AU2011201519A1 - Substituted imidazoquinolines, imidazonaphthyridines, and imidazopyridines, compositions, and methods - Google Patents

Description

S&F Ref: 859000D1 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address Coley Pharmaceutical Group, Inc., of 93 Worcester of Applicant: Street, Suite 101, Wellesley, Massachusetts, 02481, United States of America Actual Inventor(s): Bryon A Merrill Chad A Haraldson Karl J. Manske Larry R. Krepski Luke T. Dressel Michael J. Rice Philip D. Heppner Ryan B. Prince Tushar A. Kshirsagar Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Substituted imidazoquinolines, imidazonaphthyridines, and imidazopyridines, compositions, and methods The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(3505738 1) SUBSTITUTED IMIDAZOQUINOLINES, IMIDAZONAPHTHYRIDINES, AND IMIDAZOPYRIDINES, COMPOSITIONS, AND METHODS 5 CROSS REFERENCE TO RELATED APPLICATIONS The present invention claims priority to U.S. Provisional Application Serial No. 60/751,392, filed December 16, 2005, which is incorporated herein by reference. BACKGROUND 10 Certain compounds have been found to be useful as immune response modifiers (IRMs), rendering them useful in the treatment of a variety of disorders. However, 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 means. 15 SUMMARY OF THE INVENTION It has now been found that certain substituted IH-imidazo[4,5-c]quinolines, 6,7,8,9-tetrahydro-IH-imidazo[4,5-c]quinolines, 1H-imidazo[4,5-c][1,5]naphthyridines, 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridines, and IH-imidazo[4,5-c]pyridines modulate cytokine biosynthesis. In one aspect, the present invention provides 20 pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula I, II, Ila, III, IV, IVa, V, or Va: .N N \>R2 RA N~.. B N '~N N (R)~ 2 5( R ) .

\ X ' - R , 25 (R 3 ) I N N R2 1* Ila N I "-\ N N \-R2 N (R)~ -NR 5II N \>R2 (R)O (R)m IV N N (R),PRi RA X"' (R3),R IVa Rs. R2 10 RR1 V RN. '"--R, Va 15 wherein R, R1, Ria, R 2 , R 3 , R 3 0, RA, RB, RA., RB., X', X", X"', n, and m are as defined below; or pharmaceutically acceptable salts thereof. -2- The compositions comprising compounds or salts of Formulas 1, II, Ila, III, IV, IVa, V, or Va are useful for modulating cytokine biosynthesis (e.g., inducing the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals. The ability to modulate cytosine biosynthesis 5 makes the compositions 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 also provides compounds of the Formulas Ila, III, IVa, and Va, and pharmaceutically acceptable salts thereof. 10 In another aspect, the present invention provides methods of inducing cytokine biosynthesis in animal cells, treating a viral disease in an animal, and/or treating a neoplastic disease in an animal by administering to the animal a compound or salt of Formulas Ila, III, IVa, and/or Va, or a pharmaceutical composition comprising one or more compounds of the Formulas I, II, Ila, III, IV, IVa, V, and/or Va, and/or 15 pharmaceutically acceptable salts thereof. In another aspect, the invention provides methods of synthesizing the compounds of Formulas I, II, IHa, III, IV, IVa, V, and Va and intermediate compounds useful in the synthesis of these compounds. As used herein, "a", "an", "the", "at least one", and "one or more" are used 20 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 25 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. -3- DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION In one aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with a therapeutically 5 effective amount of a compound of Formula I, II, Ila, III, IV, IVa, V, or Va: N N N RA II N N R N

(R

3 ). IIa N N N 10 X1- 1 Ila N R N (R).R (R), N X 15

(R

3 ), IV -4- NN N N (R) N N -N x-R

(R

3 a)m IVa N N RB. R2N -N R R, V Rs. -R2 RW N R. X R Va wherein R, R 1 , Ria, R 2 , R 3 , R 3 ., RA, Ra, RA., RB., X', X", X"', n, and m are as defined below; or pharmaceutically acceptable salts thereof. 10 In one embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula I: N N \>-R RA WX-R 15 wherein: X' is selected from the group consisting of -CH 2 -, -CH(CH3)-, -NH-, and -0-; Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofiran-2-yl, tetrahydrofuran-3-yi, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 20 2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C,.4 alkyl, -5-

-CH

2 -Ci.2 alkylenyl-O-Ci-2 alkyl, -CH 2 -0-C.

3 alkyl, -CH 2 -OH, -CHrC] .3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen,

C

1

.

4 alkyl, C 1 .4 alkoxy, hydroxy, haloC.4 alkyl, and hydroxyC1.4 alkyl; 5 RA and RB taken together form a fused benzene or pyridine ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein the fused pyridine ring is 1N wherein the highlighted bond indicates the position where the ring is fused; or RA and Ra taken together form a fused cyclohexene or tetrahydropyridine ring 10 which is unsubstituted or substituted at a carbon atom by one or more R groups; wherein the fused tetrahydropyridine ring is OPNH wherein the highlighted bond indicates the position where the ring is fused; or RA is alkyl, and R 5 is hydrogen or alkyl; R is selected from the group consisting of: 15 halogen, hydroxy, alkyl, haloalkyl, alkoxy, and 20 -NW,)2;

R

3 is selected from the group consisting of: -Z-R4, -Z-X-R4,

-Z-X-Y-R

4 , 25 -Z-X-Y-X-Y-R4,

-Z-X-R

5 , and

-NH-Q-R

4 ; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and -6alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups; Y is selected from the group consisting of: -0-, 5 -S(0)0-2-, -S(O)2-N(Rg)-, -C(R)-,

-C(R

6 )-O-,

-O-C(R

6 )-, 10 -0-C(0)-0-, -N(R&)-Q-, -C(R)-N(R)-, -O-C(R6)-N(Rg)-,

-C(R

6

)-N(OR

9 )-, 15 -O-N(Rs)-Q-, -O-N=C(R4)-, -C(=N-0-Rs)-, -CH(-N(-O-Rs)-Q-R4)-,

N-Q

-N-C(Re) -W 20 R 7 -N- R7- -Q

R

1o ,and N -C(R)

-

N Z is a bond or -O-; -7 -

R

4 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, 5 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; 10 (dialkylamino)alkyleneoxy; and, in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R

5 is selected from the group consisting of: -N- C(R 6 ) -N- S(O) 2 -V- A -0-N- A

R

7 R (CH2)b

(CH

2 )b-' , and

((CH

2 ). -> N-C(Re)-N A R~~e. (CH2 15 R 6 is selected from the group consisting of =0 and =S;

R

7 is C 2

.

7 alkylene; R& is selected from the group consisting of hydrogen, C.- 1 0 alkyl, C 2

.

1 0 alkenyl, hydroxy-C,.1o alkylenyl, C 1 .1o alkoxy-C .lo alkylenyl, aryl-Cl.o alkylenyl, and heteroaryl-C1.10 alkylenyl; 20 R 9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene; A is selected from the group consisting of -CH 2 -, -0-, -C(O)-, -S(0)o.

2 -, and -N(-Q-R4)-; A' is selected from the group consisting of -0-, -S(O)o.

2 -, -N(-Q-R 4 )-, and -CH 2 -; 25 Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6

)-C(R

6 )-, -S(0) 2 -, -C(R 6 )-N(Rs)-W-, -S(O)2-N(R 8 )-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 6 )-N(ORg)-; V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(Rg)-C(R 6 )-, and -S(O)2-8 -8- 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 5 7; or a pharmaceutically acceptable salt thereof. In another embodiment of this pharmaceutical composition, X' is selected from the group consisting of -CH 2 -, -NH-, and 5 -0-; and R 3 is at the 7- or 8-position. In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula 11: N ' -N I R2 N (R),

(R

3 )m R, 10 II wherein: X' is selected from the group consisting of -CH2-, -CH(CH 3 )-, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 15 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 -dioxidotetrahydo 2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH2-C .4 alkyl, -CH2-C)- 2 alkylenyl-O-CI- 2 alkyl, -CH 2 -0-C1.

3 alkyl, -CH 2 -OH, -CH 2

-C

1

.

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by 20 one or more substituents independently selected from the group consisting of halogen,

C

1

.

4 alkyl, C1.4 alkoxy, hydroxy, haloC,.

4 alkyl, and hydroxyC.

4 alkyl; R is selected from the group consisting of: halogen, hydroxy, 25 alkyl, haloalkyl, alkoxy, and -N(Rg)2; n is 0, 1, or 2; -9-

R

3 is selected from the group consisting of: -Z-R4,

-Z-X-R

4 ,

-Z-X-Y-R

4 , 5 -Z-X-Y-X-Y-R4, -Z-X-Rs, and

-NH-Q-R

4 ; m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1; X is selected from the group consisting of alkylene, alkenylene, alkynylene, 10 arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups; Y is selected from the group consisting of: -0-, 15

-S(O)

0

.

2 -, -S()2-N(R)-, -C(R6)-, -C(Rc,)-O-, -0-C(R 6 )-, 20 -O-C(O)-O-, -N(Ra)-Q-,

-C(R

6 )-N(Rg)-, -O-C(Rt,)-N(Rg)-, -C(R,)-N(OR9)-, 25 -O-N(Rs)-Q-, -O-N=C(R4)-, -C(=N-0-Rs)-, -CH(-N(-0-Rs)-Q-R4)-, N-Q -10- -N-C(R) -W

R

7 -V-N R , and N-C(R,)-N 1Ri 5 Z is a bond or -O-;

R

4 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, 10 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; 15 (dialkylamino)alkyleneoxy; and, in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R

5 is selected from the group consisting of: -N-C(Rd -N-S(O) 2 -V- (CH2)A -O-N A(CH2). R R

(CH

2 )b>

\(CH

2 )b" , and

/-(CH

2 ). N-C(R,)-N A R-( . (CH2)b . 20 R 6 is selected from the group consisting of =0 and =S;

R

7 is C 2

.

7 alkylene;

R

8 is selected from the group consisting of hydrogen, Ca..io alkyl, C 24 0 alkenyl, -11hydroxy-Cl-.o alkylenyl, Ci-io alkoxy-C.o alkylenyl, aryl-Ci.io alkylenyl, and heteroaryl-C .1o alkylenyl;

R

9 is selected from the group consisting of hydrogen and alkyl; RIO is C 3

.

8 alkylene; 5 A is selected from the group consisting of -CH 2 -, -0-, -C(O)-, -S(O)o- 2 -, and -N(-Q-R4)-; A' is selected from the group consisting of -O-, -S(O)o- 2 -, -N(-Q-R 4 )-, and -CH 2 -; Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R6)-, -S(0) 2 -, -C(R)-N(Rs)-W-, -S(O) 2 -N(Rs)-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 6 )-N(ORg)-; 10 V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(Rs)-C(R)-, and -S(0)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 I to 6 with the proviso that a + b is 57; or a pharmaceutically acceptable salt thereof. In another embodiment of this 15 pharmaceutical composition, X' is selected from the group consisting of -CH 2 -, -NH-, and -0-; and R 3 is at the 7- or 8-position. In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula III: -- N N \>-R 2 N 20 (R)~ 20 R, III wherein: X' is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 25 tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2

-C

1 alkyl, - 12 -

-CH

2

-C.-

2 alkylenyl-O-CI-2alkyl, -CH 2 -0-C- 3 alkyl, -CH 2 -OH, -CH 2

-C..

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, Ci alkyl, C 1

.

4 alkoxy, hydroxy, haloC 1 4 alkyl, and hydroxyC 14 alkyl; 5 R is selected from the group consisting of: halogen, .hydroxy, alkyl, haloalkyl, 10 alkoxy, and -N(Rg)2; n is 0, 1, or 2; and Rg is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment of this 15 pharmaceutical composition, X' is selected from the group consisting of -CH 2 -, -NH-, and -0-. In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula IV: N N N 20 (R)m IV wherein: X is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 25 tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yI, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2

-C,.

4 alkyl, - 13 -

-CH

2

-CI-

2 alkylenyl-O-C..

2 alkyl, -CH 2 -0-C- 3 alkyl, -CH 2 -OH, -CH 2

-C.

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CI.4 alkyl, C 1

.

4 alkoxy, hydroxy, haloCI.

4 alkyl, and hydroxyCi.

4 alkyl; 5 R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, 10 alkoxy, and -N(Rg)2; n is 0, 1, or 2;

R

3 is selected from the group consisting of:

-Z-R

4 , 15 -Z-X-R4,

-Z-X-Y-R

4 ,

-Z-X-Y-X-Y-R

4 ,

-Z-X-R

5 , an'd

-NH-Q-R

4 ; 20 m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1; 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 by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups; 25 Y is selected from the group consisting of: -0-, -S(O)o-2-, -S(0) 2 -N(Rs)-, -- C(R6)-, 30 -C(Ro)-O-,

-O-C(R

6 )-, -O-C(O)-O-, -14- -N(RN)-Q-,

-C(R

6 )-N(Rg)-, -O-C(R6)-N(Rg)-, -C(R6)-N(OR9)-, 5 -O-N(R8)-Q-, -O-N=C(R4)-, -C(=N-O-Rs)-, -CH(-N(-O-Ra)-Q-R4)-,

N-Q

R

1 0 -- N-C(Re)- -W 10 R7 -- N- R7- -Q -V-N Ro , and N -C(R) -N Z is a bond or -0-; 15 R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyiheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyiheteroarylenyl, and heterocyclyl groups 20 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; -15- (dialkylamino)alkyleneoxy; and, in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R

5 is selected from the group consisting of: -N-C(Rs) -N-S(0) 2 -V- Af-O-N-A' A-0-N- Ax

R

7 (CH2)b (CH2b , and

,(CH

2 ). -)

N-C(R

6 )-- A 5 (Re

.

(CH2A

-

R

6 is selected from the group consisting of =0 and =S;

R

7 is C2.7 alkylene;

R

8 is selected from the group consisting of hydrogen, C.I- 0 alkyl, C2.10 alkenyl, hydroxy-C-..o alkylenyl, C.

1 0 alkoxy-CIo1 alkylenyl, aryl-CI.o alkylenyl, and 10 heteroaryl-CI.o alkylenyl;

R

9 is selected from the group consisting of hydrogen and alkyl; Rio is C 3

.

8 alkylene; A is selected from the group consisting of -CH 2 -, -0-, -C(O)-, -S(O)o- 2 -, and -- N(-Q-R4)-; 15 A' is selected from the group consisting of -0-, -S(O)o- 2 -, -N(-Q-R4)-, and -CH2-; Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6

)-C(R

6 )-, -S(0) 2 -, -C(R 6 )-N(Rg)-W-, -S(O) 2

-N(R

8 )-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 6

)-N(OR

9 )-; V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(Rs)-C(R6)-, and -S(O)2-; 20 W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from I to 6 with the proviso that a + b is 5 7; or a pharmaceutically acceptable salt thereof. In another embodiment of this pharmaceutical composition, X' is selected from the group consisting of -CH 2 -, -NH-, and -0-; and R 3 is at the 7- or 8-position. 25 In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula V: -16- NRa N R . N V wherein: X' is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, -NH-, and -0-; 5 R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 -dioxidotetrahydo 2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2

-C

1 4 alkyl, 10 -CH 2

-CI-

2 alkylenyl-O-Ci.2 alkyl, -CH2-0-C i.3 alkyl, -CH 2 -OH, -CH 2 -C 1- 3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CIA alkyl, Ci- alkoxy, hydroxy, haloC1A alkyl, and hydroxyC-A alkyl; RA is alkyl, and Ra. is hydrogen or alkyl; 15 or a pharmaceutically acceptable salt thereof. In another embodiment of this pharmaceutical composition, X' is selected from the group consisting of -CH 2 -, -NH-, and -0-. In another embodiment, the present invention provides a compound of Formula Ila: N N ->-R2 N 20 R 1 . Ila wherein: X" is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, and -0-; Ria is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo 25 2H-pyran-3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 dioxidotetrahydo-2H-thiopyran-4-yl; and

R

2 is selected from the group consisting of -CH 3 , -CH 2 -Ci 4 alkyl, - 17 - -CH2-CI-2 alkylenyl-O-C1-2 alkyl, -CH2-0-CI.3 alkyl, -CH2-OH, -CH2-Cl.3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C.4 alkyl, C.4 alkoxy, hydroxy, haloC.

4 alkyl, and hydroxyC 14 alkyl; 5 or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of Formula Ha or a pharmaceutically acceptable salt thereof, X" is -CH 2 -. In another embodiment, the present invention provides a compound of Formula III: N- N S

-R

2 N ( R ) , IHI 10 wherein: X is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo-' 15 2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2

-C

1 .4 alkyl,

-CH

2

-CI-

2 alkylenyl-O-C -2 alkyl, -CH 2 -0-CI- 3 alkyl, -CH 2 -OH, -CH 2

-C.

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, 20 C 1

.

4 alkyl, C 1

-

4 alkoxy, hydroxy, haloC.4 alkyl, and hydroxyCj.

4 alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, 25 haloalkyl, alkoxy, and -N(R9)2; n is 0, 1, or 2; and

R

9 is selected from the group consisting of hydrogen and alkyl; - 18or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of Formula III or a pharmaceutically acceptable salt thereof, X' is selected from the group consisting of -CH 2 -, -NH-, and -0-. In another embodiment, the present invention provides a compound of Formula 5 IVa: N N \>-R? N (R ) .

N -Ny (R3), la IVa wherein: X'" is selected from the group consisting of -CH 2 - and -CH(CH 3 )-; 10 R1. is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo 2H-pyran-3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 dioxidotetrahydo-2H-thiopyran-4-yl;

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C .4 alkyl,

-CH

2

-C

1

.

2 alkylenyl-O-CI- 2 alkyl, -CH 2 -0-CI.

3 alkyl, -CH 2 -OH, -CH 2

-C.

3 alkylenyl-OH, 15 and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C,.4 alkyl, C.

4 alkoxy, hydroxy, haloC 1

.

4 alkyl, and hydroxyCt.

4 alkyl; R is selected from the group consisting of: halogen, 20 hydroxy, alkyl, haloalkyl, alkoxy, and -N(R9)2; 25 nisOor 1;

R

3 . is selected from the group consisting of: -Z-R4, and -Z-X-R4; m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1; - 19 - 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 by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups; 5 Zisabondor-0-;

R

4 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, 10 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; 15 (dialkylamino)alkyleneoxy; and, in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; and

R

9 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment of the compund of Formula IVa or a pharmaceutically acceptable salt thereof, X.' is -CH 2 -; and R 3 is at the 7 20 or 8-position. In another embodiment, the present invention provides a compound of Formula Va: N N Ra. -- R2 RA. X.R Va 25 wherein: X" is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3 -yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and I , 1 -dioxidotetrahydo 30 2H-thiopyran-4-yl; -20-

R

2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C4 alkyl,

-CH

2 -CI-2 alkylenyl-O-C1-2 alkyl, -CH 2 -0-C .3 alkyl, -CH 2 -OH, -CH 2

-C.

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, 5 C 1 .4 alkyl, C1.

4 alkoxy, hydroxy, haloCj.4 alkyl, and hydroxyC1 4 alkyl; RA. is alkyl, and RB, is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of Formula Va or a pharmaceutically acceptable salt thereof, X" is -CH 2

-

10 For any of the compounds presented herein, each one of the following variables (e.g., R, R 1 , R,- R 2 , R 3 , R 3 ., RA, Ra, RA., RB', R 4 , X, X', X", X"', Y, Z, A, Q, and so on) in any of its embodiments can be combined with any one or more of the other variables in any of their embodiments and associated with any one of the formulas described herein, as would be understood by one of skill in the art. Each of the resulting combinations of is variables describes a compound or compounds which is an embodiment of the present invention, or which in combination with a pharmaceutically acceptable carrier is a composition which is an embodiment of the present invention. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, RA and RB taken 20 together form a fused benzene or pyridine ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein the fused pyridine ring is wherein the highlighted bond indicates the position where the ring is fused; or RA and RB taken together form a fused cyclohexene or tetrahydropyridine ring 25 which is unsubstituted or substituted at a carbon atom by one or more R groups; wherein the fused tetrahydropyridine ring is CNH wherein the highlighted bond indicates the position where the ring is fused; or RA is alkyl, and RB is hydrogen or alkyl. For certain embodiments, e.g., of a pharmaceutical composition comprising a 30 compound of Formula I or a pharmaceutically acceptable salt thereof, RA and RB taken -21together form a fused benzene or pyridine ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein the fused pyridine ring is Q Nwherein the highlighted bond indicates the position where the ring is fused. For 5 certain of these embodiments, RA and RB taken together form the fused benzene ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group. For certain of these embodiments, the fused benzene ring is unsubstituted. Alternatively, for certain of these embodiments, RA and RB taken together form the fused pyridine ring which is unsubstituted or 10 substituted by one or two R groups, or substituted by one R 3 group, or substituted by one

R

3 group and one R group. For certain of these embodiments, the fused pyridine ring is unsubstituted. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, RA and RB taken 15 together form a fused cyclohexene or tetrahydropyridine ring which is unsubstituted or substituted at a carbon atom by one or more R groups; wherein the fused tetrahydropyridine ring is NH wherein the highlighted bond indicates the position where the ring is fused. For certain of these embodiments, RA and RB taken together form a fused cyclohexene ring 20 which is unsubstituted or substituted by one or more R groups. For certain of these embodiments, the fused cyclohexene ring is unsubstituted. Alternatively, for certain of these embodiments, RA and RB taken together form the fused tetrahydropyridine ring which is unsubstituted or substituted at a carbon atom by one or more R groups. For certain of these embodiments, the fused tetrahydropyridine ring is unsubstituted. 25 For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, RA is alkyl, and RB is hydrogen or alkyl. For certain of these embodiments, RA and RB are both methyl. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula V, or a pharmaceutically acceptable salt thereof, RA. is alkyl, and 30 RB' is hydrogen or alkyl. For certain of these embodiments, R. and Ra. are both methyl. -22- For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I, II, or IV, or a pharmaceutically acceptable salt thereof, or of any one of the above embodiments which includes R 3 , R 3 is selected from the group consisting of -Z-R 4 , -Z-X-R4, -Z-X-Y-R 4 , -Z-X-Y-X-Y-R 4 , -Z-X-R 5 , and -NH-Q-R4. For certain of 5 these embodiments, R 3 is -Z-R 4 . For certain of these embodiments, R 4 is selected from the group consisting of aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl wherein the aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino, 10 and dialkylamino; and Z is a bond. For certain of these embodiments, R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, (aminomethyl)phenyl, pyridin-3-yl, and pyridin-4-yl. Alternatively, for certain of these embodiments where R 3 is

-Z-R

4 , R 4 is a heterocyclyl group which contains one or more nitrogen atoms and optionally a ring oxygen or ring sulfur atom, wherein the point of attachment of the 15 heterocyclyl group is one of the nitrogen atoms, and wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, aryl, and arylalkylenyl; and Z is a bond. For certain of these embodiments, the heterocyclyl group is monocyclic and contains 4 to 6 ring atoms. For certain of these embodiments, the heterocyclyl group is unsubstituted or substituted by 20 one or more substituents independently selected from the group consisting of oxo, alkyl, and arylalkylenyl. For certain of these embodiments, the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo and alkyl. For certain of these embodiments, the heterocyclyl group is selected from the group consisting of: 0 0 2 / N- NN--- O N- N- N- N 0 R1 0 O R's N S N N q FS N- N - and 250'1'01 5 wherein R is alkyl. For certain of these embodiments, the heterocyclyl group is selected from the group consisting of: -23 - 0 0 0 ON OL-' ON N D c0 c- f-- R' 0 R' N -- N N4 O N 7N- O§ \ R':sN R-N *S LSON-, and Q. 00 0 wherein R' is alkyl. For certain of these embodiments, the heterocyclyl group is selected from the group consisting of: 0 NN- N- N N 'and For certain of these embodiments, the 0 IN- O N 5 heterocyclyl group is or For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I, II, or IV, or a pharmaceutically acceptable salt thereof, or of any one of the above embodiments which includes R 3 , R 3 is -Z-X-Y-R 4 , except where R 3 is -Z-R4'. For certain of these embodiments, R 4 is selected from the group consisting of 10 hydrogen, alkyl, and heterocyclyl; Y is selected from the group consisting of -S(0) 2 -, -C(O)-, -C(O)-NH-, and -NH-S(0)2-; X is phenylene; and Z is a bond. For certain of these embodiments, R 3 is (methylsulfonylamino)phenyl (e.g., R 4 is methyl and Y is -NH-S(0) 2 -). Alternatively, for certain of these embodiments, R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroaryl, each of which is 15 unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, and alkyl; Y is selected from the group consisting of -S(0)2-, -C(O)-, and -C(O)-N(R)-; X is -N - ; and Z is a bond. Alternatively, for certain of these embodiments where R 3 is -Z-X-Y-R4, R 4 is hydrogen or alkyl; Y is -C(O)-N(Rs)- or -C(O)-O-; Rg is C 14 alkyl; X is alkylene or alkenylene; and Z is a bond. 20 For certain of these embodiments, R 4 is C 1

.

4 alkyl; Y is -C(O)-N(R 8 )-; and X is alkylene. Alternatively, for certain of these embodiments where R 3 is -Z-X-Y-R 4 , R is alkyl -24substituted by maleimidyl; Y is -NHC(O)-; X is alkylene interrupted by one -0- group; and Z is -O-. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, R 3 is selected 5 from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, 4 (aminomethyl)phenyl, 3-(methylsulfonylamino)phenyl, pyridin-3-yl, and pyridin-4-yl. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, and 10 (methylsulfonylamino)phenyl. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I, II, or IV, or a pharmaceutically acceptable salt thereof, or of any one of the above embodiments which includes R 3 , R 3 is -Z-X-Y-X-Y-R 4 except where R 3 is -Z-R 4 or -Z-X-Y-R4. For certain of these embodiments, R 3 is -Z-XrYa-Xg-Yb-R4 15 wherein R4 is hydrogen or C 1 4 alkyl, Yb is -C(0)-O-, Xg is alkylene, Ya is -NHC(O)-, Xr is alkylene interrupted by one -0- group, and Z is -0-. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula 1, II, or IV, or a pharmaceutically acceptable salt thereof, or of any one of the above embodiments which includes R 3 , R 3 is -NH-Q-R 4 except where R 3 is 20 -Z-R 4 , -Z-X-Y-R 4 , or -Z-X-Y-X-Y-R 4 . For certain of these embodiments, Q is -C(O)-, -C(0)-0-, -C(O)-N(Rs)-, or -S(0) 2 -, and R 4 is alkyl, aryl, arylalkylenyl or heteroaryl, each of which is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, and alkyl. For certain of these embodiments, Ra is hydrogen or C.-4 alkyl. For certain of these embodiments, Q is -C(O)-, and R4 is alkyl or aryl. For 25 certain of these embodiments, Q is -S(0) 2 -, and R 4 is alkyl or aryl. Alternatively, for certain of these embodiments, Q is -C(O)- and R 4 is heterocyclyl which is unsubstituted or substituted by one or more substituents independently selected form the group consisting of alkyl and oxo; and wherein heterocyclyl is a heterocyclyl group which contains one or more nitrogen atoms, wherein the point of attachment of the heterocyclyl group is one of 30 the nitrogen atoms. For certain of these embodiments, the heterocyclyl group is monocyclic and contains 5 or 6 ring atoms. For certain of these embodiments, R 4 is piperidin-1-yl. - 25 - For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula 1, 11, or IV, or a pharmaceutically acceptable salt thereof, or of any one of the above embodiments which includes R 3 (or R3a), R 3 (or R 3 ,) is at the 7- or 8 position. For certain of these embodiments, R 3 (or R3.) is at the 7-position. Alternatively, 5 for certain of these embodiments, R 3 (or R3a) is at the 8-position. The locations of the 7 and 8-positions are shown in the following formulas: N N NNN R,

R

2 N N 7 / : X..R N X R 8 i 8 For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula II, III, or IV, or a pharmaceutically acceptable salt thereof, or of 10 any one of the above embodiments which includes n, n is 0. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula II, III, or IV, or a pharmaceutically acceptable salt thereof, R is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, and

-N(R)

2 . For certain of these embodiments, R is hydroxy or -N(R 9

)

2 . For certain of these 15 embodiments, R is -N(R 9

)

2 . For certain of these embodiments, R9 is hydrogen. Alternatively, for certain of these embodiments, R9 is alkyl. For certain of these embodiments, m is 0 and n is 1. For certain of these embodiments, R is at the 7-position. For certain of these embodiments, R is at the 8-position. For certain embodiments, e.g., of a pharmaceutical composition comprising a 20 compound of Formula II or IV, or a pharmaceutically acceptable salt thereof, m is 0. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula II or IV, or a pharmaceutically acceptable salt thereof, m and n are both 0. For certain embodiments, including any one of the above embodiments, R 2 is 25 selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C1.4 alkyl,

-CH

2 -C,.2 alkylenyl-O-CI.2 alkyl, -CH 2

-O-C.

3 alkyl, -CH 2 -OH, -CH 2

-C

1

-

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, -26- C.4 alkyl, C.4 alkoxy, hydroxy, haloC.4 alkyl, and hydroxyCi.4 alkyl. For certain of these embodiments, R 2 is selected from the group consisting of -CH 3 , -CH 2

-C.

4 alkyl, -CH2-0-CI.3 alkyl, -CH 2

-CI-

2 alkyleny-O-CI- 2 alkyl, -CH 2 -OH, and

-CH

2

-C.

3 alkylenyl-OH. For certain of these embodiments, R 2 is selected from the group 5 consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. For certain of these embodiments, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl. For certain of these embodiments, R 2 is selected from the group consisting of n-propyl, n-butyl, 10 methoxymethyl, ethoxymethyl, and 2-methoxyethyl. For certain embodiments, including any one of the above embodiments, R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 15 2H-thiopyran-4-yl. For certain of these embodiments, R, is tetrahydo-2H-pyran-4-yl. For certain embodiments, including any one of the above embodiments where X is present, X' is selected from the group consisting of -CH 2 -, -NH-, and -0-. Alternatively, for certain of these embodiments, X is -CH 2 -. Alternatively, for certain of these embodiments, X is -NH-. Alternatively, for certain of these embodiments, X' is -0-. 20 For certain embodiments, e.g., of Formula Va, RA' is alkyl, and RB' is hydrogen or alkyl. For certain of these embodiments, RA. and RB. are both methyl. For certain embodiments, e.g., of Formula Ila or any of the above embodiments of Formula Va, X" is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, and -0 except where X" is -CH 2 -. For certain of these embodiments, X" is -CH 2 -. 25 For certain embodiments, e.g., of Formula IVa, X"' is -CH 2 -. For certain embodiments, including any one of the above embodiments of Formula IVa, m is 1, and R 3 a is selected from the group consisting of -Z-R 4 and -Z-X-R 4 . For certain of these embodiments, R3. is selected from the group consisting of hydroxyphenyl and (hydroxymethyl)phenyl. 30 For certain embodiments, including any one of the above embodiments of Formula III or IVa, R is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, -27alkoxy, and -N(R 9 )2. For certain of these embodiments, R is hydroxy. For certain of these embodiments n is 1. For certain embodiments, including any one of the above embodiments of Formula III or IVa, n is 0 except where n is 1. 5 For certain embodiments, including any one of the above embodiments of Formula IVa, m is 0 except where m is 1. For certain embodiments, including any one of the above embodiments of Formula IVa, m and n are both 0 except where m or n is 1. For certain embodiments, including any one of the above embodiments of Formula 10 Ila or IVa, Ria is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran-3-yi, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 dioxidotetrahydo-2H-thiopyran-4-yl. For certain of these embodiments, Ria is tetrahydo 2H-pyran-4-yl. For certain embodiments, including any one of the above embodiments of Formula 15 III or Va, R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl. For certain of these embodiments, R, is tetrahydo-2H-pyran-4-yl. For certain embodiments, including any one of the above embodiments, of 20 Formula Ila, III, IVa, or Va, R2 is selected from the group consisting of -NH 2 , -CH 3 , -CH2-C.4 alkyl, -CH 2

-CI.

2 alkylenyl-O-CI-2 alkyl, -CH 2 -O-Cl.

3 alkyl, -CH 2 -OH,

-CH

2

-CI.

3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C 1

.

4 alkyl, C 1 .4 alkoxy, hydroxy, haloC,.4 alkyl, and 25 hydroxyCJ.4 alkyl. For certain of these embodiments, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. For certain of these embodiments, R 2 is selected from the group consisting of n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl. 30 For certain embodiments, R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl -28wherein 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; 5 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. For certain embodiments, R 1 4 is selected from the group consisting of alkyl, aryl, 10 heteroaryl, and arylalkylenyl wherein the aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino, and dialkylamino. For certain embodiments, R 4 is selected from the group consisting of aryl and 15 heteroaryl each of which is unsubstituted or substituted by hydroxy, hydroxyalkyl, or aminoalkyl. For certain embodiments, R4 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, (aminomethyl)phenyl, pyridin-3-yl, and pyridin 4 -yl. 20 For certain embodiments, R 4 is alkyl, aryl, arylalkylenyl or heteroaryl, each of which is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, and alkyl. For certain embodiments, R 1 4 is alkyl or aryl. For certain embodiments, R 4 is selected from the group consisting of hydrogen, 25 alkyl, and heterocyclyl. For certain embodiments, R 4 is hydrogen. For certain embodiments, R 4 is alkyl. For certain embodiments, R 1 4 is a heterocyclyl group which contains one or more ring nitrogen atoms and optionally a ring oxygen or ring sulfur atom, wherein the point of 30 attachment of the heterocyclyl group is one of the nitrogen atoms, and wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, aryl, and arylalkylenyl. - 29 - For certain embodiments the heterocyclyl group is monocyclic and contains 4 to 6 ring atoms. For certain of these embodiments, the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, and arylalkylenyl. For certain of these embodiments, the heterocyclyl group 5 is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo and alkyl. For certain embodiments, R 4 is a heterocyclyl group selected from the group consisting of: 0 0 dN 0 N- NN- O N- N0- KN- CN O R'% O o N - N N- R N -, \-' Q\-' L-,N and \.J 00 10 wherein R' is alkyl. For certain embodiments, R 4 is a heterocyclyl group selected from the group consisting of: N- N- UN- CN- N~ -N- Is N R N -N- and o 'o b ' wherein R'is alkyl, For certain embodiments, R4 is a heterocyclyl group selected from the group 15 consisting of: 0 bN- iN- O N and\-/ 0 iN - or OVJN For certain embodiments,

R

4 is For certain embodiments, R4 is piperidin-1-yl. For certain embodiments, Rs is selected from the group consisting of: -30- 4-(CH2). f t-(CH2). -N-C(R) -- N-S() 2 -V- A(--N-( X

R

7 / (CH2 (CH2 and <-(CH 2 ). N'

N-C(R

6 )-N A Ra. (C Hz

(R

1 O

(CH

2 ).a A For certain embodiments, R 5 is '(CH 2 )b For certain embodiments, R 6 is selected from the group consisting of =0 and =S. 5 For certain embodiments, R 6 is =0. For certain embodiments, R 6 is =S. For certain embodiments, R 7 is C2-7 alkylene. For certain embodiments, R 7 is C 2 .4 alkylene. For certain embodiments, R is selected from the group consisting of hydrogen, 10 CI.io alkyl, C 2 -o alkenyl, hydroxy-Cl.lo alkylenyl, Ci.io alkoxy-Ci.io alkylenyl, aryl-Ci. oalkylenyl, and heteroaryl-Cli-o alkylenyl. For certain embodiments, R 8 is hydrogen, C..

10 alkyl, or hydroxy-Ci.-o alkylenyl. For certain embodiments, Rg is C.-4 alkyl. For certain embodiments, Rg is hydrogen. 15 For certain embodiments, R9 is selected from the group consisting of hydrogen and alkyl. For certain embodiments, R 9 is hydrogen. For certain embodiments, R 9 is alkyl. For certain embodiments, Rio is C 3 -s alkylene. 20 For certain embodiments, Rio is pentylene. For certain embodiments, R' is hydrogen, alkyl, or aryl. For certain embodiments, R' is alkyl. For certain embodiments, R' is hydrogen. For certain embodiments, A is selected from the group consisting of -CH 2 -, -0-, 25 -C(O)-, -S(O)o- 2 -, and -N(-Q-R 4 )-. -31 - For certain embodiments, A is selected from the group consisting of -CH 2 -, -0-, and -N(alkyl)-. For certain embodiments, A is -0-. For certain embodiments, A' is selected from the group consisting of -0-, -S(0)-2-, 5 -N(-Q-R 4 )-, and -CH 2 -. For certain embodiments, Q is selected from the group consisting of a bond,

-C(R

6 )-, -C(R 6

)-C(R

6 )-, -S(O) 2 -, -C(R 6

)-N(R

8 )-W-, -S(O)2-N(Rs)-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 4 )-N(ORg)-. For certain embodiments, Q is selected from the group consisting of -C(O)-, 10 -S(0) 2 -, -C(R 6 )-N(Rs)-, -S(0) 2

-N(R

8 )-, -C(O)-0-, and -C(O)-S-. For certain embodiments, Q is -C(O)-, -S(0)2-, -C(R 4 )-N(R)-, or -S(0) 2 -N(Rs)-. For certain embodiments, Q is -C(R 6 )-. For certain embodiments, Q is a bond. For certain embodiments, V is selected from the group consisting of -C(R6)-, 15 -O-C(R)-, -N(Rs)-C(R 6 )-, and -S(O) 2 -. For certain embodiments, V is -N(Rg)-C(Q)-. For certain embodiments, W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -. For certain embodiments, W is a bond. 20 For certain embodiments, 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 by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups. For certain embodiments, X is phenylene. -N N- 25 For certain embodiments, X is . For certain embodiments, X is Cm alkylene. For certain embodiments, X is methylene. For certain embodiments, Y is selected from the group consisting of -0-, -S(O)o-2-, -S(0) 2

-N(R

8 )-, -C(R 6 )-, -C(R 6 )-O-, -0-C(R 6 )-, -O-C(O)-O-, -N(Ra)-Q-, 30 -C(R 6 )-N(Rg)-, -O-C(R 6 )-N(Rs)-, -C(R 6 )-N(ORg)-, -O-N(Rs)-Q-, -0-N=C(R4)-, -32 - N-Q -- N-C(Ra) -- W -C(=-N-0-Rs)-, -CH(-N(-O-Rs)-Q-R4)-, . -N- R 7 -Q- -V-N , N -C(NR)-N

S

7 > , 1 and R, 0 ' For certain embodiments, Y is -N(Rs)-Q-. For certain embodiments, Y is selected from the group consisting of -N(Rs)-C(O)-, 5 -N(RB)-S(0) 2 -, -N(Rg)-C(R 6 )-N(Rs)-, -N(Rg)-S(O) 2 -N(Rs)-, -N(Rs)-C(R6)-O-, and -N(Rs)-C(Rs)-S-. For certain embodiments, Y is selected from the group consisting of -S(O)2-, - C(O)-, -C(O)-NH-, and -NH-S(0)2-. For certain embodiments, Y is selected from the group consisting of -S(O)2-, 10 -C(O)-, and -N(Rs)-C(O)-. For certain embodiments, Z is a bond or -0-. For certain embodiments, Z is a bond. For certain embodiments, Z is -0-. For certain embodiments, a and b are independently integers from I to 6 with the 15' proviso that a + b is <7. For certain embodiments, a and b are each independently 1, 2, or 3. For certain embodiments, a and b are each 2. For certain embodiments, m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1. For certain embodiments, m is 1, and n is 0 or 1. 20 For certain embodiments, m is 1, and n is 0. For certain embodiments, m is 0. For certain embodiments, n is 0, 1, or 2. For certain embodiments, n is 1. For certain embodiments, n is 0. 25 For certain embodiments, m is 0, and n is 0. For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I, II, III, IV, IVa, V, or Va, or a pharmaceutically acceptable salt -33thereof, or of a compound or salt of Formula III, IVa, or Va, or of any one of the above embodiments which includes an -NH 2 group in a Formula, for example when R 2 is

-NH

2 , the -NH4 2 group can be replaced by an -NH-Gj group, to form prodrugs. In such embodiments, GI is selected from the group consisting of: -C(O)-R", a-aminoacyl, a 5 aminoacyl-a-aminoacyl, -C(O)-O-R", -C(O)-N(R'")R", -C(=NY 2 )-R",

-CH(OH)-C(O)-OY

2 , -CH(OCI.4 alkyl)Yo, -CH 2 Yi, and -CH(CH 3 )Y,. For certain embodiments, 0 is selected from the group consisting of -C(O)-R", a-aminoacyl, a-aminoacyl-a-aminoacyl, and -C(O)-O-R'. Preferably, R" and R" are independently selected from the group consisting of C1.10 alkyl, C 3

.

