Indian Patents
Title of Invention

ALKOXY SUBSTITUTED IMIDAZOQUINOLINES
Abstract Imidazoquinoline compounds with an alkoxy substituent at the 6, 7, 8, or 9position, pharmaceutical compositions containing the compounds, intermediates, methods of making, and methods of use of these compounds as immunomodulators, for inducing or inhibiting cytokine biosynthesis in animals and in the treatment of diseases including viral, and neoplastic, are disclosed.
Full Text

AUKOXY SUBSTITUTED IMIDAZOQUINOLINES
CROSS-REFERENCE TO RELATED APPLICATION The present application claims priority to U.S. Provisional Patent Application Serial No. 60J508634, filed on October 3, 2003, which is incorporated herein by reference.
BACKGROUND
In the 1950's the 1H-imidazo[4,5-c]quinoline ring system was developed, and l-{6-me1hoxy-8-quinohnyl)-2-melhyl-lH-imida2o[4,5-c]quinoline was synthesized for possible use as an antimalarial agent Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, l-[2-(4-piperidyI)ethyrj-lH'-imidazo[4,5-c]quinoline was synthesized as a possible anticonvulsant and cardiovascular agent. Also, several 2-oxoimidazo[4,5-c]quinolines have been reported.
Certain liy-imidazo[4,5-c]qumolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. Subsequently, certain substituted lH-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine, tetrahydroquinoun-4-amine, naphthyridin-4-amine, and tetrahydronaphiiiyridin-4-aminee compounds as well as certain analogous thiazolo and oxazolo compounds were synthesized and found to be useful as immune response modifiers (IRMs), rendering them useful in the treatment of a variety of disorders.
There continues to be interest in and a need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other

SUMMARY
A new class of compounds useful for modulating cytokine biosynthesis has now been found. In one aspect, the present invention provides such compounds, which are of Formula I:


wherein R, n, R1, R", and R3 are as defined below; and phannaceuticaly acceptable salts thereof.
The compounds of the present invention are useful as immune response modifiers (IRMs) due to their ability to induce or inhibit cytokine biosynthesis (e.g, induce ox inhibit the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals. Compounds can be tested per the test procedures described in the Examples Section. Compounds can be tested for induction of cytokine biosynthesis by incubating human peripheral blood mononuclear cells (PBMC) in
t
a culture with the compound(s) at a concentration range of 30 to 0.014 uM and analyzing for interferon (a) or tumor necrosis factor (a) in the culture supernatant. Compounds can be tested for inhibition of cytokine biosynthesis by incubating mouse macrophage cell line Raw 264.7 in a culture with the compound(s) at a single concentration of, for example, 5 uM and analyzing for tumor necrosis factor (a) in the culture supernatant The ability to modulate cytokine biosynthesis, for example, induce the biosynthesis of one or more cytokines, makes the compounds useful in the treatment of a variety of conditions such as viral diseases and neoplastic diseases, that are responsive to such changes in the immune response.
In another aspect, the present invention provides pharmaceutical compositions containing the immune response modifier compounds, and methods of inducing or inhibiting cytokine biosynthesis in an animal treating a viral disease in an animal and treating a neoplastic disease in an animal, by administering an effective amount of one or more compounds of Formula I andJor pharmaceutically acceptable salts thereof to the animal.
hi another aspect, the invention provides methods of synthesizing compounds of Formula I and intermediates useful in the synthesis of these compounds.

As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably.
The terms "comprising" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION The present invention provides such compounds of the following Formula I:
'
wherein R, n, R', R", and R3 are as defined below; and pharmaceutically acceptable salts thereof.
Examples of compounds of Formula I are more specifically defined by Ihe following Formulas H-VHL

1




wherein R, Rls R2j R3.1, R3.2, R3-3, R3-4, R3-5, R3-6, and n axe as defined below; and pharmaceutically acceptable salts thereof.
The compounds of Formula VII and salts thereof are also useful as intermediates for the preparation of compounds and salts of Formulas I-VII. The present invention also provides intermediate compounds of Formula DC:

wherein R, R1, R2, R3, and n are as defined below.
In one aspect, the present invention provides compounds of the formul (I):

wherein:

R.3 is selected from the group consisting of -Z-Y-R4, -Z-Y-X-Y-R4,
-Z-Rs,
-Z-Het,
-Z-Het'-R4, and
-Z-Hef-Y-Rb
Z is selected from toe group consisting of alkylene, alkenylene, and aEcynylene, wherein alkylene, alkenylene, and alkynylene can be optionally intambpted wifh one or more -O- groups;
Y is selected from the group consisting of
-S(O)o-2-,
-S(O)2-N(R«),
-C(R6)-,
-C(R6)-O-S
-O-C(R6)-,
-O-C(O)-O-,
-N(Rg)-Q-,
-C(R6)-N(R8K
-O-C(R6)-NCR8K
-C(R6)-N(OR9),



X is selected from the group consisting of alkylene, alkenyiene, alkynylene, arylene, heteroarylene, and heterocycrylene wherein the alkylene, alkenyiene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, aDcenyi, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkyienyi, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocycryl wherein the alkyl, alkenyL, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxyJ and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R5 is selected from the group consisting of

R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -O-, -C(O), -S(O)o.2-, and -NCR”)-;
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,

or a phannaceuticaUy acceptable salt thereof.

wherein:
R3 is selected from the group consisting of
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R5, '
-Z-Het,
-Z-Hef-R4, and
-Z-Het'-Y-R”;
Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; nisOorl; Ri is selected from 1he group consisting of
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R5; R2 is selected from the group consisting of

haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyL, mercapto, cyano, arylazy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, hydroxyallcyleneoxvalkylenyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;
Hef is heterocyclylene -winch can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of aBqyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyi, mercapto, cyano, aryioxy, aiylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, amino, alkylamino, dialkylamino, (dialkylarnino)alkyleneoxy, and oxo;
Q is selected from the group consisting of a bond, -CCRfih -CCRbKbh -S(O)r, -CCRebNCRsbW-, -S(O)2-N(Rg)-, -C(R«)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -NfRgHXRe)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-;
a and b are independently integers from 1 to 6 with the proviso that a + b is ( 7;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
nisOor l;and
R' and R" are independently selected from the group consisting of hydrogen and non-interfering substitutents;
with the proviso that Z can also be a bond when:
R3 is -Z-Het, -Z-Hef-R4, or -Z-Het'-Y-Rb or
R3 is -Z-Y-Ri or -Z-Y-X-Y-R”, and Y is selected from -bOVr,
-S(O)2-N(R8h -CCRsK -C(R6)-O-, -CCRsbNCRsK


-X-R4,
-X-Y-R4, and
-X-R5;
X is selected from the group consisting of altylene, alkenylene, alkynylene, aryleae, heteroarylene, and heterocyclylene wherein the alkylene, alksnykas, and alkynyiene groups can be optionally interrupted or terminated with arylene, freteroarylene, or heterocycrylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of
-S(O)o-2-,
-S(O)2-N(R«K
-C(Rb)-,
-C(R6)-0-,
-O-C(R6)-5
-O-C(O)-O-,
-NCR8)-Q-,
-Cb-NfRg)-,
-O-C(R6)-N(R«K
-C(R6)-N(OR9)-5


R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyi, aryi, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteToatyloxyalkylenyL, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyL, alkynyl, aryi, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylerryl, heteroaryloxyalkylenyl, alkylheteroaiylenyl, and heterocyclyl groups can be unsnbstifuied or substituted by one or more substituenls independently selected from fee group consisting of alkyl, aflcoxy, rrydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryi, aryloxy, arylalkyleneoxy, heteroaryL, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, arrrino, alkylamino, dialkylamino, (diaIkylarnirK))alkyleneoxy, and in the case of alkyl, alkenyl, alkynyi, and heterocyclyl, oxo;
R5 is selected from the group consisting of

Ri is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
R10 is C3-8 alkylene;
A is selected from the group consisting of-0-, -0(O)-, -S(O)o-2-, and —N(R4)-;
Het is heterocyclyl which can be unsubstitated or substituted by one or more substituents independently selected from the group consisting of alkyl, aflcoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, arnino, alkylarnino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;
Het' is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy,

arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, amino, alkylamino, dialkylanrino, (dialkylamino)alkyleoeoxy, and oxo;
Q is selected from the group consisting of a bond, -CfRe)-, -€(R(;)-C(R6K -SCOb-, -Q£6)-N(R«)-W-, -SfOb-NCRg)-, -C(R«)-O-, and -CCRbOR”)-;
V is selected from the group consisting of -C(R(;)-, -O-CCRs)-, -N(Rs)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(Oy, and -8(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a+b is ( 7; with the proviso that Z can also be a bond when:
R3 is -Z-Het, -Z-Hef-R”, or -Z-Het'-Y-Rb or
R3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and Y is selected from -S(O)o-2-3
-S(O)2-N(R8)-, -CCRsK -CCRb-O-, -C(R6)N(R«K

or a phamaceutically acceptable salt thereof.
In another embodiment, the present invention provides compounds of the formula (ID):
wherein:
R3-1 is selected from the group consisting of -Z-N(R”KXR6)-R4,


Z is selected from the group consisting of alkylene, alkenylene, and alkynyiene, wherein alkylene, alkenylene, and alkynyiene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; nisOor 1;
Ri is selected from the group consisting of -R4, -X-R4, -X-Y-R4,
-X-Y-X-Y-R4, and -X-R5;
R2 is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynyiene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynyiene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of
-S(O)0-2-,
-S(O)2-N(R8K
-C(R6K -C(R6)0-,


R4 is selected from the group consisting of hydrogen, alky!, alkenyi, alkynyl, aryi, arylalkylenyl, aryloxyalkylenyi, alkylarylenyl, heteroaryl, heteroaryialkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyi, alkynyL, aryl, arylalkylenyl, aryloxyalkylenyi, alkylarylenyl, heteroaryl, heteroaryialkylenyl, heteroaryloxyalkylenyL, alkylheteroaryienyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substitaents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, njtro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyieneoxy, heterocyclyl, amino, alkykmino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyi, alkynyl, andheterocycryi, oxo;
Rs is selected from the group consisting of


Re is selected from the group consisting of =O and =S;
R? is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyi, alkoxyalkyierryi, and arylalkylenyl;
Rs is selected from the group consisting ofnydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of-O-, -C(O)-, -S(O)o-2-» aid—N(R4)-;
Q is selected from the group consisting of a bond, -C(R«)-, -C(Rs)-C(R6)-, -S(O)r, -CCRebNCRg)b-, -S(O)2-N(R8), -C(R6)-O-, and -C(R6)N(OR9)-;
V is selected from the group consisting of -C(R6), -O-C(R$)-, -N(Rg)-C(R6K and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is ( 7;
with the proviso that Z can also be a bond when R3.1 is

or apharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides compounds of me formula OV):
wherein:
R3.2 is selected from the group consisting of


Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted wife one or more -O- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; nis Oor 1;
Ri is selected from the group consisting of -R4, -X-R4, -X-Y-R4,
-X-Y-X-Y-IU, and -X-R5; R2 is selected from the group consisting of
-R4, -X-R4,
-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, aryiene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with aryiene, heteroarylene, or hetearocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of


R” is selected from the group consisting of hydrogen, alkyi, alkenyl, alkynyl, aryi, arylalkylenyl, aryloxyalkylenyl, alkylaiylenyl, heteroaryi, heteroaiylalkylenyl, heteroaiyloxyalkylenyl, aJkylheteroaryienyi, and heterocyclyl wherein the aOcyi, alkenyl, alkynyl, aryl, arylalkylenyl, azyioxyalkylenyl, alkylarylenyL, heteroaiyl, heteroarylalkyleiiyl, heteroaryloxyalkylenyL, alkylheteroarylenyl, and heterocyclyl groups can be unsubstitated or substituted by one or more sabstitaents independently selected from the group consisting of alkyi, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, nydroxy, mercapto, cyano, aryl, aiyloxy, aiylalkyleneoxy, heteroaryi, heteroaiyioxy, heteioarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,

(dialkylaminojalkyleneoxy, and in the case of alkyi, alkenyl, alkynyi, and heterocyclyi, oxo;
Rs is selected from the group consisting of

Re is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyL, aBcoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of-O-, -C(O)-, -S(O)o-2-, and -NOR4)-;
Q is selected from the group consisting of a bond, -C(ReK -C(R6)-C(R6K -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(Rs)-3 -Cb-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -CfReK -O-C(Re)-, -N(Rg)-C(R6)-s and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is ( 7;
with the proviso that Z can also be a bond when R3.2 is

or a pharmaceutically acceptable salt thereof
In another embodiment, the present invention provides compounds of the formula
(vy.


Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, ■wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyl, alkoxy, bydroxy, halogen, and triflooromethyl;
nis Oor 1;
Ri is selected from the group consisting of
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and -X-R5;

R.2 is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynyiene, zyiene, heteroarylene, and heterocyclylene "wherein the alkylene, alkenylene, and aftynylene groups can be optionally interrupted or terminated with aryiene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of -S(O)o-2-,
-S(O)2-N(R8K
-C(R6)5
-C(R6)-O-,
-O-C(R4h
-O-C(O)-O-,
-N(Rg)-Q-,
-C(R6)-N(R8)-,
-O-CbJ-NCRg)-,
-C(R6)-N(OR9)-5



R4 is selected from the group consisting of hydrogen, alkyi, afltenyl, alkynyl, aryi, aryteJkyl&xyl, aryloxyalkylenyL, alkyiarylenyl, heteroaryi, heteioarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyi, alkenyl, aflcynyi, aryi, arylalkylenyl, aiyloxyaJkyienyi, alkylarylenyl, heteroaryi, heteroaryialkyleiryi, faeteroaryioxyalkyienyi, alkylheteroarylenyi, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyi, alkoxy, hydroxyalkyi, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryi, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, arnino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyi, alkenyl, alkynyl, and heterocyclyl, oxo;
R5 is selected from the group consisting of

R$ is selected from the group consisting of =O and =S;
R7 is C2-7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyi, alkoxyalkyienyl, and aryialkylenyl;
R9 is selected from the group consisting of hydrogen and alkyi;
Rio is C3-8 alkylene;
A is selected from the group consisting of-O-, -C(O)-, -S(O)o-2-, and -N(R4)-;
Q is selected from the group consisting of a bond, -C(Re)-, -C(Re)-C(R6)-» -8(O)2-, -C(R6)-N(R8)-W-, -SCOb-NCRsK -CCRebO, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R(;)-, -O-QRG)-, -N(Rg)-C(R6K and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is ( 7;


or a pharmaceutically acceptable salt thereof
In another embodiment, the present invention provides compounds of the formula (VI):
wtKTemi
R3-4 is selected from the group consisting of -Za-CCR”)-!b, -Za-COb-O-R”, -Za-C(R6)-N(R8)R4, and

Za is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyL, alkoxy, hydroxy, halogen, and tnfhioromethyl;

n is 0 or 1;
Rj is selected from the group consisting of
-R4,
-X-R4,
-x-Y-m,
-X-Y-X-Y-R4, and -X-R5;
R2 is selected from the group consisting of -R4, -X-R4, -X-Y-R4, and
-X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, sryiene, heteroarylene, and heterocycljdene wherein the aliylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of



JU is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, aryialkyienyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyi, alkenyl, alkynyl, aryl, aryialkyienyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstinited or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, ((fia&yiammo)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R5 is selected from the group consisting of

Rg is selected from the group consisting of =0 and =S; R7 is C2-7 alkylene;
R« is selected from the group consisting of hydrogen, alkyl, alkoxyalkyienyl, and arylaJkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3.8 alkylene;

A is selected from the group consisting of -O-, -C(O)-, -S(O)o-2-, and -NCR”)-;
A1 is selected from the group consisting of -O-, -C(O)-, -S(O)o-r-, -NCR4)-, and -CHz-;
Q is selected from the group consisting of a bond, -CCbK -C(R«)-C(R6), -S(O)r, -C(R6)N(R8)-W-, -S(O)2-N(R8)-} -C(R(i)-O-, and -CCRebNCOR?)-;
V is selected from the group consisting of -C(Re), -O-C(R())-, -N(Rs)-C(R(»K and -S(O)b;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)r; aad
a and b are independently integers from 1 to 6 with me proviso mat a + b is ( 7; or a phsnnaceutically acceptable salt thereof.
In another embodiment, the present invention provides compounds of the formula (VH):

-Z-N(R«)-C(R6)C(R6)R4;
Z is selected from the group consisting of alkylene, alkenylene, and alkynyiene, ■wbaem alkylene, alkenylene, and aOcynylene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and triflooTomethyl;
nisOor 1;

Ri is selected from the group consisting of
-m,
-X-R4, -X-Y-R4,
-X-Y-X-Y-R4, and -X-R5;
R2 is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, aryiene, heteroarylene, and heterocyclylene wherein the aXkyleos, alkenylene, and alkynylene groups can be optionally interrupted or terminated with aryiene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -0- groups; Y is selected from the group consisting of
-S(O)o-2-,
-S(O)2-N(R8)-,
-C(R”K
-CCRsKK
-0-C(R6K
-O-C(O)-0-,
-N(Rg)-Q-,
-Cb-NCRg)-,
-O-C(R6)-N(R8),
-C(R«)-N(0R9)-,



IU is selected from the group consisting of hydrogen, alkyi, alkenyl, alkynyi, aryl, aryialfcylenyl, aryloxyalkylenyl, alkylaryienyl, heteroaryl, heteroarylalkylenyl, heteroaiyloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyi, alkenyl, alkynyi, aryl, arylalkylenyl, aryloxyalkylenyl, alkylatylenyl, heteroaiyl, heteroaryialkylenyL, heteroaryloxyalkylenyl, alkylheteroaiyienyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyi, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroaxylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyi, alkenyl, alkynyl, and heterocyclyl, 0x0;

IU is selected from the group consisting of =0 and =S; R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyi, alkoxyalkyienyl, and arylalkylenyl;
R$ is selected from the group consisting of hydrogen and alkyi;
Rio is C3-8 alkylene;
A is selected from the group consisting of-O-, -C(O)-, -S(OV2-5 and -N(R«)s
Q is selected from the group consisting of a bond, -C(RsK -CCRcHXRe)-, -S(O)2-,

-C(R6)N(R8)-W-, -SCObNCRsK -CfoyO-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R(;)-, -O-CCRbK -N(R«)-C(R6)-, and
-S(Q)r;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)z-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is ( 7; with the proviso that Z can also be a bond when R3.5 is

or a pfaatmaceuticaHy acceptable salt thereof.
m another embodiment, the present invention provides compounds of the formula (VBI):

wherein:

Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyL, alkoxy, hydroxy, halogen, and trifliioromethyl;
nisOor 1;
Ri is selected from the group consisting of

-R4,
-X-Rk -X-Y-R,,
-X-Y-X-Y-R4, and -X-R5;
R2 is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, aryiene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of
-S(O)o-2~,
-S(O)2-N(Rg)-,
-C(R6)-,
-C(R«))-0-,
-O-C(R6),
-O-C(O)-O-,
-N(R8)Q-S
-CCRb-NCRg)-,
-C(R6)N(OR9)-5



R” is selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyi, aryl, xyfeJkyteayl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaiyloxyalkylenyi, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aiyloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryL, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, axo;
Rs is selected from the group consisting of

Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and aryialkjdenyl;
Rs is selected from the group consisting of hydrogen and alkyl;
Rio is C3.B alkylene;
A is selected from the group consisting of-O, -C(O)-, -S(O)o-2-. and -NCR”)-;
Q is selected from the group consisting of a bond, -C(R«)-, -CObMXReK -S(O)2-,

(XR6)N(R8)-W-, -S(O)2-N(R8), -CXRfiK)-, and -CCR6)N(OR9);
V is selected from the group consisting of -CCR”)-, -O-C(ReK -NCRsKbR”)-, and -S(OV;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)r; and
a and b are independently integers from 1 to 6 with the proviso that a + b is ( 7;
with the proviso that Z can also be a bond when R3-6 is

or apbannaceutically acceptable salt thereof
The compounds of Formula VTH and salts thereof are also useful as intermediates for me preparation of compounds and salts of Formulas I-VIL
In another aspect, the present invention provides intermediate compounds of Formula IX:

R3 is selected from the group consisting of
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R.5,
-Z-Het,
-Z-Hef-R4, and
-Z-Hef-Y-IU;
Z is selected from the group consisting of alkylene, alkenylene, and alkynyleQe, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;

R is selected from the group consisting of alkyi, alkoxy, hydroxy, halogen, and trifhiaromethyl; nisOor 1; Ri is selected from the group consisting of
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R5; R2 is selected from the group consisting of
-R4, -X-R”,
-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, aiylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heteiocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of
-S(O)a-2-,
-S(O)2-N(Rs)-,
-C(Re)-,
-C(R6)-O-,
-O-C(R6K
-O-C(O)-O-,
-N(Rs)-Q-,
-C(R5)-N(R8K
-O-C(R6)N(R8K
-C(R5)-N(OR9K



R« is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyL, aryl, aryialkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryioxyaDcylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, aryialkylenyl, aryloxyaJkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloaDcoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, fceteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, ((Saftyianino)aliyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, axo:
Rs is selected from the group consisting of

Rg is selected from the group consisting of =0 and =S; R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and aryialkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene;



Certain embodiments of the present invention include non-interfering substituents. For example, in certain embodiments, R1 and R" are independently selected from the group consisting of hydrogen and non-interfering substitotents.
Herein, "non-interfering" means that the immunomodulator activity (for example, 6c abffiiy to induce the biosynthesis of one or more cytolrines or the ability to inhibit the biosyirfnesis of one or more cytokines) of the compound or salt is not destroyed. Hiastsive non-interfering R1 groups include those described herein for Ri. Illustrative 2Ctt4itferfering R" groups include those described herein for R2.
As used herein, the terms "alkyl", "aJkenyT, "aZkynyl" and the prefix "alk-" are indnave ofboth straight chain and branched chain groups and of cyclic groups, Le. cjicJoalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyi groups containing from 2 to 20 carbon atoms, hi some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.
Unless otherwise specified, "alkylene," "-alkylene-", "alkenylene", "-alkenylene-", "alfcynyiene1”, and "-alkynylene-" are the divalent forms of the "alkyl", "alkenyl", and "alkynyr groups defined above. The terms "aJkylenyl", "alkenylenyl", and "alkynylenyl" ME used, when "alkylene", "alkenylene", and "alkynylene", respectively, are substituted. For example, an arylalkylenyl group comprises an "alkylene" moiety to which an aryl soup is attached
Hie term "haloalkyl" is inclusive of alkyl groups that are substituted by one or mare halogen atoms, including perfluorinated groups. This is also true of other groups that kcmde the prefix "halo-". Examples of suitable haloalkyl groups are chloromemyl, tdfmoromeuiyL, and the like.
The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyL, naphmyL, biphenyL, fiuorenyl and indenyl.
The term "heteroatom" refers to the atoms O, S, or N.

The term "heteroaryT includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, fhienyl, pyridyl, quinolinyi, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyL, tetrazolyl, pyrazolyl, oxazolyi, tttiazolyl, benzofuranyl, benzotbaophenyl, carbazolyl, , pyrimidinyl, benzhmdazolyl, quinoxalinyi, benzothiazolyi, naphfhyridinyl, , isomiazolyl, purinyl, quinazolinyl, pyrazrayl, 1-oxidopyridyi, pyridazinyl, niaznrvi, tectazinyL, oxadiazolyl, thiadiazolyi, and so on.
Ik tsrm "b.etefocyclyln includes non-aromatic rings or ring systems mat contain at feast one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially cnsaairaEfid derivatives of the above mentioned heteroaryl groups. Exemplary heterocycKc include pyrrolidinyl, tetrahydrofuranyl, morphoKnyl, tbiomorphoKnyl, piperidinyl, miazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, , homopiperidinyl (azepanyl), homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridmyl, dihydroisoquinolin-(liO-yli octahydroisoquioohii-Clib-yl, dihydroquinolm-(2H)-yl, octahydroquinoKu-(2J0-yl, dihydro-lH-imidazolyl, and the like. When "heterocyclyl" contains a nitrogen atom, the point of attachment of the heterocyclyl group may be the nitrogen atom.
The terms "arylene", "heteroarylene", and "heterocyclylene" are the divalent forms of the "aryl", "heteroaryl", and "heterocyclyl" groups defined above. The terms "arylenyl,' " and "heterocyclylenyl" are used when "arylene", "heteroarylene", and ", respectively, are substituted. For example, an alkylarylenyl group an arylene moiety to which an alkyl group is attached.
When a group (or substitoent or variable) is present more than once in any Formula descdbed herein, each group (or substituent or variable) is independently selected, whether r not. For example, for the formula -N(Rg)-C(R6)-N(Rs)- each Rg group selected. In another example, when an R2 and an R3 group both contain m R4 group, each R” group is independently selected. In a further example, when more than one Y group is present (i.e., R3 and R3 both contain a Y group) and each Y group contains one or more Rs groups, then each Y group is independently selected, and each Rs group is independently selected.

The invention is inclusive of the compounds described herein in any of their phannaceuticaUy acceptable fonns, including isomers (e.g., diastereomers and enaniiomers), salts, solvates, polymorphs, and the like. la particular, if a compound is optically active, the invention specifically includes each of the compound's enantiamers as well as racemic mixtures of the enantiomers. It should be understood that the term "compound" includes any or all of such forms, whether explicitly stated or not (although at "sate" are explicitly stated).
For any of the compounds presented herein, each one of the following variables _ R', R", Ri, R2, R3, n, A, X, Z, and so on) in any of its embodiments can be "wife any one or more of the other variables in any of their embodiments as would be understood by one of skill in the art Each of the resulting combinations of variables is an embodiment of the present invention.
In some embodiments, compounds of Formula I-VHI induce the biosynthesis of one or more cytokines.
In some embodiments, compounds of Formula I-Vin inhibit the biosynthesis of one or more cytokines (e.g., TNF-a).
m certain embodiments, R is selected from the group consisting of alkyl, alkoxy, alogen, and trifluoromethyl.
IB same embodiments of Formula I, R' is selected from the group consisting of -X-Y-R4, -X-Y-X-Y-R4, and -X-R5.
ia some embodiments, R1 is selected from the group consisting of alkyl, , aryloxyalkylenyL, hydroxyalkyl, dihydroxyalkyl, alkylsulfonylalkylenyl, -X-, and heterocycrylalkylenyl, wherein the heteiocyclyl of the alkylenyl group is optionally substituted by one or more alkyl groups;
















Is. some embodiments of Formula IV, R3-2 is -Z-N(Rg)-S(O)2-R4- In certain samxknaBs of this formula for R3-2, R« is hydrogen, and R4 is selected from the grtrap ccaisisring of alkyi, alkenyl, aryl, aryialkylenyi, aryioxyalkyienyl, and heteroaryl, wherein the alkyi, alkenyl, aryl, aryialkylenyi, aryloxyalkylenyl, and heteroaryl groirps can be imsabsctnted or substituted by one or more substituents selected from the group consisting of alkyi, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of alkyi, oxo. In certain embodiments, R4 is selected fiom the group consisting of alkyi, aryl, alkenyl, heteroaryl, aryialkylenyi, and aQcylheteroarylenyl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy. In certain embodiments, Z is e&ylene orpropylene, Rs is hydrogen, and R4 is C1-3 alkyi.
M socffi embodiments of Formula IV, R3.2 is

In certain embodiments of this formula for R3.2, Rio is C4.6 alkylene, and R4 is selected fiom fte group consisting of alkyi, alkenyl, aryl, aryialkylenyi, aryioxyalkyienyl, and heteroaryl, wherein the alkyi, alkenyl, aryl, arylalkylenyl, aryioxyalkyienyl, and heteroaryl groups can be cnsubstituted or substituted by one or more substituents selected from the group consisting of alkyi, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, diaDcylamrno, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of





aryloxyalkylenyi, and heteroaryl groups can be unsubstituted or substituted by one or more substmisats selected from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, aryialkyleneoxy, nitro, dialkylainino, atyloxy, heterocyclyl, trifluoromethyl, txifluonneiihoxy, and in the case of alkyl, oxo. In certain embodiments W is a bond or -C(Oy. M certain embodiinents, R4 is selected from the group consisting of alkyl, aiyl, aryiaSrylcnyi, and heteroaryl; wherein aiyl can be optionally substituted with halogen, me&cxy, cyzaa, trifluoromethyl, and trifluoromethoxy. In certain embodiments, Z is a
bcBG-






substituted by one or more substituents selected from the group consisting of alkyl, halogen, and alkoxy.
3h certain embodiments, R4 is selected from the group consisting of hydrogen, alky!, alkenyl, aryl, arylalkylenyl, aJkylheteroarylenyl, heteroarylalkylenyl, arykiryalkylenyl, heteroaryl, and heterocyclyL
In certain embodiments, R4 is selected fiom the group consisting of hydrogen and mbodiments, R4 is alkyl. In certain embodiments, R4 is alkyl or aryL In embodiments, R4 is C1-3 alkyl. la certain embodiments, R4 is isopropyl.
£1 certain embodiments, R4 is alkyl, aryl, or heterocyclyL In certain embodiments, , wherein aryl can be optionally substituted with halogen, , cyano, trrflnoromethyl, and trifluoromemoxy.
m certain embodiments, R4 is selected fiom the group consisting of alkyl, aryl, aikenyi, heteroaryl, arylalkylenyl, and alkylheteroarylenyl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R4 is alkyl, aryl, or arylalkylenyl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R5 is selected from the group consisting of

Rio is Q-6 alkylene; and a and b are each independently 1 to 3.
In certain embodiments, R5 is selected from the group consisting of =0 and =S. In certain embodiments, Rg is ==0.
m certain embodiments, R7 is a C2-7 alkylene. In certain embodiments,



hi certain embodiments, X is selected from the group consisting of alkylene, arylene, heterocyclylene, heteroarylene, and alkylene terminated with heteroarylene. In certain embodiments, X is selected from the group consisting of alkylene, arylene, heteroarylene, and alkytene terminated with heteroarylene.

-QOK -C(O)-0-, -S(O)2-, -C(Re)-N(R«)-W-} and -S(O)2-N(R«)-; W is selected from the -C(O)-, and -S(O)2-; R« is selected from the group consisting from the group consisting of hydrogen, Cw alkyl, and and Rio is selected from the group consisting of Cb alkylene; X is consisting of alkylene, arylene, heterocyclylene, heteroarylene, and alkylene terminated with heteroarylene; and R4 is selected from the group consisting of bydrogen, alkyl, alkenyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, aryloxyaDEyleaiyl, heteroaryl, and heterocyclyl, wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, aflcoxy, and beterocyclyl, and wherein arylalkylenyl and heteroarylalkylenyl are unsubstituted or






-54-





WO 2005J032484 PCTJUS2004J032616
be carried out at ambient temperature, and the product can be isolated using conventional methods.
Alternatively, the redaction in step (6) can be earned out using nickel boride, prepared in situ from sodium borohydride and nickel(n) chloride. The redaction is carried oat by adding a solution of the benzvloxy-3-qumolin-4-anrine of Formula XX m a suitable solvent or solvent mixture such as dichloromethaneJmethanol to of excess sodium borohydride and catalytic nickel(U) chloride in methanol. The cat be caried out at ambient temperature. The product can be isolated using
e I, a benzyloxyquinoKne-3,4-diamine of Formula XXI is lieated with a carboxylic acid equivalent to provide a benzyloxy-lif-imidazof4,5- of Formula XXH. Suitable carboxylic acid equivalents include orthoesters of Formula R2C(O-alkyl)3, 1,1-dialkoxyalkyl alkanoates of Formula R2C(O-alkyl)2(O-C(O)-alkyl), and add chlorides of Formula R2C(O)C1. The selection of the carboxylic acid equivalent is determined by the desired substituent at R2. For example, triethyl orthoformate will provide a compound where R2 is hydrogen, and trimethyl orthovalerate will provide a compound where R2 is a butyl group. The reaction is conveniently carried out by adding the carboxylic acid equivalent to a ben2yloxyquinohne-3,4-diamine of Formula XXI m a suitable solvent such as toluene or xylenes. Optionally, catalytic pyridme can be added. The reaction is carried out at a temperature high enough drive off alcohol or water formed during the reaction. Conveniently, a Dean- be used to collect the volatiles.
(7) can be carried out in two steps when an acid chloride of is used as the carboxylic acid equivalent Part (i) of step (7) is carried out by adding the acid chloride to a solution of a benzyloxyquinohne-of Formula XXI in a suitable solvent such as dichloromethane or acetonitrile to afibrd an amide. Optionally, a tertiary amine such as triethylamine, pyridine, or 4- can be added. The reaction can be carried out at ambient
tanperature or at an elevated temperature. The amide product can be isolated and optionally purified using conventional techniques. Part (if) of step (7) involves heating the snide prepared in part (i) to provide a benzyloxy-lH-imidaz»[4,5b]qumoline of Formula





WO 2005J032484 PCT7US2004J032616
In step (11) of Reaction Scheme I, a li7-imidazo[4,5-c3qnmoline-5Jy-oxide of Formula X is amfnatpH to provide a liT-imid!azo[4,5-b]
quioolin-4-amine of Formula IL Step (11) can be carried out by the activation of an N-oxide of Formula X by conversion to an ester and then reacting the ester with an aminating agent Suitable activating agents include a2£)i- or aryisolfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl rbirrifig arjMotaenesulfonyl chloride. Suitable gminati-ng agents include ammonia, in the foot of acnnoamr-i hydroxide, for example, and ammonium salts such as ammonium bicarbonate, and ammonium phosphate. The reaction is









A are as defined above, using a coupling reagent The reaction is conveniently carried out by treating a solution of the lfr-hmdazo[4,5-clquniolnie of Formula IX, in which R3 is -Z-C(O)OH, with a secondary amine and l-[3-(dimethylarnino)propyl-3-«lhylcarbodiimide hydrochloride. The reaction can be carried out at ambient temperature in a suitable solvent such as pyridine, and the product can be treated according to steps (10) and (11) of Reaction Scheme I to provide a compound of Formula IL
In another example, an R3 group in a compound of Formula DC may contain a -S-functional group, which can be oxidized to -S(O)2- in step (10) of Reaction Scheme I using an excess of the oxidizing agent. Step (11) of Reaction Scheme I may then be carried out to provide a compound of Formula H, wherein R3 contains a -S(O)2- functional group.
For some embodiments, compounds of the invention can be prepared according to Reaction Scheme ID, where R, Ri, R2, Rs, and n are defined as above; Z is selected from the group consisting of alkylene, alkenylene, and alkynylene wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups; and R38 is -Z-N(Rg)-Q-R4 or -Z-R5, wherein R5 is

In step (1) of Reaction Scheme m, the amine of an amino alcohol of Formula XXVH is protected with a tert-butoxy carbonyl (Boc) group to provide a bydroxyalkylcarbamate of Formula XXVHL Numerous amino alcohols of Formula XXVII are commercially available; others can be prepared using known synthetic methods. The reaction is conveniently carried out by treating the amino alcohol of Formula XXVH with di'tert-butyl dicarbonate in the presence of a base such as aqueous sodram hydroxide- The reaction can be run at ambient temperature in a suitable solvent such as tetrahydrofiiraa, and the product can be isolated using conventional methods.
In step (2) of Reaction Scheme ID, a hydroxyalkylcarbamate of Formula XXVIII is converted to an iodoalkylcarbamate of Formula XXDC using conventional methods. The reaction is conveniently carried out by treating the hydroxyalkylcarbamate of Formula

