3.38-3.31 (m, IH),

3.28-3.22 (m, I H), 2.95 (t, ,/= 8.0 Hz, IH), 2.62-2.58 (m, 2H), 2.47-2.40 (m, IH),

2.14-2.09 (m, IH), 1.69 -1.60 (m, IH); HPLC (Method 7) 91. 1% (AUC), fe = 6.53 mm.; ESI+APCI-MS m/z 523 [M + Hf.

Prej3 i arat¾o i o i of i l- i (

yDigi -^

y1)-N-(2,4-dimethoxybenzy])niet1iananiine 7-8f was prepared in the same manner as 4-((((l - (2~(5-chloro~2,4~dimeihoxyphenyl)imida^

y l)methyi)aniino)methyl)-A i ,iV,3 -trimethylaniline 7-8a, using 2 ,4-dimethoxybenzaldehyde 7- 7f, and was obtained as an off-white solid ( 10% yield).

¾ NMR (300 MHz, DMSO-ifc): δ 8.26 (d, J = 7.5 Hz, IH), 8.15 (s, IH), 7.94 (s, IH), 7.23 { ./ 8.1 Hz, IH), 6.85 (s, IH), 6.54 (s, IH), 6.50-6.45 (m, 21 1 ·. 6.18 (s, I H), 3.99 i s. 3H), 3.92 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.70 (s, 2H), 3.49-3.43 (m, IH), 3.34-3.28 (m, .: ! !} . 3.09-3,04 (m, ΓΗ), 2.64-2.52 (m, 3H), 2,20-2.10 (m, ΓΗ), 1 .78-1 .69 (m, IH); HPLC (Method 7) 95.8% (AUC), te = 6.71 min .; EST+APCI-MS m/z 537 [M + H i .

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2 -ajpyridin- 7-y l)pyx roiidin- 3 - yl)-N-(4-methoxy-3-raetiiylbenzyl)metiianamine 7-8g was prepared in the same manner as 4~((((i -(2~(5-chloro-2,4-dime†hoxypheny

y])methyl)amino)methyl)-A r ,N,3-trimethylatiiline 7-8a, using 4~metboxy-3- nieiliylbenza!debyde 7-7g, and was obtained as an off-white solid (15% yield).

¾ NM (400 MHz, DMSO-ffc): δ 8.26 (d, J -- 7.6 Hz, 1H), 8.15 (s, 1H), 7.93 (s, IH), 7.13-7.1 1 (m. 2H), 6.86-6.85 i m . 2H), 6.46 (dd, J ------- 2.0, 7.6 Hz, IH), 6.18 (s, I H),

3.99 (s, 3H), 3.92 (s, 3H), 3.75 (s, 3H), 3.64 (br s, 2H), 3.45 (t J ------ 9.6 Hz, IH), 3.29-3.25

(m, IH), 3.08-3.04 (m, IH), 2.60-2.50 (m, 4H), 2.12-2.08 (m, 4H), 1.81-1.68 (m, IH); HPLC (Method 7) 97.9% (AUC), <¾ = 6.96 ram. ; ESI+APCI-MS m/z 521 [M +

Preparation of i-(l-{2-(5-c¾l ro-2,4-dimet¾oxyp¾e8¾yI)imidazo l ¾ 2-a|pyndin-7:

yI)PYrrolidin-3-yI)-A-(2,4-diflMorobei¾zyl)meth aRamine 7-8h (Example 2-26);

l-(l -(2-(5-ChIorQ-2,4-dimethoxyphenyl)im^

yl)-N-(2,4-difluorobenzyl)methanamine 7-8h was prepared in the same manner as 4-(((( l - (2~(5-chloro~2,4~dimethoxyphenyl)imidazo[l,2-a]pyridin-7-yl) pyrrolidin-3- yl)me&yl)amino)methyl)-N^,3-triraeAylaiii{ine 7-8a, using 2,4-difluorobenzaSdehyde 7-7h, and was obtained as an off-white solid (13% yield).

lH NMR (400 MHz, DMSO~a¾): δ 8.26 (d, J = 7.6 Hz, IH), 8. 14 (s, IH), 7.94 (s, IH), 7.56-7.50 (m, IH), 7.21-7.16 (m, IH), 7.09-7.05 (m, IH), 6.85 (s, I H), 6.47 (dd, ,/ = 2.4, 7.6 Hz, I H), 6.1 8 is IH), 4.00 (s, 3H), 3.93 i s. 3H), 3.75 (s, 2H), 3.48-3.44 (m, I H), 3.32-3.26 (m, I H), 3.09-3.04 (m, IH), 2.60-2.54 (in, 4H), 2.15-2.07 (m, IH), 1.77-1.86 (m, IH); HPLC (Method 15) 98.8% (AUC), te ----- 6.65 mm.; ESI+APCI-MS m/z 513 [M + H I ■

yl)pyrroIidin-3-Yl)-A ?" -(4-fluoro-3-methYlbei¾zyl)methanamine 7-8i (Example 2^21)^__ i -( l~(2-(5-Giloro~2,4~dimeihoxypbeny1)n^

y3)-A-(4-fluoro-3-methyIbenzyl)methaiianiine 7-8i was prepared in the same manner as 4- ((((1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo| 1 ,2-«Jpyridin-7-yl)pyrroiidin-3- yl)methyl)amino)methyl)-A V,3-trimethylaniline 7-8a, using 4-fluoro-3- methylbenzaldehyde 7-7i, and was obtained as an off-white solid (10% yield).

! H NMR {400 MHz, DMSO-ifc): δ 8.45 (d . ./ 7.6 Hz, i l l ). 8.14 is H I). 8.07 (s. H i ). 7.60 (†, ./ 7.2 Hz, i l l). 7.16-7.10 (ra, 2H), 6.93 (s, H i ). 6,75 (br s, i l l). 6.31 (s, H i ). 4. 13 (s, 2H), 4,03 (s, 3H), 3.96 (s, 3H), 3.66-3.62. (ra, IH), 3.56-3.52 (m, H), 3.45-3.37 (m, 2H), 3.1 1 (br s, 2H), 2.84-2.78 (m, IH), 2.42 (s, 3H), 2.27-2.21 (ni, IH), I .93-I .84 (m, IH); HPLC (Method 7) 96.4% (AUC), to = 6.92 mm.; ESI+APC1-MS m/z 509 [M + Hf. Preparation of l-{l-i2 5-chioro-2,4-dimethoxyphenyl)iinida^

1 -( 1 -(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)pyixolid -3- yl)-N-(3-fluoro-4-methylbenzyl)methanamine 7-8j was prepared in the same manner as 4- ((((1 -(2-(5-chloro-2,4-dimethoxyphenyi)imidazo| 1 ,2-«]pyridin-7-yl)pyrrolidin-3- y l)methyi)aniino)methyl)-A i ,iV,3 -trimethyiamline 7-8a, using 3 -fluoro-4- methylbenzaidehyde 7-7j, and was obtained as art off-white solid (16% yield).

¾ ΝΜΚ. (400 MHz, DMSOa'd): δ 8.28 id. ./ 7.2 Hz, IH), 8.14 (s, IH), 7.96 (s, IH), 7.35-7.06 (m, 3H), 6.86 (s, IH), 6.49 (dd, 3 ----- 2.0, 7.2 Hz, IH), 6.19 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.83 (br s, 2H), 3.50-3.42 (m, IH), 3.40-3.36 (m, IH), 3.1 1-3.07 (m, IH), 2.60-2.52 (m, 4H), 2.21 (s, 3H), 2. 17-2. 1 1 (m, IH), 1.80-1 .73 (ra, IH); HPLC (Method 15) 99.0% (AUC), fe = 6.75 ram.; ESI+APCI-MS m/z 509 [M + U | \ ylipYrrolidin-3-yi)-A-(2-fliioro-4-iiiethyibeiizYl)ineihana- nine 7-8k (Example 2-23):

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)pyrrolidin- 3 - yl)-N-(2-fluoro-4-methylbenzyl)methanainine 7-8k was prepared in the same manner as 4- ((((1 -{2-(5~chloi -2,4-diiT!ethoxyphenyl)iraidazo[i ,2- ]pyridin-7-yl)pyrrolidm-3- y])methyl)amino)methyl)-A 7' ,N,3-trimethylaniline 7-8a, using 2-fluoro-4- nietliylbenzaldehyde 7- k, and was obtained as an off-white solid (14% yield).

lH NM (400 MHz, DMSO-aV): δ 8.27 (d, J = 7.6 Hz, IH), 8.15 (s, IH), 7.94 (s, IH), 7.36 (t, J = 8.4 Hz, IH), 7.006.97 (m, 2H), 6.86 (s, IH), 6.47 (dd, ./ 2.0, 7.2 Hz, IH), 6.18 i s. IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.75 (s, 21 1 ·. 3.48-3.44 (rn, IH), 3.32-3.26 (m, IH), 3.08-3.04 (m, i l l). 2.60-2,50 (m, 4H), 2.29 (s, 3H), 2.13-2.07 (m, 1H), 1.77-1.68 (m, HPLC (Method 7) 95.1% (AUC), t& = 6.92 mm.; ESI+APCT-MS m/z 509 [M + Hf.

Scheme 3

Preparation of fe?f-b«tyl ((l-(2-amiRopyridiR-4-vi)azetidin-3-yl)methYl)carbamate 8-3j, To a solution of 4~chloropyridin~2 -amine 8-1 (2.50 g, 19.5 mrnol) in isopropanoyNN-diisopropylethylamine (50 mL/25 mL) was added /erf-butyl(azetidin-3- ylmethyl)carbamate hydrochloride 8-2 (5.60 g. 25.4 mmol). The reaction mixture was heated at 120 °C in a sealed tube for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAd and saturated sodium bicarbonate solution. The layers were separated; the organic layer was dried over sodium sulphate, filtered and concentrated . Hie residue was washed with hexanes to provide /en-butyl ((l -(2-aminopyridin-4-yl)azetidm-3- yl)methyl)carbamate 8-3 (5.2 g, 96%) as an off-white solid, which was used for next step without further purification. ESHAPCI-MS m/z 279 M - S i j .