7 cycloalkyl, phenyl, and benzyl, each 10 of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C 1 -6 alkyl, C1.

4 alkoxy, aryl, heteroaryl, arylC .4 alkylenyl, heteroarylC .4 alkylenyl, haloC,.4 alkylenyl, haloC 1 .4 alkoxy, -O-C(O)-CH 3 , -C(O)-O-CH 3 , -C(O)-NH 2 ,

-O-CH

2

-C(O)-NH

2 , -NH 2 , and -S(O) 2

-NH

2 , with the proviso that R"' can also be 15 hydrogen. Preferably, ct-aminoacyl is an acyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids. Preferably, Y 2 is selected from the group consisting of hydrogen, C1. alkyl, and benzyl. Preferably, Yo is selected from the group consisting of C1-6 alkyl, carboxyCi-. alkylenyl, aminoC1.4 alkylenyl, mono

N-C,

4 6alkylaminoC,.4 alkylenyl, and di-NN-CI- 6 alkylaminoCl.4 alkylenyl. Preferably, Y 1 20 is selected from the group consisting of mono-N-CI-6alkylamino, di-NN-Ci.

6 alkylamino, morpholin-4-yl, piperidin- 1 -yl, pyrrolidin- I -yl, and 4-C 1 .4 alkylpiperazin- 1 -yl. For certain embodiments, including any one of the above embodiments where G, is present, G, is selected from the group consisting of -C(O)-R', a-aminoacyl, and -C(O)-O-R'. 25 For certain embodiments, including any one of the above embodiments where G, is present, G, is selected from the group consisting of -C(O)-R', a-amino-C2-1 acyl, and -C(O)-O-R'. a-Amino-C 2 -1 acyl includes a-amino acids containing a total of at least 2 carbon atoms and a total of up to 11 carbon atoms, and may also include one or more heteroatoms selected from the group consisting of 0, S, and N. 30 For certain embodiments, e.g., of a pharmaceutical composition comprising a compound of Formula I, II, Ila, III, IV, IVa, V, or Va, or a pharmaceutically acceptable - 34 salt thereof, or of a compound or salt of Formula Ila, III, IVa, or Va, or of any one of the above embodiments which includes an -OH group in a Formula, for example when R2 is

-CH

2 OH, the -OH group can be replaced by an -O-G 2 group, to form prodrugs. In such embodiments, G2 is selected from the group consisting of -X 2 -C(O)-R", a-aminoacyl, cl 5 aminoacyl-a-aminoacyl,

-X

2 -C(O)-O-R", -C(O)-N(R"')R",'and -S(O)2-R". For certain of these embodiments, X 2 is selected from the group consisting of a bond; -CH 2 -0-;

-CH(CH

3 )-O-; -C(CH 3

)

2 -O-; and, in the case of -X 2 -C(O)-O-R",

-CH

2 -NH-. Preferrably, R" and R"' are independently selected from the group consisting of C 1 .jo alkyl,

C

3

.

7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by 10 one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C 1

.

6 alkyl, C 1 alkoxy, aryl, heteroaryl, aryl-C t4 alkylenyl, heteroaryl-CI4 alkylenyl, halo-CIA alkylenyl, halo-CA alkoxy, -O-C(O)-CH 3 , -C(O)-O-CH 3 , -C(O)-NH 2 , -O-CH 2

-C(O)-NH

2 , -NH 2 , and -S(O)2-NH2, with the proviso that R"' can also be hydrogen. Preferrably, a-aminoacyl is an a 15 aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids. For certain embodiments, including any one of the above embodiments which include an a-aminoacyl group, a-aminoacyl is an ct-aminoacyl group derived from a naturally occuring amino acid selected from the group consisting of racemic, D-, and L 20 amino acids. For certain embodiments, including any one of the above embodiments which include an a-aminoacyl group, ct-aminoacyl is an a-aminoacyl group derived from an amino acid found in proteins, wherein the the amino acid is selected from the group consisting of racemic, D-, and L-amino acids. 25 For certain embodiments, including any one of the above embodiments where G2 is present, G2 is selected from the group consisting of c-amino-C2-s alkanoyl, C 2

-

6 alkanoyl,

C,

6 alkoxycarbonyl, and CI.

5 alkylcarbamoyl. For certain embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any 30 one of the above embodiments of Formulas Ila, IVa, or Va in combination with a pharmaceutically acceptable carrier. -35- For certain'embodiments, the present invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of any one of the above embodiments of a pharmaceutical composition or a compound or salt of any one of the above embodiments of Formulas I, II, Ha, III, IV, IVa, V, or Va to the 5 animal. For certain of these embodiments, the cytokine is selected from the group consisting of IFN-a, TNF-a, IL-6, IL-10, and IL-12. For certain of these embodiments, the cytokine is IFN-a or TNF-a. For certain of these embodiments, the cytokine is IFN-a. For certain embodiments, the present invention provides a method of treating a viral disease in an animal in need thereof comprising administering a therapeutically 10 effective amount of any one of the above embodiments of a pharmaceutical composition or a compound or salt of any one of the above embodiments of Formulas I, II, Ila, III, IV, IVa, V, or Va to the animal. For certain embodiments, the present invention provides method of treating a neoplastic disease in an animal in need thereof comprising administering a therapeutically 15 effective amount of any one of the above embodiments of a pharmaceutical composition or a compound or salt of any one of any one of the above embodiments of Formulas 1, II, Ila, III, IV, IVa, V, or Va to the animal. As used herein, the terms "alkyl", "alkenyl", "alkynyl" and the prefix "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups, e.g., 20 cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from I to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In 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 25 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl. Unless otherwise specified, "alkylene", "-alkylene-", "alkenylene", 30 "-alkenylene-", "alkynylene", and "-alkynylene-" are the divalent forms of the "alkyl", "alkenyl", and "alkynyl" groups defined above. The terms "alkylenyl", "alkenylenyl", and "alkynylenyl" are used when "alkylene", "alkenylene", and "alkynylene", respectively, are - 36 substituted. For example, an arylalkylenyl group comprises an "alkylene" moiety to which an aryl group is attached. The term "haloalkyl" is inclusive of alkyl groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups 5 that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like. The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. Unless otherwise indicated, the term "heteroatom" refers to the atoms 0, S, or N. 10 The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., 0, S, N). In some embodiments, the term "heteroaryl" includes a ring or ring system that contains 2 to 12 carbon atoms, I to 3 rings, 1 to 4 heteroatoms, and 0, S, and/or N as the heteroatoms. Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, 15 imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quiinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on. The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at 20 least one ring heteroatom (e.g., 0, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. In some embodiments, the term "heterocyclyl" includes a ring or ring system that contains 2 to 12 carbon atoms, I to 3 rings, I to 4 heteroatoms, and 0, S, and N as the heteroatoms. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 25 1,1 -dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4 oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl, dihydroisoquinolin-(1Bl)-yl, octahydroisoquinolin-(lH)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yi, dihydro-IH-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and the 30 like. The term "heterocyclyl" includes bicylic and tricyclic heterocyclic ring systems. Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can -37include, in addition to a saturated or partially saturated ring, an aromatic ring, for example, a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings joined by two spiro atoms. When "heterocyclyl" contains a nitrogen atom, the point of attachment of the 5 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", "heteroarylenyl", and "heterocyclylenyl" are used when "arylene", "heteroarylene," and "heterocyclylene", respectively, are substituted. For example, an 10 alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached. When a group (or substituent or variable) is present more than once in any Formula described herein, each group (or substituent or variable) is independently selected, whether explicitly stated or not. For example, for the formula -N(R 9 )- each R9 group is independently selected. In another example, when more than one Y group is present, each 15 Y group is independently selected. In a further example, when more than one

-N(R

8

)-Q-R

4 group is present (e.g., more than one -Y-R 4 group is present, and both contain a -N(Rs)-Q- group) each Rs group is independently selected, each Q group is independently selected, and each R 4 group is independently selected. The invention is inclusive of the compounds described herein (including 20 intermediates) in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers 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 25 stated or not (although at times, "salts" are explicitly stated). The term "prodrug" means a compound that can be transformed in vivo to yield an immune response modifying compound in any of the salt, solvated, polymorphic, or isomeric forms described above. The prodrug, itself, may be an immune response modifying compound in any of the salt, solvated, polymorphic, or isomeric forms 30 described above. The transformation may occur by vaious mechanisms, such as through a chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic biotransformation. A discussion of the use of prodrugs is provided by T. Higuchi and W. -38- Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. Compounds (including intermediates) of the present invention may exist in 5 different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies, which are interconvertible via a low energy barrier. For example, proton tautomers (prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. When compounds or 10 compounds in compositions of the present invention have an amino group for the R 2 group, proton migration between the nitrogen atom of the amino group and the nitrogen atom at the 3-position may occur. For example, the following Formulas Ia and lb are tautomeric forms of each other: N R -NH2 >=NH RA R B RA X- R, 15 a. lb Preparation of the Compounds Compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the 20 description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth 25 Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. I 6, Pergamon Press, Oxford, England, (1995); Barry M. Trost and Ian Fleming, Comprehensive Organic Synthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin, Germany, including supplements (also available via the Beilstein online database)). -39- For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For more detailed description of the individual reaction steps, see the EXAMPLES section below. Those skilled in the art will appreciate that other synthetic 5 routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted in the reaction schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using 10 conventional methods well known to those skilled in the art. In the preparation of compounds of the invention it may sometimes be necessary to protect a particular functionality while reacting other functional groups on an intermediate. The need for such protection will vary depending on the nature of the particular functional group and the conditions of the reaction step. Suitable amino protecting groups include 15 acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9 fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include acetyl and silyl groups such as the tert-butyl dimethylsilyl group. For a general description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, USA, 1991. 20 Conventional methods and techniques of separation and purification can be used to isolate compounds of the invention, as well as various intermediates related thereto. Such techniques may include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography using common absorbents such as silica gel, and thin layer chromatography), recrystallization, and differential (i.e., liquid 25 liquid) extraction techniques. For some embodiments of the invention, compounds can be prepared according to Reaction Scheme I wherein R, R 1 , R 2 , X"', and n are as defined above and E is carbon (imidazoquinolines) or nitrogen (imidazonaphthyridines). In step (1) of Reaction Scheme I, a 4-chloro-3-nitroquinoline or 4-chloro-3 30 nitro[,5]naphthyridine of Formula XX is reacted with an amine of Formula RI-X"'-NH 2 to provide a compound of Formula XXI. The reaction can be carried out by adding the amine to a solution of a compound of Formula XX in a suitable solvent such as anhydrous - 40 tetrahydrofuran in the presence of a base such as triethylamine. The reaction can be run at ambient temperature, at a sub-ambient temperature such as, for example 0 *C, or at an elevated temperature such as, for example, 45 *C. Many compounds of Formula XX are known or can be prepared using known synthetic methods, see for example, U.S. Patent 5 Nos. 4,689,338 (Gerster), 5,268,376 (Gerster), 5,389,640 (Gerster et al.), 6,194,425 (Gerster, et al.), 6,331,539 (Crooks et al.), 6,451,810 (Coleman et al.), 6,541,485 (Crooks et al.), 6,660,747 (Crooks et al.), 6,683,088 (Crooks et al.), 6,656,938 (Crooks et al.), and U.S. Patent Application Publication No. US 2004/0147543 (Hays et al.). Some amines of Formula R 1

-X"'-NH

2 are commercially available; others can be prepared using known 10 synthetic methods. In step (2) of Reaction Scheme I, a compound of Formula XXI is reduced to provide a compound of Formula XXII. The reduction can be carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon. The reaction can be conveniently carried out on a Parr apparatus in a suitable solvent such as 15 acetonitrile, toluene, ethanol, methanol, and/or isopropanol. Other reduction processes may be used for the reduction in step (2). For example, an aqueous solution of sodium dithionite can be added to a solution or suspension of the compound of Formula XXI in a suitable solvent such as ethanol or isopropanol. The reaction can be carried out at an elevated temperature, for example, at reflux, or at ambient 20 temperature. For step (3) of Reaction Scheme I, a compound of Formula XXII is (i) reacted with an acyl halide of Formula R 2 C(O)Cl or R 2 C(O)Br and then (ii) cyclized to provide a IH imidazo[4,5-c]quinoline or IH-imidazo[4,5-c][1,5]naphthyridine of Formula XXIII. In part (i) the acyl halide is added to a solution of a compound of Formula XXII in a suitable 25 solvent such as acetonitrile or anhydrous dichloromethane optionally in the presence of a base such as triethylamine. The reaction can be run at a reduced temperature, for example, 0* C, or at ambient temperature. In part (ii) the product of part (i) is heated in an alcohol c solvent in the presence of a base. For example, the product of part (i) is refluxed in ethanol in the presence of excess triethylamine or is heated with methanolic ammonia. 30 Alternatively, step (3) can be carried out by reacting a compound of Formula XXII with a carboxylic acid or an equivalent thereof. Suitable equivalents to carboxylic acid include orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is -41selected such that it will provide the desired R 2 substituent in a compound of Formula XXIII. For example, triethyl orthovalerate will provide a compound where R 2 is butyl. The reaction can be run in the absence of solvent or in an inert solvent such as anhydrous toluene. The reaction is run at an elevated temperature. Optionally a catalyst such as 5 pyridine hydrochloride can be utilized. Alternatively, when R 2 is -NH 2 , the reaction can be carried out by reacting a compound of Formula XXII with cyanogen bromide in a suitable solvent such as ethanol. The reaction can be run at an elevated temperature, for example, at reflux. 10 Reaction Scheme I 0 No (1) N N,O (2) N NH2 CI NH NH E-E XO -E X*, XX XXI RXXII R, (3) N N \>R2 N E X*0 (R), XXIII R, For some embodiments of the invention, compounds can be prepared according to Reaction Scheme II wherein R, RI, R 2 , E, X"', and m are as defined above and R3d is as 15 defined below. IH-Imidazo[4,5-c]quinolines or 1H-imidazo[4,5-c][1,5]naphthyridines of Formula XXIV can be prepared according to Reaction Scheme I. Compounds of Formula XXIV can undergo known palladium-catalyzed coupling reactions such as the Suzuki coupling and the Heck reaction. For example, a compound of Formula XXIV undergoes Suzuki coupling with a boronic acid of Formula Rad-B(OH) 2 , an 20 anhydride thereof, or a boronic acid ester of Formula R3d-B(O-alkyl)2; wherein R3d is -R4b, -XaR4, -Xb-Y-R 4 , or -Xb-Rs; where Xa is alkenylene; Xb is arylene, heteroarylene, and alkenylene interrupted or terminated by arylene or heteroarylene; Rib is aryl or heteroaryl -42where the aryl or heteroaryl groups can be unsubstituted or substituted as defined in R 4 above; and R4, R 5 , and Y are as defined above; to provide a compound of Formula XXV. Numerous boronic acids of Formula R3d-B(OH)2, anhydrides thereof, and boronic acid esters of Formula R3-B(O-alkyl)2 are commercially available; others can be readily 5 prepared using known synthetic methods. The Heck reaction can also be used in Reaction Scheme II to provide compounds of Formula XXV, wherein R3d is -Xa-R4b and -X 8

-Y-R

4 . The Heck reaction is carried out by coupling a compound of Formula XXIV with a compound of the Formula

H

2 C=C(H)-R4b or H 2

C=C(H)-Y-R

4 . Several of these vinyl-substituted compounds are 10 commercially available; others can be prepared by known methods. The Suzuki coupling and Heck reaction can be carried out according to any of the methods described in U. S. Patent Application Publication No. 2004/0147543 (Hays et al.). Compounds of Formula XXV, wherein R3d is -Xe-R 4 , X. is alkynylene, and R 4 is as defined above, can also be prepared by palladium catalyzed coupling reactions such as the 15 Stille coupling or Sonogashira coupling. These reactions are carried out by coupling a compound of Formula XXIV with a compound of the Formula (alkyl) 3 Sn-C=C-R 4 , (alkyl) 3 Si-C=C-R 4 , or H-C=C-R 4 . Compounds of Formula XXV prepared as described above by palladium-mediated coupling reactions, wherein R3d is -Xa-R4, -Xa-Y-R 4 , -Xb 2

-Y-R

4 , -X 2 -Rs, or -X 0

-R

4 , where 20 Xb2 is alkenylene interrupted or terminated by arylene or heteroarylene, and Xa, Xr, Y, R4, and R 5 are as defined above, can undergo reduction of the alkenylene or alkynylene group present to provide compounds of Formula XXV wherein R3d is -Xd-R4, -Xd-Y-R 4 ,

-X.-Y-R

4 , or -Xe-R 5 , where Xd is alkylene; X, is alkylene interrupted or terminated by arylene or heteroarylene; and R 4 , R 5 , and Y are as defined above. The reduction can be 25 carried out by hydrogenation according to the methods described in U. S. Patent Application Publication No. 2004/0147543 (Hays et al.). A copper-mediated coupling reaction can be used to prepare compounds of Formula XXV, wherein R3d is -NH-C(R 6

)-R

4 , -NH-S0 2

-R

4 . The reaction can be carried out by combining a compound of Formula XXIV and an amide or sulfonamide of formula 30 -NH-C(R 6

)-R

4 or -NH-S0 2

-R

4 in the presence of copper (I) iodide, potassium phosphate, and racemic trans-1,2-diaminocyclohexane in a suitable solvent such as 1,4-dioxane. The reaction can be carried out at an elevated temperature such as 110 *C. Many amides and -43sulfonamides of these formulas are commercially available; others can be made by conventional methods. These reaction conditions can also be used to couple a compound of Formula XXIV with a wide variety of nitrogen-containing heterocycles to provide a compound of Formula XXV wherein R3d is -heterocyclyl, -heterocyclylene-R4, or 5 -heterocyclylene-Y-R4, wherein the heterocyclyl or heterocyclylene is attached to the quinoline or naphthyridine ring through a nitrogen atom. In addition, certain of these compounds of Formula XXV wherein R3d is -heterocyclyl, -heterocyclylene-R4, or -heterocyclylene-Y-R4, wherein the heterocyclyl or heterocyclylene is attached to the quinoline or naphthyridine ring through a nitrogen atom, 10 can be prepared using a palladium-mediated coupling, which is conveniently carried out by combining a compound of the Formula XXIV and the nitrogen-containing heterocyclyl compound in the presence of tris(dibenzylideneacetone)dipalladium, (±)-2,2' bis(diphenylphosphino)-1,1'-binaphthyl, sodium rert-butoxide, and a suitable solvent such as toluene. The reaction can be carried out at an elevated temperature such as 80 *C. The 15 synthetic methods described in International Publication No. WO 05/123080 (Merrill et al.) can also be used. These reaction conditions can also be used to prepare compounds wherein Rad is -Ni -R4. Reaction Scheme II N R2, R N N N (R)m (R)m\ .-E X" E X"' Br Rd XXIV R, XXV R, 20 For some embodiments of the invention, compounds can be prepared according to Reaction Scheme III wherein R, R 1 , R 2 , E, X"', and m are as defined above, Bn is benzyl, and R 3 , is as defined below. 25 In step (1) of Reaction Scheme III, a benzyloxyaniline or benzyloxyamninopyridine of Formula XXVI is treated with the condensation product generated from 2,2-dimethyl 1,3-dioxane-4,6-dione (Meldrum's acid) and triethyl orthoformate to provide an imine of Formula XXVII. The reaction can be carried out by adding a solution of a compound of -44- Formula XXVI to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature such as 45 *C. Many anilines and aminopyridines of Formula XXVI are commercially available; others can be prepared by known synthetic methods. For example, benzyloxypyridines of Formula XXVI can be 5 prepared using the method of Holladay et al., Blorg. Med. Chem. Lett., 8, pp. 2797-2802, (1998). In step (2) of Reaction Scheme 111, an imine of Formula XXVII undergoes thermolysis and cyclization to provide a compound of Formula XXVIII. The reaction is conveniently carried out in a medium such as DOWTHERM A heat transfer fluid at a 10 temperature in the range of 200 to 250 *C. In step (3) of Reaction Scheme III, a compound of Formula XXVIII is nitrated under conventional nitration conditions to provide a benzyloxy-3-nitroquinolin-4-ol or benzyloxy-3-nitro[ 1,5]naphthyridin-4-ol of Formula XXIX. The reaction is conveniently carried out by adding nitric acid to the compound of Formula XXVIII in a suitable solvent 15 such as propionic acid and heating the mixture at an elevated temperature such as 125 "C. In step (4) of Reaction Scheme III, a benzytoxy-3-nitroquinolin-4-ol or benzyloxy 3-nitro[1,5]naphthyridin-4-ol of Formula XXIX is chlorinated using conventional chlorination chemistry to provide a benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4 chloro-3-nitro[1-,5]naphthyridine of Formula XXX. The reaction is conveniently carried 20 out by treating the compound of Formula XXIX with phosphorous oxychloride in a suitable solvent such as DMF. The reaction can be carried out at an elevated temperature such as 100 *C. Steps (5), (6), and (7) of Reaction Scheme III can be carried out according to the methods of steps (1), (2), and (3), respectively, of Reaction Scheme I. 25 In step (8) of Reaction Scheme III, the benzyl group of a benzyloxy-IH imidazo[4,5-c]quinoline or benzyloxy-IH-imidazo[4,5-c][1,5]naphthyridine of Formula XXXI is cleaved to provide a 1H-imidazo[4,5-c]quinolinol or IH-imidazo[4,5 c][1,5]naphthyridinol of Formula XXXII. The cleavage can be carried out on a Parr apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as 30 palladium on carbon in a solvent such as ethanol. Alternatively, the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst. The transfer hydrogenation can be carried out by adding ammonium formate to a solution - 45 of a compound of Formula XXXI in a suitable solvent such as ethanol in the presence of a catalyst such as palladium on carbon. The reaction is carried out at an elevated temperature, for example, the reflux temperature of the solvent. In step (9) of Reaction Scheme III, a IH-imidazo[4,5-c]quinolinol or 1H 5 imidazo[4,5-c][1,5]naphthyridinol of Formula XXXII is converted to an ether-substituted IH-imidazo(4,5-c]quinoline or 1H-imidazo[4,5-cl[1,5]naphthyridine of Formula XXXIII using a Williamson-type ether synthesis. The reaction is carried out by treating a compound of Formula XXXII with an aryl, alkyl, or arylalkylenyl halide of Formula halide-R 4 b, halide-alkylene-R, halide-alkylene-Y-R4, or halide-alkylene-R5 in the 10 presence of a base. The reaction can be carried out by combining the halide with a compound of Formula XXXII in a solvent such as DMF in the presence of a suitable base such as cesium carbonate. The reaction can be carried out at ambient temperature or at an elevated temperature, for example 65 *C or 85 *C. Numerous alkyl, arylalkylenyl, and aryl halides of these formulas are commercially available, including substituted benzyl 15 bromides and chlorides, substituted or unsubstituted alkyl or arylalkylenyl bromides and chlorides, and substituted fluorobenzenes. Other halides of these formulas can be prepared using conventional synthetic methods. The methods described in International Publication Nos. W02005/020999 (Lindstrom et al.) and W02005/032484 (Lindstrom et al.) can be used. 20 - 46 - Reaction Scheme III 0 0

NH

2 Nj 2 N 1 (R)m .23 (R)m E (R)m OH BnO BnO BnO XXVI XXV1I XXVIII I (3) N N (5-7) N NO 2 (4) NO2 N (R)mm CI (R)m OH ..-E X" .E - BnO BnO XXXI R, XXX XXIX (8) N N N (9) \>NR N\N-R2 NNR N (R)m\ (R)m \ E X4" E X"' o HO R XXXII R, R 30 XXXIII 5 For some embodiments of the invention, compounds can be prepared according to Reaction Scheme IV wherein R, R 1 , R 2 , E, X"', and n are as defined above. In Reaction Scheme IV a 1H-Imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXIII is reduced to provide a compound of Formula XXXIV. The reaction can be carried out by suspending or dissolving a compound of Formula XXIII in 10 trifluoroacetic acid, adding platinum (IV) oxide, and hydrogenating. The reaction can be carried out on a Parr apparatus. -47- Reaction Scheme IV N N N N \>-R2 :\>-R2 N N -E X". E X'" (R) \ (R), " XXIII R, XXXIV R 1 For some embodiments of the invention, compounds can be prepared according to 5 Reaction Scheme V wherein Ri, R 2 , RA., R., and X"' are as defined above. In steps (1) through (3) of Reaction Scheme V, a 2,4-dichloro-3-nitropyridine of Formula XXXV is converted to a 4-chloro-1H-imidazo[4,5-c]pyridine of Formula XXXVI. The steps can be carried out according to the general methods of steps (1) through (3) of Reaction Scheme I. 2,4-Dichloro-3-nitropyridines of Formula XXXV are 10 known or can be prepared using known synthetic methods, see for example, U.S. Patent No. 6,525,064 (Dellaria, et al.) and the references cited therein. In step (4) of Reaction Scheme V, the chloro group is removed from a 4-chloro IH-imidazo[4,5-c]pyridine of Formula XXXVI to provide a IH-imidazo[4,5-c]pyridine of Formula Vc. The reaction can be carried out using ammonium formate and a 15 heterogeneous catalyst such as palladium on carbon in a solvent mixture comprised of ethanol and methanol. The reaction is carried out at an elevated temperature, such as for example, the reflux temperature of the solvent system. Reaction Scheme V C 01 N N,O (1-3) N N (4) N N I - - Ra' \ \>'R

R

8 . CI I N N Ro Rw .- X' ' RaX 20 XXXV XXXVI R, Vc R, For some embodiments of the invention, compounds can be prepared according to Reaction Scheme VI wherein R, Rt, R 2 , E, and n are as defined above. -48- In step (1) of Reaction Scheme VI, a 1H-Imidazo[4,5-c]quinolin-1-amine or 1H imidazo[4,5-c][l,5]naphthyridin-l-amine of Formula XXXVII is reacted with a ketone of the Formula R 1 =O under acidic conditions to provide a hydrazone of Formula XXXVIII. The reaction can be carried out by adding the ketone to a solution of a compound of 5 Formula XXXVII in a suitable solvent such as acetonitrile in the presence of an acid such as glacial acetic acid. The reaction is run at an elevated temperature, such as for example, at 110 *C. Compounds of Formula XXXVII are known or can be prepared using known synthetic methods, see for example, U.S. Patent Application Publication No. 2005/0054640 (Griesgraber et al.) and International Publication No. WO 06/026760 10 (Stoermer et al.) and the references cited therein. In step (2) of Reaction Scheme VI, a hydrazone of Formula XXXVIII is reduced to provide a 1H-imidazo[4,5-c]quinoline or IH-imidazo[4,5-c][1,5]naphthyridine of Formula XXXIX. The reaction can be carried out by adding sodium borohydride to a solution of a compound of Formula XXXVIII in a suitable solvent such as methanol. The reaction can 15 be run at ambient temperature or at a sub-ambient temperature, such as for example, 0 *C. Reaction Scheme VI N N (1) N -N (2) N N I C\-R2 0. 1 \>- R2 -- I-'\-R2 N N N -E NH 2 E -E NR (R), E NH 2 (R)" E NXX i (R) H 1 XXV1XXXV I II XXXIX 20 For some embodiments of the invention, compounds can be prepared according to Reaction Scheme VII wherein R, R 1 , R 2 , R3d, E, and m are as defined above. In steps (1) and (2) of Reaction Scheme VII, a bromo substituted 1IH-imidazo[4,5 c]quinolin-1-amine or IH-imidazo[4,5-c][1,5]naphthyridin-1-amine of Formula XL is converted to a 1H-imidazo[4,5-c]quinoline or IH-imidazo[4,5-c][1,5]naphthyridine of 25 Formula XLI using the methods of steps (1) and (2) of Reaction Scheme VI. Compounds of Formula XL are known or can be prepared using known synthetic methods, see for example U.S. Patent Application Publication No. 2005/0054640 (Griesgraber et al.) and International Publication No. WO 06/026760 (Stoermer et aL) and the references cited therein. -49- In step (3) of Reaction Scheme VII a 1H-imidazo[4,5-c]quinoline or 1H imidazo[4,5-c][1,5]naphthyridine of Formula XLI is converted to a IH-imidazo[4,5 c]quinoline or I H-imidazo[4,5-c][1,5]naphthyridine of Formula XLII using the methods described in Reaction Scheme II. 5 Reaction Scheme VII N N (1-2) N N (3) N - N N-R2 .>'-R 2 \>-R2 (R)R) N (R)m N Br .- E NH 2 Br -E-E ~R XL XLI H XLII For some embodiments of the invention, compounds can be prepared according to 10 Reaction Scheme VIII wherein R, R 1 , R 2 , R 3 ., Bn, E, and m are as defined above. In steps (1) and (2) of Reaction Scheme VIII, a benzyloxy substituted IH imidazo[4,5-c]quinolin-1-amine or IH-imidazo[4,5-c][1,5]naphthyridin-1-amine of Formula XLIII is converted to a 1H-imidazo[4,5-c]quinoline or IH-imidazo[4,5 c][1,5]naphthyridine of Formula XLIV using the methods of steps (1) and (2) of Reaction 15 Scheme VI. Compounds of Formula XLII are known or can be prepared using known synthetic methods, see for example, U.S. Patent Application Publication No. 2005/0054640 (Griesgraber et al.) and International Publication No. WO 06/026760 (Stoermer et aL) and the references cited therein. In steps (3) and (4) of Reaction Scheme VIII a IH-imidazo[4,5-c]quinoline or 1H 20 imidazo[4,5-c][l1,5]naphthyridine of Formula XLIV is converted to a 1 H-imidazo(4,5 c]quinoline or IH-imidazo[4,5-c][1,5]naphthyridine of Formula XLV using the methods described in steps (8) and (9) respectively of Reaction Scheme III. -50- Reaction Scheme VIII N N (1-2) N N (3-4) N N | WR2 | )-R 2 - R - N N N (R )R) (R ), (R)H -E N R -E N R BnO NH 2 O H 10 H XLIll BnO XLIV XLV R30 For some embodiments of the invention, compounds can be prepared according to 5 Reaction Scheme IX wherein R, R 1 , R 2 , E, and n are as defined above. In Reaction Scheme IX, IH-imidazo[4,5-c]quinoline or IH-imidazo[4,5-c][1,5]naphthyridine of Formula XXXIX is reduced to provide a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5 c][1,5]naphthyridine of Formula XLVI. The reduction can be carried out as described in Reaction Scheme IV. 10 Reaction Scheme IX N N N N w - I \RN N N E N, E, (R)., XI H R1 (R). Xn MR, XXXIX * XLVI For some embodiments of the invention, compounds can be prepared according to 15 Reaction Scheme X wherein R 1 , R 2 , RV, and RB. are as defined above. In steps (1) and (2) of Reaction Scheme X, a 4-chloro-IH-imidazo[4,5-c]pyridin-1 amine of Formula XLVII is converted to a 4-chloro-lH-imidazo(4,5-c]pyridin-I-amine of Formula XLVIII using the methods of steps (1) and (2) of Reaction Scheme VI. Compounds of Formula XLVII are known or can be prepared using known synthetic 20 methods, see for example, International Publication No. WO 06/026760 (Stoermer et al.) and the references cited therein. In step (3) of Reaction Scheme X, the chloro group is removed from a 4-chloro IH-imidazo[4,5-c]pyridin-1-amine of Formula XLVIII to provide a IH-imidazo[4,5 c]pyridin-1-amine of Formula Vd. The reaction can be carried out as described in step (4) 25 of Reaction Scheme V. -51 - Reaction Scheme X CI I N N (1-2) N N (3) N N I \>-R2 I -\>')-R2 \> '-R2 N N i'N RB.R. N Re. RA. NH 2 RA. N-R R . R, XLVII XLVIll Vd 5 For some embodiments of the invention, compounds can be prepared according to Reaction Scheme XI wherein R, RI, R 2 , E, m, and n are as defined above and D is bromo or benzyloxy. In reaction Scheme XI an N-(4-chloroquinolin-3-yl)amide or N-(4 chloro[1,5]napthyridin-3-yl)amnide of Formula XLIX is reacted with a hydroxylamine 10 hydrochloride of Formula R 1 ONH2-HCI and cyclized to provide a IH-imidazo[4,5 c]quinoline or IH-imidazo[4,5-c][1,5]naphthyridine of Formula L. The reaction can be carried out by adding the hydroxylamine hydrochloride to a solution of a compound of Formula XLIX in an alcoholic solvent such as ethanol. The reaction can be carried out at an elevated temperature, such as for example, the reflux temperature of the solvent. N-(4 15 Chloroquinolin-3-yl)amides and N-(4-chloro[1,5]napthyridin-3-yl)amides of Formula XLIX are known or can be prepared using known synthetic methods, see for example, International Publication No. WO 06/028962 (Krepski el al.). Compounds of Formula L wherein m is I and D is bromo can be further elaborated using the general methods described in Reaction Scheme II. Compounds of Formula I 20 wherein m is 1 and D is benzyloxy can be further elaborated using the general methods described in Reaction Scheme III. - 52- Reaction Scheme XI I R 2 N 'YR 2 N N I /- 0 IMR2 (R). Cl (R) XLIX L For some embodiments of the invention, compounds can be prepared according to 5 Reaction Scheme XII wherein R, Rj, R 2 , Bn, E, and n are as defined above. In step (1) of Reaction Scheme XII, an N-(4-chloroquinolin-3-yl)amide or N-(4 chloro[1,5]napthyridin-3-yl)amide of Formula LI is reacted with O-benzylhydroxylamine hydrochloride and cyclized to provide a 1-benzylox-1H-imidazo[4,5-c]quinCline or 1 benzyloxy-1H-imidazo[4,5-c)[1,5]naphthyridine of Formula LII. The reaction can be 10 carried out by adding the 0-benzylhydroxylamine hydrochloride to a solution of a compound of Formula LI in an alcoholic solvent such as isopropanol. The reaction can be carried out at an elevated temperature, such as for example, the reflux temperature of the solvent. N-(4-Chloroquinolin-3-yl)amides and N-(4-chloro[1,5]napthyridin-3-yI)amides of Formula LI are known or can be prepared using known synthetic methods, see for 15 example, International Publication No. WO 06/028962 (Krepski et al.). In step (2) of Reaction Scheme XII, the benzyl group of a 1-benzyloxy-IH imidazo[4,5-c]quinoline or 1-benzyloxy-l H-imidazo[4,5-c)[1,5]naphthyridine of Formula LII is cleaved to provide a 1H-imidazo[4,5-c]quinolin-1-ol or IH-imidazo[4,5 c][1,5]naphthyridin-1-ol of Formula LIII. The cleavage can be carried out on a Parr 20 apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium on carbon in a solvent such as ethanol. Alternatively, the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst. The transfer hydrogenation can be carried out by adding ammonium formate to a solution of a compound of Formula LII in a suitable solvent such as ethanol in the presence of a 25 catalyst such as palladium on carbon. The reaction is carried out at an elevated temperature, for example, the reflux temperature of the solvent. In step (3) of Reaction Scheme XII, a IH-imidazo[4,5-c]quinolin-l-ol or lH imidazo[4,5-c][1,5]naphthyridin-1-o1 of Formula LIII is converted to an ether-substituted - 53 - 1H-imidazo[4,5-c]quinoline or I H-imidazo[4,5-c][1,5]naphthyridine of Formula LIV. The reaction can carried out by treating a compound of Formula LIII with a halide of Formula halide-R, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction can be carried out by heating a mixture of the halide, a compound of Formula 5 LIII, and the DBU in a sealed pressure vessel at an elevated temperature, for example 120 *C. Some halides of the Formula halide-R, commercially available; others can be prepared using known synthetic methods. Reaction Scheme XII NR N(1) N (2) N N 0N (R), CI (R), (R), E E OH LI Lil Bn Lill (3) N ,.R2 (R), q E 0 R1 10 LIV For some embodiments of the invention, compounds can be prepared according to Reaction Scheme XIII wherein R, R 1 , R 2 , Bn, and n are as defined above. In step (1) of Reaction Scheme XIII, an N-(4-chloro-5,6,7,8-tetrahydroquinolin-3 15 yl)amide of Formula LV is reacted with O-benzylhydroxylamine hydrochloride and cyclized to provide a 1-benzyloxy-4-chloro-5,6,7,8-tetrahydro-IH-imidazo[4,5 c]quinoline of Formula LVI. The reaction can be carried out as described in step (1) of Reaction Scheme XII. N-(4-Chloro-5,6,7,8-tetrahydroquinolin-3-yl)amides of Formula LV are known or can be prepared using known synthetic methods, see for example, 20 International Publication No. WO 06/028962 (Krepski et al.). In step (2) of Reaction Scheme XIII, both the benzyl group and the chloro group of a 1 -benzyloxy-4-chloro-5,6,7,8-tetrahydro-1 H-imidazo[4,5-c]quinoline are cleaved to -54provide a 1H-imidazo[4,5-c]quinolin-1-ol of Formula LVII. The cleavage can be carried out as described in step (2) of Reaction Scheme XII. In step (3) of Reaction Scheme XIII, a IH-imidazo[4,5-c]quinolin-l-ol of Formula LVII is converted to an ether-substituted IH-imidazo[4,5-c]quinoline of Formula IIIb 5 using the method described in step (3) of Reaction Scheme XII. Reaction Scheme XIII C1 H C N N R 2 N N (2) N Y ( ')--R 2 2 2 i N (R), Cl (R) . (R), O OH LV LVI Bn LVII j(3) N N (R), 0 Ri 10 For some embodiments of the invention, compounds can be prepared according to Reaction Scheme XIV wherein RA, RB., R 1 , and R 2 are as defined above. In step (1) of Reaction Scheme XIV, a 2,4-dichloro-3-nitropyridine of Formula XXXV is reduced to provide a 2,4-dichloropyridin-3-amine of Formula LVIII. The reduction can be carried out using the methods described in step (2) of Reaction Scheme 1. 15 In step (2) of Reaction Scheme XIV, a 2,4-dichloropyridin-3-amine of Formula LVIII is reacted with an acyl halide of Formula R 2 C(O)Cl or R 2 C(O)Br to provide an N (2,4-dichloropyridin-3-yl)amide of Formula LIX. The reaction can be carried out by adding the acyl halide to a solution of the 2,4-dichloropyridin-3-amine of Formula LVIII in a suitable solvent such anhydrous dichloromethane optionally in the presence of a base 20 such as triethylamine. The reaction can be run at a reduced temperature, for example, 0 "C, or at ambient temperature. - 55 - In steps (3), (4), and (5) of Reaction Scheme XIV, an N-(2,4-dichloropyridin-3 yl)amide of Formula LIX is converted to an ether substituted IH-imidazo[4,5-c]pyridine of Formula Ve using the methods described in steps (1), (2), and (3) respectively of Reaction Scheme XIII. 5 Reaction Scheme XIV CI I N ~ (1)