XXVTfl with a solution of iodine, triphenylphosphine, and imidazole. The reaction can be run at ambient temperature in a suitable solvent such as dichloromethane, and the product can be isolated using conventional methods.
In step (3) of Reaction Scheme m, a lH-imidazo[4,5-c]qunK)KnDl of Formula XXIII is treated with an iodoalkylcarbamate of Formula XXTX to provide an ether-substituted Ii7-imidazo[4b-c]qmnoune of Fonnula XXX. The reaction can be carried out according to the Williamson conditions described in step (9) of Reaction Scheme I, and the product can be isolated using conventional methods.
In steps (4) and (5) of Reaction Scheme m, a liJ-imidazo[4,5-c]quinoline of Formula XXX is oxidized to a lfT-imidazx)[4,5-c3quinohn£-5JJ-oxide of Formula XXXL which is aminated to provide a li7-irmdazo[4,5-c]qumotta-4-amine of Formula XXXH, which is a subgenus Fonnula VTL Steps (4) and (5) of Reaction Scheme III can be carried out as described for steps (10) and (11), respectively, of Reaction Scheme L In step (5), the preferred conditions for arnination are the activation of an iV-oxide of Fonnula XXXI by conversion to an ester and then reacting the ester with an arninating agent. Step (5) is conveniently carried out by adding ammonium hydroxide to a solution of the N-oxide of Formula XXXI in a suitable solvent such as dichloromethane and then adding p-toluenesulfonyl chloride and stirring at ambient temperature. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (6) of Reaction Scheme H, the Boc protecting group of a LH-imidaz»[4,5-c]quinoHn-4-amine of Formula XXXH is removed to provide an amino-substituted \H-Trmda.7o[4,5b]qumolmbamine of Formula XXXm, which is a subgenus of Formula VUL The reaction is conveniently carried out by adding a solution of hydrochloric acid in ethanol to the Ii7-rmidazo[4,5b]qumolmbamine of Formula XXXH The reaction can be carried out at an elevated temperature, for example, the reflux temperature of the solvent. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
In step (7) of Reaction Scheme IE, an amino-substituted l#-imidazo[4,5-c]quinoUn-4-amine of Formula XXXIH is converted to a lJf-imidazo[4T5-c]quinolm-l-yl compound of Fonnula lid, a subgenus of Formulas I and n, using conventional methods. For example, an amino-substituted lir-imidazo[4,5b]qumolmbamine of Formula

XXXm can react with an acid chloride of Formula R4C(O)C1 to provide a compound of Formula Ed in which R3a is -Z-N(Rg)-C(O)-R4. I& addition, a liWmida2»[4,5-c]quinolin-4-amine of Formula XXXIII can react with sulfonyl chloride of Formula R+SCObCl or a sulfonic anhydride of Formula (RbObO to provide a compound of Formula Hd in which R3a is -Z-N(Rs)-S(O)2-R4. Numerous acid chlorides of Formula R4C(O)C1, sulfonyl chlorides of Formula RbCCXfeCl, and sulfonic anhydrides of Formula (R+SKOfe)b are commercially available; others can be readily prepared using known synthetic methods. Ike reaction is conveniently carried out by adding the acid chloride of Formula R«C(O)CL, sulfonyl chloride of Formula R4S(O)2C15 or sulfonic anhydride of Formula (RS(O)zhO to a solution of the amino-substituted liT-nnidazo[4,5b]quirK)lmbamine ofFomrala XXXIH in a suitable solvent such as chloroform, dichloromethane, or l-memyl-2-pyrrolidinone. Optionally a base such as triethylamine can be added. The reaction can be carried out at ambient temperature or a sub-ambient temperature such as 0 °C The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Amides of Formula Ed can alternatively be prepared by treating an amino-substituted lH-miidazo[4,5-c]qumo]iii-4-amiiie of Formula XXXHI with a carboxylic acid of Formula R4C(O)OH in the presence of a coupling reagent. The reaction is conveniently carried out by adding a solution of a carboxylic acid of Formula R4C(O)OH and a base such as triethylamine to a cooled solution of the amino-substituted l#-imidazo[4,5-c]quinoHn-4-amine of Formula XXXIII and benzotriazol-1-
yioxytris(dimemylamino)phosphonium hexafluoropbosphate. The reaction can be carried out in a suitable solvent such as dichloromethane at a sub-ambient temperature such, as 0 °C. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

can be prepared by treating an amino-substituted lif-imidazo[4,5-c]quinoIm-4-amine of Formula XXXHI, wherein Rg is hydrogen, with a chloroalkanesulfonyl chloride of Formula C1-R7S(O)2C1 or a chloroalkanoyl chloride of Formula C1-RTC(O)CL The

reaction is conveniently carried out by adding the chloroaDcanesalfonyl chloride or chloroalkanoyl chloride to a solution of the amino-substituted LHLimidazo[4I5-c}quhiolin-4-amine of Formula XXXUI in a suitable solvent such as chloroform at ambient temperature. The isolable intermediate cMoroaDcanesulfonamide or chloroalkanamide can then be treated with a base such as ljS-diazabicyclofSAOJundec-T-eiie in a suitable solvent such as DMF to effect the cyclization. The product or pharmaceutically alt thereof can be isolated using conventional methods.
Ureas of Formula Ed, where R3a is -Z-N(R«)-Q-R4, Q is -C(R€)-)J(RS)-W-J Re is =O,R8 is as defined above, and W is a bond, can be prepared by reacting an amino-substituted l#-inrio!azo[4bb]qumoIm-4-amrne of Formula XXXni with isocyanates of Formula R+NKX). Numerous isocyanates of Formula R4N=C=0 are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding the isocyanate of Formula R4NNX) to a solution of the amino-substituted liY-inudazo[4,5-c]quinoun-4-amine of Formula XXXTTT in a suitable solvent such as dichloromethane or chloroform. Optionally a base such as triethylamine can be added. The reaction can be carried out at ambient temperature or a sub-ambient temperature such as 0 °C. Alternatively, a compound of Formula XXXUI can be treated with an isocyanate of Formula R4(C0)N=C=0, a thioisocyanate of Formula R4N=C=S, a sulfonyl isocyanate of Formula R4S(O)2N=(;=O, or a carbamoyl chloride of Formula 1b-CR«)-C(C))C1 or

Q is -C(TR$)-N(R8)-W-9 where R& Rg, and W are defined as above. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Sulfamides of Formula Ed, where R3a is -Z-N(Rg)-Q-R4, Q is
and Z, R4, and Rs are as defined above, can be prepared by reacting a compound of Formula XXXni with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting

the sulfemoyl chloride with an amine of formula HN(Rg)K4. Alternatively, suliamides of Formula lid can be prepared by reacting a compound of Formula XXXIII with a sulfemoyl chloride of formula R4CR8)N-S(O)2C1. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Many amines of Formula HN(Rg)R4 and some sulfamoyl chlorides of formula R4(Rg)N-S(O)2Cl are commercially available; others can be prepared using known synthetic methods. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Compounds of Formula lid, wherein R3a is -Z-N(Rg)-R4, and Z, R4, and Rg are as defined above, can be prepared by reductive alkylation of the amino-substitnted LS-inudazo[4,5-c]quinoUn-4-amine of Formula XXXM, wherein Rg is hydrogen. The alkylation is conveniently carried out in two parts by (i) adding an aldehyde or ketone to a solution of a amino-substituted lJ?-kmdazo[4,5-c]quinomi-4-amine of Formula XXXHI or a salt thereof in a suitable solvent such as DMF in the presence of a base such as JVbiV-diisopropylethylamine. In part (ii) the reduction is carried out by adding a suitable reducing agent such as the borane-pyridine complex. Both part (i) and part (ii) can be carried out at ambient temperature, and the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods. In compounds of Formula XXXm, wherein Rg is hydrogen, it is convenient to carry out the reductive alkylation followed by reaction with an acid chloride, sulfonyl chloride, sulfonic anhydride, isocyanate, or carbamoyl chloride as described above to provide a compound of Formula lid, wherein R3S is -Z-N(Rs)Q-R4, wherein 2, R4, Rs, and Q are as defined above.




above. Steps (1) through (7) of Reaction Scheme IV can be ran as described in steps (1) through (7) of Reaction Scheme HI to provide compounds of Formula lie, a subgenos of Formulas I and IL
Alternatively, a compound of Formula XXXV can react with a lH-imidazo[4b-c]quinolinol of Formula XXHr under the Mitsunobu reaction conditions described in step (9) of Reaction Scheme I. For example, combining a lH-imidazo[4f5-c]quinonnol of Formula XXHI, triphenylphosphine, and terf-butyl 4-hydroxy-l-piperdinecarboxylate in THF at 5 °C or ambient temperature and slowly adding diisopropyl azodicarboxylate provides a compound of Formula XXXVII wherein Za is a bond and Rio is pentylene.
The oxidation in step (4) of Reaction Scheme IV can be carried out according to the reaction conditions described in step (10) of Reaction Scheme I or by heating a solution of a compound of Formula XXXVH in a suitable solvent such as ethyl acetate with peracetic acid at a temperature such as 50 °C and then adding sodium metabisulfate. The product can be isolated using conventional methods. Steps (5) through (7) of Reaction Scheme IV can then be used to provide a compound of Formula He.



compound of Formula XLI, a subgenus of Formulas I and IL The product or pharmaceuticalry acceptable salt thereof can be isolated using conventional methods.
In step (2) of Reaction Scheme V, a chloro-substituted compound of Formula XLI is treated with a cyclic secondary amine to provide a compound of Formula Uf, a subgenus of Formulas I and IL Many cyclic secondary amines are commercially available, such as msubstituted or substituted aziridines, pyrrolidines, piperidmes, morpholines, miazoh'dines, thiomorpholines, piperazines, azepanes, diazepanes, dihydroisoquinolmes, octahydroisoquinolincs, d&ydroquinolines, octahydroqutaolines, and dihydroimidazoles; others can be prepared using conventional methods. The reaction is conveniently carried out by adding a cyclic secondary amine to a compound of Formula XH in a suitable solvent such as DMF. The reaction is conveniently carried out in the presence of a base such as potassium carbonate at an elevated temperature such as 65 °C. The product of Formula Ef or a phamaceutically acceptable salt thereof can be isolated by conventional methods.
Compounds of Formula Ilf are also prepared from liJ-irmdazo[4,5-c]quinolinols of Formula XXffi, shown in Reaction Scheme I. A l#-irmdazo[4,5-c]qurnolinol of Formula XXHI is first treated with a dihalide of Formula I-Z-Cl or Br-Z-Cl according to step (1) of Reaction Scheme V. The product is then oxidized and aminated according to the methods described in steps (10) and (11) of Reaction Scheme I to provide a compound of Formula XLI, which is then treated with a cyclic secondary amine as described in step (2) of Reaction Scheme V to provide a compound of Formula Uf. The product or phamaceutically acceptable salt thereof can be isolated by conventional memods.


Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound or salt of the invention as described above in combination with pharmaceutically acceptable carrier.
The terms "a therapeutically effective amounf and "effective amount" mean an amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, immunomodulation, antitumox activity, andJor antiviral activity. Although the exact amount of active compound or salt used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound or salt, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 nanograms per kilogram (ngJkg) to about 50 milligrams per kilogram (mgJkg), preferably about 10 micrograms per kilogram (ngJkg) to about 5 mgJkg, of the compound or salt to the subject. A variety of dosage forms may be used, such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds or salts of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
Compounds or salts of the invention have been shown to induce or inhibit the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds or salts are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines whose production maybe induced by the administration of compounds or salts of the invention generally include interferon-a (IFN-oO andJor tumor necrosis factor-a (TNF-a) as well as certain interleukins QL). Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN-a, TNF-a, ILrl, IL-6, IL-10

and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making fee compounds or salts useful in the treatment of viial diseases and neoplastic diseases. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of fee invention to the animal. The animal to which fee compound or salt or composition is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of fee compound or salt may provide therapeutic treatment Alternatively, fee compound or salt may be administered to fee animal prior to fee animal acquiring fee disease so that administration of fee compound or salt may provide a prophylactic treatment
In addition to fee ability to induce fee production of cytokines, compounds or salts of fee invention can affect other aspects of fee innate immune response. For example, natural killer cell activity may be stimulated, an effect feat may be due to cytokine induction. The compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and fee production of additional cytokines. Further, fee compounds or salts may cause proliferation and differentiation of B-lymphocytes.
Compounds or salts of fee invention can also have an effect on fee acquired immune response. For example, fee production of fee T helper type 1 (THI) cytokine IFN-y may be induced indirectly and fee production of fee T helper type 2 (TH2) cytokines IL-4, IL-5, and IL-13 may be inhibited upon administration of fee compounds or salts.
Other cytokines whose production may be inhibited by fee administration of compounds or salts of fee invention include tumor necrosis factor-a (TNF-(x). Among other effects, inhibition of TNF-a production can provide prophylaxis or therapeutic treatment of TNF-a mediated diseases in animals, making fee compounds or salt useful in fee treatment of, for example, autoimmune diseases. Accordingly, fee invention provides a method of inhibiting TNF-a biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of fee invention to fee animal. The animal to which fee compound or salt or composition is administered for inhibition of TNF-a biosynthesis may have a disease as described infra, for example an autoimmune disease, and administration of fee compound or salt may provide therapeutic treatment

Alternatively, the compound or salt may be administered to the animal prior to the animal acquiring the disease so that administration of the compound or salt may provide a prophylactic treatment
Whether for prophylaxis or therapeutic treatment of a disease, and whether for effecting innate or acquired immunity, the compound or salt or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant When administered with other components, the compound or salt and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalentry linked or (b) non-covalentry associated, e.g., in a colloidal suspension.
Conditions for which IRMs identified herein may be used as treatments include, but are not limited to:
(a) viral diseases such as, for example, diseases resulting from infection by an
adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an
orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
(e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus
(e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus
(RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses, such as those
that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B
virus), a fiavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
kntivirus such as HIV);
(b) bacterial diseases such as, for example, diseases resulting from infection by
bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus,
Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,
Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Gostridmm, Bacillus,
Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Provideneia,
Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) other infectious diseases, such chlamydia, fungal diseases including but not
limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic
diseases including but not limited to malaria, pneumocystis camii pneumonia,
teishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;

(d) neoplastic diseases, such as iutraepithelial neoplasias, cervical dysplasia, actinic
keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's
sarcoma, melanoma, leukemias inchiding but not limited to myelogeous leukemia, cnronic
lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-cell
tymphoma, B-cell lymphoma, and hahy ceD leukemia, and other cancers;
(e) Tn2-mediated, atopic diseases, such as atopic dermatitis or eczema,
eosinophilia, asthma, allergy, allergic rhinitis., and Ommen's syndrome;
(f) certain autoimmune diseases such, as systemic lupus erythemaiosus, essential
mrombocythaemia, multiple sclerosis, discoid lupus, alopecia areata; and
(g) diseases associated with wound repair such as, for example, inhibition of keloid
formation and other types of scarring (e.g., enhancing wound healing, including chronic
wounds).
Additionally, an IRM compound or salt of the present invention maybe useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral andJor cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines; recombinant proteins; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemopbilus influenza b, tuberculosis, meningococcal and pneumococcal vaccines, adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.
Certain IRM compounds or salts of the present invention may be particularly helpful in individuals having compromised immune function. For example, certain compounds or salts may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HTV patients.

Thus, one or more of the above diseases or types of diseases, for example, a viral disease or a neoplastic disease may be treated in an. animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of the invention to the animal
An amount of a compound or salt effective to induce or inhibit cytokme biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or mots cytokmes such as, for example, IFN-a, TNF-ot, IL-1, IL-6, IL-10 and IL-12 mat is increased (induced) or decreased (inhibited) over a background level of such cytokmes. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ngJkg to about 50 mgJkg, preferably about 10 ugJkg to about 5 mgJkg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ngJkg to about 50 mgJkg, preferably about 10 ngJkg to about 5 mgJkg. An amount of a compound or salt effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ngJkg to about 50 mgJkg, preferably about 10 ugJkg to about 5 mgJkg.
Objects and advantages of mis invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.


PartA
A mixture of triethyl orthoformate (92 mL, 0.55 mol) and 2,2-dimethyl-[l,3]-dk)xane-4,6-dione (75.3 g, 0.522 mol) (Meldrum's acid) was heated at 55 °C for 90 minutes and then cooled to 45 °C. A solution of 3-benzyloxyaniline (100.2 g, 0.5029 mol) in methanol (200 mL) was slowly added to the reaction over a period 45 minutes while maintaining the reaction temperature below 50 °C. The reaction was then heated at 45 °C for one hour, allowed to cool to room temperature, and stirred overnight. The reaction mixture was cooled to 1 °C, and the product was isolated by filtration and washed with cold ethanol (~400 mL) until the filtrate was colorless. 5-{f(3-Benzyloxy)phenyhmmo]memyl}-2b-dimethyl-[l,3]-dioxane-456-dione (170.65 g) was isolated as a tan, powdery soh'd-
bHNMRbOOMHbDMSCWtf) 5 11.21 (d, J= 14.2 Hz, 1H), 8.61 (d,J= 14.2 Hz, 1H), 7.49-730 (m, 7H), 7.12 (dd, J= 8.1,1.96 Hz, 1H), 6.91 (dd, J= 8.4,2.1 Hz, 1H), 5.16 (s, 2HX 1.68 (s, 6H). PartB
A mixture of 5-{[(34)eaizyloxy)phenylirmbo]memyl}-2,2-dimemyl-[133-”oxane-4,6-dione (170.65 g, 0.483 mol) and DOWTHERM A heat transfer fluid (800 mL) was heated to 100 °C and then slowly added to a flask containing DOWTHERM A heat transfer fluid (1.3 L, heated at 210 °C) over a period of 40 minutes. During the addition, the reaction temperature was not allowed to fell below 207 °C. Following the addition, Ihe reaction was stirred at 210 °C for one hour, and then allowed to cool to ambient temperature. A precipitate formed, which was isolated by filtration, washed wife diethyl

emer (1.7 L) and acetone (0.5 L), and dried in an oven to provide 76.5 g of 7-
benzyloxyquinolin-4-ol as a tan powder.
“H NMR (300 MHz, VMSO-d6) 8 11.53 (s, 1H), 7.99 (dd, J= 7.4,2.4 Hz, 1H), 7.79 (d, J
= 7.4 Hz, 1H), 7.50-7.32 (m, 5H), 7.00 (s, 1H), 6.98 (dd, J= 7.4,2.5 Hz, 1H), 5.93 (d, J=
15 Hz, 1H), 5.20 (s, 2H).
PartC
A mixture of 7-benzyloxyqnmolin-4-ol (71.47 g, 0.2844 mol) and propionic acid (700 mL) was heated to 125 °C with vigorous stirring. Nitric acid (23.11 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature between 121 °C and 125 °C. After the addition, the reaction was stirred at 125 CC Bar 1 hour then allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed with water, and dried in an oven for 1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinomi-4-ol as a grayish powder.
!H NMR (300 MHz, DMSO-d”) 8 12.77 (s, IB), 9.12 (s, IE), 8.17 (dd, J= 6.3,3.3 Hz, IB), 7.51-7.33 (m, 5H), 7.21-7.17 (m, 2H), 5.25 (s, 2H). PartD
i\yV-Dimethylformamide (100 mL) (DMF) was cooled to 0 °C, and phosphorous oxychloride (27.5 mL, 0.295 mol) was added dropwise. The resulting solution was stirred for 25 minutes and then added dropwise to a mixture of 7-benzyloxy-3-m1rc)quinolin-4-ol (72.87 g, 0.2459 mol) in DMF (400 mL). Following the addition, the reaction was heated at 100 °C for 5 minutes, cooled to ambient temperature, and poured into ice water with stirring. A tan precipitate formed, which was isolated by filtration and dissolved in dlchloromethane. The resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 72.9 g of 7-benzyloxy-4-chloro-3-nrtroqumoline as a light brown solid.
lU NMR (300 MHz, DMSO-d6) 5 9.34 (s, 1H), 8.36 (d, J= 8.7 Hz, 1H), 7.71 (d, J= 2.4 Hz, 1H), 7.66 (dd, J= 9.3,2.4 Hz, 1H), 7.56-7.51 (m, 2H), 7.46-7.34 (m, 3H), 5.40 (s, 2H). PartE
Triethylamine (38.6 mL, 0277 mol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoune (72.9 g, 0.232 mol) in dichloromethane (1200 mL). Isobutylamine

(25.24 mL, 0.2540 mol) was then added, and the reaction mixture was stirred fear 18 honrs at ambient temperature. The reaction mixture was diluted with dichloromethane, washed sequentially with water (2 x) and brine, dried over anhydrous sodium sulfete, filtered, and concentrated under reduced pressure to yield 67.4 g of (7-benzyloxy-3-nitroquinolm-4-y1X2-methylpropyl)amine as a brown solid.
3H NMR (300 MHz, DMSO-d6) 8 9.29 (t, J= 4.8 Hz, 1H), 9.07 (s, 1H), 8.42 (d, J= 9.4 Hz, 1H), 7.53-7.49 (m, 2H), 7.45-7.32 (m, 4H), 7.27 (dd, J= 9.3,2.6 Hz, 1H), 532 (s, ZH), 3.60 (t, J = 6.0 Hz, 2H), 2.00 (septet, J= 6.7 Hz, 1H), 0.96 (d, J= 6.3 Hz, 6H). PartF
Sodium borohydride (29.0 g, 0.767 mol) was added in small portions to a solution of mckel(13)chloride (22.8 g, 0.096 mol) in methanol (1.25 L). A solution of (7-benzyloxy-3-nitroqumohb-4-yl)(2-me&ylpropyl)amine (67.4 g, 0.192 mol) in methanol (300 mL) and dichloromethane (300 mL) was added to the resulting mixture. A precipitate was present and was dissolved by the addition of dichloromethane (500 mL). Additional sodium borohydride (~10 g) was added in small portions until the (7-benzyloxy-3-mtroquinolin-4-yl)(2-methylpropyl)amine was consumed. The reaction mixture was filtered through a layer ofCELlTE filter aid, and the filter cake was washed with 50:50 dichloromethane:methanol. The filtrate was concentrated under reduced pressure, and the black, oily residue was treated with water and dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was treated with activated charcoal, filtered, and concentrated under reduced pressure to yield 55.4 g of 7-benzyloxy-7Jl-(2-meihyhircpyl)qumohbe-3,4bamiiae a brown semi-soEd. TH NMR (300 MHz, DMSO-Je) 5 8.26 (s, 1H), 7.94 (d, J= 9.4 Hz, 1H), 7.51-7.48 (m, 2H% 7.43-7.30 (m, 3H), 7.21 (d, J= 32 Hz, 1H), 7.10 (dd, J= 9.5,2.4 Hz, 1H), 5.18 (s, 2H), 4.92 (t, J= 7.0 Hz, 1H), 4.70 (s, 2H), 3.04 (t, J= 6.9 Hz, 2H), 1.75 (septet, J= 6.8 Hz, 1H), 0.89 (d, J= 6.3 Hz, 6H). PartG
Trimethyl orthobutyrate (29.75 mL, 0.1859 mol) was added in three portions to a solution of 7-benzyloxy-iJ-(2-me1hylpropyl)qumohbe-3,4Hiiamme (54.6 g, 0.170 mol) in toluene (795 mL). Pyridine hydrochloride (1.96 g) was then added, and the reaction was heated at 105 °C and stirred for four hours. Additional trimethyl orthobutyrate (7 mL, 40

mraol) was then added, and the reaction was stirred for three hours. The reaction was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The oily residue was treated with chloroform, which was removed under reduced pressure to remove residual toluene, and then again diluted with chloroform (1.2 L). The resulting solution was washed sequentially with 5% aqueous sodium bicarbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to yield 603 g of 7-benzyloxy-1b2-me1hyhTropyI)2-propyl-lbb cjquinoline as an oily brown solid, containing a small amount of toluene (0.93 equivalents).
7-H NMR (300 MHz, DMS0-&) 5 9.15 (s, 1H), 8.25 (d, J= 8.8 Hz, 1H), 7.68 (d, J- 2.6 Hz, 1H), 7.53-7.12 (m, 6H), 5.31 (s, 2H), 4.42 (d, J= 7.5 Hz, 2H), 2.94 (t, J= 7.5 Hz, 2H), 2.25-2.09 (m, 1H), 1.90 (sextet, J= 1A Hz, 2H), 1.04 (t, J= 7.5 Hz, 3H), 0.89 (d, J= 6.3 Hz,6H). PartH
3-Chloroperoxybenzoic acid (60% pure, 22.9 g, 79.6 mmol) (mCPBA) was added in portions to a solution of 7-benzyloxy-l-(2-methylpropyl)-2-propyl-liy-imidazo[4,5-c]quinoline (27.0 g, 72.3 mmol) in dichloromethane (1 L), and the reaction was stirred for 30 minutes. Water (1 L) was added, and the resulting mixture was stirred for 30 minutes. The organic layer was washed with 1% aqueous sodium carbonate (2 x 200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Parti
The material from Part H was dissolved in dichloromethane (800 mL), and concentrated ammonium hydroxide (300 mL) was added. p-Toluenesulfonyl chloride (16.6 g, 86.8 mmol) was added in small portions to the resulting mixture, and the reaction was stirred for 30 minutes and then dilated with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile to provide 21.4 g of7-ben2yloxy-l-(2-mtJlliylpropyi)-2bHX)pyl-lH-imidazo[4,5-c]quinoHn-4-amme as feathery, off-white crystals, mp 206.2-208.2 °C.
!H NMR (300 MHz, TMSQ-d6) 5 7.87 (d, J= 9.1 Hz, 1H), 7.52-7.28 (m, 5H), 7.12 (d, J = 2.4 Hz, 1H), 6.97 (dd, 7= 8.9,2.8 Hz, 1H), 6.38 (s, 2H), 5.20 (s, 2H), 4.28 (d, J= 6.8

Hz, 2H), 2.86 (t, J= 7.5 Hz, 2H), 2.21-2.08 (m, 1H), 1.83 (sextet, J= 13 Hz, 2H), 1.01 (t,
J= 7.5 Hz, 3H), 0.91 (4 J= 7.0 Hz, 6H).
PartJ
7-Benzyloxy-1b2-memylpropyI)-2-propyl-lif-iinibb
(21.4 g, 55.1 mmol) was dissolved in refluxing ethanol (2 L), and 10% palladimn on carbon (5.4 g, 5.1 mmol) was added to the warm solution. The reaction was placed under srydrogen pressure (50 psi, 3.4 x 105 Pa) overnight. The catalyst was removed by nitration and washed with hot efhanol (500 mL) and memanol (400 mL). The filtrate was concentrated under reduced pressure to yield 14.5 g of an off-white solid. A small portion of fee solid was recrystallized from 2-propanol to provide 4-amino-1 -(2-metlxy]piopyT)-2-propyl-lir-imidazo[4,5-c]quinolin-7-ol as white crystals, mp ) 265 °C. “H NMR (300 MHz, DMSO-b) 5 9.44 (br s, 1H), 7.78 (d, J= 8.9 Hz, 1H), 6.95 (d, J= 2.5 Hz, 1H), 6.79 (dd, J= 8.9, 2.6 Hz, 1H), 6.29 (br s, 2H), 4.26 (d, J= 7.4 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.14 (septet, J= 6.7 Hz, 1H), 1.88-1.77 (m3 2H), 1.01 (t, J= 13 Hz, 3H), 0.91(d,J=6.6Hz,6H);
13C NMR (75 MHz, DMSO-4J) 8 156.1,152.3,151.9,146.9,133.1,126.5,121.2,111.9, 109.9,108.4, 51.3, 28.8,28.7,21.0,19.3,13.9; MS (APCI) mJz 299 (M+H)+;
AnaL Calcd. for C17H22N4O: %C, 68.43; %H, 7.43; %N, 18.78. Found: %C, 68.38; %H, 7b7; %N, 18.74. PartK
A warm solution of 4-ammcblb2-memyhiropyl)-2-propvl-lfl'-imidazo[4!b-c3qnmoIm-7-ol (266 mg, 0.891 mmol) in DMF (20 mL) was cooled to approximately 0 °C. Solid cesium carbonate (580 mg, 1.78 mmol) was added. After ten minutes, 2-bromoacetophenone (186 mg, 0.935 mmol) was added in one portion, and the reaction was allowed to warm to room temperature and was stirred overnight. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material Additional 2-bromoacetophenone was added, and the reaction was stirred for six hours. The reaction was poured into deionized water (200-300 mL) and stirred for 15 hoars. The resulting precipitate was isolated by filtration and purified by column chromatography on silica gel (eluting with chlorofonnnnethanol ranging in ratios from 99.5:0.5 to 98:2). The

product was then recrystallized from acetonitrile, isolated by filtration, and dried overnight under high vacuum to provide 222 mg of 2b4-ainiao-l-(2-methylpropyl)-2-propyl-lH-imidazo[4}5-c]qbiinolin-7-yloxy)-l-phenyiethanone as white crystals, rap 178.0-180.0 °C. “H NMR (300 MHz, DMSO-b) 5 8.04-8.00 (m, 2H), 7.81 (d, J= 9.1 Hz, IE), 7.65-7.59 (m, 1H), 7.54-7.48 (m, 2H), 7.23 (d, J= 2.7 Hz, 1H), 7.12 (dd, J= 9.0,2.7 Hz, 1H), 5.42 (s, 2H), 5.36 (br s, 2H), 4.20 (d, J= 7.5 Hz, 2H), 2.86 (t, J= 7.9 Hz, 2H), 234 (septet, J= 6.8 Hz, 1H), 1.97-1.87 (m, 2H), 1.08 (t, J= 7.4 Hz, 3H), 1.00 (d, J= 6.7 Hz, 6H); -C NMR (75 MHz, DMSO-d6) 5 193.7,156.9,153.1,151.4,146.3,134.5,133.8,133.7, 128.8,127.9,125.7,121.0,113.4,110.4,108.5,70.4,52.4,29.6,29.0,21.4,19.7,14.0; MS (APCT) mJz 417 (M+H)+;
AnaL Calcd. for CbHagNb: %C, 72.09; %H, 6.78; %N, 13.45. Found: %C, 71.89; %H, 638; %N, 13.24.

PartA
The general procedure described in Part A of Example 1 was used with the following modification. A solution of 4-benzyloxyaniliae (100 g, 0.5 mol) in metnanol (150 mL) was used in lieu of a solution of 3-benzyloxyaniline. The addition of this solution was carried out over a period of one hour while maintaining the temperature between 57-60 °C. The reaction product, 5-{[(4-ben2yloxy)phenyhinino)3nieftiyI}-2b dnnemyl-[l,3]-dioxane-4,6-dione (136.7 g) was isolated as a yellow powder. 'H NMR (300 MHz, DMSO-&) 8 11.23 (d, J= 15.2 Hz, 1H), 8.46 (d, J= 143 Hz, 1H), 7J3-730 (m, 7H), 7.10-7.04 (m, 2H), 5.13 (s, 2H), 1.66 (s, 6H). PartB

A solution of 5-{[(4-benzyloxy)phenyliiinno)]memylb
4,6-dione (127.2 g, 0.360 mol) and DOWTHERM A heat transfer fluid (500 mL) was heated to 100 °C and Ihen slowly added to a flask containing DOWTHERM A heat transfer fluid (1 L, heated at 250 °Q over a period of 90 minutes. During the addition, the reaction temperature was not allowed to mil below 245 °C. Following the addition, the reaction was stirred at 250 °C for 30 minutes, and then allowed to cool to ambient temperature. A precipitate formed, which was isolated by filtration, washed with diemyl rfher (1 L) and acetone (250 mL), and dried for two hours under vacuum in to provide 65.7 g of 6-benzyloxyqumolin-4-ol as a yellow powder.
lB. NMR (300 MHz, DMSO-4J) 5 11.72 (s, 1H), 7.84 (d, J= 7.3 Hz, 1H), 7.59 (m, 8H), 5.98 (d, J= 7.0 Hz, 1H), 5.18 (s, 2H). PartC
The general method described in Part C of Example 1 was followed using 6-benzyloxyquinohn-4-ol (65.7 g, 0.261 mol) in lieu of 7-benzyloxyquinolin-4-ol. The reaction precipitate was isolated by filtration; washed with propionic acid (600 mL), isopropanol'(500 mL) and diethyl ether (500 mL); and dried for two days under vacuum to provide 46.01 g of 6-benzyloxy-3-nitroquinohn-4-ol as a tan powder, containing 5% 6-benzyloxyquinohn-4-ol.
!HNMR(300 MHz, DMSO-&) 5 12.98 (s, 1H), 9.12 (s, 1H), 7.75 (d, J= 3.3 Hz, 1H), 7.70 (d, J- 8.6 Hz, 1H), 7.53-7.30 (m, 6H), 525 (s, 2H). PartD
The general method described in Part D of Example 1 was used to convert 6-benzyk)xy-3-nitroquinohn-4-ol (46.93 g, 158.4 mmol) to 6-benzyloxy-4-chloro-3-nSroquinoline, which was isolated as a tan solid containing some DMF. lH NMR (500 MHz, DMSO-rf«j) 5 9.23 (s, 1H), 8.16 (d, J= 9.1 Hz, 1H), 7.80 (d4 J= 9.1, 2.8 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.57-7.53 (m, 2H), 7.45-7.34 (m, 3H), 539 (s, 2H). PartE
Triethylamine (44 mL, 0.32 mol) was added to a solution of the material from Part D in dichloromethane (790 mL). n-Propylamine (19.48 mL, 237.0 mmol) was then added over a period of 25 minutes, and the reaction was stirred for 18 hours. The reaction mixture was diluted with dichloromethane (500 mL), washed sequentially with water and

brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The crude product was recrystallized from 2-propanol to provide 39.1 g of (6-benzyloxv~3-
nitroqumolin-4-yl)propylaiiihie as fine, yellowish-brown needles.
JH NMR (300 MHz, DMS0-&) 6 8.89 (s, 1H), 8.57 (s, 1H), 7.93 (d, J= 3.1 Hz, VB),
7.85 (4 J= 9.5 Hz, 1H), 7.58-7.33 (m, 6H), 530 (s, 2H), 3.41-3.35 (m, 2H), 1.67 (sextet, J
= 73Hz, 2H), 0.87 (t, J= 7.5Hz, 3H).
PartF
(6-Benzvloxy-3-nitroquinolinbyl)propvlaniine (18.00 g, 53.35 mmol), 5% platinum on carbon (5.3 g), toluene (200 mL) and 2-propanol (20 mL) were added to a Parr vessel. The vessel was purged with nitrogen and then placed under hydrogen pressure (30 psi, 2.1 x 105 Pa) and shaken for 20 minutes. The reaction mixture was filtered through a layer of CELTTE filter aid, and the filter cake was washed with toluene (1 L) and 2-propanol (I L). The orange filtrate was concentrated under reduced pressure. Heptane was added to the residue and subsequently removed under reduced pressure. The residue was dried under vacuum (0.1 torr, 13.3 Pa) for 30 minutes to provide 17.0 g of 6-benzyloxy-ib-propylqumoHne-Sbdiamine as a viscous, brown oil containing some toluene.
JH NMR (300 MHz, DMSO-bj) 6 8.23 (s, 1H), 7.64 (d, J = 9.4 Hz, 1H), 7.52 (d, J= 1.9 Hz, 1H), 7.43-7.11 (m, 5H)} 7.05 (dd, J= 9.4,2.5 Hz, 1H), 5.22 (s, 2H), 4.99 (s, 2H), 4.62 (t, J= 6.7 Hz, 1H), 2.99 (q, J= 7.1 Hz, 2H), 1.47 (sextet, J= 7.3 Hz, 2H), 0.85 (t, J= 7.2 Hz,3H). PartG
A solution of ethoxyacetyl chloride (6.53 g, 53.3 mmol) in dichloromemane (65 mL) was added dropwise to a solution of the material from Part F in dichloromethane (200 aaLX and me reaction was stirred for 16 hours. A precipitate formed and was isolated by filtration and washed with cold hexanes. The solid was dried for 30 minutes under reduced pressure to provide 16.1 g ofiV-(6berizyloxy-4-propylainmcKniinohn-3-yI)-2-ethoxyacetamide hydrochloride as a tan powder.
]H NMR (300 MHz, DMSO-4J) 6 14.14 (s, 1H), 9.74 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 8.06 (d, J= 2.4 Hz, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.68 (dd, J= 9.4,2.6 Hz, 1H), 7.56-7.35

(m, 5H), 5.30 (s, 2H), 4.11 (s, 2H), 3.64 (q} J= 7.1 Hz, 2H), 3.68-3.60 (m, 2H), 1.61 (sextet, J= 7.4 Hz, 2H), 1.23 (t, J= 7.2 Hz, 3H), 0.89 (t, J= 7.2 Hz, 3H). PartH
Triefhylatnine (22.16 mT.3159.0 rranol) was added to a solution of iV-(6-benz)boxy-4-pffopyiaminoqiiinolm-3-yl)-2-tamideltydiocliIoride (16.1 g) in ethanol (265 mL), and Hie reaction mixture was heated at reflux and stirred for 3 hours. The reaction was allowed to cool to ambient temperature. The ethanol was removed under reduced pressure and me residue dissolved in chloroform. The resulting solution was washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was dissolved in acetomtrile and concentrated under reduced pressure to yield 14.32 g of 8-benzyloxy-2-ethoxymemyl-l-piopyl-liy-imidazo[4,5-c]quinonine as a brown, crystalline solid. JH NMR (300 MHz, DMSO-4?) 8 9.03 (s, 1H), 8.09 (d, J= 8.7 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.54-7.33 (m, 6H), 5.38 (s, 2H), 4.83 (s, 2H), 4.59 (at, J= 7.8 Hz, 2H), 3.57 (q, J = 7.0 Hz, 2H), 1.84 (sextet, J= 7.5 Hz, 2H), 1.16 (t, J= 7.3 Hz, 3H), 0.96 (t, J= 7.1 Hz, 3H). Parti
8-Ben2yloxy-2-emoxymemyl-l-propyl-lb-irMdbzo[4J5-c]quinonine (15.00 g, 39.84 mmol) and ethanol (300 mL) were added to a Parr vessel. A mixture of palladium nyriroxide (2.0 g, 20% on carbon) in ethanol (100 mL) was then added. The vessel was parsed with nitrogen, placed under hydrogen pressure (25 psi, 1.7 x 105), and shaken for three hours. The vessel was then refilled with hydrogen (25 psi, 1.7 x 10s) and shaken for 18 hours. The reaction mixture was filtered through a layer of CELTTE filter aid, and the fTtor cake was washed with methanol (2 L). The filtrate was concentrated under reduced pressure, and the resulting orange oil was dissolved in toluene and concentrated under reduced pressure to provide 10.7 g of 2-ethoxymemyl-l-propyl-lfl:-imidazo[4,5-c]quinolin-8-ol as a granular, orange solid.
]H NMR (300 MHz, TMSO-d6) 8 10.11 (s, 1H), 8.94 (s, 1H), 7.99 (d, J= 8.7 Hz, 1H), 7.54 (d, J= 2.5 Hz, 1H), 7.24 (dd, J= 8.8,2.5 Hz, 1H), 4.82 (s, 2H), 4.51 (at, J= 7.7 Hz, 2H), 3.57 (q, J= 7.0 Hz, 2H), 1.91 (sextet, J= 7.7 Hz, 2H), 1.16 (t, J= 6.7 Hz, 3H), 1.06 (t,J=7bHz,3H).

