AU2002300985B2

AU2002300985B2 - Imidazonaphthyridines And Their Use In Inducing Cytokine Biosynthesis

Info

Publication number: AU2002300985B2
Application number: AU2002300985A
Authority: AU
Inventors: John W. Mickelson
Original assignee: Minnesota Mining and Manufacturing Co
Current assignee: 3M Co
Priority date: 1997-12-11
Filing date: 2002-09-04
Publication date: 2004-12-02
Anticipated expiration: 2018-12-11
Also published as: AU2002300982B2; AU2002300984B2

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Minnesota Mining and Manufacturing Company Actual Inventor(s): Kyle J Lingstrom, John F Gerster Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: IMIDAZONAPHTHYRIDINES AND THEIR USE IN INDUCING CYTOKINE BIOSYNTHESIS Our Ref: 677043 POF Code: 360618/1433 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 6006q la IMIDAZONAPHTHYRIDINES AND THEIR USE IN INDUCING CYTOKINE

BIOSYNTHESIS

This application is a divisional application of Australian Patent Application 19123/99, the entire content of which is herein incorporated by reference.

Field of the Invention This invention relates to imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds, processes for making these compounds and intermediates used in their preparation. This invention additionally relates to pharmaceutical compositions containing imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators and for inducing cytokine biosynthesis in animals.

Background of the Invention The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1Hwere reported. For example, Jain et al., J. Med. Chem.

11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1Has a possible anticonvulsant and cardiovascular agent.

Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem. 18, 1537- 1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S.

Patent Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; WidskaVkspepes0DIVlSIONAL OF 11 23-99.dm lb and 5,389,640, all of which are incorporated herein by reference. Although there continues to be interest in the imidazoquinoline ring system, as seen for example in WO 98/30562, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.

The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

Summary of the Invention We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. In one aspect the present invention provides a compound of formula (IA):

NH

2 N

N

-R2

N

(R)n ,N R N R- (1A) wherein

R

1 is selected from the group consisting of: -C1-20 alkyl-NR 3

-Q-X-R

4 and -C2- 20 alkenyl-NR 3

-Q-X-R

4 wherein Q is X is

NR

3 and R 4 is aryl, or -C1-20 alkyl or C2- 20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: W:\ciskankispecies\DIVISIONAL OF 19123-O9.doc -aryl; -0-CI- 20 alkyl;

-O-(C

1 2 oalkyI) 01 -aryl; -Cl120 alkoxycarbonyl;

-S(O)

0 2

-C

12 o alkyl;

-S(O)

0 2

-(C

12 o alkyi) 01 -aryl; -N R 3

-CO-O-CI-

2 oalkyI;

-N

3 oxo; -halogen;

-NO

2 -OH; and

R

2 is selected from the group consisting of: -hydrogen; -Cl- 10 alkeyl; -aryl; -Cl-1o alkyl -O-0 110 o-alkyl; -01.10 alkyl-O-C 2 -l alkenyl; and

-C

1 10 alkyl or 02-10 alkenyl substituted by one or more substituents selected from the group consisting of:

-OH;

-halogen; -CO-Cl-lo alkyl;

-N

3 -aryl; and -CO-aryl; each R 3 is independently selected from the group consisting of hydrogen and C1.10 alkyl; W:kfka1kispecIeSVfIVISIONAL OF 191 23.99.doc each R is independently selected from the group consisting of hydrogen, C1-10 alkyl, C1.10 alkoxy, halogen and trifluoromethyl; and n is 3; or a pharmaceutically acceptable salt thereof.

The compounds of the invention are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This ability makes the compounds useful in the treatment of a variety of conditions, e.g.

viral diseases and tumors that are responsive to such changes in the immune response.

The invention further provides pharmaceutical compositions containing a compound of the invention and methods of inducing cytokine biosynthesis in an animal and/or treating a viral infection in an animal by administering a compound of the invention to the animal.

In addition, methods of synthesizing compounds of the invention and intermediates useful in the synthesis of these compounds are provided.

Further, the invention provides a method of inducing interferon biosynthesis in an animal comprising the step of administering to said animal a compound of the invention in an amount effective to induce said interferon biosynthesis, and a method of treating a viral infection in an animal comprising the step of administering to said animal a compound of the invention in an amount effective to inhibit the viral infection.

Detailed Description of the Invention The compounds of the invention are related to compounds of formula I disclosed in the co-pending application.

W:%lskank~speces0fIVISIONAL OF 19123-99.doc

NH

2 N

N

A R where in A. is =N-CR=CR-CR=; =CR-N=CR-CR=; =CR-CR=N-CR=; or =CR-

CR=CR-N=;

R, is selected from the group consisting of: -hydrogen; -Cl 1 20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; WWka~nkspeesIVISIONAL OF 19123-9g.doo WO 99129693 WO 9929693PCTIUS98/26473 -0-C 1-2o alkyl, 1.

2 oalkyl)0_,-aryl; 1.

2 oalkyl)o 1 -heteroaryl; 1 2 oalkyl) 0 1 -heterocyclyl;

-C

1 20 alkoxycarbonyl; -S(0)02 -C 1 20 alkyl; -S (0)0- 2 1 20 alkyl)o 1 -aryl; -S(0)0-2 20 alkyl) 0 1 -heteroaryl; -S (0) 0 2 1 -20 alkyl)o- I -heterocycl yl; -(32

-N

3 oxo; -halogen;

-NO

2 -OH; and -SH; and -C 1 20 alkyl-NR 3 -Q-X-R4 or -C 2 20 alkenyl-NR 3

-Q-X-R

4 wherein Q is -CO- or

SO

2 X is a bond, or -NR 3 and R 4 is aryl; heteroaryl; heterocyclyl; or -C I-20 alkyl or

C

2 20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; -0-C 1.20 alkyl, I-2oalkyI)o~l -aryl;

-O-(C

1 2 0alkYl) 0 1 -heteroaryl;

-O-(C

1 .2oalkyl)o.I -heterocyclyl; -C -20 alkoxycarbonyl; -S(0)02 -C 1 20 alkyl; 0 2 20 alkyl)o..,-aryl; 2 20 alkyl)o..,-heteroaryl; -4- WO 99/29693 WO 9929693PCTIUS98126473 -S(O)0.

2 -(1-20 alkyl)o- -heterocyclyl;

-NR

3 -CO-0-C 1 2 oalkyl;

-N

3 oxo; -halogen;

-NO

2 -OH; and -SH; or R 4 is I

(CH

2 1 -6

NR)

wherein Y is or -CR-;

R

2 is selected from the group consisting of: -hydrogen;

-C

1 10 alkyl;

-C

2 10 alkenyl; -aryl; -C I- 10 alkyl. -0-C I 1o-alkyl;

-CI-

10 alkyl-O-C 2 10 alkenyl; and

-C

1 1 o alkyl or C 2 4.

10 alkenyl substituted by one or more substituents selected from the group consisting of:

-OH;

-halogen;

N(R

3 2

-CO-C..

10 alkyl;

-N

3 -aryl; -heteroaryl; WO 99/29693 WO 9929693PCT[US98/26473 -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R 3 is independently selected from the group consisting of hydrogen and C 1 10 alkyl; and each R is independently selected fromn the group consisting of hydrogen,

C

1 10 alkyl, CI- 10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.

This invention also provides compounds of Formula HI NI-1 2 N

N

B

wherein B is -NR-C(R) 2

-C(R)

2

-C(R)

2

-C(R)

2

-NR-C(R)

2

-C(R)

2

-C(R)

2

-C(R)

2

-NR-C(R)

2 or -C(R) 2

-C(R)

2

-C(R)

2

-NR-;

R, is selected from the group consisting ofhydrogen;

-C

1 20 alkyl or C 2 20 alkenyl. that is unsubstituted. or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; -0-C 1 20 alkyl; I.2oa1k1C.I-aryl; -O4- 1 .2allyl)..-heteroaryl; WO 99129693 WO 9929693PCTfUS98/26473 1 20 akyI)o 1 -heterocycly1;

-C

1 -20 alkoxycarbonyl; -S(0) 0 2 -C I 2 o alkyl; -S 2 1 20 alkyl)o 1 -aryl; -S(0) 0 2 1-20 alkyl)o_1 -heteroaryl; S(0) 0 2 -C 1 -20 alkyl)0- I -heterocycl yl;

-N

3 oxo; -halogen;

-NO

2 -OH; and -SH; and -C 1 20 alkyl-NR 3

-Q-X-R

4 or -C 2 2 alkenyl-NR 3 -Q-X-R4 wherein Q is -CO- or

SO

2 X is a bond, or -NR3- and R 4 is aryl; heteroaryl; heterocyclyl; or -C 1 20 alkyl or

C

2 2 0 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; -0-C 1 20 alkyl,

-O-(C

1 2 oalkyl)o 1 -aryl;

-O-(C

1 2 0alkYl)0.

1 -heteroaryl;

-O-(C

1 2 oalkyl)o-i -heterocyclyl;

-C

1 -20 alkoxycarbonyl; -S(0)0- 2 -C 1 20 alkyl; -S(0)0.2 2 o allcyl)o-.

1 -aryl; -S(0)0- 2 20 alkyl)o 1 -heteroaryl; -S(0)0-2 20 alkyl)o-i -heterocyclyl;

-NR

3 -CO-O-C I- 2 0alkyl; WO 99/29693 WO 9929693PCTIUS98/26473

-N

3 oxo.

-halogen;

-NO

2 -OH1; and -SH; or R 4 is I

(CH

2 1 -6 wherein Y is or -CR-;

R

2 is selected from the group consisting of: -hydrogen;

-C

1 10 alkyl;

-C

2 10 alkenyl; -aryl -C 1-]10 alkyl-O-C 2 .io0 alkenyl; and

-C

1 10 alkyl Or C 2 10 alkenyl substituted by one or more substituents selected f-rm the group consisting of:

-OH;

-halogen; -(32

-CO-N(R

3 2

-CO-C..

10 alkyl;

-N

3 -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; -8- WO 99/29693 PCT/US98/26473 each R 3 is independently selected from the group consisting of hydrogen and C-o 1 0 alkyl; and each R is independently selected from the group consisting of hydrogen, Cl-lo alkyl, CIllo alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.

As used herein, the terms "alkyl", "alkenyl", and the prefix "-alk" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. These cyclic groups can be monocyclic or polycyclic and preferably have S 10 from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.

The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.

Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring hetero atom O, S, Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, imidazo, and so on.

"Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom O, S, Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, and imidazolidinyl.

The aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of Ci.

20 alkyl, hydroxy, halogen, N(R 3 2

NO

2 Cl-2 0 alkoxy, C 1 20 alkylthio, trihalomethyl, C1-2 0 acyl, arylcarbonyl, heteroarylcarbonyl, (Cl- oalkyl)o-_-aryl, (C -oalkyl)o- 1 -heteroaryl, nitrile, alkoxycarbonyl, oxo, arylalkyl wherein the alkyl group has from 1 to 10 carbon atoms, and heteroarylalkyl wherein the alkyl group has from 1 to 10 carbon atoms.

The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like.

-9- WO 99/29693 WO 9929693PCT[US98/26473 Preparation of the Compounds Compounds of Formulas I and 11 wherein A is =N-CR=CR-CR=~ or B is

-NR-C(R)

2

-C(R)

2

-C(R)

2 and R, R, and R 2 are as defined above can be prepared according to Reaction Scheme 1: WO 99/29693 WO 9929693PCTfUS98/26473 Reaction Scheme I 0

OH

N NH- 2

III

OH

N N N

VIII

N) 3I N H (2) i N -N I

CH

3

OH

RN

N" N N N44 0 R 0- N! N N

CH

3 (5)

RI

Ilo

N"

R N N N N N (7)N N N I =N N=N D( x

NH

N=d xi

NH

2 N

N

RR

N=P(Ph) 3 N

N

l7-R2 N N N

R

XI Ra -1I1 WO 99/29693 PCT/US98/26473 (12) NH 2 N NH -R2 HN

N

R

XV

Many 2-aminonicotinic acids of Formula III are known (see, for example, U.S.

3,917,624). The compound where R is hydrogen is commercially available. In step of Reaction Scheme I a 2-aminonicotinic acid of Formula III is reacted with acetic anhydride by heating to provide a 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one of Formula IV. The compound of Formula IV where R is hydrogen is known and its preparation has been disclosed in U.S. Patent No. 3,314,941 (Littell), the disclosure of which is incorporated herein by reference.

In step of Reaction Scheme I a compound of Formula IV is reacted with sodium azide in a suitable solvent such as acetic acid to provide a tetrazolyl nicotinic acid of Formula V. The reaction conveniently may be run at ambient conditions.

In step of Reaction Scheme I an acid of Formula V is esterified to provide a compound of Formula VI. The esterification may be carried out using conventional methods. For example, the acid may be esterified in acetone using potassium carbonate and ethyl iodide.

In step of Reaction Scheme I a compound of Formula VI is cyclized to provide a tetrazolo[1,5-a][1,8]naphthyridin-5-ol of Formula VII. The reaction may be carried out by reacting the compound of Formula VI with an alkoxide in a suitable solvent, e.g., potassium ethoxide in N,N-dimethylformamide, at ambient conditions.

In step of Reaction Scheme I a compound of Formula VII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[1,5- 1,8]naphthyridin-5-ol of Formula VIII.

In step of Reaction Scheme I a compound of Formula VIII is converted to a triflate of Formula IX. The reaction is preferably carried out by combining a compound of Formula VIII with a base, preferably a tertiary amine such as triethyl amine, in a suitable -12- WO 99/29693 PCT/US98/26473 solvent such as dichloromethane and then adding trifluoromethanesulfonic anhydride. The addition is preferably carried out in a controlled manner, adding dropwise at a reduced temperature such as, for example, at about 0°C. The product can be isolated by conventional methods or it can be carried on without isolation as described below in connection with step In step of Reaction Scheme I a compound of Formula IX is reacted with an amine of formula RINH2 where Ri is as defined above to provide a of Formula X. The reaction can be carried out by adding the amine to the reaction mixture resulting from step The reaction can also be carried out by adding the amine to a solution of the compound of Formula IX and a tertiary amine in a suitable solvent such as dichloromethane.

In step of Reaction Scheme I a compound of Formula X is reduced to provide a tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine of Formula XI. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol.

In step of Reaction Scheme I a compound of Formula XI is reacted with a carboxylic acid or an equivalent thereof to provide a JH-tetrazolo[ 1,5-a]imidazo[4,5c][1,8]naphthyridine of Formula XII. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula XII. For example, diethoxymethylacetate will provide a compound where R 2 is hydrogen and valeryl chloride will provide a compound where R 2 is butyl. The reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of a carboxylic acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.

In step (10) of Reaction Scheme I a compound of Formula XII is reacted with triphenylphosphine to provide a N-triphenylphosphinyl-1H-imidazo[4,5c][1,8]naphthyridin-4- amine of Formula XIII. The reaction can be carried out by combining a compound of Formula XII with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating.

13- WO 99/29693 PCT/US98/26473 In step (11) of Reaction Scheme I a compound of Formula XIII is hydrolyzed to provide a 1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of Formula XIV which is a subgenus of Formula I. The hydrolysis can be carried out by conventional methods such as by heating in a lower alkanol in the presence of an acid. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

In step (12) of Reaction Scheme I a compound of Formula XIV is reduced to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of Formula XV which is a subgenus of Formula II. The reduction is carried out by suspending or dissolving a compound of Formula XIV in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Alternatively, as illustrated in step (13) of Reaction Scheme I, a 6,7,8,9-tetrahydro- 1H-imidazo[4,5-c][1,8]naphthyridin-4- amine of Formula XV can be prepared by reduction of a compound of Formula XII. The reduction is carried out by suspending or dissolving a compound of Formula XII in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. As above, the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Compounds of Formulas I and II wherein A is =CR-N=CR-CR= or B is

-C(R)

2

-NR-C(R)

2

-C(R)

2 R, R 1 and R 2 are as defined above can be prepared according to Reaction Scheme II.

Reaction Scheme II 0 0 H OH OH 0 I N IN N1) N N R NH 2 R N H 3 R N XVI XVI CH XV XVI XVI CH3 xvm -14- WO 99/29693 WO 9929693PCT[US98126473 I 3 C1 N~

N

R

N:=N

OH

14 No R N N

N=N

0 OR9

NN

R

N

CH

3

NH

Ng

N

N N

X)UI

R\ 0

NHK

N N0 N N R

N=~N

=11I

NH

(8)

-N

N=N

(9)

NH

2 N2 N- I7R

R

(I12) N=P(Ph) 3 N

N

R2 N N N

I

R

XVq

N-

N

RR

xxv (13)

XXVIII

In step of Reaction Scheme UI a 3-aminoisonicotinic acid of Formula XVI is reacted with acetic anhydride by heating to provide a 2-methyl-4H-pyrido[3,4- 15 WO 99/29693 PCT/US98/26473 d][l,3]oxazin-4-one of Formula XVII. The compound of Formula XVII where R is hydrogen is known and its preparation has been disclosed in Littell cited above.

In step of Reaction Scheme II a compound of Formula XVII is reacted with sodium azide in a suitable solvent such as acetic acid to provide a tetrazolyl isonicotinic acid of Formula XVIII. The reaction conveniently may be run at ambient conditions.

In step of Reaction Scheme II an acid of Formula XVIII is esterified to provide a compound of Formula XIX. The esterification may be carried out using conventional methods. For example, the acid may be esterified in acetone using potassium carbonate and ethyl iodide or by reacting with dimethylformamide diethyl acetal in a suitable solvent such as dichloromethane.

In step of Reaction Scheme II a compound of Formula XIX is cyclized to provide a tetrazolo[1,5-a][1,7]naphthyridin-5-ol of Formula XX. The reaction may be carried out by reacting the compound of Formula XIX with an alkoxide in a suitable solvent, potassium ethoxide in N,N-dimethylformamide, at ambient conditions.

In step of Reaction Scheme II a compound of Formula XX is chlorinated using a suitable chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride or preferably phosphorus oxychloride to provide a 5-chlorotetrazolo[ a][l,7]naphthyridine of Formula XXI. The reaction can be carried out in an inert solvent or if appropriate in neat chlorinating agent. Preferred reaction conditions involve reaction in neat phosphorus oxychloride with heating at about In step of Reaction Scheme II a compound of Formula XXI is reacted with an amine of formula RINH 2 where R 1 is as defined above to provide a of Formula XXII. The reaction can be carried out by heating with an excess of the amine.

In step of Reaction Scheme II a compound of Formula XXII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[ a][1,7]naphthyridin-5-amine of Formula XXIII. Preferably the reaction is carried out in acetic acid with mild heating and an excess of nitric acid.

In step of Reaction Scheme II a compound of Formula XXIII is reduced to provide a tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine of Formula XXIV. Preferably the reduction is carried out using an excess of sodium hydrogensulfide in a suitable solvent such as acetic acid.

-16- WO 99/29693 PCT/US98/26473 In step of Reaction Scheme II a compound of Formula XXIV is reacted with a carboxylic acid or an equivalent thereof to provide a IH-tetrazolo[1,5-a]imidazo[4,5c][1,7]naphthyridine of Formula XXV. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula XXV. For example, diethoxymethylacetate will provide a compound where R 2 is hydrogen and valeryl chloride will provide a compound where R 2 is butyl. The reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of a carboxylic acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.

In step (10) of Reaction Scheme II a compound of Formula XXV is reacted with triphenylphosphine to provide a c][1,7]naphthyridin-4-amine of Formula XXVI. The reaction can be carried out by combining a compound of Formula XXV with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating.

In step (11) of Reaction Scheme II a compound of Formula XXVI is hydrolyzed to provide a 1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of Formula XXVII which is a subgenus of Formula I. The hydrolysis can be carried out by conventional methods such as by heating in a lower alkanol in the presence of an acid. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

In step (12) of Reaction Scheme II a compound of Formula XXVII is reduced to provide a 6,7,8,9-tetrahydro-H-imidazo[4,5-c][1,7]naphthyridin-4- amine of Formula XXVIII which is a subgenus of Formula II. The reduction is carried out by suspending or dissolving a compound of Formula XXVII in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Alternatively, as illustrated in step (13) of Reaction Scheme II, a 6,7,8,9tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridin-4-amine of Formula XXVIII can be prepared by reduction of a compound of Formula XXV. The reduction is carried out by suspending or dissolving a compound of Formula XXV in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen -17- WO 99/29693 WO 9929693PCT/US98/26473 pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Compounds of Formulas I and 11 wherein A is =CR-CR=CR-N= or B is

-C(R)

2

-C(R)

2

-C(R)

2 -NR- and R, R, and R 2 are as defined above can be prepared according to Reaction Scheme 111.

Reaction Scheme III RN I N, N N~ I OH 0- )x (2)N N -NH 0-) XKYJ xxx 0N

N

N N (5) N

K

R

XXXuv N~

N

.N

R

Muoll (4) T NH 2

NH

I (6)

NH

2

NH

2 N- N R2-R N NH

R

xxxv xxxvi In step of Reaction Scheme III a 3-nitro[1,5]naphthyridin-.4-ol of Formula XXIX is chlorinated using a suitable chlorinating agent such as phosphorus oxychloride t6 provide a 4-chloro-3-nitro[1,5]naphthyridine of Formula XXX. The reaction can be 18 WO 99/29693 PCT/US98/26473 carried out by reacting a compound of Formula XXIX with phosphorus oxychloride in a suitable solvent such as N,N-dimethylformamide with mild heating The compound may be isolated by conventional methods or it can be carried on without isolation as described below in connection with step The compound of Formula XXIX where R is hydrogen is known and its preparation has been disclosed in Hart, Journal of the Chemical Society pp. 212-214, (1956).

In step of Reaction Scheme III a 4-chloro-3-nitro[ 1,5]naphthyridine of Formula XXX is reacted with an amine of Formula RiNH 2 where RI is as defined above to provide a 3-nitro[1,5]naphthyridin-4-amine of Formula XXXI. The reaction can be carried out by adding water then excess amine to the reaction mixture resulting from step then heating on a steam bath. The reaction can also be carried out by adding excess amine to a solution of a compound of Formula XXX in a suitable solvent such as dichloromethane and optionally heating. The compound of Formula XXXI where RI is hydrogen is known and its preparation has been disclosed in Wozniak et al, J. R. Neth. Chem. Soc. 102 (12), pp. 511-13 (1983).

In step of Reaction Scheme III a 3-nitro[ 1,5]naphthyridin-4-amine of Formula XXXI is reduced to provide a [1,5]naphthyridine-3,4-diamine of Formula XXXII.

Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethyl acetate.

In step of Reaction Scheme III a compound of Formula XXXII is reacted with a carboxylic acid or an equivalent thereof to provide a IH- imidazo[4,5-c][1,5]naphthyridine of Formula XXXIII. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula XXXIII. For example, diethoxymethylacetate will provide a compound where R 2 is hydrogen and trimethylorthovalerate will provide a compound where R 2 is butyl. The reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of an acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.

Alternatively, step may be carried out by reacting a compound of Formula XXXII with an acylating agent; and then (ii) cyclizing the product. Part involves -19- WO 99/29693 PCT/US98/26473 reacting a compound of Formula XXXII with an acyl halide of formula R 2 C(O)X wherein

R

2 is as defined above and X is chloro or bromo. The reaction can be carried out by adding the acyl halide in a controlled fashion dropwise) to a solution of a compound of Formula XXXII in a suitable solvent such as dichloromethane at a reduced temperature The resulting amide intermediate can be isolated by removal of the solvent.

Part (ii) involves cyclizing the product of part by reacting it with methanolic ammonia at an elevated temperature 150 0 C) and pressure.

In step of Reaction Scheme III a compound of Formula XXXIII is oxidized to provide a 1H- imidazo[4,5-c][1,5]naphthyridine-5N-oxide of Formula XXXIV using a conventional oxidizing agent that is capable of forming N-oxides. Preferred reaction conditions involve reacting a solution of a compound of Formula XXXIII in chloroform with 3-chloroperoxybenzoic acid at ambient conditions.

In step of Reaction Scheme III a compound of Formula XXXIV is aminated to provide a 1H- imidazo[4,5-c][1,5]naphthyridin-4-amine of Formula XXXV which is a subgenus of Formula I. Step involves reacting a compound of formula XXXIV with an acylating agent; and then (ii) reacting the product with an aminating agent. Part (i) of step involves reacting an N-oxide with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides benzenesulfonyl chloride, methanesulfonyl choride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred, p- Toluenesulfonyl chloride is most preferred. Part (ii) of step involves reacting the product of part with an excess of an aminating agent. Suitable aminating agents include ammonia in the form of ammonium hydroxide) and ammonium salts ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula XXXIV in an inert solvent such as dichloromethane, adding the aminating agent to the solution, and then adding the acylating agent. Preferred conditions involve cooling to about 0*C to about 5C during the addition of the acylating agent. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Alternatively step may be carried out by reacting a compound of Formula XXXIV with an isocyanate; and then (ii) hydrolyzing the product. Part involves reacting the N-oxide with an isocyanate wherein the isocyanato group is bonded to a carbonyl group. Preferred isocyanates include trichloroacetyl isocyanate and aroyl WO 99/29693 PCT/US98/26473 isocyanates such as benzoyl isocyanate. The reaction of the isocyanate with the N-oxide is carried out under substantially anhydrous conditions by adding the isocyanate to a solution of the N-oxide in an inert solvent such as dichloromethane. The resulting product can be isolated by removal of the solvent. Part (ii) involves hydrolysis of the product from part The reaction can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide.

In step of Reaction Scheme III a compound of Formula XXXV is reduced to provide a 6,7,8,9-tetrahydro-H- imidazo[4,5-c][1,5]naphthyridin-4-amine of Formula XXXVI which is a subgenus of Formula II. The reduction is carried out by suspending or dissolving a compound of Formula XXXV in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Certain functional groups recited in connection with R 1 and R 2 may be incompatible with some of the reagents of Reaction Schemes I, II and III. Compounds containing such functional groups can be prepared by those skilled in the art using well known methods of functional group protection and manipulation. For example, amine groups may be protected when necessary by derivatizing with di-tert-butyl dicarbonate.