NH

2 (2) R2 Ra. R ,R CI OR . CI RA' RA. RN XXXV LVIII LIX S (3- 5)) N N> Ra' R2 0 R , Ve Compounds useful in the compositions of the invention and compounds of the .) invention can also be prepared using variations in the synthetic routes shown in Reaction Schemes I through XI that would be apparent to one of skill in the art. Compounds useful in the compositions of the invention and compounds of the invention can also be prepared using the synthetic routes described in the EXAMPLES below. 15 Pharmaceutical Compositions and Biological Activity Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound or salt described above in combination with a pharmaceutically acceptable carrier. 20 The terms "a therapeutically effective amount" and "effective amount" mean an amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect, - 56 such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral activity. The exact amount of 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 5 intended dosing regimen. In some embodiments, the compositions of the invention will contain sufficient active ingredient or prodrug to provide a dose of about 100 nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably about 10 micrograms per kilogram (pg/kg) to about 5 mg/kg, of the compound or salt to the subject. 10 In other einbodiments, the compositions of the invention will contain sufficient active ingredient or prodrug to provide a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , computed according to the Dubois method, in which the body surface area of a subject (m 2 ) is computed using the subject's body weight: m 2 = (wt k g.42s X height cm*, 7 2) x 6.007184, although in some embodiments the methods may be performed 15 by administering a compound or salt or composition in a dose outside this range. In some of these embodiments, the method includes administering sufficient compound to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m2. A variety of dosage forms may be used, such as tablets, lozenges, capsules, 20 parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like. These dosage forms can be prepared with conventional pharmaceutically acceptable carriers and additives using conventional methods, which generally include the step of bringing the active ingredient into association with the carrier. In general, the compositions may be prepared by uniformly 25 and intimately bringing the active ingredient into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired dosage form. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas that has been compressed to form a liquid. Suitable pharmaceutical carriers for use in the present 30 pharmaceutical formulations are known. The carrier may take a wide variety of forms, depending on the form of preparation desired for administration, for example, such as -57systemic administration (including but not limited to oral, parenteral, intravenous, or nasal) and topical administration. In preparing the pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical carriers may be employed, such as, for example, water, glycols, oils, and 5 alcohols in the case of oral liquid preparations (e.g., emulsions, suspensions, elixirs, solutions, syrups), and carriers such as, for example, starches, sugars (including lactose, sucrose, glucose, mannitol), silicic acid, methylcellulose, carboxymethylcellulose, alginates, pectin, dextrin, gelatin, polyvinylpyrrolidone, acacia, glycerol, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium 10 carbonate, low melting waxes, cocoa butter, cetyl alcohol, glycerol monostearate, kaolin and bentonite clay, talc, calcium stearate, magnesium carbonate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof in the case of oral solid preparations (e.g., pills, granules, powders, capsules, tablets). Aqueous solutions suitable for oral use can be prepared by dissolving the active 15 component in water and adding thereto suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents. Aqueous suspensions suitable for oral use can be made by dispersing the active component in finely divided form in water with viscous materials or thickening agents such as, for example, synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents. 20 In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions 25 as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers include water, aqueous solutions, such as saline (sotinic sodium chloride solution), Ringer's solution, dextrose solution, and Hanks' solution, ethanol, polyols (such as 1,3-butanediol, glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, 30 vegetable oils such as, for example, olive oil, corn oil, cottonseed oil, sesame oil, and castor oil, synthetic mono- or di-glyceride oils, and organic esters such as ethyl oleate and isopropyl myristate. Proper fluidity can be maintained, for example, by the use of coating - 58 materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of 5 microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. 10 In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. 15 Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms may be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of 20 drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a 25 bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Pharamaceutical compositions for topical application may include the above liquid forms, as well as ointments, creams, lotions, aerosols, sprays, dusts, and powders, which 30 are prepared by combining an active component according with conventional pharmaceutically acceptable carriers commonly used in topical, dry, liquid, cream, and aerosol formulations. Ointments and creams may, for example, be formulated with an -59aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases may include, for example, water and/or oil such as mineral oil, liquid petrolatum, white petrolatum, or a vegetable oil. Thickening agents, which may be used according to the nature of the base, include soft paraffin, aluminum stearate, cetostearyl alcohol, 5 propylene glycol, polyethylene glycols, polyoxyethylene, polyoxypropylene, hydrogenated lanolin, beeswax, and the like. Alternatively, the active component can be formulated into suitable lotions or creams containing the active component suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetostearyl alcohol, 2-octyldodecanol, 10 benzyl alcohol and water. Administration of the pharmaceutical compositions and compounds and/or salts of the invention may be in the form of an aerosol, for example, for nasal or inhalation applications. The active component may be delivered in the form of an aerosol from a pressurized pack or nebulizer with the use of a suitable propellant such as, for example, 15 carbon dioxide, air, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules or cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the active component and a 20 suitable powder base such as lactose or starch. The compounds and/or salts or compositions described herein may also be delivered in the form of transdermal patches, transmucosal patches, and the like. Matrix or reservoir type patches that are conventional in the art for transdermal or transmucosal delivery may be used for this purpose. Here the matrix, such as a pressure sensitive 25 adhesive matrix, or the carrier in the reservoir act as the pharmaceutically acceptable carrier. The compounds or salts described herein can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts described herein may be administered in combination with one another or with other active agents, 30 including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc. - 60- Compositions and compounds or salts of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds or salts or compositions are useful for modulating the immune response in a number of different ways, rendering them useful 5 in the treatment of a variety of disorders. Cytokines whose production may be induced by the administration of compounds or salts or compositions described herein generally include interferon-a (IFN-a) and tumor necrosis factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN-a, TNF 10 a, IL-1, 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 the compounds or salts or compositions useful in the treatment of viral 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 15 composition of the invention to the animal. The animal to which the 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 the compound or salt or composition may provide therapeutic treatment. Alternatively, the compound or salt or composition may be administered to the animal prior to the animal 20 acquiring the disease so that administration of the compound or salt or composition may provide a prophylactic treatment. In addition to the ability to induce the production of cytokines, compounds or salts described herein can affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine 25 induction. The compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds or salts may cause proliferation and differentiation of B-lymphocytes. Compounds or salts described herein can also have an effect on the acquired immune response. For example, the production of the T helper type 1 (THI) cytokine IFN 30 y may be induced indirectly and the production of the T helper type 2 (TH2) cytokines IL 4, IL-5 and IL-13 may be inhibited upon administration of the compounds or salts. - 61 - 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 5 or salt or composition 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) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension. Conditions for which compounds or salts or compositions identified herein may be 10 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-Il, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picomavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus 15 (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 flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a lentivirus such as HIV); 20 (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, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia, 25 Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella; (c) other infectious diseases, such as chlamydia, fungal diseases including but not limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic diseases including but not limited to malaria, pneumocystis carnii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection; 30 (d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemias including but not limited to acute myeloid -62leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma,.B-cell lymphoma, and hairy cell leukemia, and other cancers; (e) T2-mediated, atopic diseases, such as atopic dermatitis or eczema, 5 eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome; (f) certain autoimmune diseases such as systemic lupus erythematosus, essential thrombocythaemia, 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 10 wounds). Additionally, a compound or salt or composition identified herein may be useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral and/or cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, 15 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, 20 hemophilus 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. Compounds or salts or compositions identified herein may be particularly helpful 25 in individuals having compromised immune function. For example, compounds or salts or compositions 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 HIV patients. Thus, one or more of the above diseases or types of diseases, for example, a viral 30 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 or a composition comprising a therapeutically effective amount of a compound or salt of -63- Formula I, II, Ha, IH, TV, IVa, V, Va, any one of the embodiments described herein, or a combination thereof to the animal. An animal may also be vaccinated by administering an effective amount of a compound or salt of or a composition comprising an effective amount of a compound or salt of Formula I, H1, Ha, Ill, IV, IVa, V, Va, any one of the 5 embodiments described herein, or a combination thereof to the animal as a vaccine adjuvant. In one embodiment, there is provided a method of vaccinating an animal comprising administering an effective amount of a compound or salt or composition described herein to the animal as a vaccine adjuvant. An amount of a compound or salt or composition effective to induce cytokine 10 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 more cytokines such as, for example, IFN-a, TNF-a, IL-1, IL-6, IL-10 and IL-12 that is increased (induced) over a background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to 15 about 50 mg/kg, preferably about 10 .g/kg to about 5 mg/kg. In other embodiments, the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments the induction of cytokine biosynthesis may be performed by administering a compound or salt or composition in a dose outside this range. In some of these 20 embodiments, the method includes administering sufficient compound or salt or composition to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m2. 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 25 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 30 known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 pg/kg to about 5 mg/kg. An amount of a compound or salt or composition effective to treat a neoplastic condition is an amount that will cause a -64 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 ng/kg to about 50 mg/kg, preferably about 10 pg/kg to about 5 mg/kg. In other embodiments, the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 5 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments either of these methods may be performed by administering a compound or salt or composition in a dose outside this range. In some of these embodiments, the method includes administering sufficient compound or salt or composition to provide a dose of from about 0.1 mg/m 2 to about 2.0 Mg/ M 2 to the subject, for example, a dose of 10 from about 0.4 mg/m 2 to about 1.2 mg/m 2 . In addition to the formulations and uses described specifically herein, other formulations, uses, and administration devices suitable for compounds of the present invention are described in, for example, International Publication Nos. WO 03/077944 and WO 02/036592, U.S. Patent No. 6,245,776, and U.S. Publication Nos. 2003/0139364, 15 2003/185835, 2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858. Objects and advantages of this 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. 20 EXAMPLES In the examples below normal high performance flash chromatography (prep HPLC) was carried out using a COMBIFLASH system (an automated high-performance flash purification product available from Teledyne Isco, Inc., Lincoln, Nebraska, USA), a 25 HORIZON HPFC system (an automated high-performance flash purification product available from Biotage, Inc, Charlottesville, Virginia, USA) or an INTELLIFLASH Flash Chromatography System (an automated flash purification system available from AnaLogix, Inc, Burlington, Wisconsin, USA). The eluent used in each purification is given in the example. In some chromatographic separations, the solvent mixture 80/18/2 30 v/v/v chloroform/methanol/concentrated ammonium hydroxide (CMA) was used as the - 5 - 65 polar component of the eluent. In these separations, CMA was mixed with chloroform in the indicated ratio. Example 1 5 2-(2-Methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c][1,5]naphthyridine N O NN N Part A Phosphorous oxychloride (2.55 mL, 27.5 mmol) was added dropwise to a 10 suspension of 4-hydroxy-3-nitro[ 1,5]naphthyridine (5 g, 26.1 mmol) in NN dimethylformamide (DMF, 30 mL). The resulting mixture was heated to 60 *C to dissolve all of the solids. The reaction was maintained at 60 *C for 10 minutes and then allowed to cool to ambient temperature. The solution was poured into ice water (150 mL) and then stirred for 1 hour. A solid was isolated by filtration, washed with water until the filtrate 15 was neutral, and then dried under vacuum for 30 minutes to provide 4-chloro-3 nitro[1,5]naphthyridine. This material was combined with tetrahydrofuran (THF, 30 mL).. A mixture of triethylamine (7.32 mL, 52.5 mmol) and I-tetrahydro-2H-pyran-4 ylmethylamine hydrochloride (4.17 g, 27.5 mmol) in THF was added dropwise to the slurry. The reaction mixture was stirred overnight and then diluted with water. A solid 20 was isolated by filtration and dried under vacuum to provide 6.8 g of 3-nitro-N (tetrahydro-2H-pyran-4-ylmethyl)[1,5]naphthyridin-4-amine. Part B A mixture of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)[1,5]naphthyridin-4 amine (2.5 g, 8.67 mmol), 5% platinum on carbon (0.25 g), and acetonitrile (50 mL) was 25 placed under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 2.37 g of crude N4-(tetrahydro-2H-pyran-4-ylmethyl)[1,5]naphthyridine-3,4-diamine as a yellowish orange oil. - 66- Part C Under a nitrogen atmosphere a solution of N 4 -(tetrahydro-2H-pyran-4 ylmethyl)[1,5]naphthyridine-3,4-diamine (1.19 g, 4.61 mmol) in anhydrous dichloromethane (25 mL) was cooled in an ice bath for 10 minutes. Anhydrous 5 triethylamine (1.0 mL, 6.92 mmol) was added in a single portion. 3-Methoxypropionyl chloride (0.55 mL, 5.07 mmol) was added dropwise and then the reaction mixture was allowed to stir at ambient temperature until analysis by liquid chromatography (LC) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to provide crude 3-methoxy-N-(4-[(tetrahydro-2H-pyran-4 10 ylmethyl)amino][1,5]naphthyridin-3-yl}propanamide as an orange solid. This material was suspended in anhydrous ethanol (25 mL) and combined with anhydrous triethylamine (2.25 rmL, 16.14 mmol). The mixture was placed under a nitrogen atmosphere and heated at 110 *C over the weekend. The reaction mixture was concentrated under reduced pressure and then diluted with dichloromethane (100 mL). The organic layer was washed 15 sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-15% CMA in chloroform) to provide 0.82 g of an off-white solid. This material was suspended in cold methyl tert-butyl ether (MTBE, 10 mL), isolated by filtration, washed with cold MTBE, and then dried at 80 *C 20 to provide 0.39 g of 2-(2-methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)- If imidazo[4,5-c][1,5]naphthyridine as a light grey solid, mp 124-126 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.23 (s, 1H), 8.99 (dd, J= 4.1, 1.6, 1H), 8.50 (dd, J= 8.5, 1.6, lH), 7.73 (dd, J= 8.5, 4.7, IH), 4.85 (d, J = 6.3, 2H), 3.91 (t, J= 6.7, 2H), 3.78 (dd, J= 11.0, 3.2, 2H), 3.29 (s, 3H), 3.26 (t, J= 6.7, 2H), 3.14 (td, J= 11.3, 2.2, 2H), 2.24 (m, 1H), 25 1.50-1.35 (m, 4H); 3 C NMR (125 Hz, d 6 -DMSO) 8 154.5, 149.1, 145.0, 138.8, 138.7, 137.5, 134.8, 133.0, 122.2, 69.6, 66.6, 58.1, 50.2, 36.0, 29.7, 27.2; Anal. called for CisH 2 2

N

4 0 2 : C, 66.24; H, 6.79; N, 17.17. Found: C, 66.23; H, 6.99; N, 17.42. Example 2 30 2-(Ethoxymethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c][1,5]naphthyridine - 67 - N N O NN -N \--Q7O 2-(Ethoxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 c][1,5]naphthyridine was prepared according to the general methods of Example I using 5 ethoxyacetyl chloride in lieu of 3-methoxypropionyl chloride in Part C. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide 0.92 g of a brown solid. This material was suspended in cold diethyl ether (10 mL), isolated by filtration, washed with cold diethyl ether, and then dried at 80 *C to provide 0.46 g of 2-(ethoxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH 10 imidazo[4,5-c][I,5]naphthyridine as a light grey solid, mp 94-96 *C. 'H NMR (500 MHz, d 6 -DMSO) & 9.27 (s, 11), 9.00 (dd, J= 4.1, 1.6, 1H), 8.52 (dd, J= 8.5, 1.6, 1 H), 7.75 (dd, J.= 8.5, 4.7, IH), 4.88 (d, J = 6.3, 2H), 4.85 (s, 211), 3.78 (dd, J= 11.0, 3.2, 2H), 3.60 (q, J = 6.9, 2H), 3.14 (td, J= 11.3, 2.2, 2H), 2.36 (m, 1H), 1.50-1.35 (m, 4H), 1.16 (t, J= 6.9, 3H); 3 C NMR (125 Hz, d,-DMSO) 8 152.4, 149.2,145.6, 139.2, 138.4, 137.5, 135.0, 15 133.6, 122.6, 66.6, 65.6, 64.1, 50.7, 36.0, 29.8, 14.9; Anal. calcd for CisH 22

N

4 0 2 : C, 66.24; H, 6.79;N, 17.17. Found: C, 65.96; H, 7.00;N, 17.15. Example 3 [1 -(Tetrahydro-2H-pyran-4-ylmethyl) 20 lH-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol - N OH N N SN N O Under a nitrogen atmosphere a solution of N4-(tetrahydro-2H-pyran-4 ylmethyl)(1,5]naphthyridine-3,4-diamine (1.57 g, 6.08 mmol) in anhydrous 25 dichloromethane (30 mL) was cooled in an ice bath for 10 minutes. Anhydrous triethylamine (1.30 mL, 9.12 mmol) was added in a single portion. Acetoxyacetyl -68 chloride (0.75 mL, 6.69 mmol) was added dropwise and then the reaction mixture was allowed to stir at anabient temperature until analysis by liquid chromatography (LC) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to provide crude 2-oxo-2-({4-[(tetrahydro-2H-pyran-4 5 ylmethyl)aimino][1,5]naphthyridin-3-yl}amino)ethyl acetate as an orange solid. This material was suspended in anhydrous ethanol (35 mL) and combined with anhydrous triethylamine (3.0 mL, 21.30 mmol). The mixture was placed under a nitrogen atmosphere and heated at 110 *C over the weekend. 50% Sodium hydroxide (1 mL) was added and the reaction mixture was stirred at 100 "C for 1 hour. The reaction mixture 10 was concentrated under reduced pressure and then diluted with chloroform (100 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide 1.00 g of an off-white solid. This material was suspended in cold 15 diethyl ether (20 mL), isolated by filtration, washed with cold diethyl ether, and then dried at 80 *C to provide 0.94 g of [-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5 c][1,5]naphthyridin-2-yl]methanol as a light grey solid, mp 186-188 "C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.25 (s, 1H), 9.00 (dd, J = 4.1, 1.6, 1 H), 8.52 (dd, J= 8.5, 1.6, 1H), 7.75 (dd, J= 8.5, 4.7, 1H), 5.80 (t, J= 6.0, 1H), 4.90 (d, J = 6.3, 2H), 4.85 (d, J= 6.0, 20 2H), 3.78 (dd, J= 11.0, 3.2,2H), 3.14 (td, J= 11.3, 2.2, 2H), 2.36 (in, IH), 1.49-1.36 (m, 4H); 1 3 C NMR (125 Hz, d 6 -DMSO) 8 155.4, 149.2, 145.5, 139.1, 138.4, 137.5, 135.1, 133.6, 66.6,56.4, 50.6, 36.0, 29.8; Anal. calcd for C 1 6 HisN 4 0 2 : C, 64.41; H, 6.08; N, 18.78. Found: C, 64.40; H, 5.98; N, 19.11. 25 Example 4 2-Ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c][1,5]naphthyridine N & NN -6N - 69 - A mixture of N 4 -(tetrahydro-2H-pyran-4-ylmethyl)[1,5]naphthyridine-3,4-dianine (1.25 g, 4.84 mmol), triethyl orthopropionate (1.20 mL, 5.81 mmol), pyridine hydrochloride (25 mg, 0.22 mmol), and toluene (20 mL) was placed in a hot (130 *C) oil bath. After about 4 hours additional pyridine hydrochloride (25 mg) was added and the 5 reaction mixture was heated overnight. Analysis by liquid chromatography/mass spectroscopy (LC/MS) showed that the reaction was incomplete. Additional toluene (50 mL) was added and the reaction flask was equipped with a Dean-Stark trap. After 3 hours analysis by LC/MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep HPLC 10 (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide an off-white solid. This material was suspended in hexanes (20 mL), isolated by filtration, washed with hexanes, and then dried at 80 "C to provide 458 mg of 2-ethyl-1-(tetrahydro-2H-pyran-4 ylmethyl)-1H-imidazo[4,5-cl[1,5]naphthyridine as a light pink solid, mp 132-134 *C. 'H NMR (500 MHz, d 6 -DMSO) 6 9.23 (s, IH), 8.98 (dd, J= 4.1, 1.6, 1H), 8.49 (dd, J= 8.5, 15 1.6, 1H), 7.71 (dd, J= 8.5, 4.7, 1H), 4.80 (d, J = 6.3, 2H), 3.78 (dd, J= 11.0, 3.2, 2H), 3.15 (td, J= 11.3, 2.2, 2H), 3.02 (q, J= 7.5, 2H), 2.36 (in, 1H), 1.49-1.36 (in, 7H); 3 C NMR (125 Hz, d 6 -DMSO) 5 157.7, 149.0, 144.9, 138.8, 138.7, 137.4, 134.8, 133.2, 122.1, 66.6, 50.1, 35.9, 29.7, 20.0, 11.4; Anal. calcd for C 17

H

20

N

4 0: C, 68.91; H, 6.80; N, 18.90. Found: C, 68.69; H, 7.08; N, 18.81. 20 Example 5 2-Propyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c][1,5]naphthyridine N . N N O 25 A mixture of N4-(tetrahydro-2H-pyran-4-ylmethyl)[1,5]naphthyridine-3,4-diamine (1.46 g, 5.65 mmol), trimethyl orthobutyrate (1.2 mL, 6.78 mmol), pyridine hydrochloride (35 mg, 0.28 mmol), and toluene (60 mL) in a flask equipped with a Dean-Stark trap was placed in a hot (150 *C) oil bath. After 1 hour, analysis by LC/MS indicated that starting material had been consumed and that the aide intermediate had formed. Concentrated -70hydrochloric acid (3 drops) was added. After 2 hours analysis by LC/MS indicated that the amide had cyclized. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide 0.97 g of an off-white solid. This material was suspended 5 in cold diethyl ether (20 mL), isolated by filtration, washed with cold diethyl ether, and then dried at 80 *C to provide 0.55 g of 2-propyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-IH imidazo[4,5-c][1,5]naphthyridine as an off-white solid, mp 122-125 *C. 'H NMR (500 MHz, d 6 -DMSO) 5 9.23 (s, 1H), 8.98 (dd, J- 4.1, 1.6, 1H), 8.49 (dd, J = 8.5, 1.6, 1H), 7.71 (dd, J= 8.5, 4.7, 1H), 4.80 (d, J = 6.3,'2H), 3.78 (dd, J= 11.0, 3.2, 2H), 3.14 (td, J= 10 11.3, 2.2, 2H), 2.97 (q, J= 7.6, 2H), 2.24 (m, 1H), 1.93 (sextet, J= 7.6, 2H), 1.49-1.35 (m, 4H), l.04(t,J= 7.1, 3H); 'CNMR (125 Hz, d-DMSO) 6 156.6, 149.0, 144.9, 138.79, 138.74, 137.4, 134.8, 133.0, 122.1, 66.6, 50.1, 36.0, 29.7, 28.3, 20.3, 13.8; Anal. calcd for

CIH

22

N

4 0: C, 69.65; H, 7.14; N, 18.05. Found: C, 69.52; H, 7.38; N, 17.95. 15 Example 6 8-Bromo-2-(ethoxymethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline --- N O N \- O Br 20 Part A Phosphorous oxychloride (10.6 mL, 113.8 mmol) was added dropwise to a mixture of 6-bromo-4-hydroxy-3-nitroquinoline (30.00 g, 81.28 mmol) and DMF (250 mL). After 1.5 hours the reaction mixture was poured into ice water (400 mL) with stirring. A solid was isolated by filtration, washed with water, and dried under high vacuum at ambient 25 temperature overnight to provide crude 6 -bromo-4-chloro-3-nitroquinoline (>32 g). Part B Under a nitrogen atmosphere THF (75 mL) and triethylamine (14.6 mL, 104.4 mmol) were added sequentially to a mixture of crude 6-bromo-4-chloro-3-nitroquinoline - 71 - (15.0 g, 52.2 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (8.30 g, 54.8 mmol). The reaction mixture was placed in an oil bath at 45 *C for 2 hours and then concentrated under reduced pressure. The residue was diluted with THF (30 mL) and water (200 mL). The THF was removed under reduced pressure. A solid was isolated by 5 filtration and dried to provide 7.55 g of 6-bromo-3-nitro-N-(tetrahydro-2H-pyran-4 ylmethyl)quinolin-4-amine. Part C A mixture of 6-bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4 amine (7.56 g), 5% platinum on carbon (0.76 g), methanol (25 mL), and acetonitrile (95 10 mL) was placed under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 6.94 g of 6-bromo-N 4 -(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine as a yellowish-orange oil. 15 Part D 6-Bromo-N 4 -(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (6.94 g, 20.64 mmol) was reacted with ethoxyacetyl chloride (2.5 mL, 22.70 mmol) and then cyclized according to the general method of Example 1 Part C using 6-bromo-N 4 (tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine in lieu of M-(tetrahydro-2H 20 pyran-4-ylmethyl)[1,5]naphthyridine-3,4-diamine and ethoxyacetyl chloride in lieu of 3 methoxypropionyl chloride. The crude product was suspended in diethyl ether (20 mL), isolated by filtration, washed with diethyl ether, and then dried at 80 *C to provide 3.03 g of 8-bromo-2-(ethoxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 c]quinoline as an off-white solid, mp 136-139 *C. 'H NMR (500 MHz, d&-DMSO) 5 9.22 25 (s, IH), 8.46 (d, J= 2.2, 1 H), 8.10 (d, J= 8.9, IH), 7.85 (dd, J= 8.9,2.2, 1 H), 4.83 (s, 2H), 4.65 (d, J= 7.3, 2H), 3.81 (dd, J= 11.7, 2.5, 2H), 3.60 (q, J= 7.0, 2H), 3.15 (td, J 11.6, 2.2, 2H), 2.16 (in, IH), 1.54-1.42 (in, 4H), 1.16 (t, J= 6.9, 3H); 1 3 C NMR (125 MHz, d 6 -DMSO) 8 152.3, 145.4,142.8,136.5,132.6,132.4, 130.0, 123.3, 119.6,118.8, 66.5, 65.6, 64.2, 50.4, 35.6, 29.9, 14.9; Anal. calcd for C1 9

H

2 2

N

3 0 2 Br: C, 56.40; H, 5.49; 30 N, 10.39. Found: C, 56.30; H, 5.45; N, 10.26. -72 - Example 7 2-Benzyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline N N N 1- O 5 Part A Under a nitrogen atmosphere THF (90 mL) and triethylamine (17.5 mL, 125.6 mmol) were added sequentially to a mixture of crude 4-chloro-3-nitroquinoline (13.10 g, 62.81 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (10.0 g, 65.95 mmol). The reaction mixture was placed in an oil bath at 45 *C for 1 hour and then 10 concentrated under reduced pressure. The residue was diluted with THF (30 mL) and water (200 mL). The THF was removed under reduced pressure. A solid was isolated by filtration and dried to provide 16.10 g of 3-nitro-N-(tetrahydro-2H-pyran-4 ylmethyl)quinolin-4-amine as a light yellow solid. Part B 15 A mixture of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (2.50 g), 10% palladium on carbon (0.25 g), and ethanol (40 mL) was placed under hydrogen pressure on a Parr apparatus. .When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to provide 2.23 g ofN4-(tetrahydro-2H 20 pyran-4-ylmethyl)quinoline-3,4-diamine as a yellowish-orange oil. Part C

N

4 -(Tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (2.23 g, 8.67 mmol) was reacted with phenylacetyl chloride (1.25 mL, 9.54 mmol) and then cyclized according to the general method of Example 1 Part C using N 4 -(tetrahydro-2H-pyran-4 25 ylmethyl)quinoline-3,4-diamine in lieu of N4-( tetrahydro-2H-pyran-4 ylmethyl)[1,5]naphthyridine-3,4-diamine and phenylacetyl chloride in lieu of 3 methoxypropionyl chloride. The crude product was suspended in MTBE (20 mL), isolated by filtration, washed sequentially with MTBE and water, and then dried at 80 *C -73to provide 459 mg of 2-benzyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5 ciquinoline as an off-white solid, mp 177-180 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.15 (s, 1H), 8.35 (m, 1 H), 8.15 (m, IH), 7.72-7.66 (m, 2H), 7.37-7.23 (m, 51), 4.54 (d, J= 7.2, 2H), 4.44 (s, 2H), 3.77 (dd, J= 10.6, 2.8, 2H), 3.07 (td, J= 11.6, 1.8, 2H), 2.05 (m, 5 1H), 1.55-1.38 (m, 4H); 3 C NMR (125 MHz, d 6 -DMSO) 8 154.5, 144.3, 144.1, 136.8, 136.3, 133.2, 130.3, 128.8, 128.5, 126.6, 126.5, 120.8, 117.5, 66.5, 50.2, 35.7, 33.1, 29.5; Anal. calcd for C 23 H23N 3 0: C, 77.28; H, 6.49; N, 11.76. Found: C, 76.89; H, 6.44; N, 11.58. 10 Example 8 2-(Methoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline - N 0 NI> N 15 N-(Tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (1.37 g, 5.32 mmol) was reacted with methoxyacetyl chloride (0.55 mL, 5.85 mmol) and then cyclized according to the general method of Example 1 Part C using N'-(tetrahydro-2H-pyran-4 ylmethyl)quinoline-3,4-diamine in lieu of N 4 -(tetrahydro-2H-pyran-4 ylmethyl)[1,5]napbthyridine-3,4-diamine and methoxyacetyl chloride in lieu of 3 20 methoxypropionyl chloride. The crude product was suspended in MTBE (20 mL), isolated by filtration, washed sequentially with MTBE and water, and then dried at 80 "C to provide 101 mg of 2-(methoxymethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)-1 H imidazo[4,5-c]quinoline as an off-white solid, mp 136-139 "C. 'H NMR (500 MHz, d 6 DMSO) 8 9.19 (s, 1H), 8.39-8.37 (m, 1H), 8.18-8.16 (m, 11), 7.75-7.71 (m, 2H), 4.80 (s, 25 2H), 4.62 (d, J= 7.5, 2H), 3.79 (dd, J= 11.7, 2.5, 2H), 3.37 (s, 3H), 3.13 (td, J= 11.7, 1.9, 2H), 2.18 (m, 1H), 1.52-1.41 (m, 4H); 1 3 C NMR (125 MHz, d 6 -DMSO) 8 154.5, 144.3, 144.1, 136.8, 136.3, 133.2, 130.3, 128.8, 128.5, 126.6, 126.5, 120.8, 117.5,66.5, 50.2, 35.7, 33.1, 29.5; Anal. called for CgIH 2

IN

3 0 2 : C, 69.43; H, 6.80; N, 13.49. Found: C, 69.21; H, 6.77; N, 13.59. -74- Example 9 [1-(Tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol N OH N N N \-O 5 [1-(Tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinolin-2-yl]methanol was prepared according to the general method of Example 3 using N4-(tetrahydro-2H pyran-4-ylmethyl)quinoline-3,4-diamine in lieu of N 4 -(tetrahydro-2H-pyran-4 ylmethyl)(1,5]naphthyridine-3,4-diamine. The crude product was purified by prep HPLC 10 (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide 1.47 g of an off-white solid. This material was suspended in cold diethyl ether (20 mL), isolated by filtration, washed with cold diethyl ether, and then dried at 80 *C to provide 1.07 g of [I1 (tetrahydro-2H-pyran-4-ylmethyl)- 1 H-imidazo[4,5-c]quinolin-2-yllmethanol as an off white solid, mp 165-169 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.16 (s, IH), 8.39-8.37 (m, 15 1H), 8.17-8.15 (m, 1H), 7.74-7.70 (m, 2H), 5.77 (t,.J= 5.7, 1H), 4.84 (d, J= 6.0, 2H), 4.66 (d, J= 7.2, 2H), 3.79 (dd, J = 5.0, 2.5, 2H), 3.14 (td, J= 12.0, 2.2, 2H), 2.19 (in, IH), 1.51-1.40 (in, 4H); ' 3 C NMR (125 MHz, d 6 -DMSO) 8 154.7, 144.7, 144.2, 136.0, 133.5, 130.3, 126.8, 126.5, 121.0, 117.6, 66.5, 56.6, 50.3, 35.6, 29.7; Anal. calcd for C 17

HI

9

N

3 0 2 : C, 68.67; H, 6.44; N, 14.13. Found: C, 68.32; H, 6.21; N, 13.86. 20 Example 10 2-Propyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-imidazo[4,5-c]quinoline N N N \-ICO A mixture of N*-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (2.20 g, 25 8.55 mmol), trimethyl orthobutyrate (1.9 mL, 10.69 mmol), pyridine hydrochloride (50 mg, 0.43 mmol), and toluene (90 mL) in a flask equipped with a Dean-Stark trap was - 75 placed in a hot (150 0C) oil bath. After 3.5 hours, analysis by LC/MS indicated that the reaction was complete. The reaction was concentrated under reduced pressure. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide an off-white solid. This material was suspended. in cold MTBE (20 5 mL), isolated by filtration, washed with cold MTBE, and then dried at 80 *C to provide 763 mg of 2-propyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-imidazo[4,5-c]quinoline as an off-white solid, mp 126-129 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.14 (s, IH), 8.34 8.33 (m, 1H), 8.15-8.13 (m, 1H), 7.71-7.66 (m, 2H), 4.54 (d, J= 7.2,2H), 3.79 (dd, J= 10.1, 2.95,22H), 3.13 (td, J= 11.7, 2.3, 21), 2.95 (t, J= 7.6,211), 2.12 (m, 11H), 1.90 10 (sextet, J= 7.6,2H), 1.53-1.45 (in, 4H), 1.04 (t, J= 7.2, 3H); 'CNMR (125 MHz, d 6 DMSO) 5 155.9,144.2,144.0,136.3, 133.0, 130.3, 126.43,126.40, 120.7,117.5,66.5, 49.9, 35.7,29.6,28.6,20.3, 13.8; Anal. called for C 1 9 H23N 3 0 * 1.0 H 2 0: C, 69.71; H, 7.70; N, 12.84. Found: C, 69.73; H, 7.64; N, 12.85. 15 Example 11 2-Methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline N N Nwoo 2-Methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline was 20 prepared according to the general method of Example 10 using triethyl orthoacetate in lieu of trimethyl orthobutyrate. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide an off-white solid. This material was recrystallized from boiling MTBE (50 mL), isolated by filtration, washed with cold MTBE, and then dried at 80 *C to provide 763 mg of 2-methyl-1-(tetrahydro 25 2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, mp 159-162 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.10 (s, IH), 8.35-8.33 (in, 1H), 8.15-8.13 (in, 1H), 7.72-7.66 (m, 2H), 4.52 (d, J= 7.6,22H), 3.80 (dd, J= 11.0, 2.5, 2H), 3.16 (td, J= 11.6, 2.5, 2H), 2.66 (s, 3H), 2.15 (m, IH), 1.53-1.45 (m, 4H); "3C NMR (125 MHz, d 6 -DMSO) 8 152.8, 143.99, 143.95, 136.2, 133.0, 130.3, 126.45, 126.42, 120.6, 117.4, 66.5, 50.4, 35.7, - 76 - 29.7, 14.2; Anal. calcd for C 17 Hj 9

N

3 0: C, 72.57; H, 6.81; N, 14.93. Found: C, 72.84; H, 6.96; N, 15.06. Example 12 5 2-(4-Ethoxybenzyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline / \ N IN N 1- O