PartJ
A solution of di-ferf-butyl dicarboiiate (36.0 g, 0.165 mol) in tetrahydrofuran (THF) (80 mL) was added dropwise to a solution of 2-atninoethanol (10.0 g, 0.164 mol) in IHF (50 mL) and 10% aqueous sodium hydroxide (66 mL), and the reaction was stirred fer 16 hoars. A precipitate formed. The THF was removed under reduced pressure, and 15% aqueous potassium hydrogen sulfate was slowly added to adjust the resulting mixture to pH 3. The mixture was then extracted with ethyl acetate (3 x), and fhe combined extracts were washed sequentially with water and brine, dried over magnesium sulfete, Stared, and concentrated under reduced pressure to afford 23.6 g of tert-buryl 2-hydroxyemylcarbamate as a colorless oil containing some ethyl acetate. PartK
Iodine (30.46 g, 0.120 mol) was added in three portions to a solution of triphenylphosphine (28.85 g, 0.110 mol) and imidazole (7.49 g, 0.110 mol) in dichloromethane (654 mL), and the reaction was stirred until the iodine dissolved. A solution of tert-butyl 2-hydroxyethylcarbamate (17.7 g, 0.110 mol) in dichloromethane (150 mL) was added over a period of 45 minutes, and the reaction was stirred for 16 hours at ambient temperature. The reaction mixture was poured into saturated aqueous sodium ttdosulfete and stirred until the solution became colorless. The organic layer was washed sequentially with saturated aqueous sodium thiosulfate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with 80:20 beraaesremyl acetate) to provide a pale yellow oil which slowly crystallized to afford 24.6 g of H7t-butyl 2-iodoethylcarbamate as a yellow solid. PartL
Solid cesium carbonate (18.33 g, 56.22 mmol) was added to a solution of 2-efisnb'merthyl-l-propyl-lJy-in3idazo[4,5b]qbimohii-8-ol (10.7 g, 37.5 mmol), prepared in PartsA-L inDMF (185 mL). tert-Bntyi2-iodoethylcarbamate (11.17 g, 41.2mmol), prepared in Parts J and K, was added, and the reaction mixture was heated at 65 °C for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic fraction was washed with water (4 x 1 OOmL) and brine, dried over magnesium sulfete, filtered and concentrated under reduced

pressure to provide a black oil. The oil was purified by column cinematography on sIBca
gel (elating with 98:2 dicMoromethanermethano!) to yield 14.6 g of fert-butyl [2-(2-
eflx)xyme&yl-l-propyl-liy-inridazob as a tan, waxy
solid.
lH NMR (300 MHz, DMSO-tf”) 5 9.02 (s, 1H), 8.07 (d, J~ 92 Hz, 1H), 7.57 (d, J= 2.5
Hz, IB), 7.36 (dd, J= 8.9,2.8 Hz, 1H), 7.10 (t, J= 5.6 Hz, 1H), 4.84 (s, 2H), 4.64 (at, J=
8.1 Hz, 2H), 421 (t, J= 6.0 Hz, 2H), 3.57 (q, J= 7.0 Hz, 2H), 3.41 (q, J= 5.8 Hz, 2H),
2.93 (sextet, J= 7.8 Hz, 2H), 1.39 (s, 9H)51.16 (t, J= 6.8 Hz, 3H), 1.04 (t, J= 7.1 Hz,
3H).
PanM
mCPBA (60% pure, 12.76 g, 44.36 mmol) was added in one portion to a solution of tetf-butyl [2b2-ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinohnr8-yloxy)ethyl]carbamate (14.4 g, 33.6 mmol) and chloroform (150 mL); the reaction mixture was stirred for 30 minutes. The reaction mixture was then poured into saturated aqueous sodium carbonate (100 mL) and stirred for 30 minutes. Chloroform (250 mL) was added, and the organic fraction was washed sequentially with 5% aqueous sodium carbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting red oil was triturated with ethyl acetate to provide 9.7 g of tert-bnryi 2b(2-emoxymemyl-5bxido-l-prcbyl-ljH-iniidbzo[4,5-c]quinomi-8-yl)oxy]emylcarbainate as a peach-colored powder.
XHNMR (300 MHz, TMBO-d6) 8 8.87 (s, 1H), 8.71 (d, J= 9.3 Hz, 1H), 7.56 (d, J= 2.7 Hz, 1H), 7.43 (dd, J= 9.5,2.3 Hz, 1H), 7.11 (t, J= 5.6 Hz, 1H), 4.81 (s, 2H), 4.62 (at, J"= 7b Hz, 2H), 4.24 (t, J = 5.6 Hz, 2H), 3.58 (q, J= 6.9 Hz, 2H), 3.41 (q} J= 5.8 Hz, 2H), 1.92 (sextet, J= 7.6 Hz, 2H), 1.39 (s, 9H), 1.17 (t, J= 6.8 Hz, 3H), 1.03 (t, J= 1.6 Hz, 3H). PartN
Ammonium hydroxide (50 mL) was added to a solution of tert-buryl 2-[(2-cthoxymethyl-5-oxido-1 -propyl- lb-imidaz»[4,5b]qumolin-8-yl)oxy]ethylcarbamate (9.7 g, 22 mmol) in dichloromethane (120 mL), and the mixture was cooled to 10 °C. p-Tolueoesulfonyl chloride (4.16 g, 21.8 mmol) was added in small portions, while maintaining the reaction temperature below 15 °C. The reaction was stirred for 16 hours; a



MS (APCT) mJz 344.2081 (344.2087 calcd for CuRz&ifh, M+H);
Anal. Calcd. for C18H25N5O2: %C, 62.95; %H, 7.34; %N, 20.39. Found: %C, 62.68; %H,
7.22;%N, 20.26. .

Methanesulfonic anhydride (0.265 g, 1.52 mmol) was added in one portion to a solution of 8-(2-aminoethoxy)-2-e1ioxymethyl-l-propyl-lH-imidazo[4,5-c]qiunolin-4-amine (0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction was stirred for 30 minutes. A precipitate formed. Aqueous sodium hydroxide (25 mL of 10%) was ofiAf)b and the mixture was stirred for 20 minutes. The aqueous layer was separated and extracted with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated mder reduced pressure. The resulting white solid was purified by column chromatography an sQjca gel (ehrtmg with a dichloromethaneanethanol ranging in ratios from 97:3 to 94:6) and then recrystallized from acetonitrile to yield 0.302 g of iV-[2-(4-amino-2-etixn3raemyl-l-propyl-lH-imidazo[4,5b]qb idrite, granular crystals, mp 178-179.5 °C.
“H NMR (300 MHz, DMSO-4) 6 7.57 (d, J= 8.8 Hz, 1H), 7.39 (d, J= 32 Hz, 1H), 733 (t, J= 5.8 Hz, 1H), 7.15 (dd, J= 9.2,2.8 Hz, 1H), 6.36 (s, 2H), 4.77 (s, 2H), 4.56-4b1 (m, 2H)5 4.17 (t, J~ 5.6 Hz, 2H), 3.56 (q, J= 6.9 Hz, 2H), 3.40 (q, J= 5.6 Hz, 2H), 2.98 (s, 3H), 1.91 (m, 2H)51.16 (t, J= 6.9 Hz, 3H), 1.03 (t, J= 13 Hz, 3H);

UC NMR (75 MHz, DMSO-(fe) 5 152.7,150.6,148.9,140.1,132.7,127.6,126.7,117.0,
114.6,102.6, 67.3,65.3,64.2,46.7,41.9,23.3,14.9,10.8;
MS (-APO) mk 422.1850 (422.1862 calcd for C1SH27N5O4S, M+H);
AnaL Calcd. for C19H27N5O4S: %C, 54.14; %H, 6.46; %N, 16.61; %S, 7.61. Found: %C,
54.19; VoH, 6.65; %N, 16.26; %S, 7.81.

4-Morpholinecarbo:nyl chloride (0.177 mL, 1.52 mmol) was added dropwise to a solution Triethylamine (0.418 mL, 3.00 mmol) was then added, and the reaction was sacred for 16 hours. Aqueous sodium hydroxide (50%) was added, and the mixture was srirred for 30 minutes and then diluted with dichloromethane (100 mL). The organic layer was separated, washed sequentially with water and brine, dried over magnesium sulfate, Stared, and concentrated under reduced pressure. The residue was then treated with concentrated hydrochloric acid and water. A precipitate formed and was isolated by fiftration, washed with water and diethyl ether, and dried in a vacuum oven at 60 °C to 8-yI]oxy}ebyl)morphoUne-4-carboxamide hydrochloride as a white solid, mp 200-202 CC. “H NMR (300 MHz, DMSO-&) 8 13.47 (s, 1H), 8.71 (bs, 2H), 7.79 (d, J= 9.4 Hz, IB), 7.54 (d, J= 2.5 Hz, 1H), 7.40 (dd, J= 9.3,2.5 Hz, 1H), 6.84 (t, J= 5.4 Hz, 1H), 4.84 (s, 2H), 4.65 (t, J= 7.8 Hz, 2H), 4.19 (t, 7= 6.1 Hz, 2H), 3.59 (q, J= 7.0 Hz, 2H), 3.52 (t, J=

4.7 Hz, 4H), 3.50-3.40 (m, 2H), 3.26 (t, J= 4.9 Hz, 4H), 1.90 (sextet, .J= 7.4 Hz, 2H),
1.17 (t, J= 7.2 Hz, 3H), 1.03 (t, J= 7.3 Hz, 3H);
MS (APd) jwfe 457.2557 (457.2563 calcd for C23H32N6O4, M+H);
AnaL Calcd. for C23H32NeOW.OHCM.OH2O: %C, 54.06; %H, 6.90; %N, 16.45; %d,
6.94. Found: %C, 54.36; %H, 6.74; %N, 16.57; %C1,6.99.
Hie acidic filtrate was cooled to 0 °C and adjusted to pH 13 with the addition of 50% aqueous sodium hydroxide; the resulting opaque solution was extracted with dkaloranetnane. The combined extracts were washed with water and brine, dried over magpffartffl sulfele, and concentrated under reduced pressure. The resulting white solid was triturated with hot acetonitrile and isolated by filtration to yield 0.114 g of iV-(2-{[4-ammcK2bethoxymetnyl)-l-propyl-l#-ib 4-carboxamide as a white powder, mp 203-208 °C.
'HNMR (300 MHz, DMSO-bj) 5 7.55 (d, J= 9.2 Hz, 1H), 7.41 (d, J= 2.3 Hz, 1H), 7.14 (dd, J= 9.2,2.9 Hz, 1H), 6.79 (t, J= 5.2 Hz, 1H), 6.33 (s, 2H), 4.77 (s, 2H), 4.57-4.52 (m, 2H), 4.12 (t, J= 6.0 Hz, 2H), 3.59-3.42 (m, 7H), 3.28-3.24 (m, 5H), 1.97-1.81 (m, 2H), 1.16 (t, J= 7.1 Hz, 3H), 1.02 (t, J= 7.5 Hz, 3H);
Anal. Calcd. for C23H32N6O4«0.25H2O: %C, 59.92; %H, 7.11; %N, 18.23. Found: %C, :
59b9; %H, 7.10; %N, 18.15.

Isobutyryl chloride (0.160 mL, 1.53 mmol) was added dropwise to a solution of 8-
(2-ammoethoxy)-2-ethoxyme&yl-l-pn)pybb (0b00 g,






Part A
7-BoKboxy-l-(2-me&ylprop)i)-2-prDp)d-lb-imidazo[4,5b]quinoline (603 g, CIS mod), prepared as described in Parts A-G of Example 1, and 10% palladium on carbon (10 g) were mixed with ethanol (500 mL). Ammonium formate (101.53 g, 1.61 moT) and ethanol (500 mL) were then added, and the reaction mixture was heated at reflux for two hours. The mixture was allowed to cool to ambient temperature slowly and stirred overnight The reaction mixture was filtered through a layer of CELTTE filter aid, and the filter cake was washed with ethanol (1 L), meraanol (2 L) and dichloromethane (2 L). The combined filtrates were concentrated under reduced pressure to provide a tan solid, which was triturated with cold ethanol and isolated by filtration to yield 30 g of l-(2-methyipropyl)-2-propyl-liy-iimdazo[4,5-c]quinohJn-7-ol as a tan, granular solid. 'HNMR (300 MHz, DMSO-4J) 8 9.89 (s, 1H), 9.00 (s, 1H), 8.12 (d, J= 9.3 Hz, 1H), 7.41 (4 J= 2o Hz, 1H), 7.23 (dd, J= 9.3,2.5 Hz, 1H), 4.36 (d, J= 7.4 Hz, 2H), 2.91 (t, J= 7.5 Hz, 2HX 2b5-2.10 (m, 1H), 1.88 (sextet, J= 7.4 Hz, 2H), 1.03 (t, J- 7.5 Hz, 3H), 0.92 (d, J=7.1Hz,6H). PztB
The general methods described in Parts J and K of Example 2 were used to prepare 16.2 g of tert-butyi 3-iodopropylcarbamate from 3-amino-l-propanol (6.55 g, 8.72 mmol); fiie prodnct was isolated as a yellow solid. Part C
A modification of the general method described in Part L of Example 2 was used to treat 1b2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinohn-7-ol with fert-butyl 3-iodopropylcarbamate. The reaction mixture was diluted with water; a precipitate formed. The precipiate was isolated by filtration, washed with water and then with diethyl ether



13 and was isolated by filtration to provide 7-(3-animopropoxy)-l-(2-methyh7ropyI)-2-
propyl-Lff-imidazo[4,5-c]quinolin-4-ainme as a white solid, mp 173-174 °C.
“H NMR(300 MHz, DMSO-d6) 5 7.85 (d, J= 9.4 Hz, 1H), 7.06 (d, J= 3.2 Hz, 1H), 6.89
(dd, J= 8.8,25 Hz, 1H), 6.35 (s, 2H), 4.28 (d, J= 7.5 Hz, 2H), 4.10 (t, J= 6.7 Hz, 2H),
2.86 (t, J = 15 Hz, 2H), 2.72 (t, J= 6.8 Hz, 2H), 2.2-2.08 (m, 1H), 1.90-1.77 (m, 4H), 1.6
C», 2H), 1.02 (t, J= 7.6 Hz, 3H), 0.91 (d, J= 6.8 Hz, 6H);
&G (APCD mh 3562464 (356.2450 calcd for C20H29N5O, M+H);
AnaL CabL for C20H29N5O: %C, 67.58; %H, 8.22; %N, 19.70. Found: %C, 67J25; %E,
754; %N, 19.75.

Part A
lie preparation of 7-ben2yloxy-iV4-(2-methylpropyl)qumoline-3,4ban3dne is described in Parts A-F of Example 1. Under a nitrogen atmosphere, triethyl orthoacetaie (459 IBL, 25.0 mmol) was added to a solution of 74)enzyloxy-JV4-(2-gK3liyliHupyI)qumoline-3,4-diamine (8.05 g, 25.0 mmol) in xylenes (130 mL), and the rasotting solution was heated at reflux (160 °C) overnight The solvent volume was reduced to 70 mL using a Dean-Stark trap. Over a period of a few days, a precipitate fenned. Diethyl ether was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 6.81 g of 7-benzyloxy-2-methyH-(2-methylpropyl)-liy-hm'dazo[4,5-c]quinoUne as a light-brown powder. PartB






(0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 18 hours. Saturated aqueous sodium bicarbonate was added, and the reaction was stirred for 20mmntes. The aqueous layer was separated and extracted with chloroform. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting off-white solid was dissolved in concentrated hydrochloric acid; the solution was then cooled to 0 °C and adjusted to pH 13 with the addition of 50% aqueous sodium hydroxide. The opaque solution was extracted with dichloromethane. The extract was washed sequentially with and brine, dried over magnesium sulfate, filtered and concentrated under reduced The resulting solid was recrystaUized from acetonitrile to yield 0.160 g of iV-{3--2-propyl-lH-imidazo[4,5b]quinomi-7-ykixyjprofbineihanesulfonarnide as a flocculent, white solid, mp 166.5-168.5 °C. 1INMR.(300 MHz, DMSO-d6) 8 7.86 (d, J= 8.6 Hz, 1H), 7.085 (t, J= 5.5 Hz, 1H), 7.06 (bJ= 3 J Hz, 1H), 6.91 (dd, J= 8.7,2.5 Hz, 1H), 6.37 (s, 2H), 4.29 (d, J= 7.3 Hz, 2H)} W (t, J= 63 Hz, 2H), 3.14 (q, J= 6.4 Hz, 2H), 2,90 (s, 3H), 2.86 (t, 7= 7.5 Hz, 2H), 2.14 (septet, J= 7.0 Hz, 1H), 1.95 (quintet, J= 6.6 Hz, 2H), 1.83 (sextet, J= 7.3 Hz, 2H), 1.02 (t, J= 7.6 Hz, 3H), 0.91 (d, J= 7.1 Hz, 6H);
i5CNMR(125MHz,DMSO-J(y) 8 157.1,152.6,151.8,146.2,132.8,125.1,121.2,111.6, 109.0,108.0,64.7,51.2,39.4,39.2,29.3,28.7,28.5,20.9,19.1,13.8; MS (APC3) mJz 434.2235 (434.2226 calcd for C2iH31N5O3S, M+H); %C, 58.18; %H, 7.21; %N, 16.15; %S, 7.40. Found: %C, 57.87; %H, 7.56; %N, 16.02; %S, 7.72.








































Tolaenesulfonyl chloride (029 g, 1.5 mmol) was added in small portions over a period of
20 minutes. The reaction was stirred at ambient temperature overnight The reaction
mixture was partitioned between dichloromethane and 1% aqueous sodium carbonate.
The organic fraction was washed with 1 % aqueous sodium carbonate (2x30 mL), dried
over magnesium saifiate, filtered, and concentrated under reduced pressure. The crude
product was iccrystallized from ethyl acetate, isolated by filtration, washed with cold
hnranry.. and dried under Mgh vacuum at 55 °C to provide 0.391 g of 2-ethyl-l-(2-
“H SMB. (500 MHz, T3MSO-d6) 8 7.87 (d, J= 9.0 Hz, 1H), 7.05 (d, J~ 2.4 Hz, 1H), 6.94
(d4V= 9.0, 2.7 Hz, 1H), 6.4 (br s, 2H), 4.9 (s, 2H), 4.28 (d, J= 7.2 Hz, 2H), 4.9-4.28 (m,
8H)5 2.91 (q, J= 75 Hz, 2H), 2.15 (septet, J= 6.7 Hz, 1H), 1.36 (t, J= 7.5 Hz, 3H), 0.91
(d,J=6.6Hz,6H);
BC NMR(75 MHz, DMSO-b) 6 166.5,156.9,154.1,152.3,146.7,133.2,125.5,121.5,
111.8, 109.7,108.9,66.4,66.3, 51.5,45.2,42.0,29.1,20.5,19.5,12.4;
MS (ESI) mJz 4122344 (412.2349 calcd. for CzbgNsOs, M+H);
Anal. Calcd. for C22H29N5O3: %C, 64.21; %H, 7.10; %N, 17.02. Found: %C, 64.07; %H,
7b1; %N, 16-99.

Memyimime (available as a 40% solution in water, 24 mL, 0.28 mol) was added to 1 ttbrikxi of 6bb«nzyloxy-4bMoro-3-ni1xoquinohrne (15.0 g, 48.5 mmol), prepared as described in Parts A-D of Example 2, in distilled water (300 mL), and the reaction was

























MS (APO) mJz 4953080 (4953084 calcd for C27H315N6O3, M+H); AnaLCalcdforC27H3gN6O3: %C, 65.56; %H, 7.74; %N516.99. Found; %C, 6533; %H, 7.88; %N, 16.95.

Part A
A mixture of 2-bHit54-l-4nethyi-lH-imidazo[4,5-c]quinolin-8-ol (0.51 g, 2.0 mmol), prepared as described in Parts A-D of Example 31, and 2-ethyI-2-oxazoline (0.5 g, 5 mmol) were heated at 150 °C fox four hours. Additional 2~ethyl-2-oxazoline (2 mL, 2 mmol) was added, and the heating was continued for a total of four days. The reaction was dissolved in dichloromethane, and 1he resulting solution was washed with aqueous potassium hydroxide (20 mL of 4 N), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was recrystallized from methyl acetate (20 mL) to provide QL20 g of Jb2-[2-butyl-l-memyl-liy-imidazo[4,5-c]quinolm-8-yi)oxY}cdiyi}propanannde. PartB
The general meftod described in Part E of Example 30 was used to convert iV-{2-[24n”blbncfirblS:iimdaz»[4,5H:]qumomi-8-yl)oxy]ethyl}propanamide (0.18 g, 0.51 mmol) to 3.14 g atAb2b24xb-l-memyl-5bxido-lJbUTu'dazo[4,5b]quinohri-8-yi)oiy3e»iyi}propaB«nide. The reaction was complete in two hours. PartC
hydroxide (5 mL) andp-toluenesulfonyl chloride (0.072 g, 0.38 mmol) were added with rapid stirring to a solution of iVL{2-[2-butyl-l-merayl-5-oxido-lfl'-rmklizDb3b)quirK)Knb-yl)oxy]ethyl}propanarriide (0.14 g, 0.38 mmol) in dichkmnetfcaDe (15 mL), and the mixture was stirred at ambient temperature for one boor. A precipitate formed and was isolated by filtration, washed with water, and dried


Part A
7-Benz5io3b-lbHiiine&yl-lflLiniJdazo[4,5-c]quiiLoline was prepared according to the methods described in Parts A-C of Example 31. In Part C, triethyl orthoformate was used in Ben of trimeflryl orthovalerate. A solution of 7-benzyloxy-l,2- dimethyl- \H-imidazo[4,5-c]quinoline in ethanol was added to a Parr vessel with 10% palladium on carbon. The reaction was placed under hydrogen pressure (35 psi, 2.4 x 105 Pa) for 20 hours. The reaction mixture was then filtered through a layer of CELITE filter aid, and the nitrate was concentrated under reduced pressure. The residue was dissolved in acetic acid with heating and fee hot solution was filtered and concentrated under reduced pressure. The resulting beige so&d was dissolved in 1N aqueous hydrochloric acid, and deactivated carbon was added. The sohtikm was heated, filtered, and treated with 50% aqueous sodium hyfrmrida. A pmijalirifs formed and was isolated by filtration to provide 1,2-dmeflbiJfi:4imdaaiif4i)(}qninDhV8-ol as a solid, mp ) 300 °C. PartB
SnrfcHn hwckide (0.61 g, 15 mmoL, available as a 60% dispersion in mineral oil) was addoi a) a sofeako of lb-bimemyl-lbirmdazobS-cjquinohii-S-ol (2.5 g, 12 mmol) in DMF He reac&oo mixture was stirred for 30 minutes, and ethyl bromoacetate (1.96 g, 11.7 mneQ «as added. The staring was continued for five hours, and a small volume of ethanol m added. The volatQes were removed under reduced pressure, and the residue was diaauhtii in diditoromemane. The resulting solution was washed three times with dekxBxef iKMer, dried over magnesium sulfate, filtered, and concentrated under reduced

pressure. The resulting yellow solid was recrystallized from ethyl acetate to provide 1.65 g of ethyl 2-[(lb-dimefliyl-Liy-iimdazo[4,5-c]qirinoIin-8-yl)oxy]ace4ab as a white solid. PartC
Emyl 24(lb-dimediyl-lF-imidazo[4,5-c]qijinoKn-8-yl)oxy3acetate (1.6 g, 5.35 mmol) was added to a solution of potassium hydroxide (0.90 g, 0.16 mol) in a 50:50 mixture of me&aaobwBter (30 mL). The solution was stirred under a nitrogen atmosphere untilk was campte as evidenced by HPLC analysis. The methanol was removed under reduced pressure, aa& 6 N aqueous hydrochloric acid was added until the solution exhibrtod a csnsai pH. A precipitate formed and was isolated by filtration to provide 125 g of 2b(lb-bmbnblS:bnikiazo[4,5w;]qirinolm-8-yl)oxy]acetic acid as a white solid, mp 290 °C (decomposition). PartD
Morpholine (039 g, 4.4 mmol) and l-[3-(dimethylamrno)propyl]-3-ethylcarbodiimide Irydrochloride (0.85 g, 4.4 mmol) were added to a solution of 2-[(l,2-dimemyl-lH-imidazo[4,5-c]quinoHn-8-yl)oxy]acetic acid (1.20 g, 4.42 mmol) inpyridine, and the reaction was stirred for four days under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the residue was stirred with heptane, which was then removed under reduced pressure. The resulting orange solid was purified by column chromatography on sQka gel (elating with 90:10 dichloromethane:methanol) to provide 2~
[(1 p-tfimrihyi-i fEJmwfcrai[.Ab-'w-jiprinniin-R-ytyvry'l-i -mnrphr)1in-1 -yiftfhanrmp as a pale
yeHowsofitL PartE
The grrara? Tnrfhnd desaibed in Part £ of Example 30 was followed using 2-[(l,2-
diintbhyi-tllJimiArTrfA b-rjfpJTmUn-R-yibYy]-!-mbTphbTiT1-1 -ylfbitmbTlP (0.97 g, 2.85
mmoQ as ifaestartag material. The reaction was complete in two hours. The product was soluble is aneoos sommn carbcaiate; therefore, the aqueous washings were concentrated under jefkaai pressure. 2-Propanol was added to the residue with heating, and the mixture w ottered. The filtrate was concentrated under reduced pressure to provide 0.14 gof2b(lf2-dHnedryb5H3ndo-12y-irmdazbb yk&anaoc

PartF
Ammonium hydroxide (30 mL) andJ)4oluenesulfonyl chloride (0.46 g, 2.4 mmol) were added with rapid to a solution of 2-[(l,2-dimethyl-5-oxido-lff-nnidazo[4,5-c]qoinoKn-8-yl)axy3-lTnKnpfaolm-l-ylethanone (0.86 g, 2.4 mmol) in dichloromethane, and me mixfaBre was stirred at ambient temperature for two days. The volatiles were removed under reduced, and the residue was recrystallized from 2-propanol to pRmde2b(4-«BMnbO-(iiHiefliyl-liy-iinibb yieahaaoneJ»-tolBeDeailsa32c as a white solid. PartG
Gaiaen Reagent, -prepared fiom potassium hydroxide (35 g), water (25 mL), and methanol (100 mL). was added to the material from Part F, and the mixture was stirred for one hour. Hydrochloric acid (6 N) was added until the pH of the reaction mixture was neutraL A precipitate formed and was isolated by filtration to provide 0.01 g of 2-[(4-anuncHlb-dimemyi-lbbimdazobSbquinolin-S-yboxyJacetic acid as an orange solid, mp 298 °C (decomposition).

PartA
7bBeffiyfesy-4Kidoro-3-bmbx)quinoUne (14.5 g, 46.0 mmol), prepared as described
in Parts A-D of Example 1, was treated according to the general method described in Part
E of Enapfe 1. lbb&mmo-2-methylpropane (5.29 mL, 50.6 mmol) was used in lieu of
isobntybraEnc After the work-up, the crude product was passed through a layer of silica
gel (ebtiog wqnenrialry with chloroform and 96:4 cHoroformrmethanol) to provide 12.4 g
aff(2-aHiiBb2Hnetliyli»ijpyI)(74)emyloxy-b as a yellow solid.

PartB
Under a nitrogen atmosphere, a solution of (2-amino-2-methy]propylX7-benzyloxy-3-mta)quiiKjfin-4-yI)an3ine (12.4 g, 33.9 mmol) in dichloromethane (400 mL) was cooled to 0 °C. Trie&jiamme (9.43 mL, 67.8 mmol) and methanesulfonic anhydride (5.90 g, 33.9 mmoJ) were sequentially added, and the reaction was stirred at ambient temperature for two hoars. An analysis by HPLC indicated that the reaction was incomplete, and ariecional mstnanesulfonic anhydride (1.4 g, 8.0 mmol) was added. The reaction was sirred fcra; additional 90 minutes, and additional methanesulfonic anhydride (0.7 g, 4 jnaoT) was added. The reaction was stirred for an additional three hours, and sarttrattsri aqueous sodium bicarbonate (200 mL) was added. A precipitate began to form in fee organic layer, which was separated and concentrated under reduced pressure to provide a yeBow solid. The solid was triturated with water (200 mL) with heating, isolated by filtration, washed with water (3 x 100 mL) and diethyl ether (3x50 mL), and dried overnight under vacuum to provide 14.8 g of iV-[l,l-dimethyl-2-(3-nitro-7-benzyloxyqumolmbylaniino)ethyl]metiianesulfonamide as a yellow powder. PartC
N-[ 1,1 -Dimethyl-2-(3-nitro-7-benzyloxyquinoHn-4-
ylammo)ethyl]methaijeailfonamide (14.8 g, 33.3 mmol) was mixed with acetonitrile (300 mL) and added to a Pair fkwft: 5% platinum on carbon (2 g) was added. The reaction was flashed wnn nitrogen and placed under hydrogen pressure (40 psi, 2.8 x 105 Pa) for 5.5 hours wim fbe hydrogeo. replaced after two hours. An analysis by TLC indicatedthe presence of saning imMrrhl Additional acetonitrile (200 mL) and 5% platinum on carbon (2 g) wets added, snd 1he reaction was placed under hydrogen pressure overnight The reaction nBsfcnc was fikffed through a layer of CELITE filter aid, and the filter cake was washed wife acetcnariie. The filtrate was concentrated under reduced pressure. Toluene and dkiuoranieihane were added and removed under reduced pressure twice to yield 12.6 g ofbb-b3HHiDC»-7-benzyloxyqumomib-ylamino)-l,l-ffTnv 11' “tjbjy"}w”'ab»j«)b-qiiTfnTiHTnibp as a solid. PartD
Under a nitrogen atmosphere, a solution of JVr-[2b3-ammo-7-benzyloxyqumolin-4-)4amiix))-l,lH£melbbieflryrjmedianesulfonaniide (12.6 g, 30.4 mmol) in dichloromethane

(300 mL) was cooled to ~0 "C; triemylamine (4.23 mL, 30.4 tnmol) was added. Efhoxy acetyl chloride (333 mL, 30.4 mmol) was added dropwise, and the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (300 mL). Triethylamine (13 mL) was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volarLles were rsnoved under reduced pressure. The residue was dissolved in dichlcrramefisme G00 inL), and the resulting solution was washed with water (2 x 100 rnL) and bnae, dried prorsafinmsiilfate, filtered, and concentrated under reduced pressure to provide a Drown oiL The oil was purified by column chromatography on silica gel (elating with 973:2-5 cbkHofbiinzmethanol) to provide 12.4 g of JV-[2-(7-benzyloxy-2-emoxymdiryl-lJEF-mTkiaOT[4bb]qib a beige solid. PartE
A solution of #b2b74)erizyloxy-2-ethoxymethyl-l#-ib
1 J-dimethyletitiyl]methanesulfonarnide (9.38 g, 19.5 mmol) in ethanol (150 mL) was
added to a Parr vessel containing 10% palladium on carbon (0.83 g). The reaction was
placed under hydrogen pressure (5 0 psi, 3.4 x 105 Pa) over two nights. Starting material
remained as evidenced by a TLC analysis, and additional 10% palladium on carbon (1.02
g) was added. The reaction was continued for an additional eight hours. The reaction
mixture was filtered fluuugh a layer of CELITE filter aid, and the filter cake was washed
with ethanol and me&anoL The filtrate was concentrated under reduced pressure, and the
residue was several times dissolved in toluene and concentrated under reduced pressure to
yield a ydkm pectin., wfokh was dried under high vacuum to provide 7.37 g of iV-[2-(2-
tbxjtti«flpd-74yfeary-li7-ggb , 1 -
dtmetbyfeftqFi)metbaoesnffbnariide as a yellow solid. PartF
Tfce zje&ods described in Parts J and K of Example 2 were followed using 6-ammo-l-hexanoi (62 g, 0.53 mmol) in lieu of 2-aminoethanol to provide tert-butyl 6-iodohexyicari»amate as a light-yellow oil.

PartG
The general method described in Part L of Example 2 was followed. JST-[2-(2-
Eiboxymefl3yl-7-hydiob-lb-imidazo[4?5-c3qbolin-l-yl)-l,l-dimemylebI}methanEsalfbnamide (7.37 g, 18.8 mmol) was treated with tert-butyl 6-iodohexylcarbamafc; (6.75 g, 20.6 mmol). The crude product was purified by cohrmn chromatograpby on sScz gel (during sequentially with 95:5 and 92.5:7.5 dicMorame&aiwmefisQoI) to provide 8.5 g of tert-butyl {6-[2-emoxymemyl-l-(2-xse1haDesal£c7iacbb)-2'-3n3dbbnbyl)-lJ7-imidazx)[4,5b](|umo]m-l-yloxyjbfayijcartjacxse as a white solid. Part H
A mocEficaton of the method described in Part M of Example 2 was used to convert tert-bntyl {642-eih0xymeftyl-l-(2-me1iianesulfonb
miidazo{4bb]qumoliii-l--yloxy]hexyl}carbamate (8.5 g, 14.4 mmol) to fert-butyl {6-[2-e£lK)xyine(h}i-1b2-”netimesiilfOT
c]quinolin-l-yloxy]hexyl}carbamate, which was obtained as a orange solid. The reaction was complete in two hours, and the product was used without purification. Parti
Ammonium hydroxide (20 mL) andp-toluenesulfonyl chloride (2.74 g, 14.4 mmol) were added sequemiaBy wim rapid stirring to a mixture of the material from Part H in dichloronK&me (150 mL), and the reaction was stirred for two hours. The organic layer was then washed with sainrated aqueous sodium bicarbonate (2 x) and brine, dried over sodium smiale, fiUscsd. and concentrated under reduced pressure to provide fert-butyl {6-[4-bmmx)~2-«hoK5n«fli3!i-Ib-meihanesb c]quiiKiSij-[-vknryjieryi}cgfaamate as a red solid. PartJ
AsodificatiDo of fie me&od described in Part O of Example 2 was used to depnrtscs ursAyuiyi {6b4-aimiM)2-eboxymethyl-l-(2-methanesulfonylainino-2-mcfliyliwbiyVlb-inTidazo[4:b]qbmolm-l-yloxy]hexyl}caA with hydrochloric acid in eUamA (50 mL of 4.25 M). Following the treatment of the crude product with ammofanmfcydroxide and the remainder of the work-up procedure, 6.86 g of JV-{2-[4-MmTBo-7-46bnimolKaryk)xy)-2-eflK)xymemyb

dime1fayidib}me&imesnlibnainide were obtained as a tan solid and used without further
purification.
PartK
A suspension of b{24bamino-7-(6-aniinohexyloxy)-2(fthoxymethyl-li?-inridazo{4,5-r]qainofiii-1 -yl}-l,l-dime1faylemyl}memanesiuToiiamide (1.50 g, 2.96 mmol) in dichloxooismaae (50 mL) was cooled to 0 °C; triethylamine (825 uL, 5.92 mmol) and mefhanesolfcnic aniwdride (0-67 g, 3.85 mmol) were sequentially added. The reaction was stirred ■: 0 °C foc3Q in'mlflSj allowed to warm to room temperature, and stirred for four honrs. The racoon suasion was washed with saturated aqueous sodium bicarbonate (2 x) and boor, dried owb-spdram sulfete, filtered, and concentrated under reduced pressure. The resktoe was purified by column chromatography on silica gel (eluting with 90:10 dicfaloromelrtanejnetrtanol) and recrystallization firom dichloroethane. The crystals were partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and further dried for two days under high vacuum at 60 °C to provide 0.39 g of N-(2- {4-amino-2-ethoxymethyl-7- [6-(methanesulfonylamino)hexyloxy] - lbT-imidazo[4f5-c]qbolin-l-yl}-14-dimethyle1hyl)meihanesulfonamide as an off-white solid, mp 176-180 °C.
“H NMR (300 MHz, IftGOb) 5 8.16 (d, J= 9.4 Hz, 1H), 7.27 (s, 1H), 7.03 (d, J= 2.5 Hz, 1H), 6b3 (m, IB), 6M {6d,J= 8.7,2.5 Hz, 1H), 6.53 (s, 2H), 4.81 (s, 4H), 4.04 (t, J = 62Ez,2H),353 (m,2H),2.99(s, 3H), 2.94 (m, 2H), 2.87 (s, 3H), 1.76 (m, 2H), 1.50-1b7 (m, 123), 1.14 (HL 3Hfe
bCNMRTb MHAiaeCWf) 8 157.9,152.6,150.0,147.7,134.9,125.4,122.6,111.4, 109.5,108.4,67-5,65-7,65.1,57.7,54.6,44.7,42.8,29.7,29.0,26.3,25.8,25.6,15.3; MS (APCD mh 585 (M+Hf;
AoaL C”eL Sr C-sHbEeOeSTbJO H2O: %C, 50.88; %H, 6.94; %N, 14b4. Found: %C, 50.85; “H.«£3; %N, 14.10.