Some compounds of Formula I or Formula II containing certain functional groups may be readily prepared from other compounds of Formula I or Formula II. For example, compounds wherein the RI substituent contains an amide group may conveniently be prepared by reacting an acid chloride with a compound of Formula I or Formula II wherein the R, substituent contains a primary amine. Likewise, compounds wherein the RI substituent contains a urea group may be prepared by reacting an isocyanate with a compound of Formula I or Formula II wherein the R 1 substituent contains a primary amine. Further, compounds wherein the Ri substituent contains a carbamate group may be prepared by reacting a chloroformate with a compound of Formula I or Formula II wherein the R 1 substituent contains a primary amine.

Certain of the intermediate compounds useful in the preparation of compounds of Formula I and Formula II have not been previously described. Therefore, the invention also provides intermediate compounds useful in the preparation of compounds of Formula -21- WO 99/29693 PCT/US98/26473 I and Formula II. The structural formulas of these novel intermediates are set forth below.

These compounds have the following structural formulas: Intermediate Compound 1

N-N

N

i N _R2 A Ri wherein Ri, R 2 and A are as defined above for compounds of Formula I and Formula II.

Intermediate Compound 2 NV N

N

N R 1

R

wherein R, RI, and R 2 are as defined above for compounds of Formula I and Formula II.

-22- WO 99/29693 WO 9929693PCT11JS98/26473 Intermnediate Compound 3 11 1 wherein R, R, and R 2 are as defined above for compounds of Formula I and Formula 11.

Intennediate Comnound 4

R

7

A

N N

N=-N

wherein R 7 is OH, halogen or NHRi (and A and RI are as defined above for compounds of Formula I) and R 8 is H, NO 2 or NH 2 23 WO 99/29693 PCT/US98/26473 Intermediate Compound

O

A

-O-R

9

A

C,

N-N

CH3-

II

N-N

wherein A is as defined above for compounds of Formula I and R 9 is H or C-iio alkyl.

Intermediate Compound 6

N

RIO

NH

RI

wherein R and R 1 are as defined above for compounds of Formula I and Formula II with the proviso that Ri is other than hydrogen, and Rio is NO 2 or NH 2 Pharmaceutical Compositions and Biological Activity Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of Formula I or Formula II as defined above in combination with a pharmaceutically acceptable carrier. As used herein, the term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction or antiviral activity. Although the exact amount of active compound 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 -24- WO 99/29693 PCT/US98/26473 compound as well as the nature of the carrier and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100ng/kg to about 50mg/kg, preferably about 10 g/kg to about of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and so on.

The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the Test Method set forth below.

This ability indicates that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.

Cytokines that are induced by the administration of conpounds according to the invention generally include interferon (IFN) and tumor necrosis factor (TNF) as well as certain interleukins In particular, the compounds induce IFN-ao, TNF-a, IL-1, 6, and 12, and a variety of other cytokines. Among other effects, cytokines inhibit virus production and tumor cell growth, making the compounds useful in the treatment of tumors and viral diseases.

In addition to the ability to induce the production of cytokines, the compounds 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 induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.

Compounds of the invention also have an effect on the acquired immune response.

For example, although there is not believed to be any direct effect on T cells or direct induction ofT cell cytokines, the production of the T helper type 1 (Thl) cytokine IFN-y is induced indirectly and the production of the Th2 cytokine IL-5 is inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Thi response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of Formula I and Formula II to inhibit T-helper-type 2 immune response, the compounds are expected to be useful in the treatment of atopy, atopic dermatitis, asthma, allergy, allergic rhinitis; as

I

WO 99/29693 PCT/US98/26473 a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.

The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce cytokines such as IFN-a and TNF-ca, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to viral diseases e.g.

genital warts, common warts, plantar warts, Hepatitis B, Hepatitis C, Herpes Simplex Type I and Type II, molluscum contagiosm, HIV, CMV, VZV, cervical intraepithelial neoplasia, human papillomavirus and associated neoplasias; fungal diseases, e.g. candida, aspergillus, cryptococcal meningitis; neoplastic diseases, basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis; bacterial infections, tuberculosis, mycobacterium avium. Additional diseases or conditions that can be treated using the compounds of the invention include eczema, eosinophilia, essential thrombocythaemia, leprosy, multiple sclerosis, Ommen's syndrome, rheumatoid arthritis, systemic lupus erythematosis, discoid lupus, Bowen's disease and Bowenoid papulosis.

Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound of Formula I or Formula II to the animal. An amount of a compound effective to induce cytokine 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, INF-a, TNF-a, IL-1,6,10 and 12 that is increased over the 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 100ng/kg to about preferably about 10plg/kg to about 5mg/kg. The invention further provides a method of treating a viral infection in an animal comprising administering an effective amount of a compound of Formula I or Formula II 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 -26- WO 99/29693 PCT/US98/26473 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 will vary according to factors known in the art but is expected to be a dose of 100ng/kg to about preferably about 10 Og/kg to about The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.

Example 1 Compound of Formula V 2-(5-Methyl-JH-tetrazol-l-yl)nicotinic Acid Part A: 2-Aminonicotinic acid (5 g, 36 mmole) was suspended in acetic anhydride (25 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum.

The resulting residue was slurried with ethyl acetate and hexane then filtered to provide g of 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one.

Part B: The material from Part A was covered with acetic acid (75 mL), sodium azide (2 g) was added and the reaction mixture was stirred at ambient temperature over the weekend.

The resulting precipitate was isolated by filtration then dried to provide 5.6 g of methyl-IH-tetrazol-l-yl)nicotinic acid as a white solid, m.p. 178-180 0 C (gas evolution).

Analysis: Calculated for CsH 7

N

5 0 2 46.83; 3.44; 34.13; Found: 46.38; 3.36; 34.01.

-27-

I

WO 99/29693 PCT/US98/26473 Example 2 Compound of Formula VI Ethyl acid (5.6 g, 27 mmole) was suspended in acetone (250 mL), potassium carbonate (5 g) and ethyl iodide (5 mL) were added and the reaction mixture was heated at reflux for 2 hours. The acetone was removed under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, dried, then concentrated under vacuum to provide 6.3 g of ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate.

Example 3 Compound of Formula VII 1,8]naphthyridin-5-ol Ethyl 2-(5-methyl-JH-tetrazol-1-yl)nicotinate (6.3 g, 27 mmole) was covered with N,N-dimethylformamide (50 mL), potassium ethoxide (4.5 g, 54 mmole) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into ice water containing about 17 mL of acetic acid. The resulting precipitate was isolated by filtration, washed with water then dried to provide 4.5 g a][1,8]naphthyridin-5-ol as an off white solid, m.p. 2360 (decomposition). Analysis: Calculated for CsHsNsO: 51.34; 2.69; 37.42; Found: 51.23 %H, 2.77; 37.25.

Example 4 [1,8]naphthyridine Tetrazolo[1,5-a][1,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) was suspended in phosphorous oxychloride (10 mL) and heated at reflux for 4 hours. The reaction mixture was concentrated under vacuum and the residue was poured into water. Dichloromethane was added and the aqueous layer was made basic with sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate, filtered and then concentrated under vacuum. The resulting solid was recrystallized from toluene to provide 0.3 g of 5-chlorotetrazolo[1,5-a][1,8]naphthyridine as a solid, m.p. 229-230°C -28- WO 99/29693 PCTIUS98/26473 (decomposition). Analysis: Calculated for CsH 4

CIN

5 46.73; 1.96; 34.06; Found: 46.87; %H 1.54; 33.93.

Example Compound of Formula VIII 4-Nitrotetrazolo[1,5-a] [1,8]naphthryidin-5-ol Nitric acid (1.33 mL of 16M) was added to a suspension of a][1,8]naphthyridin-5-ol (4 g, 21 mmole) in acetic acid (50 mL). The reaction mixture was heated on a steam bath for 5 minutes then cooled to ambient temperature. Sodium acetate (0.3 eq) in a small amount of water was added to the reaction mixture. The resulting solid was isolated by filtration and dried to provide 5 g of4-nitrotetrazolo[1,5a][1,8]naphthryidin-5-ol as a solid, m.p. 278 0 C (decomposition). Analysis: Calculated for CsH4N 6 0 3 1.1 H 2 0: 38.12; 2.48; 33.35; Found: 37.99; 2.41; 32.82.

Example 6 Compound of Formula X NS-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a [1,8]naphthyridin-5-amine 4-Nitrotetrazolo[1,5-a][l,8]naphthryidin-5-ol (3 g, 13 mmole) was suspended in dichloromethane (3.8 mL), triethylamine (1.8 mL) was added, and the reaction mixture was cooled in an ice bath. Trifluoromethanesulfonic anhydride (2.2 mL) was added dropwise. Isobutylamine (3.8 mL) was added in a single aliquot and the reaction mixture exothermed. The reaction mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate then filtered through a layer of silica gel. The silica gel was eluted first with dichloromethane then with 5% methanol in dichloromethane. The eluant was evaporated to provide Ns-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine as a yellow solid, m.p. 171 0 C (decomposition). Analysis: Calculated for Ci 2

H

13

N

7 0 2

%C,

50.17; %H 4.56; 34.13; Found: 49.84; 4.51; 33.88.

-29- WO 99/29693 WO 9929693PCT/US98126473 Example 7 Compound of Formula XI

N

5 -(2-Methylpropyl)tetrazololI 1,5-a] [I1,81jnaph th yrid in 4,5-dia mine A catalytic amount of 5% platinum on carbon was added to a suspension of N 5 methylpropyl)-4-nitrotetrazolo[1,5-a][l,8]naphthyridine-5-amine (2.45 g, 8.5 mmoles) in ethanol (120 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi Kg/cm 2) hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst.

The filtrate was concentrated under vacuum to provide N 5 -(2-methylpropyl)tetrazolo[l1,5- 1,8]naphthyridin-4,5-diamine as an oil.

Example 8 Compound of Formula XII I -(2-Methylpropyl)-JH-tetrazoloj 1,5-aj imidazo[4,5-cJ naphthyridine The N 5 -(2-niethylpropyl)tetrazolo[ 1 1 ,8]naphthyridin-4,5-diamine from Example 7 was combined with diethoxymethylacetate (2 mL) and heated on a steamn bath for 3 hours. The reaction mixture was allowed to stand at ambient temperature overnight and then it was diluted with dichioromethane and methanol. The resulting solution was heated to remove the dichloromethane and reduce the volume of methanol to 50 mL and then cooled. The resulting precipitate was isolated by filtration to provide 1.2 g of 1 methylpropyl)-JH-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine as a solid, m.p. 248- 250TC (decomposition). Analysis: Calculated for C 13

H

13 N,7: 58.42; 4.90; %N, 36.68; Found: 58.04; 4.79; 36.23.

WO 99/29693 PCT/US98/26473 Example 9 Compound of Formula I 1-(2-Methylpropyl)-lH-imidazol4,5-c ll,8]naphthyridin-4-amine hydrate

NH

2 S

N

N N Part A: Triphenylphosphine (1.0 g, 3.7 mmole) was added to a solution of 1-(2methylpropyl)-IH-tetrazolo[ 1,5-a]imidazo[4,5-c] [1,8]naphthyridine (0.5 g, 1.87 mmole) in 1,2-dichlorobenzene (15 mL). The reaction mixture was heated at reflux for 2 hours then concentrated under vacuum to remove the majority of the 1,2-dichlorobenzene. The residue was slurried with hexanes for 30 minutes. The resulting solid 1-(2-methylpropyl)- N-triphenylphosphinyl-lH-imidazo[4,5-c][1,8]naphthyridin-4- amine was isolated by filtration and dried.

Part B: The 1 -(2-methylpropyl)-N-triphenylphosphinyl-IH-imidazo[4,5c][1,8]naphthyridin-4--amine from Part A was dissolved in methanol (15 mL).

Hydrochloric acid (10 mL of 0.6N) was added and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was concentrated under vacuum. The residue was diluted with water then made basic with sodium bicarbonate. The resulting solid was isolated by filtration, slurried with ether and then isolated by filtration. The solid was suspended in toluene (25 mL). The suspension was heated to reflux then diluted with methanol (10 mL) to dissolve the solid. The solution was refluxed to remove the methanol then cooled to ambient temperature. The resulting precipitate was isolated by filtration then coated onto silica gel. The silica gel was eluted with 10-20% methanol in ethyl acetate. The eluant was concentrated to dryness. The resulting material was recrystallized from methanol and water to provide 0.35 g 1-(2-methylpropyl)-]H-imidazo[4,5- -31 WO 99/29693 PCT/US98/26473 c][1,8]naphthyridin-4-amine hydrate as a solid, m.p. 325-330 0 C (decomposition).

Analysis: Calculated for C 1 3

H

15

N

5 V H 2 0: 63.52; 6.35; 28.49; Found: 64.02; 5.87; 28.23.

Example Compound of Formula II 6,7,8,9-Tetrahydro-l-(2-methylpropyl)- 1H-imidazo[4,5-c][1,8]naphthyridin-4- amine

NH

2 HN- N Platinum oxide catalyst was added to a solution of 1-(2-methylpropyl)-7Htetrazolo[ ,5-a]imidazo[4,5-c][1,8]naphthyridine in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm 2 hydrogen pressure for 5 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water and sodium bicarbonate. The resulting precipitate was isolated by filtration. The solid was dissolved in 1N hydrochloric acid and charcoal filtered. The filtrate was treated with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethyl acetate/methanol. The recrystallized material was dissolved in dichloromethane/methanol and placed on a silica gel column. The column was eluted with methanol in ethyl acetate. The eluant was concentrated under vacuum and the residue was recrystallized from methanol/water to provide 0.9 g of 6,7,8,9-tetrahydro-1- (2-methylpropyl)-lH-imidazo[4,5-c][1,8]naphthyridin-4-amine as a solid, m.p. 231- 233 0 C. Analysis: Calculated for C 13

H

1 9 Ns: 63.65; 7.81; /oN, 28.55; Found: %C, 62.99; 7.74; 28.33.

-32- WO 99/29693 PCT/US98/26473 Example 11 Compound of Formula XII 2-Butyl-l-(2-methylpropyl)-H-tetrazolo[l,5-alimidazo[4,5-c]11,8)naphthyridine A catalytic amount of 5% platinum on carbon was added to a suspension of N 5 methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine (5g, 17.4 mmoles) in ethanol (300 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi Kg/cm 2 hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst.

The filtrate was concentrated under vacuum to provide Ns-(2-methylpropyl)tetrazolo[ a][1,8]naphthyridin-4,5-diamine as an oil.

The oil was covered with acetic acid (300 mL), valeryl chloride (2.1 mL, 17.4 mmole) was added and the resulting mixture was heated at reflux overnight. The reaction mixture was concentrated under vacuum. The resulting residue was taken up in dichloromethane, washed with sodium bicarbonate, dried over magnesium sulfate then concentrated under vacuum. The residue was purified using flash chromatography (silica gel; eluting with 2-3% methanol in dichloromethane). The isolated product was purified further using preparatory high performance liquid chromatography eluting with 2% methanol in dichloromethane to provide 2-butyl-l-(2-methylpropyl)-IH-tetrazolo[ a]imidazo[4,5-c][1,8]naphthyridine as a solid, m.p. 182-184 0 C. Analysis: Calculated for

C

17

H

21

N

7 63.14; 6.55; 30.32; Found: 63.45; 6.60; 30.40.

-33- WO 99129693 WO 9929693PCT/1US98/26473 Example 12 Compound of Formula I 2-Butyl-1 -(2-methylpropyl)-1H-imidazo 14,5-c] 11,8 n aphthyridin-4-amine

NH

2 N

N

NN

Triphenylphosphine (0.9 g, 3.7 mmole) was added to a solution of 2-butyl- 1-(2methylpropyl)-JH-tetrazolo[ 1,5-a]iniidazo[4,s-c] [1,8]naphthyridine (0.6 g, 1.8 mmole) in 1,2-dichlorobenzene (15 mL). The resulting mixture was heated at reflux for 2 hours then concentrated under vacuum to remove most of the 1,2-dichlorobenzene. The residue was slurred with hexanes then taken up in dichioromethane and filtered through a layer of silica gel. The silica gel was eluted initially with dichloromethane to remove the 1,2dichlorobenzene, and then with 10% methanol in dichloromethane to recover 2-butyl- 1-(2methylpropyl)-N-triphenylphosphinyl-JH-imidazo[4,s-c][ 1,8]naphthyridin-4- amine.

The 2-butyl-lI-(2-methylpropyl)-N-triphenylphosphinyl-JH-imidazo[4,5c][1,8]naphthyridin-4- amine was taken up in methanol (15 mL), combined with hydrochloric acid (10 mL of 0.6N), and then heated at reflux for 1 hour. The methanol was removed under vacuum. The residue was combined with water and 10% hydrochloric acid then filtered. The filtrate was neutralized with 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried. The resulting solid was refluxed in toluene. The volume of toluene was reduced and the product was allowed to crystallize out under an argon atmosphere to provide 0.25 g of 2-butyl-1-(2-methylpropyl)-JH- 1 ,8naphthyridin-4-amnine hemihydrate, m.p. 237-240 0 C. Analysis: Calculated for C 17

H

23 Ns Y/2 H 2 0: 68.66; 7.79; 23.55; Found: 66.80; 7.62; 23.46.

34 WO 99/29693 PCT/US98/26473 Example 13 Compound of Formula II 2-Butyl-6,7,8,9-tetrahydro-l-(2-methylpropyl)- 1,8)naphthyridin-4-amine

NH

2 HN N HN4 N A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2methylpropyl)-7H-imidazo[4,5-c][1,8]naphthyridin-4-amine (2.0 g, 6.2 mmole) in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus under psi (3.5 Kg/cm 2 hydrogen pressure. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water, sodium bicarbonate and 10% sodium hydroxide. An oil was recovered and purified using reverse phase high performance liquid chromatography eluting with 30:70 buffer (7.68 g potassium phosphate, monobasic; 1.69 g of sodium hydroxide, 1 L of water):methanol to provide 2-butyl-6,7,8,9-tetrahydro-l-(2-methylpropyl)-JHimidazo[4,5-c][1,8]naphthyridin-4-amine hemihydrate as a solid, m.p. 81-84 0

C.

Calculated for C 1 7

H

27 NS 1 2 0: 65.77; 9.09; 22.56; Found: 65.57; 9.15; 22.53.

Example 14 Compound of Formula XVIII 3-(5-Methyl-1H-tetrazol-l-yl)pyridine-4-carboxylic acid 3-Aminopyridine-4-carboxylic acid (50.0 g, 0.36 mol) was suspended in acetic anhydride (250 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum. The solid residue was slurried with heptane then concentrated under vacuum. The resulting solid was covered with acetic acid (300 mL), then sodium azide (23.5 g, 0.36 mol) was added. The reaction exothermed to 50C. The WO 99/29693 PCT/US98/26473 reaction mixture was allowed to stir at ambient temperature overnight. The precipitate was isolated by filtration then slurried with methanol and filtered. The solid was dissolved in 10% sodium hydroxide. The solution was heated on a steam bath for 30 minutes, allowed to cool to ambient temperature then neutralized with 6N hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 64.5 g of 3-(5-methyl-H-tetrazol-l-yl)pyridine-4-carboxylic acid as an off white solid, m.p. 214-215 0 C (decomposition).

Example Compound of Formula XIX Ethyl 3-(5-Methyl-H-tetrazol-l-yl)pyridine-4-carboxylate Dimethylformamide diethyl acetal (46 mL) was added to a suspension of methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid (36 g) in dichloromethane (800 mL).

The reaction mixture was stirred at ambient temperature overnight then washed six times with water (500 mL), dried over magnesium sulfated, and concentrated under vacuum.

The residue was recrystallized from ethyl acetate/hexanes to provide 40 g of ethyl methyl-lH-tetrazol-l-yl)pyridine-4-carboxylate as a solid.

Example 16 Compound of Formula XX Tetrazolo[l,5-a]ll,7]naphthyridin-5-ol hydrate Potassium ethoxide (20.2 g) was added to a mixture of ethyl tetrazol-l-yl)pyridine-4-carboxylate (28 g) and dimethylformamide (280 mL). The reaction mixture was allowed to stir at ambient temperature overnight then poured into cold dilute acetic acid. The resulting precipitate was collected, washed with water and dried to provide 22.4 g of tetrazolo[l,5-a][1,7]naphthyridin-5-ol hydrate as a solid, m.p.

247-248 0 C (decomposition). Analysis: Calculated for C 8 HsN 5 0: 46.83; 3.44; 34.13; Found: 46.48; 3.42; 34.03.

-36- WO 99/29693 PCT/US98/26473 Example 17 Compound of Formula XXI 11,7lnaphthyridine A suspension of tetrazolo[l,5-a][1,7]naphthyridin-5-ol (3.5 g) in phosphorous oxychloride (15 mL) was heated at 90 0 C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was poured into ice water, dichloromethane was added followed by the addition of 10% sodium hydroxide to neutral pH. The product was partitioned into dichloromethane. The dichloromethane layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide 3.8 g of V chlorotetrazolo[1,5-a][1,7]naphthyridine as a solid, m.p. 176-177 0 C. Analysis: Calculated for CsH 4

CIN

5 46.73; 1.96; 34.06; Found: 46.80; 2.16; %N, 34.45.

Example 18 Compound of Formula XXII [1,7]naphthyridin-5-amine A suspension of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine (20 g) in isobutylamine (100 mL) was heated at reflux for several hours. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane, washed with water, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from toluene to give a material that was a mixture by thin layer chromatography. The material was purified by flash chromatography, silica gel eluting with dichloromethane, ethyl acetate in dichloromethane, and 10% methanol in dichloromethane. The fractions with the slower moving material were concentrated to provide N 5 methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine as a solid, m.p. 220-221 0

C.

Analysis: Calculated for CI 2

H

14

N

6 59.49; 5.82; 34.69; Found: 59.35; 5.89; 34.88.

-37- WO 99/29693 PCT/US98/26473 Example 19 Compound of Formula XXIII NS-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine Nitric acid (2 equivalents of 16M) was added to a solution of N-(2methylpropyl)tetrazolo[1,5-a][l,7]naphthyridin-5-amine (2.0 g, 8.26 mmol) in acetic acid.

The reaction mixture was heated on a steam bath for about an hour then concentrated under vacuum. The residue was poured into ice water and the resulting mixture was neutralized with sodium bicarbonate. The resulting precipitate was extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, and dried over magnesium sulfate. Thin layer chromatography indicated a mixture so the material was filtered through a layer of silica gel eluting with 5% ethyl acetate in dichloromethane. The reaction was rerun on 4 g of starting material but using only one equivalent of nitric acid. The resulting material was also a mixture. The material from both reactions was combined then purified by flash chromatography eluting with mixtures of hexanes/ethyl acetate. The fractions containing the slower moving material were combined to provide about 0.3 g of N 5 -(2-methylpropyl)-4-nitrotetrazolo[1,5as a yellow solid, m.p. 173-174°C. Analysis: Calculated for

C

12

H,

3

N

7 0 2 50.17; 4.56; 34.13; Found: 49.85; 4.53; /oN, 34.26.

Example Compound of Formula XXIV

N

5 -(2-Methylpropyl)tetrazolo[l,5-a I1,7]naphthyridin-4,5-diamine

N

5 -(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine (1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess of sodium hydrogen sulfide was dissolved in a minimum of water and added to the suspension. The reaction mixture turned red and all of the material went into solution. The reaction mixture was extracted twice with dichloromethane (150 mL). The extracts were combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 1.22 g of

N

5 -(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine as a light yellow solid, m.p. 203-204.5 0 C. Analysis: Calculated for: C 12

H

1 5

N

7 56.02; 5.88; 38.11; Found: 55.68; 5.81; 37.74.

-38- WO 99/29693 WO 9929693PCT[US98r26473 Example 21 Compound of Formula XXV 1-(2-Methylpropyl)-JH-tetrazolo 1,5-al i mid azo 14,5-cl 11 ,7j naphthyridine

N

5 -(2-Methylpropyl)tetrazolo[1 ,7]naphthyridin-4,5-diamine (1.1 g, 4.3 mmol) was combined with diethoxymethylacetate (2 mL) and heated on a steam bath overnight. The reaction mixture was partitioned between dichioromethane and ammonium hydroxide. The dichioromethane layer was separated, washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue was recrystallized from ethyl acetate/hexane to provide 0.85 g of 1-(2-methylpropyl)-JH-tetrazolo[ alimidazo[4,5-c][1,7]naphthyridine as a solid, m.p. 181-182.5'C. Analysis: Calculated for 9C 13

H

1 3

N

7 58.42; 4.90; 36.68; Found: 58.87; 5.04; 36.13.

Example 22 Compound of Formula 1 1 -(2-Methylpropyl)-JH-imidazol4,5-cI 11 ,7]napbthyridin-4-amine

NH

2 N

N

NJN

Part A: Triphenylphosphine (0.49 g, 1.8 rnmol) was added to a suspension of 1-(2methylpropyl)-JH-tetrazolo[1I,5-a]imidazo[4,5-c] [1 ,7]naphthyridine (0.24 g, 0.9 mmol) in dichlorobenzene (15 mL). The reaction mixture was heated at reflux overnight then concentrated under vacuum. The residue was slurried with hexane and the resulting solid I -(2-methylpropyl)-N-triphenylphosphinyl-JH-imidazo[4,5-c] [1 ,7]naphthyridin-4-amine was isolated by filtration.

Part B: -39- WO 99/29693 PCT/US98/26473 The 1-(2-methylpropyl)-N-triphenylphosphinyl-lH-imidazo[4,5c][1,7]naphthyridin-4-amine from Part A was dissolved in methanol (30 mL).

Hydrochloric acid (3 mL of 3N) was added to the solution and the reaction mixture was heated at reflux overnight before being concentrated under vacuum to remove the methanol. The aqueous residue was neutralized with sodium bicarbonate then extracted with dichloromethane. The extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5-10% methanol in dichloromethane) to provide 0.15 g of 1-(2-methylpropyl)-lHimidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 306-307 0 C. Analysis: Calculated for C 1 3

HI

5 Ns: 64.71; 6.27; /oN, 29.02; Found: 65.10; 6.28; 28.70.

Example 23 Compound of Formula II 6,7,8,9-Tetrahydro-l-(2-methylpropyl)- 1,7]naphthyridin-4-amine

NH

2

N

A catalytic amount of platinum oxide was added to a solution of 1-(2methylpropyl)-IH-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.4 g, 1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi Kg/cm 2 hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted five times with dichloromethane (100 mL). The dichloromethane extracts ri l- 1- 1 1- 1 WO 99/29693 PCT/US98/26473 were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 0.34 g of 6,7,8,9-tetrahydro-1- (2-methylpropyl)-]H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 220- 223°C. Analysis: Calculated for C 13

HI

9

N

5

H

2 0: 62.50 7.87; 28.03; Found: 62.50; 7.72; 27.46.