N

4 -(Tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (2.75 g, 10.69 mmol) was reacted with 4-ethoxyphenylacetyl chloride (2. 1 mL, 11.76 mmol) and then cyclized 10 according to the general method of Example I Part C using N 4 -(tetrahydro-2H-pyran-4 ylmethyl)quinoline-3,4-diamine in lieu of N-(tetrahydro-2H-pyran-4 ylmethyl)[1,5]naphthyridine-3,4-diamine and 4-ethoxyphenylacetyl chloride in lieu of 3 methoxypropionyl chloride. The crude product was purified by prep H4PLC (silica gel eluted with a gradient of 0-30% CMA in chloroform) to provide an off-white solid. This 15 material was recrystallized from boiling MTBE (40 mL), isolated by filtration, washed with cold MTBE, and then dried at 80 *C to provide 1.30 g of 2-(4-ethoxybenzyl)-1 (tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo(4,5-c]quinoline as an off-white solid, mp 162-166 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.15 (s, IH), 8.36-8.33 (m, IH), 8.16-8.12 (m, 1H), 7.71-7.66 (in, 2H), 7.25-7.23 (d, J= 8.7, 2H), 6.90-6.85 (d, J= 8.8, 2H), 4.52 (d, 20 J= 7.3, 2H), 4.35 (s, 2H), 3.97 (q, J= 6.9, 2H), 3.77 (dd, J= 11.3, 3.2, 2H), 3.07 (td, J= 11.7, 1.6,2H), 2.05 (i, 1H), 1.52-1.43 (m, 2H), 1.42-1.32 (m, 2H), 1.29 (t, J= 6.9, 3H); 3 C NMR (125 MHz, d 6 -DMSO) 8 157.3, 154.8, 144.3, 144.1, 136.3, 133.2, 130.3, 129.8, 128.4, 126.6, 126.4, 120.8, 117.5, 114.4, 66.6, 62.9, 50.2, 35.7, 32.3, 29.5, 14.6; Anal. calcd for C 2 5

H

2 7

N

3 0 2 : C, 74.79; H, 6.78; N, 10.47. Found: C, 74.49; H, 6.65; N, 10.47. 25 -77 - Example 13 6-(Benzyloxy)-2-(ethoxymethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl) I H-imidazo[4,5-c]quinoline N N \- O 5 Part A Under a nitrogen atmosphere, a mixture of isopropylidene malonate (72 g) and triethyl orthofornate (220 mL) was heated in an oil bath at 100 "C for 3 hours. The reaction mixture was cooled to 60 *C and 2-benzyloxyaniline (114 g) was added in 10 portions. The reaction mixture was allowed to cool to ambient temperature over night and then it was diluted with diethyl ether. A solid was isolated by filtration and washed with diethyl ether to provide 129 g of 5-{[(2-benzyloxy)phenylimino]methyl}-2,2-dimethyl [1,3]-dioxane-4,6-dione. Part B 15 The material from Part A was slowly added to hot (200 "C) DOWTHERM A heat transfer fluid (600 mL). The mixture was heated at 210 "C until refluxing ceased. The reaction mixture was cooled to ambient temperature. A solid was isolated by filtration and washed with diethyl ether to provide 67 g of 8-benzyloxyquinolin-4-ol. Part C 20 Nitric acid (3.7 mL, 1.5 eq) was added to a hot (120 *C) solution of 8 benzyloxyquinolin-4-ol (10 g, I eq) in propionic acid (100 mL). The reaction mixture was heated at 120 *C for 3 hours and then allowed to cool to ambient temperature. A precipitate was isolated by filtration and washed with water (100 mL) to provide 9.7 g of 8-benzyloxy-3-nitroquinolin-4-ol. 25 Part D Phosphorous oxychloride (3.3 mL, 35.72 mmol) was added dropwise to a suspension of 8-benzyloxy-3-nitroquinolin-4-ol (7.56 g, 25.52 mmol) in DMF (250 mL). The reaction mixture was allowed to stir overnight and then it was poured into ice water (150 mL) with stirring. A solid was isolated by filtration, washed with water, and dried -78 under high vacuum at ambient temperature to provide 8.03 g of 8-benzyloxy-4-chloro-3 nitroquinoline as a yellow solid. Part E 8-Benzyloxy-4-chloro-3-nitroquinoline (8.03 g, 25.51 mmol) was reacted with 1 5 tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (4.06 mmol, 26.79 mmol) according to the general method of Example 7 Part A using 8-benzyloxy-4-chloro-3-nitroquinoline in lieu of 4-chloro-3-nitroquinoline to provide 7.88 g of 8-benzyloxy-3-nitro-N-(tetrahydro 2H-pyran-4-ylmethyl)quinolin-4-amine as a light brown solid. Part F 10 A mixture of 8-benzyloxy-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4 amine (2.00 g), 5% platinum on carbon (0.2 g), methanol (8 mL), and acetonitrile (28 mL) was placed under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to 15 provide 1.85 g of 8-benzyloxy-N 4 -(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine as a yellowish-orange oil. Part G 8-Benzyloxy-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (1.85 g, 5.09 mmol) was reacted with ethoxyacetyl chloride (0.60 mL, 5.60 mmol) and then 20 cyclized according to the general method of Example 1 Part C using 8-benzyloxy-N (tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine in lieu of N 4 -(tetrahydro-2H pyran-4-ylmethyl)[1,5]naphthyridine-3,4-diamine and ethoxyacetyl chloride in lieu of 3 methoxypropionyl chloride. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide 758 mg of 6-(benzyloxy) 25 2-(ethoxymethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- I H-imidazo[4,5 -c]quinoline as an off-white solid, mp 106-109 "C. 'H NMR.(500 MHz, d&-DMSO) 8 9.14 (s, 1H), 7.94 (d, J 8.8, IH), 7.62 (t, J= 8.2, IH), 7.57-7.56 (m, 2H), 7.43-7.40 (m, 2H), 7.36-7.33 (m, 1H), 7.31 (d, J= 7.8, 1 H), 5.33 (s, 2H), 4.82 (s, 2H), 4'.61 (d, J= 7.3, 2H), 3.80 (dd, J= 12.0, 4.4, 2H), 3.58 (q, J= 6.9, 2H), 3.11 (td, J= 11.7, 1.6, 2H), 2.2 (in, 1H), 1.52-1.43 (i, 2H), 30 1.42-1.32 (m, 2H), 1.29 (t, J= 6.9, 3H); "C NMR (125 MHz, d 6 -DMSO) 8 155.2, 151.9, 142.9, 137.2, 136.3, 135.9, 133.6, 128.4, 127.8, 127.0, 118.8, 113.0, 108.8, 70.0, 66.6, -79- 65.5, 64.3, 50.5, 35.7, 29.7, 14.9; Anal. calcd for C 26

H

29

N

3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.12; H, 6.86; N, 9.72. Example 14 5 2-(2-Methoxyethyl)-8-phenyl-1-(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline N 0 N \- O Part A 10 6-Bromo-M-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (10.53 g, 31.32 mmol) was reacted with 3-methoxypropionyl chloride (3.7 mL, 34.45 mmol) and then cyclized according to the general method of Example I Part C using 6-bromo-N4 (tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine in lieu of NM-(tetrahydro-2H pyran-4-ylmethyl)[1,5]naphthyridine-3,4-diamine. The crude product was suspended in 15 diethyl ether (20 mL), isolated by filtration, washed with diethyl ether, and then dried at 80 *C to provide 8.59 g of 8-bromo-2-(2-methoxyethyl)- I-(tetrahydro-2H-pyran-4 ylmethyl)-lH-imidazo[4,5-c]quinoline as a white solid. Part B A mixture of 8-bromo-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl) 20 IH-imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol), phenylboronic acid (0.22 g, 1.78 mmol), triphenylphosphine (12 mg, 0.044 mmol), palladium acetate (4 mg, 0.0148 mmol), I propanol (10 mL), sodium carbonate (0.19 g, 1.78 mmol), and water (2 mL) was degassed and the backfilled with nitrogen 3 times. The yellow solution was placed in a hot (100 *C) oil bath for about 18 hours. The I -propanol was removed under reduced pressure. The 25 residue was dissolved in dichloromethane (100 mL), washed with water (50 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a light yellow solid. This material was purified by prep HPLC (silica gel eluted with a - 80gradient of 0-20% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling 2-propanol (20 mL), isolated by filtration, washed with cold 2 propanol, and dried at 60 *C to provide 375 mg of 2-(2-methoxyethyl)-8-phenyl- 1 (tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, mp 5 204-208 0 C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.15 (s, 1H), 8.44 (d,J= 1.9, 1H), 8.23 (d, J= 8.9, 1H), 8.00 (dd, J= 8.8, 1.9, 1H), 7.84-7.83 (m, 2H), 7.56-7.53 (in, 21), 7.45-7.42 (m, 1fH), 4.66 (d, J= 6.9, 2H), 3.92 (t, J= 6.6, 2H), 3.83 (dd, J= 11.1, 2.5, 2H), 3.30 (s, 3H), 3.26 (t, J= 6.6, 2H), 3.19 (td, J= 11.7, 1.9, 2H), 2.28 (m, 1 H), 1.58-1.54 (m, 4H); 1 3 C NMR (125 MHz, d 6 -DMSO) 8 153.8, 144.3, 143.3, 140.0, 138.0, 136.6, 133.0, 130.9, 10 129.1, 127.8, 127.2, 125.7, 118.5, 117.7, 69.7, 66.4, 58.1, 50.1, 35.8, 29.9,27.4,25.5; Anal. calcd for C 2 sH 2 7

N

3 02 - 0.25 H 2 0: C, 73.94; H, 6.83; N, 10.35. Found: C, 73.98; H, 6.76; N, 10.10. Example 15 15 8-( 3 -Chlorophenyl)-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline :"I >-'O N 1- O Ci 8 -Bromo-2-(2-methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- I H 20 imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 3 -chlorophenylboronic acid (0.28 g, 1.78 mmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling propyl acetate (10 mL), isolated by filtration, washed with cold propyl acetate, and 25 dried at 60 *C to provide 75 mg of 8-( 3 -chlorophenyl)-2-(2-methoxyethyl)-1-(tetrahydro 2 H-pyran- 4 -ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, mp 161-164 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.17 (s, 1H), 8.44 (d, J= 1.6, IH), 8.23 (d, J= 8.9, 1H), - 81 -.

8.02 (dd,J= 8.8, 1.0, 1H), 7.87 (s, 1H), 7.82 (dd, J= 7.6, 0.9, 1H), 7.58 (tJ= 7.9, 1H), 7.50 (d, J= 8.2, 1H), 4.66 (d, J=5.1, 2H), 3.91 (t, J= 6.6,2H), 3.85 (d, J= 10.7, 2H), 3.30 (m, 3H), 3.27-3.21 (m, 4H), 2.29 (m, IH), 1.58-1.51 (m, 4H); 1 3 C NMR (125 MHz, d 6 -DMSO) 8 153.9, 144.6, 143.5, 142.1, 136.7, 136.4, 133.9, 133.1, 130.9, 127.6, 127.1, 5 125.9, 125.5, 119.1, 117.6, 69.7, 66.4, 58.1, 50.0, 35.7, 29.9, 27.4; Anal. calcd for

C

2 sH2 6

N

3 0 2 Cl: C, 68.88; H, 6.01; N, 9.64. Found: C, 68.80; H, 5.84; N, 9.41. Example 16 {3-[2-(2-Methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl) 10 1 H-imidazo[4,5-c]quinolin-8-yl]phenylmethanol N N 0 N 1- O HO, 8 -Bromo-2-(2--methoxyethyl)-1I-(tetrahydro-2H-pyran-4-ylmethyl)-I1H imidazo[4,5-clquinoline (0.60 g, 1.48 mmol) was coupled with 3 15 (hydroxymethyl)phenylboronic acid (0.27 g, 1.78 mmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 5-30% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling acetonitri-le (20 mL), isolated by filtration, washed with cold acetonitrile, and dried at 60 "C to provide 344 mg of {3-[2-(2-methoxyethyl)-1.. 20 (tetrahydro-2H-pyran-4-ylmethyl)- IH-imidazo[4,5-c]quinolin-8-yl]phenyl) methanol as an off-white solid, mp 171-173 *C. 'H NMR (500 MHz, de-DMSO) 8 9.15 (s, 1H), 8.42 (d, J =1.6, 1 H), 8.23 (d, J= 8.5, 1H), 8.00 (dd, J= 8.8, 1.9, IH), 7.77 (s, 1H), 7.70 (dd, J= 7.6, 0. 9, 1 H), 7.49 (t, J = 7.6, 1 H), 7.3 7 (d, J = 7.6, 1H-), 5.26 (t, J= 5.7, 1 H), 4.62 (d, J =6.3, 211), 4.60 (d, J = 5.7, 2H), 3.91 (t, J = 6.6, 2 H), 3.84 (d, J-= 11. 3, 2 H), 3.3 0 (m, 3 H), 3.27 25 3.19 (m, 4H), 2.29 (m, 1H), 1.56-1.52 (m, 4H); 13C NMR.(125 MHz, d6-DMSO) 8 153.8, 144.3, 143.5, 1 43.3, 139.7, 138.1, 136.6, 133.0, 130.9, 128.9, 125.9, 125.6, 125.5, 125.2, -82- 118.4, 117.7, 69.7,66.5, 62.8, 58.1, 50.1, 35.8, 29.8, 27.4; Anal. called for C 2 6

H

29

N

3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.57; H, 6.61; N, 9.68. Example 17 5 2-(2-Methoxyethyl)-8-(2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline N N ZN' 8-Bromo-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H 10 imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 2-methoxyphenylboronic acid (0.27 g, 1.78 nmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 5-30% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling hexanes/ethyl acetate (20 mL), isolated by filtration, washed with cold hexanes, 15 and dried at 60 *C to provide 362 mg of 2-(2-methoxyethyl)-8-(2-methoxyphenyl)- I (tetrahydro-2H-pyran4-ylmethyl)-IH-imidazo[4,5-clquinoline as an off-white solid, mp 165-168 *C. 'H NMR (500 MHz, d 6 -DMSO) 6 9.14 (s, I H), 8.37 (d, J= 1.9, 1H), 8.15 (d, J= 8.8, 1fH), 7.81 (dd, J= 8.6, 1.5, 1fH), 7.46 (dd, J= 7.5, 1.6, 1 H), 7.47 (td, J= 8.5, 1.6, 1H), 7.20 (d, J= 8.2, 1 H), 7.09 (t, J = 7.2, 1H), 4.55 (d, J= 7.3, 2H), 3.91 (t, J= 6.7, 2H), 20 3.83-3.81 (m, 5H), 3.30 (in, 3H), 3.25-3.19 (m, 4H), 2.29 (m, 1H), 1.56-1.32 (m, 4H); 13C NMR (125 MHz, d 6 -DMSO) 5 156.3, 153.6, 144.1,143.0,136.4,136.0, 133.0, 130.8, 129.7, 129.4, 129.3, 128.3, 121.0, 120.9,117.2,112.0,69.7,66.4,58.1, 55.8,50.1,35.7, 29.7, 27.3; Anal. called for C 26

H

29

N

3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.14; H, 6.63; N, 9.54. 25 - 83 - Example 18 2-(2-Methoxyethyl)-S-(2-methylphenyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl) I H-imidazo[4,5-c]quinoline N N N 5 8-Bromo-2-(2-methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1IH imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 2-methylphenylboronic acid (0.24 g, 1.78 mmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% 10 CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling hexanes/ethyl acetate (20 mL), isolated by filtration, washed with cold hexanes, and dried at 60 *C to provide 408 mg of 2

-(

2 -methoxyethyl)-8-(2-methylphenyl)-1 (tetrahydro-2H-pyran-4-ylmethyl)- IH-imidazo[4,5-c]quinoline as an off-white solid, mp 180-183 *C. 'H NMR (500 MHz, d 6 -DMSO) 5 9.17 (s, 1H), 8.17 (d, J= 8.5, 1H), 8.15 (d, 15 J= 1.9, 1H), 7.70 (dd, J= 8.5, 1.6, 1H), 7.38-7.30 (m, 4H), 4.55 (d, J= 7.3, 2H), 3.90 (t, J - 7.0, 2H), 3.81 (dd, J = 11.4, 3.2, 2H), 3.29 (m, 3H), 3.24 (t, J= 6.6, 2H), 3.16 (t, J= 10.4, 2H), 2.35 (s, 3H), 2.21 (m, 1H), 1.47 (qd, J= 12.0, 4.4, 2H), 1.35-1.33 (m, 2H); ' 3 C NMR (125 MHz, d 6 -DMSO) 8 153.8, 144.3, 142.9, 141.0, 139.2, 136.6, 134.9, 132.9, 130.5,129.99, 129.95, 128.1, 127.7, -126.1, 120.7, 117.3, 69.7, 66.4,58.1, 50.0,35.6,29.7, 20 27.4, 20.2; Anal. calcd for C 2 6

H

2 9

N

3 0 2 : C, 75.15; H, 7.03; N, 10.11. Found: C, 74.84; H, 6.98; N, 10.08. Example 19 2

-(

2 -Methoxyethyl)-8-(3-methylphenyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl) 25 1H-imidazo[4,5-c]quinoline -84- N - N>JO N 8-Bromo-2-(2-methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 3-methylphenylboronic acid (0.24 g, 1.78 mmol) according to the general method of Example 14 Part B. The 5 crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling hexanes/ethyl acetate (20 mL), isolated by filtration, washed with cold hexanes, and dried at 60 *C to provide 410 mg of 2-(2-methoxyethyl)-8-(3-methylphenyl)-1 (tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline as an off-white solid, mp 10 138-141 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.14 (s, 1H), 8.41 (d, J= 1.9, 1H), 8.21 (d, J= 8.5, 1H), 7.99 (dd, J= 8.8, 1.9, 11), 7.63-7.61 (m, 2H), 7.42 (t, J = 7.5, 1H), 7.25 (d, J = 7.2, 111), 4.62 (d, J= 6.0, 2H), 3.91 (t, J= 7.0, 2H), 3.85 (d, J= 10.7, 2H), 3.30 (m, 3H), 3.27-3.21 (m, 4H), 2.40 (s, 3H), 2.21 (m, 1H), 1.57-1.52 (m, 4H); ' 3 C NMR (125 MHz, d 6 DMSO) 8 153.8, 144.2, 143.3, 139.9, 138.3, 138.1, 136.6, 133.0, 130.8, 129.0, 128.4, 15 128.0, 125.6, 124.3, 118.5, 117.6, 69.7, 66.4, 58.1, 50.1, 35.7, 29.8, 27.4, 21.1; Anal. calcd for C 26 H29N 3 0 2 : C, 75.15; H, 7.03; N, 10.11. Found: C, 75.25; H, 6.92; N, 10.00. Example 20 2-(2-Methoxyethyl)-8-(4-methylphenyl)-I -(tetrahydro-2H-pyran-4-ylmethyl) 20 1H-imidazo[4,5-c]quinoline N- N N \-CO - 85 - 8-Bromo-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- I H imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 4-methylphenylboronic acid (0.24 g, 1.78 mmol) according to the general method of Example 14 Part B. The 5 crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling hexanes/ethyl acetate (20 mL), isolated by filtration, washed with cold hexanes, and dried at 60 *C.to provide 410 mg of 2

-(

2 -methoxyethyl)-8-(3 -methylphenyl)-1 (tetrahydro-2H-pyran-4-ylmethyl)-H-imidazo[4,5-c]quinoline as an off-white solid, mp 10 150-153 0 C. 'HNMR(500MIHzd 6 -DMSO)&9.13 (s, 1H), 8.40(d,J= 1.9, IH), 8.20(d, J= 8.8, 1H), 7.97 (dd, J= 8.5, 1.9, 1H), 7.72 (d, J= 7.9, 2H), 7.35 (d, J= 7.9, 2H), 4.64 (d, J=6.4, 2H), 3.91 (t, J= 6.9, 2H), 3.83 (d, J= 12.0, 2H), 3.27 (s, 3H), 3.25 (t, J= 7.0, 2H), 3.19 (t,J= 11.6, 2H), 2.38 (s, 3H), 2.26 (m, 1H), 1.54 (qd, J= 12.9,4.4,22H), 1.47 (m, 2H); 1 3 C NMR (125 MHz, d-DMSO) 8 153.7, 144.1, 143.2, 137.9, 137.3, 137.1, 15 136.6, 133.0, 130.8, 129.7,127.0,125.5,118.0,117.7,69.7,66.4,58.1, 50.1, 35.8, 29 .9, 27.4,20.7; Anal. calcd for C 2 6

H

2 9

N

3 0 2 : C, 75.15; Rl, 7.03; N, 10.11. Found: C, 75.02; H, 6.92; N, 10.03. Example 21 20 3-[2-(2-Methoxyethyl)-I -(tetrahydro-2H-pyran-4-ylmethyl) I H-imidazo[4,5-c]quinolin-8-yl]phenol N N N HOf 8 -Bromo-2-(2-methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H 25 imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 3-hydroxyphenylboronic acid (0.25 g, 1.78 mmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-30% -86- CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling ethanol (20 mL), isolated by filtration, washed with cold ethanol, and dried at 60 *C to provide 150 mg of 3-[2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran4-ylmethyl)- I H imidazo[4,5-c]quinolin-8-yl]phenoI as an off-white solid, mp 256-259 *C. 'H NMR (500 5 MHz, d 6 -DMSO) 8 9.61 (s, 1 H), 9.14 (s, IH), 8.38 (d, J= 1.6, 1H), 8.20 (d, J= 8.5, 1H), 7.92 (dd, J= 8.5, 1.9, 1H), 7.32 (t, J= 7.8, 1H% 7.23 (d, J= 7.9, 1H), 7.18 (t, J= 2.2, 1 H), 6.83 (dd, J= 7.9, 1.5, 1H), 4.62 (d, J = 7.0, 2fH), 3.91 (t, J= 6.6, 2H), 3.83 (d, J= 10.8, 2H), 3.30 (m, 3H), 3.25 (t, J= 6.7, 2H), 3.20 (t, J= 11.3, 2H), 2.25 (m, 1 H), 1.54 (qd, J= 12.9, 3.5, 2H), 1.53-1.49 (m, 2H); '3C NMR (125 MHz, d 6 -DMSO) 8 158.0, 153.8, 144.2, 10 143.3, 141.4,138.1, 136.6, 133.0, 130.8, 130.1, 125.6, 118.3, 117.9,117.6,114.8,114.1, 69.7, 66.4, 58.1, 50.1, 35.8, 29.8, 27.4; Anal. calcd for C 2 sH 27

N

3 0 3 - 0.25 H20: C, 71.16; H, 6.57; N, 9.96. Found: C, 71.42; H, 6.32; N, 9.90. Example 22 15 8

-(

3

,

4 -Dichlorophenyl)-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline N: O N CI C1 8 -Bromo-2-(2-methoxyethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl)- I H 20 imidazo[4,5-c]quinoline (0.60 g, 1.48 mmol) was coupled with 3

,

4 -dichlorophenylboronic acid (0.25 g, 1.78 mmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling acetonitrile (20 mL), isolated by filtration, washed with cold acetonitrile, and dried 25 at 60 0C to provide 357 mg of 8-( 3

,

4 -dichlorophenyl)-2-(2-methoxyethyl)- I -(tetrahydro 2 H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, mp 192-195 *C. - 87 - 'H NMR (500 MHz, d 6 -DMSO) 8 9.17(s, IH), 8.43 (d, J= 1.8, 1H), 8.23 (d, J=8.8, 1H), 8.08 (d, J= 2.2, IH), 8.02 (dd, J=8.5, 1.9, IH), 7.86 (dd, J= 8.2, 2.2, IH), 7.80 (d, J= 8.5, IH), 4.66 (d, J= 5.4, 2H), 3.91 (t, J= 6.6, 2H), 3.83 (d, J= 11.0, 2H), 3.30 (m, 3H), 3.27-3.20 (m, 4H), 2.27 (m, IH), 1.58-1.50 (m, 4H); 3 C NMR (125 MHz, d-DMSO) 8 5 154.0, 144.7, 143.6, 140.6, 136.7, 135.3, 133.0, 131.9, 131.1, 131.0, 130.6, 129.2, 127.3, 125.4, 119.2, 117.5, 69.7, 66.4, 58.1, 50.0, 35.6, 29.9, 27.4; Anal. calcd for

C

2 sH 2 5

N

3 0 2

C

2 : C, 63.83; H, 5.36; N, 8.93. Found: C, 63.63; H, 5.07; N, 8.92. Example 23 10 8-(4-Fluorophenyl)-2-(2-methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline N N O N \-!WO F 8-Bromo-2-(2-methoxyethyl)--1-(tetrahydro-2H-pyran-4-ylmethyl)-

IH

15 imidazo(4,5-c]quinoline (0.60 g, 1.48 nimol) was coupled with 4-fluorophenylboronic acid (0.25 g, 1.78 mmol) according to the general method of Example 14 Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide a light yellow solid. This material was recrystallized from boiling hexanes/ethyl acetate (20 mL), isolated by filtration, washed with cold hexanes, and dried 20 at 60 "C to provide 267 mg of 8-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(tetrahydro-2H pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, mp 181-184 *C. 'H NMR (500 MHz, d 6 -DMSO) 8 9.15 (s, 1H), 8.40 (d, J= 1.9, 1H), 8.21 (d, J= 8.9, 1H), 7.98 (dd, J= 8.8, 1.9, IH), 7.90-7.87 (m, 2H), 7.40-7.36 (m, 2H), 4.65 (d, J= 6.7, 2H), 3.91 (t, J= 6.9,22H), 3.82 (d, J= 11.3, 1.9, 2H), 3.30 (s, 3H), 3.26 (t, J= 6.7, 2H), 3.18 (td, 25 J= 11.4,2.2,211), 2.24 (m, IH), 1.56-1.44 (m, 4H); "C NMR (125 MHz, d 6 -DMSO) S 163.1, 161.1, 153.9, 144.3, 143.2,136.7 (d, J= 36.4), 136.4 (d, J= 3.9), 133.0, 130.9, -88- 129.23, 129.16, 125.6, 118.4, 117.6, 115.9 (d, J= 22.1), 69.7, 66.4, 58.1, 50.0, 35.7, 29.9, 27.4; Anal. calcd for C 2 sH 26

N

3 0 2 F: C, 71.58; H, 6.25; N, 10.02. Found: C, 71.51; H, 5.98; N, 9.91. 5 Example 24 2-(Cyclopropylmethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline N N 10 , N-(Tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (2.23 g, 8.67 mmol) was reacted with cyclopropylacetyl chloride (1.1 mL, 9.54 mmol) and then cyclized according to the general method of Example I Part C using N4-(tetrahydro-2H-pyran-4 ylmethyl)quinoline-3,4-diamine in lieu of N4-(tetrahydro-2H-pyran-4 ylmethyl)[1,5]naphthyridine-3,4-diamine and cyclopropylacetyl chloride in lieu of 3 15 methoxypropionyl chloride. The crude product was suspended in MTBE (20 mL), isolated by filtration, and washed sequentially with MTBE and water. The resulting solid was recrystallized from boiling hexanes/ethyl acetate (20 mL), isolated by filtration, washed with cold hexanes, and dried at 80 *C to provide 572 mg of 2 (cyclopropylmethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)- IH-imidazo[4,5-clquinoline as 20 an off-white solid, mp 190-193 *C. 'H NMR (500 MHz, d 6 -DMSO) 5 9.16 (s, IH), 835 8.33 (m, 1H), 8.15-8.13 (m, 1H), 7.72-7.67 (m, 211), 4.53 (d, J= 7.3, 2H), 3.79 (dd, J= 11.1, 3.1, 2H), 3.13 (td, J= 11.7, 1.9, 2H), 2.95 (d, J= 6.6, 2H), 2.12 (m, IH), 1.48 (qd, J = 12.6, 4.1, 2H), 1.43-1.35 (m, 2H), 1.34-1.27 (m, 1H), 0.58-0.54 (m, 2H), 0.32-0.29 (m, 2H); 1 3 C NMR (125 M71z, d 6 -DMSO) 8 155.7, 144.3, 144.0, 136.4, 133.0, 130.3, 126.46, 25 124.40, 120.7, 117.5, 66.5, 50.0, 35.7, 31.4, 29.5, 9.2, 4.7; Anal. calcd for C2oH23N30: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.51; H, 7.48; N, 13.11. Example 25 2-Methyl-N-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-c]quinolin-1-amine -89- N N.N N Part A Glacial acetic acid (2 mL) was added to a suspension of 2-methyl-1H-imidazo[4,5 c]quinolin-1-amine (2.00 g, 10.1 mniol) in acetonitrile (20 mL) and a solution was 5 obtained. Tetrahydro-4H-pyran-4-one (1.86 mL, 20.2 mmol) was added. The reaction mixture was placed under a nitrogen atmosphere and heated to 110 0C. The progress of the reaction was monitored by HPLO. After 3 days the reaction mixture was cooled to ambient temperature, neutralized with 5% sodium carbonate solution (10 mL), and then concentrated under reduced pressure. The residue was partitioned between chloroform (40 10 mL) and water (10 mL). The organic layer was washed sequentially with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 2.82 g of 2 -methyl-N-(tetrahydro-4H-pyran-4-ylidene)-1H imidazo[4,5-c]quinolin-1-amine as a tan solid. Part B 15 A solution of the material from Part A (2.82 g, 10.1 mmol) in methanol (40 mL) was chilled in an ice bath. Sodium borohydride (0.764 g, 20.2 mmol) was added in portions over a period of 5 minutes. The reaction mixture was allowed to warm to ambient temperature over a period of 1.5 hours. The reaction mixture was quenched by slowly adding saturated ammonium chloride solution (5 mL) and then concentrated under 20 reduced pressure. The residue was partitioned between chloroform (75 mL) and 10% sodium carbonate solution (20 mL). The organic layer was washed sequentially with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a tan foam. This material was recrystallized twice from acetonitrile to provide 308 mg of 2-methyl-N-(tetrahydro-2H 25 pyran- 4 -yl)-lH-imidazo[4,5-c]quinolin-1-amine as tan crystals, mp 209-211 *C; 'H NMR (300 MHz, DMSO-d 6 ) 6 9.07 (s, 1 H), 8.90-8.87 (m, 1 H), 8.12-8.07 (m, 1 H), 7.70-7.65 (m, 2 H), 7.28 (d, J= 2.2 Hz, I H), 3.83-3.79 (m, 2 H), 3.52-3.42 (m, I H), 3.29-3.20 (m, 2 H), 2.68 (s, 3 H), 1.66-1.42 (m, 4 H); 3 C NMR (75 MHz, DMSO-d) 8 152.5, 143.3, 132.7, 132.5, 129.0, 126.2, 125.2, 120.7, 116.5, 64.5, 55.4, 30.2, 12.6; MS (APCI) m/z -90- 283.04 (M + H)*; Anal. Called for C 16

HISN

4 0: C, 68.06; H, 6.43; N, 19.84; Found: C, 67.85; H, 6.44; N, 20.12. Example 26 5 2 -(Ethoxymethyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-1-amine N N 0 N HO 2 -(Ethoxymethyl)-N-(tetrahydro-2H-pyran-4-y)-1H-imidazo[4,5-c]quinolin-1.

amine was prepared according to the general method of Example 25 using 2 10 (ethoxymethyl)-IH-imidazo[4,5-c]quinolin-1-amine in lieu of 2-methyl-IH-imidazo[4,5 c]quinolin-I-amine. The crude product was recrystallized from acetonitrile to provide 415 mg of 2 -(ethoxymethyl)-N-(tetrahydro-2H-pyran-4-yI)-1H-imidazo[4,5-c]quinolin-1 amine as white crystals, mp 113-116 *C; 'H NMR (300 MJ-lz, DMSO-d) 8 9.17 (s, I H), 8.97-8.94 (m, 1 H), 8.15-8.12 (m, 1 H), 7.73-7.70 (m, 2 H), 7.30 (d, J= 2.2 Hz, I H), 4.85 15 (s, 2 H), 3.85-3.81 (m, 2 H), 3.68-3.59 (m, I H), 3.67 (q, J- 7.0 Hz, 2 H), 3.25-3.17 (m, 2 H), 1.68-1.42 (m, 4 H), 1.18 (t, J= 7.0 Hz, 3 H); DC NMR (75 MHz, DMSO-d 6 ) 5 152.5, 145.1, 144.6, 133.7, 133.5, 130.1, 127.6, 126.4, 121.9, 117.7, 65.9, 65.6, 63.2, 57.0, 31.1, 15.4; MS (ESI) m/z 327.28 (M + H); Anal. Calcd for CjsH22N 4 0 2 : C, 66.24; H, 6.79; N, 17.16; Found: C, 65.92; H, 6.90; N, 17.19. 20 Example 27 2-(Ethoxymethyl)-1-[( 2 S)-tetrahydrofuran-2-ylmethyl]- IH-imidazo[4,5-c]quinoline N N 0 -N -91- Part A Under a nitrogen atmosphere, triethylamine (2.51 mL, 18.0 mmol) was added to a suspension of 4-chloro-3-nitroquinoline (1.87 g, 8.99 mmol) in dichloromethane (30 mL). The resulting solution was chilled in an ice bath and then (S)-(+)-tetrahydrofurfurylamine 5 (1.02 mL, 9.89 mmol) was added. The reaction was allowed to slowly warm to ambient temperature overnight. The reaction mixture was partitioned between chloroform (30 mL) and water (20 mL). The organic layer was washed sequentially with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 2.36 g of 3 -nitro-N-[( 2 S)-tetrahydrofuran-2-ylmethyl]quinolin-4-amine 10 as a- yellow/orange solid. Part B Platinum on carbon (0.24 g of 5%) was added to a solution of the material from Part A in acetonitrile (100 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4 X 105 Pa) for 4 hours. The reaction mixture was filtered through a layer of CELITE 15 filter agent. The filter cake was rinsed with acetonitrile until the filtrate was clear. The filtrate was concentrated under reduced pressure to provide 2.08 g of N4-[(2S) tetrahydrofuran-2-ylmethyl]quinoline-3,4-diamine as an orange oil. Part C Triethylamine (2.38 mL, 17.1 mmol) was added to a solution of the material from 20 Part B (2.08 g, 8.55 mmol) in dichloromethane (45 mL). The solution was placed under a nitrogen atmosphere and chilled in an ice water bath. Ethoxyacetyl chloride (1.10 g, 8.98 mmol) was added dropwise over a period of 2 minutes. The reaction mixture was allowed to slowly warm to ambient temperature. After 1.5 hours additional ethoxyacetyl chloride (0.50 nL) was added. The reaction was stirred for 30 minutes and then concentrated 25 under reduced pressure to provide the intermediate amide as an orange oil. The oil was dissolved in ethanol (50 mL). Triethylamine (3.58 mL, 25.7 mmol) and concentrated hydrochloric acid (2 drops) were added and the reaction mixture was heated at 100 *C for 3 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was dissolved in chloroform (60 mL). The organic 30 solution was washed sequentially with 10% sodium carbonate solution (20 mL), water (20 mL), and brine (20 nL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an orange oil. The oil was purified by prep HPLC (silica gel -92eluted with a gradient of 1-20% CMA in chloroform) to provide an orange oil. The oil was triturated with MTBE (about 40 mL) initially at ambient temperature and then in an ice water bath for 1 hour. A solid was isolated by filtration and dried under vacuum at 50 *C overnight to provide 2.10 g of 2-(ethoxymethyl)-1-[(2S)-tetrahydrofuran-2-ylmethyl] 5 1H-imidazo[4,5-c]quinoline as a white solid, mp 92-94 "C; 'H NMR (500 MHz, DMSO d) 8 9.18 (s, I H), 8.45-8.43 (m, 1 H), 8.17-8.15 (m, 1 H), 7.73-7.68 (m, 2 H), 4.94-4.90 (in, 2 H), 4.79-4.72 (m, 2 H), 4.33-4.27 (m, I H), 3.80-3.76 (m, I H), 3.61-3.55 (m, 3 H), 2 .18-2.12 (m, I H), 1.97-1.90 (m, I H), 1.88-1.74 (m, 2 H), 1.17 (t, J= 7.0 Hz, 3 H); ' 3 C NMR (125 Mz, DMSO-d 6 ) 8 152.3, 145.1, 144.7, 136.2, 134.2, 130.6, 127.3, 126.7, 10 121.7, 118.1, 77.9,67.9,65.9,64.9,49.9,29.0,25.7, 15.3; MS (APCI) m/z 312.18 (M + H); Anal. Calcd for C 1 sH 2 1

N

3 0 2 : C, 69.43; H, 6.80; N, 13.49; Found: C, 69.39; H, 6.87; N, 13.62. Example 28 15' 2-(Ethoxymethyl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-imidazo[4,5-c]quinoline N O N 2-(Ethoxymethyl)-I-[(2R)-tetrahydrofuran-2-ylmethyl]-IH-imidazo[4,5 c]quinoline was prepared according to the general methods of Example 27 using (R)-(-) 20 tetrahydrofurfurylamine in lieu of (S)-(+)-tetrahydrofurfurylamine. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-20% CMA in chloroform) to provide an orange oil. The oil was crystallized twice from MTBE to provide 2 (ethoxymethyl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-l H-imidazo[4,5-c]quinoline as white crystals, mp 89- 92"C; 'H NMR (300 MHz, DMSO-d) 8 9.18 (s, 1 H), 8.46-8.43 (in, I 25 H), 8.18-8.15 (in, 1 H), 7.75-7.67 (m, 2 H), 4.95-4.89 (m, 2 H), 4.80-4.70 (m, 2 H), 4.34 4.26 (in, 1 H), 3.82-3.75 (m, 1 H), 3.62-3.55 (m, 3 H), 2.21-2.10 (m, 1 H), 1.98-1.72 (in, 3 H), 1.17 (t, J= 7.0 Hz, 3 H); 3 C NMR (75 MHz, DMSO-d 6 ) 8 152.2, 145.1, 144.7, 136.2, 134.2, 130.6, 127.3, 126.7, 121.7, 118.1, 77.8, 67.9, 65.9, 64.9, 49.9, 29.0, 25.7, 15.3; MS -93- (APCI) m/z 312.19 (M + H)*; Anal. Called for CisH 2