Pj^aration ^ A solution of ierf-butyl ((l -(2-arainopyridin-4-y1)azetidin-3-yl)niethy1)carbamate 8-3 (10.0 g, 36.0 mmol) and 2-bromo-l-(5-chloro-2,4-dimeihoxypheny])eihanone 8-4 (13.5 g, 46.6 mmol) in acetone (200 mL) was heated at 75 °C for 16 h. The reaction mixtitre was cooled to room temperature and the white precipitate formed was collected by filtration and washed with hexanes. The crude material was taken up in water (200 mL) and saturated sodium bicarbonate solution (200 mL) and stirred at room temperature for i h. The solid was collected by filtration, washed with water and dried to afford re/t-butyi ((1- (2~(5-chJoro~2,4~dimethoxypheny^^

y])methyl)carbamate 8-5 (6.0 g, 36%) as an off-white solid. ESI+APCI-MS m/z 473 [M + Hf. yI azetidjB 3^^

To a suspension of ferf-butyi ((l-(2-(5-chloro-2,4-dimemoxyphenyl)imidazo[ l,2- a]pyridin~7-yl)azetidm~3~} )methyl)carbaniate 8-5 (6.00 g, 12.7 mmol) in H2O (40 mL) was added con. HC1 (10 mL), The reaction mixture was heated at 100 °C for 20 min. The reaction mixtare was cooled to room temperature and basified with saturated sodium bicarbonate solution (100 ml,). The aqueous layer was extracted with CH2.CI2 (2 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give (i~(2-(5-chloro-2,4~dimetlioxyphenyl)imidazo| 1,2- ojpyridm-7-yl)azetidin-3-yl)methanamine 8-6 (3.6 g, 77%) as an off-white solid.

¾ MR (400 MHz, DMSQ- e): δ 8.27 (d, J= 7,2 Hz, i l l) . 8.15 (s, 1H), 7.97 (s, 1H), 6.85 is, LH), ), 6.25 (dd, J= 2.0, 7.2 Hz, H I). 6.1 i(s, IH), 3,99 (s, 3H), 3.93 (s, 3H), 3.89 (d, J= 3,6 Hz, 2H), 3.61-3.57 (m, 2H), 2.77 (d, J= 6.8 Hz, .:! !}. 2.78-2.69 (m, 1H) Preparation of /y-benzyl-i-(1 -(2-(5-c.hloro-2,4-dimetho. yphenyl)imidazoP ,2-a]pYridm-

To a suspension of (l-(2-(5-chioro-2,4-dimethoxyphenyl)imidazo[l ,2-«Jpyridin-7- yl)azetidin-3-yl)methanamine 8-6 (60 mg, 0.16 mmol), benzaldehyde (20 mg, 0.19 mmol) in CH OH (5 mL) was added acetic acid (0.1 ml,) and the resulting mixture was stirred at room temperature tor 2 h. Sodium cyanoborohydride (20 mg, 32 mmol) was added in one protion and the reaction mixture was stirred at room temperature for 15 mm. The reaction mixture was diluted with aqueous sodium bicarbonate solution ( 10 mL) and the aqueous layer was extracted with CH2CI2 (2 χ 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaiSC , filtered and concentrated. The crude material was purified by combi-flash chromatography [silica gel; 5% H4OH in MeOH: CH2CI2 (1 :9)] to give A'-benzyl- l -(l-(2-(5-chSoro~2,4- dimemoxyphenyl)imidazo[l,2-a]pyridin-7-yl)azetidin-3-yl)meth 8-8a (20 mg, 27%) as an off-white solid.

: f i NMR (400 MHz, DMSO-<¾): δ 8.28 (d . ,/ 7.2 Hz, i l l ). 8.15 (s, 1H), 7.97 i s. IH), 7.37- 7.34 (m, 4H), 7.23 i i. 7.2 Hz, H I ). 6.85 (s, i l l ). 6.25 (dd, 2.0, 7.2 Hz, IH), 6.12 (s, 1H), 3.99 (s, 3H), 3.96-3.94 (m, 2H), 3.93 (s, 3H), 3.76 (bs, 2H), 3.60-3.57 (m, 2H), 2.89-2.79 (m, 3H); HPLC (Method 4) 97.2% (AUC), = 6.60 min.; ESI+APC1-MS m/z. 463 [M + H] ÷ .

Preparation of l-(l-(2-(5-chloro-2,4-dimethoxyphenvl)imidazoii,2-a]pYridin- 7- yj)az:etidin-3-Yl)-jV-(4-fluorobenz:yl)methai¾amine 8-8b (Example 2-6);

l -( l~(2-(5-c1i1oro-2,4 limet1ioxy

N-(4-fluorobenzyl)methanamine 8-8b was prepared in the same manner as Λ -benzyl- 1-f 1- (2-(5^Woro-2,4-dimemoxyphenyl)imidazo[l,2^]pyridm-7-yl)azeti

8-8a, using 4-fiuorobenzaldehyde 8-7b, and was obtained as an off-white solid (25% yield).

¾ NMR (400 MHz, DMSQ- e): δ 8.27 (d, J= 7.2 Hz, i l l) . 8. 15 (s, IH), 7.97 (s, H i ). 7.39-7.36 (m, 2H), 7.15-7.10 (m, 2H), 6.85 (s, IH), 6.24 (dd, J= 2.0, 7.2 Hz, IH), 6.12 (s, IH), 3.99 (s, 31 1). 3.95-3.91 (m, 5H), 3.70 (bs, 2H), 3.59-3.56 (m, 21 1). 2.83-2.72 (m, 3H); HPLC (Method 4) 99.2% (AUC), to = 6.63 min.; ESI+APCI-MS m/z 481 [M +

l-(l -(2~(5-Chloro-2,4-dimethoxyp3ien

N-(2-fluorobenzyl)me1hanamine8- 8c was prepared in the same manner as N~benzy3-I~(l - (2-(5-ehloro-2,4<limethoxypheny^

8~8a, using 2-fluorobenzaldehyde 8-7c, and was obtained as an off-white solid (33% yield).

¾ NM (400 MHz, DM O- ). δ 8.27 (d, J -- 7.6 Hz, IH), 8.15 (s, 1H), 7.97 (s,

1H), 7.50-7.46 (m. H I ). 7.35-7.26 i m . 1H), 7.19-7.12 (m. 2! I s. 6.85 (s, 1H), 6.25 (dd, J ----- 2.4, 7.6 Hz, IH), 6.15 (s, 1H), 3.99 (s, 3H), 3.95-3.94 (m, 2H), 3.93 (s, 3H),3.76 (bs, 2H), 3.59-3.54 (m, 2H), 2.83-2.76 (m, 3H); HPLC (Method 4) 98.5% (AUG), ft? = 6.62 mm.; ESI+APCI-MS m/z 481 [M + H] + .

Preparation of ί-(1 -(2-(5-c.hloro-2,4-dimetho. yphenYl)imidazoP ,2-a] yridine yI azetidiH-3-vl)-A'-(3-flMorobenzyl)methanamme 8-8d (Example ^74^

1 -( 1 -(2-(5 -Chioro-2,4-dimethoxyphenyl)imidazo j 1 ,2-o]pyridirs-7-y3)azetidm-3-yl)- N-(3-fluorobenzyl)methanamine 8-8d was prepared in the same manner as N-benzyl-l-(l- (2-(5-chloro-2,4 iimethoxyphenyi)im^

8-Sa, using 3-fluorobenzaldehyde 8-7d, and was obtained as an off-white solid (28% yield).

! H NMR (400 MHz, OMSO-de) δ 8.28 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.97 (s, IH), 7.38-7.34 (m. H i ). 7.20-7. 17 (m, 2H), 7.06-7.02 (m, i l l). 6,85 (s, IH), 6.25 (dd, J = 2.4, 7.6 Hz, I H), 6.12 (d, J= 1.6 Hz, 1H), 3.99 (s, 3H), 3.96-3.94 (ra, 2H), 3.93 (s, 3H), 3.74 (bs, II I). 3.60-3.56 (m, 2H), 2.83-2.77 (m, H I). 2.75-2.73 (m, 2H) ; HPLC (Method 4) 99.30% (AUG), ft. = 6.62 mm.; ESI+APCI-MS m/z 481 [M + Hf.

Prep ^ aratioo of l (j {2-j^

i-(l~(2-(5-CJiloro-2,4-dimethoxyphenyl)imidazo[i,2-a]py

I¥-(2-niethy!benzy1)niethanamine 8-8e was prepared in the same manner as N-benzyl- 1 -(l- (2~(5-chloro~2,4~dmieihoxyphenyl)im

8-8a, using 2-methylbenzaidehyde 8-7e, and was obtained as an off-white solid (36% yield), f i NMR (400 MHz, DMSO fe): δ 8.27 (d, J ------ 7.2 Hz, IH), 8.15 (s, I i f ). 7.97 i s.

IH), 7.32-7.30 (m, IH), 7.18-7.13 (m, 3H), 6.85 (s, IH), 6.26 (dd, J --- 2.4, 7.2 Hz, IH), 6.12 (s, IH), 3.99 (s, 3H),3.97-3.95 (m, 2H), 3.93 (s, 3H),3.69 (bs, 2H), 3.61-3.59 (m, 2H), 2.94-2.76 (m, 3H), 2.30 (s, 3H) ; HPLC (Method 7) 99.4% (AUC), te = 6.75 min., EST+APCI-MS m/z 477 [M + Hf.