Example 24 Compound of Formula XXV 2-Methyl-l-(2-methylpropyl)-IH-tetrazololl,5-alimidazo[4,5-c][1,7]naphthyridine Acetic anhydride (2-3 mL) was added to a solution of N-(2methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (0.8 g, 3.1 mmole) in acetic acid. The reaction mixture was heated on a steam bath for several hours then concentrated under vacuum. The residue was partitioned between dichloromethane and water. The aqueous layer was made basic with 10% sodium hydroxide then the dichloromethane layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with methanol in dichloromethane) to provide 0.25 g of 2-methyl-1-(2-methylpropyl)- 1H-tetrazolo[ ,5-a]imidazo[4,5-c][1,7]naphthyridine as a solid, m.p. 157-158 0

C.

Analysis: Calculated for C 14

H

15

N

7 59.77; 5.37; 34.85; Found: 59.64; 5.48; 34.98.

-41- WO 99/29693 WO 9929693PCT[US98/26473 Example Compound of Formula I 2-Methyl-I -(2-methylpropyl)-JH-imidazo 11,71 naphthyridin-4-amine

NH

2 N

N

NNN

Part A: Triphenyiphosphine (2.5 g, 9.6 mmol) was added to a suspension of 2-methyl-I (2-methylpropyl)-JII-tetrazolo[ 1,5-a]imidazo[4,5-c] [1 ,7]naphthyridine (1 g, 4 mmol) in dichlorobenzene. The reaction mixture was heated at reflux overnight then concentrated under vacuum. The residue was slurried with hexane and the -42 WO 99/29693 PCT/US98/26473 resulting solid 2-methyl- -(2-methylpropyl)-N-triphenylphosphinyl-]H-imidazo[4,5c][l,7]naphthyridin-4-amine was isolated by filtration.

Part B: The 2-methyl-1-(2-methylpropyl)-N-triphenylphosphinyl- 1,7]naphthyridin-4-amine from Part A was dissolved in methanol (100 mL).

Hydrochloric acid (10 mL of 3N) was added to the solution and the reaction mixture was heated at reflux overnight before being concentrated under vacuum to remove the methanol. The residue was purified by flash chromatography silica gel eluting with dichloromethane and gradually increasing the polarity to 5% methanol in dichloromethane) to provide 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5- 1,7]naphthyridin-4-amine as a solid, m.p. 322-324 0 C. Analysis: Calculated for

C

14

H

17 Ns: 65.86; 6.71; 27.43; Found: 65.81; 6.64; 27.41.

Example 26 Compound of Formula II 6,7,8,9-Tetrahydro-2-methyl-l-(2-methylpropyl)- 1H-imidazo[4,5-c] [1,7]naphthyridin-4-amine

NH

2

N

A catalytic amount of platinum oxide was added to a solution of 2-methyl-1-(2methylpropyl)-JH-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi Kg/cm 2 hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated, and the aqueous layer was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under -43- WO 99/29693 PCT/US98/26473 vacuum. The resulting residue was recrystallized from toluene to provide 6,7,8,9tetrahydro-2-methyl- I -(2-methylpropyl)- H-imidazo[4,5-c] 1,7]naphthyridin-4-amine as a solid, m.p. 226-230 0 C. Analysis: Calculated for C 1 4

H

21

N

5 1.75 H 2 0: 57.81; %H, 8.49; 24.07; Found: 57.89; 8.04; 23.45.

Example 27 Compound of Formula I 2-Butyl-l-(2-methylpropyl)-IH-imidazol4,5-c][l,7]naphthyridin-4-amine

NH

2 NT N

N

Part A: Valeryl chloride (0.76 mL, 6.4 mmol) was added to a solution of N 5 methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (1.5 g, 5.8 mmol) in acetonitrile (15 mL). The reaction mixture was allowed to stir at ambient temperature for several hours. The resulting precipitate was isolated by filtration. Thin layer chromatography indicated that the material contained two components. The solid was dissolved in acetic acid and heated at reflux overnight. The reaction mixture was concentrated under vacuum, and the residue extracted with dichloromethane. The dichloromethane extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to provide a mixture of 2-butyl -1-(2-methylpropyl)-IHtetrazolo[1,5-a]imidazo[4,5-c][ 1,7]naphthyridine and the acylated, but uncyclized intermediate.

Part B: Triphenylphosphine (2.4 g) was added to a suspension of the material from Part A in dichlorobenzene. The reaction mixture was heated at reflux overnight then concentrated under vacuum. The residue was slurried with hexane and the resulting -44- WO 99/29693 PCT/US98/26473 solid 2-butyl-1 -(2-methylpropyl)-N-triphenylphosphinyl-lH-imidazo[4,5c][1,7]naphthyridin-4-amine was isolated by filtration.

Part C: The 2-butyl- -(2-methylpropyl)-N-triphenylphosphinyl-IH-imidazo[4,5c][1,7]naphthyridin-4-amine from Part B was dissolved in methanol. Hydrochloric acid (3N) was added to the solution and the reaction mixture was heated at reflux overnight before being concentrated under vacuum to remove the methanol. The aqueous residue was mixed with dichloromethane then neutralized with aqueous sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with dichloromethane and gradually increasing the polarity to 5% methanol in dichloromethane) to provide 2-butyl- -(2-methylpropyl)- 1H-imidazo[4,5c][1,7]naphthyridin-4-amine as a solid, m.p 213-214 0 C. Analysis: Calculated for

C

1 7

H

23

N

5 68.66; 7.80; 23.55; Found: 68.26; 7.69; 23.41.

Example 28 Compound of Formula II 2-Butyl-6,7,8,9-tetrahydro -1-(2-methylpropyl)- IH-imidazo 4,5-c] naphthyridin-4-amine

NH

2 N- N

N

UN

A catalytic amount of platinum oxide was added to a solution of 2-butyl methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.5g, 1.68 mol)) in trifluoroacetic acid (20 mL). The reaction mixture was reduced on a Parr apparatus at psi (3.5 Kg/cm 2 hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium WO 99/29693 PCT/US98/26473 bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted three times with dichloromethane (100 mL).

The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene then purified by flash chromatography (silica gel eluting with 20% methanol in dichloromethane with a trace of ammonium hydroxide) to provide 6,7,8,9-tetrahydro-2butyl-l-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p.

164-166 0 C. Analysis: Calculated for C 17

H

2 7

N

5 0.5 H 2 0: 65.77; 9.09; %N, 22.56; Found: 65.99; 8.71; 22.23.

Example 29 Compound of Formula XXXI N-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amine Phosphorous oxychloride (0.6 mL, 6.44 mmol) was reacted with N,Ndimethylformamide then added to a solution of 3-nitro[1,5]naphthyridin-4-ol (1.0 g, 5.23 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was warmed using a jacketed flask with refluxing acetone as a heat source. After 3 hours the reaction mixture was poured into ice water, isobutylamine (2.0 mL, 20.1 mmol) was added and the mixture was heated on a steam bath. After several hours the reaction mixture was cooled to ambient temperature, filtered and washed with water. The aqueous layer was extracted with dichloromethane. The dichloromethane extract was washed with aqueous sodium bicarbonate, washed with water, dried over magnesium filtrate then loaded onto a layer of silica gel. The silica gel was eluted initially with dichloromethane to remove an impurity then with 5% methanol in dichloromethane to recover the product. The eluant was concentrated to dryness to provide N 4 -(2-methylpropyl)-3-nitro[ 1,5]naphthyridin-4-amine as a solid, m.p. 97-99 0

C.

-46- WO 99/29693 PCT/US98/26473 Example Compound of Formula XXXIII I-(2-Methylpropyl)-lH-imidazo[4,5-c] 11,5]naphthyridine Part A: A catalytic amount of 5% platinum on carbon was added to a solution of N 4 methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (1.0 g, 4.1 mmol) in ethyl acetate mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm 2 hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N 4 -(2-methylpropyl)[1,5]naphthyridin- 3,4-diamine as a crude solid.

Part B: The crude solid from Part A was combined with diethoxymethylacetate (2 mL) then heated on a steam bath overnight. The reaction mixture was taken up in dichloromethane, washed with water, dried over magnesium sulfate then filtered through a layer of silica gel. The silica gel was eluted with dichloromethane to remove excess diethoxymethylacetate then with 5% methanol in dichloromethane to recover the product.

The eluant was concentrated to provide an oil which was purified by flash chromatography (silica gel eluting with 50% ethyl acetate/hexane then with ethyl acetate) to provide 0.25 g of 1-(2-methylpropyl)-IH-imidazo[4,5-c][1,5]naphthyridine as a solid m.p. 82-84 0

C.

Analysis: Calculated for C 13

H

14

N

4 69.00; 6.24; 24.76; Found: 68.79; 6.44; 24.73.

Example 31 Compound of Formula XXXIV 1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,51naphthyridine-5N-oxide 3-Chloroperoxybenzoic acid (3.7 g of 50%) was added in small portions over a period of 30 minutes to a solution of 1-(2-methylpropyl)-7H-imidazo[4,5- (1.5 g) in chloroform at ambient temperature. After 3 hours the reaction mixture was diluted with chloroform, washed twice with 2.0 M sodium hydroxide and once with water, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from ethyl acetate/hexane to provide 1.2 g of 1-(2- -47- WO 99/29693 WO 9929693PCTIUS98/26473 1,5]naphthyridine-5N-oxide as a solid, m.p. 183-185'C.

Analysis: Calculated for C 13

H-

1 4

N

4 0: 64.45; 5.82; 23.12; Found: %C, 64.15; 5.92; 23.02.

Example 32 Compound of Formula I 1-(2-Methylpropyl)-IH-imidazol4,5-cI [1,51naphthyridin-4-amine

NH

2

N

N N r Ammonium hydroxide (10 mL) was added to a solution of 1-(2-methylpropyl)-JHimidazo[4,5-c][1,5]naphthyridine-5N-oxide (0.6 g) in dichloromethane (3OmL). The reaction mixture was cooled in an ice bath then tosyl chloride (0.5 g) in dichloromethane was added while the reaction was being rapidly stirred. The reaction mixture was stirred at ambient temperature overnight. The dichloromethane layer was separated, washed with aqueous sodium bicarbonate, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from ethyl acetate/hexane to provide 0.2 g of I (2-methylpropyl)-JH-imidazo[4,5-c] [1 ,5]naphthyridin-4-amine as a solid, m.p. 230- 231.5'C. Analysis: Calculated for C 13

H

15

N

5 64.71; 6.27; 29.02; Found: 64.70; 6.01; 29.08.

-48- WO 99/29693 PCT/US98/26473 Example 33 Compound of Formula II 6,7,8,9-Tetrahydro-l-(2-methylpropyl)- 1H-imidazoj4,5-c]1l,5]naphthyridin-4-amine

NH

2 N.

N

NH

A catalytic amount of platinum oxide was added to a solution of 1-(2methylpropyl)-7H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.46 g) in trifluoroacetic acid (10 mL). The reaction mixture was reduced on a Parr apparatus under 45 psi (3.15 Kg/cm 2 hydrogen pressure for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added.

The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 6,7,8,9tetrahydro- -(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a solid, m.p. 222-226 0 C. Analysis: Calculated for C 13

HI

9

N

5 63.65; 7.81; 28.55; Found: 63.07; 7.51; 28.00.

-49- WO 99/29693 PCT/US98/26473 Example 34 Compound of Formula XXXIII 2- Methyl-1-(2-methylpropyl)-lH-imidazo[4,5-c][11,5]naphthyridine Part A: Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbon were added to a solution of N 4 -(2-methylpropyl)-3-nitro[ 1,5]naphthyridin-4-amine (4.0 g, 16.2 mmol) in ethyl acetate (250 mL). The reaction mixture was reduced on a Parr apparatus at psi (3.5 Kg/cm 2 hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N 4 methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

Part B: The crude solid from Part A was taken up in acetic acid, combined with acetic anhydride then heated at reflux overnight. The reaction mixture was concentrated under vacuum. The resulting residue was combined with methanol to decompose excess acetic anhydride then concentrated under vacuum. The resulting residue was combined with cyclohexane then concentrated under vacuum to remove the acetic acid. The resulting residue was recrystallized from hexanes to provide 2.2 g of 2- methyl-1-(2-methylpropyl)- 1H-imidazo[4,5-c][1,5]naphthyridine as off-white needles, m.p. 118-119 0 C. Analysis: Calculated for C, 4

H

6

N

4 69.97; 6.71; /oN, 23.31; Found: 69.24; 6.67; 23.23.

Example Compound of Formula XXXIV 2-Methyl-l-(2-methylpropyl)-IH-imidazo[4,5-c] [1,5]naphthyridine-5N-oxide 3-Chloroperoxybenzoic acid (4.5 g of 50%, 13.1 mmol) was added in small portions over a period of 30 minutes to a solution of 2-methyl-1-(2-methylpropyl)-IHimidazo[4,5-c][1,5]naphthyridine (2.1 g, 8.7 mmole) in chloroform at ambient temperature. After 3 hours the reaction mixture was diluted with chloroform, washed twice with 2.0 M sodium hydroxide, once with water, and once with brine, dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 2- WO 99/29693 PCT/US98/26473 methyl- I -(2-methylpropyl)-JH--imidazo[4,5-c] 1,5]naphthyridine-5N-oxide as a solid, m.p. 228-230'C. Analysis: Calculated for C1 4

H

16

N

4 0: 65.61; 6.29; 21.86; Found: 65.73; 6.3 1; 21.95.

Example 36 Compound of Formula I 2-Methyl-1-(2-metbylpropy)-1H-imidazol4,5-c 11,5j iiaphthyridin-4-amine

NH

2 N-

N

N N r Ammoniumi hydroxide (10 mL) was added to a solution of 2-methyl- 1-(2- [1,5]naphthyridine-5N-oxide 1 g, 4.29 mimol) in dichioromethane (5OmL). The reaction mixture was cooled in an ice bath then tosyl chloride (0.82 g, 4.29 mmol) in dichloromethane was added. The reaction was warmed to about 30'C while being rapidly stirred. The reaction mixture was stirred at ambient temperature overnight. The dichloromethane layer was separated, washed with sodium hydroxide, water and brine, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 0.8 g of 2-methyl-I- (2-methylpropyl)-JH-imidazo[4,5-c][ 1,5]naphthyridin-4-amine as a solid, m.p. 228- 230'C. Analysis: Calculated for C 14

H

17

N

5 65.86; 6.71; 27.43; Found: %C, 65.65; 6.69; 27.59.

-51- WO 99/29693 PCT/US98/26473 Example 37 Compound of Formula XXXIII 2- Butyl-1 -(2-methylpropyl)-IH-imidazo 4,5-c 1,51 naphthyridine Part A: Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbon were added to a solution of N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (3.0 g, 12.2 mmol) in ethyl acetate (150 mL). The reaction mixture was reduced on a Parr apparatus at psi (3.5 Kg/cm 2 hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N 4 methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

Part B: The crude solid from Part A was taken up in acetonitrile then combined with valeryl chloride (1.5 mL, 12.2 mmol). The mixture was stirred at ambient temperature for 30 minutes. The resulting precipitate was isolated by filtration, washed with a small amount of acetonitrile and air dried to provide 2.75 g of methylpropylamino)[1,5]naphthyridin-3-yl)valeramide hydrochloride as a solid.

Part C: The solid from Part B was suspended in acetic acid and heated at reflux overnight.

The reaction mixture was concentrated under vacuum and the resulting residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate and concentrated under vacuum to provide 2.3 g of 2-butyl-l-(2-methylpropyl)-IH-imidazo[4,5as an oil.

-52- WO 99/29693 PCT/US98/26473 Example 38 Compound of Formula XXXIV 2-Butyl-l-(2-methylpropyl)-1H-imidazo[4,5-c 11,5]naphthyridine-5N-oxide 3-Chloroperoxybenzoic acid (5.3 g of 50%, 15.2 mmol) was added in small portions over a period of 30 minutes to a solution of 2-butyl-l-(2-methylpropyl)-lHimidazo[4,5-c][1,5]naphthyridine (2.3 g, 10.2 mmole) in chloroform at ambient temperature. After 3 hours the reaction mixture was diluted with chloroform, washed twice with 2.0 M sodium hydroxide, once with water, and once with brine, dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash 9' chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 2butyl-l -(2-methylpropyl)- H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide. Analysis: Calculated for C 17

H

22

N

4 0: 68.43; 7.43; 18.78; Found: 67.67; %H, 6.73; 18.13 Example 39 Compound of Formula I 2-Butyl-l-(2-methylpropyl)-JH-imidazol4,5-c][1,5]naphthyridin-4-amine

NH

2

N

NN

Ammonium hydroxide (25 mL) was added to a solution of 2-butyl-1-(2methylpropyl)-lH-imidazo[4,5-c][1,5]naphthyridine-5N-oxide (2.0 g, 6.7 mmol) in dichloromethane (100mL). The reaction mixture was cooled in an ice bath then tosyl chloride (1.3 g, 6.7 mmol) in dichloromethane was added. The reaction was warmed to about 30 0 C while being rapidly stirred. The reaction mixture was stirred at ambient temperature overnight. The dichloromethane layer was separated, washed with sodium hydroxide, water and brine, dried over magnesium sulfate then concentrated under -53- WO 99/29693 PCTIUS98/26473 vacuum. The residue was recrystallized from hexane to provide 1.55 g of 2-butyl-l-(2methylpropyl)-lH-imidazo[4,5-c][1,5]naphthyridin-4-amine as a solid, m.p. 115-116 0

C.

Analysis: Calculated for C 17

H

23 Ns: 68.66; 7.80; 23.55; Found: 69.52; 7.72; 21.72 Example Compound of Formula II 6 ,7,8,9-Tetrahydro-2-butyl-l-(2-methylpropyl)- 1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

NH

2 N N

N

NH

A catalytic amount of platinum oxide was added to a solution of 2-butyl-l-(2methylpropyl)-7H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.5 g) in trifluoroacetic acid (15 mL). The reaction mixture was reduced on a Parr apparatus under 50 psi (3.5 Kg/cm 2 hydrogen pressure overnight. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added. The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 1-5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from hexane/ethyl acetate to provide 6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-7H-imidazo[4,5-c][1,5]naphthyridin-4amine as a solid, m.p. 143-147 0 C. Analysis: Calculated for C 17

H

27

N

5 67.74; %H, 9.03; 23.23; Found: 61.90; 7.51; 19.91.

-54- WO 99/29693 PCT/US98/26473 Example 41 Compound of Formula XXXI 1,1-Dimethylethyl N-{4-[(3-Nitroll,5]naphthyridin-4-yl)amino]butyl}carbamate Phosphorus oxychloride (4 mL, 0.31 mole) was combined with N,Ndimethylformamide (100 mL) while cooling in an ice bath. The resulting mixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (50 g, 0.26 mole) in N,Ndimethylformamide (500 mL). The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was poured into ice water and then extracted with W dichloromethane (1800 mL). The organic layer was separated and then combined with triethylamine (45 mL). Tert-butyl N-(4-aminobutyl)carbamate was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated under vacuum and the residue was treated with water (-1500 mL). The resulting solid was isolated by filtration, washed with water and dried to provide 76 g of 1,1 -dimethylethyl N- nitro[1,5]naphthyridin-4-yl)amino]butyl} carbamate as a solid. A small sample was recrystallized from isopropyl alcohol to provide a pure sample, m.p. 137-138C. Analysis: Calculated for C 17

H

23

N

5 0 4 56.50; 6.41; 19.38; Found: 56.26; %H, 6.30; /oN, 19.53.

Example 42 Compound of Formula XXXII 1,1-Dimethylethyl N-(4-I(3-Amino1,5]naphthyridin-4-yl)amino]butyl}carbamate 1,1-Dimethylethyl N- {4-[(3-nitro[ 1,5]naphthyridin-4-yl)amino]butyl} carbamate (42.7 g, 0.12 mole), platinum on carbon (2 g) and ethyl acetate (500 mL) were combined and then hydrogenated on a Parr apparatus at 30 psi (2.1 Kg/cm 2 hydrogen pressure for 1 hour. The catalyst was removed by filtration and rinsed with ethyl acetate. The filtrate was concentrated under vacuum to provide 1,1-dimethylethyl amino[1,5]naphthyridin-4-yl)amino]butyl} carbamate as a bright yellow-orange solid.

WO 99/29693 PCT/US98/26473 Example 43 Compound of Formula XXXIII 1,1-Dimethylethyl N-14-(2-Butyl-lH-imidazo(4,5-c] Freshly distilled trimethyl orthovalerate (41 mL, 0.24 mole) was added to a mixture of 1,1-dimethylethyl N- {4-[(3-amino[ 1,5]naphthyridin-4yl)amino]butyl}carbamate (39 g, 0.12 mole) in warm xylene (500 mL). The reaction mixture was heated at reflux overnight. Thin layer chromatography showed that at least half of the starting material was still present. p-Toluenesulfonic anhydride monohydrate (6 I g) was added. After a short time thin layer chromatography showed that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was concentrated under vacuum to provide an oily residue. The residue was triturated with hexane to provide a dark pink solid. This solid was recrystallized from acetonitrile to provide 1,1-dimethylethyl N-[4-(2-butyl-lH-imidazo[4,5as a pale peach solid, m.p, 96.0-98.0"C.

Analysis: Calculated for C 22

H

31

N

5 0 2 66.47; 7.86; 17.62; Found: %C, 66.29; 7.78; 17.76.

Example 44 SCompound of Formula XXXIV 1-{4-[(1,1-Dimethylethylcarbonyl)amino]butyl)-2-butyl- 1H-imidazo[4,5-c [1,5]naphthyridine-5N-oxide 3-Chloroperbenzoic acid (1 eq at 57%) was added in portions to a solution of 1,1dimethylethyl N-[4-(2-butyl-1H-imidazo[4,5-c][ 1,5]naphthyridin-l-yl)butyl]carbamate in chloroform (50 mL). The reaction mixture was allowed to stir at ambient temperature for 2 hours at which time thin layer chromatography showed that no starting material remained. The reaction mixture was diluted with dichloromethane and then washed twice with 1M sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under vacuum to provide -56- WO 99129693 PCT/US98/26473 dimethylethylcarbonyl)amino]butyl}-2-butyl- 1H-imidazo[4,5-c][ 1,5]naphthyridine-5Noxide as an orange oil which solidified on standing.

Example Compound of Formula I 1,1-Dimethylethyl N-14-(4-Amino-2-butyl-1

NH

2 N

N

N NH 0 Ammonium hydroxide (20 mL) was added to a solution of 1- dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5Noxide (19.4 g) in chloroform. Tosyl chloride (9 g) was slowly added. Thin layer chromatography indicated that the reaction was proceeding slowly. Additional tosyl chloride was added twice. After thin layer chromatography indicated that the reaction was complete, the layers were separated. The organic layer was washed with dilute aqueous sodium carbonate, dried over magnesium sulfate and then concentrated under vacuum.

The residue was covered with methyl acetate (10 mL), hexane (5 mL) was added and the mixture was allowed to stand overnight. The resulting crystalline solid was isolated by filtration, washed with hexane and then dried to provide 15.1 g of 1,1-dimethylethyl N-[4- (4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-l-yl)butyl]carbamate, m.p. 148.5- 149.5"C. Analysis: Calculated for C 2 2

H

3 2

N

6 0 2 64.05; 7.82; 20.37; Found: 64.15; 7.82; 20.55.

-57- WO 99/29693 WO 9929693PCT/US98/26473 Example 46 Compound of Formula I 4-(4-Amino-2-butyl-1H-imidazo[4,5-cI [I ,5Jnaphthyridin-1-yI)butaneamine

NH

2 N

N

NH

2 A suspension of 1,1 -dimethylethyl N-[4-(4-amino-2-butyl- c] 5 ]naphthyri din-1I-yl)butyl] carbamnate (13.8g) in IN hydrochloric acid (140 mL) was heated on a steam bath for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and then it was made basic (pH>I 1) with 50% sodium hydroxide. The resulting precipitate was isolated by filtration, washed with water and then dried to provide 9.5g of 4-(4-amino-2-butyl- 1H-imidazo[4,5-c] [1 ,Slnaphthyri din- 1-yl)butaneaxnine as a white solid, m.p. 212-213'C. Analysis: Calculated for C 17

H

24

N

6 65.36; %H, 7.74; 26.90; Found: 65.16; 7.65; 27.29.

Example 47 Compound of Formula I N-I4-(4-Amino-2-buty-1H-imidazo4,5-cI [1,5jnaphthyridin-1 -yI)butyll-

NH

2

N

0 Under a nitrogen atmosphere, phenyl isocyanate (52 LiL, 0.48 mmol) was added to a suspension of 4-(4-amnino-2-butyl- 1H-imidazo[4,5-c][1 ,5]naphthyridin- 1-yl)butaneamine 58 WO 99129693 WO 9929693PCT[US98/26473 15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL). The reaction mixture was stirred for 20 minutes at which time it had turned homogeneous and thin layer chromatography indicated no starting material remained. Aminomethyl resin (280 mg of 1% cross linked, 100-200 mesh available from BACHEM, Torrance, California) was added and the reaction mixture was allowed to stir for 0.5 hr. Silica gel (0.4 g) was added and the mixture was concentrated under vacuum to provide a solid. The solid was purified by flash chromatography eluting with 95/5 dichloromethane/methanol to give a white solid which was dried under vacuum at 60*C to provide 0. 12 g of N-[4-(4-amino-2-butyl- 1H- [1 ,5)naphthyridin- 1-yl)butyl]- N'-phenylurea. Analysis: Calculated for

C

24

H

29

N

7 0 1/5 H 2 0: 66.25; 6.81; 22.53; Found: 66.27; 6.63; %1N, 22.83 Example 48 Compound of Formula I N-[4-(4-Amino-2-butyl-1H-imidazo[4,5-cI [1 ,Sjnaphthyridin-1 -yI)butylJ- N'-cyclohexylurea

NH

2 N

N

Using the general method of Example 47, cyclohexyl isocyanate (61 [LL, 0.48 mnmol) was reacted with 4-(4-amino-2-butyl- 1H-imidazo[4,5-c] 1,5]naphthyridin- I1yl)butaneaniine (0.15 g, 0.48 mmole) to provide 0.14 g of N-[4-(4-arnino-2-butyl-IH- 1 ,]naphthyridin- 1-yI)butyl]- cyclohexylurea as a white solid.