:N

3 0 2 : C, 69.43; H, 6.80; N, 13.49; Found: C, 69.31; H, 6.98; N, 13.68. Example 29 5 2-(Ethoxymethyl)- 1 -[(2S)-tetrahydrofuran-2-ylmethyl] 6,7,8,9-tetrahydro- I H-imidazo[4,5-c]quinoline hydrochloride N - N 0 N H-Cl Platinum (IV) oxide (0.430 g, 1.89 mmol) was added to a solution of 2 10 (ethoxymethyl)-I-[(2S)-tetrahydrofuran-2-ylmethyl]- H-imidazo[4,5-c]quinoline (0.590 g, 1.89 mmol) in trifluoroacetic acid (25 mL). The mixture was placed under hydrogen. pressure (50 psi, 3.4 x 105 Pa) on a Parr apparatus for 24 hours. The reaction mixture was diluted with chloroform (20 mL) and methanol (5 mL) and filtered through a layer of CELITE filter agent. The filter cake was rinsed with additional solvent and the filtrate 15 was concentrated under reduced pressure to provide a clear colorless oil. The oil was suspended in water (15 mL), the pH of the mixture was adjusted to 13 by the dropwise addition of 10% sodium hydroxide, and then it was extracted with dichloromethane (4 x 15 mL). The combined extracts were washed with brine (15 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a clear colorless 20 oil. The oil was purified by prep HPLC (silica gel eluted with a gradient of 5-20% CMA in chloroform) to provide a clear colorless oil. The oil was combined with diethyl ether (15 mL) and a solution of hydrochloric acid in ethanol was added dropwise until a precipitate formed. The solid was triturated and chilled in an ice water bath for 30 minutes. The solid was isolated by filtration and dried overnight in a vacuum desiccator to 25 provide 108 mg of 2-(ethoxymethyl)- I -[(2S)-tetrahydrofuran-2-ylmethyl]-6,7,8,9 tetrahydro-1H-imidazo[4,5-c]quinoline hydrochloride as a white solid, mp 156-159 *C; 'H NMR (300 MHz, D20) 8 8.83 (s, 1 H), 4.98-4.83 (m, 2 H), 4.64 (d, J= 2.4 Hz, 1 H), 4.54 4.45 (m, I H), 4.31-4.22 (m, I H), 3.89-3.82 (m, 1 H), 3.74-3.62 (m, 3 H), 3.35-3.28 (m, 1 H), 3.13-3.08 (in, 3 H), 2.24-2.14 (m, I H), 2.04-1.85 (m, 6 H), 1.78-1.66 (in, 1 H), 1.18 (t, -94- J= 7.1 Hz, 3 H); 1 3 C NMR (75 MHz, D20) 8 159.6, 145.0, 144.8, 137.1, 131.4, 121.9, 79.1, 69.1, 67.7, 64.6, 50.4, 28.9,27.7, 25.8, 24.2, 21.1, 20.6, 14.4; MS (APCI) m/z 316.18 (M + H)+; Anal. Calcd for Cl&H 2 6

CN

3 0 2 '0.5H 2 0: C, 59.91; H, 7.54; N, 11.64; Found: C, 59.52; H, 7.57; N, 11.52. 5 Example 30 2-(Ethoxymethyl)-1-[( 2 R)-tetrahydrofuran-2-ylmethyl] 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline hydrochloride N- N

O

N H-CI 10 2-(Ethoxymethyl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinoline hydrochloride was prepared and purified according to the methods of Example 29 using 2-(etboxymethyl)- 1 -[( 2 R)-tetrahydrofuran-2-ylmethyl]- 1 H imidazo[ 4 ,S-c]quinoline in lieu of 2-(ethoxymethyl)-1-[(2S)-tetrahydrofuran-2-ylmethyl] 15 1H-imidazo[4,5-c]quinoline. The product was provided as a white solid, mp 153-155 "C; 'H NMAR (300 MHz, D 2 0) 8 8.83 (s, I H), 4.90 (q, J= 16.5 Hz, 2 H), 4.64 (d, J= 13.3 Hz, 1 H), 4.49 (dd, J= 15.6, 9.8 Hz, I H), 4.31-4.22 (m, 1 H), 3.89-3.81 (m, 1 H), 3.73-3.62 (in, 3 H), 3.35-3.28 (m, 1 H), 3.14-3.07 (m, 3 H), 2.24-2.13 (m, I H),.2.02-1.85 (m, 6 H), 1.78-1.67 (m, 1 H), 1.18 (t, J= 7.0 Hz, 3 H); 3 C NMR (75 MHz, D 2 O) S 159.6, 145.0, 20 144.8, 137.0, 131.4, 121.9, 79.1, 69.1, 67.7, 64.6, 50.4, 28.9, 27.7, 25.8, 24.2, 21.1, 14.4; MS (APCI) m/z 316.19 (M + H)+; Anal. Calcd for CisH2 6 ClN 3 02-0.7H 2 0: C, 59.32; H, 7.58; N, 11.53; Found: C, 59.17; H, 7.80; N, 11.46. Example 31 25 1-Cyclohexylmethyl-2-(2-methoxyethyl)-IH-imidazo[4,5 -c]quinoline - 95 - N- N O N I-Cyclohexylmethyl-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline was prepared according to the general methods of Example 27 using cyclohexanemethylamine 5 in lieu of (S)-(+)-tetrahydrofurfurylamine in Part A and 3-methoxypropionyl chloride in - lieu of ethoxyacetyl chloride in Part C. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-12% CMA in chloroform) to provide a yellow solid. The solid was recrystallized twice from acetonitrile and dried in a vacuum oven at 80 *C to provide 1-cyclohexylmethyl-2-(2-methoxyethyl)-1 H-imidazo[4,5-c]quinoline as white 10 crystals, mp 129-131 *C; 'H NMR (300 MHz, DMSO-d) 8 9.15 (s, I H), 8.32-8.29 (m, 1 H), 8.17-8.14 (m, 1 1-1), 7.74-7.66 (m, 2 H), 4.49 (d, J= 7.4 Hz, 2 H), 3.90 (t, J= 6.8 Hz, 2 H), 3.31 (s, 3 H), 3.23 (t, J= 6.7 Hz, 2 H), 1.92-1.80 (m, I H), 1.67-1.54 (m, 5 H), 1.26 0.99 (m, 5 H); "C NMR (75 MHz, DMSO-d 6 )8 154.0, 144.6, 144.4, 136.6, 133.3, 130.7, 126.9, 126.8, 121.0, 117.9, 70.1, 58.5, 51.0, 38.6, 30.0, 27.8, 26.1, 25.7; MS (ESI) m/z 15 324.23 (M + H)*; Anal. Calcd for C 20

H

2 5 NIO: C, 74.27; H, 7.79; N, 12.99; Found: C, 74.08; H, 7.82; N, 12.77. Example 32 2-(2-Methoxyethyl)-I-(tetrahydro-2H-pyran-2-ylmethyl)-IH-imidazo[4,5-c]quinoline N N 0 N 20 Part A Under a nitrogen atmosphere, sodium azide (2.18 g, 33.5 mmol) was added to a solution of 2 -(bromomethyl)tetrahydro-2H-pyran (5.00 g, 27.9 mmol) in DMF. The 25 mixture was heated to 50 *C. After 24 hours additional sodium azide (1.5 g) was added. -96- After a total of 3 days the reaction mixture was cooled to ambient temperature, diluted with diethyl ether (90 mL), and filtered. The organic portion was washed sequentially with water (2 x 30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 3.88 g of 2-(azidomethyl)tetrahydro 5 2H-pyran as a yellow oil. Part B Palladium on carbon (0.39 g of 10%) was added to a solution of the material from Part A in ethanol (30 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4 X 105 Pa) on a Parr apparatus for 15 hours. The reaction mixture was filtered through a 10 layer of CELITE filter agent. The filter cake was rinsed with 1:1 methanol:ethanol. The filtrate was concentrated without heating to provide 2.41 g of 1 -tetrahydro-2H-pyran-2 ylmethylamine as a clear pale oil. Part C 2-(2-Methoxyethyl)-1 -(tetrahydro-2H-pyran-2-ylmethyl)-IH-imidazo[4,5 15 c]quinoline was prepared according to the general methods of Example 27 using 1 tetrahydro-2H-pyran-2-ylmethylamine in lieu of (S)-(+)-tetrahydrofurfurylamine in Part A and 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part C. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-15% CMA in chloroform) to provide a yellow oil. The oil was crystallized and then recrystallized from 20 MTBE/hexanes to provide 2-(2-methoxyethyl)-1 -(tetrahydro-2H-pyran-2-ylmethyl)- I H imidazo[4,5-c]quinoline as white crystals, mp 108-110 *C; 'H NMR (300 MHz, DMSO d) 8 9.14 (s, I H), 8.35-8.32 (m, 1 H), 8.16-8.13 (m, I H), 7.70-7.67 (in, 2 H), 4.75 (dd, J = 5.7, 3.0 Hz, I H), 4.59 (dd, J= 15.8, 9.0 Hz, I H), 3.88 (t, J= 7.0 Hz, 2 H), 3.77-3.69 (m, 2 H), 3.32 (s, 3 H),.3.28-3.24 (m, 2 H), 3.16-3.08 (m, I H), 1.92-1.82 (in, 2 H), 1.50 25 1.41 (m, 4 H); 3 C NMR (75 MHz, DMSO-d 6 ) 8 154.5, 144.5, 136.5, 133.5, 130.6, 126.9, 126.7, 121.2, 117.8, 76.5, 70.0, 68.0, 58.4, 55.3, 50.2, 29.0, 27.8, 25.7, 22.8; MS (APCI) m/z 326.20 (M + H); Anal. Calcd for C 9 H23N 3 0 2 : C, 70.13; H, 7.12; N, 12.91; Found: C, 70.31; H, 7.16; N, 13.08. 30 Example 33 2-[1-(Tetrahydro-2H-pyran-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]ethanol - 97 - NN -OH N N I 0 A solution of 2-(2-methoxyethyl)- I -(tetrahydro-2H-pyran-2-ylmethyl)- I H imidazo[4,5-c]quinoline (0.54 g, 1.66 mmol) in dichloromethane (17 mL) was placed 5 under a nitrogen atmosphere and chilled in an ice water bath. Boron tribromide (1.74 mL of I M in dichloromethane) was added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to provide a tan solid. The solid was combined with a solution of ammonia in methanol (20 mL of 7 N) and stirred for 2 hours. Silica gel (5 g) was added 10 and the mixture was concentrated under reduced pressure to a fine powder. This material was loaded onto a prep HPLC column (100 g of silica gel) and the column was eluted with a gradient of 1-20% CMA in chloroform. The fractions containing product were combined and concentrated under reduced pressure to provide a white foam. The foam was triturated with diethyl ether (10-15 mL) for 2 hours. A solid was isolated by filtration 15 and dried overnight in a vacuum oven to provide 57 mg of 2-[1-(tetrahydro-2H-pyran-2 ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]ethanol as an off-white solid, mp 151-153 *C; 'H NMR (300 MHz, DMSO-d 6 ) 8 9.14 (s, 1 H), 8.36-8.33 (m, I H), 8.17-8.13 (m, I H), 7.71-7.67 (in, 2 H), 4.87 (t, J= 5.4 Hz, 1 H), 4.76 (dd, J= 15.6, 3.0 Hz, I H), 4.62(dd, J= 15.7, 6.8 Hz, I H), 3.96-3.90 (m, 2 H), 3.78-3.69 (m, 2 H), 3.21-3.09 (m, 3 H), 1.93-1.90 20 (m, 1 H), 1.84 (br, 1 H), 1.51-1.41 (m, 4 H); 1 3 C NMR (75 MHz, DMSO-ds) 8 155.2, 144.5, 136.5, 133.4, 130.6, 126.9, 126.7, 121.2, 117.9, 76.5, 68.0, 59.6, 50.3, 31.0, 29.1, 25.7, 22.8; MS (APCI) m/z 312.20 (M + H)*; Anal. Calcd -or C 18

H

21

N

3 0 2 : C, 69.43; H, 6.80; N, 13.49; Found: C, 69.08; H, 6.76; N, 13.28. 25 Example 34 1-Cyclopentylmethyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline -98 - N N 1 -Cyclopentylmethyl-2-(ethoxymethyl)- 1 H-imidazo[4,5-c]quinoline was prepared according to the general methods of Example 27 using cyclopentylmethylamine 5 hydrochloride in lieu of (S)-(+)-tetrahydrofurfurylamine in Part A. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-15% CMA in chloroform) to provide a tan solid. This material was recrystallized from n-propyl acetate to provide 1 cyclopentylmethyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline as amber crystals, mp 95-98 *C; 'H NMR (500 MHz, DMSO-d) 8 9.19 (s, 1 H), 8.40-8.38, 1 H), 8.18-8.16 (m, 10 1 H), 7.75-7.71 (m, 2 H), 4.84 (s, 2 H), 4.68 (d, J= 7.6 Hz, 2 H), 3.59 (q, J= 7.0 Hz, 2 H), 2.55-2.50 (m, 1 H), 1.69-1.56 (m, 4 H), 1.51-1.44 (m, 2 H), 1.43-1.36 (m, 2 H), 1.16 (t, J= 7.0 Hz, 3 H); "C NMR (125 MHz, DMSO-d 6 ) 8 151.7, 145.2, 144.7, 136.4, 133.8, 130.7. 127.4, 127.0, 121.5, 118.0, 65.9, 64.8, 50.0, 40.5, 29.8, 24.7, 15.3; MS (ESI) m/z 310.32 (M + H) 4 ; Anal. Called for C1 9 H23N 3 0: C, 73.76; H, 7.49; N, 13.58; Found: C, 73.83; H, 15 7.42; N, 13.61. Example 35 [1-(Cyclopentylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol N N OH N 20 A solution of I -cyclopentylmethyl-2-(ethoxymethyl)-1 H-imidazo[4,5-c]quinoline (120 mg, 0.39 mmol) in dichloromethane (20 mL) was placed under a nitrogen atmosphere and chilled in an ice water bath. Boron tribromide (0.58 mL of 1 M in dichloromethane) was added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was quenched with methanol (5 mL) and 25 then concentrated under reduced pressure to provide an orange solid. The solid was combined with a solution of ammonia in methanol (10 mL of 7 N) and stirred for 30 - 99minutes. Silica gel (3 g) was added and the mixture was concentrated under reduced pressure to a fine powder. This material was loaded onto a prep HPLC column (40 g of silica gel) and the column was eluted with a gradient of 1-25% CMA in chloroform. The fractions containing product were combined and concentrated under reduced pressure to 5 provide an off white solid. The solid was recrystallized from acetonitrile and dried in a vacuum oven at 80 *C for 3 hours to provide 46 mg of [1-(cyclopentylmethyl)-1H imidazo[4,5-c]quinolin-2-yl]methanol as white crystals, mp 168-170 *C; 'H NMR (500 MHz, DMSO-d 6 ) 8 9.17 (s, I H), 8.40-8.38 (m, 1 H), 8.17-8.15 (m, 1 H), 7.74-7.70 (m, 2 H), 5.79 (t, J= 5.8 Hz, 1 H), 4.84 (d, J= 5.9 Hz, 2 H), 4.72 (d, J= 7.7 Hz, 2 H), 2.54-2.49 10 (in, 1 H), 1.70-1.58 (m, 4 H), 1.52-1.44 (m, 2 H), 1.42-1.35 (m, 2 H); "C NMR (125 MHz, DMSO-d 6 ) 8 154.4, 144.6, 144.1, 135.9, 133.3, 130.2, 126.7, 126.4, 121.0, 117.6, 56.6, 49.4, 40.1, 29.4, 24.2; MS (APCI) m/z 282.11 (M + H)*; Anal. Calcd for C 1 7 H 19

N

3 0: C, 72.57; H, 6.81; N, 14.93; Found: C, 72.60; H, 6.72; N, 15.02. 15 Example 36 2 -(Ethoxymethyl)-6,7-dimethyl-N-(tetrahydro-2H-thiopyran-4-yl) 1H-imidazo[4,5-c]pyridin-1-amine N N 0 N H S 20 Part A A mixture of 2

,

4 -dichloro-5,6-dimethyl-3-nitropyridine (40 g, I eq), triethylamine (50.4 mL, 2.0 eq), tert-butyl carbazate (47.8 g, 2.0 eq), and anhydrous DMF (400 mL) was heated at 65 *C under a nitrogen atmosphere for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 10% sodium 25 carbonate (500 mL) and dichloromethane (500 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organics were concentrated under reduced pressure to provide a dark brown solid: The solid was purified by prep HPLC (silica gel eluted with a gradient of 40-60% ethyl acetate in hexanes) to provide an amber oil. The oil was stirred with toluene and then concentrated - 100 under reduced pressure to provide 43.5 g of tert-butyl 2-(2-chloro-5,6-dimethyl-3 nitropyridin-4-yl)hydrazinecarboxylate as tan crystals. Part B A mixture of tert-butyl 2-(2-chloro-5,6-dimethyl-3-nitropyridin-4 5 yl)hydrazinecarboxylate (39.1 g), 5% platinum on carbon (4.0 g), and toluene (800 mL) was placed under hydrogen pressure (50 psi, 3.4 X 10 5 Pa) on a Parr apparatus for 16 hours. The reaction mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with methanol and dichloromethane. The filtrate was concentrated under reduced. pressure to provide 32.8 g of tert-butyl 2-(3-amino-2-chloro-5,6 10 dimethylpyridin-4-yl)hydrazinecarboxylate as a tan solid. Part C A mixture of tert-butyl 2-(3-amino-2-chloro-5,6-dimethylpyridin-4 yl)hydrazinecarboxylate (24.75 g, 86.3 mmol), triethylamine (18.0 mL, 129 mmol), and dichloromethane (500 mL) was chilled in an ice bath. Ethoxyacetyl chloride (11.6 g, 94.9 15 mmol) was added dropwise. The reaction mixture was kept cool for 1 hour and then allowed to warm to ambient temperature overnight. Additional ethoxyacetyl chloride (0.3 eq) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was washed with water (100 mL). The organic layer was filtered and then concentrated under reduced pressure to provide the amide intermediate. This material was dissolved in 20 ethanol (175 mL) and water (50 mL). Sodium hydroxide (10.4 g, 259 mmol) was added and the reaction mixture was stirred for-2 hours. The pH of the reaction mixture was adjusted to 11 with hydrochloric acid and sodium carbonate. The reaction mixture was diluted with water (300 mL) and then extracted with dichloromethane (3 x 100 mL). The combined organics were filtered and then concentrated under reduced pressure to provide 25 27.2 g of tert-butyl 4-chloro-2-(ethoxymethyl)-6,7-dimethyl-IH-imidazo[4,5-c]pyridin-1 ylcarbamate as an orange solid. Part D Under a nitrogen atmosphere, trifluoroacetic acid (50 mL) was added over a period of 5 minutes to a chilled (ice bath) solution of the material from Part C in dichloromethane 30 (200 mL). The reaction mixture was kept cool for 1 hour and then allowed to warm to ambient temperature. The reaction mixture was concentrated under reduced pressure to provide an amber oil. The oil was partitioned between dichloromethane (250 mL) and -101water (250 mL). The pH of the aqueous layer was adjusted to about 12 with sodium carbonate and then the aqueous layer was extracted with dichloromethane (3 x 250 mL). The combined organics were concentrated under reduced pressure to provide an amber oil. The oil was triturated with ethyl acetate to provide 5 g of 4-chloro-2-(ethoxymethyl)-6,7 5 dimethyl-lH-imidazo[4,5-c]pyridin-l-amine as tan crystals. The mother liquor was purified by prep HPLC (silica gel eluted with a gradient of 0-10% methanol in dichloromethane) to provide 10.8 g of 4-chloro-2-(ethoxymethyl)-6,7-dimethyl-iH imidazo[4,5-c]pyridin-1-amine as an amber oil which slowly solidified. Part E 10 Under a nitrogen atmosphere a mixture of 4-chloro-2-(ethoxymethyl)-6,7 dimethyl-1H-imidazo[4,5-c]pyridin-1-amine (5.95 g, 23.4 mnol), tetrahydrothiopyran-4 one (5.43 g, 46.7 mmol), acetonitrile (60 mL), and glacial acetic acid (20 mL) was heated at reflux for 48 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated under reduced pressure to provide a brown oil. The oil was 15 partitioned between dichloromethane (100 mL) and 10% sodium carbonate (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were concentrated under reduced pressure to provide a brown oil. The oil was purified by prep HPLC (silica gel eluted with a gradient of 0-7% methanol in dichloromethane) to provide 6.2 g. of 4-chloro-2-(ethoxymethyl)-6,7 20 dimethyl-N-(tetrahydro-4H-thiopyran-4-ylidene)-1H-imidazo[4,5-c]pyridin-1-amine as a yellow solid. Part F Under a nitrogen atmosphere sodium borohydride (2.0 g, 52.7 mmol) was added over a period of 5 minutes to a solution of the material from Part E (17.6 mmol) in 25 methanol (120 mL). After 2 hours the reaction was quenched with saturated ammonium chloride (40 mL) and then stirred for 5 minutes. The methanol was removed under reduced pressure. The remaining aqueous was combined with sodium carbonate (5 g ) and water (100 mL) and then extracted with dichloromethane (3 x 100 mL). ). The combined organics were concentrated under reduced pressure to provide an amber oil. The oil was 30 purified by prep HPLC (silica gel eluted with a gradient of 0-6% methanol in dichloromethane) to provide 4.96 g of 4-chloro-2-(ethoxymethyl)-6,7-dimethyl-N (tetrahydro-2H-thiopyran-4-yl)-H-imidazo[4,5-c]pyridin-1-amine as a light yellow solid. - 102 - Part G A mixture of 4-chloro-2-(ethoxymethyl)-6,7-dimethyl-N-(tetrahydro 2H thiopyran-4-yl)-IH-imidazo[4,5-c]pyridin-1-amine (0.5 g, 1.41 mmol), ammonium formate (0.9 g, 14.8 mol), ethanol (50 mL), and methanol (25 mL) was flushed with 5 nitrogen. 10% Palladium on carbon (0.5 g) was added and the reaction mixture was heated to 80 *C. After 3 hours the reaction mixture was cooled to ambient temperature, additional ammonium formate (0.9 g) and 10% palladium on carbon (0.5 g) were added, and then the reaction mixture was heated at reflux for an additional 3 hours. The reaction mixture was cooled to ambient temperature and then filtered through a layer of CELITE 10 filter agent. The filtrate was concentrated under reduced pressure to provide a clear oil. The oil was partitioned between 5% sodium hydroxide (100 mL) and dichloromethane (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 0.45 g of a clear oil. is This material was purified by prep HPLC (silica gel eluted with a gradient of 0-7% methanol in dichloromethane) to provide a clear oil (0.34 g). The oil was crystallized and then recrystallized from ethyl acetate and then dried under high vacuum at 50 *C for 16 hours to provide 0.16 g of 2-(ethoxymethyl)-6,7-dimethyl-N-(tetrahydro-2H-thiopyran-4 yl)-IH-imidazo[4,5-c]pyridin-1-amine as white crystals, mp 109-111 "C. 'H NMR (300 20 MHz, DMSO-d 6 ) 8 8.57 (s, IH), 6.71 (d, J= 1.6 Hz, 1H), 4.71 (s, 2H), 3.61 (q, J= 7.0 Hz, 2H), 3.14 (m, lH), 2.61 (s, 3H), 2.61-2.53 (m, 4H), 2.50 (s, 3H), 1.84 (m, 2H), 1.49 (m, 2H), 1.15 (t, J= 7.0 Hz, 3H); MS (ESI) m/z 321 (M + H)*; Anal. Calcd for C1 6

H

24

N

4 0S-0.50 H 2 0: C, 58.33; H, 7.65; N, 17.01. Found: C, 58.18; H, 7.63; N, 16.91. 25 Example 37 N-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-(ethoxymethyl)-6,7-dimethyl IH-imidazo[4,5-c]pyridin-1-amine N N 0 N N . H g -103- Part A Under a nitrogen atmosphere a mixture of 4-chloro-2-(ethoxymethyl)-6,7 dimethyl-N-(tetrahydro-2H-thiopyran-4-yl)-IH-imidazo[4,5-cjpyridin-1-amine (1.00 g, 2.82 mol) and dichloromethane (20 mL) was cooled in an ice bath. 3-Chloroperbenzoic 5 acid (1.78 g of 60%, 6.20 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. Analysis by HPLC indicated that the reaction was complete after 1 hour. The reaction was rerun using 3.46 g of starting material. The two reaction mixtures were combined, washed with 5% sodium carbonate, and then concentrated under reduced pressure to provide 4.2 g of crude 4-chloro-N-(1,1-dioxidotetrahydro-2H 10 thiopyran-4-yl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-amine as a light orange solid. Part B A mixture of 4-chloro-N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-2 (ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-amine (0.5 g, 1.28 mmol), 15 ammonium formate (0.85 g, 13.5 mol), ethanol (40 mL), and methanol (20 mL) was flushed with nitrogen. 10% Palladium on carbon (0.5 g) was added and the reaction mixture was heated to 80 *C for 3 hours. The reaction mixture was cooled to ambient. temperature and then filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide a white solid. The solid was partitioned 20 between 5% sodium hydroxide (100 mL) and dichloromethane (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 0.40 g of a white solid. This material was purified by prep H-PLC (silica gel eluted with a gradient of 0-10% methanol in dichloromethane) to provide 25 a white solid (0.34 g). The solid was recrystallized from ethyl acetate/methanol and then dried under high vacuum at 80 *C for 16 hours to provide 0.23 g of N-(1,1 dioxidotetrahydro-2H-thiopyran-4-yl)-2-(ethoxymethyl)-6,7-dimethyl-IH-imidazo[4,5 c]pyridin-1-amine as white crystals, mp 194-196 *C. 'H NMR (300 MHz, DMSO-d) 8 8.59 (s, 1H), 6.94 (d, J= 1.3 Hz, 1H), 4.72 (s, 2H), 3.62 (q, J= 7.0 Hz, 2H), 3.44 (in, 1H), 30 3.21-2.95 (m, 4H), 2.62 (s, 3H), 2.51 (s, 3H), 1.96-1.76 (m, 4H), 1.16 (t, J= 7.0 Hz, 3H); MS (ESI) m/z 353 (M + H)*; Anal. Calcd for C,H 24

N

4 0 3 S: C, 54.53; H, 6.86; N, 15.90. Found: C, 54.54; H, 7.05; N, 15.90. - 104 - Example 38 2-Ethyl-i -(tetrahydro-2H-pyran-4-yl-methyl)- 1H-imidazo[4,5-c]quinoline N Nj N N 0 5 Triethyl orthopropionate (0.938 mL, 4.66 mmol) and pyridine hydrochloride (50 mg, 0.47 mmol) were added sequentially to a solution of N 4 -(tetrahydro-2H-pyran4 ylmethyl)quinoline-3,4-diamine (1.2 g, 4.66 mmol) in toluene (40 mL). The mixture was heated at reflux for 4 hours and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and then washed with water. The organic was dried 10 over sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting solid was dissolved in refluxing acetonitrile. The solution was allowed to cool and then it was concentrated under reduced pressure. The bulk of the residue was again dissolved in refluxing acetonitrile (a small amount of solid remained) and the mixture was allowed to cool. A solid was isolated by filtration, washed with acetonitrile, and dried under vacuum 15 for 2 hours to provide 1.05 g of 2-ethyl-i -(tetrahydro-2H-pyran-4-yl-methyl)- I H imidazo[4,5-c]quinoline as pale green crystals, mp 169-170 *C. MS (ESI) n/z 296.33 (M + H)'; Anal. Calcd for Ci sH 2

N

3 0: C, 73.19; H, 7.17; N, 14.23. Found: C, 72.99; H, 7.21; N, 14.39. 20 Example 39 2-(Ethoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinoline N N N 0 Ethoxyacetyl chloride (0.476 g, 3.89 mmol) was added dropwise to a solution of N*-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (1.0 g, 3.89 mmol) in a 25 mixture of dichloromethane (40 mL) and triethylamine (0.540 mL, 3.89mmol). After 30 - 105 minutes the dichloromethane was removed under reduced pressure. The crude amide intermediate was dissolved in ethanol (40 mL). Triethylamine (2.6 mL) was added and the reaction mixture was heated to reflux. After 4 hours additional triethylamine (1 mL) was added and the reaction mixture was heated at reflux overnight. Additional 5 triethylamine (1 mL) was added and the reaction mixture was heated at reflux for an additional 2 hours. The reaction mixture was allowed to cool to ambient temperature and then the ethanol was removed under reduced pressure. The residue was dissolved in dichloromethane and then washed with water. The organic was concentrated under reduced pressure. The residue was purified by prep HPLC (silica gel eluted with a linear 10 gradient of 2-15% CMA in chloroform) followed by treatment with refluxing acetonitrile. A solid was isolated by filtration and then dried under vacuum overnight to provide 0.97 g of 2-(ethoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, m.p. 123.5-125 *C. MS (ESI) m/z 326.24 (M + H)+; Anal. Calcd for CiH23N 3 0 2 : C, 70.13; H, 7.12; N, 12.91. Found: C, 70.25; H, 7.25; N, 13.00. 15 Example 40 2-Butyl-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline N N N 2-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)- IH-imidazo[4,5-c]quinoline was 20 prepared according to the general method of Example 38 using trimethyl orthovalerate in lieu of triethyl orthopropionate. The crude product was purified by prep HPLC (silica gel eluted with a linear gradient of 2-15% CMA in chloroform) followed by crystallization from acetonitrile to provide 2-butyl- I -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-imidazo[4,5 c]quinoline as a white solid, m.p. 135-136.5 "C. MS (ESI) m/z 324.05 (M + H)*; Anal. 25 Calcd for C 2 0

H

25

N

3 0: C, 74.27; H, 7.79; N, 12.99. Found: C, 74.25; H, 7.91; N, 13.00 - 106 - Example 41 2-(2-Methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline hydrochloride N - N O N 0 5 2-(2-Methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H-inidazo[4,5 c]quinoline hydrochloride was prepared according to the general methods of Example 39 using 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride. The crude product was purified by prep HPLC (silica gel eluted with a linear gradient of 2-15% CMA in chloroform) followed by treatment with refluxing acetonitrile. The resulting oil was 10 diluted with diethyl ether and then combined with a solution of hydrogen chloride in diethyl ether (1.0 mL of 1.0 M). The resulting solid was isolated by filtration, washed with diethyl ether, and dried to provide 0.550 g of 2

-(

2 -methoxyethyl)-I-(tetrahydro-2H pyran- 4 -ylmethyl)-1H-imidazo[4,5-c]quinoline hydrochloride as an off-white solid, m.p. 217 *C, decomposition. MS (ESI) m/z 326.19 (M + H); Anal. Calcd for 15 C 19

H

23

N

3 0 2 -1.OHCI: C, 63.06; H, 6.68; N, 11.61; Cl, 9.80. Found: C, 62.84; H, 6.57; N, 11.33; Cl, 9.55. Example 42 2-Ethyl-I -(tetrahydro-2H-pyran-4-ylmethyl) 20 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline dihydrochloride N N 0 A solution of 2-ethyl-1-(tetrahydro-2H-pyran-4-yl-methyl)- IH-imidazo[4,5 c]quinoline (0.400 g, 1.36 mmol) in trifluoroacetic acid was added to a Parr vessel containing platinum IV oxide (0.300 g, 1.25 mmol) wetted with trifluoroacetic acid. The 25 vessel was placed under hydrogen pressure over the weekend. The reaction mixture was - 107 filtered through a layer of CELITE filter agent. The filter cake was rinsed with 10% methanol in dichloromethane. The filtrate was concentrated under reduced pressure. The residue was made basic with saturated aqueous sodium carbonate and a small amount of 50% sodium hydroxide and then extracted with dichloromethane (2 x 50 mL). The 5 combined organics were washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by prep HPLC (silica gel eluted with a gradient of 5-25% methanol in chloroform) and then dissolved in dichloromethane. The solution was evaporated and the residue was dissolved in diethyl ether (5 mL) and treated with a solution of hydrogen chloride in 10 diethyl ether (3.0 mL of 1.0 M). The resulting precipitate was isolated by filtration. The solid was combined with acetonitrile and heated to reflux. The mixture was allowed to cool with stirring. A solid was isolated by filtration, washed with acetonitrile, and then dried under vacuum to provide 0.224 g of 2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl) 6,7,8,9-tetrahydro-1H-imidazo[4,5-clquinoline dihydrochloride as a white powder, m.p. 15 251-252.5 *C. MS (ESI) m/z 300.21 (M + H)*; Anal. Calcd for CjSH2sN 3 0-2.0HCl-l.0H 2 O: C, 55.39; H, 7.49; N, 10.77; Cl, 18.17. Found: C, 55.42; H, 7.87; N, 10.73; Cl, 18.26. Example 43 20 N-[2-(2-Methoxyethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinolin-7-yl]-2-methylpropanamide N N 0 N H N 0 0 Dioxane (1.3 nL) was added to a mixture of 7-bromo-2-(2-methoxyethyl)- I (tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline (0.500 g, 1.23 mmol), 25 tris(dibenzylideneacetone)dipalladium (32 mg, 0.031 mmol), cesium carbonate (0.560 g, 1.72 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54 mg, 0.093 mmol), and isobutyramide (0.127 g, 1.47 mmol) in a vial equipped with a stir bar. The vial was flushed with nitrogen, sealed with a TEFLON lined cap, and then heated at 80 *C - 108 overnight. The reaction mixture was diluted with chloroform containing a trace amount of methanol and then purified by prep HPLC (silica gel eluted with a linear gradient of 2 15% CMA in chloroform). The resulting foamy residue (0.476 g) was dissolved in acetonitrile and then allowed to stand over night. A solid was isolated by filtration, rinsed 5 with acetonitrile, and dried to provide 0.129 g of N-[2-(2-methoxyethyl)-1-(tetrahydro-2H pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-2-methylpropanamide as a white solid, m.p. 203-204.5 *C. MS (ESI) m/z 411.28 (M + H)*; Anal. Calcd for C23H 3 0

N

4 0 3 : C, 67.29; H, 7.37; N, 13.65. Found: C, 67.28; H, 7.45; N, 13.57. 10 Example 44 (5-[2-(2-Methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl) I H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl }methanol N- N 0 N OH N N 0 15 1,2-Dimethoxyethane (5 mL) and water (2.5 mL) were added to a mixture of 7 bromo-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 c]quinoline (0.500 g, 1.24 mmol), 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3 boronic acid (0.398 g, 1.49 mmol), and potassium carbonate (0.598 g, 4.34 mmol) and the resulting slurry was sparged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) 20 (0.043 g, 0.062 mmol) was added. The mixture was sparged with nitrogen and then heated at reflux for 1 hour. The organic layer was purified by prep HPLC (silica gel eluted with a linear gradient of 2-10% CMA in chloroform). The resulting solid was dissolved in a mixture of THF (10 mL) and water (5 mL). Acetic acid (5 mL) was added and the mixture was stirred overnight. The reaction was made basic with 2 M aqueous sodium carbonate 25 and the THF was removed under reduced pressure. A solid was isolated by filtration, washed with water, and dried to provide 0.368 g of {5-[ 2

-(

2 -methoxyethyl)-1-(tetrahydro 2H-pyran-4-ylmethyl)- IH-imidazo(4,5-c]quinolin-7-yl]pyridin-3-yl }methanol as a white -109- -powder, m.p. 218-220 *C. MS (ESI) m/z 433.20 (M + F); Anal. Calcd for C2sH2SN 4 03-1.0H 2 0: C, 66.65; H, 6.71; N, 12.43. Found: C, 66.51; H, 6.39; N, 12.34. Example 45 5 2-(2-Methoxyethyl)-7-pyridin-3-yl-l-(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline N 0 N N 0 1,2-Dimethoxyethane (5 mL) and water (2.5 mL) were added to a mixture of 7 10 bromo-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5 c]quinoline (0.500 g, 1.24 mmol), pyridin-3-ylboronic acid (0.183 g, 1.49 mmol), and potassium carbonate (0.598 g, 4.34 mmol) and the resulting slurry was sparged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (0.043 g, 0.062 mmol) was added. The mixture was sparged with nitrogen and then heated at reflux for I hour. The 15 organic layer was purified by prep HPLC (silica gel eluted with a linear gradient of 2-15% CMA in chloroform). The resulting oil was dissolved in dichloromethane and then the solvent was removed under reduced pressure. This procedure was repeated using acetonitrile to provide 0.474 g of a pale yellow oil. The oil was triturated with diethyl ether and then allowed to stand overnight. A solid was isolated by filtration, washed with 20 diethyl ether, and dried to provide 0.345 g of 2

-(

2 -methoxyethyl)-7-pyridin-3-yl-1-(tetrahydro-2H-pyran-4-ylmethyl)- IH-imidazo[4,5 c]quinoline as a white solid, m.p. 150-151 "C. MS (ESI) m/z 403.25 (M + H')*; Anal. Calcd for C 2 4

H

2 6

N

4 0 2 : C, 71.62; H, 6.51; N, 13.92. Found: C, 71.90; H, 6.85; N, 14.09. 25 Compound 1 7-Benzyloxy-2-ethyl-1-(tetrahydro-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline -110- N N N 0 0 Part A Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydro-2H pyran-4-carboxylate (20 mL, 150 mmol) in methanol (500 mL), and the reaction was 5 stirred overnight at ambient temperature. Additional ammonium hydroxide (500 mL) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.4 g of tetrahydro 10 2H-pyran-4-carboxamide as a white solid. Part B A solution of tetrahydro-2H-pyran4-carboxamide (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0 *C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in six portions over a period of ten minutes. The reaction flask was purged with nitrogen 15 between the additions. When the reaction mixture was no longer bubbling, it was heated at reflux for six hours. The reaction was then cooled to 0 *C, and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15% aqueous sodium hydroxide (10 mL), and water (30 mL) were sequentially added. The organic fraction was decanted off, and the remaining gray 20 solid was washed with chloroform. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tetrahydro 2H-pyran-4-ylmethylanine. Part C 7 -(Benzyloxy)-3-nitroquinolin-4-ol (12.3 g, 41.6 mmol) was slurried in DMF (83 25 mL). Phosphorous oxychloride (4.2 mL, 45 mmol) was added in one portion and the mixture was heated at 100 "C for 5 minutes. The solution was allowed to cool to 40 *C and was then poured into ice water (total volume 400 mL) resulting in a tan precipitate. The precipitate was filtered and washed with water. After drying, the solid was dissolved - 111 in dichloromethane and the residual water was separated. The organic fraction was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate (about a 50/50 mixture). The organic fraction was filtered into a reaction flask (total volume of organic with 7 (benzyloxy)-3-chloro-4-nitroquinoline is about 425 mL). The flask was cooled to 8 *C 5 and triethylamine (11.6 mL, 83.Ommol) was added. (Tetrahydro-2H-pyran-4 yl)methylamine (6.0 g, 52 mmol) in dichloromethane (50 mL) was added dropwise to the mixture. The cooling bath was removed and the reaction was stirred for 16 hours. Water (200 mL) was added followed by stirring for 30 minutes. The layers were separated and the organic fraction was sequentially washed with saturated aqueous sodium chloride, 10 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from 2-propanol provided 14.1 g of 7-(benzyloxy)-3-nitro-N-(tetrahydro 2H-pyran-4-ylmethyl)quinolin-4-amine as a yellow powder. PartD 7 -(Benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (14.1 15 g, 35.6 mmol) and 5% platinum on carbon (2.0 g) were added to a Parr vessel. The solids were covered with acetonitrile (200 mL) and placed on a hydrogenator. The vessel was degassed three times, charged with 50 psi (3.4 x 105 Pa) hydrogen and allowed to shake for 3 hours, replenishing the hydrogen as needed. After 6 hours, the catalyst was removed by filtration through CELITE filter agent. The CELITE was washed with acetonitrile until 20 the filtrate ran clear (- 300 mL). The solvent was evaporated to /2 volume under reduced pressure and cooled to 8 "C. Propionyl chloride (3.15 mL, 35.6 mnol) was added dropwise to the solution over 3 minutes. The cooling bath was removed and the reaction was stirred for 16 hours. The resulting precipitate was filtered and washed with acetonitrile. Drying under vacuum for 1 hour provided 14.2 g of N-{7-(benzyloxy)-4 25 [(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl)propanamide dihydrochloride as a tan solid. Part E N-{7-(Benzyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl propanamide dihydrochloride (14.2 g, 31.1 mmol) was slurried in ethanol (150 mL) and diluted with 30 water (50 mL). Potassium carbonate (12.3 g, 89 mmol) in water (15 mL) was added and the reaction was stirred until dissolution (-30 minutes). The reaction was then heated to 60 *C for 16 hours. The ethanol was evaporated under reduced pressure and the remaining - 112water was extracted with dichloromethane. The organic fraction was sequentially washed with water, followed by saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to provide a brown viscous oil. The oil was crystallized from acetonitrile (about 200 mL) to provide 8.4 g of 7-(benzyloxy)-2-ethyl- 1 -(tetrahydro 5 2 H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline as a white solid, m.p. 143-145 *C. Anal. Calcd for C 2 5