Preparation of l-(l-(2-(5-chIoro-2,4-dimethoxYphenyl)imidazoil,2-al pyridin-7-

1 -( 1 -(2-(5 ~Chloro-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a ipyridin~7~yl)azetidin-3~yl}- N-(4-methylbenzyl)methanamine 8-8f was prepared in the same manner as N-benz l-l-(l- (2-(5~chloro-2,4-(nmethox\ heny^

8-8a, using 4 -methyl ben zaidehyde 8-7f, and was obtained as an off-white solid (28% yield).

lH NMR (300 MHz, DMSO-a¾): δ 8.28 (d, J= 7.2 Hz, IH), 8.15 (s, III), 7.98 (s, 1H), 7.25 (d, J ------- 6.6 Hz, 2H), 7.16 (d, J = 6.6 Hz, 2H), 6.85 (s, IH), 6.26 (dd, J = 2.4, 7.2

Hz, IH), 6. 15 (s, IH), 4.00 (s, 3H),3.96-3.90 (m, 5H), 3.75 (bs, 2H), 3.62-3.55 (m, 2H), 2.85-2.72 (m, 3H), 2.28 (s, 3H) ; HPLC (Method 7) 99.3% (AUC), = 7.25 min.;

ES1+APCI-MS m/z 477 M + H] + . yl)azetidin-3-yi -A-(3-niethvjbenzyl)meth anamine 8-8g (Example 2-S j

l~(l -(2-(5~Ch!oro-2,4-dimethoxyphen^

N-(3-methylbenzyl)methanamine 8-8g was prepared in the same manner as Λ-benzyl-l -i 1- (2-(5-chioro-2,4-dimethoxyphenyl)imidazo| l ,2-o]pyridin-7-y3)azetidm-3-yl)metha amine 8-8a, using 3-methylbenzaldehyde 8-7g, and was obtained as an off-white solid (34% yield).

¾ NMR (400 MHz, DMSO-ifc): δ 8.28 id. ./ 7.2 Hz, IH), 8.15 (s, IH), 7.98 (s, IH), 7.23-7.14 (m, 3H), 7.05 (d, 3 --- 6.8 Hz, IH), 6.85 (s, IH), 6.26 (dd, J = 2.4, 7.2 Hz, IH), 6.15(s, IH), 3.99 (s, 3H), 3.96-3.95 (m, 2H), 3.93 (s, 3H),3.73 (bs, 2H), 3.60-3.57 (m, 2H), 2.91-2.81 (m, 3H), 2.29 (s, 3H) ; HPLC (Method 4) 98.9% (AUC), te = 6.69 mm.; ESI+APCI-MS m/z 477 [M + Hf.

4-(((( l-(2-(5 -CUoro-2,4-dimethoxyphenyl)iniidazo [ 1 ,2-a ]pyridin-7-yl)azetidin-3 - yl)metiiyl)amino)methyl)-N,N-dimetiiylaniiine 8-8h was prepared in the same manner as N- benzyl-l-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyri

y1)niethanamine 8-8a, using 4-(dimethylamino)benzaldehyde 8-7h, and was obtained as an off-white solid (19% yield).

¾ NM (400 MHz, DM O- ). δ 8.28 (d, J -- 7.2 Hz, IH), 8.15 (s, 1H), 7.97 (s,

IH), 7.16 (d, J ------ 8.8 Hz, 2H), 6.85 (s, 1H), 6.68 id. ./ 8.4 Hz, 2H) 6.2.5 (dd, J = 2.0, 7.2 Hz,

H I ). 6.12 (s, I H), 3.99 (s, 3H), 3.96-3.94 (m, 21 1 ·. 3.93 (s, 3H), 3.66 (bs, 2H), 3.59-3.56

(m, 2H), 2.86 (s, 6H), 2.82-2.79 (m, 3H) ; HPLC (Method 4) 97.2% (AUC), ftt = 6.42 mm. ; ESI+APCI-MS m/z 506 [M + \ \ [ .

Preparation of 2-((((l-(2-(5-c¾l r -2,4-dimei¾ xyp¾enyI)imjdazo l ¾ 2-a|pyridjn^

YSja¾etid¾n-3-vl)mei¾yS amino)met¾YS}-A r t A ' -d¾met¾ySanjSine 8-8¾ (Example 2-77);,

2-(((( 1 -(2-(5 -Chloro-2,4-dimethoxypheny 3)imidazo [ 12-a pyridin-7-yl)azetidin-3 - yl)meroyl)ainino)meroyl)-A " ,A " -dimethylai:niine 8-81 was prepared in the same manner as Λ- benzyl- 1 -( 1 ~(2-( 5-chloro-2,4-dimethoxy phenyl) imidazo [ 1 ,2~ ]pyridin~7~yl)azetidin-3 - yl)methanamine8- 8a, usmg 2-(dimethylamino)benzaldehyde 8-7i, and was obtained as an off-white solid (31% yield).

lH NMR (400 MHz, DMSO-a¾): δ 8.35 (d, ./= 7.2 Hz, 1H), 8.12 (s, !H), 8.04 (s,

1H), 7.52-7.50 (m, 1H), 7.39 (†, J = 7.2 Hz, ΓΗ), 7.28 (d, J= 7.6Hz, 1H), 7.17 it, J= 7.6 Hz,

IH), 6.88 (s, i l l}. 6.38-6.33 (ni, 1H), 6.20 (d . ./ 2.0Hz, 1H), 4.23 (bs, 2H), 4.06 (i ./ 8.0 Hz, 2H), 4.01 (s, 3H), 3.93 (s, 3H), 3.75-3.71 (m, 2H), 3.27 (d, J= 6.4Hz, 2H), 3.13-3.06

(m, IH), 2.66 i s. 6H); HPLC (Method 4) 99.0% (AUC), : < === 6.62 min.: ESHAPCl-MS m/z 506 [M + Η Γ yJ¼zetidin-3-vI rnethyj)-3,3-dimet¾ySbistan-i-amine 8-8j (Example 2-40);

N-((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin -7-yl)aze y3)methyi)-3,3-dimethylbutaii-l -aj:nine 8-8j was prepared in the same manner as N-benzyl- l-(l-(2-(5-chioro-2,4-dimethoxyphenyl)imidazo| l ,2-o]pyridin-7-yl)azetidin-3- yl)methanamine 8-8a, using 3,3-dimethylbutanal 8-7j, and was obtained as an off-white solid (29% yield).

! H MR {400 MHz, DMSO-ifc): δ 8.28 (d . J 7.2 Hz, i l l). 8.15 is H I). 7.97 (s. IH), 6.85 (s, IH), 6.25 (dd, J= 2.0, 7.6 Hz, IH), 6.13 (s, IH), 3.99 (s, 3H), 3.98-3.95 (m, 2H), 3.93 is, 3H), 3.57-3.56 (m, 2H), 2.81-2.71 (m, 3H), 1.38-1 ,31 (m, 11 1). 0.9 (s, 9H); HPLC (Method 4) 96.4% (AUG), fe = 6.69 mm.; ESI+APCI-MS m/z 457 [M + Hf.

Pre ) ratioM in of l- i {l-(2 :i { -chSoro 2 i 4

l-(l-(2~(5-Chloro-2,4-dimethoxy

N-(cyc1opent\'{methy1)methanamine 8-8k was prepared in the same manner as N-benzyl-1- (l -(2~(5-chIoro-2,4-dimetihoxypheny])imida^

yl)methanarame 8-8a and was obtained as an off-white solid (29% yield),

lH NM (400 MHz, DM O- ). δ 8.29 (d, J -- 7.2 Hz, IH), 8.15 (s, IH), 7.98 (s, IH), 6.86 (s, IH), 6.27 (dd, J= 2.0, 7.2 Hz, IH), 6.15 (s, I H), 3.99 (s, 3H), 3.97-3.96 (m, 2H), 3.93 (s, ill), 3.64-3.61 (m, 2H), 2.95-2.91 (m, ill), 2.67-2.62 (m, 2H), 2.07-2.01 (m, IH), 1.76-1.70 (m, 2H),1.69-1.53 (m, 4H), 1.29-1.15 (m, 2H); HPLC (Method 4) 95.7% (AUC), tR = 6.59 mm.; ESI+APCI-MS m/z 455 [M + Hf.

Preparation of ί-(1 -(2-(5-c.hloro-2,4-dimetho. yphenYl)imidazoP ,2-a pyr¾dm-7- vI)azetidiH-3-yl)-A'-(cyclohexylmethYl)methanamine 8-81 (Example 2-16^

1 -( 1 -(2-(5 -Chioro-2,4-dimethoxyphenyl)imidazo 11 ,2-a]pyridin-7-yl)azetidin-3-yl)- N-(cyclohexyimethyl)methanamine 8-81 was prepared in the same manner as A ' -benzyl-l-

(l~(2-(5-chioro-2,4~dimethoxyphenyl)imidazo[ l,2-a]pyridin-7-yl)azetidin-3- yl)methanamine 8-8a and was obtained as an off-white solid (22% yield).

! H NMR (300 MHz, DMSO- e); δ 8.28 (d, J = 7.2 Hz, IH), 8.15 (s, IH), 7.98 (s,

IH), 6,85 (s, IH), 6.26 (d, ./= 6,6 Hz, IH), 6.14 (s, IH), 3,99 (s, 3H), 3 ,97-3.94 (m, 2H), 3.93 (s, 3H), 3,70-3.59 (m, 2H), 2.91-2.89 (m, 3H), 2,49-2.48 (m, 2H), 1 .75-1.55 (m, 4H),

1.55- 1 .33 (m, IH), 1.23-1 , 17 (m, 4H),1.07-0.97 im . Ill); HPLC (Method 4) 98.1 %

(AUC), tR ----- 6.71 mm.; ESI+APCI-MS m/z 469 [M + Hf.