Analysis: Calculated for C 24

H

35

N

7 0: 65.88; 8.06; 22.41. 'H NMR (300 MIHz, CDCI 3 8 8.60 (dd, J 4.4, 1.4 Hz, 1 8.08 J 8.5 Hz, I 7.44 (dd, J 4.4 Hz, 1 5.55 (br s, 2 4.92 J =5.8 Hz, 1 4.82 (apparent t, J 7.8 Hz, 2 H), 4.13 J 8.6 Hz, I 3.48 (in, 1 3.35 (apparent q, J 6.4 Hz, 2 2.93 (apparent t, J 7.8 Hz, 2 1.80-2.05 (in, 4 1.45-1.75 (mn, 6 1.2-1.4 (mn 2 1.0-1.2 (in, 2 59 WO 99/29693 WO 9929693PCT/US98/26473 1.03 7.4 Hz, 3 HR-MS (El) calcd for C 2 4 H1 3 5

N

7 0 (M 4 437.2903, found 437.2903.

Example 49 Compound of Formula I N-[4-(4-Amino-2-butyl-IH-imidazo[4,5-cI 11,5] naphthyridin-1 -yi)butyl]- N'-butylurea

NH

2 N

N

NH H N N Using the general method of Example 47, butyl isocyanate (54 gL, 0.48 rnol) was reacted with 4-(4-amino-2-butyl- 1H-imidazo[4,5-c][ [1,5]naphthyridin- 1yl)butaneamine (0.15 g, 0.48 mnmole) to provide 0.13 g of N-14-(4-anino-2-butyl-IH- [1 ,5]naphthyridin- 1-yl)butyl]- N'-butylurea as a white solid. Analysis: Calculated for C 22

H

33

N

7 0: 64.21; 8.08; 23.82; Found: 64.05; %H, 7.97; 24.00.

Example Compound of Formula I Phenyl N-[4-(4-Amino-2-butyl- 1H-imidazo[4,5-cJ 11,51 naphthyridin-1 -yI)butylj carbamate

NH

2 N 1

N

H

Ny 200 WO 99129693 WO 9929693PCTJUS98/26473 Using the general method of Example 47, phenyl chioroformate (61 gil, 0.48 mmol) was reacted with 4-(4-amino-2-butyl- 1H-i'midazo[4,5-c] [1 ,5]naphthyridin- 1yl)butaneamine 15 g, 0.48 mmole) to provide 0. 12 g of phenyl N-[4-(4-amino-2-butyl- 1 H-imidazo[4,5-c][1I,5]naphthyridin-1I-yl)butyl]carbamate as a solid. Analysis: Calculated for C 24

H

28

N

6 0 2 66.65; 6.53; 19.43; Found: 66.49; 6.59; %N, 19.32.

Example 51 Compound of Formula I N-[4-(4-Amino-2-butyI-lH-imidazo[4,5-cJ 11,5lnaphthyridin-1-yl)butyll- 2-furamide

NH

2 N

N

H

NN

-~0 Using the general method of Example 47, furoyl chloride (15.8 JtL, 0. 16 mmol) was reacted with 4-(4-amino-2-butyl- lH-imidazo[4,5-c][ I ,5]naphthyridin- I1yl)butaneamnine (0.05 g, 0.16 mmole) to provide 0.019 g of N-[4-(4-amino-2-butyIlHimidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide as a white solid. 'H NMR (300 MHz, CDC1 3 5 8.5 8 (dd, J 1.5 Hz, I 8.06 (dd, J 8.6, 1.6 Hz, I 7.41 (dd, J 8.5, 4.4 Hz, 1 7.33 (in, 1 7.08 (dd, J 3.5, 0.6 Hz, 1 6.84 (in, 1 6.47 (dd, J 3.5, 1.7 Hz, I 4.86 (apparent t, J 7.7 Hz, 2 3.59 (apparent q, J =6.5 Hz, 2 H), 2.92 (apparent t, J 7.8 Hz, 2 1.7-2. 1 (in, 6 1.51 (in, 2 1.00 J 7.3 Hz, 3 H); HRMS (El) calcd for C 2 2

H

2 6

N

6 0 2 406.2117, found 406.2121.

-61- WO 99/29693 WO 9929693PCT1US98/26473 Example 52 Compound of Formula I N-14-(4-Amno-2-butyl- I ,5jnaphthyridin-1-yl)butylj beozamide

NH

2 N

N

H

N 0 Using the general method of Example 47, benzoyl chloride (56 jiL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl- lH-imidazo[4,5-cI [1 ,5]naphthyridin- 1yl)butaneamine 15 g, 0.48 mmole) to provide 0. 11 g of N-[4-(4-amino-2-butyl- IH- [1 ,5]naphthyridin- 1-yl)butyl]benzamide as a white solid. Analysis: Calculated for C 24

H

28

N

6 0 1/4H 2 0: 68.47; 6.82; 19.96: Found: 68.24; 6.76; 19.90.

Example 53 Compound of Formula I is N-14-(4-Amino-2-butyl-1H-imidazol4,5-cl ti ,5jnaphthyridin-1-yI)butyIj- N'-benzylurea Benzyl isocyanate (59 gL, 0.48 nunol) was added at ambient temperature to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1-yl)butaneamine 62 WO 99/29693 PCT/US98/26473 (0.15 g, 0.48 mmol) in tetrahydrofuran (60 mL). A solution was obtained in less than minutes and thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (280 mg) was added and the reaction mixture was stirred for 15 minutes. The solvent was removed under vacuum. The residue was purified by column chromatography to provide 0.16 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin- -yl)butyl]-N'benzylurea as a white solid. Analysis: Calculated for C 25

H

3 1

N

7 0: 67.39; 7.01; 22.00; Found: 67.43; 6.92; 22.02.

Example 54 Compound of Formula I

N

3 -14-(4-Amino-2-butyl- 1H-imidazo[4,5-c]

NH

2

N^N

N

N 0

N

4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin- -yl)butaneamine (0.050 g, 0.16 mmol) was suspended in tetrahydrofuran (30 mL). N,N-diisopropylethylamine (28 IiL, 0.16 mmol) was added to the suspension and then nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour by which time a solution was obtained. Thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (100 mg) was added and the reaction mixture was stirred for 5 minutes. The solvent was removed under vacuum. The residue was dissolved in dichloromethane and placed on a layer of silica gel. The silica gel was eluted first with dichloromethane and then with 9:1 dichloromethane:methanol. The cleanest fractions were combined and then concentrated under vacuum to provide N 3 -[4-(4-amino-2-butyl- -63- WO 99/29693 PCT/US98/26473 1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]nicotinamide as a white powder. 'H NMR (300 MHz, CDCI 3 6 8.91 1 8.68 J 4.5 Hz, 1 8.45 J 4.3 Hz, 1 H), 8.03 2 7.30-7.40 2 6.98 2 5.51 1 4.86 (apparent t, J 7.9 Hz, 2 3.66 J 6.5 Hz, 2 2.92 (apparent t, J 7.7 Hz, 2 2.05 2 1.75-1.95 4 1.51 2 1.00 J 7.3 Hz, 3 HRMS (EI) calcd for C 23

H

2 7

N

7 0 (M 417.2277, found 417.2276.

Example Compound of Formula I N-[4-(4-Amino-2-butyl- 1H-imidazo[4,5-c][1,5]naphthyridin-l-yl)butyl]phenylaceatamide

NH

2 N,

N

H

Phenylacetyl chloride (21 L, 0.16 mmol) was added to a suspension of 4-(4amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin- I-yl)butaneamine (0.050 g, 0.16 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at ambient temperature for 1 hour by which time a solution was obtained. Thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (100 mg) was added and the reaction mixture was stirred for 5 minutes. The solvent was removed under vacuum to provide a white powder. This material was placed on a short column of silica gel and purified by eluting first with dichloromethane and then with 9:1 dichloromethane:methanol. The cleanest fractions were combined and then concentrated under vacuum to provide a colorless oil. The oil was dissolved in dichloromethane, hexane was added just until the solution started to become cloudy, and then the solvent was removed to provide amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-l-yl)butyl]phenylacetamide as a white powder. Analysis: Calculated for C 25

H

3 0

N

6 0 2 67.24; 6.77; /oN, 18.82; Found: -64- WO 99/29693 WO 9929693PCT/IJS98/26473 67.52; 6.85; 18.38. 'HNMR (300 MHz, CDC1 3 6 8.51 (dd, J 4.4, Hz, 1 8.11 (dd, J 8.4, 1.4 Hz, 1 7.43 (dd, J 8.4, 4.4 Hz, 1 7.10-7.20 (in, 6.30 (br s, 2 5.83 (in, I 4.72 (apparent t, J 7.8 Hz, 2 3.54 2 3.35 (apparent q, J 6.5 Hz, 2 2.88 (apparent t, J 7.8 Hz, 2 1.80-1.90 (in, 4 1.45- 1.65 (in, 4 1 .00 J 7.3 Hz, 3 HRMS (El) calcd for C 25

H

3 oN 6 0 430.248 1, found 430.2490.

Example 56 Compound of Formula I Benzyl N-[4-(4-Amino-2-butyl- 11

NH

2 N 1

N

H

N N>0 0 Using the general method of Example 55, benzyl chioroformate (83 gL, 0.58 mmol) was reacted with 4-(4-amino-2-butyl- 1 H-imidazo[4,5-c] 1,5]naphthyridin- 1 yl)butaneamine 15 g, 0.48 inmol) to provide 0. 18 g of benzyl N-[4-(4-arnino-2-butyl- 1H-imidazo[4,S-c] [I,5]naphthyridin- 1-yl)butyl)carbamate as a white powder.

65 WO 99/29693 WO 9929693PCT/US98/26473 Example 57 Compound of Formula I 9H-9-Fluorenylmethyl N-14-(4-Amino-2-butyl- I H-imidazo 14,5-cJ 11,5] n aphthyridin-1 -yI)bu tyll carb amate NI1 N N

N

H

Ny N 0 Using the general method of Example 55, 9-fluorenylmethyl chloroformate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin- I -yl)butaneaniine 105 g, 0.33 nimol) to provide 0. 125 g of 9H-9-fluorenylmethyl N-[4- (4-amino-2-butyl- 1H-imidazo[4,5-c][ 1,5]naphthyridin- 1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C 32

H

34

N

6 0 2 1/4H 2 0: 71.29; 6.45; 15.59; Found: 70.99; 6.35; 15.55.

Example 58 Compound of Formula I Ethyl N-14-(4-Amino-2-butyl- 1H-imidazo[4,5-c] naphthyridin-1-yl)butylj carbamate

N

2 N

N

N H N' 0 0 Using the general method of Example 55, ethyl chloroformnate (46 IiL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl- 1H-imiidazo[4,5-c] [1 ,5]naphthyridin-1 yl)butaneamine 15 g, 0.48 mmol) to provide 0. 15 g of ethyl N-[4-(4-amino-2-butyIlH- 66 WO 99/29693 PCTUS98/26473 imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C 2 oH 28

N

6 0 2 62.48; 7.34; 21.86; Found: 61.73; %H, 7.28; 21.62.

Example 59 Compound of Formula XXXI 1,1 -Dimethyl-2-[(3-nitro[l,5] naphthyridin-4-yl)amino]ethanol Phosphorus oxychloride (4 mL, 43 mmol) was reacted with N,Ndimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.9 g, 36.1 mmol) in N,N-dimethylformamide mL). The reaction mixture was warmed in an oil bath to 60 0 C. After 3 hours the reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water. The wet crude 5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150 mL). Diisopropylethylamine was added followed by the slow addition ofhydroxyisobutylamine (3.4 g, 40 mmol). The reaction mixture was refluxed for 2 hours and then combined with water (-100 mL). The resulting precipitate was isolated by filtration to provide 7.2 g of 1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4yl)amino]ethanol. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 184.5-186C. Analysis: Calculated for C 12

H

1 4

N

4 0 3 54.96; 5.38; 21.36; Found: 54.63; 5.36: /oN, 21.51.

-67- WO 99/29693 PCT/US98/26473 Example Compound of Formula XXXIII 1,l-Dimethyl-2-(2-butylll,5]napthyridin-l-yl)ethanol Part A A catalytic amount of 5% platinum on carbon was added to a suspension of 1,1dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (7 g, 26 mmol) in isopropanol (300 mL). The mixture was hydrogenated on a Parr apparatus at 50 psi (3.5 Kg/cm 2 hydrogen pressure for 3 hours. The reaction mixture was fileted to remove the catalyst.

The filtrate was concentrated under vacuum. Toluene was added to the residue and the mixture was concentrated under vacuum to remove all of the alcohol and provide crude 1,1 -dimethyl-2-[(3-amino[ 1,5]naphthyridin-4-yl)amino] ethanol.

Part B Trimethylorthovalerate (3.6 mL, 20 mmol) was added to a suspension of 1,1dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13 mmol) in xylene (100 mL). The reaction mixture was heated at reflux for two days. The mixture was diluted with methanolic ammonia, placed in a Parr vessel and then heated at 110 0 C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and water. The layers were separated. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide an oil. The oil was recrystallized from methyl acetate/benzene to provide 2.8 g of 1,1-dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol as a solid, m.p. 85-88.5"C. Analysis: Calculated for C 17

H

22

N

4 0: 68.43; 7.43; 18.78; Found: 68.04; %H, 7.18; 19.09.

Example 61 Compound of Formula XXXIV 2-Butyl-1-(2-hydroxy-2-methylpropyl)-IH-imidazo[4,5-c] 1,5]naphthyridine-5Noxide 3-Chloroperbenzoic acid (2.6 g, 9.5 mmol) was added in 3 portions to a solution of 1,1-dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol (2.6 g, 8.7 mmol) in chloroform mL) in a flask covered with aluminum foil. The reaction mixture was stirred at ambient temperature for 4 hours; then it was washed twice with dilute aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate and then concentrated under vacuum.

-68- WO 99/29693 PCT/US98/26473 The residue was recrystallized from methyl acetate to provide 2.25 g of 2-butyl-1-(2hydroxy-2-methylpropyl)- 1H-imidazo[4,5-c][ 1,5)naphthyridine-5N-oxide, m.p. 156- 158 0 C. Analysis: Calculated for: C 17

H

22

N

4 0 2 4

H

2 0: 64.03; 7.11; 17.57; Found: 63.96; 6.84; 17.71.

Example 62 Compound of Formula I 1,l-Dimethyl-2-(4-amino-2-butyl[1,5]napthyridin-l-yl)ethanol

NH

2 N

N

NN

OH

Ammonium hydroxide (15 mL) was added to a solution of 2-butyl-l-(2-hydroxy-2methylpropyl)-lH-imidazo[4,5-c][1,5]naphthyridine-5N-oxide (1.9 g, 6.0 mmol)in dichloromethane (40 mL). Tosyl chloride (1.2 g, 6.4 mmol) was slowly added. Thin layer chromatography indicated that the reaction was proceeding slowly. Additional tosyl chloride was added twice. After thin layer chromatography indicated that the reaction was complete, the layers were separated. The organic layer was washed with dilute aqueous sodium carbonate, dried over magnesium sulfate and then concentrated under vacuum.

The residue was covered with methyl acetate (10 mL), hexane (5 mL) was added and the mixture was allowed to stand overnight. The resulting crystalline solid was isolated by filtration to provide 0.9 g of 1,1-dimethyl-2-(4-amino-2-butyl[1,5]napthyridin-1yl)ethanol, m.p. 177-179°C. Analysis: Calculated for C 1 7

H

23

N

5 0: 65.15; 7.40; 22.35; Found: 64.97; 7.33; 22.71.

-69- WO 99/29693 PCT/US98/26473 Example 63 Compound of Formula XXXIII 1,1 -Dimethyl-2-(2-phenylemethyll Part A Phenylacetyl chloride (2.0 mL, 20 mmol) was added to a suspension of 1,1dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13 mmol) in dichloromethane (100 mL). The reaction mixture was heated at reflux until thin layer chromatography indicated that the reaction was complete. The reaction mixture was taken on to the next step.

Part B The material from Part A was combined with 7% ammonia in methanol (100 mL), placed in a sealed vessel, and then heated at 150°C for 6 hours. The reaction mixture was concentrated under vacuum. The residue was combined with water (100 mL) and then extracted with dichloromethane (2 X 75 mL). The extracts were combined, washed with water (100 mL), dried over magnesium sulfate and then concentrated under vacuum. The residue was recrystallized from methyl acetate to provide 2.1 g of 1,1-dimethyl-2-(2as a solid, m.p. 150-152C. Analysis: Calculated for C 20

H

20

N

4 0: 72.27; 6.06; 16.85; Found: 72.11; %H, 6.01; 17.00.

Example 64 -4 Compound of Formula XXXIV 2-Phenylmethyl-l-(2-hydroxy-2-methylpropyl)- 1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide 3-Chloroperbenzoic acid (1.8 g, 6.6 mmol) was added in 3 portions to a solution of 1,1-dimethyl-2-(2-phenylmethyl[1,5]napthyridin-1-yl)ethanol (2 g, 6 mmol) in chloroform mL) in a flask covered with aluminum foil. The reaction mixture was stirred at ambient temperature overnight; then it was washed twice with dilute aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate and then concentrated under vacuum. The residue was recrystallized from isopropanol to provide 2.25 g of 2phenylmethyl-1-(2-hydroxy-2-methylpropyl)- 1H-imidazo[4,5-c][1,5]naphthyridine-5N- WO 99/29693 PCT/US98/26473 oxide, m.p. 204-206°C. Analysis: Calculated for: C 20

H

20

N

4 0 2

V

2

H

2 0: 67.21; %H, 5.92; 15.68; Found: 67.05; 5.65; 15.39.

Example Compound of Formula I 1,1-Dimethyl-2-(4-amino-2-phenylmethyll

NH

2 NI-12

N

OH

Ammonium hydroxide (10 mL) was added to a solution of 2-phenylmethyl-1-(2hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide (1.5 g, 4.3 mmol) in dichloromethane (40 mL). Tosyl chloride (0.8 g, 4.3 mmol) was slowly added.

Thin layer chromatography indicated that the reaction was proceeding slowly. Additional tosyl chloride was added twice. After thin layer chromatography indicated that the reaction was complete, the layers were separated. The organic layer was washed with dilute aqueous sodium carbonate, dried over magnesium sulfate and then concentrated under vacuum. The residue was covered with methyl acetate (10 mL), hexane (5 mL) was added and the mixture was allowed to stand overnight. The resulting crystalline solid was isolated by filtration to provide 1,1-dimethyl-2-(4-amino-2-phenylmethyl[1,5]napthyridinl-yl)ethanol, m.p. 211-213*C. Analysis: Calculated for C 20

H

21

N

5 0: 69.14; 6.09; 20.16; Found: 69.10; 6.12; 20.48.

Example 66 Compound of Formula XXXI N-Phenylmethyl-3-nitro[1,5]naphthyridin-4-amine Phosphorus oxychloride (3.5 mL, 37.7 mmol) was reacted with N,Ndimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.0 g, 31.4 mmol) in N,N-dimethylformamide mL). The reaction mixture was warmed in an oil bath to 60 0 C. After 3 hours the -71 WO 99/29693 PCT/US98/26473 reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water. The wet crude 5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150 mL). Diisopropylethylamine (1.2 eq) was added followed by the slow addition ofbenzylamine (4.7 mL g, 40 mmol). The reaction mixture was refluxed for 2 hours and then combined with water (-100 mL). The layers were separated and the organic layer was concentrated under vacuum to provide 5.5 g of Nphenylmethyl-3-nitro[1,5]naphthyridin-4-amine. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 127-129C. Analysis: Calculated for

C

1 sH 12

N

4 0 2 64.28; 4.32; 19.99; Found: 63.89; 4.40: 20.35.

Example 67 N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamide Hydrochloride A catalytic amount of platinum on carbon was added to a suspension of Nphenylmethyl-3-nitro[1,5]naphthyridin-4-amine (5.1 g, 18.2 mmol) in toluene (300 mL).

The reaction mixture was hydrogenated on a Parr apparatus under a hydrogen pressure of psi (3.5Kg/cm 2 for 1 hour. The reaction mixture was filtered to remove the catalyst.

The filtrate was concentrated under vacuum to a volume of about 200 mL and then reacted with ethoxyacetyl chloride (2.5 g, 20 mmol). The resulting yellow precipitate was isolated by filtration, suspended in diethyl ether, and then isolated by filtration to provide 5.8 g of N-(4-phenylmethylamino[ 1,5]naphthyridin-3-yl) ethoxyacetamide hydrochloride, m.p.

205-212 0 C. Analysis: Calculated for C 19

H

20

N

4 0 2 HCl: 61.21; 5.68; 15.03; Found: 60.90; 5.38; 15.38.

Example 68 Compound of Formula XXXIII 2-Ethoxymethyl-l-phenylmethyl-lH-imidazo[4,5-c[1,l]naphthyridine N-(4-Phenylmethylamino[ 1,5]naphthyridin-3-yl)-ethoxyacetamide hydrochloride (5.8 g, 15.5 mmol) was combined with a 7 solution of ammonia in methanol (100 mL), placed in a sealed Parr vessel and then heated at 150°C for 6 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, washed with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was -72- WO 99/29693 PCT/US98/26473 recrystallized from methyl acetate to provide 4:3 g of 2-ethoxymethyl-1-phenylmethyl- 1H-imidazo[4,5-c][1,5]naphthyridine, m.p. 118-119 0 C. Analysis: Calculated for

C

1 9

H

18

N

4 0: 71.68; 5.70; 17.60; Found: 71.44; 5.60; 17.66.

Example 69 Compound of Formula XXXIV 2-Ethoxymethyl-l-phenylmethyl- 1H-imidazo[4,5-c] [1,5]naphthyridine-5N-oxide 3-Chloroperbenzoic acid (3.7 g, 13.4 mmol) was added in 3 portions to a solution of 2-ethoxymethyl-l-phenylmethyl-lH-imidazo[4,5-c][1,5]naphthyridine (3.9 g, 12.2 mmol) in chloroform (100 mL) in a flask covered with aluminum foil. The reaction mixture was stirred at ambient temperature overnight; and then it was washed twice with dilute aqueous sodium bicarbonate and once with brine. The chloroform layer was divided into two portions. One portion was used in the example below. The second portion was concentrated under vacuum. The residue was recrystallized from isopropyl alcohol to provide 2-ethoxymethyl-l-phenylmethyl- 1H-imidazo[4,5-c][1,5]naphthyridineas a solid, m.p. 187.5-189C. Analysis: Calculated for C 1 9

H

8

N

4 0 2 /4 H 2 0: 67.52; 5.49; 16.58; Found: 67.56; 5.36; 16.77.

Example Compound of Formula I 2-Ethoxymethyl-l-phenylmethyl-1H-imidazo[4,5-c] 1,5]naphthyridin-4-amine NH2

N

I j

N

Ammonium hydroxide (20 mL) was added to the chloroform solution of 2ethoxymethyl-l-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide from the example above. Tosyl chloride was slowly added. Thin layer chromatography indicated -73- WO 99/29693 PCT/US98/26473 that the reaction was proceeding slowly. Additional tosyl chloride was added twice. After thin layer chromatography indicated that the reaction was complete, the layers were separated. The organic layer was washed with dilute aqueous sodium carbonate, dried over magnesium sulfate and then concentrated under vacuum. The residue was covered with methyl acetate (10 mL), hexane (5 mL) was added and the mixture was allowed to stand overnight. The resulting crystalline solid was isolated by filtration to provide 2ethoxymethyl-l-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, m.p. 173- 174°C. Analysis: Calculated for C 19

H

1 9 NsO: 68.45; 5.74; 21.01; Found: 68.35; 5.83; 21.27.

Example 71 Compound of Formula XXXI

N

4 -(3-Isopropoxypropyl)-3-nitroll,5 naphthyridin-4-amine Part A Phosphorus oxychloride (3.4 mL, 30 mmol) was added to chilled (ice bath) N,Ndimethylformamide (15 mL). The resulting solution was added dropwise to a solution of 3-nitro[1,5]naphthyridin-4-ol (5.73 g, 30 mmol) in N,N-dimethylformamide (35 mL). The reaction mixture was maintained at ambient temperature for 5 hours and then it was poured onto ice. The resulting yellow precipitate was isolated by filtration and then partitioned between dichloromethane (200 mL) and water (150 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and then concentrated under vacuum to provide 4.2 g of crude 4-chloro-3-nitro[ Part B 4-Chloro-3-nitro[1,5]naphthyridine (4.1 dichloromethane (150 mL), triethylamine (4.1 mL, 29.5 mmol), and 3-isopropoxypropylamine (3.3 mL, 23.8 mmol) were combined. The reaction mixture was maintained at ambient temperature overnight and then quenched with water (100 mL). The phases were separated. The aqueous phase was extracted with dichloromethane (100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 4.8 g of N 4 -(3-isopropoxypropyl)-3-nitro[1,5]naphthyridin-4amine as a yellow powder, m.p. 62.5-63.5*C. Analysis: Calculated for C 14 Hi 8

N

4 0 3

%C,

-74- WO 99/29693 WO 9929693PCTJIJS98/26473 57.92; 6.25; 19.30; Found: 57.96; 6.19; 19.51. 'H NMR (300 MHz. CDClj): 8 10.08 (broad s, I 9.3 8 (broad s, I 8.78 (in, I 8.21 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, IH), 4.57 (broad s, 2H), 3.65-3.57 (in, 3H), 2.05 J=5.6 Hz, 2H), 1.19 J=6.0 Hz, 6H); MS in/e 290.1366 (290.1378 calc'd for C1 4

H,

8

N

4 0 3 Example 72 Compound of Formula XXXII N 4-(3-Isopropoxypropyl)1,5J naphthyridine-3,4-diamine N 4 -Isopropoxypropyl)-3 -nitro[ I ,51naphthyridin-4-amnine (4.2 g, 14.5 mmol), platinum on carbon (1.1I g of and ethyl acetate (100 mL) wyere placed in a hydrogenation flask. The mixture was shaken under a hydrogen pressure of 50 psi Kg/cm 2 for 2.5 hours. The reaction mixture was filtered and the catalyst was washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 3.6 g of N 4 isopropoxypropyl)[ 1,5]naphthyridine-3,4-dianline as a bright yellow oil. 1 H NMR (300 MHz, CDC13): 8 8.70 (dd, J=4.1,1.6 Hz, 1H), 8.39 lH), 8.17 (dd, J=r8.4,1.6 Hz, 111), 7.37 (dd, J=8.4,4.1 Hz, 111), 5.99 (broad s, 1H), 3.98 (broad s, 2H),3.63-3.55 (in, 5H), 1.87 (pentet, J=6.2 Hz, 2H), 1.17 J=6.1 Hz, 6H); MS m/e 260.1630 (260.1637 calc'd for C1 4 11 20

N

4 0).