H

2 7

N

3 0 2 : C, 74.79; H, 6.78; N, 10.47. Found: C, 74.58; H, 7.05; N, 10.50. Compound 2 10 2-Ethyl-I -(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinolin-7-oI No NN HO 0 7-(Benzyloxy)-2-ethyl- -(tetrahydro-2H-pyran-4-ylmethyl)- IH-imidazo[4,5 c]quinoline (8.3 g, 20.7 mmol) was added to a Parr vessel containing 10% palladium on 15 carbon (1.5 g) wetted with acetonitrile. Methanol (160 mL) was added and the vessel was placed on the hydrogenator. The vessel was degassed three times and charged with 50 psi (3.4 x 105 Pa) hydrogen. The vessel was allowed to shake for 16 hours, replenishing the hydrogen as needed. The catalyst was removed by filtration through glass fiber filter paper. The catalyst was washed with 3:1 chloroform/methanol. The filtrates were 20 combined and concentrated under reduced pressure provide 6.1 g of a gray solid. A small portion of this material was purified by prep HPLC (silica gel eluted with a linear gradient of 2-25% CMA in chloroform). The residue was slurried with methanol. The mixture was heated to reflux and then allowed to cool to ambient temperature overnight. A solid was isolated by filtration, washed with methanol, and dried to provide 110 mg of 2-ethyl-I 25 (tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinolin-7-ol as a white solid, m.p. 318 *C, decomposition. MS (ESI) m/z 312.07 (M + H)*; Anal. Called for CigH 2 1

N

3 0 2 : C, 69.43; H, 6.80; N, 13.49. Found: C, 69.42; H, 6.89; N, 13.45. -113- Example 46 2-Ethyl-7-(tetrahydrofuran-2-ylmethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline N N% NN 00 5 2-Ethyl-I -(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol (0.800 g, 2.57 nmol), tetrahydrofurfuryl chloride (0.293 mL, 2.70 mmol), cesium carbonate (1.67 g, 5.14 mmol), and DMF (20 mL) were combined and then beated to 65 *C. After 3 hours analysis by LC/MS did not show product. An additional equivalent of 10 the acid chloride was added and the reaction mixture was heated at 100 *C overnight. The reaction mixture was allowed to cool to ambient temperature, diluted with water (80 mL), and then extracted sequentially with ethyl acetate, diethyl ether, and dichloromethane. The ethyl acetate and diethyl ether extracts were combined and then washed with water (2 x 50 mL). The dichloromethane extract was washed with water (3 x 50 mL). The 15 organics were combined, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified twice by prep HPLC (silica gel eluted with a linear gradient of 2-20% CMA in chloroform and then silica gel eluted with a linear gradient of 1-20% CMA in chloroform). The residue was dissolved in a small amount of refluxing ethyl acetate. The solution was diluted with hexanes until it became cloudy and 20 then was allowed to stand. A solid was isolated by filtration and dried to provide 0.214 g of 2 -ethyl-7-(tetrahydrofuran-2-ylmethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[4,5-c]quinoline as a white solid, m.p. 146-147.5 *C. MS (ESI) m/z 396.07 (M + H)*; Anal. Calcd for C23H 2 9

N

3 0 3 : C, 69.85; H, 7.39; N, 10.62. Found: C, 69.75; H, 7.43; N, 10.50. 25 Example 47 2-Ethoxymethy-7-(morpholin-4-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline -114- N- N |Wo N 'N 0") Under a nitrogen atmosphere, toluene (2.50 mL) was added to a vial containing 7 bromo-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline 5 (0.50 g, 1.24 mmol), morpholine (0.11 mL, 1.49 mmol), tris(dibenzylideneacetone)dipalladiurn (39 mg, 0.037 mmol), (b)-2,2' bis(diphenylphosphino)- 1,1 '-binaphthyl (46 mg, 0.074 mmol), and sodium tert-butoxide (0.17 g, 1.74 mmol). Nitrogen was bubbled through the mixture. The vial was sealed with a TEFLON lined cap and then heated at 80 "C for 15 hours. The reaction mixture was 10 diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to provide an orange solid. The solid was purified by prep HPLC (silica gel eluted with a gradient of 1-15% CMA in chloroform) to provide a yellow solid. This material was recrystallized from n-propyl acetate to provide 150 mg of 2-ethoxymethy-7-(morpholin-4-yl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 15 c]quinoline as white crystals, mp 197-199 "C; 'H NMR (500 MHz, DMSO-d) 8 9.04 (s, I H), 8.22 (d, J= 9.2 Hz, 1 H), 7.53 (d, J= 9.2 Hz, 1 H), 7.47 (d, J= 2.6 Hz, I H), 4.79 (s, 2 H), 4.56 (d, J= 7.4 Hz, 2 H), 3.82-3.80 (m, 6 H), 3.58 (q, J= 7.0 Hz, 2 H), 3.31-3.29 (m, 4 H), 3.19-3.10 (m, 2 H), 2.23-2.14 (m, 1 H), 1.52-1.44 (m, 2 H), 1.42-1.35 (m, 2 H), 1.16 (t, J= 7.0 Hz, 3 H); 3 C NMR (125 MHz, DMSO-d 6 ) 8 151.1, 150.2, 146.6, 145.1, 135.1, 20 134.4, 122.0, 117.9, 112.5, 111.0, 67.0, 66.5, 65.8, 64.7, 50.7, 48.5, 35.9, 30.1, 15.3; MS (APCI) n/z 411.10 (M + H) t ; Anal. Calcd for C23H 3 oN 4 03: C, 67.29; H, 7.37; N, 13.65; Found: C, 67.18; H, 7.70; N, 14.00. Example 48 25 1-[2-Ethoxymethy-1-(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one - 115 - N-/ N 0 %y | N< N Under a nitrogen atmosphere, toluene (2.50 mL) was added to a vial containing 7 bromo-2-ethoxymethyl-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline 5 (0.50 g, 1.24 mmol), 2 -pyrrolidinone (0.13 mL, 1.49 mmol), tris(dibenzylideneacetone)dipalladium (39 mg, 0.037 mmol), (+)-2,2' bis(diphenylphospino)- 1,1 '-binaphthyl (46 mg, 0.074 mmol), and sodium tert-butoxide (0.17 g, 1.74 mmol). Nitrogen was bubbled through the mixture. The vial was capped with a TEFLON lined cap and then heated at 80 *C for 15 hours. The reaction mixture 10 was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to provide a green solid. The solid was purified by prep HPLC (silica gel eluted with a gradient of 1-15% CMA in chloroform) to provide a yellow solid. This material was recrystallized from n-propyl acetate/heptane to provide 0.114 g of 1-[2-ethoxymethy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-imidazo[4,5 15 c]quinolin-7-yl]pyrrolidin-2-one as white crystals, mp 145-147 *C; 'H NMR (300 MHz, DMSO-d) 8 9.16 (s, I H), 8.39 (d, J- 9.2 Hz, 1 H), 8.30 (dd, J= 9.2, 2.3 Hz, I H), 8.22 (d, J= 2.3 Hz, I H), 4.82 (s, 2 H), 4.61 (d, J= 7.4 Hz, 2 H), 4.02 (t, J= 7.0 Hz, 2 H), 3.85 3.75 (m, 2 H), 3.59 (q, J= 7.0 Hz, 2 H), 3.20-3.08 (m, 2 H), 2.59 (t, J= 8.0 Hz, 2 H), 2.29 2.09 (m, 3 H), 1.56-1.35 (m, 4 H), 1.17 (t, J= 7.0 Hz, 3 H); "C NMR (75 MHz, DMSO 20 d)S 174.7,151.8,145.7,145.2,138.8,135.9,134.0,121.8,119.8,118.8, 114.2, 67.0, 65.9, 64.7, 48.5, 36.0, 32.8, 30.1, 17.8, 15.3; MS (APCI) n/z 409.08 (M + H)*; Anal. Calcd for C 2 3

H

2 aN 4 0 3 : C, 67.63; H, 6.91; N, 13.72; Found: C, 67.45; H, 7.10; N, 13.46. Example 49 25 N-(Cyclopropylmethyl)-2-(ethoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinolin-7-amine -116- N.- N 0 NN Under a nitrogen atmosphere, toluene (2.50 mL) was added to a vial containing 7 bromo-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline 5 (0.50 g, 1.24 mmol), cyclopropylmethylamine (0.13 mL, 1.49 mmol), tris(dibenzylideneacetone)dipalladium (39 mg, 0.037 mmol), ( )-2,2' bis(diphenylphosphino)-1,1'-binaphthyl (46 mg, 0.074 mmol), and sodium tert-butoxide (0.17 g, 1.74 mmol). Nitrogen was bubbled through the mixture. The vial was capped with a TEFLON lined cap and then heated at 80 "C for 15 hours. The reaction mixture 10 was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to provide an orange solid. The solid was purified by prep HPLC (silica gel eluted with a gradient of 1-15% CMA in chloroform) to provide a yellow solid. This material was recrystallized from acetonitrile to provide 0-26 g of N-(cyclopropylmethyl)-2-(ethoxymethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- I H 15 imidazo[4,5-c]quinolin-7-amine as yellow crystals, mp 161-163 *C; 'H NMR (300 MHz, DMSO-d 6 ) 8 8.92 (s, I H), 8.05 (d, J= 7.1 Hz, 1 H), 7.16 (dd, J= 9.0, 2.3 Hz, 1 H), 7.05 (d, J= 2.3 Hz, I H), 6.22(t, J= 5.4 Hz, 1 H), 4.75 (s, 2 H), 4.50 (d, J= 7.4 Hz, 2 H), 3.85 3.75 (m, 2 H), 3.56 (q, J= 7.0 Hz, 2 H), 3.20-3.07 (in, 2 H), 3.03 (t, J= 6.0 Hz, 2 H), 2.24 2.09 (in, 1 H), 1.53-1.33 (in, 4 H), 1.18-1.08 (in, 4 H), 0.55-0.49 (m, 2 H), 0.30-0.25 (in, 2 20 H); 1 3 C NMR (75 MHz, DMSO-d 6 ) S 150.4, 148.5,147.4,144.5,134.8, 134.2, 121.7, 117.6, 108.8, 106.8, 67.0, 65.7, 64.7, 50.6, 47.7, 35.9, 30.1, 15.3, 10.8, 4.0; MS (APCI) m/z 395.09 (M + H)+; Anal. Calcd for C 2 3

H

3 0N 4 0 2 : C, 70.02; H, 7.66; N, 14.20; Found: C, 69.81; H, 7.65; N, 14.17. 25 Compound 3 8-(Benzyloxy)-2-(ethoxymethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline - 117 - N O N 8-(Benzyloxy)-2-(ethoxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[4,5-c]quinoline was prepared according to the general methods of Example 13 5 using 4-benzyloxyaniline in lieu of 2-benzyloxyaniline in Part A. The crude product was purified by recrystallization from heptane/ethyl acetate to provide 8-(benzyloxy)-2 (ethoxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an off-white solid, mp 105-108 *C. Anal. calcd for C 26 H2N 3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.50; H, 6.60; N, 9.70. 10 Compound 4 7-(Benzyloxy)-2-(ethoxymethyl)- I -(tetrahydro-2H-pyran-4-ylmethy I) IH-imidazo[4,5-c]quinoline N OO 15 -7-(Benzyloxy)-2-(ethoxymethyl)- I-(tetrahydro-2H-pyran-4-ylmethyl)- 1H imidazo[4,5-c]quinoline was prepared according to the general methods of Example 13 using 3-benizyloxyaniline in lieu of 2-benzyloxyaniline in Part A. The crude product was purified by recrystallization from heptane/ethyl acetate to provide 7-(benzyloxy)-2 20 (ethoxymethyl)-1I-(tetrahydro-2H-pyran-4-ylmethyl )- I H-imidazo[4,5 -ciquinoline as an off-white solid, mp 136-139 *C. Anal. called for C 26

H

29

N

3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.27; H, 7.05; N, 9.76. - 118 - Example 50 8-(Benzyloxy)-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-cjquinoline I N 5 8-(Benzyloxy)-2-(2-methoxyethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl)- I H imidazo[4,5-c]quinoline was prepared according to the general methods of Example 13 using 4-benzyloxyaniline in lieu of 2-benzyloxyaniline in Part A and 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part G. The crude product was purified by 10 recrystallization from heptane/ethyl acetate to provide 8-(benzyloxy)-2-(2-methoxyethyl) I -(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline as a beige solid, mp 133 136 *C. Anal. calcd for C 2 6 H29N 3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.05; H, 6.99; N, 9.60. 15 Example 51 7-(Benzyloxy)-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl) IH-imidazo[4,5-c]quinoline N 20 7-(Benzyloxy)-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H imidazo[4,5-c]quinoline was prepared according to the general methods of Example 13 using 3-benzyloxyaniline in lieu of 2-benzyloxyaniline in Part A and 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part G. The crude product was purified by recrystallization from heptane/ethyl acetate to provide 7-(benzyloxy)-2-(2-methoxyethyl) -119- 1-(tetrahydro-2H-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinoline as a light orange solid, mp 119-122 *C. Anal. calcd for C 26

-

29

N

3 0 3 : C, 72.37; H, 6.77; N, 9.74. Found: C, 72.26; H, 7.06; N, 9.80. 5 Example 52 7-Bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-amine N- N N Br O Part A Triethylarnine (43 mL, 0.31 mol) was added in a single portion to a chilled (ice 10 bath) suspension of 7 -bromo-4-chloro-3-nitroquinoline (60 g, (0.21 mol) in DMF (200 mL) to provide a solution. A solution of I -tetrahydro-2H-pyran-4-ylmethylamine (36 g, 0.31 mole) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was chilled in an ice bath, then quenched with water (150 mL), and then stirred for 30 minutes. A solid was isolated by 15 filtration, washed sequentially with water and diethyl ether, and then dried at 65 *C in a vacuum oven to provide 36.2 g of ( 7 -bromo- 3 -nitroquinolin-4-yl)(tetrahydro-2H-pyran4 ylmethyl)amine as a yellow solid. Part B A Parr vessel was charged sequentially with the material from Part A, acetonitrile 20 (1 L), and platinum on carbon (3.7 g). The vessel was placed under hydrogen pressure until analysis by LC/MS indicated that the reaction was complete. Magnesium sulfate was added to the reaction mixture and then it was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide 35 g of crude 7-bromo-NM (tetrahydro-2H-pyran4-ylmethyl)quinoline-3,4-diamine as an amber oil. 25 Part C A mixture of 7-bromo-M4-(tetrahydro-2H-pyran4-ylmethyl)quinoline-3,4-diamine (3 g, 9 mmol), cyanogen bromide (1.4 g, 13 mmol), and ethanol (100 mL) was heated at reflux overnight. Analysis by LC/MS indicated that the reaction was incomplete. Two additional equivalents of cyanogen bromide were added. Heating was continued until -120analysis by LC/MS indicated that the reaction was about 80% complete. The reaction mixture was concentrated under reduced pressure to provide a thick brown oil. The oil was dissolved in dichloromethane and washed with water. A precipitate formed in the aqueous layer and was isolated by filtration. This material was converted to the free base 5 by stirring with 2N sodium hydroxide (200 mL) at ambient temperature for 2 hours. The free base was purified by prep HPLC (silica gel eluted with 6.7% methanol in dichloromethane containing 0.4% ammonium hydroxide), washed with diethyl ether, and dried to provide 300 mg of 7-bromo- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- I H-imidazo[4,5 c]quinolin-2-amine as a reddish brown solid, mp >275 *C. Anal. calcd for CI 6

HJ

7 BrN 4 0 10 0.20 HBr: C, 50.95; H, 4.54; N, 14.85. Found: C, 50.58; H, 4.38; N, 14.66. Examples 53 - 92 A solution of 8-bromo-2-ethoxymethyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H imidazo[4,5-c]quinoline (20 mg, 0.10 mmol) in 7:3 volume:volume (v:v) 15 chloroforn:methanol (2 mL) was added to a test tube, and the solvent was removed by vacuum centrifugation. The boronic acid (0.11 mmol) indicated in the table below and n propanol (1.6 mL) were sequentially added. The test tube was purged with nitrogen. Palladium (II) acetate (150 pL of a 4 mg/mL solution in toluene, 0.0026 mmol), 2 M aqueous sodium carbonate solution (600 pL), deionized water (113 pL), and a solution of 20 0.15 mol% triphenylphosphine in n-propanol (53 pL, 0.0078 mmol) were sequentially added. The test tube was purged with nitrogen, capped, and then heated at 80 *C overnight in a sand bath. For Example 92, glacial acetic acid (500 pL), tetrahydrofuran (500 pL), and deionized water (500 pL) were added to the test tube. The reaction was heated for 2 hours at 60 *C. 25 The contents of each test tube were passed through a Waters Oasis Sample Extractions Cartridge MCX (6 cc) according to the following procedure. Hydrochloric acid (3 mL of I N) was added to adjust each example to pH <5; and the resulting solution was passed through the cartridge optionally using light nitrogen pressure. The cartridge was washed with methanol (5 mL) optionally using light nitrogen pressure and transferred 30 to a clean test tube. A solution of 1% ammonia in methanol (2 x 5 mL) was then passed through the cartridge optionally using light nitrogen pressure, and the eluent was collected and concentrated by vacuum centrifugation. - 121 - The compounds were purified by preparative high performance liquid chromatography using a Waters FractionLynx automated purification system. The fractions were analyzed using a Waters LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. 5 Reversed phase preparative liquid chromatography was performed with non-linear gradient elution from 5-95% B where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile. The fractions were collected by mass-selective triggering. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. 10 N N 0- ' SN R Measured Example Reagent R Mass Q\l+H) 53 Furan-3-boronic acid 392.1949 54 Phenylboronic acid 402.2162 55 Pyridine-3-boronic acid 6 403.2130 56 Pyridine-4-boronic acid 403.2136 N 57 3-Methylphenylboronic acid 416.2337 - 122 - 58 4-Methylphenylboronic acid 416.2325

CH

3 59 o-Tolylboronic acid

H

3 0 416.2321 60 3 -Hydroxyphenylboronic acid 418.2174 6 1 _H H Oi 61 2-Fluorophenylboronic acid F 420.2082 62 3 -Fluorophenylboronic acid 420.2075 F 64 2 -Fluoropyridine-5-boronic acid N 421.2043 F 65 3-Cyanophenylboronic acid 427.2116 66 4-Cyanophenylboronic acid 427.2153 67 (2-Hydroxymethylphenyl)boronic acid HO dehydrate 432.2285 - 123 - 68 2-Methoxyphenylboronic acid H3C 432.2315 69 3-(Hydroxymethyl)phenylbororiic acid 432.2251 OH 70 4 -(Hydroxymethyl)phenylboronic acid 432.2274 HO 71 4-Methoxyphenylboronic acid 432.2293

H

3 C 0 72 3-Chlorophenylboronic acid C1 436.1789 73 2-Chloophenylboronic acid C 436.1830 74 4-Chlorophenylboronic acid 436.1783 Cl 75 2,4-Difluorophenylboronic acid 438.1984 76 (3-Aminocarbonylphenyl)boronic acid 445.2210

H

2 N 45 -124- 77 3-Carboxyphenylboronic acid 1446.2083 HO 78 [ 3

-(

3 -Hydroxypropyl)phenyl]boronic .~I460.2553 acid j6 ___ ___ ___ ___ ___ ___ ___ __OH

H

3 C , 0 79 2,4-Dimethoxyphenylboronic acid H3 - . H 462.236 81 3,4-Dimethoxyphenylboronic acid H 3c. 462.2392 ____________________0. 0

CH

3 82 3,4-Dichlorophenylboronic acid I470.1398 Cli 3 -(N,N 83 Dirnethylaminocarbonyl)phenylboronic 4322 acid 473.252 _____________ _H__

H

3 C, NOH 3 84 4 -(Methanesulfonyl)phenylboronic 4012 acid 4012 - 125 - 8 5 4 8 7 .2 6 9 85 Isopropylaminocarbonyl)phenylboronic acid.HO9N ____________acid__ _

OH

3 1 H 86 Propylaniinocarbonyl)phenylboronic 0 - 487.2708 acid NH H 3 C 87 ~~3-(Pyrrolidine-l- 04929 87 carbonyl)phenylboronic acid 499269 N 884-(Pyrrolidine -1- 499.270 88 ~carbonyl)phenylboronic acid 4920 _ a 0 4-6 89 (Isobutylaminocarbonyl)phenylboronic 501.2860 acid HN 0 CH 3 903-(Morpholine-4- 0 51.22 90 carbonyl)phenylboronic acid 51.22 -126- 91 ~4-(Morpholine-4- 5526 91 carbonyl)phenylboronic acid 515.2667 92 5-(tert-butyldimethy.lsilanyloxy methyl)pyridine-3-boronic acid N43 4 OH Examples 93 - 128 Part A 5 8-Bromo-2-(2-methoxyethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[4,5-c]quinoline was prepared according to the general methods of Example 6 using 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part D. The crude product was triturated with diethyl ether, isolated by filtration, and dried to provide 8 bromo-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 10 c]quinoline as a white solid. Part B The compounds in the table below were prepared and purified according to the methods of Examples 53 - 92, except that the reactions were heated for 4 hours instead of overnight and 8-bromo-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H 15 imidazo[4,5-c]quinoline was used in lieu of 8-bromo-2-ethoxymethyl- I-(tetrahydro-2H pyran-4-yhnethyl)-1H-imidazo[4,5-c]quinoline. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. 20 N N R - 127 - Measured Example Reagent R Mass 93 Phenylboronic acid 402.2181 94 Pyridine-3-boronic acid 403.2119 95 Pyridine-4-boronic acid 403.2134 96 Thiophene-3-boronic acid 408.1734 97 3-Methylphenylboronic acid 416.2346

H

3 C6 98 4-Methylphenylboronic acid 416.2347

CH

3 99 o-Tolylboronic acid HaC 416.2316 100 3 -Hydroxyphenylboronic acid 418.2113 101 4-Hydroxyphenylboronic acid 418.2138 OH 102 2-Fluorophenylboronic acid F 420.2074 - 128 - 103 3-Fluorophenylboronic acid F 420.2082 104 4-Fluorophenylboronic acid 420.2090 F 105 2 -Fluoropyridine-5-boronic acid 421.2070 F 106 4-Cyanophenylboronic acid 427.2119 107 2 -(Hydroxymethyl)phenylboronic acid HO 432.2302 108 2 -Methoxyphenylboronic acid

H

3

C

0 432.2308 109 3 -(Hydroxymethyl)phenylboronic acid 432.2285 OH 110 4 -(Hydroxymethyl)phenylboronic acid 432.2278 HO 111 4-Fluoro-2-hydroxyphenylboronic acid HO 436.2050 F - 129 ppT 0L3 tuo~ joIq(uaqdoxoqzj,' £ oz i U79 I .0HPOU O!uojoq1uqd~xoflounj,,6 £ 611 VV.9 pTOu -!uoioqI~uaqdAxop;)u(Itu.f'Z 811 HO pp091 potu-o~~adldi~op()E Lit1 10 ppe 3fluoiqjiuuqdoiolqo.

7 'tr L 907. 10lii p!pg otcolu~djt- Ell L I*9, p iuoioq uo ojoiD 121 3-NVDmtyancdoy~peyboo 0 , 473.2595 ___ ___ ___ ___ ___ ___ ___ ___ ___ H 3

C*NCH

3 122 4-(Methanesulfonyl)phenylboronic acid 480.1987 123 3 -(N-Isopropylaminocarbonyl)phenylboronic 0 .. 45872120 acid 1

H

3 C <l NH _______

H

3 124 3 -(N-Propylaminocarbonyl)phenylboonic acid 0 '- 487.2713. NH

H

3 C 4-(N,O 124 Dimethylhydroxylaminocarbonyl)phenylboronic 489.2453 126 4 -Borono-DL-phenylalanine 489.2492

H

2 N _ _0 OOH - 131 - 127 3-(Piperidine-1-carbonyl)phenylboronic acid 1 513.2829 N 128 3-(N-Benzylaminocarbonyl)phenylboronic acid NH 535.2704 Examples 129 - 157 Part A 5 7-Bromo-2-ethoxymethyl- 1-(tetrahydro-2H-pyran-4-ylmethyl)-I H-imidazo[4,5 c~quinoline was prepared according to the general methods of Example 6 using 7-bromo 4-chloro-3-nitroquinoline in lieu of 6-bromo-4-chloro-3-nitroquinoline in Part B. The crude product was triturated with diethyl ether and then recrystallized twice from acetonitrile to provide product as a white crystalline solid. 10 Part B The compounds in the table below were prepared and purified according to the methods of Examples 53 - 92, except that the reactions were heated for 4 hours instead of overnight and 7-bromo-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[4,5-c]quinoline was used in lieu of 8-bromo-2-ethoxymethyl-I-(tetrahydro-2H 15 pyran-4-ylmethyl)- I H-imidazo[4,5-c]quinoline. Example 156 was prepared according to the method used for Example 92, except that it was heated for 4 hours instead of 2 hours. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. 20 -132- N N 0-/ N RO Ex Reagent Measued (M+H) 129 Phenylboronic acid 402.2155 130 Pyridine-4-boronic acid 403.2127 131 3 -Methylphenylboronic acid h 416.2328 -- CH 3 132 4 -Methylphenylboronic acid HaC K416.2325 133 o-Tolylboronic acid H 416.2361 134 3-Fluorophenylboronic acid 420.2122 135 4-Fluorophenylboronic acid F V420.2130 F O 136 2 -Fluoropyridine-5-boronic acid F 421.2059 137 4 -Cyanophenylboronic acid 427.2166 138 2 -(Hydroxymethyl)phenylboronic acid 432.2277 OH - 133 - 139 3-(Hydroxymethyl)phenylboronic acid 432.2299 ____ HO 140 4 -(Hydroxymethyl)phenylboronjc acid -. 432.2272 141 4-Methoxyphenylboronic acid 0.-II~ 432.2289 142 3-Chlorophenylboronic acid 1j7K436.1785 143 2 ,4-Difluorophenylboronic acid F- 438.2017 144 ( 3 -Aminocarbonylphenyl)boronic acid 445.2227 O NH 2 ____ 145 4 -CNN-Dimethylaniino)phenylboronic acid H3C.NhIV 445.2577 ____ 6H 3 146 2,4-Dimethoxyphenylboronic acid IZ.II3I 462.2397 ___ ___ ___ ___ __ ___ ___ ___ _ 6H 3

OH

3 147 3 -(NN- 473.2523 Dimethylaniinocarbonyl)phenylboropnjc acid H 3 C.N 9

OH

3 18 4 -(Methoxycarbonylamino)phenylboronic HCO' HI7.27 148acid 3 0 727 -134- 149 4-{Methanesulfonyl)phenylboronic acid 480.1941 H3§ 150 3-(N-Isopropylaminocarbonyl)phenylboronic 487.2729 acid HN 0 ___________________H_

H

3 C O H 3 4-(NO-0 151 Dimethylhydroxylaminocarbonyl)phenylboro 489.2533 nic acid 0~ NCH 3 6H 3 152 3 -(Methylsulfonylaxnino)phenylboronic acid 495.2061 o NH o N0 13 4 -GIsobutylaminocarbonyl)phenylboronicNH5124 153 ~~acidNH5124 HC

OCH

3 154 3 -(Morpholine-4-carbonyl)phenylboronic 515.2653 acid rN 0 N0 155 4 -(Morpholine-4-carbonyl)phenylboronic 0 515.2626 156 5-(tert-butyldimethylsilanyloxy. H 0 N3.25 methyl)pyridine-3-boronic acid N 3329 - 135 - 157 (4-Aminomethylphenyl)boronic acid, | 431.2473 pincacol ester, HCI

NH

2 Examples 158 -204 Part A 7-Bromo-2-ethoxymethyl-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo(4,5 5 c][1,5]naphthyridine was prepared according to the general methods of Example 6 using 7-bromo-4-hydroxy-3-nitro[1,5]naphthyridine in lieu of 6-bromo-4-hydroxy-3 nitroquinoline in Part A. The crude product was triturated with diethyl ether, isolated by filtration, rinsed with diethyl ether, and dried to provide product as a white solid. Part B 10 The compounds in the table below were prepared and purified according to the methods of Examples 53 - 92, except that the reactions were heated for 4 hours instead of overnight and 7-bromo-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH imidazo[4,5-c][1,5]naphthyridine was used in lieu of 8-bromo-2-ethoxymethyl-l (tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline. Example 204 was 15 prepared according to the method used for Example 92, except that the reaction was heated for 4 hours instead of 2 hours. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. N N 0O N R N Measure Ex Reagent R d Mass (M+H) 158 Furan-3-boronic acid O 393.1937 159 Phenylboronic acid [ 403.2137 -136- 160 Pyridine-3-boronic acid 404.2075 N) 161 Pyridine-4-boronic acid 404.2068 162 Thiophene-3-boronic acid s 409.1674 163 3 -Methylphenylboronic acid 417.2297

CH

3 164 4 -Methylphenylboronic acid 417.2301 165 o-Tolylboronic acid 6QiHa 417.2288 166 2 -Hydroxyphenylboronic acid H 419.2082 167 3 -Hydroxyphenylboronic acid 419.2094 ____ ____ ___ ____ ___ ____ ___OH 168 4 -Hydroxyphenylboronic acid 419.2086 169 3 -Fluorophenylboronic acid 421.2050 170 4 -Fluorophenylboronic acid 421.2038 171 2 -Fluoropyridine-5-boronic acid 422.1982 172 3 -Cyanophenylboronic acid 428.2107 N - 137 - 173 4-Cyanophenylboronic acid N 428.2080 174 2 -(Hydroxymethyl)phenylboronic acid 433.2243 OH 175 2-Methoxyphenylboronic acid 433.2224

CH

3 176 3 -(Hydroxymethyl)phenylboronic acid H 433.2223 ____ ___ ____ ___ ____ ___ ___HO 177 4 -(Hydroxymethyl)phenylboronic acid 433.2221 ____ ____ ___ ____ ___ ____ ___OH 178 4-Methoxyphenylboronic acid 0 433.2199 6H 3 179 2-Chlorophenylboronic acid 437.1726 180 4-Chlorophenylboronic acid 437.1754 181 ( 3 -Aminocarbonylphenyl)boronic acid 446.2185 O

NH

2 182 4 -(N,N-Dimethylamino)phenylboronic acid H3C. 446.2524

CH

3 183 [ 3 -(3-Hydroxypropyl)phenyl]boronic acid 461.2575 - 138 - 184 2,4-Dimethoxyphenylboronic acid J i463.2331

H

3 C. 185 2,6-Dimethoxyphenylboronic acid LJ 463.2362 ____ ___ ____ ___ ___ ____ ___ __

H

3 186 3,4-Dimethoxyphenylboronic acid H 3 0 C Io 463.2343 ___ ___ ___ ___ ___ ___ ___ ___ _ CH 3 187 3-(NN-Dimethylaminocarbonyl)phenylboronic 474.2512 acid H CN 0 188 4-(Methoxycarbonylamino)phenylboronic acid HW 476.2258 0 0" &H 189 Methylhydroxylamninocarbonyl)phenylbororuc H3C 0' 476.2281 acid 0 190 4-(Methanesulfonyl)phenylboronic acid 0.481.1879 H0 6 191 4 -(Cyclopropylaminocarbonyl)phenylboronic 0486.2466 acid NH N 192 3 -(NV-Isopropylaminocarbonyl)phenylboronic 488.2660 acid H _____ ____ ____ ____ ____ ____ ____ ____ H 3

C__OH

3 _ _ _ _ - 139- 193 3 -(N-Propylaminocarbonyl)phenylboronic acid 488.2617 HN 0 8.21 .. CH3 194 4 -Borono-DL-phenylalanine 490.2462 HO

NH

2 195 3 -(Methylsulfonylamino)phenylboronic acid 496.1994 0.. NH Ha 3 0 196 4 -(Methylsulfonylamino)phenylboronic acid HN496.1989 O 197 3-(Pyrrolidine-1-carbonyl)phenylboronic acid 500.2642 N 198 4-(Pyrrolidine- I-carbonyl)phenylboronic acid 500.2633 0 199 3 -(Morpholine-4-carbonyl)phenylboronic acid 516.2590 o N 200 4 -(Morpholine-4-carbonyl)phenylboronic acid N 516.2601 - 140 - 201 4

-(

4 -Oxopiperidine-1-carbonyl)phenylboronic 0tIINiIiII:r 528.2632 acid 0 202 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2- HOq 449.2158 dioxaborolan-2-yl)phenol 0

CH

3 203 3 -(N-Benzylaminocarbonyl)phenylboronic acid HN o 536.2637 204 5-(tert-butyldimethylsilanyloxy- HO methyl)pyridine-3-boronic acid N 434.2174 Examples 205 - 240 Part A 7-Bromo-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- I H 5 imidazo[4,5-c][1,5]naphthyridine was prepared according to the general methods of Example 6 using 7-bromo-4-hydroxy-3-nitro[ 1,5]naphthyridine in lieu of 6-bromo-4 hydroxy-3-nitroquinoline in Part A and 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part D. The crude product was triturated with MTBE, isolated by filtration, rinsed with MTBE, and dried to provide product as a beige solid. 10 Part B The compounds in the table below were prepared and purified according to the methods of Examples 53 - 92, except that the reactions were heated for 4 hours instead of overnight and 7-bromo-2-(2-methoxyethyl)-1 -(tetrahydro-2H-pyran-4-ylmethyl)-I

H

imidazo[4,5-c][1,5]naphthyridine was used in lieu of 8-bromo-2-ethoxymethyl-1 15 (tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. -141- N/ N N R - N Measured Example Reagent R Mass (M+H) 205 Furan-3-boronic acid OCf 393.1906 206 Phenylboronic acid 403.2107 207 Thiophene-3-boronic acid s 409.1692 208 4 -Methylphenylboronic acid 417.2249 209 2 -(Hydroxyphenyl)boronic acid 419.2054 o H 211 3 -Fluorophenylboronic acid 421.2014 F 212 4 -Fluorophenylboronic acid 421.2009 213 2 -Fluoropyridine-5-boronic acid . F422.1990 F 'N 214 ( 2 -Hydroxymethylpheny)boronic acid 4332233 dehydrate OH 215 3-(Hydroxymethyl)phenylboronic acid 433.2220 HO - 142 - 216 4-(Hydroxymethyl)phenylboronic acid 433.2195 ____ ___ ____ ___ ____ ___ OH 217 3-Aminophenylboronic acid 418.2204 monohydrate NH2 218 3-Chlorophenylboronic acid 437.1721 2____ _ac C4 219 2-Chlorophenylboronic acid 437.1715 220 4-Chlorophenylboronic acid C1437.1736 221 2,4-Difluorophenylboronic acid 439.1952 222 (3-Aminocarbonylphenyl)boronic acid 446.2159 o

NH

2 223 3-Carboxyphenylboronic acid 447.2000 0 OH 224 4-Carboxyphenylboronic acid HO 447.2018 0 225 [3-(3-Hydroxypropyl)phenyl]boronic 461.2507 acidHO 226 3,4-Dichlorophenylboronic acid C1 471.1342 - 143 - 227 4-(2-Carboxyvinyl)phenylboronic acid 473.2168 3-(N,N 228 Dimethylaminocarbonyl)phenylboronic 474.2458 acid H3C.N CH3 229 4 -(Methanesulfonyl)phenylboroic 0 .'Z 481.1862 3-CM.N 230 Isopropylaminocarbonyl)phenylboronic 488.2625 acid HN 0 ___ ___ ___ ___ ___ ___ ___ __ H 3 C CH 3 231 ~acid 4 8 2 4

CH

3 232 4 -(Ethylsulfonyl)phenylboronic acid C495.2034 233 3 -(Methylsulfonylarnino)phenylboronic 496.1984 acidNH HC§ 3 0 234 4 -(Methylsulfonylanlino)phenylboronjc N 4618 acid HN4618 - 144- 235 3-(Pyrrolidine-1- 500.2636 carbonyl)phenylboronic acid N 236 4-(Pyrrolidine -1- 0 500.2630 carbonyl)phenylboronic acid N 4- 0 237 (Isobutylaminocarbonyl)phenylboronic 502.2810 acid NH

H

3 C

CH

3 238 3-(Morpholine-4- 516.2607 carbonyl)phenylboronic acid 560 N 0 O" 239 4-(Morpholine-4 carbonyl)phenylboronic acid N516.2592 240 2 -Methoxy-4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)phenol HO 449.2159