A vao&scman of the method described in Park K of Example 45 was followed using acetyi chloride (0.23 mL, 3.26 mmol) in lieu of methanesulfonic anhydride. A precipitate was present at the end of the reaction and was isolated by filtration, stirred with water for 30 mrnnteK and isolated by filtration. The remaining reaction solution was subjected to the aqueous work-up procedure. The two solids were combined and purified by column chromatography on silica gel (eluting sequentially with 90:10 and 85:15 dichloromethane:methanol) to provide 0.51 g of iV-(6b{[4-amino-2-ethoxymethyl-l-(2-mdnanesulfonylaimno-2-rnbylprcpyl)-b yl]oxy}hexyl)acetamide as an off-white powder, mp 169-171 °C. “H NMR (300 MHz, DMSO-40 8 8.17 (d, J= 9.4 Hz, 1H), 7.79 (m, 1H), 7.28 (s, 1H), 7.04 (d, J=2_5 Hz, 1H), 6J&5 (dd, J= 8.7,2.5 Hz, 1H), 6.56 (s5 2H), 4.82 (s, 4H), 4.04 (m, 2H), 354 (q, J=6bHzJ 2HX 3.02 (m, 2H), 2.99 (s, 3H), 1.79 (s, 3H), 1.75 (m, 2H), 1.45-1.28 (m, I2H), 1.14 bn, SHf,
13CNMRr5MHzJDMSO(b8169.2,157.9,152.6,150.0,147.6,134.9,125.4,122.6, 111.4,1G9J3,108.4, 676,65.75 65.1,57.7,54.6,44.7,38.8,29.5,29.0,26.6,25.8,25.7, 22-9,15-3;
MS(APC2)JK=: 549(MbH)+;
AnaL CAi $x CjsHbNeQb: %C, 56.91; %H, 7.35; %N, 15.32. Found: %C, 56.70; %B, 7.49: ««!L 15.26.


Part A
Under a nitrogen atmosphere, a solution oftert-butyi ib4-aminobutyl)carbarnate (13.8 g, 73.4 mmol) and triemylamme (15.3 mL, 110 mmol) was cooled to 0 °C. Methanesulibnyl chkrride (63 mL, 81 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight Aqueous acetic acid (200 mL of 10%) was added. The organic layer was then separated and washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL), and brine; dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 18.9 g of tert-butyl [4bmemanesulfonylamino)butyl]carbarnate as an off-white solid. PartB
A softgaon ofimfcochkric acid in ethanol was added to a solution oftert-butyl [4-(rne1ianeailHHr3iammo1biayi3carbamate (18.9 g, 71.1 mmol) in ethanol (100 mL), and the reaction was heaisd at 100 °C for two hours. The solvent was removed under reduced pressure. Ansbdure of dichtorosnethaneihexanes was added to the resulting oil and removed raier reduced pressure; fins process was repeated several times. The residue was dried for fare diys wrier vacuum to provide 14.3 g ofN-{4-anrmnlwiqii”)rH«ham-fcglEw wiiirfe hydrochloride as a tan solid. PartC
A notification of me method described in Part E of Example 1 was used to treat 7-benzyk)x5b”(fckffo~3-mtroquirK)line (14.4 g, 45.8 mmol) withiV-(4-ainiiiubtflyOMdhaoesaflbiiamide hydrochloride (10.2 g, 50.4 mmol) and triethylamine (19.2 mL, 137 mmol). The reaction mixture was concentrated under reduced pressure, and

the residue was triturated with water while heating at reflux. The resulting solid was isolated by filtration, washed wife water and diethyl ether (2 x 100 mL), and dried under high vacuum to provide 16.8 g of iV-[4-(3-nitro-7-benzyloxyquinonii-4-ylaiiuno)biityl]me&aQesiilfoiiamide as a yellow powder. PattD
The method described in Part C of Example 45 was used to convert iV-[4-(3-nitro-
7-4)enzylo3yqaEMii)b}iamn»)bab (16.8 g, 37.8 mmol) to 15.1 g
nf “£[bUar?j«|ri-7bii»EryfoqfyTmTibb which Was
obtained as a cane befiow sand. PartE
The mediod described in Part D of Example 45 was used to treat iV-[4-(3-amino-7-
benzyloxyqirinolm-byIanTmo)burb (15.1 g, 36.5 mmol) withbutyryl
chloride {4.77 mL, 46.2 mmol). The crude product was purified by column chromatography on silica gel (elating with 96:4 chloroform:methanol containing ammonium hydroxide) to provide 11.8 g of iV-[4-(7-benzyloxy-2-propyl-lfT-imidazo[4,5-c]qumoun-l-yl)bulyl3memanesulfonaniide as a tan solid. PartF
The method described in Part E of Example 45 was used to convert JV-[4-(7-
1vyi7y1nTy-?-pmpyl-1 fg-irmrfarafAb-rjqmnniiTi-i -y1)hiity1]mftthanftsii1fnnamirip. (7.60 g,
16.3 mmol) to 5.75 g of3b4b-iydroxy-2-propyl-libimidazo[4,5-c]quiQonn-l-yl)biityI]Tneni3nesTiJL6)nanBce, wiricii was obtained as a light-yellow solid. PartG
The general mtatood dtsaSxd in Part L of Example 2 was followed. #-[4-(7-
hyifcrrry-7-fBapyUI ff-imiArrtbi 'Jb-yjtnnnMnb -yT)Vmfy1]mP!»)ianfwni1fr)namiHft (5.75 g, 15.3
mmol) was seated vrA tert-batyl 6-iodohexylcarbamate (5.50 g, 16.8 mmol). The crude product -was pacified by colanm cfaomatography on silica gel (eluting sequentially with 95:5 and SF2-5zT5 dicnkHaniemanennethanol) to provide 6.19 g of terf-butyl (6-{l-[4-(memaneatffac?ianmb)batyl3-2-propyl-liif-iinida2b yk)xy}bexyi)cKbamate as a yellow solid.

PartH
A modification of the method described in Part M of Example 2 was used to convert tert-butyl (6b{144bine11ianesulfonylainmo)butyl]b
c]qirinoliibl-5ioxy}hexyi)caibamate (2.51 g, 4.36 mmol) to 2.54 g of tert-butyl (6-{l-[4-(merfnanesulfboviaimno)boEyi3-5M3xibb
yloxy}hexyT)carbamai£, winch was obtained as a yellow solid. The reaction was allowed to ran overnight, and tic product was used without purification. Parti
The method descziaed in Part I of Example 45 was used to convert tert-butyl (6- {1-
yloxy}hexyQcarbam2te (234 g, 4.29 mmol) to 2.51 g of tert-bntyl (6-{4-amino-l-[4-
(methanesnlfbnylainnTO)bnr}13-2-prob
yloxy}hexyl)carbamate, obtained as a tan solid.
PartJ
The method described in Part J of Example 45 was used to deprotect fert-butyl (6-{4-ammo-l-[4bme1nanesulfonylaim
yloxy}hexyl)carbamate (2.51 g, 4.25 mmol). The crude product was recrystallized from
acetonitrile to provide 0.75 g of JV--{4-[4-ammo-7-(6-aminohexyloxy)-2-propyl-liI-.
hnidazo[43wr3q°™lbl-y0fcpotyl}metiianesub as a tan solid The mother liquor
was concentrated msier redocsd pressure, and the residue was recrystallized from dichloroeaiaDe to provide 0.48 g of b-{4-[4-ammo-7-(6-aminohexyloxy)-2-propyl-lJf-inndazo[4:bHbOTiiK3i!ibI-5bitfb}methanesulfonamide as a brown powder. PartK
A laodficatkai of fee mdhod described in Part K of Example 45 was followed usmg.Vb44”-”ma»-7b6-”mix”exvloxy)b
vl]bTityi}ibn3nesnIftTmpride (0.S6 g, 1.8 mmol) as the starting material. MethanesoSbnic aaAydride (470 mg, 2.7 mmol) was added over a period of 24 hours. The crude prates was purified by column chromatography on silica gel (eluting sequentially with 90:10 nd &5:15 dk&kHomethane:methanol), recrystallization from ethyl acetate, and a urmui RaysaQizaticHi from 2-propanol to provide 0.38 g of N-(4-{4-amino-7-[6-

(metlianesal&nyIanmo)he!xyloxy]-2-
yl}butyl)meth2nesulfonamide as a white powder, rap 138-140 °C.
'H NMR (300 MHz, DMSO-&) 5 7.92 (d, J= 9.4 Hz, 1H), 7.05 (d, J= 3.1 Hz, 1H), 6.98-
6.88 (m, 3H), 6.38 (s, 2H), 4,46 (m, 2H), 4.04 (t, .J= 62 Hz, 2H), 2.99-2.92 (m, 6H), 2.87
(s, 3H), 2.86 (s, SH), L82 (ao, 6H), 1.61 (m, 2H), 1.44 (m, 6H), 1.03 (m, 3H);
13CNMR(75MHz,I»b)bs)5 157.7,152.4,152.2,146.7,133.1,1253,121.4,112.1,
1092,108.3,67.6, UA, 42J, 4Z4,3933,39.49,29.7,29.0,28.7,27.4,26.7,26.3,25.6,
213,14.2;
MS (APCI) m& 569 (M + H)”;
AnaL Calcd. £br Cz&jgs&Si- %C, 52.80; %H, 7.09; %N, 14.78. Fomd: %C, 52.61;
%H, 7.13; %N, 14b2.

A modSScatioo of fee metibod described in Park K of Example 45 was followed using acetyt driaride (135 aL, 1.91 mmol) in lieu of methanesulfonic anhydride and N-{4-
yi]btfyi}me»3aacsuifi3oaadc (0.85 g, 1.7 mmol) as the starting matfiriai. The crude product was bf iiVH bjr coJonm cfaromatography on silica gel (eluting sequentially with 90:10 and 8?h20 iichloKioae&aiiennethanol). The resultmg white powder was stirred with water, i niwnTij fffrnbFbF. and dissolved in 50:50 dichloromethanennethanoL The solution was dnd over sodium snl-fetet filtered, and concentrated under reduced pressure. The resulting mmd was recrystalHzed from acetonitrile, and the crystals were dissolved in dicMoTOSDeftaneaneftanol, concentrated under reduced pressure, and further dried overnight itadff hibi vacuum at 60 °C to provide 0.30 g of b-(6-{4-ammo-l-[4-

(memanesulfbnyianmio)foutyI3-2-pb
yloxy}hexyl)acetamide as a white powder, mp 168-172 CC.
“H NMR (300 MHz, CDCk) 8 7.91 (d, J = 9A Hz, 1H), 7.78 (m, 1H), 7.04 (d, J= 2.5 Hz,
1H), 6.98 (m, 1H), 6.89 (dd,J= 9.4,2.5 Hz, 1H), 6.35 (s, 2H), 4.46 (m, 2H), 4.03 (t, J=
6.2 Hz, 2HX 3.04-2.96 (m,4H), 2.86 (m, 5H), 1.78 (m, 9H), 1.62 (m, 2H), 1.42 (m, 6H),
1.03(tJJ=75Hz,3H)
UC NMR (75 MHE, DMSCMJ) 5169b, 157.8,152.4,152.3,146.9,133.1,125.3,121.4,
112.1,1092,108.4,6b.6,44.6,42.4,39b, 38.8,29.5,29.0,28.7,27.4,26.6,25.7,23.0,
21.3,14.2;
MS(APO)»z 533 (M-rEf;
AnaL Calcd. forC2&a«bfiO4S- 0b5 H2O: %C, 58.13; %H, 7.60; %N, 15.64; %S, 5.97.
Found: %C, 57.90; %H, 7.69; %N, 15.54; %S, 6.23.

Part A
Uaderaaittogen wOacephab, a solution of (2-amino-2-methylpropylX7-
benzyk)xy-3-qbxjtnDoiiihb--yI)annae (6.5 g, 17.5 mmol), prepared in Part A of Example
45, in dicfafaEDBadtiane (200 mL) -was cooled to 0 °C; triethylamine (4.87 mL, 35.0 mmol)
and acetyi &kw&e (137 mL, 192 mmol) were sequentially added. The reaction was
stirred at 0 °C isr 30 mimd”“. allowed to warm to ambient temperature, and stirred for
three boors. The reaction was washed with saturated aqueous sodium bicarbonate (2 x)
and brine, dried over sodram sulfate, filtered, and concentrated under reduced pressure to
provide bM-droemyl-2-(3-m1ro-7-bemzytobb as a

PartB
The method described in Part C of Example 45 was used to convert the material from Part B to 6.16 g of 7yT-[2b3-ainmo-7-benzyloxyqtrinolmbylamino)-l,l-ditnethyletfayQacetamide, obtained as an orange solid. PartC
A modificatkEs of fee mefijod described in Part D of Example 45 was followed
using ?b2b3-amiaO"7-”GB»4aayqamb (6.16
g, 21.0 mmol) as foe ga.-rnw matbraT A solution of the intermediate in ethanol was heated at refine fix 34 hoots. Sodium hydroxide (1.25 g) and water (25 mL) were added, and the reaction was heated at igfitnr ft)r an additional 32 hours. The mixture was allowed to cool to ambient temperatere, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 4.79 g of iV'-[2-(7-benzyloxy-2-emoxymei3iyl-liy-imidazo[4,5'c]qumolin-l-yl)-l,l-dmethylethyT]acetamide as a yellow solid. PartD
The method described in Part E of Example 45 was used to convert N-[2-(7-benzytoxy-2--elfcorvBieablff-iirrida7b
(4.79 g, WJmaacS) to Ab;2b-bdMiymethvl-7-hydroxy-lb-iniidb2X)[455b]qumoub-l-yl) 1 J-dmiethyiefcyracetxiafc, obtained as a yellow solid. PartE
The aefcod described in Part L of Example 2 was followed. The material from Part D was tinted with “o-”-baryi 6-todohexylcarbamate (3.86 g, 11.8 mmol), and the reaction was (-"T”“p in fear hours. The crude product was purified by column chromatogcapfey (» siHca gd (elating sequentially with 95:5 and 92.5:7.5 (KrliinfrmwAMw rrvrtrenrJ) and the resulting solid was dried overnight under high vacaum to imorA, 4.69 g of terf-butyl {6-[l-(2-acetylamino-2-methylpTopyl)-2-etboryiiKdrbliWmida2X)[4bb]quinohb-7-yloxy]hexyl}caibamate as an off-white solid.

PartF
A modificaton of the method described in Part M of Example 2 was used to convert tert-butyl {6-[l-(2-acebaniHK)-2-methylpropyl)-2bthoxymethyl-li?-inuda2o[4,5-c]quraom)7-yloxy]hcxyl}carbamate (4.69 g, 8.44 mmol) to fert-butyl {6-[l-(2-acetylamino-2-bnfflbyipTcipb
yloxyjbexytycarbamate. ootsaued as a orange solid. The reaction was complete in one hour, and the product was used without purification. PartG
The me&od described in Part I of Example 45 was used to convert the material
from Part F to 4.S5 g of ierzJaasyi {64H2-acetylamino-2-methyh)iopb
e1ioxyme1hyi-lbbEraid3Eo(4J5-(r}quinoKn-7-yloxy]hexyl}carb obtained as an orange
solid. PartH
A modification of the method described in Part O of Example 2 was used to deprotect the material from Part G with hydrochloric acid in ethanol (100 mL of 3 M). Following the treatment of me crude product with ammonium hydroxide and the remainder of the work-up procedure, 3.64 g of iV- {2-[4-arnino-7-(6-aminohexyloxy)-2-emoxymemyl-15'-nnidazo[4?5-cjqumolin-1 -yl] -1,1 -dimethylethyl} acetami de were obtained as a tan solid and used wimout farmer purification. Parti
A modification of fee method described in Part K of Example 45 was followed ttsmg3T-{244-bnaci-7b6-bminoiicxykb
yl]-l,l-dmieaijfc(fayl}Ketenide (IJ2 g, 2.5 mmol) as the starting material. The reaction was roa in l-Hjefeyi-2-pjaio5doaie (55 mL), and after completion, the reaction was poured into dejomzjed vater (400 cL) aid stirred over three days. The mixture was extracted with dichloromeftaae {31200 mL), and the combined extracts were washed with brine, dried over sodium an”R'“i'». Uttered, and concentrated under reduced pressure. The residue was dissolved in &4mi dfaer (100 mL) and treated with a solution of hydrochloric acid in ethanoL A soW farmed, and me diethyl ether was decanted. The solid was partitioned between djefekmsnethane and dilute ammonium hydroxide. The aqueous layer was separated and a ti acted wim dichlorometnane (3 x 100 mL). The combined organic

fractions were washed, wife brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The resulting orange oil was triturated with diethyl ether
overnight to form a solid, winch was isolated by filtration and purified by column
chromatography on salica gel (elating with 92:8 dicMoromethaneanethanoI). The resulting
solid was dried oversight nnder high vacuum at 60 °C to provide 0.47 g of JV-(2-{4-amino-
2(thasyme”rjyl-7b6bmsfisaDesurihDyto
lb-diradh)1e(iryl)aL)elturtide as an off-white powder.
lH. NMR (300 MHz, DM9CW”) 5 S.20 (d, J= 9.1 Hz, 1H), 7.70 (s, 1H), 7.01 (d, J= 2.7
Hz, IE), 6.92 (HL 12), 6.S4 {m, 1H), 6.50 (s, 2H), 4.93 (s, 2H), 4.69 (s, 2H), 4.03 (m, 2H),
3.50 (q, J= 7,0 Hz. 2H), 2-92 (m, 2H), 2,86 (s, 3H), 1.80 (s, 3H), 1.74 (m, 2H), 1.48-1.38
(m, 6H), 1.18 (brs, 6H), 1.11 (t, J=7.0 Hz, 3H);
13CNMR(75 MHz,DMSOb) 5170.3,157.9,152.6,149.8,147.6,135.0,125.3,122.6,
111.4,109.6,108.4,67.6,65.7,64.6, 55.0,51.1,42.8,29.7,29.0,26.3, 25.9,25.6,24.0,
15.3;MS(APCI)m& 549(M + H)+;
Anal. Calcd. for Q-eKwNeOsS'OJO H2O: %C, 55.64; %H, 7.44; %N, 14.97. Found: %C,
55.98; %H, 7.29; %N, 14.87.

A modtficatMQ of CE roeahod described in Fart K of Example 45 was followed using JVb2b4-aHno»-7b6-an3inohexyloxy)-2-emoxyb
yi]-l,l-dhacAjfcAyI}acetarnide (12 g, 2.5 mmol) as the starting material and acetyl chloride (200 pL, 3 mmol) in Hen of methanesulfonic anhydride. Following cfaromatographic birHinttim the soHd was recrystallized from acetonitrile, and the crystals were dissolved in dichloromefliane:methanol, concentrated under reduced

pressure, and further dried under Mgh vacuum at 60 °C to provide 0.47 g of N-(2-{7-[6-
(acerylamino)hexyioxy]-4-amino-2-bioxymethyl- liy-imidazo[4,5-c]quiiiolin-1 -yl} -1,1-
dimethyletiiyl)acetainife as a white powder, mp 190-192 °C.
JH NMR (300 MHz, DMSOb) 8 &20 (d, J= 9.0 Hz, 1H), 7.77 (m, 1H), 7.70 (s, 1H),
7.01 (d, J= 2.6 Hz, 1H), 6J&3 (dd, J= 9.0,2.6 Hz, 1H), 6.50 (s, 2H), 4.93 (s, 2H), 7.69 (s,
2H), 4.02 (t, J= 6.4 Hz, 2H), 3.50 (m, 2H), 3.01 (m, 2H), 1.80 (s, 3H), 1.77 (s, 3H), 1.74
(m, 2H), 1.41 (m, 6H)r L18 fw s, 6H), 1.11 (t, J= 7.0,3H);
bCNMRbSMHz, DMSCWb 5 l?»-3f 169.2,157.9,152.6,149.8,147.6,135.0,125.4,
122.6,111.4,109-6, 108.4 57-6, 65.7,64.6, 55.0, 51.6, 38.8,29.5, 29.0,26.6,25.9, 25.7,
24.0,23.0,153;
MS (APCI) mJz 513 (M-i-Hf;
Anal. Cakd. facCriBbtbOb Q.m£): %C, 61.53; %H, 7.96; %N, 15.95. Founi %C,
61.65; %H, 8.05; %N, 15.88.

Part A
Hie rabhnth descahed in Parts A-H, M, and N of Example 2 were followed using 3-beazykgyaniSai in fiec of 4-bcnzyioxyaniline. The crude product was recrystallized fiom acetonfefle t» provide 7b)enzykixy-2-ethoxyrnethiyl-l-propyi-lJJ-iniidazo[4,5-c]qumoBn-4-aBHBe as a flocculent, white solid, mp 188-189 °C.
“H NMR (300 MHz, DMSOb) : 8 7.91 (4 J= 9.1 Hz, 1H), 7.52-7.30 (m, 5H), 7.13 (d, J = Z7 Hz, 1H% 7J» (dd, J= 8b, 2.6 Hz, 1H), 6.53 (s, 2H), 5b1 (s, 2H), 4.74 (s, 2H), 4.49-

4.44 (m, 2H), 3.54 (q, J= 7.0 Hz, 2H), 1.92-1.78 (m, 2H), 1.15 (t, J= 6.9 Hz, 3H), 1.00 (t,
.7=7.4 Hz, 3H).
13C NMR (75 MHz, DMSO-4J): 8 1573, 152.3,148.1,146.9,137.2,133.4,128.4,127.7,
127.6,124.9,1213,111.9,108.9,108.7,69.1,65.3, 64.2, 46.6,23.0,14.9,10.7.
MS (ESI) mfz 391.2134 (5912117 calcd for C23H26N4O2, M+H4).
Anal. Calcd. for CZSHKJVOZ; %C, 70.75; %H, 6.71; %N, 14.35. Found: %C, 70.49; %H,
6.57; %N, 14.22.
PartB
7-Benzyloib2H3bax5rofldbl-prop34-liibbb (3.9 g,
9.99 nnnol) was mixed wife e&aaoi and added to a Parr flask charged with 10% palladium on carbon (0.390 g) in ethanoL The flask was placed under hydrogen pressure and shaken for 18 hours. The reaction mbctnre was filtered through a layer of CEL1TE filter aid, and the filter cake was washed with warm DMF. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to yield 2.4 g of 4-amino-2-e1hoxymemyl-l-prc»pyl-lif-imidazo[4,5-c]quinohn-7-ol as a white solid, mp )250°C. “H NMR (300 MHz, DMS0-&) : 5 9.50 (s, IE), 7.82 (d, J= 8.9 Hz, 1H), 6.96 (d, J= 2.5 Hz, 1H), 6.81 (dd, J= 8.8,2.6 Hz, 1H), 6.45 (s, 2H), 4.73 (ss 2H), 4.47-4.41 (m, 2H), 3.54 (q, J= 7.0 Hz, 2H), 1.92-1.78 (m, 2H), 1.15 (t, J= 6.9 Hz, 3H), 1.00 (t, J= 7.4 Hz, 3H); I3CNMR(75MHZ,DMSC)BF) : 5 156.4,152.1,147.7,147.1,133.6,124.5,121.2,112.0, 109.8,1075,65.2,64.2,46.6,23.0,14.9,10.7;
AnaL Cakd. fir dbsoNb: %C 63.98; %H, 6.71; %N, 18.65. Found: %C, 63.71; %H, 6.48; bStf, 18-53, PartC
The meADddescxfecd in Pact L of Example 2 was used to treat 4-amino-2-eflM)xyjiiefib-l-prapyi-l&iamfazb4bb]quinoMn-7-ol (1.89 g, 6b9 mtnol) with cesium carbonate (4.10 & 12.6 umact) and icrt-buryl 2-iodoethylcarbamate (1.79 g, 6.60 mmol). Following iliinwihig ijilik porification, the product was recrystallized from acetonitrile to provide 1b6 f af»t-batyi pb4-amino-2-ethoxymethyl-l-propyl-lff-iniidazo[4,5-cjquinohb7-ykiryieflryrjcait)amate as a flocculent, white solid.

PartD
The method described in Part O of Example 2 was used to treat the material from Part C with 4 M hydrochloric add in ethanol to provide 7-(2-aminoethoxy)-2-emoxymeiihji-lbHapjblff-imViazbbbJqumolmbamiae, which was used without purificatioiL PartE
A suspension of 7b-”nmoeflwry)-2-e1iioxymemyl-l-propyl-lb-iinidazo[4b-c]qumduBbaraiae {Q-S7b g, 1.66 nmol) in dichloromethane (11 mL) was cooled to 0 °C. Methanesulfbmc anbytinde (0.503 g, 1.74 mmol) was added, and the mixture was stirred for 16 hours and allowed to rxn to ambient temperature. Saturated aqueous sodium carbonate (25 mL) was added, and the mixture was stirred for 20 minutes. The aqueous layer was separated and extracted with chloroform (3 x SOmL). The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was purified by column chromatography on silica gel (eluting with chloroform:methanol:ammonium hydroxide ranging in ratios from 99.6:0.36:0.04 to 97:2.7:0.3) and subsequent recrystallization from acetonitrile to yield 0.500 g of i\r-[2-(4-amino-2-ethoxymethyl-l-propyl-lH-miidazo[4bb]qranolin-8-yloxy)emyl]methanesulfonamide as white, granular powder mp 182-184-5b
!H NMR (300 Wfr, DABCMf) 5 7.93 (d, J= 9.1 Hz, 1H), 7.31 (t, J-= 62 Hz, 1H), 7.08 (d, J= 3.2 Hz, 1H), 6b5 (dd, J= 9X 2-6 Hz, 1H), 6.54 (s, 2H), 4.75 (s, 2H), 4.50-4.45 (m, 2H), 4.13 (t,J= 5b Hz, 2H), 3_55 (q, J= 7.0 Hz, 2H), 3.39 (q, J= 5.8 Hz, 2H), 2.98 (s, 3H), liB-1.79 BB, 2HX L15 (t, J= 7JO Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H); MS (APd) mt 422.1864 (b2.1862 calcd for CibyNbS, M+H); AnaLCafcd.&rCBHb(4=aS: %C 54.14; %H, 6.46; %N, 16.61; %S, 7.61. Found: %C, 54b3; bB, 6-5& %N, 16b6; %S, 7.63.


Part A
The methods described in Parts E, F, and G of Example 1 were used to convert 7-benzyloxy-4-cbloro-3-mteoquinDfine, prepared in Parts A-D of Example 1, to 7-benzyloxy-2-etnyl-l-(2-ph«K)xysfli5d)-lb-Jinidazo[4,5-c3quinoline. 2-Pheraoxyethylarame was used in lieu of isobutylamine in Part E, and triethyi orthopropionate was used in lieu of trimethyl orthobutyrate in Part G. PartB
The method described in Part J of Example 1 was used to convert 7-benzyloxy-2-emyl-lbbheooxyemylbLff-imidazobb-cJquinoline to 2-ethyl-l-(2-phenoxyethyl)-lif-
imirifl7j)[4.J5-J?]qnmnlTTt-7-rt1
PartC
A suspenaoBof2-”ifayl-4-(2-plieiK)xyemyl)-liybb (1.0
g, 3.0 mmol) and cssknn rsahrmate (1.49 g, 4.57 mmol) in DMF was stirred for 15 minutes; l-bxansagnacokor (0-6 mL, 4_5 mmol) was added dropwise. The reaction was heated at 65 "C md sored for 20 hoars, and then the solvent was removed under reduced pressure. The rcsadae was tBssuivBd in dichloromethane, and the resulting solution was washed seqnaaHity wim waer (3 x) and brine, dried over magnesium sulfate, filtered, and concentrated under endnced pnaauie to provide 1.3 g of l-[2-ethyM-(2-phenoxyethyl)-li7-bda2o[4,b)qniDab7-3iaxy}-3b-dime(}iyIbutan-2-one as an orange solid. ]H babR (300 Mat DMSOB) 5 9.06 (s, 1H), 8.44 (d, J = 9.3 Hz, 1H), 7.45 (d, J= 2.5 Hz, lH), 734 (dlJ= 9.1, US Hz, 1H), 7.23-7.18 (m, 2H), 6.91-6.86 (m, 1H), 6.78-6.75 (m, 2H), 532 {t, 2H), 5.05-4.98 (m, 2H), 4.44 (t, J= 5.0 Hz, 2H), 3.08 (q, J= 13 Hz, 2H), 1.43 (t,J= 7.6 Hi. ffl), 1-23 (s, 9H).

PartD
The method described in Part M of Example 2 was used to oxidize l-[2-ethyl-l-(2-
phenoxyefoyl)-lff-itmdazo[4bb]qmiiob (1.3 g, 3.0
mmol) to 1.4 g of 1b2-(fe)b5KJxido-l(2-phenoxyethyl)-libirQidazo[4,5-c]quiiiolin-7-yloxy]-33-dun£&yfbata&-2-cne, winch was isolated as an orange solid and used without purification.
JH NMR (300 MHz, m!SO-d£ 5 8.96 (s, 1H), 8.55 (d, J = 92 Hz, 1H), 8.12 (d, J = 22 Hz, 1H), 7.48 (dd, J=93? 3.0 Hz, IB), 7.23-7.17 (m, 2H), 6.91-6.86 (m, 1H), 6.76-6.73 (m, 2H), 5.38 (s, 2H), 5.04-4.99 (IB, 2H), 4.44 (t, J= 5.0 Hz, 2H), 3.07 (q, J= 7.5 Hz, 2H), 1.41 (t, J= 7.1 Hz, jnt, 1b4 (s, 9SS. PartE
Ammonium hydroacuk (6 mL) was added to a solution of the material from Part D in dichloTomethane (20 mL). p-Tohienesulfonyl chloride (0.629 g, 3.30 mmol) was added in two portions, and the mixture was stirred for 16 hours. The mixture was then diluted with dichloromethane and water. The aqueous layer was separated and extracted twice with chloroform. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was recrystallized from acetonitrile twice to yield 0360 g of l-[4-ainiQCK2-efiblbbpheiMbethyl)-lbb
3,3-dimearyIbutaB-2-one as fesfbexj, Tsirite needles, mp 238-239 °C (decomposition). JH NMR (300 MHz,DMSO-dt) 5 8.06 (d, J= 92 Hz, 1H), 7.24-7.2 (m, 2H), 6.96 (d, J= 2.5 Hz, 1H), 6SI-&M On, 2B), 6b4-6b0 (m, 2H), 6.36 (s, 2H), 5.19 (s, 2H), 4.96-4.88 (m, 2H), 4.40 (t,J= 5.032,22b 3.01 (q,J= 7.5 Hz, 2H), 1.40 (t, 7=7.2 Hz, 3H), 1.20 (s, 9H);
MS (APC3) mJz 447b402 (447 2396 cakd for CzeHsoNba, M+H); AnaL Cakd. fcr CjboNbObl-OHb %C, 67.22; %H, 6.94; %N, 12.06. Found: %C, 67.29; %H, 6b1: %R, 1ZQ5.


Part A
The methods nebrfntsA m parts A-D of Example 30 were used to convert 7-benzylox3bJV4b2-bjbenoxycflb!)quinoliiffi-3,4-diaEQiae to 2-ethyl-7-(2-morpholin-4-yl-2-oxoe&oxybl-ClbjfittJxyEflb-Lff-iinidazobS-cjquinoiine. IQ Part D, after the reaction mixture was filtered, the filtrate was allowed to stand for three days. Crystals formed and were isolated by filtration and washed with diethyl ether. The filtrate was concentrated under reduced pressure, and the resulting oil with triturated with a mixture of ethyl acetate and water. The resulting solid was isolated by filtration, washed with diethyl ether, and combined with the crystals isolated from the reaction mixture. The combined solids were recrystallized from methanoL, isolated by filtration, washed with cold hexanes, and dried overnight under twgfr vacuum at 70 °C to provide 2-ethyl-7-(2-morpholin-4-yl-2-oxoemoxy)-lb-5iieiiDxyeabblH4midazo[4,5-c]quinolitte as a white solid, mp 190-191 °C.
Anal. Cafcd. for CaS”N”Gk: SC, 67.81; %H, 6.13; %NS 12.17. Found: %C, 67.44; %H, 6.20; %N, 12.G5. PartB
The me&oA amJLicd k Pact E of Example 30 was used to convert 2-efhyl-7-(2-
morpnoln)byb2-(in)eaiaabl-(2-b”tbb (0.855 g,
1.86 mmoO to 0JC 5 rf2-(fib7b2biHHpholm-4-yl-2-oxoethoxy)-5-oxido-l-(2-pfaeiK)xyettrjbli?4EBdazD[4b-c'}qumolme. PartC
Under aiitiugm atmosphere, trichloroacetyl isocyanate (0.35 mL, 2.9 mmol) was added diopwise to a nhmon of me material from Part B in anhydrous dichloromethane

(335 mL), and fee reaction was stirred for two hours. The solvent was removed under
reduced pressure. The residue was diluted with methanol (23 mL), and a solution of
sodium methoxide (0.17 mL, 23 mmol, 25% in methanol) was slowly added. The
reaction was stirred overnight, and a precipitate formed. The precipitate was isolated hy
filtration, washed with three times with cold hexanes, and recrystaHized from ethyl acetate
to provide 0.495 g of 2-e&jd-7b-bnoEphohiH4-yl-2H3Xoethoxy)-1b2-phenoxyemyl)-lH-
Trniday-nbb-rjqnTnoJinbl-igrbpf as a white powder, mp 208-209 °C.
JH KMR (300 MHz, m£SO-di} S S.Q7 (d, J= 93 Hz, 1H), 7.22 (m, 2H), 7.05 (d, J= 2.7
Hz, 1H), 650 (t, J= ZJ Hz, IH), $30 (4 J= 9.0 Hz, 1H), 6.82 (d, J= 0.9 Hz, 1H), 6.79
(d, J= 0b Hz, IK), 639 (s, 2H), 451 (s, 4H), 439 (t, J= 4.8 Hz, 2H), 3.54 (m, 8H), 3.01
(q, J= 7.5 Hz, 2H), 1.40 (t, J= 15 Hz, 3H);
13C NMR(75 MHz, DMSO-d5) 5166J, 158.2,157.0,154.4,152.3,146.8,133.4,129.8,
125.3,121.7,121.4,114.6,111.8,109.6,108.8,66.7,66.4,66.3,45.2,44.6,42.0,20.3,
12.2;
MS (El) mJz 476.2282 (476.2298 calcd for C26H29N5O4);
Anal. Calcd for Cb-jNsO” %C, 65.67; %H, 6.15; %N, 14.73. Found: %C, 65.48; %H,
6.01; %N, 14.59.