Example 73 Compound of Formula XXXIII 2-Butyl-1 -(3-isopropoxypropyl)-1H-imidazol4,5-c1 11,51 naphthyridine Part A Valeryl chloride (1.53 mL, 12.9 ninol) was added dropwise over a 15 minute period to a chilled (ice bath) solution of N 4 -(3-isopropoxypropyl)[1,5]naphthyridine-3, 4 diamine (3.2 g, 12.3 mmol) in dichloromethane (40 mL). The cooling bath was removed and the reaction mixture was maintained at ambient temperature for I hour. The solvent was removed under vacuum to provide a dark tan solid.

75 WO 99/29693 PCT/US98/26473 Part B The material from Part A and a 7.5% solution of ammonia in methanol (100 mL) were placed in a pressure vessel. The vessel was sealed and then heated at 150C for 6 hours. After the mixture was cooled to ambient temperature it was concentrated under vacuum. The residue was partitioned between dichloromethane (150 mL) and water (150 mL). The fractions were separated and the aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a brown oil. The oil was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide 3.1 g of 2-butyl-l-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as a colorless oil. 'H NMR (300 MHz, CDCI 3 8 9.32 1H), 8.90 (dd, J=4.3,1.7 Hz, 1H), 8.49 (dd, J=8.5,1.7 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz, 1H), 4.94 J=7.0 Hz, 2H), 3.56 (pentet, J=6.1 Hz, 1H), 3.44 J=5.7 Hz, 2H), 3.05 J=7.9 Hz, 2H), 2.29-2.20 2H), 2.01-1.90 2H), 1.60- 1.48 2H), 1.15 J=6.1 Hz, 6H), 1.03 J=7.3 Hz, 3H); MS m/e 326.2104 (326.2106 calc'd for C 19

H

26

N

4 0).

Example 74 Compound of Formula XXXIV 2-Butyl-l-(3-isopropoxypropyl)-1H-imidazo[4,5-c] 3-Chloroperbenzoic acid (1.2 g of 57-86%) was added in four portions over a period of 20 minutes to 2-butyl-l-(3-isopropoxypropyl)-1H-imidazo[4,5- (1.4 g, 4.3 mmol) in chloroform (20 mL). The reaction mixture was maintained at ambient temperature for 2 hours and then it was washed with saturated sodium bicarbonate (2 x 15 mL) and water (20 mL). The organic fraction was dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil.

The oil was purified by column chromatography (silica gel eluting with 95:5 ethyl acetate:methanol) to provide 0.95 g of 2-butyl-l-(3-isopropoxypropyl)- 1H-imidazo[4,5as a yellow solid, m.p. 92.0-93.0*C. Analysis: Calculated for C19H 26

N

4 0 2 66.64; 7.65; 16.36; Found: 66.18; 7.39; %N, 16.26. 'H NMR (300 MHz, CDCl): 8 9.24 (dd, J=8.8,1.6 Hz, 1H), 9.05 1H), 8.98 (dd, J=4.3,1.6 Hz, 1H), 7.65 (dd, J=8.8,4.3 Hz, 1H), 4.89 J=7.0 Hz, 2H), 3.56 (pentet, J-6.1 -76- WO 99/29693 WO 9929693PCT/JS98/26473 Hz, IH), 3.44 J=5.7 Hz, 2H), 3.02 J=7.9 Hz, 2H), 2.27-2.18 (in, 2H), 1.97-1.87 (mn, 2H), 1.59-1.47 (mn, 2H), 1.15 J=6.1 Hz, 6H), 1.02 J=7.3 Hz, 3H).

Example Compound of Formula I 2-B utyl-1 -(3-isopropoxypropyl)-1H-imidazo4,5-cI 11 ,51 n aphthyrid in e-4-a mine

NH

2

N

Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.42 mL, 3.5 minol) was added dropwise to a solution of 2-butyl-l-(3-isopropoxypropyl)-1H-imidazo[4,5c][1,5]naphthyridine-5N-oxide (0.8 g, 2.3 mmol) in dichloromethane (25 mL). The reaction mixture was maintained at ambient temperature for 2 hours and then concentrated under vacuum to provide a yellow oil. The oil was dissolved in methanol (15 mL) and then sodium methoxide (0.8 mL of 25% in methanol, 3.5 inmol) was slowly added. The reaction was maintained at ambient temperature overnight. The resulting precipitate was isolated by filtration and then recrystallized from methyl acetate to provide 0.47 g of 2butyl-lI-(3-isopropoxypropyl)- 1H-imidazo[4,5-c) [1 ,5]naphthyridine-4-amine as a white crystalline solid, m.p. 1 74-175 0 C. Analysis: Calculated for C 19

H

27

N

5 0: 66.83; %H, 7.97; 20.5 1; Found: 66.70; 7.8 1; 20.75. 'H NMR (300 MHz. CDCI 3 8 8.50 (dd, J=4.3,1.5 Hz, 1H), 7.90 (dd, J=8.4,1.5 Hz, 11H), 7.42 (dd, J=8.4,4.3 Hz, 111), 6.75 2H), 4.77 3=6.8 Hz, 211), 3.50 (pentet, J=6.1 Hz, 111), 3.35 (mn, 2H), 2.95 (t, J=7.8 Hz, 2H), 2.13-.2.04 (in, 1.86-1.76 (mn, 2H), 1.52-1.40 (mn, 2H), 1.05 J=6.1 Hz, 6H), 0.97 J=7.3 Hz, 3H).

77 WO 99129693 WO 9929693PCT/IJS98/26473 Example 76 Compound of Formula XXXI

N

4 -(3-Butoxypropyl)-3-nitro[ 1,51 naphthyridin-4-amine Under a nitrogen atmosphere, 3-butoxypropylamine (4.0 mL, 26 mmol) was added dropwise over a period of 10 minutes to a solution of 4-chloro-3 -nitro[ (4.6 g, 22 mmol) and triethylamine (4.6 mL, 33 mmol) in. dichloromethane (150 mL). The reaction mixture was maintained at ambient temperature overnight. Water (100 mL) was added and the phases were separated. The aqueous phase was extracted with dichioromethane (100 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1: 1 ethyl acetate:hexanes) to provide 5.3 g of N 4 -(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a colorless oil.

'H NMR (300 MHz. CDCI 3 8 10.08 (broad s, IH), 9.38 (broad s, 1H), 8.78 (in, IH), 8.22 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 111), 4.57 (broad s, 2H), 3.63 J=5.8 Hz, 2H), 3.46 J=6.7 Hz, 2H), 2.10-2.03 (in, 2H), 1.65-1.55 (in, 2H), 1.44-1.32 (mn, 2H), 0.92 J=7.3 Hz, 3H); MS m/e 304.1535 (304.1535 calc'd for C1 5

H

2 0

N

4 0 3 Example 77 Compound of Formula XXXII N 4 -(3-Butoxypropyl)1,51 naphthyridine-3,4-diamine Using the method of Example 72, N 4 -(3-butoxypropyl)-3-nitro[ 1,5]naphthyridin-4amine (4.9 g, 16 mmol) was reduced to provide 4.3 g of N 4 .butoxypropyl)[ 1,5]naphthyridine-3,4-diamine as a bright yellow oil. Analysis: Calculated for C1 5

H

22

N

4 0: 65.67; 8.08; 20.42; Found: 65.48; 8.07; 20.4 1. 'H NMR (300 MHz. CDC1 3 8 8.70 (dd, J=4.1,1.6 Hz, III), 8.39 IH), 8.18 (dd, J=8.4,1.6 Hz, 1H), 7.37 (dd, J=8.4,4.1 Hz, 1H), 5.97 (broad s, 1H), 3.96 (broad s, 2H), 3.63-3.56 (in, 4H), 3.44 J=6.7 Hz, 2H), 1.89 (pentet, J=6.2 Hz, 2H), 1.63-1.53 (in, 2H), 1.44-1.32 (in, 2H), 0.93 J=7.3 Hz, 3H); MS m/e 274.1799 (274.1793 calc'd for CjsH 22

N

4 0).

78 WO 99/29693 WO 9929693PCTfUS98/26473 Example 78 Compound of Formula XXXIII 1 utoxyp ropyl)-2-b utyl-1 H-i midazo 14,5-cJ 111,5 n aphthy rid in e Using the general method of Example 73 Part A and Part B, N 4 butoxypropyl)[ 1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) was reacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resulting amide intermediate was cyclized to provide 2.9 g of l-(3-butoxypropyl)-2-butyl- IH-imidazo[4,5-c] [l,5lnaphthyridine as a colorless oil. A small portion was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide a pure sample as a white powder, m.p. 56.5 -57.5*C.

Analysis: Calculated for C 20

H

28

N

4 0: 70.56; 8.29; 16.46; Found: %C, W 70.48; 8.25; 16.61. 'H NMR (300 MHz. CDCl- 3 6 9.32 1H), 8.90 (dd, J=4.3,1.6 Hz, IH), 8.49 (dd, J=8.5,1.6 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz, IH), 4.94 Hz, 2H), 3.45-3.39 (in, 4H), 3.04 J=7.9 Hz, 2H), 2.26 (pentet, J=6.1 Hz, 2H), 2.01-1.91 (in, 2H), 1.62-1.48 (in, 4H), 1.45-1.33 (mn, 2H), 1.03 J=7.3 Hz, 3H), 0.94 J=7.3 Hz, 3H).

Example 79 Compound of Formula XXXIV 1-(3-Butoxypropyl)-2-butyl-1H-imidazof 4,5-cl [1,5Jnaphtbyridine-5N-oxide Using the general method of Example 74, 1-(3-butoxypropyl)-2-butyl-1Himidazo[4,5-c][1,5]naphthyridine (2.2 g, 6.47 inmol) was oxidized to provide 1.6 g of 1- (3-butoxypropyl)-2-butyl-1H-iinidazo[4,5-c][1 ,5]naphthyridine-5N-oxide as a yellow powder, m.p. 126.5-127.5*C. Analysis: Calculated for C 20

H

2

SN

4 0 2 67.39; 7.92; 15.72; Found: 67.13; 7.69; O%N, 15.82. 'H NMR (300 MHz, CDCI 3 6 9.22 (dd, J=8.8,1.5 Hz, IH), 9.04 1H), 8.99 (dd, J=4.3,1.5 Hz, 1H), 7.65 (dd, J=8.8,4.3 Hz, IH), 4.89 J=7.0 Hz, 2H), 3.46-3.39 (in, 4H), 3.01 J=7.9 Hz, 2H), 2.28-2.20 (mn, 2H), 1.97-1.87 (mn, 2H), 1.62-1.46 (in, 4H), 1.45-1.33 (in, 2H), 1.03 J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

79 WO 99129693 WO 9929693PCT/US98/26473 Example Compound of Formula I I -(3-Butoxypropyl)-2-butyl-1H-imidazo4,5-cI 11,51 naphthyridin-4-amine

NH,)

NI

N

0 x Using the general method of Example 75, 1-(3-butoxypropyl)-2-butyl-1Himidazo[4,5-c][1,5]naphthyridine-5N-oxide (1.2 g, 3.4 mmol)-'as reacted with trichioroacetyl isocyanate (0.6 mL, 5.0 mmol) and the resulting intermediate was hydrolyzed to provide 0.86 g of 1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5c][1,5]naphthyridin-4-amine as a white powder, m.p. 101.0-1 01.5*C. Analysis: Calculated for C 20

H

29

N

5 0: 67.58; 8.22; 19.70; Found: 67.55; 7.96; %N, 10. 'H NMR (300 MHz. DMSO): 8 8.50 (dd, J=4.4,1.5 Hz, 1H), 7.91 (dd, J=8.4,1.6 Hz, IH), 7.42 (dd, J=8.4,4.4 Hz, 1H), 6.77 2H), 4.78 J=6.9 Hz, 211), 3.38-3.30 (in, 4H), 2.93 J=7.8 Hz, 2H), 2.11 (pentet, J=6.1 Hz, 2H1), 1.82 (pentet, J=7.6 Hz, 2H), 1.5 1- 1.39 (in, 4H), 1.37-1.25 (mn, 211), 0.96 J=7.3 Hz, 3H), 0.88 J=7.2 Hz, 3H1).

Example 81 Compound of Formula XXXI

N

4 -(2-Phenoxyetbyl)-3-nitroll ,5J naphthyridin-4-amine Using the general method of Example 76, 4-chloro-3-nitro[1,5]naphthyridine g, 24 minol) was reacted with 2-phenoxyethylamine (3.5 mL, 27 inmol) to provide 6.6 g of

N

4 -(2-phenoxyethyl)-3 -nitro[l1,5]naphthyridin..4-amine as a yellow solid, m.p. 107-108TC.

Analysis: Calculated for C1 6 H,1 4

N

4 0 3 61.93; 4.55; 18.05; Found: %C, 61.99;) 4.58; 18.42. 1 H NMR (300 MHz. DMS0): 8 10.25 (broad s, 1H), 9.39 (broad s, 1H), 8.81 (dd, J=4.1,1.7 Hz, 1H), 8.25 (dd, J=8.5,1.7 H~z, 1H), 7.67 (dd, J=8.5,4.1 Hz, 1H1), 7.34-7.26 (mn, 2H), 7.01-6.96 (mn, 3H1), 4.89 (broad s, 2H), 4.35 J=5.1 Hz, 2H); MS m/e 310.1065 (310.1065 calc'd for C, 6

H,

4

N

4 0 3 WO 99/29693 WO 9929693PCTIUS98/26473 Example 82 Compound of F'ormula XXXII

N

4 -(2-Phenoxyethyl) n aphthyridin e-3,4-dia mine Using the general method of Example 77, N 4 -(2-phenoxyethyl)-3nitro[ 1,5]naphthyridin-4-amine (5.4 g, 17.4 mmol) was reduced to provide 4.6 g of N 4 phenoxyethyl)[ 1,5]naphthyridine-3,4-diamine as a bright yellow oil. H NMR (300 MHz, DMSO): 858.68 (dd, J=4.1,1.7 Hz, I1H), 8.40 I1H), 8. 10 (dd, J=8.4,1.7 Hz, I 7.39 (dd, J=8.4,4.1 Hz, IH), 7.28-7.22 (in, 2H), 6.94-6.90 (in, 3H), 6.12 J=7.0 Hz, 11H), 5.15 (s, 2H), 4.13 J=5.5 Hz, 2H), 3.93-3.87 (in, 2H); MIS m/e 281 Example 83 Compound of Formnula XXXIII 2-(2-Butyl-IH-imidazo[4,5-cl 11,51 naphthyridin-1 -yl)ethyl Phenyl Ether Using the general method of Example 73 Part A and Part B, N 4 phenoxyethyl)[ 1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 inmol) was reacted with valeryl chloride (1.95 mL, 16.4 inmol) and the resulting amide intermediate was cyclized to provide 4.0 g of 2-(2-butyl- 1H-imidazo[4,5-c][1I,5]naphthyridin- 1-yl)ethyl phenyl ether as a white solid, m.p. 150-150.5*C. Analysis: Calculated for C 2 1

H

2 2

N

4 0: 72.81; %H, 6.40; 16.17; Found: 72.78; 6.40; 16.3 1. 'H NMR (300 MHz. DMS0): 8 9.25 1H), 9.00 (dd, J=4.3,1.7 Hz, 1H), 8.52 (dd, J=8.4,1.7 Hz, 114), 7.74 (dd, J=8.4,4.3 Hz, 1H), 7.25-7.20 (in, 2H), 6.91-6.84 (in, 3H), 5.22 J=5.2 Hz, 2H), 4.53 (t, J=5.2 Hz, 2H), 3.09 J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H), 1.55-1.43 (mn, 2H), 0.97 J=7.3 Hz, 3H); MS m/e 346.1794 (346.1793 calc'd for C 2 1

H

2 2

N

4 0).

Example 84 Compound of Formula XXXIV 2-Butyl-1 -(2-phenoxyetbyl)-lH-imidazo[4,5-cI 11,51 Using the general method of Example 74, 2-(2-butyl-1H-iinidazoj4,5c] [1,Sjnaphthyridin-lI-yl)ethyl phenyl ether (0.6 g, 1.7 mmol) was oxidized to provide 0.44 g of 2-butyl-1 -(2-phenoxyethyl)- 1H-imidazo[4,5-c] [1 ,5]naphthyridine-5N-oxide as a yellow powder. 'H NMR (300 MHz, CDCI"1: 8 9.10-9.03 (in, 3H), 7.81 (dd, J=8.7,4.3 Hz, 81 WO 99/29693 WO 9929693PCTIUS98/26473 1H), 7.25-7.20 (in, 2H), 6.92-6.83 (in, 3H), 5.1 6 3=4.9 Hz, 2H), 4.51 J=4.9 Hz, 2H), 3.06 J=7.7 Hz, 2H1), 1.93-1.83 (in, 2H), 1.54-1.41 (in, 2H), 0.96 J=7.3 Hz, 3H); MIS inle 363 Example Compound of Formula I 2-Butyl-1 -(2-phenoxyethyl)-1H-imidazo[4,5-c 11,51 naphthyridin-4-amine

NH

2 N

N

Using the general method of Example 75, 2-butyl-1-(2-phenoxyethyl)-1Himidazo[4,5-c][1,5]naphthyridine-5N-oxide (0.38 g, 1.05 mniol) was reacted with trichioroacetyl isocyanate 19 mL, 1.6 mmol) and the resulting intermediate was hydrolyzed to provide 0.23 g of 2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5c][l,5]naphthyridin-4amine as a white powder, m.p. 159.0-159.2-C. 'H NMR (300 MHz.

DMS0): 8 8.52 (dd, J=4.4,1.5 Hz, 1H), 7.92 (dd, J=8.4,1.5 Hz, 1H), 7.45 (dd, J=8.4,4.4 Hz, 1H), 7.26-7.21 (in, 2H), 6.92-6.86 (in, 3H), 6.79 2H) 5. 13 J=5.2 Hz, 2H), 4.48 (t, J=5.2 Hz, 2H), 3.00 J=7.8 Hz, 2H), 1.91-1.81 (pentet, J=7.4 Hz, 2H), 1.52-1.40 (in, 2H), 0.95 J=7.3 Hz,3H); MS in/e 361.1899 (361.1902 calc'd for C 21

H

23

N

5 0).

Example 86 Compound of Formula XXXI 1 ,1-Dimethylethyl N-{2-[3-Nitro[1 ,5J naphthyridiu-4-yl)aminoj ethyl) carbainate A solution of diisopropylethylamine (13.47 g, 0. 10 mole) in dichlorornethane mL) was added to a solution of 5-chloro-3-nitro[ 1,5]naphthyridine (18.2 g, 0.086 mol) in dichloromethane (250 inL). A solution of tert-butyl N-(2-aminoethyl)carbamate (16.7 g, 0. 10 mol) in dichloroinethane (75 mL) was slowly added to the reaction mixture. The reaction mixture was heated at reflux overnight. Additional tert-butyl N-(2- 82 WO 99/29693 PCT/US98/26473 aminoethyl)carbamate (1 g) was added and the reaction mixture was heated at reflux for an additional 3 hours. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with additional dichloromethane, washed with water and with brine, dried, and then concentrated under vacuum to provide a dark solid. This solid was purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1-dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethylcarbamate as a canary yellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL) and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p. 149-151 C. Analysis: Calculated for C 1 5

H

19

N

5 0 4 54.05; 5.75; 21.01; Found: 54.17; %H, 10 5.73; 20.90.

Example 87 Compound of Formula XXXII 1,1-Dimethylethyl N-{2-[(3-Aminoll,5]naphthyridin-4-yl)amino]ethyl}carbamate 1,1 -Dimethylethyl N- {2-[(3-nitro[ 1,5]naphthyridin-4-yl)amino]ethyl} carbamate g, 0.03 mol), ethyl acetate (800 mL) and platinum on carbon catalyst were combined in a Parr bottle and then the mixture was hydrogenated overnight. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide 9.1 g of 1,1-dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate Sas a yellow syrup. Analysis: Calculated for C 1 5

H

2 1 NO0 2 0.1 CH 3

CO

2

C

2

H

5 59.25; 7.04; 22.43; Found: 58.96; 6.87; 22.46.

Example 88 Compound of Formula XXXIII 1,1-Dimethylethyl N-12-(B-butyl-lH-imidazo[4,5-c]l,5]naphthyridin-l-yl)ethyl]carbamate 1,1 -Dimethylethyl N- {2-[(3-amino[ 1,5]naphthyridin-4-yl)amino]ethyl} carbamate 0.6 g, 2 mmol), trimethyl orthovalerate (0.35 g, 2.1 mmol), and toluene (25 mL) were combined and heated at reflux for 2 hours. Additional trimethyl orthovalerate (1 eq.) was added and the reaction mixture was heated at reflux overnight. Xylene was added and the toluene was distilled off. The reaction was heated at reflux for an additional 8 hours. The -83- WO 99/29693 PCTIUS98/26473 bulk of the xylene was distilled off leaving a volume of about 5 mL. The reaction mixture was allowed to cool. The resulting precipitate was isolated by filtration, washed with heptane and dried to provide 0.35 g of 1,1-dimethylethyl N-[2-(2-butyl-IH-imidazo[4,5- 1-yl)ethyl]carbamate as an ivory powder, m.p. 198-199°C. Analysis: Calculated for C 2 oH 27

N

5 0 2 65.01; 7.36; 18.95; Found: 64.75; %N, 7.57; 19.09.

Example 89 Compound of Formula XXXIII 1-{2-[(1,l-dimethylethoxycarbonyl)amino]ethyl}-2-butyl- 1H-imidazo[4,5-c][l,51naphthyridine-5N-oxide 3-Chloroperbenzoic acid (0.7 g of 57-86%) was dissolved in chloroform (10 mL).

One half of this solution was added to a solution of 1,1-dimethylethyl N-[2-(2-butyl-1Himidazo[ 4 ,5-c]1,5]naphthyridin-l-yl)ethyl]carbamate (1.0 g, 2.7 mmol) in chloroform mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then the remaining half of the chloroperbenzoic acid solution was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for a total of 2.5 hours and then it was diluted with chloroform (50 mL); washed with sodium carbonate, with sodium hydroxide, with water, and with brine; dried and concentrated under vacuum to provide 1.1 g of a yellow solid. This material was recrystallized twice from acetonitrile to provide 1.0 g of 1- -dimethylethoxycarbonyl)amino] ethyl) -2-butyl-lHimidazo[4,5-c][1,5]naphthyridine-5N-oxide. Analysis: Calculated for C 20

H

2 7

N

5 0 3

%C,

62.32; 7.06; 18.17; Found: 62.03; 6.73; 18.10.

-84- WO 99/29693 PCT/US98/26473 Example Compound of Formula I 1,1-Dimethylethyl N-[2-(4-Amino-2-butyl- 1H-imidazo[4,5-c] [1,51naphthyridin-l-yl)ethyl]carbamate

NH

2 N N

N

H

N

O

Trichloroacetyl isocyanate (4.8 mL, 40 mmol) was added via a syringe to a solution of 1- -dimethylethoxycarbonyl)amino]ethyl} -2-butyl- 1H-imidazo[4,5c][1,5]naphthyridine-5N-oxide (10.4 g, 27 mmol) in dichloromethane (75 mL). The reaction mixture was stirred at ambient temperature for 1 hour. Sodium methoxide (9 mL of 25% sodium methoxide in methanol) was added and the reaction mixture was stirred at ambient temperature overnight. Thin layer chromatography indicated that the reaction was not complete so additional sodium methoxide was added twice with each addition being followed by 2 hours of stirring at ambient temperature. The reaction mixture was diluted with dichloromethane; washed with sodium carbonate, water, and then brine; dried and then concentrated under vacuum to provide 10.4 g of a yellow solid. This material was purified by column chromatography (silica gel eluting with dichloromethane) to provide 8.5 g of a solid. This solid was recrystallized from toluene (20 mL) to provide g of 1,1 -dimethylethyl N-[2-(4-amino-2-butyl- H-imidazo[4,5-c][1,5]naphthyridin-1yl)ethyl]carbamate as ivory crystals, m.p. 118-120 0 C. Analysis: Calculated for

C

20

H

28

N

6 0 2 62.48; 7.34; 21.85; Found: 62.31; 7.23; 22.13.

HRMS (El) calcd for C 2 oH 28

N

6 0 2 384.2273, found 384.2273 WO 99/29693 WO 9929693PCTIUS98/26473 Example 91 Compound of Formula I 2-(4-A min o-2-b uty-1 H-imid azo4,5-c1 11 ,51 n aphthyri din-1I -yI)eth aneamin e

NH

2 N

N

NN NI- 2 Trifluoroacetic. acid (5 mL) was added to a solution of 1, 1 -dimethylethyl amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1-yl)ethyllcarbamate (5.7 g, 15 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with dichioromethane and then extracted with 10% hydrochloric acid. The hydrochloric acid extract was washed twice with dichioromethane and then it was made basic with anmnonium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 3.7 g of 2-(4-amino-2-butyl-IH- [1,5]naphthyridin- I-yl)ethaneamine as a white powder, mn.p. 175-176*C.