O'CH

3 Examples 241 - 277 Part A 5 A solution of 3-methoxypropionyl chloride (4.37 g, 35.7 mmol) in dichloromethane (25 mL) was added to a solution of crude 7-bromo-N 4 -(tetrahydro-2H pyran-4-ylmethyl)quinoline-3,4-diamine (32.5 mmol) in dichloromethane (350 mL). The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure. The resulting amide intermediate was slurried in ethanol (300 mL). A solution of - 145 potassium carbonate (6.73 g, 49 mmol) in water (100 mL) was added, resulting in complete dissolution. The solution was heated at reflux overnight and then cooled to ambient temperature. The ethanol was removed under reduced pressure and the resulting aqueous slurry was extracted with dichloromethane (2 x 350 mL). The combined extracts 5 were washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a red-violet solid. This material was purified by prep HPLC (silica gel eluted with a gradient of 1-10% CMA in chloroform) followed by recrystallization from acetonitrile to provide 6.5 g 7-bromo-2-(2 methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-imidazo[4,5-c]quinoline as a tan 10 crystalline solid. Part B The compounds in the table below were prepared and purified according to the methods of Examples 53 - 92, except that the reactions were heated for 4 hours instead of overnight and 7-bromo-2-(2-methoxyethyl)- I -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H 15 imidazo[4,5-c]quinoline was used in lieu of 8-bromo-2-ethoxymethyl- 1 -(tetrahydro-2H pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinoline. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. . N O 'N R :! \- O Measured Ex Reagent R Mass (M+ 241 Phenylboronic acid 402.2170 242 Pyridine-3-boronic acid 403.2115 243 Pyridine-4-boronic acid 403.2098 -146- 244 Thiophene-3-boronic acid S 408.1740 245 3-Methylphenylboronic acid 416.2302

CH

3 246 4-Methylphenylboronic acid 416.2305 247 o-Tolylboronic acid aJ H3 416.2303 248 3 -Hydroxyphenylboronic acid 418..090 249 2-Fluorophenylboronic acid .j 420.2052 250 3-Fluorophenylboronic acid 420.2065 F 251 4 -Fluorophenylboronic acid 420.2058 252 2 -Fluoropyridine-5-boronic acid 421.2027 253 3-Cyanophenylboronic acid 427.2146 N 254 4-Cyanophenylboronic acid N 427.2105 255 2-Methoxyphenylboronic acid 432.2287 -147- 256 3 -(Hydroxymethyl)phenylboronic acid 432.2268 HO 257 4-(Hydroxymethyl)phenylboronic acid 432.2267 O H 258 4 -Methoxyphenylboronic acid AhIr 432.2270 6CH 3 259 3-Chlorophenylboronic acid 436.1756 CI 260 2 -Chlorophenylboronic acid ICI 436.1763 261 4-Chlorophenylboronic acid _ C436.177 262 2

,

4 -Difluorophenylboronic acid FI438.1998 263 [ 3

-(

3 -Hydroxypropyl)phenyl]boronic acid 460.2587 HO 264 2

,

4 -Dimethoxyphenylboronic acid 0 .xA 462.2371

CH

3 CH 3 265 3

,

4 -Dimethoxyphenylboronic acid

H

3 CO 462.2380

O.CH

3 266 3 ,4-Dichlorophenylboronic acid CI 470.1409 -C4 - 148 - 27 Dimethylaminocarbonyl)phenylboronic acid 47 .255 3 N 0 __ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ 6H 3 28 4 -(Methoxycarbonylamino)phenylboronic HNI h7.234 268 acid 47.24 4-(0- 269 Methylhydroxylaminocarbonyl)phenylboropaic H C A 7.23 acid 0 4 52 3 270 3 -(N-Isopropylaminocarbonyl)phenylboronc 4726 acid 48.26 HN 0 ___ ___ ___ ___ ___ ___ ___ ___ ___ H 3 C CH 3 271 3 -(N-Propylaxninocarbonyl)phienylborornic -487.2679 acid HNy 0 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ H 3 272 4-Borono-DL-phenytalanine 489.2482 HO

I'NH

2 0 9~H 3 0 273 3

,

4 ,5-Trimethoxyphenylboronic acid 9 -S 492.2477 9Cl;r 274 4-Q'yrrolidine-1 -carbonyl)phenylboronic acid T499.2718 _ _ _ _ __ _ _ _N -149- 275 4 -(Isobutylaminocarbonyl)phenylboronic acid 501.2862

H

3 C

CM

3 276 3 -(N-Benzylaminocarbonyl)phenylboronic acid HN 0 535.2708 277 ( 4 -Aminomethylphenyl)boronic acid, 4 pincacol ester, HCI 431.2430

NH

2 Examples 278 - 285 5 A solution of 7-bromo-1-(tetrahydro-2H/-pyran-4-ylmethyl)-IH-imidazo[4,5 c]quinolin-2-amine (18 mg, 0.10 mmol) in 7:3 volume:volume (v:v) chloroform:methanol (2 mL) was added to a test tube, and the solvent was removed by vacuum centrifugation. The boronic acid (0.11 mmol) indicated in the table below and n-propanol (1.6 mL) were sequentially added. The test tube was purged with nitrogen. Palladium (II) acetate (150 10 pL of a 4 mg/mL solution in toluene, 0.0026 rnmol), 2 M aqueous sodium carbonate solution (600 tiL), deionized water (63 pL), and a solution of 0.15 mol% triphenylphosphine in n-propanol (53 iL, 0.0078 mmol) were sequentially added. The test tube was purged with nitrogen, capped, and then heated at 80 *C overnight in a sand bath. Palladium (II) acetate (150 pL of a 4 mg/mL solution in toluene, 0.0026 mmol) was 15 added and the tubes were heated for an additional 4 hours. For Example 285, glacial acetic acid (500 pL), trifluoroacetic acid (500 pL), and deionized water (500 pL) were added to the test tube. The reaction-was heated for 4 hours at 60 *C. The reaction mixtures were purified according to the methods of Examples 53 - 92. The table below shows the reagent used for each example, the structure of the resulting compound, and the 20 observed accurate mass for the isolated trifluoroacetate salt. -150- R NN N Example Reagent RMassre 278 Phenylboronic acid 359.1869 279 Pyridine-3-boronic acid N6.13 280 3-Hydroxyphenylboronic acid HO375.1826 3-(NM-0 281 Diniethylaminocarbonyl)phenylboronic

H

3 C.N N 430.2254 acid

OH

3 0 282 Propylarninocarboriyl)phenylboronic NN 444.2399 acid I 3- O'S 28 (ethylsulfonylamino)phenylboronic H C Y 'K 4217 ______ acid O~ 0 284 carbonyl)phenylboronic acid 3N I4620 285 5-(tert-butyldimethylsilanyloxy N 390.1932 methyl)pyridine-3-boronjc acid ____ ___ ____ ___ ____ ___HO Compound 5 5 2 -Ethoxymethy1-6,7-dimethy..N(tetrahydropyran-4.yI1H-imidazo[4,5-c~pyridin- 1 amine - 151 - N % N 0- J Under a nitrogen atmosphere, 4 -chloro-2-ethoxymethyl-6,7-dimethyl-N (tetrahydropyran-4-yi)-1H-imidazo[4,5-c]pyridin-1-amine (1.00 g, 1 eq) was combined with ammonium formate (1.94 g, 10.5 eq), methanol (40 mL) and ethanol (80 mL). The 5 mixture was flushed with nitrogen for several minutes, 10% palladium on carbon (1.00 g) was added, and then the reaction mixture was heated to 80 *C for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then it was filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure. The residue was partitioned between 5% sodium hydroxide (100 mL) and dichloromethane 10 (100 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 3% methanol in chloroform) to provide 0.52 g of a clear oil which slowly solidified. This material was dried under vacuum at 40 *C for 16 hours to provide 0.52 g of 2 15 ethoxymethyl-6,7-dimethyl-N-(tetrahydropyran-4-yl)-1H-imidazo[4,5-c]pyridin-1 -amine as a white solid, mp 94-97 *C. 'H NMR (300 MHz, CDCl 3 ) 8 8.75 (s, 1H), 5.46 (d, J= 3.2 Hz, I H), 4.87 (br s, 2H), 4.00 (m, 2H), 3.63 (q, J= 7.0 Hz, 2H), 3.45-3.25 (m, 3H), 2.68 (s, 3H), 2.60 (s, 3H), 1.77-1.44 (m, 4H), 1.26 (t, J- 7.0 Hz, 3H); MS (APCI) m/z 305 (M + H)*; Anal. Calcd for C1 6

H

2 4

N

4 0 2 -0.50 H20: C, 61.32; H, 8.04; N, 17.88. Found: C, 20 60.92; H, 7.93; N, 17.75. Compound 6 2 -Ethxoymethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1 amine N-N

O

N N N 25 N O - 152 - 2-Ethxoymethyl-N-(tetrahydro-2H-pyran-4-y)-1H-imidazo[4,5 c][1,5]naphthyridin-I-amine was prepared as described in Example 36 of International Publication No. WO 06/026760. 5 Compound 7 [1-(Tetrahydro-2H-pyran-4-yl)amino-IH-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol N N OH N N Under a nitrogen atmosphere boron tribromide (2.00 mL of I M in dichloromethane, 2 eq) was added dropwise to a chilled (ice water bath) solution of 2 10 ethxoymethyl-N-(tetrahydro-2H-pyran4-yl)-IH-imidazo[4,5-c][1,5]naphthyridin-1-amine (0.327 g, 1 eq) in dichloromethane (10 mL). The reaction was allowed to slowly come to ambient temperature and was stirred overnight. After 18 hours the reaction was quenched with the dropwise addition of water (2 mL) and methanol (10 mL) was added. The dichloromethane and methanol were removed under reduced pressure to provide an 15 aqueous slurry. A solution of ammonia in methanol (10 mL of 7 M) was added and the mixture was stirred for 1 hour. Silica gel (3 g) was added and the slurry was loaded on a prep HPLC column which was then eluted with a gradient of 1 - 30 % CMA in chloroform to provide a yellow solid. The solid was purified by prep HPLC (40 g of silica gel eluted with a gradient of 1 - 25% CMA in chloroform) to provide 15 mg of a light 20 yellow solid. This material was recrystallized from acetonitrile to provide 5 mg of [1 (tetrahydro-2H-pyran-4-yl)anino-IH-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol as light yellow crystals, mp 203-205 *C. 'H NMR (500 MHz, DMSO-d) 8 9.26 (s, 1 H), 9.04 (dd, J= 4.2, 1.6 Hz, I H), 8.53 (dd, J= 8.5, 1.6 Hz, 1 H), 7.76 (dd, J= 8.5,4.2 Hz, 1 H), 6.96 (d, J= 2.5 Hz, 1 H), 5.56 (t, J= 6.1 Hz, 1 H), 4.83 (d,J=6.1 Hz, 2 H), 3.88-3.82 25 (m, 2 H), 3.82-3.75 (m, 1 H), 3.24-3.20 (m, 2 H), 1.65 (br, 2 H), 1.57-1.50 (m, 2 H); 1 3 C NMR (125 MHz, DMSO-d 6 ) & 156.1, 149.6, 145.5, 138.7, 137.3, 137.1, 134.3, 132.1, 122.5, 65.2, 56.4, 54.7, 30.6; MS (APCI) m/z 300.17 (M + H)*; Anal. Calcd for

C

is Hi 7

N

5 0 2 : C, 60.19; H, 5.72; N, 23.40; Found: C, 59.91; H, 5.41; N, 23.05. - 153 - Example 286 2-(Ethoxymethyl)-8-morpholin-4-yl- 1 -(tetrahydro-2H-pyran-4-ylmethyl) 1H-imidazo[4,5-c]quinoline N N 0 N 5 Under a nitrogen atmosphere, toluene (2.50 mL) was added to a vial containing 8 bromo-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (0.45 g, 1.11 mmol), morpholine (0.12 mL, 1.33 mmol), tris(dibenzylideneacetone)dipalladium (35 mg, 0.033 mmol), (+)-2,2' 10 bis(diphenylphosphino)-1,1'-binaphthyl (42 mg, 0.0664 mmol), and sodium tert-butoxide (0.15 g, 1.55 mmol). Nitrogen was bubbled through the mixture. The vial was sealed with a TEFLON lined cap and then heated at 80 *C for 20 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to provide an orange solid. The solid was purified by 15 prep HPLC (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide an off-white solid. This material was recrystallized from ethyl acetate/heptane to provide 178 mg of 2 -ethoxymethy-8-(morpholin-4-y)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[4,5-c]quinoline as an off-white solid, mp 167-170 *C; 'H NMR (500 MHz, d, DMSO) 8 8.94 (s, IH), 8.00 (d, J= 9.2, 1H), 7.54 (dd, J= 9.1, 2.9, 1H), 7.43 (d, J = 2.8, 20 1 H), 4.80 (s, 2H), 4.62 (d, J= 7.3, 2H), 3.81 (m, 6H), 3.57 (q, J= 6.9, 2H), 3.32 (m, 4H), 3.16 (td, J= 11.3, 1.9, 2H), 2.25 (m, IH), 1.50 (qd, J= 12.9, 4.4, 2H), 1.47 (m, 2H), 1.15 (t, J= 7.0, 3H); 1 3 C NMR (125 MHz, d 6 -DMSO) 8 151.4, 149.0, 141.6, 139.1, 136.4, 132.8, 130.9, 118.4, 102.5, 66.5, 66.0, 65.4, 64.3, 50.5, 48.4, 36.0, 29.9, 14.9; Anal. calcd for C23H 3 0N 4 0 3 : C, 67.29; H, 7.37; N, 13.65. Found: C, 67.46; H, 7.19; N, 13.78. 25 - 154 - Example 287 1-[2-(Ethoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl) . H-imidazo[4,5-c]quinolin-8-yl]pyrrolidin-2-one N N 0 K' N oO 5 Under a nitrogen atmosphere, toluene (2.50 mL) was added to a vial containing 8 bromo-2-ethoxymethyl-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (0.45 g, 1.11 mmol), 2-pyrrolidinone (0.10 mL, 1.33 mmol), tris(dibenzylideneacetone)dipalladium (35 mg, 0.033 mmol), (+)-2,2' 10 bis(diphenylphosphino)-1, I'-binaphthyl (42 mg, 0.066 mmol), and sodium Iert-butoxide (0.15 g, 1.55 mmol). Nitrogen was bubbled through the mixture. The vial was capped with a TEFLON lined cap and then heated at 80 "C for 20 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to provide a green solid. The solid was purified 15 by prep HPLC (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide an off-white solid. This material was recrystallized from ethyl acetate/heptane to provide 65 mg of 1-[2-ethoxymethy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 c]quinolin-8-yl]pyrrolidin-2-one as an off-white solid, mp 152-155 "C; 'H NMR (500 MHz, d 6 -DMSO) 8 9.10 (s, 111), 8.90 (d, J= 2.2, 1ff), 8.16 (d, J= 9.1, I H), 7.90 (d, J= 20 9.2, 2.2, 1M), 4.80 (s, 2H), 4.58 (d, J= 7.6, 2H), 4.04 (t, J= 7.2, 2H), 3.81 (t, J= 11.1, 2H), 3.59 (q, J= 6.9, 2H), 3.16 (m, 2H), 2.60 (t, J= 8.2, 2H), 2.34 (m, IH), 2.14 (quin, J 7.6, 21), 1.49 (m, 4H), 1.16 (t, J= 6.9, 3H); 3 C NMR (125 MHz, d 6 -DMSO) S 174.5, 151.7, 143.8, 140.8, 137.6, 136.2, 133.2, 130.6, 119.2, 117.5, 109.5, 66.6, 65.5, 64.3, 50.6, 48.2, 35.5, 32.5, 29.7, 17.4, 14.9; Anal. calcd for C23H 2 8

N

4 0 3 : C, 67.63; H, 6.91; N, 25 13.72. Found: C, 67.47; H, 6.87; N, 13.62. - 155 - Example 288 2-Propyl-l-(tetrahydro-2H-pyran-4-yloxy)-1H-imidazo[4,5-c]quinoline N N O Part A 5 N-(4-Chloroquinolin-3-yl)butyramide (8.4 g, 33.8 mmol), 0-benzylhydroxylamine hydrochloride (7.0 g, 43.9 mmol), and isopropanol (100 mL) were combined and then heated at 60 *C for 7 hours. The reaction mixture was allowed to cool to ambient temperature and a precipitate formed. The supernatant was decanted off. The precipitate was partitioned between dichloromethane (100 mL) and saturated aqueous sodium 10 carbonate (50 mL). The layers were separated and the organic layer was washed with water (2 x 25 mL), dried over potassium carbonate, filtered, and then concentrated under reduced pressure to provide 7.3 g of 1-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinoline as a dark oil which started to crystallize on standing. Part B 15 A mixture of the material from Part A (23 mmol), 10% palladium on carbon (0.50 g), and ethanol (90mL) was placed under hydrogen pressure (30 psi, 2.1 X 105 Pa) for 3 hours. The reaction mixture was filtered through a layer of CELITE filter agent. The filtrate was diluted with dichloromethane (25 mL) and a precipitate formed. The precipitate was isolated by filtration to provide 1.6 g of 2 -propyl-1H-imidazo[4,5 20 c]quinolin-1-ol. The filtrate was concentrated under reduced pressure to obtain additional product. Part C 2 -Propyl-1H-iiidazo[4,5-c]quinolin- 1 -ol (0.4 g, 1.8 mmol), 4 chlorotetrahydropyran (0.4 g, 3.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g, 25 2.6 mmol) were combined in a pressure vessel. The vessel was sealed and then heated in an oven at 120 *C for 22 hours. The reaction was repeated on a larger scale (x8). The small and larger scale reaction mixtures were combined and then partitioned between dichloromethane (150 mL) and saturated aqueous sodium carbonate (25 mL). The organic layer was separated, washed with water (3 x 25 mL), dried over potassium carbonate, -156filtered, and then concentrated under reduced pressure to provide 4.8 g of crude product as a brown oil. This material was purified by column chromatography (silica gel eluted with 5% methanol in dichloromethane containing 5 mL of ammonium hydroxide per liter of dichloromethane) to provide 0.98 g of 2-propyl- I -(tetrahydro-2H-pyran-4-yloxy)- I H 5 imidazo[4,5-c]quinoline as a yellow oil. HRMS (ESI) calcd for Ci1H2 1

N

3 0 2 + H*: 312.1712, found 312.1712. Example 289 2-(Ethoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinolin-6-ol N - N

O

HO N O 10 A solution of 6 -(benzyloxy)-2-(ethoxymethyl)- 1 -(tetrahydro-2H-pyran-4 ylmethyl)-1H-imidazo[4,5-c]quinoline (407 mg, 0.943 mmol), prepared as described in Example 13, in 45% HBr in acetic acid (10 mL) was heated at 65 *C for 1.5 hours. The reaction mixture was cooled in an ice bath and was adjusted slowly to pH 7 with 50% aqueous sodium hydroxide solution. A pale brown precipitate was isolated by filtration, 15 washed, and dried. The solid was recrystallized from boiling hexanes/ethyl acetate (15 mL) to yield 117 mg of 2-(ethoxymethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-IH imidazo[4,5-c]quinolin-6-ol as grey needles, mp 173-177 *C. Anal. calcd for C 19

H

2 3

N

3 0 3 0.20 H20: C, 66.15; H, 6.84; N, 12.18. Found: C, 66.13; H, 6.84; N, 12.02. 20 Example 290 2-(2-Methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol N - N O0 N HO"' O A mixture of 7-(benzyloxy)-2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4 ylmethyl)-lH-imidazo[4,5-c]quinoline (1.00 g, 2.32 mmol, prepared as described in 25 Example 51), 10% palladium hydroxide on carbon (0.1 g), and ethanol (20 mL) was hydrogenated for 18 hours sing a Parr apparatus. The mixture was filtered through - 157 - CELITE filter agent and the filtrate was concentrated under reduced pressure. The resulting oil was purified by prep HPLC (silica gel eluted with 0-35% CMA in chloroform) to yield an off-white solid. The solid was suspended in boiling acetonitrile (20 mL), filtered, washed with cold acetonitrile, and dried to afford 0.429 g of 2-(2 5 methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol as white needles, mp 242-245 *C. Anal. calcd for CI 9 H2N 3 0 3 : C, 66.84; H, 6.79; N, 12.31. Found: C, 66.72; H, 6.68; N, 12.22. Examples 291-293 10 A mixture of 2-(2-methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[4,5-c]quinolin-7-ol (0.75 g, 2.2 mmol, prepared as described in Example 290), cesium carbonate (3.59 g, 11 mmol), and DMF (20 mL) was heated at 75 *C for 30 minutes. A reagent (2.75 mmol) from the Table below was added to the mixture, which 15 was then heated between 17 and 23 hours. The DMF was removed under reduced pressure at 65 *C. The residue was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was separated and washed with brine (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude oil was purified by prep HPLC (silica gel eluted with 10-35% CMA in 20 chloroform) to yield a pale yellow solid. The solid was dissolved in eathanol (10 mL) and anhydrous hydrogen chloride in ethanol was added (3.0 M, about 5 mL). The solution was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure and the pale yellow solid was suspended in cold ethanol (about 15 mL). The solid was isolated by filtration, washed with cold ethanol, and dried to afford the 25 hydrochloride salts of the structures shown in the Table below. N N O0 N, N Example Reagent R -158- 291 c 292 293 Example 291: 576 mg of 2

-(

2 -methoxyethyl)-7-(2-morpholin-4-ylethoxy)-1-(tetrahydro 2 H-pyran- 4 -ylmethyl)-1H-imidazo[4,5-c]quinoline was isolated as beige needles, mp 220-224 *C. Anal. calcd for C 2 5

H

34

N

4 0 4 . 2.40 HCI: C, 55.39; H, 6.77; N, 10.34. Found: 5 C, 55.41; H, 6.97; N, 10.19. Example 292: 273 mg of 2

-(

2 -methoxyethyl)-7-(2-pyrrolidin-1-ylethoxy)-1-(tetrahydro 2 H-pyran- 4 -ylmethyl)-IH-imidazo[4,5-c]quinoline was isolated as brown needles, mp 205-209 *C. Anal. calcd for C 2 6H 36

N

4 0 3 - 3.25 HCl: C, 54.68; H, 6.93; N, 9.81. Found: C, 54.68; H, 6.84; N, 9.66. 10 Example 293: 401 mg of 2

-(

2 -methoxyethyl)-7-(2..piperidin-1-ylethoxy)-I-(tetrahydro 2 H-pyran- 4 -ylmethyl)-IH-imidazo[4,5-c]quinoline was isolated as brown needles, mp 205-209 *C. Anal. calcd for C 26

H

36

N

4 0 3 - 3.25 HCl: C, 54.68; H, 6.93; N, 9.81. Found: C, 54.68; H, 6.84; N, 9.66. 15 Example 294 1-(Cycloheptylmethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline N O N A mixture of cycloheptyl cyanide (3.00 mL, 22.5 mmol), 10% palladium on carbon 20 (0.42 g), and 3 M hydrogen chloride in ethanol (45 mL) was hydrogenated on a Parr apparatus overnight. Platinum oxide (0.10 g) was added to the reaction mixture, which was then hydrogenated on a Parr apparatus for 4 hours. The reaction mixture was filtered through CELITE filter agent, which was rinsed afterwards with ethanol. The filtrate was -159concentrated to yield a solid that was treated with diethyl ether (50 mL). A white solid was isolated by filtration and was dried to provide 1.57 g of 1-cycloheptylmethanamine hydrochloride. 1-(Cycloheptylmethyl)-2-(ethoxymethyl)-IH-imidazo[4,5-c]quinoline was 5 prepared according to the general methods of Example 27 using 1 cycloheptylmethanamine hydrochloride in lieu of (S)-(+)-tetrahydrofurfurylamine in Part A, and palladium on carbon (10% w/w) as the catalyst and methanol/acetontrile as the solvent in Part B. The crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-15%% CMA in chloroform) to provide a yellow oil. The oil was dissolved 10 in methanol/chloroform and treated with about 0.25 g of activated carbon for 2 hours. The mixture was filtered through CELITE filter agent and the filtrate was concentrated and dried to yield I-(cycloheptylmethyl)-2-(ethoxymethyl)-H-imidazo[4,5-c]quinoline as a yellow oil; Anal. Called for C 21

H

27

N

3 0 - 0.2CH40: C, 74.05; H, 8.15; N, 12.22; Found: C, 73.84; H, 8.13; N, 12.17. 15 Examples 295-320 A toluene solution (250 pL) containing 8 -bromo-2-ethoxymethyl-1-(tetrahydro 2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (prepared as described in Example 6) (40 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.6 mg, 0.06 equivalents), and (+/-)- 2 ,2'-bis(diphenylphosphino)-1,1'-binapthalene (7.6 mg, 0.12 equivalents) was 20 added to a test tube containing 1 M potassium tert-butoxide in THF (150 pL) and one of the reagents (1.5 equivalents) listed in the table below. The test tube was purged with nitrogen, capped, and then heated at 80 *C overnight in a sand bath. The solvent was removed on a vacuum centrifuge and the product was purified as described above in Examples 53-92. The table below shows the reagent used for each example, the structure 25 of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. N 0-CH 3 N 1- O R Example Reagent R Measured Mass -160- (M+ 295 Acetamide H3C NH 383.2085 0 296 2-Pyrrolidone o N 409.2206 297 Cyclopropyanecarboxamide 0 NH 409.2233 298 Morpholine N411.2355 299 l,l-Dimethylurea 0 NH 412.2338

H

3 C'N

CH

3 NH 300 N,N-Dimethylethylenediamine

H

3

C.

1 N 412.2702

CH

3 301 3-Methoxypropylamine NH 413.2518

H

3 C N 302 1I-Methyl-2-imidazolidinone 424.2321

IH

3 0 N 303 1 -Methylpiperazine (424.2677

CH

3 NH 304 Tetrahydrofurfurylamine 425.2547 - 161 - NH 305 2-(Aminoniethyl)pyridine N432.2416 NH 306 3-Picolylarnine 432.2394 NH 307 4-Picolylamine 432.2442 N 308 3 ,5-Dimethylpiperidine H3' C3 437.2884 NH 309 Aminomethylcyclohexane 6437.2878 N 310 2,6-DimethyImorpholine (3 0 H 439.2697 311 4-(Hiydroxyniethyl)piperidine r2II 439.2683 HO

H

3 C NH 312 (R)-(+)-1-Phenylethylamine 445.2570 -162-

H

3 C ,NH 313 (S)-(-)- 1 -Phenylethylamine 445.2570 o NH 314 1 -Carbamylpiperidine N 452.2629 315 1]-(2-Hydroxyethyl)-2-N 315 imidazolidinone ND 454.2412 HO NH 316 4-(2-Aminoethyl)morpholine 454.2796 N O 317 NV-(2-Hydroxyethyl)piperazine N 454.2816 OH N 318 1,2,3,4-Tetrahydroisoquinoline 457.2572 319 1,1-Dioxidotetrahydrothien-3- NH 459.2025 ylarme <Ys O~b N 320 4-Phenylpiperidine 485.2876 - 163 - Examples 321-350 A toluene solution (250 pL) containing 7-bromo-2-ethoxymethyl- 1 -(tetrahydro 2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (prepared as described in Examples 5 129-157) (40 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.3 mg, 0.03 equivalents), and (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binapthalene (4.0 mg, 0.06 equivalents) was added to a test tube containing 1 M potassium tert-butoxide in THF (150 pL) and one of the reagents (1.2 equivalents) listed in the table below. The test tube was purged with nitrogen, capped, and then heated at 80 *C overnight in a sand bath. A 10 toluene solution (250 ptL) containing tris(dibenzylideneacetone)dipalladium(0) (3.3 mg, 0.03 equivalents) and (+/-)-2,2'-bis(diphenylphosphino)--1,1'-binapthalene (4.0 mg, 0.06 equivalents) was added to each test tube. The test tube was purged with nitrogen, capped, and then heated at 80 "C overnight in a sand bath. The solvent was removed on a vacuum centrifuge and the product was purified as described above in Examples 53-92. The table 15 below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. CH N N 0-'/ 3 R O Example Reagent R Measured Mass HN 321 Acetamide 0 383.2081 0 CH 3 322 2-Pyrrolidone 409.2197 HN 323 Cyclopropanecarboxamide 0 409.2232 324 Morpholine 411.2372 -164- 325 NN-Dimetbylethylenediamine 412.2680 _______ __________________

H

3 C. CH 3 HN 326 3-Methoxypropylamine f,413.2531 HN 327 Cyclohexylamine jJ423.2738 328 1 -Methyl-2-imidazolidinone N IIIL 424.2351 HN 309 T ethyolifryaine0 425.2585 HN 331 Benzylamine &- 431.2417

H

3 C. 332 N-Methylaniline 431.2426 HN~ 333 2-(Aminomethyl)pyridine 432.2358 HN 334 3-Picolylainine **.432.2364 - 165- HN 335 4-Picolylamine No 432.2362 HN 336 Aminomethylcyclohexane 437.2911 337 N-Methylcyclohexylamine 437.2877

H

3 C N 338 2,6-Dimethylmorpholine O 439.2698

CH

3 339 4-(Hydroxymethyl)piperidine 439.2688 _____ ____OH HN 340 Benzamide - o 445.2212 HN 341 (R)-(+)-1-Phenylethylamine CH, 445.2561 342 (S)-(-)-1-Phenylethylamine

CH

3 445.2571 NN 343 1-Acetylpiperazine HC .. r N 452.2667 HN 344 1-Carbamylpiperidine N o 452.2635 -166- HN 345 4-(2-Aminoethyl)morpholine N 454.2778 CN] rN 346 N-(2-Hydroxyethyl)piperazine N 454.2782 HO 347 1, 2

,

3

,

4 -Tetrahydroisoquinoline 457.2596 348 1,2,3,4-Tetrahydroquinoline 457.2556 349 4-Phenylpiperidine N 485.2935 N 350 1-Phenylpiperazine N 486.2866 Example 351 5-{[2-(2-{[2-(2-Methoxyethyl)-1-(tetrahydro-2H-pyran4-ylmethyl)-IH-imidazo[4,5 c]quinolin-7-yl]oxy)ethoxy)ethyl]amino}-5-oxopentanoic acid N 0 N 0 o N 50 Part A A stirring solution of 2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H imidazo[4,5-c]quinolin-7-ol (2.00 g, 5.86 mmol), tert-butyl 2-(2 hydroxyethoxy)ethylcarbamate (1.38 g, 6.74 mmol) and triphenylphosphine (1.77 g, 6.74 - 167 mmol) in tetrahydrofuran (40 mL) was placed under an atmosphere of nitrogen and cooled to 0 *C. Diisopropyl azodicarboxylate (1.3 mL, 6 .74-mmol) was added dropwise over 5 minutes via syringe. The resulting solution was allowed to warm to ambient temperature and stirred overnight. After 26 hours, the volatiles were removed under reduced pressure 5 and the resulting residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 - 35% CMA-80/chloroform). The product containing fractions were combined and concentrated under reduced pressure to yield 2.77g of tert-butyl 2-(2-{[2-(2-methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-iH imidazo[4,5-c]quinolin-7-ylloxy~ethoxy)ethylcarbamate as a light brown solid. 10 Part B 3 M HCI in ethanol (5.1 mL, 15.2 mmol) was added dropwise to a stirring solution of tert-butyl 2-(2-{[2-(2-methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo( 4 ,5-c]quinolin-7-yl]oxy)ethoxy)ethylcarbamate (2.67 g, 5.05 mmol) in ethanol (25 mL). The resulting solution was stirred at reflux 2 hours, cooled to ambient 15 temperature and concentrated under reduced pressure to yield 2.54 g of 2-(2-{[2-(2 methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7 yljoxy}ethoxy)ethanamine hydrochloride as a brown foam. Part C Glutaric anhydride (0.14 g, 1.20 mmol) was added to a stirring solution of 2-(2 20 {[2-(2-methoxyethyl)-I-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7yl]oxy}ethoxy)ethanamine hydrochloride (0.50 g, 0.997 mmol) in pyridine (2 mL) at ambient temperature. After 18 hours, the solution was concentrated under reduced pressure and the resulting residue dissolved in water (10 mL). The pH was adjusted to 10 with I M sodium carbonate (aq) and the mixture was transferred to a separatory funnel. 25 The aqueous layer was extracted with dichloromethane (1 x 20 mL) and ethyl acetate (2 x 20 mL) and the organic layers were discarded. The pH of the aqueous layer was adjusted to 4 with 6 M HCl (aq) and extracted with dichloromethane (2 x 30 mL) and ethyl acetate (I x 30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to yield 332 mg of 5-{[2-(2-{[2-(2-methoxyethyl)-I 30 (tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7 yl]oxy}ethoxy)ethyl]amino}-5-oxopentanoic acid as a tan foam. Anal. called for C2gH 3 sN 4

O

7 -0.8H 2 0: C, 60.37; H, 7.17; N, 10.06. Found: C, 60.49; H, 6.96; N, 9.77. - 168 - Example 352 3-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-[2-(2-{[2-(2-methoxyethyl)-1-(tetrahydro 2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy)ethoxy)ethyl]propanamide 0 -N o o0 5 1-(3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropyl)-1H-pyrrole-2,5-dione (0.156 g, 0.588 nmol) was added to a stirring solution of 2 -(2-{[2-(2-methoxyethyl)-1-(tetrahydro 2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinolin-7-yl]oxy}ethoxy)ethanamine (0.229 g, 0.534 mmol) in dichloromethane (6 mL) at ambient temperature. After 21 hours, the 10 solution was loaded directly onto a 2 mm silica gel plate and purified by radial chromatography; eluting with 5% methanol in dichloromethane. The product containing fractions were combined and concentrated to yield 200 mg of 3-(2,5-dioxo-2,5-dihydro IH-pyrrol-1-yl)-N-[2-(2-{[2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H imidazo[ 4 ,5-c]quinolin-7-yl]oxy}ethoxy)ethyl]propanamide as a light yellow foam. Anal. 15 calcd for C 30

H

3 7

N

5 0 7

.H

2 0: C, 60.29; H, 6.58; N, 11.72. Found: C, 59.94; H, 6.73; N, 12.03. Example 353 3-[2-Ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl] N,N-dimethylpropanamide . N N 20 N Part A A thick walled glass vessel, equipped with stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5 c]quinoline (0.56 g, 1.5 mmol) in N,N-dimethylformamide (10 mL). To this solution was 25 added in succession a solution of palladium acetate (0.1 eq., 37 mg, 0.15 mmol) and tri -169ortho-tolylphosphine (0.2 eq., 91 mg, 0.3 mmol) in N-dimethylformamide (5 mL); triethylamine (3.0 eq. , 0.6 mL); and a solution of NN-dimethylacrylamide (1.2 eq., 178 mg, 1.8 mmol) in NN-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen and the vessel was sealed and heated to 120 'C for 18 hours. The reaction vessel 5 was cooled to ambient temperature. The reaction mixture was transferred to a round bottom flask and concentrated to dryness under reduced pressure. The residue was treated with water and 10% NaOH, adjusting to pH=12. The mixture was then extracted with dichloromethane. The organic fractions were combined, dried (MgSO 4 ) and concentrated to dryness. Purification of the residue with a HORIZON HPFC system (silica cartridge, 0 10 15% CMA/chloroform) followed by recrystallization from acetonitrile provided 0.54 g of (2E)-3-[2-ethyl-l -(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl] N,N-dimethylprop-2-enamide as a white crystalline solid, mp 235-237 *C. MS (APCI) m/z 393 (M + H)*; Anal. Calcd for C 23

H

2

&N

4 0 2 : C, 70.38; H, 7.19; N, 14.27. Found: C, 70.29; H, 7.12; N, 14.28. 15 Part B A glass Parr bottle (500 mL) was charged with 10% palladium on carbon (0.1 g) wetted with ethanol (5 mL) and a solution of (2E)-3-[2-ethyl- I-(tetrahydro-2H-pyran-4 ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide (0.5 g, 1.27 mimol) in methanol (250 mL). The vessel was placed on a Parr apparatus, evacuated and 20 charged with hydrogen (-50 psi). The mixture was shaken at ambient temperature for 24 hours and then monitored for completion by HPLC/mass-spec. The reaction was re charged with additional catalyst and hydrogen and maintained at ambient temperature for an additional 24 hours. The reaction mixture was filtered through a 0.2 micron PTFE membrane filter and the filtrate was concentrated to dryness under reduced pressure. 25 Purification using a HORIZON HPFC system (silica cartridge, 0-10% CMA/chloroform) followed by recrystallization from acetonitrile provided 0.16 g of 3-[2-ethyl-1-(tetrahydro 2H-pyran-4-ylmethyl)-IH-imidazo[4,5-c]quinolin-7-yl]-N,V-dimethylpropanamide as a white crystalline solid, 176-178 "C. MS (APCI) m/z 395 (M + -1)*; Anal. Calcd for C23HoN 4

O

2 : C, 70.02; H, 7.66; N, 14.20. Found: C, 69.83; H, 7.62; N, 14.26. 30 -170- Example 354 3-[2-Ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid N N OH 5 PartA A thick walled glass vessel, equipped with stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-imidazo[4,5 c]quinoline (3.7 g, 10.0 mmol) in NN-dimethylformamide (70 mL). To the solution was added in succession a solution of palladium acetate (224 mg, 1.0 mmol) and tri-ortho 10 tolylphosphine (608 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL); triethylamine (4.2 mL, 30.0 mmol); and a solution of ethyl acrylate (1.2 g, 12.0 mmol) in NN dimethylformamide (2 mL). The reaction mixture was purged with nitrogen and the vessel was sealed and heated to 120 "C for 18 hours. The reaction vessel was cooled to ambient temperature. The reaction mixture was transferred to a round bottom flask and 15 concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (150 mL) and washed with saturated potassium carbonate solution. The fractions were separated. The organic fraction was dried (MgSO 4 ) and concentrated. Purification using a HORIZON IPFC system (silica cartridge, 0-12% CMA/chloroform) followed by recrystallization from acetonitrile provided 2.5 g of ethyl (2E)-3-[2-ethyl-I 20 (tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a white solid, mp 210-212 "C. MS (APCI) m/z 394 (M + H)*; Anal. Calcd for C 2 3

H

2 7

N

3 0 3 : C, 70.21; H, 6.92; N, 10.68. Found: C, 70.19; H, 6.93; N, 10.67. Part B A glass Parr bottle (500 mL) was charged with 10% palladium on carbon (0.25 g) 25 wetted with ethanol (5 mL) and a slurry of ethyl (2E)-3-[2-ethyl-1-(tetrahydro-2H-pyran 4 -ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate (2.4 g, 6.1 mmol) in methanol (250 mL). The vessel was placed on a Parr apparatus, evacuated and charged with hydrogen (-50 psi). The mixture was then shaken at ambient temperature for 48 hours. The reaction was monitored by HPLC/mass-spec and found to be complete. The reaction - 171 mixture was filtered through a 0.2 micron PTFE membrane filter and the filtrate was concentrated to dryness under reduced pressure. Purification using a HORIZON HPFC system (silica cartridge, 0-11% CMA/chloroform) followed by recrystallization from 60:30 hexane/ethyl acetate (30 mL) provided 1.9 g of ethyl 3-[2-ethyl-1-(tetrahydro-2H 5 pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate as a white crystalline solid, mp 113-115 *C. MS (APCI) m/z 396 (M + H)+; Anal. Calcd for C 23

H

29

N

3 03-0.75 H 2 0: C, 67.54; H, 7.52; N, 10.27. Found: C, 67.25; H, 7.67; N, 10.26. Part C To a stirred solution of ethyl 3

-[

2 -ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H 10 imidazo(4,5-c]quinolin-7-yl]propanoate (1.8 g, ) in methanol (3 mL) was added Claisen's alkali (5 mL). The reaction mixture was heated to 70 'C and maintained for 18 hours. The reaction mixture was removed from the heat and treated with citric acid, adjusting to pH=5. The mixture was then concentrated to dryness under reduced pressure. The resulting solid was taken up in water and neutralized to pH=7 with saturated potassium 15 carbonate solution. A white crystalline solid formed. The crystalline solid was collected by vacuum filtration and air dried to provide 1.4 g of 3-[ 2 -ethyl-l-(tetrahydro-2H-pyran-4 ylmethyl)-lH-imidazo[4,5-c]quinolin-7-yl]propanoic acid as a white solid, mp 198-200 *C. MS (APCI) m/z 368 (M + H)+; Anal. Calcd for C 2 1

H

25

N

3 0 3 : C, 68.64; H, 6.86; N, 11.44. Found: C, 68.42; H, 6.67; N, 11.35. 20 Exemplary Compounds and Pharmaceutical Compositions Certain exemplary compounds, including some of those described above in the Examples, have the following Formula (I1b, IIIa, IVb, Vb, or Vla) and an X'. group and an R2a substituent shown in the following table, wherein each line of the table is matched 25 with the Formula (lb, Ila, IVb, Vb, or Via) to represent a specific embodiment of a compound (or pharmaceutically acceptable salt thereof) of the invention or a pharmaceutical composition of the invention comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of the specific embodiment of a compound (or a pharmaceutically acceptable salt thereof). -172- N N N N \ N R2.