Prejjaratiosi of i ter -b yS iii 2 :i {{((l- i (2 i { gll¾ ld p- ^^

tert-Butyl 2-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyrid in-7- yl)azetidin-3-yl)methyl)amin^ S-8m was prepared in the same manner as N-benzyl- 1 -( 1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2- ]pyridin-7- yl)azeiidm~3~yl)methanamine 8-8a and was obtained as an off-white solid (37% yield).

1 H NMR (400 MHz, DMSO-ds): δ 8.28 (d, J = 7.2 Hz, IH), 8.15 (s, IH), 7.97 (s, IH), 6.85 (s, H), 6.26 (dd, J= 2.4, 7.2 Hz, i l l). 6.15 (d, J= 2.0 Hz, IH), 4.14 (bs, 1H), 3.99 (s, 3H), 3.97-3.93 (m, 5H), 3.79-3.74 (m, 1H), 3.59-3.56 (m, 2H), 2.82-2.76 (m, 4H), 2.67-2.66 (ra, 3H), 1.73-1.70 (m, ΓΗ), 1.59-1 .48 (m, 4H), 1 ,38 (s, 9H);

HPLC (Method 4) 98.3% (AUG), fo = 6.79 mm.; ESI+APC1-MS m/z 570 [M + Hf. tert-Butyl 3-((((l-(2-(5-chloro-2,4-dime1hoxyphen^

y\l)azetidin-3-yl)methy4)amino 8-8n was prepared in the same manner as N-benzyl-l-(l-(2-(5-chloro-2,4-dimetto

yl)azetidin-3-yl)methanamine 8-8a and was obtained as an off-white solid (47% yield). lH NM (400 MHz, DM O- ). δ 8.28 (d, J= 7.2 Hz, 1H), 8.15 (s, 1H), 7.97 (s, Π !) 6.85 (s, IH), 6.24 (d, ./ 4.0 Hz, i l l}. 6.15 (s IH), 3.99 (s, 3H), 3.97-3.95 (m, 3H),

3.93 (s, 3H), 3.77-3.74 (m, 1H), 3.62-3.56 (m, 2H), 2.78-2.67 (m, 4H), 2.41-2.35 (m, 2H),

1.75-1.73 (m, IH), 1.59-1.50 (m, 21 1 ·. 1.38 (s, 9H), 1.37- 1.26 (m, 2H), 1.10-1.07 (m, H I ).

HPLC (Method 7) 99.3% (AUC), ¾ = 7.25 mm.; ESI+APCI-MS m/z 570 [M + Hf .

Preparation of tert-butyl 4-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo^l,2- a]pYridii¾-7-yl)az:etidin-3-Yl)methYl)amiRo)methyl)piperidi ne-l-carboxylate 8-8 tert-Butyl 4-((((l-(2-(5-chloro-2,4-dime1boxyphenyl)imidazo| " l ,2-«]pyridin-7- yl)azetidin-3-yl)meiliyi)amino)meiliyi)piperidine-l-carboxyl ate 8-8o was prepared in the same manner as N-benzyi- 1 -( 1 -(2-(5-chloro-2,4-dimetho7£yphenyl)imidazo[ 1 ,2-a]pyridin-7- yl)azetidin-3-yl}methanamine 8-8a and was obtained as an off-white solid (33% yield), lH NMR (400 MHz, DMSO-a¾): δ 8.28 (d, J = 7.2 Hz, 1H), 8.15 (s, III), 7.97 (s, 1H), 6.85 (s, 1 ! !}. 6.26 (dd, J ------- 2.4, 7.2 Hz. i i i.s. 6. i 2(d. J ------ 2.0 Hz. I H), 3.99 (s, 3H), 3.93-3.91 (m, 7H), 3.58-3.55 (m, 2H), 2.83-2.75 (m, 4H), 2.41 (d, J= 6.4 Hz, 2H), 1 .67 (d, ,/ 8.8 Hz, 2H), 1.61- 1 .51 (m, IH), 1.38 (s,10H), 1 .0-0.91 (m, 2H); HPLC (Method 7) 98.7% (AUC), to = 6.83 min.: ES1+APCI-MS m/z 570 [M + H] + . ajpyridin-7-yl)azetidin-3-yl)methyl)amino)methyl)pYrrolidine -l-carbosylate 8-8Q_ (Ex m S ^Tj

re /'/-Butyl 3-((((l-(2-(5-chloro-2,4-dime1hoxyphenyl)imidazo| " l ,2-«]pyridin-7- yl)azetidin-3-yl)meihyl)amino)meihyl)pyrroIidine-I-carboxyIa te 8-8p was prepared in the same manner as N-benzyl- 1 -( 1 -(2-( -chloro-2,4~dnnetlioxypheny l)nnidazo [ 1 ,2-o]pyridin-7- yl)azetidin-3-yl)methanamine 8-8a and was obtamed as an off-white solid (45% yield).

¾ NMR (400 MHz, DMSO- e): 5 8.28 (d, J= 7.2 Hz, LH), 8.15 (s, IH), 7.97 (s,

IH), 6.85 (s, IH), 6.26 (dd, J= 2.4, 7.2 Hz, IH), 6.12 (d, J= 2.0 Hz, IH), 3.99 (s, 3H), 3.96-3.94 {:··:. 2H), 3.93 (s, 3H), 3.58-3.56 (m, 2H), 3.32-3.26 (IH), 3.21-3, 18 (m, 2H), 3.16-3.14 (m, I H), 2.93-2.88 (m, IH), 2.77-2.67 ( , 3H), 2.30-2.25 (m, IH), 1 ,99-1.90 (in. I H), 1.60- 1 .58 (m, 2H), 1.39 (s, 10H); HPLC ( cihod 7) 98.2% (AUC), to = 6.86 min.: ESI+APCl-MS m/z 556 [M + Hj + .

Scheme 14

To a solution of 4-diloropyridin-2 -amine 9-1 (2.0 g, 16 mmol) in a mixture of isopropanol and N, iV-diisopropylethyl amine (40 mL/20 raL), was added fe/t-butyi (2- (piperidin-4-yl)ethyl)carbamate 9-2 (5.3 g, 23 mmol). The reaction mixture was heated in a sealed tube at 120 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCC solution (300 mL/iOO mL). The layers were separated and the EtOAc layer was washed with brine (100 mL), dned over a?.S04, filtered and concentrated. The residue was triturated with hexanes, and dned to provide tert-butyl (2-(l-(2- aminopyridin-4-yl)piperidin-4-yl)etliyi)carbamate 9-3 (3.1 g, 62%) as an off-white solid, which was used directly for next step without further purification , ESI+APCI-MS nv'z 321 \ S\ H |

Preparation of tert-butyl (2-(1 -(2-(5-c.hloro-2,4-dimethoxyphenyI)imidazop.^:

A mixture of tert-butyl (2-( 1 -(2-aminopyridin-4-yl)piperidin-4-yi)ethy l)carbamate 9-3 (1.0 g, 3.1 mmol) and 2-bromo-l-(5-cliloro-2,4-dimetlioxyphenyl}etliaiione 9-4 (1.0 g, 3.4 mmol) in acetone (20 ml.) was heated at 75 °C for 16 h. Tlie reaction mixture was cooled to room temperature. The precipitate formed was collected by filtration, washed with hexanes (100 ml,), and dried . The hydrobrornide salt was taken up in saturated sodium bicarbonate solution (1200 mL) and was stirred at room temperature for 1 h. The solid was collected by filtration, washed with water and dried to afford

to give ten -butyl (2 -( 1 ~(2-(5 -chloro-2,4-dimethoxyphenyl)imidazo ] 1 ,2 - ]pyridm-7- yl)piperidm-4-yl)ethyl)carbamate 9-5 (650 mg, 41%) as an off-white solid. ESI+APCI- MS /z 5 l5 | M · H j .

Preparation of 2-(l-(2-{ ' S-chjoro-2 ¾ 4-dimethoxYphenYi¾imidazo l,2-ali)yridin-7- yl)piperidm-4-yI)ethan-i-amine 9-6 __

To a suspension of iert-butyl (2-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2- «Jpyridin-7-yi)piperidin-4-yl)ethyi)carbaniate hydrobrornide 9-5 (500 mg, 0.9 mmol) in CH2CI2 (10 mL) was added a solution of HC1 (4.0 M in 1,4-dioxane, 2 mL) and the reaction mixture was stirred at room temperature for 16 h. The solid obtained in the reaction was collected by filtration, washed with CH2CI2 (20 mL) and dried . The solid was then suspended in water (10 mL) and basified with saturated sodium bicarbonate solution (10 mL) by stirring at room temperature for 1 h. The solid was collected by filtration, washed with water and dried to provide 2-(l-(2-(5-chloro-2,4-dimelhoxyphenyl)imidazo[l,2- a]pyridin-7-yl)piperidin-4-yl)ethan-i -amine 9-6 (180 mg, 45%) as an off-white solid.

ESI+APCI-MS m/z 415 [M + Hf.

Prep r tion ^

To a suspension of 2-( l-(2-(5-cliloro-2,4-diniethoxyphenyl)iniidazo[l ,2~a]pyridm- 7-yl)piperidin-4-yl)ethan- 1 -amine 9-6 (100 mg, 0.24 mmol), tert-butyl 3-formylpyrrolidine- 1 -carboxylate 9-7a (72 mg, 0.36mmol) in CH3OH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium

cyanoborohydride (45 mg, 0.72 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 15 rain. The reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2 χ 20 ml,). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Ma?.Si)4, filtered and concentrated. The residue was purified by combi-flash

chromatography [silica gei; 5% NH4OH in MeOH: CH2CI2 ( 1 :9)] to give tert-butyl 3-(((2- ( l-(2-(5-chioro-2,4-dimethoxyphenyl)imidazo[ L2-o]pyridin-7-yl)pipendin-4~

y4)erayl)amino)methyl)pynOlidine-l-carboxylate 9-8a (20 mg, 14%) as an off-white solid.