Analysis: Calculated for C1 5 H1 20

N

6 63.36; 7.09; 29.55; Found: 62.98; 6.92; 29.89. FIRMS (El) calcd for C, 5

H

20

N

6 284.1749, found 284.1748.

Example 92 Compound of Formula I N' -[2-(4-Amino-2-butyl- 1H-imidazol4,5-cJ 11,51 oaphthyridin-1 -yl)ethyll acetamide N11 2 N

N

H

NN

N

86 WO 99/29693 WO 9929693PCTiUS98126473 Under a nitrogen atmosphere, acetyl chloride (50 piL, 0.7 mmole) in dichloromethane (25 mL) was added dropwise to a cooled (ice bath) solution of 2-(4amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) in dichloromethane (50 mL). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After 30 minutes thin layer chromatography indicated that the reaction was complete. The reaction mixture was washed with sodium hydroxide, water and brine; dried; and concentrated under vacuum to provide 0.25 g of crude product. This material was purified by column chromatography (silica gel eluting with dichioromethane) to provide 0.2 g of a solid. This solid was recrystallized from acetonitrile (30 mL) to provide 0.18 g of N'-[2-(4-amino-2-butyl-lH-imidazo[j4,5- W c] [1 ,5]naphthyridin-1I-yl)ethyl] acetamide as a white powder, m.p.228-230'C. Analysis: Calculated for C 1 7

H

2 2

N

6 0: 62.56; 6.79; 25.75; Found: 62.50; %H, 6.59; 26.04. HRMS (El) calcd for C 2 2

H

2 6

N

6 0 2 326.1855, found 326.1846 Example 93 Compound of Formula I N'-[2-(4-Amino-2-butyll- 1H-imidazol4,5-cI [1 ,5J naphthyridin-1 -yI)etbylj-(E)-2-buteuamide

NH

2 N

N

I H N

N

0 Using the general method of Example 92, crotonyl chloride (68 [tL, 0.7 mrnol) was reacted with 2-(4-amino-2-butyl-l H-imidazo[4,5-c][ 1,5]naphthyridin- 1-yl)ethaneamine (0.2 g, 0.7 mnmol) to provide 0.2 g of N'-[2-(4-ainino-2-butyl-IH-imidazo[4,5- -yl)ethy]-(E)-2-butenamide as a white powder, m.p. 198-200*C.

Analysis: Calculated for C, 9

H

24

N

6 0: 64.75; 6.86; 23.85; Found: %C, 64.25; 6.68; 23.99. HRMS (El) caled for C 19

H

2 4

N

6 0 352.2011 found 352.1996 87 WO 99/29693 WO 9929693PCTIUS98/26473 Example 94 Compound of Formula I Nl-12-(4-Amino-2-butyl-1H-imidazol4,5-cl 11,51 naphthyridin-I -yl)ethylj- I -cyclohexanecarboxamide

NH

2 NI

N

H

N

0 Using the general method of Example 92, cyclohexanecarbonyl chloride (94 tL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-IH-imidazo[4,5-c][1,5]naphthyridin-l yl)ethaneamine (0.2 g, 0.7 mnmol) to provide 0.2 g of N'-[2-(4-amino-2-butyl-1H- 1,5]naphthyridin- 1 -yl)ethyl]- 1 -cyclohexanecarboxamide as a white powder, m.p. 188-190'C. Analysis: Calculated for C 22 H1 30

N

6 0: 66.98; 7.66; 21.30; Found: 66.72; 7.57; 21.48. HRMS (El) calcd for C 22

H

3 oN 6 0 394.2481 found 394.2475.

Example Compound of Formula I N'-[2-(4-amino-2-butyl-1H-imidazo[4,5-cI 11,51 naphthyridin-l -yI)ethyl]- 3,5-di-(1,I -dimethylethyl)-4-bydroxybenzamide

NH

N

H-

88 WO 99/29693 PCT/lJS98/26473 Using the general method of Example 92, 3,5-di-(1,lIdim ethyl ethyl)-4hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reacted with 2-(4-amino.-2-butyl-1IJimidazo[4,5-c][l,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N'1 [2-(4-amino-2-butyl- IlH-imidazo[4,5 1 naphthyri din- I -yl)eth yl -di 1, dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 248-250 0 C. Analysis: Calculated for C 3 0OI-N 6 0 2 69.74; 7.80; 16.27; Found: 69.65 %H, 7.69; 16.42. HRVS (El) calcd for C 30

H

40

N

6 0 2 516.3212 found 516.3226 Example 96 Compound of Formula I Nl-12-(4-Amino-2-butyl-lH-imidazo[4,5-c] 1l,5lnaphthyridin-1 -yl)ethyll- 3-phenyipropanamide Hydrochloride NH1 2 N

N

I HI N

N

0 Using the general method of Example 92, hydrocinnamoyl chloride (0.1 g, 0.7 mmol) was reacted with 2-(4-amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1yl)ethaneamine (0.2 g, 0.7 mmol). After one hour the reaction mixture was poured directly onto a silica gel column and eluted with dichloromethane at first, then 15% methanol/ dichioromethane to provide 0.2 g of a solid. This solid was recrystallized from toluene to provide 0.2 g of N' -[2-(4-amino-2-butyl-1 H-imidazo[4,5-c] [1 ,5]naphthyridin- 1-yl)ethyl]- 3-phenylpropanamide hydrochloride as a white powder, m.p. 183-1 85'C. Analysis: Calculated for C 24

H

28

N

6 0 HCl: 63.64; 6.45; 18.55; Found: 63.68; 6.43; 18.55.

89 WO 99129693 WO 9929693PCTIUS98/26473 Example 97 Compound of Formula I N-12-(4-Amino-2-butyl-1H-imidazol4,5-cl 11,51 naphthyridin-1 -yI)ethyll- 5-oxotetrah ydro-2-fu ran carboxa mid e

NH

2 NI

N

I H N ~N0 0 A solution of (S)-(+)-5-oxo-2-tetrahydroflirancarboxylic acid (0.23 g, 1.7 mmole in anhydrous dichloromethane (30 mL) was slowly added to a solution of 2-(4-amino-2butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 inmol) in anhydrous dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then a solution of 1 -13-(dimethoxyamino)propyl]-3ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol) in anhiydrous dichioromethane mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then filtered to remove solids. The filtrate was washed twice with sodium hydroxide and then with brine, dried, and then concentrated under vacuum to provide 0.3g of crude product. This material was purified by column chromatography (silica gel eluting witlI dichioromethane) followed by recrystallization from acetonitrile to provide 0.1 g of N-[2-(4-amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin-1I-yl)ethyl] oxotetrahydro-2-furancarboxamide as a white powder, m.p. 153-1 54*C. Analysis: Calculated for C 20

H

24

N

6 0 3 60.5 9; 6. 10; 21.19; Found: 60.34; %H, 6.14; 21 .13. HRMS (El) calcd for C 20

H

24

N

6 0 3 396.1909 found 396.1905 90 WO 99/29693 WO 9929693PCT/US98t26473 Example 98 Compound of Formula I N'-j2-(4-Amino-2-butyl-1 H-imidazol4,5-cl 11,5] naphthyridin-1-yI)ethylj- 2-(3-hydroxyphenyl)acetamide

NH

2 NI

N

I H NN

OH

0 Using the general method of Example 97 3-hydroxyphenyl acetic acid (0.26 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl- I H-imidazo[4,5-c] 1,5]naphthyridin- I yl)ethaneamnine (0.5 g, 1.7 mimol) to provide 0.13 g of N'-[2-(4-amino-2-butyl-IHimidazoli4,5-c] [1 ,5]naphthyridin- 1-yl)ethyl].2-(3-hydroxyphenyl)acetamide as a white powder, m.p. 208-210*C. Anal'ysis: Calculated for C 23

H

26

N

6 0 2 66.01; 6.26; 20.08; Found: 65.63; 6.11; 20.30. FIRMS (El) calcd for C 23

H

26

N

6 0 2 418.2117 found 418.2109.

Example 99 Compound of Formula I N-[2-(4-Amino-2-butyl-H-imidazol4,5-c 11,5]naphthyridin-I -yI)ethylj- 6-hydroxy-2-pyridinecarboxamide

N

2 N

N

I H NY OH 0 Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl- 1H-imidazoE4,5-cl 1 -91- WO 99129693 WO 9929693PCT1US98/26473 yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.15 g of N-[2-(4-amino-2-butyl-lIH- [1 ,5]naphthyridin- 1-yI)ethyl]-6-hydroxy-2-pyridinecarboxamide as a white powder, m.p. 258-260*C. Analysis: Calculated for C 21

H-

23

N

7 0 2

V

2

CH

3 CN: 62.03; 5.80; 24.66; Found: 61.87; 5.70; 24.60.

Example 100 Compound of Formula I Nl-12-(4-Amino-2-butyl-1H-imidazo4,5.cI [I ,5J naphthyridin-1-yl)ethyll- 3,7-dimethyl-6-octenamide

NH

2 N

N

I H 0 Using the general method of Example 97 citronellic acid (0.3 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin-1 -yl)ethaneamine g, 1.7 mmol) to provide 0.5 g of N'-[2-(4-arnino-2-butyl-IH-iniidazo[4,5c] 1,5]naphthyridin- 1 -yl)ethyl]-3,7-dimethyl-6-octenarnide as a white whispy solid, m.p.

163-164'C. Analysis: Calculated for C 25

H

36

N

6 0: 68.77; 8.3 1; 19.25; Found: 68.84; 8.14; 19.58. HRMvS (El) calcd for C 25

H

36

N

6 0 436.2950 found 436.2952.

92 WO 99/29693 WO 9929693PCTIUS98/26473 Example 101 Compound of Formula I 1,1 -Dimethylethyl 12-(4-Amino-2-butyl-1H-imidazol4,5-cI 11,51 napbthyridin-1 -yI)ethylJ amino) carbonyl)-3-methylbutyljcarbamate

NH

2 N ~N0 N H IN

N

0 Using the general method of Example 97 N-t-BOC-L-leucine (0.41 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl- lH-imidazo[4,5-c] [1 ,5]naphthyridin- 1yl)ethanearmne (0.5 g, 1.7 mmol) to provide 0.5 g of 1, 1-dimethylethyl amino-2-butyl- 1 H-imidazo[4,5-c] 1,5]jnaphthyridin- 1 -yl)ethyll amino)} carbonyl)-3- Smethylbutyl]carbamate as a white solid, m.p. 184-1 85*C. HRVS (El) calcd for

C

26

H

39

N

7 0 3 497.3114 found 497.3093.

Example 102 Compound of Formula I N'-I2-(4-Amino-2-buty1-1H-imidazo 14,5-cl[1,5J naphthyridin-1 -yl)ethyl]- 2-amino-4-methylpentan amide

NH

2 N

N

4\ H

NH

2 N N 0 1,1-Dimethylethyl {[2-(4-amino-2-butyl- 1H-imidazo[4,5c] [1,5]naphthyridin- I -yl)ethylj amino) carbonyl)-3-methylbutyl~carbamate (0.35 g, 0.7 mniol) was combined with I N hydrochloric acid (40 mL) and heated on a steam bath for 93 WO 99/29693 WO 9929693PCTIUS98/26473 minutes. The reaction mixture was allowed to cool and then it was made basic with sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0. 15 g of N'1 -[2-(4-amino-2-butyl- I H-imidazo[4,5-c] 1,5 ]naphthyridin- I -yl)ethyl] 2-amino-4-methylpentami de as a white solid, m.p.60-65*C. Analysis: Calculated for

C

2 1 H1 3 1

N

7 0: 63.27; 7.86; 24.66; Found: 62.27; 7.67; 24.77.

HRMS (EI) calcd for C 2 1

H

31

N

7 0 397.2590 found 397.2582.

Example 103 Compound of Formula I N-12-(4-Amino-2-butyl-1H-imidazo 14,5-cl 11,51 naphthyridin-1 -yI)ethyl]- 3,5-dimethyl-4-isoxazolecarboxamide Nil 2

N

I

IH

INI

0 Using the general method of Example 97 3,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mniole) was reacted with 2-(4-ainino-2-butyl-1H-imidazo[4,5c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mnmol) to provide 0.23 g of amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1-yl)ethyl]-3 ,5-dimethyl-4isoxazolecarboxainide-as a white powder, m.p. 188-189*C. Analysis: Calculated for

C

2 1

H

2 5

N

7 0 2 61.90; 6.18; 24.06; Found: 61.92; 6.15; 24.28.

HRMS (El) caled for C 2 1

H

2 5

N

7 0 2 407.2069 found 407.2068 94- WO 99129693 WO 9929693PCT/US98/26473 Example 104 Compound of Formula 11 N -12-(4-Amino-2-butyl-6,7,8,9-tetrahydro- 1H-imidazo 14,5-cl 11,51 n aph thyrid in-1I -y I)eth yll ,I -dimethyl ethyl)-4-Iiyd roxybenza mid e NH1 2 N

N

NH 0

N

H

OH

A solution of N' -[2-(4-amino-2-butyl- IH-imidazo[4,5-c](1 ,5]naphthyridin- 1yl)ethyl]-3,5-di-(1, I-dimethylethyl)-4-hydroxybenzamide 1 g, 0. 19 mmol) in trifluoroacetic acid (15 mL) and platinum oxide 1 g) were combined and hydrogenated overnight on a Parr apparatus. The reaction mixture was filtered to remove the catalyst.

The filtrate was concentrated under vacuum. The residue was dissolved in dichioromethane. The dichioromethane solution was washed twice with 10% sodium hydroxide and with brine, dried and then concentrated under vacuum to provide crude product. This material was purified by chromatography eluting with 10% methanol in dicbloromethane. The resulting oil was triturated with acetonitrile to provide 0.05 g of N'- [2-(4-amino-2-butyl-6,7,8,9-tetrahydro- 1H-imidazo[4,5-c] [I,5]naphthyridil- I -yl)ethyl]- 3,5-di-(1I,l-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 208-2 1 M 0 Analysis: Calculated for CA 30 H4N 6

O

2 0.1 CF 3

CO

2 H: 68.17; 8.35; 15.79; Found: 68.48; 8.29; 16.08.

WO 99/29693 WO 9929693PCT/US98126473 Example 105 Compound of Formula I N1-14-(4-Amino-2-butyl -IH-imidazo4,5-cJ 11,51 naphthyridin-1-yI)butyll- 5-(l, 3 -dimethyl-2,6..oxo-2,3,6,7-tetrahydro-1 H-purinyl)pentamide

NH

2 N

N

H

N N

N

0 0

N-

0 4-(4-Amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin- I -yl)butaneamine (0.2 g), 1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1 H-purinyl)pentanoic acid (0.18 g) and dichioromethane (100 mL) were combined and stirred at ambient temperature for minutes. 1-[3-(Dimethylaniino)propy]-3-ethylcarbodiimide (0.12 g) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction was filtered through a column of silica gel and eluted with 10% methanol in dichioromethane to provide 0.2 g of N'-[4-(4-amnino-2-butyl 1H-imidazo[4,5-c] [1 ,5]naphthyridin-1I-yl)butyl]- 1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro- 1H-purinyl)pentaxnide, m.p. 153.5-1 Analysis: Calculated for C 29

H

38

N

10 0 3 60.61; 6.66; 24.37; Found: %C, 60.65; 6.66; 24.32.

96 WO 99/29693 WO 9929693PCT1US98/26473 Example 106 Compound of Formula I N'-[4-(4-Amnino-2-butyl -1H-iniidazoj4,5-c] 11,5] naphthyridin-1-yl)butyl)- 6-morpholinonicotinamide N H 2 0o

N

Using the general method of Example 105 6-morpholinonicotinic acid 12 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1 ,5]naphthyridin-1 yl)butaneamine (0.2 g, 0.64 mmol) to provide N'-[4-(4-amino-2-butyl -1H-imidazo[4,5c] [1,5]naphtbyridin-lI-yl)butyl]-6-morpholinonicotinamide as a white solid, m.p. 100 0 Calculated for C 2 7 H34N 8 0 2 1 2

H

2 0: 63.39; 6.90: 21.90; Found: 63.69; 6.95; 21.52.

Example 107 Compound of Formula 1 N 1-14-(4-Amino-2-butyl -1H-imidazol4,5-cl 11,5] naphtbyridin-1 -yl)butyll- 6-quinolinecarboxamide

NH

Using the general method of Example 105 6-quinolinecarboxylic acid 11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl- IH-imidazo[4,5-c] [1 ,5]naphthyridin- 1- 97 WO 99/29693 WO 9929693PCT/US98/26473 yl)butaneamine (0.2 g, 0.64 mmol) to provide N 1 -[4-(4-arnino-2-butyl c][l1,5)naphthyridin-lI-yl)butyl]-6-quinolinecarboxamide as a white solid, m.p. 190-191PC.

Analysis: Calculated for C 2 7 H4 2 9

N

7 0 1/4H 2 0: 68.70; 6.30; 20.77; Found: 68.54; 6.21; 20.93.

Example 108 Compound of Formula I N-14-(4-Amino-2-butyl -1H-imnidazol4,5-cl 11,51 naphthyridin-I -yl)butyll- 2-(4-hydroxy-5-methyl-2-oxo-1 ,2-dihydro-1 -pyrimidinyl)acetamide NH2

N

NN

0 N OH Using the general method of Example 105 2-(4-hydroxy-5-methyl-2-oxo-1,2dihydro- I-pyrimidinyl)acetic acid 12 g, 64 mmol) was reacted with 4-(4-aniino-2-butyl- IH-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamnine (0.2 g, 0.64 mimol) to provide 0.06 g of N' -[4-(4-amino-2-butyl -1 H-imidazo[4,5-c][ 1,5]naphthyridin-1I-yl)butyl]-2-(4in 15 hydroxy-5-methyl-2-oxo-1,2-dihydro..1-pyrimidinyl)acetamide as a solid, m.p. 2224C 98 WO 99/29693 WO 9929693PCTIUS98/26473 Example 109 Compound of Formula I N'-14-(4-Amino-2-butyl -1H-imidazo[4,5-cl 11,5]naphthyridin-1 -yI)butylj- 2-(2-pyrimidinylsulfanyl)acetamide N H-

N

Using the general method of Example 105 (2-pyrimidinylthio)acetic acid 11 g, 64 numol was reacted with 4-(4-amino-2-butyl-IH-imidazo[4,5-c][1,5lnaphthyridin-lyl)butaneamine (0.2 g, 0.64 mmnol) to provide N'-[4-(4-amino-2-butyl -I1H-imidazo[4,5c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide as a white solid, mn.p.

156-160tC (dec.).

Example 110 Compound of Formula I N'-14-(4-Amino-2-butyl -1H-imidazo 14,5-cl 11,5] naphthyridin-1-yI)butylj- 2-(4-pyridylsulfanyI)acetamide

NH

2 Using the general method of Example 105 (4-pyridylthio)acetic acid 11 g, 64 mimol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.1 g of N'-[4-(4-arnino-2-butyl -1H- -99- WO 99/29693 PCT/US98/26473 imidazo[4,5-c][1,5]naphthyridin-l-yl)butyl]-2-(4-pyridylsulfanyl)acetamide as a solid, m.p. 127.5-129°C.

Example 111 Compound of Formula I 4-(4-amino- 1H-imidazo[4,5-c][1,5]naphthyridin-I -yl)butaneamine

NH

2

N

S

N

VNH

2 Part A Triethylorthoformate (2.8 mL, 16.6 mmol) was added to a solution of 1,1dimethylethyl N-{4-[(3-amino[ ,5]naphthyridin-4-yl)amino]butyl}carbamate (5.0 g, 15.1 mmol) in toluene (150 mL). The reaction was heated at reflux overnight with ethanol being collected in a Dean Stark trap. The reaction mixture was heated at reflux for an additional 6 hours and then p-toluenesulfonic acid (1.4 g, 7.5 mmol) was added and the reaction was refluxed overnight. A dark orange/brown oil had formed. The toluene supematant was decanted off and concentrated under vacuum to provide 1.1 g of 1,1dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-l-yl)butyl]carbamate. The oil was identified as 4-(1H-imidazo[4,5-c][1,5]naphthyridin-l-yl)butaneamine. This material was reacted with 1,1-dimethylethyl-dicarbonate to provide an additional 1 g of 1,1dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-l-yl)butyl]carbamate. The two lots were combined and carried on to the next step.

Part B 3-Chloroperbenzoic acid (1.86 g of 60%) was added in small portions to a solution of the material from Part A in chloroform (25 mL). The reaction was maintained at ambient temperature overnight and then it was diluted with 5% sodium carbonate solution.

The layers were separated. The organic layer was concentrated under vacuum. The residue was slurried with hot methyl acetate, cooled and then filtered to provide 2.0 g of 1- -100- WO 99/29693 PCT/US98/26473 -dimethylethylcarbonyl)amino]butyl} -1H-imidazo[4,5-c] 1,5]naphthyridine-5Noxide.

Part C Tosyl chloride (0.64 g, 3.37 mmol) was slowly added in small portions to a solution of the material from Part B (1.2 g, 3.37 mmol) in dichloromethane (20 mL).

After 4 hours an additional 100 mg of tosyl chloride was added to drive the reaction to completion. The reaction was quenched with concentrated ammonium hydroxide (5 mL) and water (10 mL) and stirred at ambient temperature over the weekend. The layers were separated. The organic layer was concentrated under vacuum to provide a tan solid. This solid was slurried in hot methyl acetate, cooled and the filtered to provide 0.9 g of 1,1-dimethylethyl N-[4-(4-amino-l H-imidazo[4,5-c] [1,5]naphthyridin-1yl)butyl]carbamate.

Part D A mixture of the material from Part C and 1 N hydrochloric acid (25 mL) was heated at reflux until thin layer chromatography indicated that the reaction was complete.

The mixture was adjusted to pH 14 with 6 N sodium hydroxide. The resulting precipitate was isolated by filtration to provide 0.2 g of4-(4-amino-1H-imidazo[4,5c][1,5]naphthyridin-1-yl)butaneamine as a pale yellow solid, m.p. 161-163*C. Mass spec (M 1) 257.09.

-101 WO 99/29693 PCT/US98/26473 Example 112 Compound of Formula I Nl-[4-(4-Amino-2-butyl-H-imidazo[4,5-c] [1,5 naphthyridin-l-yl)butylj- 4 -{(2-(dimethylamino)ethoxyl(phenyl)methyl}benzamide

NH

2

N-

II

NA N N H

IN

O

Part A Under a nitrogen atmosphere phenyl magnesium bromide (39 mL of 3 M in ether) was added via a syringe over a period of 30 minutes to a solution of methyl 4formylbenzoate (19.2 g, 117 mmol). The mixture was allowed to stir for an additional minutes and then it was quenched by the addition of 1 M hydrochloric acid (125 mL). The reaction mixture was extracted with diethyl ether (2 X 200 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. This material was purified by flash chromatography (silica gel eluting with 6:1 hexanes:ethyl acetate) to provide 6.9 g of methyl 4-(a-hydroxybenzyl)benzoate as a clear oil.

Under a nitrogen atmosphere a suspension of p-toluenesulfonic acid monohydrate (10.7 g, 56 mmol) in toluene (70 mL) was heated at reflux. Water mL) was collected in a Dean Stark trap. The heating mantle was removed. To the warm mixture was added a solution of methyl 4-(a-hydroxybenzyl)benzoate (3.47 g, 14 mmol) and N,Ndimethylethanolamine (2.9 mL, 28 mmol) in a minimal amount of toluene. The mixture was heated at reflux for 20 minutes and then allowed to cool to ambient temperature. The reaction mixture was partitioned between diethyl ether and saturated aqueous sodium bicarbonate (the aqueous layer was basic). The aqueous layer was extracted with an -102- WO 99/29693 PCT/US98/26473 additional 100mL of diethyl ether. The combined organic layers were dried and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with then 10% methanol in dichloromethane) to provide 2.49 g of methyl 4- [a-(2-N,N-dimethylaminoethoxy)benzyl]benzoate as a colorless oil.

1 N Sodium hydroxide (2.54 mL) was added to a solution of methyl dimethylaminoethoxy)benzyl]benzoate (0.53 g, 1.7 mmol) in methanol (10 mL). The solution was heated at reflux for 1 hour, allowed to cool to ambient temperature and then neutralized (pH 5-6) with 1 N hydrochloric acid (2.54 mL). The mixture was concentrated under vacuum (bath at 45C). The resulting residue was extracted into a mixture of dichloromethane (15 mL) and methanol (3 mL). The extract was filtered and the filtrate was concentrated under vacuum to provide a viscous residue. Trituration with several portions ofdiethyl ether provided 0.39 g of dimethylaminoethoxy)benzyl]benzoic acid as a white powder.

Part B 4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin- -yl)butaneamine (0.130 g, 0.4175 mmol) and 4-[a-(2-N,N-dimethylaminoethoxy)benzyl]benzoic acid (0.125 g, 0.4175 mmol) were combined in dichloromethane (150 mL) and stirred at ambient temperature until a clear solution was obtained. 1-[3-(Dimethylamino)propy]-3ethylcarbodiimide hydrochloride (0.088 g, 0.46 mmol) was added and the reaction was maintained at ambient temperature for 2 days. The volume of dichloromethane was reduced and the concentrate was purified by flash chromatography (silica gel eluting with methanol in dichloromethane) to provide 0.085 g of N'-[4-(4-amino-2-butyl-1H- 1,5]naphthyridin- -yl)butyl]-4- [2- (dimethylamino)ethoxy](phenyl)methyl}benzamide as a solid, m.p. 105-108°C. Mass spec (M 1) 594.30.

-103- WO 99/29693 WO 9929693PCT/IJS98/26473 Example 113 Compound of Formnula I Nl-14-(4-Amino-2-butyl-1H-imidazol4,5-cl [1 ,5j naphthyridin-1 -yI)butyll- 4-benzoylbenzamide

NH

2

N

1 N 0

NN

Using the general method of Example 112 Part B, 4-benzoylbenzoic acid (72 mg, 0.32 mmole) was reacted with 4-(4-amino-2-butyl- 1H-imidazo[4,5-cI [1 ,5]naphthyridin- 1yl)butaneamine (100 mg, 0.32 mnmol) to provide 30 mg of N'-[4-(4-amino-2-butyl-IH- [1,5]naphthyridin- 1-yl)butyl]-4.-benzoylbenzainide as a white solid. Massspec (M 1 5 21.3 1).