The mrthodf described in Parts L-N of Example 2 were used to treat l-(2-inethyhKopyl)-2-propblibmaidaz»[4bb]quinoliQ-7-ol. In Part L, 2-0Kutnc»meflryl)leU4iijdio-2H-pyran was used as the alkylating agent The crude product was rccrystalfiaod bean acctonitrQe to yield l-(2-methylpropyI)-2-propyl-7-

(tefrahy(tabyrait-2-ytoe£hoxy)b as tan crystals, mp
126 °C (decomposition).
“H NMR (300 MHz, DMSO-b) 5 7.85 (d, J= 9.6 Hz, 1H), 7.03 (d, J= 3.0 Hz, 1H), 6.90
(dd, J= 92,2.9 Hz, IH), 6.37 (s, 2H), 4.28 (d, ,J= 7.6 Hz, 2H), 4.02-3.86 (m, 3H), 3.71-
3.61 (m, 1H), 3.46-334 (m, IH), 2.86 (t, J= 7.8 Hz, 2H), 2.21-2.05 (m, 1H), 1.90-1.77 (m
3H), 1.72-1.63 (m, IH), 1b8-1b7 (m, 4H), 1.02 (t, J- 7.4 Hz, 3H), 0.91 (d, J = 6.7 Hz,
6H);
MS (APC3) JHA 397J2600 (39bb604 cafcd fi)r C23H32N4O2, M+H);
AnaL Cakd, for CbbSbhb.lSSbk %C, 6737; %H, 8b3; %N, 13.66. Foimd: %C,
67.06; %H, 8.06; bSN, 1332.

Part A
3-HydiuxyfcaahydioiiiLtm (0375 mL, 4.64 romol) was added to a suspension of 1-(2-mei3bsq)b2bE5w!-ia4Bm&zof4b-c]qirinolin-7-ol (1.0 g, 3.5 mmol) and triphenyiplKKpiHDe (IS g, 5.7 TTHOOJ) in THF. Diisopropyl azodicafboxylate (1.1 mL, 5.6 mmol) was added dmpwse over a period of three minutes, and the reaction was stirred for 48 hoars. The sairesbwss removed under reduced pressure, the residue was purified by column ohromaogaafcy 00 sifica gel (elating with 98:2 dichloromethaneimethanol) to provide 1.1 gof !bHneftrygHtJ|]9b2-piopyl-7-(te1ib cjtjuinoline as an off-white, crystalline solid.

PartB
The method described in Part M of Example 2 was used to treat l-(2-
methylpropyl)-2-propyl-7btetrahb (1.1 g,
3.1 mtnol) with mCPBA (1.07 g, 3.72 mmol). The crude product was purified by column
chromatography on sifica gel to ad&ni 0388 g of 1b2-memylpropyi)-5-oxido-2-propyl-7-
(tetxahydrofiiran-3-ykary)-ljJ-«aklazb as a yellow solid.
PartC
Th” TbbVbd 4"““" flmj w. pair F of F-xampiR 57, was nsftd to aminate me material
from Part B. The erode product was ieczystaHized from acetonitrile to afford 0242 g of 1-
(2-methybmjpyl)-2-bgo;yl-7btaiiLydi.oforan-3b lH-imidazo[4,5b]quinolui-4-
arnine as wMte needles, Tnp 178-182 °C.
“H NMR (300 MHz, DMSCWs) 5 7.87 (d, J= 9.0 Hz, 1H), 7.02 (d, J= 2.7 Hz, 1H), 6.89 (dd, J= 8.9,2.7 Hz, 1H), 6.40 (s, 2H), 5.13-5.09 (m, 1H), 4.29 (d, 7= 7.3 Hz, 2H), 3.96-3.73 (m, 4H), 2.86 (t, J= 7.5 Hz,2H), 2.33-1.97 (m, 3H), 1.84 (sextet, J= 7.5 Hz, 2H),
1.02 (t, J= 7.4 Hz, 3H), 0.91 (d, J= 6.4 Hz, 6H);
13CNMR(75 MHz,DMSO-id) 5 155.6,152.6,152.0,146.4,132.7,125.2,121.4,112.0,
109.2,109.0, 76.9, 72.3,66.4, 51.2,32.5,28.7, 28.5,20.9,19.1,13.8;
MS (APO) mJz 3692298 (3692291 calcd for C2iH2sN4O2, M+H);
Anal. Calcd. for CziHzsNbOs: %C 68.45; %H, 7.66; %N, 15.20. Found: %C, 68.11; %H,
7.87; %N, 15.01.


The methods drscribad ia pans A and B of Example 51 were used to prepare 2-(2-methoxyeth3i)-l-propyi-lj9:imklazoi4pb]quinoliii-7-ols which was treated according to the methods described in Example 55. The erode product was purified by column chromatography on silica gel and subsequent recrystallization from 2-propanol to afford 2-(2-methoxye1hyl)-l-prof)yl-7bt«Siahyb amine as a tan powder, mp 192-194 °C.
“H NMR (300 MHz, DMSCMr) 5 7.90 (d, J= 9.2 Hz, 1H), 7.02 (d, J=- 2.6 Hz, 1H), 6.89 (dd, J = 9.0,2.6 Hz, 1H), 6.41 (s, 2H), 5.14-5.10 (m, 1H), 4.46-4.41 (m, 2H), 3.97-3.74 (ms 6H), 3.30 (s, 3H), 3.16 (t, J= 6.8 Hz, 2H), 2.33-2.21 (m, 1H), 2.08-1.98 (m, 1H), 1.87-1.74 (m bH), 0.98 (t, J- 7.4 Hz, 3H);
MS (APC1) mb 3TL2074 (37120E3 calcd fijr C20H26N4O3, M+H); Anal. Cakd. for CafizsN,b: %Q 64.85; %H, 7.07; %N, 15.12. Found: %C, 64.88; %H, 7.03; %N, 15b0.
Examples 57-92
An acid ndnri”“- (l.; eqanvaleras) was added to a culture tube containing a solution of7b3-aaiiaopropu&y}-l-(2-Hg&)l|b
(4.4 mgJmL) in tidumfcun (5 mL). The culture tubes were capped and placed on a shaker overnight (18 hownt TbevolMiks were removed by vacuum centrifugalion. The compounds were pacified by preparative high performance liquid chromatography (prep HPLCJusing a Wjfeo Fraction Lynx automated purification system. TheprepHPLC fractions were amrvzed using a Micromass LC-TOFMS, and the appropriate fractions

were centrifuge evaporated to provide fee triflaoroacetate salt of the desired compound. (Column: Phenomenex Luna Cl 8(2), 212x50 mm, 10 micron particle size, 100A pore; flow rate: 25 mLJmin.; non-Enear gradient elution from 5-95% B in 9 TTUTI3 then hold at 95% B for 2 min., where A is 0.05% triflmnoacetic acidJwater and B is 0.05% trifluoroacetic acidJacstantoile: fraction collection by mass-selective triggering.) The table below shows the stroctore mads in each example and the observed accurate mass for the isolated trifluoroacetste saiL









































































The methods described in Parts A-I of Example 2 were followed using 3-benzyloxyaniline in lieu of 4-benzyloxyaniline and methoxypropionyl chloride in lieu of ethoxyacetyl chloride. 2-(2-Me1hoxye1hyI)-l-propyl-lb-imidazo[4,5-ci]qunioliti-7-ol (2.0 g, 7.0 mmol), 4-(dimethylamino)pyridine (0.085 g, 0.70 nanol), and tetrahydrofuran (70 mL) were combined, and the mixture was cooled to 7 °C with an iceJwater bath. Isopropyl isocyanale (0.689 mL, 7.01 mmol) was added duywise to the mixture. After 20 minutes the cooling bath was removed and the reaction was srirred for an additional 24 hours. Analysis by HPLC indicated that no product had fenned. M-batyltin dilaurate (1 drop) was added, and the reaction was stored at “&&”“““ tsmpectore for 2.5 hours and then heated at reflux for 48 hours. The safoeci was evaluated under reduced pressure, and the residue was dissolved in dichkxroinettane. The organic fiaction was washed sequentially with water and brine, dried over filtered, and concentrated under reduced pressure. Purification by coSannt cbromatography on silica gel (eluting with a chlorofonnbQeihariorbnrrnonram Ljbrrande gradient) provided 1.97 g of 2-(2-me1hoxyemyl)-lbKopyl-Lff-hiDda2o£AT5(jJquincdm-7-yl isopropylcarbamate as a white solid.

PartB
2b2-Methoxyethyl)-l-propyl-liy-ib
(1.89 g, 5.10 mmol) was dissolved in cMorofbnn (41 mL). 3-Chloroperoxybenzoic acid (60% pure, 1.60 g, 5.56 mmol) was added in one portion. After 30 minutes the golden solution was diluted with ammonium hydroxide (41 mL), andb-toluenesulfonyl chloride (0.927 g, 4.86 mmol) was added. The reaction was sfered for labours. The layers were separated and the aqueous fraction was extracted wife. dicMoromethane. The organic fractions were combined, washed sequeniii2y witt-mmer atri Isine, dried over magnesium suliate, filtered, and concentrated under mftireai prgstaiie. The solid residue was recrystaHized from acetonitrile tD provide CL9S6 g of 4-amrao-2-(2-methoxyetibyl)-l-prcbl-1b-inridazo[4,5-c]qumolin-7-yl isopropylcarbamate as a granular, peach-colored solid, mp 144.0-146.0 °C.
JH MMR (300 MHz, DMSO-(fc) 5 7S6 (d, J= 9.0 Hz, 1H)5 7.68 (d, J= 7.62 Hz, 1H), 7.22 (d, J= 2.43 Hz, 1H), 7.01 (dd, J= 2.5, 8.9 Hz, 1H), 633 (s, 2H), 4.48-4.43 (m, 2H), 3.81 (t, J= 6.7Hz, 2H), 3.67 (sextet, J= 6.8 Hz, 1H), 3.28 (s, 3H), 3.17 (t, J= 6.7 Hz, 2H), 1.81 (sextet, J= 7.4 Hz, 2H), 1.14 (d, J= 6.6 Hz, 6H), 0.97 (t, J= 7.3 Hz, 3H); 13CNMR(75 MHz,DMSO-tf(;) 8 153.5,152.1,150.5,149.5,145.7,132.2,126.0,120.5, 117.4,116.0,111.9,70.1,58.1,46.1,42.6,27.1,23.0,22.4,1016; MS (ESI) mJz 386.2177 (386.2192 cafcd fix Cafe-NsQs, M4-H);
AnaL Calcd. for CaoEbNsOs: %C, 6232; %H, 7.06; SS, 18.17. Found: %C, 62.02; %H, 6.94; %N, 17.92.


PartA
2-Ethyl-H2i)faemoxyeaiyI)lHb (1.5 g, 4.5 mmol),
chlorofonn (45 mL), and triemylamine {0JS97 mL, 5-00 mmol) were combined. Methanesulfonyl chloride (0.348 mL, 430 mmol) was added dropwise to the mixture; a flocculent precipitate formed. The reaction was stirred for 72 hours and then quenched with methanol. The volatiles were removed under reduced pressure, and the residue was purifed by column chromatography on silica gel (eluting with a dichloromethane:methanol gradient) to provide 0.628 g of 2b&yl-1b2~pheno3bmyl)-lJ7-irriidazo[4,5-c]quinolin-7-yl methanesulfonate as a white solid. PartB
(0.625 g, 1.52 mmol) was dissolved in cMorofoon (15 mL). 3-Chloroperoxybenzoic acid (60% pure, 0.437 g, 1.52 mmol) was added in cos portion, and me reaction was stirred for 25 minutes. Ammonium hydroxide (25 mL) was added. A precipitate formed, and the reaction was stirred until the ptw;ipitam dissolved. jvTofaiaoesnifonyl chloride (0.290 g, 1.52 mmol) was added in one portion, ancfbereacaunimiiure was stirred for an additional 16 hours. The layers were Msbrntmb bb the aqueous fraction was extracted with dichloTomethane followed by chtarafem- The uigauics were combined, washed sequentially with water and brine, dried o”er sodzom snlrate, filtered and concentrated under reduced pressure. Purification brmkmm chromatogrbihy on silica gel (eluting with a fthinmfarm-TWfirtumnl n7t»nvniJTiTTi Tiyrimririe gradient) followed by recrystallization from acetonitrile provided 0.150 g of 4-amno-2-(diyl-1b2benoxyemyl)-lif-imidazo[4,5-c]quinoliu-7-yl methjKsotfcoate as an. anoge solid, mp 213.0-214.5 °C.

“H NMR (300 MHz, DMSO-tf”) 5 8.26 (d, J= 9.0 Hz, 1H), 7.50 (&,J= 2.5 Hz, 1H), 7.23-
7.17 (m, 3H), 6.88 (t, J= 7.3 Hz, 1H), 6.80-6.76 (m, 2H), 6.67 (s, 23), 4.98-4.94 (m, 2H),
4.42-439 (m, 2H), 3.39 (s, 3H), 3.04 (q, J = 7.5 Hz, 2H), 1.40 (t, J= 1.5 Hz, 3H);
13C NMR (75 MHz, DMSO-d”) 6 157.8,155 3,152.6,147.4,145.7,132.4,129.5,126.4,
122.0,121.0,118.2,115.0,114.2,113.8,66.4,44.4, T1X 20.0,11.7;
MS (ESI) mh 427.1444 (427.1440 calcd far CJIBBSBB M-+H);
AnaL Calcd. for C21H22K4O4S: %C 59.14; %SL 5J2&, %K, 13.14; %S, 7.52. Found: %C,
58.90; %H, 4.95; %N, 13.13; %S, 7b5.

Isopropyl isothiocyanate (255 jd”238 nnnoQ """s abd to a stirred suspension of iV-{2b4-ainincH7-(6-aiiunohexyk)xy)-2-edb
l,l-dmethyle&yl}acetamide {prepared as described m Part I of Example 49,1.02 g, 2.17 mmol)indichloromeihaiie(100mL)at0:)C The nriainrc -was stirred for 30 minutes at 0 °C, them was allowed to warm to room tanpexXtars and was stirred over the weekend. The solution was concentrated under reduced pEcssare. The exude product was purified by flash chromatography (silica gel, gratfio” efo&Hi with. 73-10% mefhanol in dichloTomethane) followed by recry.biT]iig”ni tram acetooitrile. The crystals were dissolved in 1:1 dichkMomethaneJmcftaBcl mad the resulting solution was concentrated under reduced pressure to afford a wfarte powder that was dried under vacuum at 60 °Cto yield 0.43 g of iVK2-{4-anrhx)-2(e&DX5inoiivl)-7-[(6-

{[(isopiupylaiirino)carbonotMoyi]aiimio}b
dime1hyle1hyl)acetamide as a white powder, mp 110-120 °C.
]H NMR (300 MHz, DMSO-J«r) 5 8 22 (d, J= 9.0 Hz, 1H), 7.71 (s, 1H), 7.23 (br s, 1H),
7.11 (d, J= 7.8 Hz, 1H), 7.03 (d, J= 2.6 Hz, 1H), 6.85 (dd, J= 9.0,2.6 Hz, 1H), 6.51 (s,
2H), 4.94 (s, 2H), 4.70 (s, 2H), 422 (hr s, 1H), 4.04 (1, J= 63 Hz, 2H), 3.51 (q, J= 7.0
Hz, 2H), 1.81 (s, 3H), 1.76 (m, 2H), 1.48 (m, 4H). 136 (in, 2H), 1.19 (s, 6H), 1.12-1.07
(m, 11 H);
13C NMR (75 MHz, DMSObs) S 1813,1703,157_9T 152.6, 149.8,147.6,135.0,125.3,
122.6,111.4,109.6,108.4,67.6,65.7,64.6,55.0,51.1,45.1,43.6,29.1,29.0,26.6, 25.9,
25.7,24.0,22.7,153;
MS (APCI) mfz 572 (M + H)+;
AnaL calcd for C29H45N7O3S”0.40 H2O: C, 60.16; H, 737; N, 16.93; S, 5.54. Found: C,
60.16; H, 8.08; N, 16.84; S, 5.54.

Part A
Isopropyl isocyasBatc (2.05 mL, 2SL9 tnmol) was added to a stirred suspension of (2-
aamo-2-me&ylpropyI)(7-baizykacy-3-Bta (prepared as described in
Part A of Example 45,6.95 g, 19.0 mmoO m dichloromethane (200 mL) at 0 °C. After appTOxknately 30 niiny”"". ttie rractioB 'wis1"1b was allowed to warm to room temperature

and was stirred overnight The solvent was removed under reduced pressure to afford 8.49 g of iV"(2-{[7-(beii2yloxy)-3-nitroqranolm-4-yi]amino}-l,l -dimethylethyl)-2V!-isopropylurea. PartB
A mixture of Ab2-{[7-(benzyloxy)-3biitrobnnolmbyI3ainmo}-l ,1-dimethyiefhrybJV'-isoiHXJpylurea (4.24 g, 939 mmof) arid 5% ptenrmm on carbon (1.0 g) in acetanrtrile (700 mL) was hydrogenaled at 30 pa (Z.l x 105 Pa) overnight on a Parr apparatus. Hie mixture was filtered through CELZTE Stasz agent, which was subsequently rinsed with acetardtrile and dichlorome&aae. The fEfcate was concentrated under reduced ) pressure to yield 3.67 g of JVb2-{[3-aminc)-7-(benz34axy)qimK)mir4-yl3arnino}-l,l-
dimethylefliyl)-7V-isopropylurea as a pale yeBow foam feat was used without purification. PartC
The material from Part B was combined with ib2-{[3-anrino-7-
(benzyloxy)qumolmb-yl]amiBo}-l,l-dii]bb from another
experiment, suspended in toluene, and concentrated under reduced pressure. The N-(2-{[3-ammo-7-()enzyloxy)qumolmbyl]ainmb
g, 10.8 mmol) was converted into i\b{2-[7-(benzyloxy)-2-(emoxymemyl)-lif-imidazo[4,5-c]qumohb-l-yl]-l,l-dime1hylethyl}-JVI-isopropylurea using the method described in Part D of Example 45. The crude product was purified using flash cfaromatography (silica gel, I elution with 6% methanol in dichtoiomemzne) to afrani 3b1 g of AT-{2-[7-(ben2yloxy)-2-(e&oxyme1hyl)-lH-imida2»[4J5b]qinnolE-l-y13-M-drabrbb an off white solid. PartD
A mixture of N-{2-[7-(Joesriyk3xjbbbabmf&yblBb
yl]-14-bmie1faylemyl}-JV'-isopiopyinrea QJB2 g, 7 JO mnxS) and 10% palladium on carbon (0.92 g) in ethanol (100 mL) was bydjogeuaeri at 50 psi (5.5 x 105 Pa) overnight on a Parr apparatus. The mixture was filtered ibmimfr. OEUTE filter agent and the filtrate was concentrated under reduced pressnrc ID yieifi 3.17 g of 3T-{2-[2-(e1hoxymethyl)-7-hydroxy-lff-imidazo[4bb]qtihi(rfm-l-v!]-lJl-biiMefibeflryl}b-isoprob as a yellow solid.

PartE
Following the method described in Part L of Example 2, JV~{2-[2-(ethoxymethyl)-
74iydroxy-li?-iimdazo[4,5-c]quinolm-l-yb (3.12 g,
7.80 nnnol) was treated with tert-butyl 6-iodonexykarbamzte (2.81 g, 8.58 mmol) to afford 4.31 g of tert-buryl 6-{[2-(elhoxynieiiFyl)4-(2b[(iso|ttupyiainb
2be&ylpropyl)-liy-iinidazo[4,5b3bb 'boe material was
used without purification in the next step.
PartF
A modification of the method described in Part M of Example 2 was used to convert iert-butyl 6-{[2bethoxvmefhyl)-lbb(iMUbu|)yLiiinb
methylpiopyty-liiZ-imidazobSblqimb (4.31 g, 7.20 mmol)
into teJt-butyl 6b{[2betlK)xyme&yI)-1b2-{[(isoprop)iaim
me1hylpropyl)-5HDxido-lif-niridazo[4,5b]qb which was
used without purification in the next step. PartG
The material from Part F was converted into 4.20 g of te7?-butyl 6-{[4-amino-2-(ethoxymemyl)-l-(2-{[(isc)propylanTmo)carbonyl]amino}-2-methylpropyl)-liir-inndazo[4,5b]qumohbn-7-yl]oxy}hexylcarbamate using the method described in Part I of Example 45. PartH
A solution of terf-butyl 6b{[4-amiao--2-(€fifflxymeaiyI)-I-(2-{[(isopropylammo)catbonyl]amrao}-2-”Deb
yl]oxy}hexylcarbamate (4.20 g, 6.84 mraoQ B3M BQ in efljaool (50 mL, 150 mmol) was heated at reflux for five nmsbes, tans flowed to cooi to room temperature and was concentrated under reduced basam. Tic resahang orange solid was dissolved water and the solution was washed with dk&oconasdiane (2 x). The aqueous layer was treated with ammonium hydroxide until a bask sfiis readied, then was extracted with dichloromemane (3 x). The combined O|BC layos were washed with brine, dried over sodium sulftte, filtered, 2nd concentiatod to jidd 258 g of 7J-{2-[4-amino-7-[(6-ammohexyl)oxy]-2befliorymearblbiBnd»Dcb4bb]qimiomi-l-yl3-lJ-bb Ab-isopropylureaasadwkorangesohd-

Parti
Isopropyl isocyanate (190 uL, 1.93 nnnol) was added to a stirred solution ofiV-{2-[4-amincH74(6-ammohexyl)oxy]-2bethoxym
dime«fayle£byl}-JV-isopropylurea (0.90 g, 1.75 mmol) in cBcbkiramethane (50 mL) at 0 °C. Afler approximately 30 minutes, the solution was allowed to warm to room temperature. A precipitate formed and themixture was stirred avsrt3se weekend. The solvent was removed under reduced pressure and the erode protect was panSed by flash chromatography (silica gel, gradient station wife £-10% nje&anoi in dichloromethane) to provide a solid that was dried under vacwua at 60 X to ykid 034 g of iV-(2-{4-amino-2-(ethoxymethyl)-7-[(6- {[(is0propylamiix))carbocryIjarsb
c]quinolin-l-yl}-l ,l-dimethylet&yl)-#bsopiopyhirea as a tan solid, mp 205-209°C. lH NMR (300 MHz, DMSObr) 8 %J2 (d, J= 9.1 Hz, 1H), 7.03 (d, J= 2.5 Hz, 1H), 6.85 (dd, J= 9.0,2.5 Hz, 1H), 6.57 (s, 2H), 5.70-5.65 (m, 3H% 5.57 (d, J= 7.7 Hz, 1H), 4.93 (s, 2H), 4.70 (br s, 2H), 4.04 (t, J= 6.3 Hz, 2H), 3.73-3.63 (m, 2H), 3.51 (q, J= 7.0 Hz, 2H), 2.97 (m, 2H), 175 (m, 2H), 1.44-1.35 (m, 8H), 1.12 (t, J= 7.0 Hz, 3H), 1.07-0.99 (m, 16H)i
13C NMR (75 MHz, DMSO-(Jtf) 6 157.9,157.8,157.2,152.5,150.2,1473,135.0,125.3, 122.6,111.5,109.6,108.2, 67.6,65.6,64.4,54.2,52-0,41.1,40.9,39.4,30.4,29.1,26.6, 26.4,25.7,23.6,153; MS (APO) mJz 598 (M + H)+;
AnaL calcd for CsiHsoNgObl .00 Hb C, 6037; H, 830; K, 18.17. Found: C, 60.65; H, 8.66; N, 1820.


Acetyl chloride (180 fiL, 2.53 mmol) was added to a stirred solution of iV-{2-[4-
anmio-7-[(6-ammohexyl)oxy]-2bethoxyinetiryI)b 1 -
dimeihylethyl}-iV-isopropylurea (prepared as described in Parts A-H of Example 369,1.18
g, 2.30 mmol) and trietbylamine (0.64 mL, 4.60 mmol) in dichloromethane (100 mL) at 0
°C. After approximately 20 minutes, the solution was allowed to warm to room
temperature and was stirred overnight The solution was transferred to a separatory funnel
and washed with water (2 x). The organic layer was dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The erode product was purified by flash
chromatography (silica gel, elution with 10% methanol in dfchkromethane) to yield 0.34 g
of N-(6- {[4-ainmo-2-(emoxymet%b1b2-{[(isqpro|b amino} -2-
TnefayTprnpyl)-1 H-imiAa7rt[dbypmcahb%.ybbhbb)i!ubvmiAe: as a tan Solid, mp 90-
110 °C.
JH NMR (300 MHz, DMSO-d6) 5 821 (d, J= 9.1 Hz, 1H), 7.79 (m, 1H), 7.03 (d, J = 2.6
Hz, 1H), 6.85 (dd, J= 9.1,2.6 Hz, 1H), 657 b 2H), 5.70-5b5 (m, 2H), 4.93 (s, 2H), 4.73
(br s, 2H), 4.04 (t, J= 6.4 Hz, 2H), 3.72 b 1H), 3b1 (m, 2H), 3.03 (m, 2H), 1.78 (s, 3H),
1.76 (m, 2H), 1.42 (m, lffl), 1.12 (t, 7- ~3 Hi, 3H), 1.07-1.04 (m, 8H);
13C NMR (125 MHz, DMSCW”) 5 169Jb 1S&A 157 3,152.5,150.3,147.4,135.1,125.4,
122.6,111.6,109.8,108.7,67.8,65.7,643,54 J, 52.2,41.0,38.9,29.5,29.0,26.6,26.5,
25.7,23.6,23.0,153;
MS (APCT) mJz 556 (M + H)+;

AnaL calcd for C29H45N7O4»0.50 H2O: C, 61.68; H, 8.21; N, 1736. Found: C, 61.81; H, 8.43; N, 1722.

Methanesulfonic aahydride (0.34 g, 1.93 mmol) was added to a stirred solution of N- {2-[4-ammo-7-[(6-ammohexyl)oxy]-2bethoxymebb
yl]-1,1 H3imethylethyl} -iV-isopropylurea (prepared as described in Parts A-H of Example 369,10.9 g, 1.75 mmol) and triethyiamine (035 mL, 3-5 mmol) in dichloromethane (50 mL) at 0 °C. After approximately 30 mim”b the sofadxxi was allowed to warm to room temperature and was stirred overnight The fbQowing morning, me solution was cooled to 0 °C and additional methanesulfonic anhydride (0.13 g) was »Mb After 30 minutes, the solution was allowed to warm to room tsHperzmre. After 2 bcRss, the solution was transfenb to a separatoryfumiel and washed-wife waEr (21) and brine. The organic layer was dried over sodium sulfate, fihaxd, and coocaiated under reduced pressure. The crude product was purified by flash diromatograpiry (si&ca gel, elution with 10% memanol in dichloromethane) followed b'bb'rm by chromatography on a HORIZON HPFC system (an automated, modular htjHh-j—bii “i unit"“ ffcrfh purification product available fixnn Biotage, Bnc, Charktiesvilk, Vrgima, USA) (silica gel, gradient elution wimO-40%CMAmchkmrfbrmwbeicCMAttasohitiOTof80:18:2 chloroformJmethanolJconcajtrated ammuwia hydroxide) to yield 031 g of iV-(6-{[4-amino-2-(ethoxymethyI)-l-(2- {[(Moprop3ri)nBPo)carfaonyIjamiDo}-2-memyipropyl)- \H~

nmdazo[4bb}qumolin-7-yl]oxy}hexb)medianesulfon2n3ide as an off white solid, mp
190-194°C.
“H NMR (300 MHz, DMS0-&) 5 8.21 (d, J= 9.1 Hz, 1H), 7.02 (d, J= 2.6 Hz, 1H), 6.94
(t, J- 5.8 Hz, 1H), 6.85 (dd, J= 9.1,2.6 Hz, 1H% 632 (s, 2H), 5.70 (s, 1H), 5.66 (d, J=
7.6 Hz, 1H), 4.93 (s, 2H), 4.72 (br s, 2H), 4.04 (t, y = 6-3 Hz, 2H), 3.72 (m, 1H), 3.51 (q, J
= 7.0 Hz, 2H), 2.94 (m, 2H), 2.87 (s, 3H), 1-76 (m, 2E), 130-130 (m, 12H), 1.21 (t, J=
7.0 Hz, 3H), L05 (d, J= 6.5 Hz, 6H);
DC NMR (75 MHz, DMSCW”) 5157.8,1571!, 15i6,150.1,147.6,134.9,125.3,122.6,
111.4,109.7,108.4, 67.5,65.6,64.4,54.2,51.9,42.8, 40.9,29.7,29.0,26.4,26.3,25.6,
23.6,153;
MS (APCT) mJz 592 (M + H)+;
Anal calcd for C28H45N7O5S«0.12 H2O: C, 56_57; H, 7.6S; N, 16.49. Found: C, 56.25; H,
8.09; N, 16.37

PartA
Triethylatnine (31.88 mL, 228.77 na«30fcflo«»bb2b-dmiettiyl-13-dioxolan-4-metnanamine (20.0 g, 15231 mmol) were added to m sokakm of 7-benzyloxy-4-chloro-3-nitroquinoline (48.00 g, 15231 mmol) m mcaiactHiicteiic (400 mL), which was then stirred at ambient temperature for 6 newts- He erode reaction mixture was concentrated under reduced pressure, and lie resulting mid was treated with water. The mixture was stirred for 1 hour. The solid was collected by filtration, washed wife water, dried, suspended in diethyl ether (400 mL), sonkjtni, and the resulting precipitate material was collected by filtration. TheptodoctwasdbedK)dervacuiimat40DCforl2hoursto
-205-

afford 60.1 g of (7-ben2boxy-3-nifro-qamo6ib
yi)methyl]aniine as a yellow solid, mp 154-155 °C.
!H-NMR (300 MHz, CDC13) 5 9.74-9.62 (br m, 1H), 932 (s, IB), 8.15 (d, J= 9.4 Hz,
1H), 7.51-731 (m, 6H), 7.15(dd, J= 9.4,2.7 Hz, 1H), 5.21 (s, 2H), 4.48-4.37 (m, 1H),
4.16-4.05 (m, 2H), 4.04-3.93 (m, 1H), 3.74 (dd, J= 8.5, 5.9 Hz, 1H), 1.54(s, 3H), 1.40(s,
3H);
MS (APC1) Jӣ 410.1 (M4H)+.
PartB
A solution of sodium difhionate (85% pare, 135-07 g, 659.42 mmol) and potassium
carbonate (101.27 & 732.73 mmol) in water (450 mL) was added dropwise to a
mechanically stared mixture of ethyl viologen dlbromlde (1.1 g, 2.93 mmol) and (7-
benzyioxy-3-mtro-quinomi4-yl)[(2,2-dimedbb (60.0 g,
146.54 mmol) in dichloromethane (500 mL) and water (50 mL). "The reaction mixture was stirred at ambient temperature overnight and then dilated with water (600 mL) and stirred for an additional 10 minutes. The organic phase was separated and the aqueous layer was reextracted with dichloromethane (400 mL). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford 55.60 g of 74)enzyloxy-iV4-[(2b-dimethyl[l,3]dioxolan-4-yl)methyl]quinoline-3,4-diamine as a brown foam.
b-NMR (300 MHz, CDCI3) 5 8.38 (s, 1H), 7.B3 ((L J~ 93 Hz, 1H), 7.51-7.28 (m, 6H), 7.18 (dd, J= 92,2.5 Hz, 1H), 5.16 (s, 2H), 4J5 (brs, 1H), 430-4.18 (m, 1H), 4.02 (dd, J = 8.3,6.5 Hz, 1H), 3.81 (br s, 2H), 3.68 {6d,J= 83, dJ Hz, IH), 3.60-3.46 (m, 1H), 3.40-3.25 (m, 1H), 1.52 (s, 3H), 1.37 (s, 3H); MS (APCT) mJz 380.0 (M+H)+. PartC
Triethylamme (25.53 mL, 183.17nsaob was added ID a sohnian of 7-benzyioxy-
Jb-[(2b-dmethyl[l,3]diOTolan-4-yl)mefi»jl|bDofinb (55.60 g, 146.54
mmol) in dichloromemane (500 mL) at 0 "C Qropwise addition of ethoxyacetyl chloride (22.45 g, 183.17 mmol) to the reaction mixtae followed, aid the reaction mixture was ilium 1. J In lii On 1 limn M in ill iji ill ii nipiiaMi The reaction mixture was concentrated under reduced pressure aad flie reskfaie wm added to a mixture of triethylamine (61.3 mL,

440 mmol) in ethanol (350 mL) and heated to reflux far 16 hours. The reaction mixture
was concentrated under reduced pressure, extracted with dichloromefhane (3 x 300 mL),
washed wifh water (300 mL) and brine (300 mL) and dried over sodium sulfate. The crude
material was purified by flash column chromatography (silica ge&, emted with 5% CMA in
chloroform) and concentrated under reduced pressure to erre 42b g of material as abrown
solid. The material was recrystallized from (fietibyi efiw to aftbrd 37.5 g of 7-benzyloxy-
l-[(2b-(mnedryI[133dioxolaib4-yl)memb
as a white crystalline solid, mp 110-111 °C
b-NMR (300 MHz, CDC13) 5 9.23 (&, 1H), 8.161± J= 92Hz, 1H), 7.75 (d, J= 2.7Hz,
1H), 735-7.31 (m, 6H), 525(&, 2H), 5.00 (d, J= 12.7 Ez, IH), 4.93-”.75 (m, 3H), 4.72-
4.60 (m, IH), 4.18 (dd, J= 8.6, 62 Hz, IH), 3.87 (dd, J= &J, 62 Hz, IH), 3.63 (q, J= 7.0
Hz, 2H), 1.45 (s, 3H), 1.29 (s, 3H), 1b5 (t, J= 7.0 Hz, 3Hfe 13C-NMR (75 MHz, CDC13) 6
157.8,150.9, 146.9, 145.7,136.5,135.4,134.9,128.7,128.2,127.7,1212,118.9,112.4,
111.5,1103, 74.7, 70.2,66.8,66.4,65.5,48.4,26.6,25.1,15.0;
MS (APC1) mJz 448.1 (M+H)+;
AnaL calcd for C26H29N3O4: C, 69.78; H, 6.53; N, 9.39. Found: C, 69.82; H, 6.74; N,
9.34.
PartD
Palladium hydroxide (Peariman's catalyst) (20 % wt% palladium on carbon, 2.2 g)
was added to a solution of 7-ben2yioxy-H(2b-bmefirjbLb)diaxoIanbyl)metiiyi]-2-
emoxymeihyl-lb-imidazo[4b-c]quinolme (222 g, 49.6 mmol) in acetonitrile (400 mL)
and the reaction mixture was hydiogenated (30 pa, 2.1 x 105 Pa) for 24 hours on a Parr
tipparat'ip, The crude reaction rrtixlu1b was jffln”wii with. 1:1 cfaksrofonjiJrnethanol (1 L),
men was filtered through a layer of CELTTE fUerageifi. The fikrate was concentrated
under reduced pressure and tritmated wim amwiliTk. The resulting crystalline material
was collected by filtration, washed wim araJnwtrfK and died to afford 16.55 g of l-[(22-
dmemyl-13boxolan-4-yl)tiiemyl}-2be&b as a
white powder, mp 239-240 °C. MS (APCI) mJz 358.1 (M+H)+;
AnaL calcd for C19H23N3O”: C, 63b5; H, 6.49; N, 11.76. Found: C, 63.88; H, 6.78; N, 11.75.