¾ NMR (400 MHz, CD3OD): δ 8.02 (d, J= 7.6 Hz, i l l). 7.97 (s, 1H), 7.86 (s, IH), 6.69 (s, IH), 6,66 (dd, J= 2.4, 7.6 Hz, 1H), 6.56 (d, J= 2,4 Hz, 1H), 3,92 (s, 3H), 3.84 (s, 3H), 3.73 (d, J= 12.8 Hz, 2H), 3.50-3.42 (m, IH), 3.38-3.32 (m, IH), 2.92-2.84 (m, IH), 2,73-2,53 (m, 6H), 2.32-2.26 (m, IH), 1 ,96 (br s, 1H), 1.75 (d, J = 13.2 Hz, 2H), 1 .57-1.41 (m, 4H), 1.36 i s. 9H), 1 .31 -1 .18 (m, 3H); HPLC (Method 7) 99.1 % (AUG), t& = 6.82 min .; ESI+APCI-MS m/z 598 [M + Hf.

Prejjaratioo fJ-ll-j ' l

2-(l~(2-(5-Chioro-2,4-dimethoxyphenyl)imidazo[l,2-a]py

yl)-N-(cyelohexylmethyl)ethan- 1 -amine 9-8b was prepared in the same manner as tert-butyl 3~(((2-(l~(2-(5-ch]oro~2,4~dime^

yl)ethyl)ainino)methyl)pyrrolidine-i -carboxylate 9-8a, using cyclohexanecarbaldehyde 9- 7b, and was obtained as an off-white solid (10% yield).

] H NMR (400 MHz, CD3OD): δ 8.02 (d, J= 7.6 Hz, 1H), 7.97 (s, 1H), 7.85 (s, IH), 6.69 (s, IH), 6.65 (dd, ./ 2.4, 7.6 Hz, IH), 6.55 (d, ./ 2.0 Hz, i l l). 3.92 (s, 3H), 3.85 (s, 3H), 3.72 (d, J= 12.4 Hz, 2H), 2.72-2.64 (m, 4H), 2.46 (d, ./ 6.8 Hz, 2Ή), 1.75-1.58 (m, 7H), 1.49-1.43 (m, 3H), 1.30-1.08 (m, 6H), 0.91-0.81 (m, 2H); HPLC (Method 4) 98.3% (AUC), tR = 6.84 min.; ESI+APCI-MS m/z 511 [M + H] + . tert-Butyl 4-(((2-(l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-<i]pyridin-7- yl)piperidin-4-yl)ethyl)aniino)methyl)piperidine- 1 -carboxyiate 9-8c was prepared in the same manner as teri-huiy] 3-{((2~(l -(2-(5-chloro-2,4-diraethoxy^

a]pyridin-7-yl)piperidin-4-y])etbyl)^ 9-8a, using tert-butyl 4-fonnylpiperidine-l -carboxylate 9-7c, and was obtained as an off-white solid ( 12% yield).

1 H NMR (400 MHz, DMSO-ds): δ 8.27 l 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 6.86 (s, 1H), 6.77 (d, J= 6.0 Hz, i l l). 6.62 (s, W D. 4,00 (s, 3H), 3.93 (br s, 5H), 3.76 (d, ./ 12.0 Hz, 2H), 2.72-2.66 (m, 4H), 2.50-2.40 (m, 2H), 2.37 id. ./ 6.8 Hz, 2H), 1.75-1.65 (ra, 4H), 1.53 (br s, 2H), 1.38 (s, 11H), 1.26-1.18 (m, 2H), 0.99-0.91 (m, 2H); HPLC (Method 7) 98.1 % (AUG), fo = 7.76 min.; ESI+APC1-MS m/z 612 [M + Hf. a]pyridin-7-Yi)piperidin-4-vI)ethvI)amino)-nethyI)pirteridin e-l-carbo¾vIate 9-8d tert-Butyl 3-(((2-(l-(2-(5-chloro-2,4^imethoxyphenyl)imidazo[l ,2-«]pyridin-7- yl)piperidin-4-y3)ethyl)arn.ino)met yI)piperidine-l-carboxy3ate9- 8d was prepared in the same manner as teri-huiy] 3-{((2-(l -(2-(5-cbloro-2,4-dimetboxyp1ienyl)imidazo[i ,2- a]pyridm-7-yi)piperidin~4~y3)e1hyi)amino 9-8a, using tert-butyl 3-formylpiperidine-l -carboxyiate 9-7d, and was obtained as an off-white solid ( 10% yield).

: H WiR i ' 400 MHz, DMSOa'd): δ 8.27 l 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 6.86 (s, 1H), 6.78 (dd, ./ 2.0, 7.6 Hz, i l l). 6.62 id. ./ 2.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 4H), 3.78-3.72 (m, 3H), 2.79-2.67 (m, 3H), 2.59-2.55 (m, 2H), 2.45-2.39 (m, 3H), 1.74 (d, J = 10.8 Hz, 3H), 1.59-1.49 (ra, 3H), 1.38 (s, I IH), 1.30-1.08 (m, 4H); HPLC (Method 16) 97.2% (AUC), iv, = 6.95 mm.; ESI+APCI-MS m/z 612 [M + H] + .

7~yl)piperidin-4-vI)ethan-l~amine 9-8e (Example 2-111);

N-benzyl-2-( 1 -(2-(5 -chloro-2,4-dimethoxy pheny l)imidazo [ 1 ,2- ]pyridin-7- yl)piperidin-4-yl)ethan- 1 -amine 9-8e was prepared in the same manner as tert-huty] 3-(((2- (l~(2-(5-chloro-2,4-dimethoxyphenyl)im^

yl)ethyl)amino)methyl)pyrrolidine- 1 -carboxylate 9-Sa, using benzaldehyde 9-7e, and was obtained as an off-white solid (16% yield).

¾ NM (400 MHz, DM O- ). δ 8.26 (d, J= 7.6 Hz, IH), 8.16 (s, 1H), 7.99 (s,

IH), 7.34-7.28 (m, 4H), 7.24-7.20 (m, IH), 6.86 (s, IH), 6.77 (dd, J = 2.4, 7.6 Hz, 1 H), 6.61 id. ./ 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.75 (d, J= 12.4 Hz, 2H), 3.70 (s, 2H), 2.72-2.66 (m, 2H), 2.56-2,51 (m, 2H), 1.71 (d. ./ 12.0 Hz, 2H), 1.60-1.50 (m, IH), 1.43-1.37 (m, 2H), 1.25-1.17 (m, 2H); HPLC (Method 16) 99.3% (AUG), m = 6.77 mm.; EST+APCI-MS m/z 505 [M + H] \

Preparation of 4-(((2-(l-(2-(5-chloro-2,4-dimethox^henyI)imidazo^l,2-a|pyri din^

4-(((2-( 1 -(2-( 5 -Chlofo~2,4~dimethoxyphenyi)imidazo [ 1 ,2 -a]pyridin-7-y i)piperidin~ 4~yl)ethyl)ammo)methyl)benzonitrile 9-8f was prepared in tlie same manner as iert-batyl 3~ (({2-(l~(2-{5-ehloro-2,4-dimethoxyphenyi}miKlazo[l ,2~ jpyrid^

yi)ethyl)amino)methyl)pyrrolidine-i -carboxylate 9-8a and was obtained as an off-white solid ( 14% yield).

! H MR {400 MHz, DMSO-cfo): δ 8.26 (d . ./ 7.2 Hz, IH), 8.16 is IH), 7.99 (s, IH), 7.78 (d, J= 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 6.86 (s, IH), 6.77 (dd, ./ 2.0, 7.6 Hz, IH), 6.62 (s, I H), 4.00 is 3H), 3.93 is. 3H), 3.77-3.74 (m, 4H), 2.72-2.66 im . 2H),

2.51 -2.49 (m, 2H), 1.71 (d. ./ 12.0 Hz, 2H), 1.55 (brs, I H), 1.42- 1.38 (m, 2H), 1.24-1.16 (m, 2H); HPLC (Method 4) 98.8% (AUC), fe = 6.73 mm.; ESl+APCl-MS m/z 530 [M + H] + . Scheme IS

Preparation of teti-butyl ((l-(2-amiRopyridiR-4-Yl)piperidii¾-3-yl)methyl)carbamate 10-3;

To a solution of 4-chloropyridin-2-amine 10-1 (2.00 g, 15.6 mmol) in a mixture of isopropanol and N, JV-diisopropylethyl amine (40 mL/ 20 mL), was added ferf-butyl (piperidin-3-ylmethyl)carbamate 10-2 (4.34 g, 20.3 mmol). The the reaction mixture was heated in a sealed tube at 120 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCC solution (300 mL: 100 ml,). The layers were separated and the EtOAc layer was washed with brine (100 mL), dried over NajSQ-s, filtered and concentrated. Hie cmde material was triturated with hexanes, filtered and dried to provide tert-bvAyl ((l-(2-ammopyridm-4-yi)piperidin-3-yl)methyl)carbamate 10-3 (2.5 g. 52%) as an off-white solid, which was used directly in next step without further purification.

ESI+APCI-MS m/z 307 [M + H]

7^1)piperidin-3-yi)methyl)carbamate lj jjjL .

A mixture of ¾rt-butyl ((i-(2-aniinopyndin-4-yl)piperidin-3-y])methyl)carbamate 10-3 (2.50 g, 8.1 mmol) and 2-bromo-l-(5-chloro-2,4-dimethoxyphenyl)ethanone 10-4 (2.62 g, 8.9 mmol) in acetone ( 100 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature. Hie precipitate formed was collected by filtration, washed with hexan.es (100 mL), and dried. The hydrobromide salt was taken up in water (50 mL) and saturated sodium bicarbonate solution (100 mL) and stirred at room temperature for .1 h. The solid was collected by filtration, washed with water and dried to give teri-batyl ((l-(2-(5-c oro-2,4- limethoxypte

3-yl)methyl)carbamate 10-5 (3.10 g, 76%) as an off-white solid. ESI+APCI-MS m/z 501 [M + H | .