Example 114 Compound of Formula I Nl-14-(4-Amino-2-butyl-lH-imidazo[4,5-cI 11,51 naphthyridin-1-yI)ethyll- 2-(5-methyl-2,4-dioxo-1 ,2,3,4-tetrahydro-1 -pyrimidinyl)acetamide

NH

2 N

N

1 0

N

N~

N

00 Using the general method of Example 112 Part B, thymine-1I-acetic acid (13 0 mg, 0.70 mmole) was reacted with 4-(4-ainino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1yl)ethaneamine (200 mg, 0.70 mnmol) to provide 68 mg of N1-[4-(4-amino-2-butyl-1H- 104 WO 99t29693 WO 99/29693 CTUUS8/1264 3 [1,5]naphthyridin- I -yl)ethyl -m ethyl -2,4-di oxo- 1 ,2,3,4-tetrahydro- I1pyrimidinyl)acetamide as a white solid, m.p. 241-242TC. Mass-spec (M I 451.24).

Example 115 Compound of Formula I N'-[4-(4-Amino-2-butyl-1H-imidazo 14,5-cl 11,51 naphthyridin-1-yI)ethyj- 6-(5-methyl-2-oxo-4-imidazolidinyl)hexamide

NH

2 N

N

N H I NH 0 Using the general method of Example 112 Part B, D-desthiobiotin (151 mg, 0.70 mmole) was reacted with 4-(4-amino-2-butyl-lIH-imidazo[4,5-c]1 ,5]naphthyridin- 1yl)ethaneamine (200 mg, 0.70 mmol) to provide 231 mg of N'-[4-(4-amino-2-butyl-IH- [1 ,5]naphthyridin- 1-yl)ethyl]- 6-(5-methyl-2-oxo-4-imidazolidinyl)hexamide as a white solid, m.p. 184-186*C. Mass spec (M 1 481.35).

105 WO 99/29693 WO 9929693PCT/US98126473 Example 116 Compound of Formula I Nl-14-(4-Aminio-2-butyI-lH-imidazo4,5-cI 11 ,5Jnapbthyridin-1 -yI)ethylj methanesulfonamide N11 2

N

NN

HN

II

Using the method of Examples below, 4-(4-amino-2-butyl-1H-imidazo[4,5c][1,5]naphthyridin-1I-yl)ethaneamine (14 mg, 50 tmol) was reacted with methanesulfonyl chloride (4 gL, 50 jttmol) to provide 5.3 mg of N'-[4-(4-amino-2-butyl-1H-imidazo[4,5c] l,5]naphthyridin- I-yl)ethyl]methanesulfonamide. I H NMR (500 MHz,. d6-DMSO) 6 8.49 (dd, J=4.3; 1.5 Hz, I 7.92 (dd, J=8.0; 1.5 Hz, 1 7.44 (dd, J=8.0; 4.3 Hz, 1 H), 7.30 J=6 Hz, 1 6.76 2H), 4.77 J=6 Hz, 2 3.50 J=6 Hz, 2 2.98 (t, J=7 Hz, 2 2.85 3H), 1.82 (quintet, J=7 Hz, 2 1.46 (in, 2 0.96 J=7 Hz, 3 Mass spec by APCI plug injection gave desired MW.

-106- WO 99/29693 WO 9929693PCTIUS98/26473 Example 11 7 Compound of Formula I N' -[4-(4-Amino-2-butyl-1H-imidazo 14,5-cl naphtbyridin-1-yI)ethyllbenzenesulfonamide

NH

2

N

7

N

NN

0 Using the method of Examples 118-152 below, 4-(4-amino-2-butyl-1IH- [l,5]naphthyridin-lI-yl)ethaneamine (14 mg, -50 tmol) was reacted with benzenesulfonyl chloride (6 IiL, 50 glmol) to provide 10.9 mg of N'-[4-(4-amino-2-butyl- 1H-iinidazo[4,5-c][1I,5]naphthyridin-1 -yl)ethyl]benzenesulfonamide. I HNMR (500 MHz.

d6-DMSO) 6 8.43 (dd, J=4.4; 1.5 Hz, 1 7.94 J=6 Hz, 1 7.89 (dd, J=8.4; Hz, I 7.68 J=8 Hz, 2 7.58 J=8 Hz, 1 7.50 J=8Hz, 2H), 7.41 (dd, J=8.4; 4.4 Hz, 1 4.72 J=6 Hz, 2 3.34 (in, 2 2.97 J=7 Hz, 2 1.81 (quintet, J=7 Hz, 2 1.45 (sextet, J=7 Hz, 2 0.97 J=7 Hz, 3 Mass spec by APCI plug injection gave desired MW.

Examples 118 -152 Compounds of Formula I The compounds of Examples 118-152 shown in the table below were prepared according to the following method. 4-(4-Axnino-2-butyl-l1H-imidazo[4,5c][l,5]naphthyridin-1-yl)ethaneainine (50 jltmol) was dissolved in dichloromethane mL) in a screw-capped test tube and the solution was cooled in an ice-water bath. An acid chloride (50 g±mol) of the formula RACOCI was added as a solution in 100 [LL of dichioromethane (Acid chlorides that are solids were either dissolved or suspended in -400 jiL of dichioromethane and then added). The mixture was vortexed for 15 seconds to 1 minute, becoming cloudy, and then -80 mg of an aminomethyl polystyrene resin 107 WO 99/29693 PCT/US98/26473 (0.62 meq/g, 100-200 mesh, 1% crosslink, Bachem #D-2100, lot FM507) was added, and the mixture was vortexed for another 30 seconds. The mixture was applied to a short column (3 x 1 cm of silica gel conditioned with dichloromethane. The product was eluted with 10:1 dichloromethane:methanol, collecting -2 mL fractions. Thin layer chromatography of the fractions was performed, and fractions with the product spot were pooled and stripped to dryness in a Savant SpeedVac. Purity was checked by reversed phase-HPLC (HPLC conditions refer to using a Hewlett Packard HP 1090 system fitted with a C18 Rainin Microsorb MV column, 4.6 x 50 mm, particle size 3 microns, pore size 100 Angstroms. Gradient elution: linear gradient from 100% water +0.1% trifluoroacetic acid to 100% acetonitrile 0.1% trifluoroacetic acid over 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm). APCI-mass spectral data confirmed presence of the expected molecular ion, and proton nmr data supported the expected structure.

108- WO 99/29693 WO 9929693PCT/US98/26473 Example #RA Fragment 'H NMR (500 MHz, solvent indicated) (d 6 -DMSO) 8 8.51 (dd, J=4.4, 1.5 Hz, 1lH), 118 7.91 (dd, J=8.3, 1.5 Hz, 1 7.46 J=6 Hz, Hv~k 7.44 (dd, 4.4 Hz, 1 6.73 (br H s, 2H), 4.80 J=6 Hz, 2H), 3.60 J=6 Hz, 2H), 2.87 J=7 Hz, 2H), 2.0-1.8 (in, 17H), 1.43 (sextet, J=7 Hz, 2H), 0.96 J=7 Hz, 3H) 6 -DMSO) 6 8.49 J=4.5 Hz, 1 7.93 119 ki(d, J=8 Hz, 1 7.65 J=6 Hz, I1H), 7.45 (dd, J-4.5, 8 Hz, I 7.29 J=8 Hz, 2H), 7.17 J=8 Hz, 2H), 6.92 (br s, 2H), 4.69 (t, J=6 Hz, 2H), 3.59 J=6 Hz, 2H), 2.60 (t, CI J=7 Hz, 2H), 2.28 (in, 2H), 1.67 (in, 4H), 1.5-1.3 (in, 6H), 0.92 J=7 Hz, 3H) Cl ~(d 6 -DMSO) 868.96 J=6 Hz, 1 8.49 (dd, 120 J=4.0, 1 1H), 7.92 (dd, J=8, 1.5 Hz, 1H), 0 .7.50 J=8 Hz, 2H), 7.44 (dd, J=8, 4.0 Hz, Cl 1IH), 7.40 J=8 Hz, 1IH), 6.76 2H), 4.85 J=6 Hz, 2H), 3.88 J=6 Hz, 2H), 3.03 (t, J=7 Hz, 2H), 1.80 (quintet, J=7 Hz, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.96 J=7 Hz, 3H) (d 6 -DMSO) 6 8.52 (dd, J=4.2, 1.5 Hz, 1IH), 121 .08.04 J=6 Hz, 1IH), 7.95 (dd, J=8.5, 1.5 Hz, I 7.45 (dd, 4.2 Hz, I 7.4-7.2 (mn, 5H), 7.00 (br s, 2H), 4.84 J=6 Hz, 2H), 4.37 2H), 3.74 2H), 3.65 J=6 Hz, 2H), 2.87 J=7 Hz, 2H), 1.77 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.94 J=7 Hz, 3H) -109- WO 99/29693 WO 9929693PCTfIJS98/26473 (d 6 -DMSO) 5 8.50 (dd, J=4.4, 1 .5 Hz, 1 H), 122 7.97 J=6 Hz, 1lH), 7.92 (dd, J=8.4, 1.5 Hz, 1 7.45 (dd. J=8.4, 1.5 Hz, 1 6.75 (br s,

CH

3 2H), 4.762 J=6 Hz, 2H), 3.57 3H), 2.88 J=7 Hz, 2H), 2.27 J=7 Hz, 4H), 2.18 (t, J=7 Hz, 2H), 1.93 J=7 Hz, 2H), 1.80 (quintet, J=7 Hz, 2H), 2.6-1.1 (in, 12H), 0.96 J=7 Hz, 3H) (d 6 -DMSO) 8 8.52 (dd, J-4.4, 1.5 Hz, 1 H), 123 c1 7.97 J=6 Hz, 1IH), 7.95 (dd, J=8.3, 1.5 Hz, 1~ 7.45 (dd, J=8.3, 4.4 Hz, 1 6.88 (br s, 2H), 5.79 (in, 1IH), 4.98 J1l5 Hz, 1 H), 4.91 J=1 3 Hz, 1IH), 4.76 J=6 Hz, 2H), 3.57 J=6 Hz, 2H), 2.88 J=7 Hz, 2H), 2.00 J=7 Hz, 2H), 1.93 J=6 Hz, 2H), 1.80 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 2H), 1.5-1.1 (in, 12H), 0.96 J=6 Hz, 3H) (d 6 -DMSO) 8 8.51 (dd, J=4.4, .1.7 Hz, 1 H), 124 7.96 J=6Hz, 1 7.92 (dd, J=8.3, 1.5 Hz, 1 7.44 (dd, J=8.3, 4.4 Hz, 1 6.81 (br s, 2H), 3.76 J=6 Hz, 2H), 3.59 J=6 Hz, 2H), 2.90 J=7 Hz, 2H), 1.94 (in, 3H), 1.80 (quintet, J=7 Hz, 2H), 1.58 (mn, 2H), 1.55- 1.40 (mn, 6H), 0.96 (in, F F (d 6 -DMSO) 859.32 J=6 Hz, 1 8.51 (dd, 125 F J=4.4, 1.5 Hz, I 8.29 (br s, I 8.26 (br s, 2H), 7.97 J=8 Hz, 1 7.44 (dd, J=8, 4.4 Hz, 1 7.42 (br s, 2H), 4.97 J=6 Hz, F 2H), 3.88 J=6 Hz, 2H), 2.86 J=7 Hz, F F 2H), 1.73 (quintet, J=7 Hz, 2H), 1.30 (sextet, J=7 Hz, 2H), 0.80 J=7 Hz, 3H) (d 6 -DMSO) 8 8.68 J=4.5 Hz, 1 8.61 (t, 126 J=6 Hz, 1IH), 8.12 J=8 Hz, 1 8.1 (br s, 2H), 7.62 (dd, J=8.0, 4.5 Hz, 1 7.44 (dd, cl~ J=7.5, 2 Hz, 1 7.41 (dt, J=7.5, 2.0 Hz, 1H), 7.31 (dt, J=7.5, 2.0 Hz, 1IH), 7.12 (dd, 2 Hz, 1 4.91 J=6 Hz, 2H), 3.83 J=6 Hz, 2H), 3.00 J=7 Hz, 2H), 1.83 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 0.94 J=7 Hz, 3H) -110- WO 99/29693 WO 9929693PCT1US98/26473 (d 6 -DM SO) 8 8.69 J=6 Hz, 1 8.63 (dd, 127 cl J=4,1.5 Hz, 1H), 8.07 J=8.5 Hz, 1H), 7.80 (br s, 2H), 7.65 J=2 Hz, 1 7.57 CI (dd, J=8.5, 4.5 Hz, 1IH), 7.42 (dd, J=8, 2 Hz, 1 7.15 J=8 Hz, 1 4.91 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 2.98 J=7 Hz, 2H), 1.82 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.94 J=7 Hz, 3H) (d 6 -DMSO) 858.48 (dd, J=4.3, 1.5 Hz, 1 H), 128 H C-0 8.25 J=6 Hz, 1 7.91 (dd, J=8.5, 1.5 Hz, I 7.42 (dd, J=8.5, 4.3 Hz, 1IH), 7.25 (t, J=8 Hz, I 6.74 (br s, 2H), 6.61 J=8 Hz, 2H), 4.80 J=6 Hz, 2H), 3.76 J=6 CH 3 Hz, 2H), 3.33 6H), 3.00 J=7 Hz, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.95 J=7 Hz, 3H) 129 F (dr 6 -DM SO) 858.66 J=6 Hz, 1IH), 8.57 (dd, 129 J=4.3, 1.2 Hz, 1H), 8.00 (dd, J=8.5, 1.2 Hz, I 7.69 (dd, J=9, 5.8 Hz, 2H), 7.50 (dd, J=8.4, 4.3 Hz, I 7.30 (br s, 2H), 7.25 (t, J=9 Hz, 2H), 4.91 J=6 Hz, 2H), 3.81 (q, J=6 Hz, 2H), 2.81 J=7 Hz, 2H), 1.70 (quintet, J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 0.81 J=7 Hz, 3H) (d 6 -DMSO) 5 8.72 J=6 Hz, 1IH), 8.52 (dd, 130 -a CI J=4.3, 1.5 Hz, 1 7.93 (dd, J=8.0, 1.5 Hz, 1 7.72 J=8 Hz, 2H), 7.50 J=8 Hz, 2H), 7.44 (dd, J=8, 4.3 Hz, 1 6.80 (br s, 2H), 4.90 J=6 Hz, 2H), 3.81 J=6 Hz, 2H), 2.79 J=7 Hz, 2H), 1.70 (quintet, J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.81 (t, Hz, 3H) FH3 alo (d 6 -DMSO) 8 8.55 (dd, J=4.3, 1.5 Hz, 1 H), 8.49 J=6 Hz, I 7.95 (dd, J=8.4, 1.5 Hz, 1 7.69 J=8 Hz, 2H). 7.46 (dd, J=8.4, 4.3 Hz, 1 6.93 J=8 Hz, 2H), 6.91 (br s, 2H), 4.90 J=6 Hz, 2H), 3.8 Jft6 Hz, 2H), 3.79 3H), 2.79 J=7 Hz, 2H), 1.69 (quintet, J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.80 J=7 Hz, 3H) CI (d6 8 -DMSO) 5 8.76 J6 Hz, I 8.53 (dd; jJ=4.3, 1.5 Hz, 1H), 7.95 (dd, J=8.5. 1.5 Hz, 1 7.67 (br s, I 7.65 J=8 Hz, 1 H), III WO 99/29693 PCT/US98/26473 7.57 (in, 1 7.48-7.43 (in, 2H), 7.02 (br s, 2H), 4.91 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 2.81 J=7 Hz, 2H), 1.71 (quintet, J=7 Hz, 2H), 1.31 (sextet, J=7 Hz, 2H), 0.82 (t, J=7 Hz, 3H)

CH

3

~CH

3 H 3 (d 6 -DMSO) 5 8.69 (dd, J=4.4, 1.2 Hz, 1H), 8.57 J=6 Hz, 1H), 8.22 (br s, 2H). 8.12 (dd, J=8.0, 1.2 Hz, IH), 7.61 3H), 7.41 J=9 Hz, 2H), 4.92 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 2.84 J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 1.27 (sextet, J=7 Hz, 2H), 1.27 9H), 0.78 J=7 Hz, 3H) (d 6 -DMSO) 8 8.55 J=6 Hz, IH), 8.54 (dd, 134 CH3 J=4.5, 1.5 Hz, 1 7.94 (dd, J=8.5, 1.5 Hz, 1H), 7.60 J=8 Hz, 2H), 7.46 (dd, J=8.2, Hz, 1H), 7.21 d, J=8 Hz, 2H), 6.87 (br s, 2H), 4.90 J=6 Hz, 2H), 3.80 J=6 Hz, 2H), 2.80 J=7 Hz, 2H), 2.32 3H), 1.69 (quintet J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.81 J=7 Hz, 3H) CH_ (d 6 -DMSO) 8 8.58 (dd, J=4.4, 1.5 Hz, 1H), 135 CV 3 8.00 (dd, J=8.4, 1.5 Hz, 1H), 7.97 J=6 Hz, H3C CH 3 1 7.52 (dd, J=8.4,4.4 Hz, 1 7.35 (br s, 2H), 4.77 J=6 Hz, 2H), 3.58 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 1.85 2H), 1.81 (quintet, J=7 Hz, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.96 J=7 Hz, 3H), 0.87 9H)

(CDC

3 at 60 0 C) 8 8.56 (dd, J=4.0, 1.5 Hz, 136 1H), 8.06 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (dd, J=8.8, 4.0 Hz, 1H), 6.80 (br s, 1H), 5.70 (br s, 2H), 4.94 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 0.99 (m, 1H), 0.99 J=7 Hz, 3H), 0.79 2H), 0.54 2H) (CDCl 3 8 8.59 (dd, J=4.5, 1.5 Hz, 1H), 8.10 137 (dd, J=8.3, 1.5 Hz, I 7.46 (dd, J=8.5, Hz, 1 6.79 (br s, 1 6.02 (br s, 2H), 4.96 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 2.18 (quintet, J=7 Hz, 1H), 1.90 (quintet, J=7 Hz, 2H), 1.65-1.35 10H), 1.00 J=7 Hz, 3H) (CDCl 3 68.58 (dd, J=4.4, 1.5 Hz, 1 8.09 138 (dd, J=8.0, 1.5 Hz, 1 7.46 (dd, J=8.3, 4.4 Hz, 1 7.00 (br s, 1 5.85 (br s, 2H), -112- WO 99/29693 WO 9929693PCTIUJS98/26473 4.96 J=6 Hz, 2H), 3.81 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.88 (in, 3H), 1.52 (in, 6H), 1.50 (in, 2H), 1.49 (in, 2H), 1.291 (q, 2H), 1.01 J=7 Hz, 3H), 0.85 (in, 2H) (CDC13) 568.52 (dd, J=4.4, 1.5 Hz, 1 8.26 139 f-N(br t, 1 8.09 (dd, J=8.5, 1.5 Hz, 1 7.47 J=8 Hz, 2H), 7.46 (dd, J=8.5, 4.4 Hz, 1 7.34 J=8 Hz, 2H), 5.92 (br s, 2H),.

5.12 J=6 Hz, 2H), 4.04 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 1.92 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.00 J=7 Hz, 3H)

(C~DC

3 6 8.65 (dd, J=4.4, 1.5 Hz, 1 8.03 140 (dd, J=8.5, 1.5 Hz, 1 7.59 (br t, 1 7.45 (dd, J=8.5, 4.4 Hz, 1 7.35 (dd, J=5, 1.2 Hz, I 7.10 J=3, Hz, 1 6.89 (dd, 3 Hz, 1 6.32 (br s, 2H), 5.08 J=6 Hz, 2H), 4.02 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.47 (sextet, J=7 Hz, 2H), 0.96 J=7 Hz, 3H) (CDC1 3 6 8.45 (dd, J=4.4, 1.5 Hz, 1 8.08 141 (dd, J=8.4, 1.5 Hz, 1H), 7.43 (dd, J=8.3, 4.4 Ds Hz, 1 7.07 (dd, J=5, 1.6 Hz, 1 6.84 br t, 1 6.7.8 (dd, J=5, 3.4 Hz, I 6.51 (dd, J=3, 1 Hz, 1 6.05 (br s, 2H), 4.94 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 3.49 2H), 2.89 J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 J=7 Hz, 3H) I

(C~DC

3 6 8.52 (dd, J=4.4, 1.5 Hz, 1IH), 8.42 142 O2(br t, 1IH), 8.08 (dd, J=8.3, 1.5 Hz, 1 8.01 J=9 Hz, 2H), 7.48 (dd, J=8.4, 4.4 Hz, 1 7.39 J=9 Hz, 2H), 5.80 (br s, 2H), 5.12 J=6 Hz, 2H), 4.05 J=6 Hz, 2H), 2.94 J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) H3C (C~DC 3 8 8.21 (dd, J=4.4, 1.5 Hz, 1 8.05 143 CH(dd, J=8.4, 1.5 Hz, 1 7.53 (br t, I 7.28

\/C

3 (dd, J=8.3, 4.4 Hz, 1IH), 6.68 2H), 6.23 H3C (br s, 2H), 5.02 J=6 Hz, 2H), 4.00 J=6 Hz, 2H), 3.03 J=7 Hz, 2H), 2.21 3H), 1.99 6H), 1.94 (quintet, J=7 Hz, 2H), 1.59.

(sextet, J=7 Hz, 2H), 1.03 J=7 Hz, 3H) 113- WO 99/29693 PCT/US98126473

Q

0 3 (ODC1 3 at 29 0 C) 8 8.59 (dd, J=4.0, 1.5 Hz, 1 8.14 (d d, J 1.5 Hz, 1 8.09 (d d, J=8, 1.5 Hz, 1 7.87 J=6 Hz, 1 7.42 J =8 Hz, 1 7.4 2 (d d, J 4. 0 Hz, 1 H), 7.06 J=8 Hz, 1 6.87 J=8 Hz, 1IH), 6.19 (br s, 2H), 5.07 J=6 Hz, 2H), 4.04 (q, J=6 Hz, 2H), 3.68 3H), 2.89 J=7 Hz, 2H), 1.80 (quintet, J=7 Hz, 2H), 1.39 (sextet, J=7 Hz, 2H), 0.88 J=7 Hz, 3H) (CDC1 3 568.60 (dd, J=4.4, 1.5 Hz, 1 8.11 145 0(dd, J=8.5, 1.5 Hz, I 7.47 (dd, J=8.5, 4.4 Hz, 1IH), 7.01 (br t, 1 6.43 (br s, 2H), 4.95 O-CH J=6 Hz, 2H), 3.81 J=6 Hz, 2H), 3.63 3H), 2.93 J=7 Hz, 2H), 2.19 J=7 Hz, 2H), 1.92 (in, 4H), 1.51 (sextet, J=7 Hz, 2H), (mn, 4H), 1.00 J=7 Hz, 3H) 0 O (CDC1 3 8 8.23 (dd, J 1.5 Hz, 1IH), 8.52 146 ILJ(br s, 1IH), 8.10 (dd, J 1.5 Hz, 1IH), 7.53 (dd, J=8.3, 4.4 Hz, I 7.21 J=4 Hz, 1 7.06 J=4 Hz, I 6.1 (br s, 2H), 5.11 J=6 Hz, 2H), 4.04 J=6 Hz, 2H), 2.94 J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.53 (sextet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) cl

(CDCI

3 6 8. 39 (dd, J=4.4, 1.5 Hz, 1 8.31 147 -N (dd, J=5.0, 2 Hz, 1IH), 8.21 (br t, J=6 Hz, 1 8.00 (dd, J=8.4, 1.5 Hz, 1IH), 7.42 (dd, 8 Hz, I 7.33 (dd, J=8.5, 4.4 Hz, 1 H), 7.07 (dd, J=8, 5 Hz, I 5.84 (br s, 2H), 5.06 J=6 Hz, 2H), 4.05 J=6 Hz, 2H), 2.97 J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.53 (sextet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) 18N l(C~DC 3 at 601C) 6 8.54 (dd, J 1.5 Hz, 148 SfCI1 8.33 J=2 Hz, 1 8.06 (dd, J=8.4, Hz, 1 8.06 (br s, 1IH), 7.56 (dd, 8.5, 2 Hz, I 7.45 (dd, J=8.4, 4.4 Hz, 1IH), 7.15 J=8 Hz, 1 5.72 (br s, 2H), 5.08 J=6 114- WO 99f29693 WO 9929693PCT/US98/26473 Hz, 2H), 4.03 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.00 J=7 Hz, 3H) 149 0

(CDCI

3 8 8.61 (dd, J=4.4, 1.5 Hz, 1 8.03 149(dd, J=8.3, 1.5 Hz, 1 7.50 J=6 Hz, I H), 7.44 (dd, J=8.3, 4.4 Hz, 1 7.42 J=8 Hz, 2H), 6.73 J=8 Hz, 2H), 6.45 (br s, H 3 2H), 5.06 J=6 Hz, 2H), 4.00 J=6 Hz, 2H), 3.90 J=7 Hz, 2H), 2.90 J=7 Hz, 2H), 1.84 (quintet, J=7 Hz, 2H), 1.74 (quintet, J=7 Hz, 2H), 1.42, m, 4H), 1.28 (in, 6H), 0.93 J=7 Hz, 3H), 0.87 3H) 0 ~(CDCI 3 8 8.61 (dd, J=4.4, 1.5 Hz, 1 8.09 150 G J=8.5 Hz-, 1IH), 7.90 J=8 Hz, 2H), 7.84 H C (br s, 1 7.48 (dd.J=8.5, 4.4 Hz, 1 7.44 J=8 Hz, 2H), 6.4 (br s, 2H), 5.12 J=6 Hz, 2H), 3.94 J=7 Hz, 2H), 3.91 3H), 2.94 J=7 Hz, 2H), 1.91 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 0.99 J=7 Hz, 3H) CI (CDCI 3 8 8.48 (br s, 1 8.22 (dd, 151 cl1. 5 Hz, I 8.04 (dd, J 1.5 Hz, 1 H), /0 C 7.33 2H), 7.30 (dd, J=8.4, 4.4 Hz, 1 H), cl 5.96 (br s, 2H), 5.00 J=6 Hz, 2H), 4.03 (q, J=6 Hz, 2H), 2.99 J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.54 (sextet, J=7 Hz, 2H), 1.03 J=7 Hz, 3H) (CDC3) 8 8.41 (dd, J=4.4, 1.5 Hz, I 8.06 152 (dd, J=8.3, 1.5 Hz, 1H), 7.41 (dd, J=8.5, 4.4 Hz, 1IH), 6.75 J=8 Hz, 2H), 6.64. J=8 O-CH 3Hz, 2H), 6.60 (br t, I 6.02 (br s, 2H), 4.92 J=6 Hz, 2H), 3.80 J-4.6 Hz, 2H), 3.76 3H), 3.22 2H), 2.88 J=7 Hz, 2H), 1.87 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 J=7 Hz, 3H) -115- I II WO 99/29693 PCTIUS98/26473 Examples 153- 190 Compounds of Formula I The compounds of Examples 153-190 shown in the table below were prepared according to the following method. 4-(4-Amino-2-butyl-lH-imidazo[4,5- (25 pmol) was dissolved in dichloromethane mL) in a screw-capped test tube and the solution was cooled in an ice-water bath. An acid chloride (25 pmol) of the formula RACOCI was added as a solution in 100 tL of dichloromethane (Acid chlorides that are solids were added directly.). The mixture was vortexed for 15 seconds to 1 minute, becoming cloudy, and then -80 mg of an aminomethyl polystyrene resin (0.62 meq/g, 100-200 mesh, 1% crosslink, Bachem #D- 2100, lot FM507) was added, and the mixture was vortexed for another 30 seconds. The mixture was applied to a short column (3 x 1 cm of silica gel conditioned with dichloromethane. The product was eluted with 10:1 dichloromethane:methanol, collecting -2 mL fractions. Thin layer chromatography of the fractions was performed, and fractions with the product spot were pooled and stripped to dryness in a Savant SpeedVac. Purity was checked by reversed phase-HPLC (HPLC conditions refer to using a Hewlett Packard HP 1090 system fitted with a C18 Rainin Microsorb MV column, 4.6 x 50 mm, particle size 3 microns, pore size 100 Angstroms. Gradient elution: linear gradient from 100% water trifluoroacetic acid to 100% acetonitrile 0.1% trifluoroacetic acid over 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm). APCI-mass spectral data confirmed presence of the expected molecular ion, and proton nmr data supported the expected structure.