PartE
Using a modification on the procedure described in Part L of Example 2, l-[(2,2-dmiemyI-13boxolanbyl)memyl]-2-(etbxb
(8.50 g, 23.8 mmol) was treated with tert-butyi 2-iodoe”n}icaibamate (7.10 g, 26.2 rrrmol)
and cesium carbonate (11.62 g, 35.67 mmol) in DMF (120 mL). During the workap, after
the reaction mixture was concentrated under redaced pressure, the residue was treated with
water (75 mL) and stirred for 30 minutes. A [i re q»'bf »g ra)fcrt?fl by filtration and
washed with dierhyl ether to yield 8.7 g of tert-kfoyl 2-b-{(2bdninemyI-l,3-dioxolan-4-
yl)methyl]-2betlicbyme11ryl)-l#bb as an
off-white solid, mp 152-153 °C. MS (ESI) mJz 501.3 (M+H)+;
Anal, calcd for CabeWe: C, 62.38; H, 7.25; N, H-19- Found: C, 62.33; H, 7.45; N, 11.08. PartF
mCPBA (75% pure, 7.6 g, 34 mmol) was added to a stirred solution of tert-butyl 2-{[H(2,2-dmemyl-13-dioxolatt-4-yl)me&ybb
c]qumolin-7-yl]oxy}ethylcarbamate (8.5 g, 17 mmol) in dichloromethane (100 mL) at room temperature. The reaction mixture was stirred for 4 hours, then was diluted with dichloromethane (50 mL), washed with 4% aqaeoos sodium carbonate (2 x 75 mL), brine (100 mL), and concentrated under reduced pressure. The issadoe was dissolved in dichloromethane (100 mL) and concentrated ammonium hydroxide (50 mL) was added. The mixture was cooled to 0 °C andp-tolaepesaliraryi chloride (4.04 g, 21.2 mmol) was added in portions. The reaction mixtee was afiowed to wxm to room temperature and was stirred for 16 hours, then was diluted m& dk&knamdteBK (200 mL) and washed with 2 M aqueous sodium carbonate (2 x 150 mL). The aqueous layer was back-extracted with dichloromethane (100 mL), The ccanhraed organic lasers were washed with brine, dried over sodium sulfate, filtered, and coocBmacd. The sobd was triturated with diethyl ether and isolated by filtration to yield 3-55 g aCtBr£batyL 2-{[4-amino-l-[(2)diraethyl-lb-dioxolanbyi)me1hyI]-2befl»xjTOe&y9-lb yl]oxy}ethylcarbamate as a white powder, mp S2-S4 °C. MS (APCI) mJz 5163 (M+H)”;

AnaL calcd for C26H37N5O6: C, 60.57; H, 7.23; N, 13.58- Focrnd: C, 60.28; H, 7.55; N, 13.45.

A suspension of tert-butyl 2-{[4-amiiK)-14(2b2-dnnefliyl-13-dioxolaa-4-
yl)memyl]-2-(emoxymeAyl)4i?-imidazo[4,5b3(Ibb
(prepared in Example 372,1.5 g, 2.9 mmol) in ethanol (20 mL) and 4.3 M HC1 in ethanol
(2.70 mL, 17.5 mmol) was heated at reflux overnight. The reaction mixture was allowed
to cool to room temperature and a white solid was collected by filtration, washed with
ethanol, and dried under vacuum at 60 °C to yield 0.85 g of 7-(2-aminoethoxy)-l-[(2,2-
dmemyl-l,3boxolanbyl)memyl]-2bethoxyineb
dihydrochloride as a white solid, mp 221-223 °C
MS (APCT) mJz 376.1 (M+H)+;
AnaL calcd for C26H37N5O6'22HCM).5H2O: Q 4647; H, 6,09; N, 14.95. Found: C,
46.48; H, 6.13; N, 14.97.


A solution of diisopropyldiazodicarboxyiate (0.710 g, 3.50 nnnol) in
tetrahydrofuran (6 mL) was added dropwise to a mixture of l-[(2,2-dimefliyi-l,3-dioxolaa-
:- 4-yl)me1hyl3-2bethoxymetfcyl)-liy~irmb (prepared as described in
. Parts A-D of Example 372,1.00 g, 2.80 mmol), fert-butyi 4-hydiuxypiperidme-l -carboxylate (0.70 g, 3.50 mmol), and triphenyiplxjsphine {0.920 g, 350 mmol) in tetrahydrofaran (35 mL) at 0 °C. Hie resulting sointkm bss allowed to warm to room s temperature over 16 hours. The sohirionwascoaKxataadTniffa-rsdnced pressure. The erode product was purified by chromatograpiry (siSca gsi, gradaaot ehaaon with 0-50% CMA in chteroform) to provide 1.16 g of ierr-bntyi &-?n J{7 7-tfime4hyi~'\ ;b-dif)Yn1an-4-yl)meAyrj-2beflK)xymethyl)-lH-inHdazc)[4bb3(sm]Dfibbb carboxylate as a white foam. MS (ESI) mJz 541.4 (M+H)+. PartB
Using the method described in Part F of Example 372, tert-butyl 4-{f l-[(2,2-dimemyl-13-dioxolan-4-yl)memyl]-2-(emoxymemyl)-li?-miidazo[455-c]quinolm-7-yl]oxy}piperidine-l-carboxylate (12.66 g, 23.42 mmol) was converted into 7.04 g of ?ert-butyl4-{[4-ammo-l-[(2b-dimemyl-13-dioxolan-4-yl)me1hyl]-2-(ethoxymethyl)-liy-irmdazo[4,5-c3qumohn-7-yl]oxy}piperidme-l(arboxylate, which was isolated as a white solid, mp 158-159 °C. MS (ESI) mJz 556.6 (M+H)+;
AnaL calcd for C29H41N5O6: C, 62.68; H, 7.44; K 12.60. FOTnd: Q 6Z29; H, 7.40; N, 12J7.


Using the method described in Example 373, lert-buryl 4-{[4-amino-l-[(2,2-dtae&yl-l,3-dioxolan-4-yl)methyl]-2-(eraoxymeb
yl]oxy}piperidine-l-carboxylate (7.00 g, 12.6 mmol) was converted into 522 g of 3-[4-anmo-2bed»xymethyl)-7-(piperidiBb
1,2-diol dfoydrochloride, which was isolated as a tan -pctw&a, mp 278-280 °C. MS (ESI) mJz 416.2 (M+H)+;
AnaL calcd for C21H29N5O4«2HC1: C, 51.64; H, 6-40: N, 14J4; O, 14.52. Found: C, 51.48; H, 6.38; N, 14.13; 0,14.49.
Examples 376-386
A reagent (0.10 mmol, 1.1 equivalents) from the table below was added to a test tube containing a solution of 3-[4-anmo-7-(2-animDeftoxy)-2-{e1iK)xyme1hyl)-liy-imidazobjS-cJquinolin-l-yypropane-lb-diol dihydrochlcride (43 mg, 0.09 mmoL, prepared as described in Example 373) and AbbKisopaxbyiefhyiamine (0.051 mL, 0.29 mmol) in 7b,iV-dimethylacetamide (1 mL). The test tubes were capped and shaken for 8 hours at room temperature and then two drops of water were added to each test tube. The solvent was removed by vacuum centrifugation. The compounds were purified by preparative high performance liquid chromatography (prep HPLC) using a Waters FractionLynx automated purification system. The prep HPLC fractions were analyzed using a Waiare LCJTOF-MS, and the appropriate fractions wsre cestn&ge evaporated to provide the trifluoroacetate salt of the desired oanpound. Reversed phase preparative liquid chromatography was performed with noBrboear grari?qf# duiimi finm 5-95% B where A is 0.05% rnHuoroacetic acidJwater and 3 is 0.Q5N tjiSooroacetic acidJacetonitrile. Fractions were collected by mass-sdectzve tnggEnng. The table below shows the reagent added to each test tube, fee “ji™”mb o£fie resubing compound, and the observed accurate mass for the isolated trifluonaacstate salt





31.9 mmol) in tertrahydrofuran (25.5 mL) was added dropwise to a mixture of 2-(2-
mefhoxyetih5d)-l-propyl-lH-iinida2o[4,5(r]qamolin-7-ol (7.28 g, 253 mmol),
uiphenylphosphine (8,36 g, 31.9 mmol), and f-butyl 4-hydroxypiperidme-l-carboxylate
(6.42 g, 31.9 mmol) in tetrahydrofuran (191 mL) at 5 °C. The mixture was allowed to
warm to room temperature. After 2 days, the solvent was removed under reduced pressure
and the residue was purified by flash chromatography (stria, geL, gradient elation with 1.5-
4% meihanol in dicMoromethane) to yieid 9.77 g of iert-bifiyl 4-{[2-(2-nisflioxyethyl)-l-
piopyl-Iff-imid32o(4,5K:]qirinolm-7-yi}axb as a gray amorphous
solid. PartB
A stirred solution of tert-butyi 4-{[2-(2-mebKJxyeftyl)”l-jaopyl-lH-imidazo[4,5-c3qumolin-7-yl]oxy}piperidine-l-caiboxylate (9.77 g, 20,8 mmol) in chlorofoim (175 mL) at room temperature was treated with mCPBA (55% pure, 6.54 g, 20.8 mmol). After 45 minutes, concentrated ammonium hydroxide (175 mL) was added, followed by p-toluenesulfonyl chloride (3.97 g, 20.8 mmol). The mixture was stirred for 62 hours, then the layers were separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (silica geL, gradient elution with 1.5-12.5% CMA in chloroform) followed by reciystailrrafion. inm acetonitrile to afford 6.3 g of tert-butyl 4-{[4-amiiK)-2-(2-nie1hoxyemb yl]oxy}piperidme-l-carboxylate as tan crystals, rap 173-175 °C !H NMR (300 MHz, DMSOO 5 7.89 (d, J= 9 J. HE, 13b 7J0 (d, J= 2.A Hz, 1H), 6.93 (dd, J= 9.0,2.6 Hz, 1H), 6.39 (s, 2H), 4.70-4b1 {m, 1H), 4,46-4.41 (m, 2H), 3.81 (t, J= 6.7 Hz, 2H), 3.75-3.67 (m, 2H), 3b9 (s, 3B), 3-26-3L12 (OL 4H), 2.02-1.91 (m, 2H), 1.87-1.75 (m, 2HX 1.64-1.51 (m, 2H), 1.41 (s, 9H), 0.97 ft J= 73 Hz, 3H); MS (ESI) mJz 4842923 (484b924 cakd for CsHbbiO, MbH4); AnaL calcd for C26H37N5O4-0-75H2O: C, 62 82; H, 7.81; N, 14.09. Foond: C, 62.48; H, 8.16; N, 14.01.


Part A
tert-Butyl 4- {[4-aniino-2b2-me1hoxyeftbl-piopyl-lib yl]oxy}piperidine-l-carboxylate (prepared as described in Example 387,2.11 g, 4.36 mmol) was treated with concentrated hydrochloric acid (3 mL). After vigorous bubbling, a solution formed. The solution was diluted with ethanol (50 mL) and evaporated (3 x). The resulting oil was dissolved in brine (15 mL) and water (5 mL) and made basic with 50% aqueous sodium hydroxide (approximately 1.5 mL). The aqueous layer was extracted with dichloromethane (3 x). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfete, Shard, and coocssfratcd under reduced pressure to provide 1.7 g of 2b2-memcTyeflryb7-bpberikfirt4-boxy)-lbiTopyl-li?-mida2o[4,5-c]qumomi-4-ylamine as a white solid. PartB
Isopropyl isocyanate (0.256 mL, 2.61 wanof) was added dropwise to a stirred mixture of 2b2-methoxyemyI)-7-(piperidnMb
4-ylamine (1.00 g, 2.61 mmol) in chloroform atC “"C The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The solvent was evaporated under reduced pressure. The erode product was parrfird by flash cfaromatography (silica gel, gradient elution with 4-12% CMA in chlorafccn) followed by recrystalHzation from acetonitrile to afford 0b30 g of 4-{[4-anrino-2(Zb«emoxyetfiYlHiib in3idb2o[4)5b3qTimomi-7-yl](gy}-At4aDbupy%iyQ kftne-l-carboxamide as white crystals, mp 176-179 °C.

!H NMR (300 MHz, DMSO-d6) 5 7.88 (d, J= 9.1 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.91
(dd, J= 9.0,2.6 Hz, 1H), 6.36 (s, 2H), 6.17 (d, J= 7.4 Hz, 1H), 4.66-4.56 (m, 1H), 4.47-
4.37 (m, 2H), 3.80 (t, J= 6.7 Hz, 2H), 3.77-3.66 (m, 3H), 3.28 (s, 3H), 3.17-3.04 (m, 4H),
2.00-1.87 (m, 2H), 1.86-1.72 (m, 2H), 1.58-1.44 (m, 2H), 1.05 (d, J= 6.6 Hz, 6H), 0.96 (t,
J=73Hz,3H);
MS (ESI) mJz 469.2912 (469.2927 cakd &r CzsHabkCb, \fc-S");
Anal, calcd for C25H36N6O3: C, 64.08; H, 7.74; N, 1733. Bound: C, 63.73; H, 7.73; N,
17.76.

Isobutyryl cMoride (0.273 mL, 2b1 mmol) -was added dropwise to a stirred solution of 2b2-methoxye£hyl)-7-(piperidmbykaQbl-pbb 4-yiamine (prepared as described in Part A of Example 388,1-00 g, 2b1 mmol) in chloroform at 0 °C. After 2 hours, the solution TO aflowedio izm to ambient temperatnre for 1 hour. Saturated aqueous so6aaa.aabanaas (15 mL) and water (10 mL) were added and nie mixture was allowed to stir we 16 boos. The mixture was transferred to a separatory funnel, the layers were separated, md me aqueous layer was extracted with dichloromethane (2 x 30 mL). Hie organic Uym me mndmeA washed with water and saturated aqueous sodium chloride, dried over MAVBPOOS sodtimi sulfate, filtered, and concentrated under reduced pressure. RecrystalizxkHi from acetonitrile afforded 1.00 g of7-[(l-isoburyrybiperidai-4~yf)oacy}-2-C2-meab c]quinolm-4-amine as a floccufcnt while solid, mp 165-166 °C.

“H NMR (300 MHz, DMSO-d6) 5 7.88 (d, J= 9.1 Hz, 1H), 7.11 (4 J= 2.6 Hz, 1H), 6.92 (dd, J= 9.0,2.6 Hz, 1H), 6.37 (s, 2H), 4.75-4.65 (m, 1H), 4.47b.37 (m, 2H), 3.98-3.85 (m, 1H), 3.85-3.77 (m, 1H), 3.80 (t, J= 6.8 Hz, 2H), 3.47-3.34 (m, 1H), 3.28 (s, 3H), 3.30-3.19 (m, 1H), 3.15 (t, J= 6.8 Hz, 2H), 2.94-2.84 (m, 1H), 2.06-1.89 (m, 2H), 1.86-1.72 (m, 2H), 1.69-1.46 (m, 2H), 1.00 (d, J= 6.7 Hz, 63), 0b6 (t, J= 7.4 Hz, 3H); MS (ESI) mtz 454b810 (454b818 calcd far C25H35N5O5, M-Hl; AnaL calcd for CbssNsCb: C, 66b0; H, 7.78; N, 15.44. ?oand: C, 65b5; H, 8.09; N, 15.43.

Using the method described in Scample 389,2-(2-mboxyeflryI)-7-(piperidin-4-yloxy)-l-piopyl-liy-iinidazo[4,5-c]quiiiolinr4-b5ifflisne (1.00 & 2.61 mmol) was converted into 2b2-methoxyeihyl)7-{[Hmethylsulfbb
imidazobS-cjquinolin-bamiiie, pang meflugteatf foe vi dfloride (0b02 mL, 2.61 mmol) in lieu of isobutyiyi chloride. The crude pandndvspodBsd by fitadi chromatography (silica gel, ehiting with a step gradient of CMAin cfakaofcim (4-12% CMA increasing by 2% CMA every 500 mL) followed by tritotatioaisife acetanitrile to affijrd 1.1 g of 2-(2-me&oxyemyO-7-{[l-(memvlsulfiravl)pipeadiiK”-5QaiyJ-l-|bb c]quinoUn-4-amine as a white sofid, mp 224-22b.5 aC
lB. NMR (300 MHz, DMSO-b) S 7b0 (d, J= 9A Hr, 1H), 7.12 (d, J= 2.6 Hz, 1H), 6.95 (dd, J= 9.0,2.6 Hz, 1H), 639 (s, 2HX 4.7O4.62 (ia, 1H), 4.46-4.41 (m, 2H), 3.81 (t, J=

6.7 Hz, 2H), 3.44-3.34 (m, 2H), 3.29 (s, 3H), 3.19-3.12 (m, 4H), 2.92 (s, 3H), 2.12-2.00
(m, 2H), 1.87-1.73 (m, 4H), 0.97 (t, J= 7.4 Hz, 3H);
MS (ESI) 7nJz 462.2184 (462.2175 calcd for CbHsiNsCb, M+H”);
AnaL calcd for CsHaiNsCUS-O.lOCbaz: C, 56.47; H, 6.69; N, 14.90; S, 6.82. Found: C,
56.36; H, 6.93; N, 14.80; S, 6.96.

Trimethylsilylisocyanate (0.225 mL, 1.67 mtnol) was added dropwise to a slurry of
?b7-Tn«f)tnvyp!rtiyl)-7-(pipm-irliTi-4-ylnTfy)-1 -pmpyi-1 l?'-itTrtb8r7rt[i,jSw]brttnn1in-4,-y1aniiTii»
(fffepared as described in Part A of Example 388,0.640 g, 1b7 mmol) in chloroform (16 mL)at0°C. Tbe reactioji mixture was s&redfor 40 minutes aid wber (10 mL) was added. The reaction mixture was stirred vigoronsrjfer 2 horns, fflntod Trim 200 mL ethanoL and then concentrated under reduced pressure to approximately 100 mL. Another 100 mL ethanol was added and the solution was evajaimlHi to aSbnl a white solid that was recrystallized fiom ethanol to provide 0.625 g of 4-{£4-giinp-2-(2-giefeGxyethyI)-1 -
pmpyi-1 H-ivniAa7n[&J;w]qiiinn!fn-7-yT]nnry}pipHipinfv-1 -rzHhtmrrriAf. as granular off-
white crystals, mp 207-208.5 °C.
]H mm (300 MHz, DMSO-4s) 5 7.88 (d, J = 9.0 Ht 1H), 7.09 (d, J= 2.5 Hz, 1H), 6.92 (dd, J= 9.0,2.5 Hz, 1H), 6.37 (s, 2H), 5.94 (s, 2H), i6S4b8 (m, 1H), 4.44-4.39 (m, 2H), 3.80 (t, J= 6.7 Hz, 2H), 3.75-3.63 (m, 2H), 3b8 (s, 3H), 3.17-3.04 (m, 4H), 1.99-1.87 (m, 2H), 1.86-1.71 (m, 2H), 1.60-1.44 (m, 2H), 0.96 (t, J “ 73 Hz, 3H);

13C NMR (75 MHz, DMSO-4?) 6 158.0,1553,151.9,149.8,146.5,132.6,125.1,121.1,
112.5,109.9,109.0, 72.2, 70.2,58.1,46.1,40.9,30.6,27.1,23.0,10.6;
MS (ESI) mJz 427.2443 (427.2458 calcd for CBH-JONCOS, M+H4);
AnaL calcd for CbHaoNeOs-O.SOHaO: C, 60.67; H, 7.17; N, 1930. Found: C, 61.03; H,
7.60; N, 19.61.

Part A
A modification on the methods described in Parts A-H of Example 2 were used to prepare 2b2-inemoxyethyl)-l-propyl-liy-imida2xb4;bb]quiiioni!r7-()l, -with 3-benzyloxyaniline and 3-methoxypropanoyl chloride used in Boa of 4~benzyk)xyaniliiie and ethoxyacetyl chloride, respectively. Diisopropyl azodiearboxylate (2.07 mL, 10.5 mmol) was added dropwise to a slurry of 2b2-me&oxyefirjblbropyI-Lffiriida2o[4,5-c]quinolin-7-ol (2.00 g, 7.01 mmol), tripfosBybjkobateae (2.75 g, IOLS mmol), and 3-(methylthio)propan-l-ol (1.08 mL, 10.5 mmol) in BggiqJdrofigan (70 mL) at 0 °C. The solution was stirred for 30 minutes at 0 °C, men XKXB vznbcassrs fer 16 hours. The solvent was removed under reduced pressure and the tesidoe -»as dissolved methyl acetate, treated with 1M hydrochloric acid (40 relb, »d stirred Sx 30 minutes. The layers were separated and the aqueous layer was mi aural «am emyl acetate (2 x 25 mL). The aqueous layer was adjusted to approximately pH 14 «im 50% aqueous sodium hydroxide and then was extracted with dkfakaoiueflianc (3 x 50 mL). The organic layers were combined, washed with water and g”“»n4M aqocom •odium chloride, dried over anhydrous sodium sulfele, filtered, and oonxobaied mder reduced pressure. The crude

product was purified by flash clirornatography (sflica gel, gradient elation with 1-4% mefhanol in dichloromethane) to provide 2.0 g of 2-(2-mefboxyethyI)-7-t3-(me1hj4Mo)propoxy]-l-propyl-liy-iinidazo[4,5b3quiiK)]ine as an opaque solid. PartB
3-ChloropeToxybenzoic acid (4.63 g, 16.1 mmol) was added to a solution of 2-(2-
memoxyethy!)-7-[3bnTethylurio)proDoxyb (2.0 g,
5.3S imnol) in chloroform (45 mL). After 1 hour, canpestrated. “tnffw'b"|im hydroxide (45 mL) was added and Hie mixture was stirred for 30 minuses. p-Tcfosaesclibixyl chloride (1.07 g, 5.62 mmol) was added in two portions. Afier the insure was allowed to stir for 16 hours, the layers were separated and the aqueous fewer was extracted wife dichloromethane. The combined organic layers were washed wMi 14% aqueous ammonium hydroxide, water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting oil was crystallized from hot acetonitrile to afford a tan solid that was isolated by SHraHon. The solid was subjected to flash column chromatography (silica gel, gradient elution with 2-14% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.510 g of 2-(2-methoxyemyl)-7-[3-(memylsulfonyl)propoxy)-l-propyl-liy-imidazo[4,5-c]quinoHn-4-amine as red-violet crystals, mp 170-171 °C.
)H NMR (300 MHz, DMSO-&) 6 7.91 (d, J= 9.0 Hz, IE), 7.07 (i J= 2.6 Hz, 1H), 6.92 (dd, J= 9.0,2.6 Hz, 1H), 6.40 (s, 2H), 4.46-4.41 (m, 2H), 4.18 & J= 62 Hz, 2H), 3.81 (t, J- 6.7 Hz, 2H), 3.34-3.29 (m, 2H), 3.29 (s, 3H), 3.16 (t, J= 6.8 Hz, 2H), 3.03 (s, 3H), 2.27-2.14 (m, 2H), 1.87-1.75 (m, 2H), 0.97 (t, J= 7.4 Hz, 3H); MS (ESI) mJz421.1903 (421.1910 calcd for CbbsbbyfbSTf, AnaL calcd for C2oHbgN404S: C, 57.12; H, 6.71; N, I13) S, 7b2. Sound: C, 57.16; H, 6.70; N, 13.46; S, 7.74.


Part A
A modification on the methods described in Parts A-H of Example 2 were used to prepare 2-(2-methoxyethyl)-1 -propyl- lH-inndazo[4,5-c]qwnolmr7-o\ "with 3-benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of 4-benzyloxyamline and ethoxyacetyl chloride, respectively. 2-(2-MethoxyemyI)-l-propyl-lH'-Bnidazo[4J5-c]quinolin-7-ol (20.0 g, 70 mraol) was converted into fert-butyl {3-[2-(2-methoxyethyl)-l-propyl-lb-imida2»[4,5b]qumolm-7-yloxy]piopvl}carbamate using a modification of the method described in Part C of Example 7. The reaction was wcdasd up by removing the solvent under reduced pressure. The residue was partitioned bclweui emyl acetate and water. The aqueous layer was extracted wkh emyl acetate. The organic layers were combined, washed with water (2 x 500 mL) and bone, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pna&mg to yield Jert-butyl {3-[2-(2-
mftfhmryrthyl)-! -pmpyl-1 W-irm(Wr)[.lJ?b]qntivigw-7bii»uybw«w)T}t;j«lfcunate as abrown
oil, which Was used without farther purification. PartB
The material from Part A was dissolved is cateofbcm (700 mL) and treated with mCPBA (60% pure, 21.96 g, 75 mmol). After 1 kot &e reaction mixture was poured into 2% aqueous sodium carbonate. The layers wane «parated and the organic layer was washed with water and saturated aqueous sodium dtknde. The organic layer was dried over anhydrous magnesium suffiac, filtered and cvippgited. The erode product was

purified by flash chromatography (silica gel, gradient ehdion with 2-7% me&anol in dichloromethane) to afford 19.3 g of tert-bxxkyl 3-{[2-(2-methoxycthyI)-5-Qxido-l-propyl-li7-iiriida2o[4,5-c]qumolin-7-yl]oxy}propylcarbamate as a tan foam. PartC
J)-Toluenesulfonyi chloride (8.0 g, 42 mmol) was added over ten -"imntpy to a stiired mixture of terf-butyl 3-{[2b2-methoxyeftb)-5-03ado-l5B5bjyl-lH-4niida2o[4,5-c]quinoBib7~yI]oxy}propylcarbamate (193 g, 42.0 mmol) in dkakstnne&ane (300 mL) and concentrated ammonium hydroxide (300 mL) at 7 °C Tie nixtore-was allowed to stir for 20 minutes, then the cooling bam was removed aod the unarm”, was allowed to stir at ambient temperature far 2 hours. The layers were sepaibed and me aqoeotts layer was extracted with dichloromethane. The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Recrystaffization ftom acetomtrile afforded 12.0 g of tert-butyl 3-{[4-ammo-2-(2-memoxyebyl)l-propylTlfl'-imidazo{4,5b]qumoh7i-7-yl]oxy}propylcarbamate as flocculent white crystals, mp 133.5-135 °C. JH NMR (300 MHz, DMSO-4J) 8 7.89 (d, J= 9.0 Hz, 1H), 7.05 (d, J= 2.7 Hz, 1H), 6.95-6.87 (m, 1H), 6.89 (dd, J= 9.0,2.7 Hz, 1H), 6.37 (s, 2H), 4.46-4.41 (m, 2H), 4.05 (t, J= 6.2 Hz, 2H), 3.81 (t, J= 6.8 Hz, 2H), 3.29 (s, 3H), 3.18-3.08 (m, 4H), 1b1-1.74 (m, 4H), 138 (s, 9H), 0.97 (t, J= 73 Hz, 3H);
MS (ESI) mJz 458.2758 (458.2767 calcd for CabajNsG”, MbH”); Anal, calcd for C24H35N5(V0.73H2O: Q 61b4; H, 7b1; N, 14b8. Foimd: C, 61.23; H, 7.62; N, 14.78.


Concentrated hydrochloric acid (8.5 mL) was added to a solution of iert-butyl 3-{[4-anrrao-2-(2-methoxyethyI)4-propbb
yl]oxy}propylcarbamate (prepared as described in Example 393,12 g, 26 mmol) in ethanol (300 mL). The solution was heated at reflux for 4 horns. Upon cooling to ambient temperature a precipitate formed. The solid was isolated by ffltretimi and the filtrate was evaporated to afford a white solid. The solids were combined and dissolved in water (40 mL). The solution was adjusted to approximately pH 12 with 50% aqueous sodium hydroxide and then was extracted with dichloromethane (4 x 250 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated to yield a solid thai was purified by trituration in hot acetonitrile to provide 6.5 g of 7-(3-annnopXDponb2b2-”rabxye1hyl)-l-prcpyl-lb-hmdazo[4,5b]quinoUn-4-amme as yellow crystals, wp 165-166.5 °C. lH NMR (300 MHz, DMSO-&) 8 7.88 (d, J= 9.0 Hz, 1H), 7.06 (d, J= Z6 Hz, 1H), 6.89 (dd, J= 9.1,2.6 Hz, 1H), 637 (s, 2H), 4.46-4.41 (m, 2H), 4.10 (t, J= 6.4 Hz, 2H), 3.81 (t, J= 6.7 Hz, 2H), 3b9 (s, 3H), 3.16 (t, J= 6.7 Hz, 2H)L2-72 (t,J= 6.7 Hz, 2H), 1.87-1.74 (m, 4H), 1.47 (br s, 2H), 0.97 (t, J= 7.4 Hz, 3H); MS (ESI) mJz 358.2231 (358.2243 calcd fiH-CisBfebOb Mrfi”); Anal, calcd for CibbNsCb: C, 63.84; H, 7.61; H »J9. Fount C, 63b0; H, 7.75; N, 19.46.


Part A
Isobutyryl chloride (0.375 mL} 3.58 mmol) was added dropwise to a slurry of 7-(3-ammopropoxy)-2-(2~methoxyethyl)-l-propb
(prepared as described in Example 394,1.28 g, 3.58 mmol) in dichloromethane (22 mL) at 0 °C. The reaction mixture was allowed to stir for 30 minutes at 0 °C, then me reaction mixture was allowed to stir for 16 hours at ambient temperature. Saturated aqueous sodium carbonate was added and the reaction mixture was stirred for 1 hour, resulting in the formation of a flocculent solid. The solid was isolated by filtration and dissolved in dichloromethane. The dichloromethane was washed with water aid. satraated aqueous sodium chloride, dried over anhydrous sodium satiate, Qtered, and concentrated under reduced pressure. The resulting white solid was recrystaflized from acetamtrfle to afford 1.14 g of iVK3-{[4-aminc)-2-(2-metaye1fcyb yl]oxy}propyl)-2-methyipropanamide as an off-white sofid. PartB
A 1.0 M solution ofboron tribromide in dkfckiKxaefiiaDe (2_55 TTJT., 2-55 mmol) was added over 1 minute to a slurry of JVb3b4-anaHDbb-mefhax3bhybl-jprop imidazo[4T5b3qumohb7-yl]oxy}pmpyl)-2-mcQiJlt«ibM«mkir (L09 g, Z5S mmol) at 0 °C. The clumpy slurry was allowed to stir for IS in'""ft at 0 °C, men was allowed to stir for another hour at ambient tempenttare. Addrtiaral baron tribromide solution (0.6 mL, 0.6 mmol) was added. After 16 boors, the reaction wm quenched with 6 M hydrochloric acid (10 mL), stirred until all me sofids diadved, and ibe dichlorome&ane was removed

under reduced pressure. The aqueous layer was adjusted to apjaoxliiiateiy pH 13 with
50% aqueous sodium hydroxide and was extracted with ethyl acetate. The organic layer
was washed with water and saturated aqueous sodium chloride, dried over anhydrous
sodium sulfate, filtered, and evaporated. The material was purified by dromatography on
a HORIZON HPFC system (siHca gel, gradient elation wim 2-22% CMA in chloroform)
followed by trituration with acetonitrile to afford 0.325 g of bK3-{[4-ammo-2-(2-
hydroxyetiry!)-l-piopyl-Lff-imidaOT[4,5b
methylpropanamide as a white solid, mp 1903-192 °C
JH NMR (300 MHz, DMSObj) 6 7.89 (d, J= 9.1 Hz, IHL 7-81 fc J= 55 Hz, 1H), 7.05
(4 •J= 2.6 Hz, 1H), 6.90 (dd, J= 9.0,2.6 Hz, 1H), 6.43 (s, 2H), 4b8 (L J= 55 Hz, 1H),
4.47-4.42 (m, 2H), 4.06 (t, J= 6.3 Hz, 2H), 3.90-3.84 (m, 2H), 3.26-3.20 (m, 2H), 3.06 (t,
J= 6.6 Hz, 2H), 2.42-2b8 (m, 1H), 1.93-1.75 (m, 4H), LOO (d,-f= 6-9 Hz, 6H), 0.98 (t, J
= 7.3Hz,3H);
13C NMR (75 MHz, DMSO-tf(j) 6 176.0,157.2,151.9,150.5,146J, 132.6,125.0,120.9,
111.6,108.9,108.1, 65.1, 59.6,46.0,35.4, 34.0,30.2,28.9,22.9,19.5,10.6;
MS (EST) mJz 414.3 (M+H)+;
Anal, calcd for C22H31N5O3: C, 63.90; H, 7.56; N, 16.94. Found: C, 63.76; H, 7.78; N,
16.92.


Using the procedures described in Parts A and B of Example 395, with nicotinoyl chloride hydrochloride (0.627 g, 3.52 mmol) used in Keu of isobatyryl chloride, 7-(3~ ammoprc»poxy)2-(2-methoxyefcyb
(prepared as described in Example 394,1.28 g, 3.58 mmol) was converted into 0.230 g of AK3-{[4-amiao-2-(2-hydroxyethyl)4-pro
yl]oxy}propyl)mcotinatnide after recrystallization from acetonitrile to yield pale yellow needles, mp 183.5-184.5 °C.
“H NMR (300 MHz, VMSO-d6) 8 9.02 (dd, J= 2,4,0.7 Hz, 1H), 8.77 (t, J= 5.4 Hz, 1H), 8.70 (dd, .7=4.7,1.7Hz, 1H), 821-8.17 (m, 1H), 7.90(d,J=9J Hz, IH), 752-7.48 (m, 1H), 7.08 (4 J= 2.6 Hz, 1H), 6.91 (dd, J= 9.0,2.6 Hz, 1H), 6.41 (s, 2H), 4.88 (t, J= 5.6 Hz, 1H), 4.47-4.42 (m, 2H), 4.14 (t, J= 62 Hz, 2H), 3.90-3-84 (m, 2H), 332-3.46 (m, 2H), 3.06 (t, 7 = 6.6 Hz, 2H), 2.09-2.00 (m, 2H), L88-l_75 (m, 2S), O98 (t, J= 13 Hz, 3H);
13C NMR (75 MHz, DMSCMtf) 5 157.2,151.9:151.7, 15GJ5T 1483,146.5,134.8,132.6, 130.0,125.0,1233,120.9,111.6,108b, 1082,652,39.6,46.0,36.4, 302,28.8,22.9, 10.6;
MS (ESI) mh 449.3 (M+H)+;
AnaL calcd for C24H2gN6O3: C, 6427; H, 629; N, 18.74. Found: C, 63.99; H, 6.53; N, 18.87.


Part A
Using a modification on the procedure described in Part E of Example 2, terf-butyl 4-{[7-(benzyloxy)3-nitroqiiinolnibyl]amino}but54carbamate was synthesized using 7-benzyloxy-3-nitroquinolin-4-ol (prepared as described in Steps A-C of Example 1) and teJ?-butyl 4-aminobutylcarbamate in lieu of the 6-benzyloxy-3-nitroqumonn-4-ol and propylamine, respectively. PartB
A mixture of terf-butyl 4-{[7benzyloxy)-3-nirnxpimo£!M-yl]amino}butylcarbamate (30.0 g, 64.3 mmol) and 5% plafimsn cm. carbon (3.0 g) in toluene (675 mL) and 2-propanol (100 mL) was hydrogemted on a Fax apparatus for 12.5 hoursat24psi(L7xl05Pa). The mixture was filtered tooaghCEUTE filter agent, which was rinsed afterwards with 1:1 tolueneJ2-propanoL aid 2-fwcpasxA. The combined filtrates were concentrated under reduced pleasure to afiord 28 % o£tert-tomyi 4-{[3-amino-7benzyloxy)qumohnbyl]arnino}butylcarbanate as a. vmxos biack oil that was used in the next step without purification. PartC
Efhoxyacetyl chloride (7.87 mL, 643 mrool) wm added dropwise to a stirred solution of the material from Part B in dichlonanethne {319 mL). After 1 hour, the solution was concentrated under redaced picssuie. The residue was dissolved in ethanol (319 mL) and triethyiamine (35.84 ««T. 257 mmol) and fee solution was heated at reflux

for 4 hours, then was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromemane and washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfete, filtered, and concentrated under reduced pressure. The resulting semi-solid was dissolved in hot acetonitrfle and allowed to cool Evaporation, of fee acetonitrile under reduced pressure afforded 30 g of terf-boryl 4b1bbesxykx9y2bdisDxymeQsyiyiH-mndazo[4bb]qumohn-l-yl]butylcarbarnate as a chnnkyhnyira solid. PartD
A mixture of terf-buryl 4-[7-(benzyloxy)-2beaicxyBBbb
c]qirinolm-l-yl]burykaAamate (15 g, 29.7 mmol) and 109% paBaSnm cm carbon (4.5 g, wetted with ethanol) in 1:1 ethanolJmethanol (400 mL) was hydrogenated using a Parr apparatus at 28 psi (1.9 x 105 Pa) for 16 hours. The mixture was filtered mrough CELTTE filter agent, which was subsequently washed with methanol. The filtrate was concentrated under reduced pressure to afforded 10.8 g of tort-butyl 4b2-(ethoxvmeihyI)-74iydroxy-l#-imidazo[4,5-c]quinomi-l-yl]butylcafbamate as a green-yellow solid. PartE
Using the conditions described in Part A of Example 392, tart-butyl 4-[2-
(emoxymemyl)-74tydroxy-l#-imidazo[4,5-c]quinomb (3.50 g, 8.44
mmol) was converted into tert-butyl 4-{2-(ethoxvmeihyl)-7-[3b2-oxopyriotidmb
yl)piopoxy]-lH-irmdazo[4,5-c]qumohb-l-yl}butylca?bab 1-P-
hydroxypropyl)pyrrolidin-2-one (1.64 mL, 12.7 mmol) in leu of 3-(mefir«imio)propan-l-ol. The reaction was worked up by removing me sorrcaraderTedDcad pressure. The residue was subjected to flash chromatography (siHca ad, btoticp vim efiryi acetate followed by gradieiit ehition with 1-5% methanol in dkakjromeflHnc) to yidd 3.79 g of ferf-butyl 4- {2(eiiK)xymemyl)-7-[3(2-oxopynofidinh4bfipKjpQb) c]qumoErbl-yl}butylMrbamate as a viscous yeDow ofl. PartF
Using a modification on the procedure bwBrrb”H m Part B of Example 392, terf-butyl 4- {2bemoxvme1hyr)7-[3-(2H3A.upyiralbb
c]qiumohbl-yl}butylcarbamate (3.79 g, 7.02 mmol) w» converted into fert-buryl 4-{4-ammo-2-(emoxyme1hyl)-7-[3b2bx£9ynoiMJbl-yQ|)ob

l-yl}butylcarbarnate. After &eb-tolueaesulfonyl chloride was added, the mixture was allowed to stir for 72 hours. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 5% aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated. Recrystaffizarkn irom acetonitrile afforded 3.1 g of tert-buryl 4-{4-aimrK)-2be&0xyinetir)!)-7bb
yt)prnpmry]-1 H-imAa7p[d. JJ-rjqpTmftltTt-i -ytyhfttytofatni3» as X •wiile SoSd, mp 134.5-
136 °C.
JH NMR (300 MHz, DMSObfc) 6 7.90 (d, J= 9.0 Hz, IE), 7.04 (4 -T= 2-5 Hz, 1H), 6.90
(dd, J~ 8.8,23 Hz, 1H), 6.81 (t, J= 5.0 Hz, 1H), 6 Jl (s, 2H), 4.74 (s, 2H), 4b2-4.47 (m,
2H), 4.04 (t, J= 62 Hz, 2H), 3.55 (q, J= 7.0 Hz, 2H), 3.42-3.34 (m, 4H), 2.99-2.93 (m,
2H), 2.22 (t, J= 8.0 Hz, 2H), 2.00-1.88 (m, 4H), 1.87-L74(m, 2H), 1.61-1b0 (m, 2H),
1.33 (s, 9H), 1.16 (t, J= 7.0 Hz, 3H);
MS (ESI) mJz 555.3287 (555.3295 calcd for C29EU2N6O5, M+Hb);
Anal, calcd for CzsbNeOs'l.25H2O: C, 60.35; H, 7.77; N, 14.56. Found: C, 60.35; H,
7.83; N, 14.12.