To a solution of re/t-butyi ((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2- a]pyridin-7-yl)piperidm-3-yl)methyI)carbaraate H ) ~5 (3.00 g, 6,0 ramol) in CH2Q2 (30 mL) was added a solution of HQ (4.0 M in 1,4-dioxane, 30 mL) and the reaction mixture was stirred at room temperature for 16 h. The solid obtained was collected by filtration, washed with CH2CI2 (100 mL). The solid was then suspended in water (70 mL) and stirred in saturated sodium bicarbonate solution (70 mL) for 1 hour.liie off-white solid precipitated was collected by filtration, washed with water and dried to provide (l~(2-(5- ehloro~2,4~dffliethoxyphenyi)ffliKlazo[l,2~a]py 10-6 ( 1.60 g, 67%) as an off-white solid. ESI+APCT-MS m/z 401 [M + H] ÷ .

Preparation of fe?f~h tyl 3-((((1-(2-(5-chloro-2,4-dimetho¾yphen^ iExamffleJ^JJj^

To a solution of ( 1 ~(2-(5-chloro-2,4~dimethoxyphenyl)imidazo[ 1 ,2~a]pyridin-7~ yl)piperidin-3-yl)meihanamine 10-6 (100 mg, 0.25 mmoi), tert-butyl 3 -formy lpyrrolidine- 1 - carboxylate 10-7a, (74 mg, 0.37 mmoi) in CH3OH (5 mL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium

cyanoborohydride (47 mg, 0.75 mmoi) was added in one portion and the reaction mixture was stirred at room temperature for 15 min. Hie reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2 - 20 mL). Hie combined organic extracts were washed with brine (20 mL), dried over anhydrous NazSCfe, filtered and concentrated. The residue was purified by combi-flash

chromatography [silica gel; 5% Ni hOi i in MeOH: ( ί ! ·( I < (1 :9)] to give fen-butyl 3-((((l - (2- 5-ehloro-2,4-dimethoxyphenyl)im^

yl)meihyl)aramo)meihy3)pyrro]idine-.l-carboxy3ate 10-8a (20 mg, 14%) as an off-white solid.

¾ MR (400 MHz, DMSO^fe): δ 8.30 (d, ·/ 7.6 Hz, 1H), 8.16 (s, 1H), 8.00 (s, IH), 6.86 (s, 1H), 6.78 (d, J 7.6 Hz, 1H), 6.69 (s, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.82 (d, J ------ 11.6 Hz, 1H), 3.7 ! (d. ./ 11.6 Hz, 1H), 3.45 (br s, 1H), 3.22-3.16 (m, IH), 2.99-2.94 (m,

IH), 2.79-2.73 (m, 1H), 2.58-2.43 (m, 6H), 1.98-1.97 (m, 2H), 1.82-1.71 (m, 3H), 1.59-1.49 (ra, 2H), 1.39 (s, 9H), 1.18-1.12 (rn, IH); HPLC (Method 4) 98.3% (AUG), fe = 6.83 mm.; ESI+APCI-MS m/z 584 [M + H] \

1 -( 1 ~(2-(5 -Chlof o-2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-3 - yl)-N-(cyclohexylmethyl)methanamine 10-8b was prepared in the same manner as tert- butyl 3~((((l -C2~(5~e oro-2,4-dimetho

yl)methyl)amino)methyl)pyrrolidine- 1-carboxylate 1.0-8a, using cyclobexanecarbaldehyde 10- 7b, and was obtained as an off-white solid (18% yield).

lH NMR (400 MHz, DMSO~a¾, 362 K): δ 8.19-8.16 (ni, 2H), 7.91 (s, IH), 6.84 (s, IH), 6.66 (d, J = 8.0 Hz, IH), 6.60 (s, IH), 3.98 (s, 3H), 3.91 (s, 3H), 3.70 (d, J = 13.2 Hz, IH), 3.60 {ά, J ------ 11.6 Hz, IH), 2.86 (br s, IH) 2.66-2.61 (ni, IH), 2.51-2.42 (rn, 4H),

1.81-1.55 (m, 9H), 1.45- 1.41 (ni, IH), 1.25-1.18 (rn, 4H), 0.98-0.90 (ni, 21 1 ·; HPLC (Method 4) 98,7% (AUC), fe = 6.85 ram. ; ESI+APCI-MS m/z 497 [M + Hf.

Preparation of tert-butyl 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidaz:o|l a 2^ a]pYridin-7-Yl)piperidin-3-yl)methvl)amino)methyl)piperidine -l-carboxylate 1.0-8c. re /'/-Butyl 3-((((l-(2-(5-chloro-2,4-dime1hoxyphenyl)imidazo| " l ,2-«]pyridin-7- yl)piperidin-3~yl)methyi)amino)methyi)piperidine-l-earboxyla te 10-8c was prepared in the same manner as fert-butyl 3-((((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-«]pyri din- 7-yi)piperidin-3-yl)methyl)annno)meth.yl)pyrrolidine-l-carbo x5''laielO~ 8a, using tert-butyl 3-formylpiperjdine- 1 -carboxylate 10-7c, and was obtained as an off-white solid (9% yield).

:fi NMR (400 MHz, DMSO fc): δ 8.29 (d. ,/ 7.6 Hz, ill).8.16 (s, 1H), 7.99 is. 1H), 6.86 (s, 1H), 6.77(d,■/ 7.2 Hz, 1H), 6.68 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H),

3.84-3.70 (m, 3H), 3.42-3.37 (m, 111·.2.76 (t, J = 10.4 Hz, 2H), 2.59-2.53 (m, 6H), 1.81-1.70 (m, 4H), 1.62-1.49 (m, 311).1.39 is.9H), 1.38-1.27 (m, Hi).1.17-1.11 (m, 2H); HPLC (Method 4) 94.3% (AUC), fe = 6.91 mm.; ESI+APCI-MS m/z 598 [M + H] + .

Scheme 16

Preparation of ferf-b«tyl 4-((((l-(2-(5-c.hl r -2,4-dim th ¾yphenyI)imida¾ ll ¾ 2 :

To a suspension of (l-(2-(5-chloro-2,4-dimeth.oxyphenyl)imidtizo[i,2-«]pyridin -7- yl)piperidin~4~yl)methanamine 11-1 (150 mg, 0.37 mmoi), tert-butyl 4-fonnylpiperidine-l- carboxylate 11-2 (48 mg, 0.56 mmoi) in CH3OH (5 ml.) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (861 irsg, 13.7 mmol) was added in one portioin and the reaction mixture was stirred at room temperature tor 15 min. The reaction mixture was diluted with aqueous sodium bicarbonate solution (100 mL) and the aqueous layer was extracted with CH2CI2 (2 χ 50 mL). The combined organic extracts were ashed with water and brine (50 mL), dried over anhydrous NazSCU, filtered and concentrated. The residue was purified by combi- fiash chromatography [silica gel ; 5% N H iOH m MeOH; CH2CI2 (1 :9)J to tert-butyl 4~((((i~ (2~(5-chioro~2,4~dimethoxyph^

yl)methyl)amir)o)methyl)piperidine- 1 -carboxylate 11-3 (550 rag, 33%) as an off-white solid , ESI+APCI-MS m/z 598 [M + Hf.

To a solution of re/t-butyi 4-(((( 1 -(2-(5-ch1oro-2,4-dimethoxyphenyl)imidazo[ 1 ,2- ]pyridiii-7~yl)piperidin~4~y3)methyl)am 11-3 (100 rag,

0.16 mmol) and EtjN (0.07 mL, 0.50 mmoi) in CH2CI2 (10 ml,) was added 2,2,2- tnchloroethyl carbonochloridate (88 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with CH2CI2 (2 χ 20 mL). The combined organic layer was dried over NaaSCfo, filtered and concentrated to give tert-butyl 4-(((( 1 -(2-(5 -c oro-2,4-d ne thoxyphenyl)imidazo [1,2- a]pyridin-7-yl)piperidin-4-yl)methy

piperi dine- 1 -carboxylate 11-4 (1 10 mg, crude) as an off-white solid. ESI+APCI-MS m z 772 [M + H j

Preparation of 2,2,2-trkhloroethyI ((l-(2-(5-chloro-2,4-dimethoxypheRvI)imidazoXl 3 2^

To a solution of im-butyl 4-((((l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2- a]pyndin-7-yi)pipeiidin~4-yl)methyi)((2,2,2- trichloroeAox\')car onyl)amino)raeAyl)piperidine- 1 -carboxylate 11-4 (100 mg, 0.12 mmol) irs CH2CI2 ( 10 mL) was added a solution of HCI in 1 ,4-dioxane (4.0 M, 1 mL) and the reaction mixture was stirred at room temperature tor 2 h. The solid formed was collected by filtration, washed with CH2Q2 ( 10 mL) and dried. The hydrochloride salt obtained was then suspended in water (10 mL) and basified with saturated sodium bicarbonate solution ( 10 mL) by stirring at ambient temperature for 1 h. The yello solid was collected by filtration, washed with water and dried to provide 2,2,2-trichloroethyl ((1-

yi)methyl)(piperidin~4-ylniethyi)carbamate 11-5 (45 mg, 52%) as an off-white solid.