>-R

2 . N N lIb IIla N N N N N "-N I >R 2 \ '>-R, N N RaN -N

X.Y[

7 NH y. .C O IVb VIa Vb 5 X'a R2a -NH- n-propyl -NH- n-butyl -NH- methoxymethyl -NH- ethoxymethyl -NH- 2-methoxyethyl

-CH

2

-

n-propyl

-CH

2

-

n-butyl

-CH

2

-

methoxymethyl

-CH

2

-

ethoxymethyl

-CH

2

-

2-methoxyethyl Certain exemplary compounds, including some of those described above in the Examples, have the following Formula (IIc) and an R2. and an R3b substituent shown in the following table, wherein each line of the table is matched with the Formula (Ic) to 10 represent a specific embodiment of a compound, a therapeutically effective amount of which (or a pharmaceutically acceptable salt thereof) in combination with a pharmaceutically acceptable carrier is a specfic embodiment of a pharmaceutical composition of the invention. - 173 - NN N N __ _ __ _ _ __ _ _ __ _ _ R3b n-propyl 4 -(aminomethyl)phenyl n-butyl 4 -(aininoniethyl)phenyl methoxymethyl 4 -(aminomethyl)phenyl ethoxymethyl 4 -(aniinomethyl)phenyl 2-methoxyethyl 4 -(aminomethyl)pheny-l n-propyl 3 -(miethylsulfonylaniino)phenyl n-butyl 3 -(methylsulfonylaxnino)phenyl methxymehyl 3 -(methylsulfonylaniino)phenyl ethoxymethyl 3 -(methylsulfonylamino)phenyl 2-methoxyethyl 3 -(methylsulfonylamino)phenyl n-propyl2-hydroxyphenyl n-butyl2-hydroxyphenyl methoxynietbyl -yrxpel ethoxymethyl -yrxpey 2-methoxyethyl -yrxpel n-propyl -yrxpel n-butyl -yrxpel methoxymethyl -yrxpel ethoxyinethyl -yrxpel 2-methoxyetbyl -yrxpel n-propyl -yrxpel n-butyl -yrxpel inethoxymethyl -yrxpey ethoxymethylxphny - 174- 2-methoxyethyl 4-hydroxyphenyl n-propyl 2-(bydroxymethyl)phenyl n-butyl 2 -(hydroxymethyl)phenyj methoxymethyl 2 -(hydroxyniethyl)phenyl ethoxyethyl2-(hydroxymethyl)phenyl 2-methoxyethyl 2 -(hydroxymethyl)phenyl n-propyl 3 -(hydroxymetbyl)phenyl __________________ 3 -(hydroxymethyl)phenyl methoxymethyl 3 -(hydroxymethyl)phenyl ethoxymethyl 3 -(hydroxymethyl)phenyl 2-metboxyethyl 3 -(hydroxymethyl)phenyl n-propyl 4 -(hydroxyniethyl)phenyl n-butyl 4 -(hydroxymethyl)phenyl methoxymethyl 4 -(hydroxymethyl)phenyl ethoxymethyl 4 -(hydroxymethyl)phenyl 2-methoxyethyl 4 -(hydroxymethyl)phenyl n-propyl pyridin-3-yI n-butyl pyridin-3-yJ methoxyinethyl pyridin-3 -yI ethoxymethyl pyridin-3 -yi 2-methoxyethyl pyridin-3 -yl n-propyl yiin4y n-butyl prdn4y methoxymethyl prdn4y ethoxymethyl prdn4y n-propyl (cyclopropylinethyl)amnino methoxymethyl (cyclopropylmeth yl)amjino ethoxymethyl (cyclopropylniethyl)axnino 2-methoxyethyl (cyclopropylrnethyl)azmjno - 175n-propyl (N) _____ ____ ____ ____ __ 0 n-butyl I N _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0 methoxymethylI (N) 2-ethoxyethylI (N) 2methoxyethyl n-propyl -176n-butyl I O4zz N methoxymethyl ethoxymethyl 2-methoxyethyl Certain exemplary compounds, including some of those described above in the Examples, have the following Formula (Id) and an R2b and an R 3 a substituent shown in the following table, wherein each line of the table is matched with the Formula (Id) to 5 represent a specific embodiment of a compound, a therapeutically effective amount of which (or a pharmaceutically acceptable salt thereof) in combination with a pharmaceutically acceptable carrier is a specfic embodiment of a pharmaceutical composition of the invention. N N \-R2b N \-oO RU 10 lId R2b R3. n-butyl 4-(aminomethyl)phenyl 2-methoxyethyl 4-(aminomethyl)phenyl n-butyl 3 -(methylsulfonylamino)phenyl 2-methoxyethyl 3 -(methylsulfonylamino)phenyl n-butyl 2-hydroxyphenyl 2-methoxyethyl 2-hydroxyphenyl -177n-butyl 3-hydroxyphenyl 2-methoxyethyl 3-hydroxyphenyl n-butyl 4-hydroxyphenyl 2-methoxyethyl 4-hydroxyphenyl n-butyl 2-(hydroxymethyl)phenyl 2-methoxyethyl 2-(hydroxymethyl)phenyl n-butyl 3-(hydroxymethyl)phenyl 2-methoxyethyl 3-(hydroxymethyl)phenyl n-butyl 4-(hydroxymethyl)phenyl 2-methoxyethyl 4-(hydroxymethyl)phenyl n-butyl pyridin-3-yl 2-methoxyethyl pyridin-3-yl n-butyl pyridin-4-yl 2-methoxyethyl pyridin-4-yl Compounds described herein have been found to modulate cytokine biosynthesis by inducing the production of interferon a and/or tumor necrosis factor a in human cells 5 when tested using one of the methods described below. CYTOKINE INDUCTION IN HUMAN CELLS An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon (a) and tumor necrosis factor (a) (IFN-a and 10 TNF-a, respectively) secreted into culture media as described by Testerman et. al. in "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995). Blood Cell Preparation for Culture 15 Whole blood from healthy human donors is collected by venipuncture into vacutainer tubes or syringes containing EDTA. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham -178 - Biosciences Piscataway, NJ). Blood is diluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced Salts Solution (HBSS). Alternately, whole blood is placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL) centuifuge frit tubes containing density gradient medium. The PBMC layer is collected 5 and washed twice with DPBS or HBSS and re-suspended at 4 x 106 cells/mL in RPMI complete. The PBMC suspension is added to 96 well flat bottom sterile tissue culture plates containing an equal volume of RPMI complete media containing test compound. Compound Preparation 10 The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. The compounds are generally tested at concentrations ranging from 30-0.014 pM. Controls include cell samples with media only, cell samples with DMSO only (no compound), and cell samples with reference compound. 15 Incubation The solution of test compound is added at 60 pM to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the 20 desired range (usually 30-0.014 p.M). The final concentration of PBMC suspension is 2 x 106 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37*C in a 5% carbon dioxide atmosphere. Separation 25 Following incubation the plates are centrifuged for 10 minutes at 1000 rpm (approximately 200 x g) at 4"C. The cell-free culture supernatant is removed and transferred to sterile polypropylene tubes. Samples are maintained at -30 to -70 0 C until analysis. The samples are analyzed for IFN-a by ELISA and for TNF-a by IGEN/BioVeris Assay. 30 - 179 - Interferon (a) and Tumor Necrosis Factor (a) Analysis IFN-a concentration is determined with a human multi-subtype colorimetric sandwich ELISA (Catalog Number 41105) from PBL Biomedical Laboratories, Piscataway, NJ. Results are expressed in pg/mL. 5 The TNF-a concentration is determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8 analyzer from BioVeris Corporation, formerly known as IGEN International, Gaithersburg, MD. The immunoassay uses a human TNF-a capture and detection antibody pair (Catalog Numbers AHC3419 and AHC3712) from Biosource International, Camarillo, CA. Results are expressed in pg/mL. 10 Assay Data and Analysis In total, the data output of the assay consists of concentration values of TNF-a and IFN-a (y-axis) as a function of compound concentration (x-axis). Analysis of the data has two steps. First, the greater of the mean DMSO (DMSO 15 control wells) or the experimental background (usually 20 pg/mL for IFN-a and 40 pg/mL for TNF-a) is subtracted from each reading. If any negative values result from background subtraction, the reading is reported as " * ", and is noted as not reliably detectable. In subsequent calculations and statistics, " * ", is treated as a zero. Second, all background subtracted values are multiplied by a single adjustment ratio to decrease 20 experiment to experiment variability. The adjustment ratio is the area of the reference compound in the new experiment divided by the expected area of the reference compound based on the past 61 experiments (unadjusted readings). This results in the scaling of the reading (y-axis) for the new data without changing the shape of the dose-response curve. The reference compound used is 2-(4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-a,a 25 dimethyl- H-imidazo[4,5-c]quinolin-1-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91) and the expected area is the sum of the median dose values from the past 61 experiments. The minimum effective concentration is calculated based on the background subtracted, reference-adjusted results for a given experiment and compound. The 30 minimum effective concentration (prmolar) is the lowest of the tested compound concentrations that induces a response over a fixed cytokine concentration for the tested -180cytokine (usually 20 pg/mL for IFN-m and 40 pg/mL for TNF-a). The maximal response is the maximal amount of cytokine (pg/ml) produced in the dose-response. CYTOSINE INDUCTION IN HUMAN CELLS 5 (High Throughput Screen) The CYTOKINE INDUCTION IN HUMAN CELLS test method described above was modified as follows for high throughput screening. Blood Cell Preparation for Culture 10 Whole blood from healthy human donors is collected by venipuncture into vacutainer tubes or syringes containing EDTA. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham Biosciences Piscataway, NJ). Whole blood is placed in Accuspin (Sigma) or LeucoSep 15 (Greiner Bio-One, Inc., Longwood, FL) centrifuge frit tubes containing density gradient medium. The PBMC layer is collected and washed twice with DPBS or HBSS and re suspended at 4 x 106 cells/mL in RPMI complete (2-fold the final cell density). The PBMC suspension is added to 96-well flat bottom sterile tissue culture plates. 20 Compound Preparation The compounds are solubilized in dimethyl sulfoxide (DMSO). The compounds are generally tested at concentrations ranging from 30 - 0.014 pM. Controls include cell samples with media only, cell samples with DMSO only (no compound), and cell samples with a reference compound 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-ac-dimethyl 25 IH-imidazo[4,5-c]quinolin-1-yl]ethanoI hydrate (U.S. Patent No. 5,352,784; Example 91) on each plate. The solution of test compound is added at 7.5 mM to the first well of a dosing plate and serial 3 fold dilutions are made for the 7 subsequent concentrations in DMSO. RPMI Complete media is then added to the test compound dilutions in order to reach a final compound concentration of 2-fold higher (60 - 0.028 pM) than the final 30 tested concentration range. - 181 - Incubation Compound solution is then added to the wells containing the PBMC suspension bringing the test compound concentrations to the desired range (usually 30 - 0.014 pM) and the DMSO concentration to 0.4 %. The final concentration of PBMC suspension is 5 2x10 6 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37"C in a 5% carbon dioxide atmosphere. Separation Following incubation the plates are centrifuged for 10 minutes at 1000 rpm 10 (approximately 200 g) at 4"C. 4-plex Human Panel MSD MULTI-SPOT 96-well plates are pre-coated with the appropriate capture antibodies by MesoScale Discovery, Inc. (MSD, Gaithersburg, MD). The cell-free culture supematants are removed and transferred to the MSD plates. Fresh samples are typically tested, although they may be maintained at -30 to -70*C until analysis. 15 Interferon-a and Tumor Necrosis Factor-a Analysis MSD MULTI-SPOT plates contain within each well capture antibodies for human TNF-a and human IFN-a that have been pre-coated on specific spots. Each well contains four spots: one human TNF-a capture antibody (MSD) spot, one human IFN- a capture 20 antibody (PBL Biomedical Laboratories, Piscataway, NJ) spot, and two inactive bovine serum albumin spots. The human TNF-a capture and detection antibody pair is from MesoScale Discovery. The human IFN-a multi-subtype antibody (PBL Biomedical Laboratories) captures all IFN-a subtypes except IFN-c F (IFNA21). Standards consist of recombinant human TNF-a (R&D Systems, Minneapolis, MN) and IFN-a (PBL 25 Biomedical Laboratories). Samples and separate standards are added at the time of analysis to each MSD plate. Two human IFN-a detection antibodies (Cat. Nos. 21112 & 21100, PBL) are used in a two to one ratio (weight:weight) to each other to determine the IFN-a concentrations. The cytokine-specific detection antibodies are labeled with the SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeled detection antibodies 30 to the wells, each well's electrochemoluninescent levels are read using MSD's SECTOR HTS READER Results are expressed in pg/mL upon calculation with known cytokine standards. - 182 - Assay Data and Analysis In total, the data output of the assay consists of concentration values of TNF-i or IFN-a (y-axis) as a function of compound concentration (x-axis). 5 A plate-wise scaling is performed within a given experiment aimed at reducing plate-to-plate variability associated within the same experiment. First, the greater of the median DMSO (DMSO control wells) or the experimental background (usually 20 pg/mL for IFN-a and 40 pg/mL for TNF-a) is subtracted from each reading. Negative values that may result from background subtraction are set to zero. Each plate within a given 10 experiment has a reference compound that serves as a control. This control is used to calculate a median expected area under the curve across all plates in the assay. A plate wise scaling factor is calculated for each plate as a ratio of the area of the reference compound on the particular plate to the median expected area for the entire experiment. The data from each plate are then multiplied by the plate-wise scaling factor for all plates. 15 Only data from plates bearing a scaling factor of between 0.5 and 2.0 (for both cytokines IFN-a; TNF-ct) are reported. Data from plates with scaling factors outside the above mentioned interval are retested until they bear scaling factors inside the above mentioned interval. The above method produces a scaling of the y-values without altering the shape of the curve. The reference compound used is 2

-[

4 -amino-2-ethoxymethyl-6,7,8,9 20 tetrahydro-a,a-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91). The median expected area is the median area across all plates that are part of a given experiment. A second scaling may also be performed to reduce inter-experiment variability (across multiple experiments). All background-subtracted values are multiplied by a 25 single adjustment ratio to decrease experiment-to-experiment variability. The adjustment ratio is the area of the reference compound in the new experiment divided by the expected area of the reference compound based on an average of previous experiments (unadjusted readings). This results in the scaling of the reading (y-axis) for the new data without changing the shape of the dose-response curve. The reference compound used is 2-[4 30 amino-2-ethoxy1ethyl-6,7,g,9-tetrahydro-a, -dimethyl-1H-imidazo[4,5-c]quinolin-1 yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91) and the expected area is the sum of the median dose values from an average of previous experiments. - 183 - The minimum effective concentration is calculated based on the background subtracted, reference-adjusted results for a given experiment and compound. The minimum effective concentration (pmolar) is the lowest of the tested compound concentrations that induces a response over a fixed cytokine concentration for the tested 5 cytokine (usually 20.pg/mL for IFN-a and 40 pg/mL for TNF-a). The maximal response is the maximal amount of cytokine (pg/ml) produced in the dose-response. The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually 10 incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention 15 intended to be limited only by the claims set forth herein as follows. -184-

Claims (53)

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula I: NN N R \-R2 RB N 5 RA R, wherein: X' is selected from the group consisting of -CH 2 -, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 10 tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3 -yl, tetrahydo-2H-pyran-4-yi, tetrahydo-2H-thiopyran-4-yI, and 1,1 -dioxidotetrahydo 2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C.-4 alkyl, -CH 2 -CI- 2 alkylenyl-O-CI- 2 alkyl, -CH 2 -0-CI- 3 alkyl, -CH 2 -OH, -CH 2 -C,. 3 alkylenyl-OH, 15 and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C1. 4 alkyl, CI.4 alkoxy, hydroxy, haloC 14 alkyl, and hydroxyCI. 4 alkyl; RA and RB taken together form a fused benzene or pyridine ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or 20 substituted by one R 3 group and one R group; wherein the fused pyridine ring is N wherein the highlighted bond indicates the position where the ring is fused; and wherein R 3 is at the 7- or 8-position; or RA and Ra taken together form a fused cyclohexene or tetrahydropyridine ring which is unsubstituted or substituted at a carbon atom by one or more R groups; wherein 25 the fused tetrahydropyridine ring is NH wherein the highlighted bond indicates the position where the ring is fused; or RA is alkyl, and R9 is hydrogen or alkyl; - 185 - R is selected from the group consisting of: halogen, hydroxy, alkyl, 5 haloalkyl, alkoxy, and -N(R9)2; R 3 is selected from the group consisting of: -Z-R 4 , 10 -Z-X-R4, -Z-X-Y-R4;' -Z-X-Y-X-Y-R 4 , -Z-X-Rs, and -NH-Q-R 4 ; 15 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 by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups; Y is selected from the group consisting of: 20 -0-, -S(0)0-2-, -S(O)2-N(RsB)-, -C(R6)-, -C(R,6)-O-, 25 -O-C(R6)., -0-C(0)-0-, -N(Rg)-Q-. -C(R6)-N(Rs)-, -O-C(R,6)-N(R8)-, 30 -C(R6)-N(OR,)-, -O-N(R-)-Q-, -O-N=C(R4)-, - 186 - -C(=N-O-Rg)-, -CH(-N(-O-Rg)-Q-R4)-, N-Q -N-C(R)- -W R 7 -N- R7---Q 5 R 7 -V-NKR 0 ,n ,i and N-C(R 6 ) -N 1Ri Z is a bond or -0-; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, 10 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 15 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; 20 R 5 is selected from the group consisting of: - 187- -N- C(R 6 ) -N- S(O) 2 -V- (CH2). O-N R R7 (CHA )-/ (CH 2 )b-.I , and (H 2 ). -> N-C(R)- ( A R (CHA R 6 is selected from the group consisting of =0 and =S; R7 is C 2 . 7 alkylene; 5 R8 is selected from the group consisting of hydrogen, Ci.- alkyl, C 2 . 1 o alkenyl, hydroxy-Cl-.o alkylenyl, C1-2o alkoxy-CI- 10 alkylenyl, aryl-CI-io alkylenyl, and heteroaryl-Ci-io alkylenyl; R 9 is selected from the group consisting of hydrogen and alkyl; Rio is C3.. alkylene; 10 A is selected from the group consisting of -CH 2 -, -0-, -C(O)-, -S(0) 0 - 2 -, and -N(-Q-R4)-; A' is selected from the group consisting of -0-, -S(0) 0 - 2 -, -N(-Q-R 4 )-, and -CH 2 -; Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R6)-C(R 6 )-, -S(0) 2 -, -C(R4)-N(RB)-W-, -S(O) 2 -N(R 8 )-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 6 )-N(ORg)-; 15 V is selected from the group consisting of -C(R6)-, -0-C(R6)-, -N(Rs)-C(R 6 )-, and -S(O)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 I to 6 with the proviso that a + b is 5 7; or a pharmaceutically acceptable salt thereof. 20

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula II: NN \>-R2 N (R), (R 3 ), II 25 wherein: - 188 - X' is selected from the group consisting of-CH 2 -, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran

3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and I,1-dioxidotetrahydo 5 2H-thiopyran-4-yl; R 2 is selected from the group consisting of-NH 2 , -CH 3 , -CH 2 -C. 4 alkyl, -CH 2 -CI- 2 alkylenyl-O-CI- 2 alkyl, -CH 2 -0-C 1 . 3 alkyl, -CH 2 -OH, -CH 2 -C:. 3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, 10 C .4 alkyl, C1.4 alkoxy, hydroxy, haloCI.4 alkyl, and hydroxyC..4 alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, 15 haloalkyl, alkoxy, and -N(Rg) 2 ; n is 0, 1, or 2; R 3 is selected from the group consisting of: 20 -Z-R4, -Z-X-R4, -Z-X-Y-R 4 , -Z-X-Y-X-Y-R4, -Z-X-Rs, and 25 -NH-Q-R 4 ; R 3 is at the 7- or 8-position; m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and 30 alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -0- groups; Y is selected from the group consisting of: -189- -0-, -S(0)0-2-, -S(O)2-N(Rs)-, -C(R 6 )-, 5 .- C(R6)-O-, -O-C(R,)-, -O-C(O)-o-, -N(Rs)-Q-, -C(R6)-N(Rg)-, 10 -0-C(R 6 )-N(Rs)-, -C(R 4 )-N(ORg)-, -O-N(Rg)-Q-, -O-N=C(14)-, -C(=-N-0-Rg)-, 15 -CH(-N(-O-R)-Q-R4)-, NQ R 10 ' -- N-C(Rr)- -W -- N-- R -Q -- V-N 1Ri, and 20 -RI N-C(R6) - Z is a bond or -0-; 14 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, -190- 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; 5 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; R 5 is selected from the group consisting of: -N-C(R.) -- N-S() 2 -V- A(CH2). -O-N (CH 2 ) 1 0 R 7 ~- 0 N -A ' 10 R(CHz)R7 , (CH 2 )bI/ , and N - C(R6 - (C 2 A R (CH 2 ) 8 Rio 2 R4 is selected from the group consisting of =0 and =S; R 7 is C 2 . 7 alkylene; Rg is selected from the group consisting of hydrogen, CI.1 0 alkyl, C 2 -10 alkenyl, 15 hydroxy-C.oalkylenyl, C.i 0 alkoxy-C..I 0 alkylenyl, aryl-C- 1 . 0 alkylenyl, and heteroaryl-C .I.o alkylenyl; R9 is selected from the group consisting of hydrogen and alkyl; Rio is C 3 .s alkylene; A is selected from the group consisting of -CH 2 -, -0-, -C(O)-, -S(O)D.2-, and 20 -N(-Q-R4)-; A' is selected from the group consisting of -O-, -S(O)o- 2 -, -N(-Q-R4)-, and -CH2-; Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R)-N(Ra)-W-, -S(O) 2 -N(Rs)-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 6 )-N(ORg)-; V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(Ra)-C(R 6 )-, and 25 -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 I to 6 with the proviso that a + b is 5 7; or a pharmaceutically acceptable salt thereof. -191- 3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula III: N N >-R 2 N (R), 5 I wherein: X' is selected from the group consisting of -CH 2 -, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 10 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C1.4 alkyl, -CH 2 -Ci-2alkylenyl-O-Ci- 2 alkyl, -CH 2 -0-C. 3 alkyl, -CH 2 -OH, -CH 2 -C1. 3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by 15 one or more substituents independently selected from the group consisting of halogen, C- 4 alkyl, C,. 4 alkoxy, hydroxy, haloC1. 4 alkyl, and hydroxyC 1 . 4 alkyl; R is selected from the group consisting of: halogen, hydroxy, 20 alkyl, haloalkyl, alkoxy, and -N(R 9 )2; n is 0, 1, or 2; and 25 R 9 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula IV: - 192 - N N NN (R),N (R 3 )m IV wherein: X is selected from the group consisting of -CH 2 -, -NH-, and -0-; 5 R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C 1 4 alkyl, 10 -CH 2 -CI- 2 alkylenyl-O-CI-2 alkyl, -CH 2 -0-C.. 3 alkyl, -CH 2 -OH, -CH 2 -C 1 .3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C .4 alkyl, C 1 . 4 alkoxy, hydroxy, haloC .4 alkyl, and hydroxyC 14 alkyl; R is selected from the group consisting of; 15 halogen, hydroxy, alkyl, haloalkyl, alkoxy, and 20 -N(R9)2; n is 0, 1, or 2; R 3 is selected from the group consisting of: -Z-R 4 , -Z-X-R 4 , 25 -Z-X-Y-R 4 , -Z-X-Y-X-Y-R4, -Z-X-R 5 , and -NH-Q-R 4 ; R 3 is at the 7- or 8-position; -193 - m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1; 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 by arylene, heteroarylene or 5 heterocyclylene and optionally interrupted by one or more -0- groups; Y is selected from the group consisting of: -0-, -S(0)0-2-,. -S(O)2-N(Rg)-, 10 -C(R)-, -C(R 6 )-O-, -O-C(R)-, -O-C(O)-O-, -N(Ra)-Q-. 15 -C(R6)-N(Ra)-, -O-C(R-6)-N(Ra)-, -C(R6)-N(ORg)-, -O-N(Rs)-Q-, -O-N=-C(R4)-, 20 -C(=N-0-Rs)-, -CH(-N(-0-Rs)-Q-R4)-, -- N-C(Re) -- W R7 -N-- R--Q R., -- V-N 25 R , and - 194 - N -C(R.) -N Z is a bond or -0-; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, 5 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; 10 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; R 5 is selected from the group consisting of: -N-C(Rs) -N-S(O) 2 (CH2). -- O - (CH2). 1S R7 R7 (CH2)b- , (CH2)b , and N e- (CH2 ). N4-C(Rd) A R (CH 2 )A R 4 is selected from the group consisting of =0 and =S; R7 is C 2 . 7 alkylene; Ra is selected from the group consisting of hydrogen, CI.Io alkyl, C 2 -o alkenyl, 20 hydroxy-C.-o alkylenyl, C,. 1 0 alkoxy-CI. 0 alkylenyl, aryl-Ci.o alkylenyl, and heteroaryl-C I-1 0 alkylenyl; R 9 is selected from the group consisting of hydrogen and alkyl; RIO is C 3 . 8 alkylene; A is selected from the group consisting of -CH 2 -, -0-, -C(O)-, -S(O)o- 2 -, and 25 -N(-Q-R4)-; A' is selected from the group consisting of -0-, -S(O)o- 2 -, -N(-Q-R 4 )-, and -CH 2 -; - 195 - Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R)-C(R)-, -S(O) 2 -, -C(R 6 )-N(Rs)-W-, -S(O) 2 -N(Rs)-, -C(R 6 )-O-, -C(R 6 )-S-, and -C(R 6 )-N(OR,)-; V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(Rs)-C(R 6 )-, and -S(0)2-; 5 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 5 7; or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier in 10 combination with a therapeutically effective amount of a compound of Formula V: N -~N RB. N RA. X'R, V wherein: X is selected from the group consisting of -CH 2 -, -NH-, and -0-; 15 RI is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yi, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yi, and 1,1 -dioxidotetrahydo 2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -CI 4 alkyl, 20 -CH 2 -CI- 2 alkylenyl-O-CI- 2 alkyl, -CH 2 -0-C- 3 alkyl, -CH 2 -OH, -CH 2 -Cr- 3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CI- alkyl, Ci 4 alkoxy, hydroxy, haloCi 4 alkyl, and hydroxyCI 4 alkyl; RA' is alkyl, and RB. is hydrogen or alkyl; 25 or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 5 wherein RA- and RB. are both methyl.

7. The pharmaceutical composition of any one of claims 1, 2, and 4 wherein R 3 is - 196- -Z-R 4 .

8. The pharmaceutical composition of claim 7 wherein R 4 is selected from the group consisting of aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl wherein the aryl, 5 arylalkylenyl, heteroaryl, and heteroarylalkylenyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino, and dialkylamino; and Z is a bond. 10

9. The pharmaceutical composition of claim 7 wherein R4 is a 4 to 7 membered heterocyclyl group which contains one or more ring nitrogen atoms and optionally a ring oxygen or ring sulfur atom, wherein the point of attachment of the heterocyclyl group is one of the nitrogen atoms, and wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting 15 of oxo, alkyl, and arylalkylenyl; and Z is a bond.

10. The pharmaceutical composition of claim 9 wherein the heterocyclyl group is selected from the group consisting of: 0 0 Q N- [ -dN-_ O N- -- N O R'0 0 0 -\ N- %N- .SN- aN S' , O \f N-an N 20 wherein R' is alkyl.

IH. The pharmaceutical composition of any one of claims 1, 2, and 4 wherein R 3 is -Z-X-Y-R 4 . 25

12. The pharmaceutical composition of claim 11 wherein R 4 is selected from the group consisting of hydrogen, alkyl, and heterocyclyl; Y is selected from the group consisting of -S(0) 2 -, -C(O)-, -C(O)-NH-, and -NH-S(0)2-; X is phenylene; and Z is a bond. -197-

13. The pharmaceutical composition of claim 11 wherein R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroaryl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting 5 of halogen, hydroxy, and alkyl; Y is selected from the group consisting of -S(O) 2 -, -C(O)-, -N N and -C(O)-N(Rs)-; X is ; and Z is a bond.

14. The pharmaceutical composition of claim 11 wherein R 4 is hydrogen or alkyl; Y is -C(O)-N(RB)- or -C(O)-O-; Ra is CI.4 alkyl; X is alkylene or alkenylene; and Z is a bond. 10

15. The pharmaceutical composition of claim 11 wherein R 4 is alkyl substituted by maleimidyl; Y is -NHC(O)-; X is alkylene interrupted by one -0- group; and Z is -0-.

16. The pharmaceutical composition of any one of claims 1, 2, and 4 wherein R 3 is 15 -Z-XfrYa-Xg-Yb-R 4 , and wherein R 4 is hydrogen or C1.4 alkyl, Yb is -C(O)-O-, Xg is alkylene, Y. is -NHC(O)-, Xr is alkylene interrupted by one -0- group, and Z is -0-.

17. The pharmaceutical composition of any one of claims 1, 2, 4, 7, and 8 wherein R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, 20 (aminomethyl)phenyl, pyridin-3-yl, and pyridin-4-yl.

18. The pharmaceutical composition of any one of claims 1, 2, 4, 11, and 12 wherein R 3 is (methylsulfonylamino)phenyl. 25

19. The pharmaceutical composition of claim 1 or 2 wherein R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, 4-(aminomethyl)phenyl, 3 -(methylsulfonylamino)phenyl, pyridin-3-yl, and pyridin-4-yl.

20. The pharmaceutical composition of claim I or 4 wherein R 3 is selected from the 30 group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, and (methylsulfonylamino)phenyl. - 195 -

21. The pharmaceutical composition of any one of claims 1, 2, 4, and 7 through 20 wherein R 3 is at the 7-position. 5

- 22. The pharmaceutical composition of any one of claims 1, 2, 4, and 7 through 20 wherein R 3 is at the 8-position.

23. The pharmaceutical composition of any one of claims 2, 3, 4, and 7 through 22 except as dependent on claim 1 wherein n is 0. 10

24. The pharmaceutical composition of claim 2 or 4 wherein m is 0.

25. The pharmaceutical composition of claim 2 or 4 wherein m and n are both 0. 15

26. The pharmaceutical composition of any one of claims 1 through 25 wherein R 2 is selected from the group consisting of -CH 3 , -CH 2 -C 1 .4 alkyl, -CH 2 -- CI.3 alkyl, -CH 2 -C-- 2 alkylenyl-O-CI- 2 alkyl, -CH2-OH, and -CH 2 -C. 3 alkylenyl-OH.

27. The pharmaceutical composition of claim 26 wherein R 2 is selected from the group 20 consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.

28. The pharmaceutical composition of claim 27 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, 25 ethoxymethyl, and 2-methoxyethyl.

29. The pharmaceutical composition of claim 28 wherein R 2 is selected from the group consisting of n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.

30 30. The pharmaceutical composition of any one of claims I through 29 wherein R, is tetrahydo-2H-pyran-4-yl. - 199-

31. The pharmaceutical composition of any one of claims I through 30 wherein X' is -CH 2 -.

32. The pharmaceutical composition of any one of claims I through 30 wherein X is 5 -NH-.

33. The pharmaceutical composition of any one of claims 1 through 30 wherein X is -0-. 10

34. A compound of Formula Ila: N N \>R2 N Ila wherein; X" is -CH 2 -; 15 Ria is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo 2H-pyran-3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 dioxidotetrahydo-2H-thiopyran-4-yl; and R 2 is selected from the group consisting of -CH 3 , -CH 2 -C,. 4 alkyl, -CH 2 -Cj.2 alkylenyl-O-C -2 alkyl, -CH 2 -0-C i.3 alkyl, -CH 2 -OH, -CH 2 -C 1 .3 alkylenyl-OH, 20 and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C1. 4 alkyl, C1. 4 alkoxy, hydroxy, haloC 1 .4 alkyl, and hydroxyC. 4 alkyl; or a pharmaceutically acceptable salt thereof. 25

35. A compound of Formula III: N -N N (R), \ III2. - 200 - wherein: X is selected from the group consisting of -CH 2 -, -NH-, and -0-; R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 5 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C,- alkyl, -CH 2 -C,.2 alkylenyl-O-CI- 2 alkyl, -CHz-0-CI.3 alkyl, -CH 2 -OH, -CH 2 -Ci- 3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by 10 one or more substituents independently selected from the group consisting of halogen, C 1 . 4 alkyl, CI-4 alkoxy, hydroxy, haloC, 4 alkyl, and hydroxyC 1 4 alkyl; R is selected from the group consisting of: halogen, hydroxy, 15 alkyl, haloalkyl, alkoxy, and -N(R 9 )2; n is 0, 1, or 2; and 20 R 9 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.

36. A compound of Formula IVa: N N (R)N (Rs),, R 10 25 IVa wherein: X'" is -CH 2 -201- Ria is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo 2H-pyran-3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1 dioxidotetrahydo-2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C.-4 alkyl, 5 -CH 2 -C -2 alkylenyl-O-C- 2 alkyl, -CH 2 -O-Ci-3 alkyl, -CH 2 -OH, -CH 2 -CI.3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C:. 4 alkyl, Ci-4 alkoxy, bydroxy, haloCI. 4 alkyl, and hydroxyC1. 4 alkyl; R is selected from the group consisting of: 10 halogen, hydroxy, alkyl, haloalkyl, alkoxy, and 15 -N(Reh; nis0, 1,or2; R3a is selected from the group consisting of: -Z-R 4 and -Z-X-R4; 20 R 3 . is at the 7- or 8-position. m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1; 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 by arylene, heteroarylene or 25 heterocyclylene and optionally interrupted by one or more -0- groups; Z is a bond or -0-; R 4 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, 30 alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected - 202 - 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, 5 oxo; and R9 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.

37. A compound of Formula Va: N .. N R\>. R2 10 RK. R, Va wherein: X" is -CH 2 R, is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 15 tetrahydrofuran-2-yl, tetrahydrofuran-3-yi, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yI, and 1,1-dioxidotetrahydo 2H-thiopyran-4-yl; R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH2-C1- alkyl, -CH 2 -CI- 2 alkylenyl-O-CI-2alkyl, -CH 2 -0-C. 3 alkyl, -CH 2 -OH, -CH 2 -C-3 alkylenyl-OH, 20 and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C 1 4 alkyl, C 1 4 alkoxy, hydroxy, haloC] 4 alkyl, and hydroxyC 1 4 alkyl; RA. is alkyl, and Ra. is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof. 25

38. The compound or salt of claim 37 wherein RA. and R. are both methyl.

39. The compound or salt of claim 35 wherein X' is -CH 2 -. 30

40. The compound or salt of claim 35 wherein X' is -NH-. - 203 -

41. The compound or salt of claim 35 wherein X' is -O-.

42. The compound or salt of claim 36 wherein R 3 . is selected from the group 5 consisting of hydroxyphenyl and (hydroxymethyl)phenyl.

43. The compound or salt of any one of claims 35, 36, and 39 through 42 wherein n is 0. 10

44. The compound or salt of claim 36 wherein m is 0.

45. The compound or salt of claim 36 wherein m and n are both 0.

46. The compound or salt of any one of claims 34, 36, 42, 43 as dependent on claim 36 15 or 42, 44, and 45 wherein Ria is tetrahydo-2H-pyran-4-yl.

47. The compound or salt of any one of claims 35, 37, 38, 39, 40, 41, and 43 as dependent on claim 35, 39, 40, or 41 wherein RI is tetrahydo-2H-pyran-4-yl. 20

48. The compound or salt of any one of claims 34 through 47 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropyhnethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.

49. The compound or salt of claim 48 wherein R 2 is selected from the group consisting 25 of n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.

50. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of claims 34 through 49 in combination with a pharmaceutically acceptable carrier. 30 - 204 -

51. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a pharmaceutical composition of any one of claims I through 33 and 50 or a compound or salt of any one of claims 34 through 49 to the animal. 5

52. A method of treating a viral disease in an animal in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition of any one of claims I through 33 and 50 or a compound or salt of any one of claims 34 through 49 to the animal. 10

53. A method of treating a neoplastic disease in an animal in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition of any one of claims 1 through 33 and 50 or a compound or salt of any one of claims 34 through 49 to the animal. Dated 4 April, 2011 Coley Pharmaceutical Group, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON - 205 -