A solution of terf-butyl 4-{4-acnnK)-2beflwx3Med5fb7-{b2Hoxopyrrolidm-l-ylbropKixyJ-liy-aniidazobjS-clqiumlm-l-bbiirykariMBBrte (prepared as described in Example 397,2.90 g, 5.23 mmol) in 4 M ethsBiofic Ysydsapsi chloride was heated at reflux for 2 hours. The solution was allowed to cooi to room teaperature and a precipitate formed that was isolated by filtration to affivd 2S1 % of l-(3-{[4-anrino-l-(4-arnmoburyl)-

2-(e1hoxymetfryI)-liy-iimdazo[4,5-c]qijinbb
dihydrochloride as a white powder, mp )250 °C. “H NMR (300 MHz, UMSO~d6) 513.92
(s, 1H), 930-8.40 (br s, 23), 8.15 (d, J= 9.2 Hz, 1H), 8.13-8.00 (m, 3H), 730 (d, J= 2.5
Hz, 1H), 7.20 (dd, J= 9.1,2.4 Hz, 1H)5 4.83 (s, 2H), 4.6S4.60 (m, 2H), 4.10 (t, J= 6.1
Hz, 2H), 3.60 (q, J= 7.0 Hz, 2H), 3.41-337 (m, 4H), 2.87-2.76 (ra, 2H), 2b2 (t, J= 8.0
Hz, 2H), 2.04-1.85 (m, 6H), 1.81-1.70 (m, 2H), 1.19 (t J=7.0 Hz, 3H);
MS (ESI) mJ: 455 J1784 (4552771 calcd ftn: Ca«H34NriOi Mbfi");
Anal, calcd for C24H34N6O3-L60H2()2.15HCl: C, 512&; H, 7.06;)C 14b5; 0,13.59.
Found: C, 51J29; H, 736; N, 14.93; Cl, 13.48.

Isopropyi isocyanate (0.187 nxL, 1.90 mmoT) was «dded dropwse toasdned
solution of l-(3-{[4-amincHl-(4-aminobrityi)-2-(efeoi5SBcbbl£f-inadazo[4b-
c]quinolin-7-yi]oxy}pTop)4)pyTrolidin-2-oiie d3tydnxzdo3dc (piqiaied as described in
Exanq)le 398,1.0 g, 1b0 nnnol) and trie&yianBne (QJS3Q 31L, 3 JSOmaxS) ia
dichloroniediane (20 mL) at room temperautre. Afla" 13 tours, &c soiveot was removed
under reduced pressure and the residue was purified brfarii chrosnatography (silica gel,
gradient elation with 2-12% CMA in chlorofonn) followed \j ieaySalHzation from
acetonitrile to yield 0.730 g of JVK4-{4-amino-2-{ediaiyine&y!)b
yl)piopoxy]-liMmidazo[4,5-c]quibb as an opaque solid,
mp 98-101 °C.

TH NMR (300 MHz, DMSO-&) 5 7.90 (d, J=- 9.0 Hz, 1H), 7.05 (4 J= 2.6 Hz, 1H), 6.91
(dd, J= 9.0,2.6 Hz, 1H), 6.55 (s, 2H), 5.69 (t, J= 5.7 Hz, 1H), 5.57 (d, J= 7.7 Hz, 1H),
4.74 (s, 2H), 4.53-4.48 (m, 2H), 4.04 (t, J= 6.3 Hz, 2H), 3.69-3.58 (m, 1H), 335 (q, J=
7.0 Hz, 2H), 3.40-334 (m, 4H), 3.03 (q, J= 6.3 Hz, 2H), 2b2 (t, J= 8.0 Hz, 2H), 2.00-
1.88 (m, 4H)S 1.88-1.76 (m, 2H), 1.58-1.48 (m,2H), 1.16(t,J= 7.0Hz, 3H), 0b8 (d, J=
6.5 Hz, 6H);
I3C NMR (75 MHz, T)MSO-d6) 5173.9,1573,157.4,152-2,148.C, 146.8,133.4,124.8,
121.4,111.7,108.7,108.0,65.3, 642,463,45.1,40.8,39.1,30.4,2T3,26.7,232,17.5,
14.9;
MS (ESI) mJz 5403315 (5403298 calcd for C2SBU1N7O4, M”&);
AnaL calcd for C28H41N7O4: C, 62.32; H, 7.66; N, 18.17. Found: C, 61b5; H, 7.90; N,
18.46.

Using the procedure described in Example 399, l-(3-{[4-amHiD-l-(4-ammobutyI)-2-(etfaox)me&yi)-lff-iimdazo[43-c]qiaiK)lin-7-)boAb}bwblbb dihydrochloride (prepared as described in Example 398,1.0 5. ISO nanol) was converted into AK4-{4-ainino-2-(ethoxymetti3b
itnidazo[43b]qTxinoKn-l-yi}butyl)rQefeanesulfenaiiDdc wsmg me&aocsnlfoiiyi chloride (0.147 mL, 1.90 mmol) in lieu of isopropyl isocyanate. Recrystallization from acetonitrile afforded 0J246 g of Nb4-{A-annao-2bdSxf3cyta0iryiy-l~bb
b yf-TmidflTbbSbqiiinoim-i b}hntyt)nbrt)anwaiirntbWwbi as white crystals, mp 157 °C.

“H NMR (300 MHz, DMSO-d6) 5 7.96 (d, J= 9.0 Hz, 1H), 7.06 (d, J= 2.6 Hz, 1H), 6.99
(dd, J= 9.0,2.6 Hz, 1H), 6.93 (dd, J= 9.0,2.6 Hz, 1H), 6.65 (s, 2H), 4.75 (s, 2H), 4.55-
4.50 (m, 2H), 4.04 (t, J= 62 Hz, 2H), 3.56 (q, J= 7.0 Hz, 2H), 3.40-334 (m, 4H), 2.99 (q,
J= 6.3 Hz, 2H), 2.87 (s, 3H), 2b2 (t, J= 8.0 Hz, 2H), 2.00-1.83 (m, 6H), 1.69-1.59 (m,
2H), 1.17 (t, J= 7,0 Hz, 3H);
MS (ESI) mJz 533b565 (533b546 calcd for CISRM&(&& Mb-Hl;
AiiaL calcd for C25H36N6O5S: C, 56.37; H, 6.81; N, 15.78; S, 6.02. Some: C, 56.08; H,
6.74; N, 15.47; S, 6 Jl.

Part A
A solution of tert-batyl 4-[7-(baizyloxy)2-(bMn53neaiyb'lS-inndaztb4b-
c]quinolin-l-yl]butylcaibamate Q)rq)ared as described m Parts A-C of Ejcanbde 397,21.0
g, 41.6 mmol) and concentrated hydrocbloric acid (13 tol..) m efcaaoi (100 mL) was heated
at reflux for 1 hour. The solution was allowed to cooltoToanitcQqsabce aid a
precipitate formed that was isolated by filtration to yidd 12.10 g of 4-{7-(benzyk)xy)-2-
(diioxymethyl)-li7-iinidazo[4,5b]qm]TOHn-l-yi]bataib ffiSaydrodikxide as a light
brown solid. PartB
3-Chloropropanesulfonyl chloride (4.58 mL, 37.7 mmol) was added dropwise to a solution of 4b7-(ben2yloxy)-2-(ethobnie1hyO-lff-iB»d«Bs(4bb](piTO amine dihydrochloride (12.1 g, 253 nnnol) aadtdethyfanwie (14.0 mL, 101 mmol) in

dicHoromethane (168 mL) at room temperature. The solution was stirred for 17 hours, then transferred to a separatary tunnel and washed with 5% aqueous sodium carbonate, water, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (168 mL) and treated with l,8-diazabieyclcb5 A0]undec-7~eae (5.70 mL, 38 mmol). The solution was stirred for 40 hours, ihen fee DMF was removed under reduced pressure. The residue was dissolved mdicHoroEK&aaeand washed repeatedly with water then saturated aqueous sodium carbcralfc Ths organic lays-was dried over anhydrous sodium sulfate, filtered, and evaporated to arsons 7-(benzyloxy)-l-[4-(l,lboxifoisofhiazoBdinr2-yl)butybb
almost quantitative yield with some residual l,8bazabicyclo{5.4.0|andec-7-ene as a brown oil, which was used without further purification. PartC
A mixture of 7-(beozyloxy)-l-[4-(l,l-dioxidoiso1mazoHdiii-2-yl)butyI]-2-
(emoxymemyl)-lff-imidazo[4,5-c]quinoune (4.6 g, 9.04 mmol) and palladium hydroxide
(1.5 g) in acetonitrile (50 mL) and methanol (75 mL) was hydrogenated on a Parr
apparatus at 50 psi (3.5 x 105 Pa) for 28 hours. The mixture was filtered through CELITE
filter agent, which was rinsed afterwards with 40% methanol in acetonitrile (600 mL). The
filtrates were combined and concentrated under reduced pressure to yield a yellow solid
that was triturated wim acetonitrile and isolated by fQtraticaito af&nl 22 g of l-{4-(l,l-
dioxidoisothia2»Hdm-2-yI)butyl]-2bemoxb as a
pale yellow powder. PartD
Using a modification of the method described is Part A of Example 392, l-[4-(l,l-
dioxidoiso1rriaz»fidm-2-yl)bufylbb (1.1 g,
2.63 mmol) was converted into l-[4-{l ,l-dioxiriotsouTi3»iiidif h2-yTpjQ&yfy-2-
(ethoxymefoyl)-7btetrahydrofuran-b using 3-
hydroxytetrahydmfui-au (0.320 mL, 334 mmol) in Hen of 3-coefliyiflHo)propan-l-ol. The reaction mixture was allowed to stir at ambient temperatec far 72 bouts, men was treated with 3 M hydrochloric acid (30 mL) and extracted with efliyl acetate. The aqueous layer was adjusted to a basic pH with saturated aqueous sodium cxbanate and was extracted

with dichloromethane. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1.0 g of l-[4-(l,l-dioxidoisotlriazolidm-2-yl)bxb (tetrahydrofuimi-3-yloxy)-ljy-iinidazo[4,5b]qumohTie as a yellow waxy solid. PartE
Using a modification of the method described in Pat B ofExacgjte 392,1-[4~(1,1-diorafoisotbiazoh'dinr2-yi)bab
nnidazo[4J5-c3quinoUne (1.0 g, 2,05 mmol) was converted uto l-[4-(M-flo:ridoiso1iTiazobbin-2-yr)toitylj-2-(etbb
irmdazo[4J5-c]quinoKn-4-amme. In the workup, the layers were sepsraaal and the aqueous was extracted wifh chloroform. The combined organic layere were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium solfate, filtered, and evaporated under reduced pressure. The crude product was recrystallized from acetonitrile to 0.511 g of l-[4b14boxidoisothiazoUdm-2-yl)butyi]-2-(ethoxymeaiyI)-7-(te1rahydrofuran-3-yloxy)-lH-imidbo[4,5-c]qiimohbbamine as red-tan crystals, mp 195.5-197 °C.
JH NMR (300 MHz, DMSO-rf6) 5 7.95 (d, J= 9.0 Hz, 1H), 7.02 (d, J= 2.6 Hz, 1H), .6.90 (dd, J= 9.0,2.6 Hz, 1H), 6.57 (s, 2H), 5.17-5.10 (m, 1H), 4.75 (s, 2H), 4.58-4.48 (m, 2H), 3.97-3.74 (m, 4H), 3.55 (q, J= 7.0 Hzs 2H), 3.19-3.13 (m, 4H), 2.93 (t, J= 6.6 Hz, 2H), 2.33-2.14 (m, 3H), 2.08-1b9 (m, 1H), 1.92-1.82 (m, 2H), 1.76-1.66 {m, 2H), 1.16 (t, J= 7.0Hz,3H);
13C NMR (75 MHz, DMSO-rftf) 8 156.1,152.3,148.1,14&9,1333,124.9,121.7,112.2, 109.0,108.8,77.0,72.3,66.5,65.3,64.2,46.5,46.1,45A 43.7,325,27.1,243,183, 14.9;
MS (ESI) mJz 504.2276 (504.2281 calcd for CzbssNsQsS.if+H4); AnaL calcd for CzbaNsOsS: C, 57.24; H, 6.60; N, 13b1; S, 637. Bjonct C, 56.91; H, 6.47; N, 13.73; S, 6.50.


Using a modification of the procedures described in Parts D and E of Example 401, l-[4-(l,l-dioxidoisomia2»Edm-2-yI)butyl]-2-(emb
7-ol (prepared as described in Steps A-C of Example 401,1.1 g, 2.63 mmol) was
converted into 1b3-{[4-arnmo-l-[4-(14-dioxidoisotinazofidin-2-bb
(emoxymemyl)-liI-imidazo[4,5-c]quinonn-7-yl]oxy}b
hydroxypropyl)pyrrolidrn-2-one in lieu of 3-hydroxytetrahydrofuran in step D.
Purification by chromatography on a HORIZON HPFC system (silica gel, gradient elution
with 1-20% CMA in chloroform) followed by trituration with acetonitrile and isolation by
filtration afforded 0.551 g of l-(3-{[4-ammo-l-[4-(l,lH£ojrid0isothiab
(emoxymerthyl)-LH'-nTm3a2»[4,5-c]qumb ffi a white
solid, mp 142-144 °C.
!H NMR (300 MHz, DMSO-b) 5 7.94 (d, J= 9.0 Hz, 1H), 7.05 (d, J=2£ Hz, ffi), 6.91 (dd, J= 8.9,2.6 Hz, 1H), 6.52 (s, 2H), 4.75 (s, 2H), 4.55-150 bn, 2b 4JM (t, J= 62 Hz, 2H), 3.55 (q, J= 7.0 Hz, 2H), 3.40-334 (m, 4H), 3.18-3.13 (ia, ffl), 2b4 (t, J= 6.6 Hz, 2H), 2.24-2.14 (m, 4H), 2.00-1.82 (m, 6H), 1.76-1.66 (m, 2HX 1.16 (t, J= 7.0 Hz, 3H); 13C NMR (75 MHz, DMSCWd) 8173.9,157.5,1523,14&£r 147.0,1333,124.8,121.4, 111.7,108.7,108.0,653,653,64.1,46.5,46.1,44.9,43-Z 39 X 30,4, 27.1,26.7,243, 183,17.5,14.9;
MS (ESI) mJz 559.2718 (559.2703 calcd for CCTHSSHSOSS, M-H”); Anal, calcd for CzvHstjNeOsS: C, 58.05; H, 6.86; N, 15.04. F«m± C, 5755; H, 7b2; N, 15.15.


The preparation of 2-methyi-l-(2-methy]propyI)-7b2-|)beridin-byieihoxy)-LH'-imidazo[4J5-c]quinolin-4-amine is described in Example 24. Cyclohexyl isocyanate (0.100 mL, 0.786 mmol) was added dropwise to a stirred solution of 2-methyl-l-(2-methylpropyl)-7-(2-piperidinbylethoxy)-lH-iinidazo[4,5b]quinonnbaTmne (0.300 g, 0.786 tomol) in dichloromethane (10 mL) at 0 °C. After 30 minutes, the solution was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, sequential elution with 2% and 5% me&anoi m dichloroniethane) followed by recrystallization from emanoi to aScad 0.141 g of 4-{2-[(4-ammo-l-isobutyl-2-meiiiyl-lif-imidazobb
cyclohexylpberidme-l-carboxamide as a white powder, xap 213.7-215.7 °C !H NMR (300 MHz, VMSO-d6) 8 7.85 (d, J= 9.5 Hz, XB), 7.Q5 (d, J= 3i) Hz, 1H), 6.89 (dd, J= 8.6, IS Hz, 1H), 6.43 (s, 2H), 6.06 (d, J= 7.6 Hz, IH), 427 (d, J= 15 Hz, 2H), 4.09 (t, J= 6.0 Hz, 2H), 4.0-3.92 (m, 2H), 3.44-330 (m, IH), 2.64-236 (m, 2H), 2.56 (s, 3H), 223-2.09 (m, IH), 1.77-1.50 (m, 10H), 1.3-0b6 b 7H), 0.93 (d,J= 6.7 Hz, 6H); MS (ESI) mJz 5073465 (5073448 calcd fbr C2j»HcN«Oi, ifr«), Anal, calcd for CzbNeQa-O.SHjO: Q 6734; H, 8.41; N, 1630. Found: C, 67.78; H, 8.43; N, 16.46.


Part A
Di-tert-butyl dicarbonate (19.05 g, 0.087 mol) in dicMorome&ane (218 mL) was added dropwise over 2 hours to a solution of piperazine (15.0 g, 0.174 mol) in dichloromethane (436 mL). The reaction mixture was allowed to stir for 16 hours, then the solution was concentrated under reduced pressure to yield a solid that was treated with water (500 mL). The mixture was stirred vigorously and a white solid was isolated by filtration and washed with water. The solid was discarded. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrocs sodkm sslia&e, filtered, and concentrated under reduced pressure to yield 12.7 g of tert-hsXyi piperazme-1-carboxylate as clear yellow crystals. PartB
Bromoacetyi bromide (2.97 mL, 34.1 mmol) in didikname&aac (25 mL) was added dropwise to the solution of tert-butyl piperazine-l-caBiwGcylaae (635 g, 34.1 mmol) and diisopropylethylamine (5.8 mL, 33.3 mmol) in dkhloroBjefljane (3S mL) at 0 °C. The solution was allowed to warm to ambient temperature and was stirred far 2 bouts, then was poured into a separately farmel. The solution was rafaei wim water, dried over anhydrous sodium sulfate, filtered, and concentrated nodcradBced pressure. Purification by flash chromatography (silica gel, erating sequentially wt& 20%, 33%, and finally 50% ethyl acetate in hexanes) afforded 4.05 g oftert-batyl 4b-lwamoaccty!)pq)eraane-l-carbamate as a brown crystalline solid.

PartC
The synthesis of 2bethoxymethyl)-l-propyl-liy-iMdazo[4,5-c]quiiioliij7-8-ol is
described in Parts A-I of Example 2. A mixture of 2-ethoxymethyl-l-piopyl-LHr-
imidazo[4,5-c]qmnolm-8-ol (4.5 g, 15.8 mmol), tert-buAyl 4b2-t»roinoacetyi)pq)erazine-l-
carbamate (4.57 g, 14.9 mmol), and potassium carbonate (527 g, 23.7 mmd) in DMF
(158 mL) was heated to 55 °C for 2.5 hours, then was allowed to cod m loom tamperatnre
and was stirred for 16 hours. The solution was poured mto wata" (500 inLX wfakii was
extracted with dieoiyl ether (300 mL), ethyl acetate (300 mL) and dkhkAXoe&ane (300
mL). The combined organic layers were concentrated undcrrsdBced prcssiEt. The crude
product was purified by flash chromatography (silica gel, gradient efetikm wim 0-5%
methanol in dichloromethane to provide 7.9 g of tert-Jratyl 4b{[2bethoxyroe(hyl)-l-
propyl-liI-imidazo[4,5-c]qumolm-8-yrjoxy}acetyb as a tan waxy
solid that contained 15% of DMF by weight PartD
The material from Part C was dissolved in chloroform (150 mL) and treated with mCPBA (70% wJw, 3.80 g, 15.4 mmol). The solution was stirred for 30 minutes, and additional mCPBA (1.0 g) was added. After 1 hour, the reaction was diluted with chloroform (150 mL) and washed with 1:1 saturated aqueous sodium carbonateJwater. The layers were separated and the aqueous layer was extracted with chtofofbim- The organic layers were combined, washed with water and satarbed aqueous sodium chloride, uxi6CL over souimn solxste. fiytCT'bQi 3HQ. COTICCTI MttttJO TTHQfiy FHffmbfiQ prgsssffB to 3 rHm i \ 4.9 g of approximately 54% pure tert-butyl 4b{[2bethoxyniefeb5-oxido-lbrofJ3b-LEr-imida2o[4b-c]qiiinohii-8"yr|oxy} acetyl)piperazine-l-(3rfaaibate ins sofafrri as a red-orange oiL which was used in the next step without ponficnoc. PartE
A modification of the procedure described in Part C offiarnple 393 was used to convert the material from Part D into rert-butyl 4b{[4-anBQtv24eflioncyinemyI)-l-pTopyl-
toluenesulfonyl chloride (2.93 g, 15.4 mmol) was added, the reaction mixture was allowed to stir for 1 hour, then the ice bam was replaced with a wjcerMh and ftic reaction mixture was allowed to stir for 16 hours. The mixture was diluted witk dichlorornetharie and the

layers were separated. The reaction was worked vp as described in Example 393 and the
exude product was reciystaffized from acetonitrile to yield 4.7 g of terf-butyl 4-({[4-amino-
2bethoxymeliiyl)-l-propyl-liy-rmidazo[4,5-cb
carboxylate as tan crystals, rap 192-197 °C (decomposition).
“H NMR (300 MHz, DMSCW”) 5 7.55 (d, J= 9.1 Hz, 1H), 7.41 (d, J= 2.1 Hz, 1H), 7.15
(dd, J= 9.1,2.6 Hz, 1H), 636 (s, 2H), 4.% (s, 2H), 4.77 (s, 2HX 4.54-4,49 (IDL 2H), 3b9-
331 (m, 10H), 1.93-1.81 (m, 2H), 1.41 (s, 9H), 1.16 (t, 7= 7.0 Hz, 3H), LD2 (t, J= 7.3
Hz,3H);
13C NMR (75 MHz, DMSO-4J) 5 166.4,153.7,152-5,15Q.6,149.0,1402,132.7,127.5,
126.6,117.0,114.4,102.8,79.2,66.9,653,64.2,46.7,44b, 4Llr2S.G, 33T143,10.8;
MS (ESI) mJz 5212992 (5212922 calcd for C27H38N6O5, M-+B4);
Anal, calcd for C27H38N6O5: C, 61.58; H, 7.27; N, 15.%. Foond: C, 61.41; H, 7.49; N,
15.96.

Part A
The Synthesis nf 9-(rfhrtyymi»rtiyl)-1 -pmpyM F-bblfb- b)|T»nn,iTTw5t-n1 is
described in Parts A-I of Example 2. A modification of fbc ndnd described in Part A of Example 392 was used to convert 2-ethoxymethyi-l-piX)pybL3-iirkiazo{4b-c]qmnolin-8-ol (1.5 g, 526 mmol) into H3-(2-ethaxynrfryM-$rop)blI£ibb yloxy)propyl]-pyrrolidin-2-one using H3-hydiuxy|mopyrjpyrotidin-2-(3ce (1.02 mL, 7.88

mL) in lieu of 3bmemylthio)propan-1 -ol. After the reaction mixture was allowed to stir for 16 hours at ambient temperature, additional diisopropyl azodicarboxylate, triphenylphosphine, and l-(3-hydroxypropyl)pyrrolidin-2-one (0.5 equivalent of each) were added and the reaction mixture was allowed to stir for 2 hours. The solvent was removed under reduced pressure and the resulting residue was purified by flask chromatography (silica gel, elution with ethyl acetate followed by graSeat elision with 1-5% methanol in dichloromemane) to yield 2.9 g of l-{3-(2-efiici5meiteyl-l-propyi-Lfir-irmdazo[4,5b]qumolin-8-yloxy)propyl]bynoKdin-2-oije a pale yefloir soEd. PartB
3-CMoroperoxybenzoic acid (50% pure, 1.8 g, 526 mmol) was adtferi to a solation of 1 -[3-(2-e1iioxymethyl-l -propyl- lH-iimdam[4,5b]quMKfbS-&axyypnx”pffi 2-one (2.9 g, 526 mmol) in chloroform (50 mL). After 30 minutes, saturated aqueous sodium carbonate (20 mL) was added to the solution and the resulting mixture was allowed to stir for 1 hour. The layers were separated and the aqueous layer was extracted with chloroform (3 x 50 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 1-4% methanol in dichloromethane) to yield 1.56 g of l-(3-{[2be1hoxymemyl)-5-oxido4-propyl-L£f4nbb yl]oxy}propyl)pyrrolidin-2-one as a tan foam. StepC
J)-Toluenesulfonyl chloride (0.700 g, 3.66 mmol) was added to a stirred mulme of 1b3-{[2-(ethoxyme1hyl)-5K)xido-l-propyl-lb
yl]oxy}propyl)pvrrolidm-2-one (1.56 g, 3.66 mmol), anmxiKBi hydroxide (24 mL), and dichloromethane (36 mL) at room temperature. After 16 hows, die IZJKXS were separated and the aqueous layer was extracted with dichloromefeane p x 50 mL). The organic layers were combined, washed with water and saturated b""'bs sodiisn chloride, dried
ovftr anhyHmne gftfKiTm gnifiitp fHtfrwH and rrmr”n”nxti)”\ mnA”~ f”Anr”“i pnitmn”
RecrystalHzation from acetonitrile afforded 0.759 g of l-(3-{[4-ainmo-2-(eflioxymemyl)-
l-propyl-lb-irmdazo[4bb]quiiiohn-8-vQafy}ptop3f5pynb “s ofF-white
needles, mp 188.5-190 °C.

!H NMR (300 MHz, DMS(Wtf) 6 7.54 (d, J= 9.1 Hz, 1H), 7.36 (d, J= 2.6 Hz, 1H), 7.11
(dd, J= 9.1,2.6 Hz, 1H), 633 (s, 2H), 4.76 (s, 2H), 4.53-4.48 (m, 2H), 4.07 (t, J= 62 Hz,
2H)3 3.54 (q, J= 7.0 Hz, 2H), 3.37 (t, J= 7.0 Hz, 4H), 2.22-2.17 (m, 2H), 2.00-1,83 (m,
6H), 1.15 (t, J= 7.0 Hz, 3H), 1.02 (t, J= 73 Hz, 3H);
l3C NMR (75 MHz, DMSCWtf) 5 173.8,153.0,150.5,148.9,140.0,13Z7,127.6,126.6,
117.2,114.6,1023,65.8, 653, 64.2,46.8,46.4, 39.1,30.4,26.8,233, I7j, US, 10.7;
MS (ESI) ntJz 426.2518 (426.2505 calcd for CnEvStCh, Mbff);
AnaL calcd for QBHSINSOS: C, 64.92; H, 734; N, 16.46. F«md: C, 64.30; H, 6b9; N,
1637.

The synthesis of 2b&hoxymdhyiyi-propyl-W-iinkb is
described in Parts A-I of Example 2. A modification of the method described in Pact A of Example 405 was used to convert 2-ethoxymetfayl-lbgpp3b1g4TTriria7n[4-5bj(yig)lm-8-ol into 2betnoxymetliyl)-l-propyI-8-(tetrahydro
cjquinoline using 3-hydroxytefcihydroniraa ni Ken of l-(3bi9bacypixjpf)pjaxbdanr2-one. Modifications of the methods described in Parts B and C ofEramnSe 405 were used to convert 2-(ethoxyme1hyI)-l-piop9d-8-(tetrahb c]quino]ine into 2befaxymdhbl-propylr8bteto&y(ko&bb cjquinolxn-4-amine. Parts B and C were axnbmed by omitting fce aqoeoos work iq) of Part B, in other words, the ammonium hydroxide andp-toturiu ■wlfouyl chbxide reagents used in Part C were added to the reaction mjxrnre in Part B. The reaction was worked up

as described in Part C of Example 405. 2HEthoxymeb)bl-prcbyl-8-{tetrahydiDfi2ran-3-
yloxy)llf-iinida2»[4,5b]quinolin-4-aniine was isolated as tan needles, mp 173-175 °C.
!H NMR (300 MHz, DMSO-J”) 8 7.56 (d, J= 9.1 Hz, 1H), 734 (d, J= 2.7 Hz, IB), 7.11
(dd, J= 9.1,2.6 Hz, 1H), 636 (s, 2H), 5.21-5.14 (m, 1H), 4.78 (s, 2H), 4.58-4.48 (m, 2H),
3.97-3.76 (m, 4H), 3b6 (q, J= 7.0 Hz, 2H), 231-2.19 (m, 1H), 2.13-2.04 (m, 1H), 1.97-
1.84 (m, 2H), 1.16 (t, J= 7.0 Hz, 3H), L02 (t, J= 7.4 Hz, 3H);
13CNMR(75 MHz,DMSO-dtf) 5 151.5,150.6,148.9,140.4,132.6,127b, 126,7,117.8,
114.6,1033, 77.4, 72.2,66.4,653,64.2,46.8,323,233,14.9,10 J;
MS (ESI) mJz 371.2084 (371.2083 calcd for C20H26N4O3, MrfET%
Anal calcd for C20H26N4O3: C, 64.85; H, 7.07; N, 15.12. Foani C, 64b0; H, 7.09; N,
15.29.

Part A
The synthesis of 2-(ethoxyme&yl)-l-fnopyl-lJ7-iibb is
described in Parts A-I of Example 2. The general method duuibtd in Pat L of Example 2 was followed. 2-(EthoxymethyI)-l-propyI-Lff-inrida2o[4b-c}qoinofiij-8-oI (4.43 g, 15.5 mmol) was treated with fert-bulyl 6-iodohcryicaibamate (pnpatoi as desaribed in Part F of Example 45,6.1 g, 18.6 mmol). After the work “p, the crwfc product was not purified

to yield 9.9 g of tert-butyl 6-{[2be1hoxymediyl)-l-prop5d-lff-iiiridazo[44b]quinoHn-8-yl]oxy}hexylcarbamate as a tan waxy solid that contained DMF and dichloromefhane. PartB
A modification of the procedure described in Part B of Example 392 was used to convert the crude tert-butyi 6-{[7bbo\ym?tTiy!)-1 -pmryb-1 b-JH”bb4.5-b3q«"K»iTn-R-yi]oxy}hexylcarbamate ftom Part A into tetf-butyi 6b{[4-atoa»-2-(edioxyaKaiyi)-l-piopyl-lif-imidazo[4)(r]qiinK)fo-8-yl]cby}hex)4caibaniatb The reactsao mixture was transferred to a separately funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 100 mL). The organic layers were combined, washed with 5% aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The aiide product was purified by flabchrcbnalography (silica gel, gradient elution 1-5% methanol in dichloromethane) to afford 4.60 g of terf-butyi 6-{[4-ammo-2-(emoxymethyl)-l-propyl-ljy-rmidazo[4,5b]quinoIm-8-yl]oxy}hexylcarbamate as a tan solid that contained some impurities but was used in the next step without further purification. PartC
A solution of the material from Part B in 4.0 M ethanolic hydrogen chloride (22
mL) was heated at reflux for 1 hour. The solution was allowed to cool to room
temperature and was concentrated under reduced pressure to yield an aflyiessiae. Water
(approximately 10 mL) and saturated aqueous sodium rhXcm&i (10 mL) were added to the
oily residue, then the solution was adjusted to approTijirrfirJy pH 33 wife 50% aqueous
sodium hydroxide. The aqueous solution was extracted with 9:1 dikao&nairjethanol (2 x
100 mL). The organic layers were combined, dried over anbveroes magnesjom satiate,
filtered, and concentrated under reduced pressure. The cradc induct ws trnmzted with
acetonitrile and a solid was isolated by filtration to afrord 3.1 g ra 8-b6-amrnobexyloxy)-2-
(emoxymethylH-propy!-L#-rrmdazo[4bbJbb K apak violet soh'd.
PartD
Isobutyryl chloride (0.236 mL, 2.25 xnmol) was added dmpwise, followed by triethylarnine (0.2 mL, 1.4 mmol), to a stirred slurry of 8-(6-anHKihexyloxy)-2-(ethoxymethyl)-lbropyl-lJJ-irrnda2o[4,5b]qomoHnbyiB3nac (&900 g, 2J25 mmol) in

dichloromethane (25 mL) at room temperature. After 30 minutes, water (15 mL) was
added and the mixture was allowed to stir for 30 minutes. The layers were separated and
the aqueous layer was extracted with dichlormethane. The organic layers were combined,
washed with water and brine, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Purification by flash cfanoiinatograpby(salica gel,
gradient elution wim 1-6% CMA in chloroform) followed by recrvstaBizarion fhxa
acetonitrile afforded 0.285 g of ib6-{[4-amino-2-(e”boxymefiiyO-I-propyi-lHr-
iimdaa»[4,5w:](nunolm-8-yi]o:xy} as antate zrfsaSans solid,
mp 136-138 °C.
!H NMR (300 MHz, DMSOb) 5 7.64 (t, J= 5.5Hz, IH), 7.53 (4 J=9-1 Ez, IH), 7.35
(d, J= 2.6 Hz, IH), 7.10 (dd, J= 9.1,2.6 Hz, 1H), 6.31 (s, 2H), 4.76 (s, 2H), 453-4.48 (m,
2H), 4.07 (t, J= 6.5 Hz, 2H), 3.54 (q, J= 7.0 Hz, 2H), 3.02 (q, J= 6.1 Hz, 2H), 237-2.23
(m, IH), 1.96-1.83 (m, 2H), 1.80-1.71 (m, 2H), 1.50-1.26 (m, 6H), 1.15 ft J= 7.0 Hz,
3H), 1.02 ft J= 7.4 Hz, 3H), 0.96 (d, J= 6.9 Hz, 6H);
13C NMR (75 MHz, DMSO-4”) 5 175.8,153.2,150.5,148.8,139.9,132.7,127.6,126.6,
117.2,114.6,102.1, 67.6, 65.3,64.2, 46.7, 38.2,34.0,29.1,28.7,26.1,253,233,19.6,
14.9,10.7;
MS (ESI) mJz 4703118 (4703131 calcd for CasH&NsQfc M+fl4);
Anal, calcd for CxRi&Jh: C, 66.50; H, 837; N, 14.91. Found: C, 66J24; H, 835; N,
14.77.