EST+APCI-MS m/z 672 [M + H]

Preparation of 2,2,2-trichloroethyl ((l-(2-(5-chloro-2,4-dimethoxypheRvi)imidazo l ,¾:

6a;

A solution of 2,2 ,2 -trichloroethyl (( 1 -(2-(5 -chloro-2,4- dimethoxyphenyi)miKlazo[l ,2~a]pyridin~7-yl)pipendin-4-yi)methyl){piperidin-4- yime†hyl)carbamate 11 -5 (50 nig, 0,07 mmol) in CH2Q2 (5 mL) was charged with pivaloyi chloride (0.01 mL, 0.08 mmol). The reaction mixture was stirred at room temperature for 10 min . The reaction mixture was diluted with water and extracted with CH2Q2 (2 * 10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 2,2,2-trichloroethyl ((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1,2- a]pyndin-7-yi)piperidin-4-yl)methyi)((l-pivaloylpiperidin-4- y ll-6a (55 mg, crude) as an off-white solid. ESI+APCI-MS m/z 756 [M + H | .

yj)piperidin-4-yl)methvI)amino)methYl)piperidin-l -yl)-2,2-dimethyIpropai¾-l-one 1 1 - 7a (Example 2~5Q j,

To a suspension of 2,2,2-trichloroethyl (( l-(2-(5-chloro-2,4- dimemoxyphenyl)irnidazo l,2-a]pyridin-7-yl)piperidin-4-yl)methyl)((

4-yl)metliyl)carbamate 11- 6a (50 mg, 0.06 mmol) in AcOH (1 mL) and H2O ( 1 mL) was added Zn (10 mg). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2CI2 (2 x 20 ml,). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by combi-flash chromatography [silica gel; 5% NI¾OH in MeOH: CH2CI2 (1 :9)] to give l -(4-((((l -(2-(5-chloro-2,4-dimethoxypheRyl)imidazo[l ,2- a]pyridm~7-yi)piperidin-4-y l)meihyl)amino)methyl)piperidm~ 1 -yl)-2,2-dimethylpropan- 1 - one ll-7a (15 mg, 39%) as an off-white solid.

1 H NMR (400 MHz, CDCb): δ 8.33 (s, ΓΗ), 7.87 (d, J= 7.2 Hz, 1H), 7.84 (s, lH), 6.82 id. ./ 1.6 Hz, 1H), 6.58-6.56 (m, 2H), 4.42 id. ./ 12.4 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.74 (d, J= 12.4 Hz, 2H), 2.81-2.73 (m, 4H), 2.56-2.52 (ra, 4H), 1 .87-1.71 (m, 4H), 1.43-1 ,31 (m, 4H), 1.27 (s, 9H), 1 .18-1.09 (m, 2H); HPLC (Method 7) 95.2% (AUC), to = 6.73 mm.; ESI+APC1-MS m/z 582 [M + H] + .

Pre )arafioH or

To a suspension of 2,2,2-trichSoroethyJ ((i-(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-y])piperidin-4-y!)meth

ylme†hyl)carbamate 11-5 (120 mg, 0.17 mmo!) and K2CO3 (73 mg, 0.53 mrnol) in DMF (2 mL), was added 1 -iodo-2-methylpropane (0.03 mL, 0.26 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diiuted with water and extracted with CH2CI2 (2 χ 10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 2,2,2-trichloroethyl ((l~{2.~(5-chloro~2,4~ dime†hoxyphenyl)imidazo[L2-a]pyridin-7-yJ)piperidm~4-yl)me thy

yl)methyl)carbamate 11 -6b (129 mg, crude) as an off-white solid. EST+APCI-MS m/z 728 [M + | | | .

l-(l-(2~(5-Chloro-2,4-dimethoxyp3

yl)-N-((l-isobutylpiperidin-4-yl)raethyl)!nethao.arn.ine 11 -7b was prepared in the same manner as l-(4~((((l-(2~(5-chioro-2,4-dimei oxypheny

yi)piperidin~4~y])methy1)amino 11 -7a and was obtained as an off-white solid (16% yield).

¾ MR (400 MHz, DMSO^fe): δ 8.27 (d, ·/ 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 6.86 (s, i l l). 6.78 (dd, J= 2.4, 8.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.79-3.76 (m, 2H), 2.78-2.64 (m, 4H), 2.44-2.37 (m, 4H), 1.97 (d, J= 7.6 Hz, 2H), 1.80-1.70 (m, 51 11. 1.67-1.57 (m, 3H), 1.41-1.31 (m, 1H), 1.26-1.06 (m, 4H), 0.83 id. ./ 6.4 Hz, 6H); HPLC (Method 7) 95.3% (AUC), fe = 6.46 min.; ESI+APCI-MS m/z 554 [M + Hf.

yj)methy])carbam

To a suspension of 2,2,2-trichloroethyl (( 1 -(2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-a]pyri^

y1methy!)carbamate 11-5 (250 mg, 0.36 mmol), cyclobutanecarbaldehyde (37 rag, 0.44 mmol) in CH3OH (5 niL) was added acetic acid (0.1 mL) and the resulting mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (43 nig, 1.82 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with CH2CI2 (2 χ 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 S04, filtered and concentrated. The crude materia] was purified by combi -flash chromatography [silica gel; 5% NH4OH in MeOH: CH2CI2 (1 :9)] to give 2,2,2-tnchloroethyl {ί \ -{2-{5-ά ο:- >-2Α- dimemoxyphenyl)imidazo[l,2-a]pyridin-7-yI)piperidin-4-yl)met hyl)(( l- (cyclobutylmeihyl)piperidin-4-yl)methyl)carbamate I -6c (220 mg, 80%) as an off-white solid. ESH-APCI-MS m/z 740 [M + H] + . yl)piperidin-4-yi)-A^Cl-fcveIobiityta 1.1. -7c l-( l-(2-(5-Chloro-2,4-dimetliQxyphenyl)imida^^

yl)-N-(( 1 -(cyclobut lmethyl)piperidin-4-yl)methyl)methananiine 11 -7c was prepared in the same manner as 1 -(4-(((( 1 -(2-(5 -chloro-2,4-diinethoxyphenyl)imidazo [ 1 ,2-o jpy ridin-7- y l)piperidin~4~yl)meth}4)amino)methyi)piperidin- 1 -y l)-2,2-dimethy Ipropan- 1 -one 1 l-7a and was obtained as an off-white solid (13% yield),

! H NMR (400 MHz, DMSO-de): δ 8.26 (d, J = 7.6 Hz, H), 8.16 (s, 1H), 7.99 (s, IH), 6.86 (s, i l l). 6.77 (dd, 2.4, 7.6 Hz, IH), 6.62 id ./ 2.0 Hz, IH), 4.00 (s, 3H), 3.93 (s, 3H), 3.77 (d, J= 12.4 Hz, 2H), 2.72-2.60 (m, 4H), 2.46-2.32 (m, 4H), 2.27 (d, J = 7.2 Hz, 2H), 2.00-1.94 (m, 2H), 1.85- 1.74 (m, 6H), 1.64-1.57 (m, 5H), 1.31- 1.1 1 (m, 4H), 1.09-1.06 (m, 2H); HPLC (Method 4) 93.9% (AUC), = 6.31 mm.; ESI+APCI-MS m/z 566 [M + H] \

Scheme 17:

To a suspension of l-(2-(5~chloro-2,4-dimemoxy^lieny )imidazc 1,2 ipyridin~7~ yl)piperidine~4-carbaldehyde 11-8 (1.0 g, 2.50 mmol), tert-hutyl 4~(2~ aminoethyl)piperidine- 1 -carboxylate 11-9 (628 mg, 2.75 ramol) in CH OH (50 mL) was added acetic acid (0.5 mL) and the resulting mixture was stirred at room temperatare for 2 h . Sodium cyanoborohydride (788 mg, 12.53 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with aqueous MaHCO. solution and extracted with CH2CI2 (2 χ 100 mL). The combined organic extracts were dried over anhydrous NaiSi filtered and concentrated. The crude material was purified by corabi-flash chromatography [silica gel; 5% H40H in MeOH: CH2CI2 (1:9)] to tert-hutyl 4-(2-(((l-(2-(5-chloro-2,4-dime1hox heny{)iraida∞[l,2- ]pyridm yl)piperidin-4-yl)methyl)amin^ 1.1-10 (480 mg, 73%) as an off-white solid.

i f NMR (400 MHz, CD3OD): δ 8.03 (d, ./ 7.6 Hz, 1H),7.97 (s, 1H),7.86 (s, I H), 6.67 (dd, ./ 5.2, 8.0 Hz, 2H), 6.57 (s, IH), 3.98 id. ./ 8.4 Hz, 2H), 3.92 (s, 3H), 3.85 (s,3H), 3.76 (d, J ----- 12.8 Hz, 2H ), 2.74-2.59 (m, 6H), 2.48 ( d, J - 6.8 Hz, 2H), 1.79 (d, J ------ 12.8 Hz, 2H), 1.60 (d, J ------ 12.8 Hz, 3H), 1.43-1.39 (m, 2H), 1.35 (s, 9H), 1.28-1.21 (m, 3H),

1.03-0.98 (m, 2H); ESI+APC1 MS m/z 612 \ \\ + H] \

Preparation of tert-hutyl 4-(2-(((1 -(2-(5-chloro-2,4-dimethoxyphenyl)imidazojj J 2 =. a|pYridii¾-7-Yl)piperidin-4-yl)methyl)((2,2,2- To a solution of tert-hutyl 4-(2-(((l-(2-(5-chioro-2,4- dimeihoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-y l)piperidin-4- yl)niemyl)amino)ethyl)piperidine-l-carboxylate 11-10 (500 mg, 0.81 mmol) and ΈΐϊΝ (0.35 mL, 2.44 mmol) in CH2CJ2 (25 mL) was added 2,2,2-trichJoroethyJ carbonochloridate (190 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with CH2CI2 (2 x 50 ml,). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give fen-butyl 4-(2-(((l-(2-(5-chlQro-2,4-dime&oxypheny

yl)piperidin-4~yl)methyi)((2,2,2-tnchloroethoxy)carbonyr) ainin carboxylate 11-11 (450 mg, erode) as an off-white solid. ESI÷APCI-MS m/z 786 [M + Hf.