A modification of the procedure described in Part A of Example 369 was used to convert 8-(6-ammohexyloxy)-2-(ethoxymethyl)-l-prt)pyM
ylamine (prepared as described in Parts A-C of Example 407,0,900 g, 2.25 mmol) into N-(6-{[4-ammo-2-(ethoxymetiiyl)-l-propyHjEf-b
isopropylurea. The crude product was purified by flash chromatography followed by recrystallization from acetonitrile to provide 0.528 g of AK6b{[4-anriiK)-2-(eaioxymethyI)-l-propyl-liy-iimdb2o[4J5b]qumolm-8-yl]oxy}hexyr)JVI-isopropbrea as ffonraitaitf wirite crystals, mp 167-169 °C.
]H NMR (300 MHz, DMSO-d6) 6 7.53 (d, J= 9.1 Hz, 1H), 735 (d, J= 2.6 Hz, 1H), 7.10 (dd, J= 9.1,2.6 Hz, 1H), 631 (s, 2H), 5.63 (t, J= 5.6 Hz, 1H), 534 (d, J= 7.7 Hz, 1H), 4.76 (s, 2H), 4.53-4.48 (m, 2H), 4.07 (t, J= 6.5 Hz, 2H), 3.70-357 (m, 1H), 334 (q, J= 7.0 Hz, 2H), 2.96 (q, J= 6.1 Hz, 2H), 1.96-1.83 (m, 2H), 1.80-1.71 (m, 2B), L49-L26 (m, 6H), 1.15 (t, J= 7.0 Hz, 3H), 1.02 (t,J= 7.3 Hz, 3H), 0b8 (d, J=&5 Hz, 6H); 13C NMR (75 MHz, DMSO-&) 8 157.4,153b, 1503,148.8, 139J9? 132.7,127.6,126.6, 117.2,114.6,102.1,67.7,653,64.2,46.8,40.7,39.0,30.0, 2XJ7,3Si 253,233,23b, 14.9,10.7;
MS (ESI) mJz 4853237 (4853240 calcd for C2tH4oN6Q3, MbH”); Anal, calcd for C26H40N6O3: C, 64.44; H, 832; N, 1734. Fom”± C, 64.15; H, 8.43; N, 17.21.


A modification of the procedure described in Part D of Example 407 was used to convert 8-(6-ammohexyloxy)-2bemoxymetbyl)-l -propyl-Lff-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Parts A-C of Example 407,0.900 g, 2.25 mraoT) into N-(6- {[4-amino-2-(ethoxymethyl)-1 -propyl- Lff-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)methanesulfonamide- The reaction was run using me&anesnMboyi chloride (0.174 mL, 2.25 mmol) in lieu of isobutyryl chloride and wifbona: tristirvianine. The reaction was quenched with saturated aqueous sodium carbonate (10 mL) »n(fe-art of water. The crude product was purified by flash chromatograpby followed by recrystalfizatksi from acetonitrile to afford 0.350 g of iVb6b{[4-amino~2beflMQSbaaedryI)-l-{jn}pyi-LSL inudazot4,5b]qirinolm-8-yl]oxy}hexyl)memanesulfonanride as fkxxakzl wfsse crystals, mp 164-167 °C.
!H NMR (300 MHz, DMSO-&) 5 7.53 (d, J= 9.1 Hz, 1H), 736 (c,y= Z6 Bz, JJB), 7.10 (dd, J= 9.1,2.6 Hz, 1H), 6.91 (t, J= 5.8 Hz, 1H), 6.31 (s, 2H), 4.75 (s, 2H), 434-4.48 (m, 2H), 4.08 (t, J= 6.5 Hz, 2H), 3.54 (q, J= 7.0 Hz, 2H), 2b2 feJ= 6L6 HZ, 2H), 2.86 (s, 3H), 1.96-1.84 (m, 2H), 1.81-1.72 (m, 2H), 133-1 Jl (m, 6H), LL5 (t, J= 7.0 Hz, 3H), 1.02 (t, .7=7.4 Hz, 3H);
13C NMR (75 MHz, DMSO-rf”) 5 153b, 1503,148.8,139.9,13Z7,127.6,126.6,117.2, 114.6,102.1,67.6,65.3, 642,46.8,42.4,39.1,29.4,28.6, 25b, 25,2,233,145,10.7;

MS (ESI) mJz 478.2485 (478.2488 calcd for C23H35N5O4S, M+H”);
AnaL calcd for C23H35N5O4S: C, 57.84; H, 7.39; N, 14.66. Found: C, 57.97; H, 7.60; N,
14.67.

Part A
The synthesis of 2-(e1hoxymetiiyl)-l-propyl-lH-iiiiidazo[455-c]quiiiohii-8-ol is described in Parts A-I of Example 2. The general method described in Part A of Example 374 was followed starting with 2be1iioxymemyI)-l-propylrlffbnikJa2o[4b5(5qiniK)ED-8-ol (6.0 g, 21.0 nnnol). The crude product was purified by flash chrotnatograpfay (a&ca gel, gradient elution with 1-7% CMA in chloroform) to yield 9.76 g of tertAxtyi 4-Q2-(pth"Xymfifayl)-1-pnTpyH b-iTnidaznbb-bqtnnnib-R-yfjnbpqieyMTnft-i-rabnTyiata as a slightly impure tan semi-solid that was used in the next step wifaoat further purification. PartB
A solution of the material from Part A (9.7 g, 20.7 mmd) and 32% paacebc acid in acetic acid (7.36 mL, 31.0 mmol) in e%l acetate (69mL) wasIratedat 50 "C fi)r35 hours. A solution of sodium metabisulfite (4.92 g, 25.9 mmoQ in wieer (10 mL) was added over 15 minutes. The reaction mixture wasallowcd to sir at 50°C for 30 minutes. Healing was discontinued and the reaction was adjusted to pH 10 with 50% aqueous sodium hydroxide. The mixture was allowed to cool to ambient tenpaatnrc and was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layos were combined and washed with water

and saturated aqueous sodium chloride. The aqueous layers were combined and were back-extracted with dichloromethane. All the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 10-22% CMA in chloroform) to yield 4.5 g of K7t-bnryi 4~$2-(ethoxyme&yl)-5-orido-l-propyl-liy-bb carboxylale as a orange-white solid. PartC
Trichloroacetyi isocyanate (L22 mL, 10J2 mmol) was added drapwac a saned solution of tert-butyl 4-{[2-(ethoxyme”hyI)-5-oxtocHl-projb-Lff-inb 8-yl]oxy}piperidine-l-carboxylate (4.5 g, 9.29 mmol) in dichlorome&ane (90 mL) at room temperature. After 1.5 hours, ammonium hydroxide (4.5 mL) was added and fee mixture was allowed to stir for 1 hour. Saturated aqueous sodium carbonate (60 mL) and water (20 mL) were added to the mixture. After 30 minutes, the mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with chloroform (2 x 100 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatogtaphy on a HORIZON HPFC system (silica geL gradient elution with 1-25% CMA in chloroform) followed by recrystallization from acetonftrifc to yield 23 g aftert-batyl 4-{[4-ammo-2-(ethoxyme&yi)-l-piopyl-lif-ib carboxylate as a gray solid, mp 179.5-181 °C.
:H NMR (300 MHz, DMSO-d6) 5 7.55 (d, J= 9.0 Hz, IB), 7.42 {i, 7= 23 Hz, 1H), 7.16 (dd, J= 9.0,2.6 Hz, 1H), 6.36 (s, 2H), 4.77 (s, 2H), 4.69-4.61 (BL 1H}, 4J5-4_50 (m, 2H), 3.75-3.65 (m, 2H), 336 (q, J= 7.0 Hz, 2H), 3b8-3.15 (m, 2H), 2i3l-I.S2 baL 4H), 1.6S-1.54 (m, 2H), 1.41 (s, 9H), 1.16 (t, J= 7.0 Hz, 3H), 1.03 (t, J= 7.4 3z, 3H); MS (ESI) mlz 484.5 (M+H)+;
AnaL calcd for C26H37N5O4: C, 64.57; H, 7.71; N, 14.48. Fooai C 6433; H, 7S1; N, 14.52.


A solution of tert-bnryl 4-{[4-anrino-2befb£»xymeihyr)l-j)rop3bbb c]qumomi-8-yl]oxy}piperidme-l-caiboxylate (prepared as described in Exangrie 41G, 13 g, 6.0 mmol) and 4 M emanolic hydrogen chloride (15 mL) in ethano! (20 mL) -was heated at reflux for 2 hours. The solution was allowed to cool to ambient temperature and was concentrated under reduced pressure to approximately 17 mL, causing a sofid to form. Water was added to dissolve the solid and the remainder of the ethanol was evaporated under reduced pressure. The aqueous solution was adjusted to approximately pH 13 with 50% aqueous sodium hydroxide, then was extracted with chloroform. The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was recrystaUization from acetonitrile to yield 1.25 g of 2be1hoxynieftyI)-8-(pbieridin-4-yloxy)-l-prcpyl-lff-iimdazo[4,5b3qumohb-4-amine as off-whits needles, rap 176-178 °C. 1HNMR(300MHz,DMSOrftf) 5 7.54 (d, .7=9.0 Hz, 1H), 7.39 (4b=2.6 Hz, 1S% 7.11 (dd, J= 9.0,2.6 Hz, 1H), 6.33 (s, 2H), 4.77 (s, 2H), 4.54-4.44 (m, 3H), 356 ((t J= 7.0 Hz, 2H)5 3.02-2.95 (m, 2H), 2.62-2.54 (m, 2H), 2.07-1.83 (m, 5H), 137-1.45 fa, 2H), 1.16 (t, J= 7.0 Hz, 3H), 1.04 (t, J= 7.4 Hz, 3H);
13C NMR (75 MHz, DMSO-b) 5 151.4,150.5,148b, 140JJ, 13Z£, 127.7,126 6,1183, 114.6,104.0,74.1,65 3,642,46.8,43.8,32.4,23 3,14.9,10.7; MS (ESI) mJz 384.2414 (384.2400 calcd for CnEz&Jh, M+HJL AnaL calcd for C21H29N5O2: C, 65.77; H, 7.62; N, 18.26. Fomrf: C 6535; H, 7.60; N, 18.17.


Isopropyl isocyanate (0.190 mT., 1.90 mmol) was added dropwise to a sctoion of 2-(emoxymetnyl)-8-(piperidin-4-yloxy)4-propyl-liI-b
(prepared as described in Example 411,0.730 g, 1.90 mmol) in dkhlorome&ane (15 mL) at room temperature. The reaction was diluted with dichloromethane and stirred vigorously. A precipitate formed that was isolated by filtration to afford 0.743 g of 4- {[4-anmc)-2-(ethoxymemyI)-l-propyl-liJ-iimb
isopropylpiperidme-1-carboxamide as a white solid, mp 236.5-239 °C. “H NMR (300 MHz, DMSO-tf,;) 5 7.55 (d, J= 9.0 Hz, 1H), 7.42 (d, J= 23 Hz, 1H), 7.15 (dd, J= 9.0,2.5 Hz, 1H), 6.35 (s, 2H), 6.20 (t, J= 7.6 Hz, 1H), 4.78 (s, 2HX 4b7-4_59 (m, 1H), 4.55-4.50 (m, 2H), 3.82-3.69 (m, 3H), 3.56 (q, J= 7.0 Hz, 2H), 3.16-3.07 (m, 2H), 2.01-1.82 (m,4H), 1.65-1.49 (m, 2H), 1.16 (t, J=7.0Hz,3H),1.06{d5J'=6bHz,6HX 1.03(t,J=7.4Hz,3H);
13C NMR (125 MHz, DMS0H&) 5 156.7,1513,150.6,148,9,14QJ, 13Z6, O7.7,126b, 118.4,114.7,104.6,73.0,653,64.2,46.7,41.7,40.9,30.5,232”223, 14b, 1O8; MS (ESI) mJz 469.2936 (4692927 calcd for CjsHaeNfiCb, M+Hb AnaL calcd for CbLbb. C, 64.08; H, 7.74; K, 17.93. Fount C, a3-85;H, 7.67; N, 17.89.


Methanesulfonic anhydride (02.95 g, 1.69 mmol) was added in one pcatjou to a stiired solution of 2bemoxymetlryl)-8biperidmbyloxy)-l-propyI-L£rbb c]quinolin-4-aniine (prepared as described in Example 411,0.650 g, 1.69 mmol) in dichloromethane (15 mL) at room temperature, resulting in a white precipitate. After 16 hours, 2.0 M aqueous sodium carbonate was added and the reaction mixture was allowed to stir for 45 minutes. The precipitate dissolved and the mixture was transferred to a separatory funnel where the layers were separated. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pmssuie. The exude product was purified by trituration in boiling acetonitrile and isolated by filtrafcoa fc) yield 0.650 g of 2-(e&oxymemyl)8-{[Hmemylsulfonyl)pib
irm'dazo[4,5-c]qiiraolm-4-amine as an off-white crystalline solid, nip 240-2435 SC !H NMR (300 MHz, DMSOwfc) 5 7.57 (d, J= 9.0 Hz, 1H), 7.43 (db= 23 Hz, IH), 7.18 (dd, J= 9.0,2.5 Hz, 1H), 638 (s, 2H), 4.78 (s, 2H), 4.704.61 (HL ffl), 455-L50 (m, 2HX 3.56 (q, J= 7.0 Hz, 2H), 3.44-336 (m, 2H), 3b0-3.12 (m, 2HX 2b2 (s, SH), 2.10-ZOO (m, 2H), 1.95-1.79 (m, 4H), 1.16 (t, J= 7.0 Hz, 3H), 1.03 (tsJ=7.4Her3ate 13C NMR (125 MHz, DMSOJtf) 5 151.3,150.7,148.9,140.3,132b 127.7,126b, 118.4, 114.7,105.0,71.4, 653, 642,46.7,42.5,34.4,29-8,232,14.9, IflLS; MS (ESI) mJz 4622172 (4622175 calcd for Czz&nNjO+S, M+H”): AnaL calcd for CzjHaiNsCUS-O.lSCHCfe: C, 55.49; H, 635; N, 14.61; d, 333. Found: C, 55.51; H, 6.71; N, 14.66; O, 325.


A modification of the procedure described in Example 413 was used. 2-(Ethoxyme1hyl)-8-(pipmdmbyloxy)-lb
(prepared as described in Example 411,0.650 g, 1.69 mraol) was treated with isobutyryl chloride instead of the metiianesulfonic anhydride. After the work vp, the erode product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.500 g of 2-(emoxymetiiyl)-8-[(l-isobutyrylpiperidm-4-yl)oxy]-l-propyl-liy-imida2o[4,5-c]quinonn-4-amine as a white solid, mp 177-179 °C.
“H NMR (300 MHz, DMSO-d”) 8 7.56 (d, J= 9.0 Hz, 1H), 7.44 (d,J - 2.6 Hz, IB), 7.17 (dd, J= 9.1,2.6 Hz, 1H), 6.36 (s, 2H), 4.78 (s, 2H), 4.78-4.68 (m, IB), 45)4S0 b 2H), 3.96-3.74 (m, 2H), 3.56 (q, J= 7.0 Hz, 2H), 3.46-3.36 (m, 1H), 2b8-2b3 (m, IH), 2.09-1.80 (m, 4H), 1.76-1.53 (m, 2H), 1.16 (t, J= 7.0 Hz, 3H), 1.03 (t, J= 7.402,32), 1.01 (d, J= 6.7 Hz, 6H);
13C NMR (125 MHz, DMSCWtf) 5 174.1,1512,150.6,148.9,1402,152.6,127.7,126.6, 118.3,114.6,104.8,72.6,653,64b, 46.7,41.9,383,313,303,2”5,23.2,15.4, 14.9, 10.7;
MS (ESI) mJz 454.2819 (4542818 calcd for C25H35N5O3, M+H”X Anal, calcd for C25H35N5O3: C, 66.20; H, 7.78; N, 15.44. Found: C, 66-05; H, 7.72; N, 15.57.


Part A
2bthox3one&yl)-l-prop3d-lbiinidazo[4J5-c]qianoIm-7-ol (3.00 g, 10,5 mmol) and triphenylphosphhie (3.43 g, 13.1 mmol) were slurried in THF (105 mL) and cooled with an iceJwater bath. tert-Bntyl 4-hydroxypiperidine-l-carboxylate (2.64 g, 13.1 mmol) was added followed by the dropwise addition of diisopropyl azodicarboxylate (2.58 mL, 13.1 mmol). The water bath was removed and the mixture was stirred for 72 hours under nitrogen. The solvent was removed under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient ejution with 1-15% CMA in chloroform) to afford 5.17 g of tert-butyl 4-{[2beSxaryme&b-l-fsapb-lB-iiddazo[4,5w;]qumolm-7-yI]oxy}piperidine-l-carboxylate as an off-white crystaBme sold. PartB
To a stirring solution of tert-hvtyl b{Pbemoxyme&yO-l-bKpyi-lffmiidazxbp-c]qiunoIm-7-yl]oxy}piperidme-l-carboxylate (5.17 g, 10.5 mmol) m c&forofcnH (100 mL) was added 3-chloroperoxybenzoic acid (3.62 g, 10.5 mmol, based cm 50% parity). After 30 minutes, concentrated ammonium hydroxide (50 mL) was addaLand themiime was stirred for 30 minutes. p-Toluenesnlfonyl chloride (2.00 g, 103 maxS) im added in 3 portions and the mixture was stirred for 16 hours. The layen woe xpmaOcd and me organic fraction was sequentially washed with 5% aqueous sodimiKVbange, water, and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. i?w lyuimiffp BM»I from acetonitrile afforded 2.58 g of tert-butyl 4-{[4-aminc)2betharymedrb

c3qmnolin-7-54]oxy}piperidJne-l-cait)oxylate as a reddish-tan crystalline solid, mp 194-
195 °C.
“H NMR (300 MHz, DMS0-&) 5 7.90 (d, J- 9.0 Hz, 1H), 7.11 (d, J» 2.6 Hz, IB), 6.95
(dd, J= 9.0,2.6 Hz, 1H), 6.51 (s, 2H), 4.75 (s, 2H), 4.71-4.60 (m, 1H% 453-4.41 (m, 2H),
3.77-3.65 (m, 2H), 3.56 (q, J= 7.0 Hz, 2H), 327-3.12 (m, 2H), 2.03-1.91 (m, 2H), 1.91-
1.78 (m, 2H), 1.64-1.49 (m, 2H), 1.41 (s, 9H), 1.16 (t, J= 7.0 Hz, 3H), LOO (t, J= 7.4 Hz,
3H);
MS (ESI) iwfe 484.3 (M + H)+;
Anal, calcd for C26H37N5O4: C, 64.57; H, 7.71; N, 14.48. Found; C, 64J6; SL 7b6; N,
14.65.

ter£0Bixt5d 4-{[4-anmo-2-(e1toxymb
yl]oxy}piperidine-l-caiboxyiate (2.45 g, 5.07 tnmol) was takai xg) in 4.0M d&ssx&c hydrogen chloride (15 mL) and heated to 65 °C for 1 hour. Hie heatbeas lemoved and tiie reaction was allowed to cool to ambient temperature. The e&anol vss removed nndcx reduced pressure and the solid residue was dissolved in water (10 BBL) wad sasmmol aqueous sodium chloride (10 mL). The solution was brought to pfi 13 wifli 50% aqoeocs sodium hydroxide and men extracted with chloroform. The organic iraction was sequentially washed with water and saturated aqueous sodium chloride, tided over anhydrous sodium sulfete, filtered and evaporated. Trituratkm wim acartirtriVi, followed by filtration afforded 1.70 g of 2-(emoxymemyI)7-(piperidmbb imidazo[4,5-c]quinoUn-4-atnine as a tan solid, mp 202-204 °C.

“H NMR. (300 MHz, DMSO-J”) 5 7.89 (d, J= 9.0 Hz, 1H), 7.07 (d, J= 23 Hz, 1H), 6.92
(dd, J= 9.0,2.5 Hz, 1H), 6.51 (s, 2H), 4.74 (s, 2H), 4.54-4.39 (m, 3H), 3.55 (q, J= 7.0 Hz,
2H), 3.03-2.90 (m, 2H), 2.67-2.54 (m, 2H), 2.03-1.78 (m, 5H), 1.57-1.40 (m, 2H), 1.16 (t,
J= 7.0 Hz, 3H), 1.00 (t, J= 7.3 Hz, 3H);
MS (ESI) m£ 384.2 (M + H)+;
AnaL calcd for CZJHZBNSOJ: C, 65.77; H, 7.62; N, 18.26. Found: C, 65.61; E, 7.62; N,
18b3.

amine (0.500 g, 1.3 mmol) was slurried in dichloromethaie (13 mL). Isopropyi isocyaoate was added drcbwise to the slony and 1he reaction was stiired for 16 boors. The reaction was purified by chromatography on a HORIZON HPFC system (sxEcz gd, gcatSo” etetioa with 2-22% CMA in chlorofiwcm) followed by recrystallizatkm firaa anmnitnir, yidded 0.430 g of 4~{[4-aniino-2(etbx)xymethyl)-l-pro iST-isopropylpiperidine-l-caiboxamide as a white solid, mp 163-1645 :aC TH NMR (300 MHz, DMSO-&) 5 ISO (d, J~ 9.0 Hz, 1H), 7.11 (4b=2.6 Hz, 1H), 6\94 (dd, J= 9.0,2.6 Hz, 1H), 6.52 (s, 2H), 6.19 (d, J= 7.6 Hz, 1H), 4.75 {x m), 438-432 (m, 1H), 4.52-4.41 (m, 2H), 3.84-3.66 (m, 3H), 335 (q, b= 7.0 Hz, 2H), 3.18-3.04 (m, 2H), 2.02-1.77 (m, 4H), 1.62-1.44 (m, 2H), 1.16 (t, J= 7.0 Hz, 3H), 1.06 (d, J= 6.6 Hz, 6H), 1.00(t,b=7.3Hz,3H);

nC NMR (125 MHz, DMSO-&) 5156.7,155.9,152.3,148.1,147.0,133.4,1245,121.4, 112.6,109.8,108.9, 72.3,653,64.2,46.7,41.7,40.9,30.5,23.0,22.9,14.9,10.7; MS (APCT) mJz 469.3 (M + H)+; AnaL calcd for CasHseNeQs-ObHaO: C, 63.11; H, 7.80; N, 17.66. Found: C, 63.20; H,
7.94; N517.92.
Examples 418-422
A solution of 1 M boron tribixmnfem heptane (400 pL)w«addri to a O5b stirred solution of a starting material from the table below (approximately 25 zcg) in dichloromethane (1 mL). The reaction mixture was stirred at 0 °C for 50 "rinmw; aod thai at room temperature overnight Methanol (1 mL) and 6 M aqueous hydrochloric add (250 uL) was added to each reaction vessel, which was vortexed shortly afterwards. The volatiles were removed by vacuum centrifugation. The compounds were purified using the method described in Examples 376-386. The table below shows the starting material added to each reaction vessel, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt



Examples 423-438
A reagent (0.11 mmoL, 1.1 equivalents) from the table below was added to z fes: tube containing b-[4-fmiTPb7b?-trTTiT'fMb"b)-7bbbnTfym”bT|y0-T bbiAx-mbtjb-c]qumolin-l-yl]propane-l,2-diol dflrydrochloride (45 mg, 0.1 mmoL prepared as described in Example 373) and AyV-diisopropylefoylamine (0.071 inL, 0.40 mmol) in NJt-ditnethylacetamide (1 mL). The test tubes were capped and shaken overnight at room temperature and then two drops of water were added to each test tube. The solvent was removed by vacuum centriiagation. The compounds were purified using the method described in Examples 376-386. The table below shows the reagent added to each test tube, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.





Examples 439-459
The free base of 3-[4-amiQO-2be&ax5anetib)-7--(piperidiii-4-yiD!iy)-lSb inudazo[4,5-c3quinolin-l-yi]propane-lb-diol dflrydrochloride (prepared as described in Example 375) was prepared. A reagent (0.11 mmol, 1.1 equivalents) from the table below was added to a test tube containing 3b4-amino-2be1iioxymeth5d)-7-(pb)eridiD-4-yioxy)-lif-imidazobb-cjquinolin-l-yljpropane-lb-diol (42 mg, 0.10 mmol) sndNJf-diisopropylethylamine (0.033 mL, 0.20 mmol) in Ab-dimethylacetamide (1 mL). The test tubes were capped and shaken overnight at room temperature and then two drops of water were added to each test tube. The solvent was removed by vacuum centrifugation. The compounds were purified using the method described in Examples 376-386. The table below shows the reagent added to each test tube, the structure of the resulting compocnd, and the observed accurate mass for the isolated trifhioroacetate salt






Example 375) was prepared. An aldehyde or ketone (0.125 mmol, 1.25 equivalents) fixnn the table below was added to a test tube containing 3-[4-amino-2-(e1hoxymethyI)-7-(piperidin-4-yloxy)-lH-imidazo[4bb]quinolin-l-yl3propane-lb-diol (42 mg, 0.10 mmd) in i\yb-dimethylacetainide (1 mL). The test tubes were capped and shaken for 30 TFbWTtes
5 at room temperature. Borane-pyridme complex (16 p.L, 0.13 nimol) was added to eau± of the tubes. The test tubes were capped and shaken overnight at room temperature, ihsatwo drops of water were added to each test tube. The solvent was removed by vacrarc centrifugation. The compounds were purified using the method described in Exaanpies 376-386. The table below shows the aldehyde or ketone added to each test mbe, ta”
) structure of the resulting compound, and the observed accurate mass ibribe isolated txifhioroacetate salt


1. A compound of the formula (II):

wherein:
R.3 is selected from the group consisting of
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R5,
-Z-Het,
-Z-Het'-R,, and
-Z-Het'-Y-R4; Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -0- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; nisO or 1; Ri is selected from the group consisting of
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R5; R2 is selected from the group consisting of
-R4,
-X-R4,

-X-Y-R4, and -X-R5;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, rylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and lkynylene groups can be optionally interrupted or terminated with arylene, eteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of


R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
Rs is selected from the group consisting of

R.6 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of-0-, -C(0)-, -S(0)o-2-, and -N(R4)-;
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;
Het' is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy,

arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(0)2-, -C(R6)-N(R8)-W-, -S(0)2-N(R8)-, -C(R6)-0-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -0-C(R6)-, -N(R8)-C(R6)-, and
-S(0)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is R3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R^ or
R3 is -Z--Y-R4 or -Z-Y-X-Y-R4, and Y is selected from -S(O)0.2-,
-S(0)2-N(R8)-, -C(R6)-5 -C(R6)-0-, -C(R6)-N(R8)-,

5
or a pharmaceutical^ acceptable salt thereof.
2. The compound or salt of claim 1 wherein R3 is -Z-Y-R4 or -Z-Y-X-Y-R4.
3. The compound or salt of claim 2 wherein
Y is selected from the group consisting of
-S(0)o.2--C(O)-, -C(0)-0-, -O-C(O)-,
-N(R8)-Q-5 -C(R6)-N(R8)-,


wherein Q is selected from the group consisting of a bond, -C(O)-, -C(0)-0-, -S(0)2-, -C(R6)-N(Rg)-W-, and -S(0)2-N(R8)s W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; R6 is selected from the group consisting of =0 or =S; R8 is selected from the group consisting of hydrogen, CM alkyl, and alkoxyalkylenyl; and R]0 is selected from the group consisting of C4-6 alkylene;
X is selected from the group consisting of alkylene, arylene, heterocyclylene, heteroarylene, and alkylene terminated with heteroarylene; and R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl,
arylalkylenyl, alkylheteroarylenyl, heteroary lalky lenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl,
wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and heterocyclyl, and wherein arylalkylenyl and heteroary lalky lenyl are unsubstituted or substituted by

one or more substituents selected from the group consisting of alkyl, halogen, and alkoxy.
4. The compound or salt of claim 1 wherein R3 is -Z-R5.
5. The compound or salt of claim 4 wherein R5 is selected from the group consisting
of

a and b are each independently 1 to 3.
6. The compound or salt of claim 1 wherein R3 is -Z-Het, -Z-Het'-R4 or
-Z-Het'-Y-R4.
7. The compound or salt of claim 6 wherein Z is a bond.
8. The compound or salt of claim 1 wherein R3 is -Z-N(Rg)-C(R6)-R4.
9. The compound or salt of claim 8 wherein R8 is hydrogen, R6 is =0, and R4 is
selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl,
and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and
heteroaryl groups can be unsubstituted or substituted by one or more substituents selected
from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro,
dialkylamino, aryloxy, heterocyclyl, trifluoromethyl, trifluoromethoxy, and in the case of
alkyl, oxo.
10. The compound or salt of claim 1 wherein R3 is -Z-N(R8)-S(0)2-R4.

11. The compound or salt of claim 10 wherein R8 is hydrogen, and R4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo.
12. The compound or salt of claim 11 wherein Z is ethylene or propylene, R8 is hydrogen, and R4 is Ci_3 alkyl.
13. The compound or salt of claim 1 wherein R3 is
14. The compound or salt of claim 13 wherein R, is C3.5 alkylene.
15. The compound or salt of claim 1 wherein R3 is

16. The compound or salt of claim 15 wherein 2 is a bond.
17. The compound or salt of claim 15 wherein R8 is =0 or =S, R8 is hydrogen or
C1-4 alkyl, Rio is C4-6 alkylene, W is a bond, -C(0)-, or -S(0)2-, and R4 is selected from
the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and
heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and
heteroaryl groups can be unsubstituted or substituted by one or more substituents selected
from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro,

dialkylami.no, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo.
18. The compound or salt of claim 17 wherein R3 is

19. A compound of the formula (VI):

wherein:
R3-4 is selected from the group consisting of

Za is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
n is 0 or 1;
R] is selected from the group consisting of -R4,

-X-R4, -X-Y-R4,
-X-Y-X-Y-R4, and -X-R5; R2 is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, and -X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of



R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of-0-, -C(0)-, -S(0)o-2-, and -N(R4)-;
A' is selected from the group consisting of-0-, -C(0)-, -S(O)0-2-, -N(R4)-, and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-,


W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is 20. The compound or salt of claim 19 wherein R3.4 is -2a-C(R6)-R4.
21. The compound or salt of claim 20 wherein R.6 is =0 or =S, and R4 is alkyl, aryl, or heterocyclyl.
22. The compound or salt of claim 19 wherein R3.4 is

23. The compound or salt of claim 22 wherein Re is =0 or =S, a and b are each independently 1 to 3, and A' is selected from the group consisting of -CH2-, -S(0)2-, and -0-.
24. The compound or salt of claim 23 wherein Za is methylene, R6 is =0, a is 1 or 2, b is 2, and A' is -CH2-.
25. The compound or salt of claim 23 wherein Z9 is methylene, R$ is =0, a and b are each 2, and A' is -0-.

26. The compound or salt of claim 19 wherein Za is a bond or alkylene.
27. The compound or salt of claim 1 wherein:


28. The compound or salt of any one of claims 1 through 27 wherein n is 0.
29. The compound or salt of any one of claims 1, 6, or 7 wherein Het or Het' is
selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, 1,3-
dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,
aziridinyl, azepanyl, diazepanyl, dihydroisoquinolin-(l//)-yl, octahydroisoquinolin-(l-ft)-
yl, dihydroquinolin-(2/f)-yl, octahydroquinolin-(2//)-yl, dihydro-l//-imidazolyl, and
piperazinyl.
30. The compound or salt of any one of claims 1 through 27 wherein Ri is selected
from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl,
dihydroxyalkyl, alkylsulfonylalkylenyl, -X-Y-R4, -X-R5, and heterocyclylalkylenyl,
wherein the heterocyclyl of the heterocyclylalkylenyl group is optionally substituted by
one or more alkyl groups; wherein X is alkylene; Y is

31. The compound or salt of claim 30 wherein Ri is selected from the group
consisting of 2-hydroxy-2-methylpropyl, 2-methylpropyl, propyl, ethyl, methyl, 2,3-
dihydroxypropyl, 2-phenoxyethyl, 4-[(methylsulfonyl)amino]butyl, 2-methyl-2-

[(methylsulfonyl)amino]propyl, 2-(acetylamino)-2-methylpropyl, 2-{[(isopropylamino)carbonyl]amino} -2-methylpropyl,
4-{[(isopropylamino)carbonyl]amino}butyl, 4-(l,l-dioxidoisothiazolidin-2-yl)butyl, tetrahydro-2//-pyran-4-ylmethyl, and (2,2-dimethyl-1,3-dioxolan-4-yl)methyl.
32. The compound or salt of any one of claims 1 through 27 wherein R2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
33. The compound or salt of claim 32 wherein R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl, methoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.
34. The compound or salt of any one of claims 1 through 6, 8 through 11, 13, 14, 15, 17, and 27 wherein Z is alkylene.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of claims 1 through 27, and 28 through 34 as dependent on claim 1 in combination with a pharmaceutically acceptable carrier.
36. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of any one of claims 1 through 27, and 28 through 34 as dependent on claim 1 to the animal.
37. A method of treating a viral disease in an animal in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1 through 27, and 28 through 34 as dependent on claim 1 to the animal.
38. A method of treating a neoplastic disease in an animal in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1 through 27, and 28 through 34 as dependent on claim 1 to the animal.

39. A compound of the formula (IX):

wherein:
R3 is selected from the group consisting of -Z-Y-R4, -Z-Y-X-Y-R4, -Z-R5, -Z-Het,
-Z-Het'-R4, and -Z-Het'-Y-R4; Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more-O- groups;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; n is 0 or 1; Ri is selected from the group consisting of
-R4,
-X-R4, -X-Y-R4,
-X-Y-X-Y-R4, and -X-R5; R2 is selected from the group consisting of
-R4, -X-R4,
-X-Y-R4, and

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of

R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyi, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,

alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R5 is selected from the group consisting of

R R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o-2-, and -N(R4)-;
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;
Het' is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;
Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(R6)-,

Documents:

1139-CHENP-2006 AMENDED CLAIMS 24-10-2011.pdf

1139-CHENP-2006 CORRESPONDENCE OTHERS 24-10-2011.pdf

1139-CHENP-2006 FORM-3 24-10-2011.pdf

1139-CHENP-2006 OTHER PATENT DOCUMENT 24-10-2011.pdf

1139-CHENP-2006 AMENDED PAGES OF SPECIFICATION 18-04-2011.pdf

1139-CHENP-2006 AMENDED CLAIMS 18-04-2011.pdf

1139-CHENP-2006 FORM-13 18-04-2011.pdf

1139-chenp-2006 form-3 18-04-2011.pdf

1139-CHENP-2006 OTHER PATENT DOCUMENT 18-04-2011.pdf

1139-CHENP-2006 POWER OF ATTORNEY 18-04-2011.pdf

1139-CHENP-2006 CORRESPONDENCE OTHERS 13-10-2011.pdf

1139-CHENP-2006 CORRESPONDENCE OTHERS.pdf

1139-CHENP-2006 CORRESPONDENCE PO.pdf

1139-CHENP-2006 EXAMINATION REPORT REPLY RECIEVED 18-04-2011.pdf

1139-CHENP-2006 FORM-18.pdf

1139-CHENP-2006 CORRESPONDENCE OTHERS 20-08-2010.pdf

1139-chenp-2006-abstract.pdf

1139-chenp-2006-assignment.pdf

1139-chenp-2006-claims.pdf

1139-chenp-2006-correspondence others.pdf

1139-chenp-2006-description complete.pdf

1139-chenp-2006-form 1.pdf

1139-chenp-2006-form 26.pdf

1139-chenp-2006-form 3.pdf

1139-chenp-2006-form 5.pdf

1139-chenp-2006-pct.pdf

1139-chenp-2006-priority document.pdf


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Patent Number 250918
Indian Patent Application Number 1139/CHENP/2006
PG Journal Number 06/2012
Publication Date 10-Feb-2012
Grant Date 07-Feb-2012
Date of Filing 03-Apr-2006
Name of Patentee 3M INNOVATIVE PROPERTIES COMPANY
Applicant Address 3M Center, Post Office Box 33427, Saint Paul, Minnesota 55133-3427
Inventors:
# Inventor's Name Inventor's Address
1 LINDSTROM, Kyle, J. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
2 MERRILL, Bryon, A. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
3 HARALDSON, Chad, A. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
4 RICE, Michael, J. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
5 KSHIRSAGAR, Tushar, A. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
6 HEPPNER, Philip, D. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
7 WURST, Joshua, R. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
8 NIWAS, Shri Post Office Box 33427, Saint Paul, Minnesota 55133-3427
9 JOHANNESSEN, Sarah, C. Post Office Box 33427, Saint Paul, Minnesota 55133-3427
PCT International Classification Number A61K 31/4745
PCT International Application Number PCT/US2004/032616
PCT International Filing date 2004-10-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/508,634 2003-10-03 U.S.A.