Preparation of 2,2,2-trk oroethyl ((l-(2-{5-chI ro-2 ¾ 4-dimethoxyphenyl)im¾da¾ojL 2 :: To a solution of tert-hutyl 4-(2-(((l-(2-(5-chloro-2,4- dunemoxyphenyl)miidazo[l,2-a]pyri^

trichloroethoxy)cafbonyl)amino)ethyl) piperidine- 1 -carboxylate 11-11 (600 mg, 0.77 mmol) in CH2CI2 (50 mL) was added a solution of HQ in 1,4-dioxane (4.0 M, 2 mL) and the reaction mixture was stirred at room temperature for 2 h. The solid formed was collected by filtration, washed with CH2CI2 and dried. The hydrochloride salt was then suspended in water ( 10 mL) and basitied with saturated sodium bicarbonate solution (10 mL) by- stirring at room temperature for 1 h. The pale yellow solid precipitated was collected by filtration, washed with water and dried to provide 2,2,2-trichloroethyl ((l-(2-(5-chloro-2,4- dimeAoxyphenyl)imidazo[l,2-tf]pyridin- yl)e†hyl)carbamate 11-12 (400 mg, 76%) as an off-white solid. ESI+APCI-MS m/z 686 [M H |

Preparation of 2,2,2-trichloroethyl ((l-(2-(5-chloro-2,4-dimethoxypheRyl)imidazorL 1 2 : ; a}gYridin-7-Yl)piperidin-4-yl)methvl)(2-(l -pivaloylpiperidm-4-yl)ethyl)carbamate 11- 13;

To a solution of 2,2,2-trichloroethyl ((l-(2-(5-chloro-2,4- dimemoxyphenyl)imidazo[l,2-a]pyridin-^^

yl)ethyl)carbamate 11-12 (100 mg, 0.14 mmol) in CH2CI2 (10 mL) was added pivaloyl chloride (0.02 mL, 0.16 mmol). The reaction mixture was stirred at room temperature for 10 rain. The reaction mixture was diluted with water and extracted with ( " I (2 χ 20 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 2,2,2-trichloroethyl ((l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l,2-a]pyridin- 7-yl)piperidin-4-yl)methyl)(2-(l-pivaloylpiperidin-4-yl)eihy l)carbamaie 11-13 (110 mg, crude) as an off-white solid. ESI+APQ-MS m/z 770[M + H] \

yj)piperidin-4-yl)methyl)amino)ethvi)piperidm^ llzlUL (Example 2-69}

l-(4-(2-(((l-(2-(5-Chloro-2,4-dimethoxyphenyl)imidazo[ l,2-ii]pyridm-7- yl)piperidin-4-yl)meftyl)amino)eftyl)piperid 11-14 was prepared in the same manner l-(4-((((l-(2-(5-chloro-2,4-dimethoxyphenyl}imidazo| 1,2- ]pyridin-7-yl)piperidin-4-yl)metiiyl)atnino)methyl)piperidm- l-yl)- one ll-7a and was obtained as an off-white solid (14% yield).

! H NMR (400 MHz, DMSO-de): δ 8.26 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 6.86 (s, 1H), 6.77 (dd, J= 2.0, 7.6 Hz, 1H), 6.62 (d, J= 1.6 Hz, 1H), 4.24 (d, J= 12.8 Hz, 2.H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 (d, J= 13.2 Hz, 2H), 2.73-2.67 (m, 4H), 2.40 (d, J = 6.4 Hz, 2H), 1.79 (d, J= 1 1.2 Hz, 21 ! }. 1.67-1.56 (m, 5H), 1.36-1.31 (m, 2H), 1.25- 1.18 (m, 3H), 1.17 (s, 9H), 1.01-0.91 (m, 2H); ESI+APCI-MS m/z 596 [M + Hp.

Compounds of the invention of this application not particularly described in the Examples above were also be synthesized by similar or analogous methods by referring to the above-mentioned Examples and such.

Next, the pharmacological activities of compound (I) will be described in the following Test Examples.

[Test Examples]

Preparation of compoimd dilution plates (96 well plate)

To the test compound 100% DMSO was added to obtain a stock solution with a final concentration of 10 mM and the solution was incubated overnight on a shaker at 150 rpm . In a 96 well plate, 75 ( uL of 50% DMSO (in water) was dispensed to all wells from Col 3 to Col 1 1, 76 μΐ of 50% DMSO was added to Col 2 (Row A-RowH).24 μί of lOmM compound stock was added to Col 2 (Row A-Row H) to obtain a final concentration of 2.4 mM. The mixture (25 μΐ) in each well of Col 2 was mixed and transferred to a corresponding well of Col 3. Similar proceedure was repeated till Col 1 1 to obtain 10 serial dilutions (1 :4) of each compound. Assay buffer (18 μ 1) was added in Row A, Col 3-1 1, and Sinefungin (24μ1,

12.5mM) was added to Col 2. The mixture (6 μΐ) in Row A- Col 2 was transferred to the corresponding wells of Col 3. The mixture (24μ1) in wells of Col 3 were mixed and transferred to Col 4, and the similar procedure was continued till Col 1 1 to obtain a 10 point serial dilution of Sinefungin.

Water (0.25 μΐ) was added to Col 1 and Col 23 (minimum and maximum signal wells respectively), and 50% DMSO (0.25 μί) was added to Col 2. and Col 24 (minimum and maximum signal wells respectively). The test compounds (0.25 μί) were added to the respective wells in 'Row A- Row N\ 'Row O' contained the internal standard compound. Sinefungin (4 μΐ) was added to ' Row P' . Each compound concentration was tested in duplicates.

S i B ; 9 i H2 iii ass¾y M

Assay buffer (4 μΐ,) was added into all the wells, including test compound and control wells (except for Sinefungin control wells), usmg the Multidrop Combi, The plate was centrifuged at 1 OOOrpm for 1 min . Substrate mix (8 μΤ) containing radiolabelled 3 H- SAM (final cone: l OOnM) and H3 Hi stone Peptide (final cone: 350nM) was added to all wells using Multidrop Combi and centrifuged at 1000 rpm for lrnin. SUV39H2 (8pL, final cone: optimized for each lot of the enzyme based on specific activity) was added by using the Multidrop Combi. The assay plate was centrifuged at 1000 rpm for Imin.

Assay buffer was used as background control , and incubated at room temperature for 3hours, The reaction was stopped with 20μΤ of 2.5mg/mL Streptavidin SPA beads (final cone, 5C^ig/well) in buffer using the Multidrop Combi and centrifuged for Imin. The plate was loaded into the Trilux-Microbeta, counter and a delayed read of 10 hours was made. The radioactive signal was measured at 1 min/ well. Sinefungin and the internal standard compound were used as tool compounds to determine assay performance.. .

Data Analysis The following caiculations were made usmg the obtained CPM raw data: Software used: XLFit from IDBS. Model used was- Dose Response One Site - Model 205

1 % DMSO/ water Negative Control (minimum signal- Column 1 and 2) =

Average of ail background control wells

1 % DMSO/ water Positive Control (maximum signal- Column 23 and 24)

== Average of all control wells

Signal Ratio :::: (Positive Control) / (Negative Control)

Z' === l-(((3*StdDev Negative Control) + (3*StdDev Positive Control)) /

(Avg. Positive Control - Avg. Negative Control))

% Inhibition of test compound = (100-((AVG. CPM test com ound - Avg.

CPM Negative Ctrl) / (Avg. CPM Positive Ctrl - Avg. CPM Negative Ctrl)) xlOO) ach test plate the following results were calculated:

Average, Standard Deviation, and % CV of Background Controls

Average, Standard Deviation, and % CV of Positive Controls

T value of the plate

IC50 values of standard and test compounds (in nM)

R 2 value of fitted concentration respon se curve

Hill slope coefficient of fitted concentration response curve

Signal to Noise Ratio

ach sample compound the following results were reported:

Concentration dependent response curve for each compound

Concentration of compound causing 50% inhibition of enzyme activity (ICso values (in nM))

% Inhibition at Maximum Concentration tested.

Maximum Concentration tested

R 2 value of fitted concentration response curve

Hill slope coefficient of fitted concentration response curve ICso values of the typical compounds of the present invention are sh own in the following table 3:

Western blot analjfgis

To evaluate the expression status of SUV39H2 in several cell lines, western blot analysis was perfonned using crude ceil lysate collected from those cells. Anti- SUV39H2 antibody was used to visualize the expression. Cancer cell lines, A549, HCT-116, HFL1, CCD-I8C0 and PC14, expressed SUV39H2 significantly.

Cg : sg-d. ss¾.Y

Active candidate inhibitors against SUV39H2 were evaluated for their target- specific cytotoxicity using A549. 100 micro-L of cell suspension was seeded onto 96-well microliter plate (ViewPlate-96FTC, PerkinElmer). The initial cell concentration of A549 was 3,000 cells/well, 2,000 cells/well and 2,500 cells/well, respectively. Cellular growth was determined using Cell Counting Kit-8 (DOJINDO) at 72 hours after the exposure of the candidate inhibitors. ICso was used as an indicator of the anti-proliferative activity of the inhibitors, and calculated by serial dilution method (0, 1 ,5625, 3.125, 6,25, 12,5, 25, 50, and 100 micro-M). Accurate ICso values were calculated as described previously.

ICso values of the typical compounds {Examples I i.068) of the present invention are shown in the following tables 3-1 and 3-2:

Table 3-1:

Table 3-2

i I "SUV39H2 "A549 j

Ex, Structure iCso (mkroM)" IC59 !