-116- WO 99/29693 WO 9929693PCr11JS98I26473 Example RA Fragment 1 lH NMR (500 MHz, solvent indicated) Br (CDC1 3 at 29 0 C) 8 8.53- (dd, J 1.5 Hz, 153 1 8.12 (dd, J=8.5, 1.5 Hz, 1 7.83 J=2 Hz, I1H), 7.59 J =8 Hz, 1 7.57 J =8 Hz, 1 7.42 (dd, J=8.5, 4.4 Hz, I 7.23 (t, J=8 Hz, 1 6.73 J=6 Hz, 1 6.50 (br s, 2H), 4.84 J=6 Hz, 2H), 3.60 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 2.04 (quintet, J=7 Hz, 2H), 1 .88 (quintet, J=7 Hz, 2H), 1.80 (in, J=7 Hz, 2H), 1.48 (in, 2H),..0.99 J=7 Hz, 3H)

(CDCI

3 at 29*C) 8 8.60 (dd, J=4A4 1.5 Hz, 154 1 8.09 (dd, J=8.5, 1.5 Hz, 1 7.43 (dd, 4.4 Hz, 1 6.32 (br s, 2H), 5.75 (t, H J=6 Hz, I 4.81 J=6 Hz, 2H), 3.35 (q, J=6 Hz, 2H), 2.91 (t,J=7 Hz, 2H), 2.1-1.6 (in, ca. 21 1.51 (sextet, J=7 Hz, 2H), 1 .01 (t, J=7 Hz, 3H) (COC13 at 60"C) 8 8.44 (dd, J=4.4, 1.5 Hz, 155, 1. 1H), 8. 10 (dd, J=8.5, 1.5 Hz, I H) 7.43 (dd, 4.4 Hz, 1 7.10 4H), 6.00 (br s, 2H), 5.60 J=6 Hz, 1IH), 4.63 J=6 Hz, 2H), 3.30 J=6 Hz, 2H), 2.86 J=7 Hz, CI 2H), 2.37 (in, 2H), 2.0-1.4 (in, 14H), 1.01 (t, J=7 Hz, 3H) (COCIk at 60*C) 8 8.33 J-4.4 Hz, 1 H) 156 8.08 (dd, J=8.5, 1.5 Hz, 1H), 7.5-7.0 (in,)4H), 6.70 (br s, 1 6.25 (br s, 2H), 4.85 J=6 Cl Hz, 2H), 3.67 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 2.08 (quintet, J=7 Hz, 2H), 1.89 (in, 1.53 (sextet, J=7 Hz, 2H), 1.02 J=7 117 WO 99129693 WO 9929693PCTIUS98/26473 Hz, 3H) (CDC1 3 at 60 0 C) 8 8.59 (dd, J=4.4, 1.5 Hz, 157 01 8.10 (dd, J=8.5, 1.5 Hz, 1 7.40 (dd, 4.4 Hz, 1 7.28 (in, 3H), 7.21 (in, 8 2H), 6.84 J=6 Hz, 1 6.4 (br s, 2H), 4.81 J=6 Hz, 2H), 4.49 2H), 3.96 2H), 3.42 J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1 .95 (quintet, J=7 Hz, 2H), 1 .90 (quintet, J=7 Hz, 2H), 1.69 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) 0 (d 6 -DMSO at 29 0 C) 8 8.50 (dd, J=4.4, 1.5 Hz, 158 0 1 7.91 (dd, J=8, 1 .5 Hz, 1 7.71 J=6 I1H), 7.43 (dd, J 4,4 Hz, 1 6.80 C3(br s, 2H), 4.79 J=6 Hz, 2H), 3.57 3H), 3.05 J=6 Hz, 2H), 2.28 J=7 Hz, 4H), 2.20 J=7 Hz, 2H), 1.98 J=7 Hz, 2H), 1.80 (in, 4H), 1.6-11 (mn, 14H), 0.96 J=7 Hz, 3H) 159CH., (d 6 -DMSO at 29-C) 8 8.51 (dd, J=4.4, 1.5 Hz, 159~1 7.92 (dd, J=8.5, 4.4 Hz, I1H), 7.72 J=6 Hz, 1 7.43 (dd, J=8.5, 4.4 Hz, 1 6.86 (br s, 2H), 5.77 (in, 1 4.98 (dd, J=2 Hz, 1 4.92 (in, I1H), 4.79 J=6 Hz, 2H), 3.08 J=6 Hz, 2H), 2.94 J=7 Hz, 2H), 1.98 (quintet, J=7 Hz, 2H), 1.80 (in, 2H), 1.55-1.1 20 0.96 J=7 Hz, 3H) (d 6 -DMSO at 29 0 C) 868.49 (dd, J=4.4, 1.5 Hz, 160 1H), 7.90 (dd, J=8.2, 1.5 Hz, 1 7.71 J=6 Hz, I1H), 7.42 (dd, J=8.2, 4.4 Hz, 1 6.74 (br s, 2H), 4.79 J=6 Hz, 2H), 3.06 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 2.04 (mn, 1H), 1.96 (mn, 2H), 1.82 (mn, 4H), 1.6-1.3 (mn, 1OH), (mn, 2H), 0.96 J=7 Hz, 3H) FF F (d6-DMSO at 291C) 8 8.95 J=6 Hz, 1 H), 161 F8.44 (mn, 3 8.31 1 7.88 (dd, 1.5 Hz, 1H), 7.37 (dd, J=8.5, 4.4 Hz, I H), 6.76 2H), 4.82 J=6 Hz, 2H), 3.38 (in, F 2H), 2.91 J=7 Hz, 2H), 1.90 (in, 2H), 1.76 F F(mn, 2H), 1.64 (mn, 2H), 1.39 (mn, 2H), 0.86 (t, =7 Hz, 3H) Hlc (dr 6 -DMSO at 29 0 C) 8 8.44 (dd, J=4.4, 1.5 Hz, 162 0 1H), 8.39 J=6 Hz, 1lH), 7.89 (dd, J=8.2, _0CH Hz, 1IH), 7.39 (dd, J=8.2, 4.4 Hz, 1 7.12 2H), 6.75 (br s, 2H), 4.81 J=6 Hz, 2H), 0-CR 3 3.78 6H), 3.68 3H), 3.32 (in, 2H), 2.92 (mn, 2H), 1.90 (in, 2H), 1.80 (in, 2H), 1.60 (in, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.91 J=7 -118.

WO 99/29693 WO 9929693PCTIUS98/26473 Hz, 3H) F F (d 6 -DMSO at 290C) 5 8.89 J=6 Hz, 1KH), 8.51 (dd, J=4.4, 1.5 Hz, 1KH), 7.93 FHz, 1KH), 7.44 (dd, J=8.5, 4.4 Hz, 1 6.95 F F (br s, 2H), 4.83 J=6 Hz, 2H), 3.34 (in, 2H),.

2.95 J=7 Hz, 2H), 2.90 (in, 2H), 2.85 (in, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.45 (in, 2H), 0.96 J=7 Hz, 3H) -Qp

C'

(d 6 -DMSO at 290C) 5 8.50 (dd, J=4.3, 1.5 Hz, 1KH), 8.38 J=6 Hz, 1KH), 7.91 (dd, J=8.4, Hz, 1KH), 7.44 (dd, J 1 Hz, 1KH), 7.39 (dt, J=8, 1 Hz, 1KH), 7.43 (dd, J=8.4, 4.3 Hz, 1KH), 7.31 (dt 1 Hz, 1KH), 7.27 (dd, J=8, 1 Hz, 1IH), 6.74 2H), 4.83 J=6 Hz, 2H), 3.26 J=6 Hz, 2H), 2.94 J=7 Hz, 2H), 1.95 (in, 2H), 1.83 (in, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.45 (in, 2H), 0-95 J=7 Hz, 3H)

I

CI-C

(d 6 -DMSO at 291C) 8 8.49 (dd, J=4.3, 1.5 Hz, I1H), 8.44 J=6 Hz, 1IH), 7.91 (dd, J=8.2, Hz, 1KH), 7.64 J=2 Hz, 1 7.43 (dd, J=8.2, 4.3 Hz, 1KH), 7.42 (dd, J=8, 2 Hz, 1KH), 7.30 J=8 Hz, 1 6.75 (br s, 2H), 4.82 (t, J=6 Hz, 2H), 3.25 J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 1.90 (in, 2K), 1.82 (in, 2H), 1.60 (in, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.95 (t, J=7 Hz, 3H) 166 F(d 6 -DMSO at 29 0 C) 8 8.46 (dd, J=4.3, 1.5 Hz, 166~~ 8.46 (mn, 1KH), 7.89 (dd, J=8.5, 1.5 Hz, 1KH), 7.84 (dd, J=8, 5 Hz, 2H), 7.40 (dd, 4.3 Hz, 1KH), 7.26 J=9 Hz, 2H), 6.74 (br s, 2H), 4.81 J=6 Hz, 2K), 3.31 J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1.88 (in, 2K), 1.79 (in, 2K), 1.60 (quintet, J=7 Hz, 2H), 1.45 (in, 2H), 0.91 J=7 Hz, 3H)_ 167 cl (d 6 -DMSO at 290C) 8 8.53 J=6 Hz, 1IH), 167 \~CI8.46 (dd, J=4.4, 1.5 Hz, 1KH), 7.89 (dd, Hz, 1KH), 7.79 J=8 Hz, 2K), 7.50 (d, Hz, 2K), 7.40 (dd, J=8.5, 4.3 Hz, 1KH), 6.74 2H), 4.81 J=6 Hz, 2K), 3.30 (q, J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1.92 (in, 2H), 1.78 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2K), 1.40 (sextet, J=7 Hz, 2H), 0.90 J=7 Hz, 3H) -119- WO 99129693 WO 9929693PCT/US98/26473 3 (d 6 -DMSO at 2900) 58.47 (dd, J=4.3. 1.5 Hz, 168 1 8.29 J=6 Hz, 1 7.89 (dd, J=8.5, Hz, 1IH), 7.76 J=8 Hz, 2H), 7.40 (dd, 4.3 Hz, I1H), 6.96 J=8 Hz, 2H), 6.74 2H), 4.81 J=6 Hz, 2H), 3.79 (s, 3H), 3.39 J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1.86 (in, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.41 (sextet, J=7 Hz, 2H), 0.91 J=7 Hz, 3H) F (d 6 -DMSO at 2900) 8 8.67 J=6 Hz, 1 H), 169 F8.46 (dd, J=4.0, 1.5 Hz, 1IH), 7.97 J=8 Hz, F 2H), 7.89 (dd, J=8, 1.5 Hz, 1 7.39 (dd, J=8, 1.5 Hz, 1H), 7.38 J=8 Hz, 2H), 6.74 2H), 4.82 J=6 Hz, 2H), 3.32 (in, 2H), 2.91 J=7 Hz, 2H), 1.89 (mn, 2H), 1.78 (quintet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.89 J=7 Hz, 3H) CH 3(ds-DMSO at 2900) 8 8.46 (dd, J=4.0, 1.5 Hz, 170 IH 1H), 8.35 J=6 Hz, IH)y, 7.89 (dd, J=8.5, CH3 Hz, I 7.71 (K J=8 Hz, 2H), 7.43 J=8 Hz, 2H), 7.40 (dd, J=8, 4.0 Hz, 1IH), 6.73 (s, 2H), 4.80 J=6 Hz, 2H), 3.30 J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 2.80 (quintet, J=7 Hz, 2H), 1.60 (in, 2H), 1.39 (sextet, J=7 Hz, 2H), 1.29 9H), 0.90 J=7 Hz, 3H) (d 6 -DMSO at 290C) 8 8.47 (dd, J=4.0, 1.5 Hz, 171 -JCH 3 1 8.35 J=6 Hz, 1 7.89 (dd, J=8.0, Hz, 1IH), 7.69 J=8 Hz, 2H), 7.40 (dd, 4.0 Hz, 1 7.23 J=8 Hz, 2H), 6.74 2H), 4.81 J=6 Hz, 2H), 3.28 (q, J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 2.34 (s, 3H), 2.90 (in, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.41 (sextet, J=7 Hz, 2H), 0.91 J=7 Hz, 3H) -120- WO 99/29693 PCTUS98/26473 )(d 6 -DMSO at 290C) 8 8.49 (dd, J=4.5, 1.5 Hz, 172 CH 3 1H), 7.90 (dd, J=8.5, 1.5 Hz, 1H), 7.67 J=6

H

3 C CH 3 Hz, 1H), 7.42 (dd, J=8.5, 4.5 Hz, 1H), 6.74 2H), 4.79 J=6 Hz, 2H), 3.06 J=6 Hz, 2H), 2.91 J=7 Hz 2H), 1.87 2H), 1.82 (quintet, J=7 Hz, 4H), 1.46 (sextet, J=7 Hz, 4H), 0.96 J=7 Hz, 3H), 0.86 9H) (d 6 -DMSO at 290C) 8 8.50 (dd, J=4.5, 1.5 Hz, 173 1H), 8.00 J=6 Hz, 1H), 7.90 (dd, J=8.5, Hz, 1H), 7.43 (dd, J=8.5, 4.5 Hz, 1H), 6.75 2H), 4.79 J=6 Hz, 2H), 3.10 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.82 4H), 1.45 5H), 0.94 J=7 Hz, 3H), 0.60 4H) (d 6 -DMSO at 290C) 8 8.49 (dd, J=4.3, 1.5 Hz, 174 1H), 7.90 (dd, J=8.4,1.5 Hz, 1H), 7.68 J=6 Hz, 1H), 7.42 (dd, J=8.4, 4.3 Hz, 1H), 6.73 (br s, 2H), 4.80 J=6 Hz, 2H), 3.06 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 2.44 1H), 1.81 4H), 1.70-1.30 12H), 0.96 J=7 Hz, 3H) ~Jj (d 6 -DMSO at 290C) 8 8.50 (dd, J=4.5, 1.5 Hz, 175 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.73 J=6 Hz, 1H), 7.42 (dd, J=8.0, 4.5 Hz, 1H), 6.75 2H), 4.78 J=6 Hz, 2H), 3.06 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.99 J=7 Hz, 2H), 1.81 4H), 1.63 3H), 1.6-1.3 (m, 1 OH), 1.00 2H), 0.97 J=7 Hz, 3H) 1(d 6 -DMSO at 290C) 8 8.69 J=6 Hz, I H), 176 N8.45 (dd, J=4.3, 1.5 Hz, 1H), 7.91 4H), 7.89 (dd, J=8.3, 1.5 Hz, 1H), 7.40 (dd, J=8.3, 4.3 Hz, 1H), 6.74 2H), 4.81 J=6 Hz, 2H), 3.31 2H), 2.91 J=7 Hz, 2H), 1.90 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (m, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.90 J=7 Hz, 3H) 121 WO 99/29693 WO 9929693PCT/US98126473

S

-o (d 6 -DMSO at 2900) 6 8.46 (dd, J=4.3, 1.5 Hz, 1 8.45 J=6 Hz, 1IH), 7.89 (dd, J=8.4, Hz, 1 7.72 (dd, J=5, 1 Hz, 1 7.67 (dd, J=3, 1 Hz, 1 7.40 (dd, J=8.4, 4.3 Hz, 1 H), 7.11 (dd, J=5, 3 Hz, 1IH), 6.74 2H), 4.82 (t, J=6 Hz, 2H), 3.28 J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.87 (in, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.42 (sextet, J=7 Hz, 2H), 0.91 J=7 Hz, 3H) 4

S

(d 6 -DMSO at 2900) 8 8.49 (dd, J=4.3, 1.5 Hz, 1H), 8.05 J=6 Hz, 1IH), 7.91 (dd, J=8.2, Hz, 1 7.43 (dd, J=8.2, 4.3 Hz, 1IH), 7.29 (dd, J=5, 1 Hz, 1IH), 6.89 (dd, J=5, 3 Hz, 1 H), 6.82 (dd, J=3, 1 Hz, I 6.77 (br s, 2H), 4.79 J=6 Hz, 2H), 3.56 2H), 3.09 J=6 Hz, 2H), 2.90 J=7 Hz, 2H), 1.75 (in, 4H), 1.45 (in, 4H), 0.95 J=7 Hz, 3H) -a NO,(d 6 -DMSO at 290) 8 8.77 J=6 Hz, 1 H), 179 8.46 (dd, J=4.4, 1.5 Hz, 1IH), 8.28 (dd, Hz, 2H), 8.00 (dd, J=8.5 2.5 Hz, 2H), 7.89 (dd, J=8.3, 1.5 Hz, 1IH), 7.39 (dd, J=8.3, 4.4 Hz, 1IH), 6.75 2H), 4.82 J=6 Hz, 2H), 3.32 (in, 2H), 2.92 J=7 Hz, 2H), 1.90 (in, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.63 (in, 2H), 1.42 (sextet, J=7 Hz, 2H), 0.91 J=7 Hz, 3H)

H

3 C (d 6 -DMSO at 290C) 8 8.48 (dd, J=4.3, 1.5 Hz, 180 1 8.14 J=6 Hz, 1IH), 7.91 (dd, J=8.4,

\/CH

3 Hz, 1IH), 7.42 (dd, J=8.4, 4.3 Hz, 1IH), 6.78

H

3 C 2H), 6.75 (br s, 2H), 4.82 J=6 Hz, 2H), 3.22 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 2.50 3H), 2.03 6H), 1.90 (mn, 2H), 1.85 (quintet, J=7 Hz, 2H), 1.58 (mn, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.96 J=7 Hz, 3H) 122 WO 99/29693 PCT/US98/26473 F (d 6 -DMSO at 29 0 C) 8 9.48 J=6 Hz, 1 H), 181 F F 8.52 J=4.3 Hz, 1H), 7.94 J=8 Hz, 1H), F F 7.45 (dd, J=8.0, 4.3 Hz, 1 7.09 (br s, 2H), F F F F 4.80 J=6 Hz, 2H), 3.25 J=6 Hz, 2H), F F F 2.92 J=7 Hz, 2H), 1.81 4H), 1.58 (m, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.95 J=7 Hz, 3H) 0 (d 6 -DMSO at 29 0 C) 8 8.50 (dd, J=4.3, 1.5 Hz, 182 1 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.75 J6 Hz, 1H), 7.42 (dd, J=8.0, 4.3 Hz, 1H), 6.77

CH

3 (br s, 2H), 4.78 J=6 Hz, 2H), 3.56 3H), 3.06 J=6 Hz, 2H), 2.90 J=7 Hz, 2H), 2.25 2H), 2.00 2H), 1.81 4H), 1.44 8H), 0.96 J=7 Hz, 3H) cl (d 6 -DMSO at 29 0 C) 8 8.55 J=6 Hz, 1 H), 183 -N 8.50 (dd, J=4.3, 1.5 Hz, 1H), 8.43 (dd, J=5, 2 Hz, 1KH), 7.91 (dci, 1.5 Hz, 1KH), 7.74 J=8.0, 2 Hz, 1 7.43 (dd, J=8, 4.3 Hz, 1 7.42 (dd, J=8, 5 Hz, 1 6.75 (br s, 2H), 4.83 J=6 Hz, 2H), 3.27 J=6 Hz, 2H), 2.94 J=7 Hz, 2H), 1.92 2H), 1.83 (quintet, J=7 Hz, 2H), 1.60 2H), 1.46 (sextet, J=7 Hz, 2H), 0.95 J=7 Hz, 3H) -84N (d 6 -DMSO at 291C) 5 8.77 (dd, J=2.5, 0.5 Hz, 184 CI 1H), 8.70 J=6 Hz, 1H), 8.46 (dd, J=4.3, Hz, 1H), 8.16 (dd, J=8, 3 Hz, 1H), 7.91 (dd, J=8.4, 1.5 Hz, 1H), 7.62 (dd, J=8, 0.5 Hz, 1 7.43 (dd, J=8.4, 1.5 Hz, 1 6.76 (br s, 2H), 4.81 J=6 Hz, 2H), 3.31 2H), 2.92 J=7 Hz, 2H), 1.89 2H), 1.79 (quintet, J=7 Hz, 2H), 1.61 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.91 J=7 Hz, 3H) F F (d 6 -DMSO at 29°C) 8 8.55 J=6 Hz, 1H), 185 F 8.45 (dd, J=4.3, 1.5 Hz, 1H), 7.90 J=8 Hz, 2H), 7.89 (dd, J=8, 1.5 Hz, 1H), 7.43 J=8 Hz, 2H), 7.39 (dd, J=8, 4.3 Hz, 1H), 6.74 (br s, 2H), 4.81 J=6 Hz, 2H), 3.30 2H), 2.91 J=7 Hz, 2H), 1.88 2H), 1.78 (quintet, J=7 Hz, 2H), 1.63 2H), 1.34 (sextet, J=7 Hz, 2H), 0.89 J=7 Hz, 3H) ct (d 6 -DMSO at 29 0 C) 5 8.64 J=6 Hz, 1H), 186 8.49 (dd, J=4.4, 1.5 Hz, 1H), 7.90 (dd, 1.5 Hz, 1 7.69 2H), 7.42 (dd, J=8.5, 4.3 cl Hz, 1H), 6.74 2H), 4.84 J=6 Hz, 2H), 123 WO 99/29693 WO 9929693PCT/US98/26473 3.26 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 1.90 (in, 2H), 1.83 (quintet, J=7 Hz, 2H), 1.60 (in, 2H), 1.46 (sextet, J=7 Hz, 2H), 0.96 (t, J=7 Hz, 3H)

O-CH,

(d 6 -DMSO at 2900) 5 8.49 (dd, J=4.3, 1.5 Hz, 1IH), 7.92 J=6 Hz, 1IH), 7.90 (dd, J=8.5, Hz, 1IH), 7.42 (dd, J=8.5, 4.3 Hz, 1 7.07 J=8 Hz, 2H), 6.76 J=8 Hz, 2H), 6.74 (br s, 2H), 4.79 J=6 Hz, 2H), 3.70 3H), 3.25 2H), 3.08 J=6 Hz, 2H), 2.89 (t, J=7 Hz, 2H), 1.80 (in, 4H), 1.46 (in, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.95 J=7 Hz, 3H) (d 6 -DMSO at 2900) 8 8.47 (dd, J=4.3, 1.5 Hz, 188 1IH), 8.15 J=6 Hz, 1IH), 7.90 (dd, J=8.4, Hz, 1 7.64 (dd, J=8, 2 Hz, 1 7.41 (dt, J=8, 2 Hz, 1 7.40 (dd, J=8.4, 4.3 Hz, 1 H),

CH

3 7.06 J=8 Hz, 1IH), 6.98 (dt, J=8, 2 Hz, 1IH), 6.74 2H), 4.82 J=6 Hz, 2H), 3.70 3H), 3.33 (in, 2H), 2.92 J=7 Hz, 2H), 1.90 (in, 2H), 1.80 (quintet, J=7 Hz, 2H), 1.60 (in, 2H), 1.43 (sextet, J=7 Hz, 2H), 0.92 (t, J=7 Hz, 3H) cl (d6-DMSO at 290C)58 8.56 J=6 Hz, 1 H), 189 8.46 (dd, J=4.4, 1.5 Hz, 1IH), 7.89 (dd, J=8.4, Hz, I 7.82 J=2 Hz, 1IH), 7.74 (td, J=8, 2 Hz, I 7.58 (td, J=8, 2 Hz, 1IH), 7.47 J=8 Hz, 1 7.39 (dd, J=8.4, 4.4 Hz, 1 H), 6.74 2H), 4.81 J=6 Hz, 2H), 3.31 (q, J=6 Hz, 2H), 2.91 J=7 Hz, 2H), 1.88 (in, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.61 (mn, 2H), 1.36 (sextet, J=7 Hz, 2H), 0.90 J=7 Hz, 3H) 190 0 (d6-DMSO at 29 0 C) 5 8.46 (dd, J=4.3, 1.5 Hz, 190 IH), 8.27 J=6 Hz, 1IH), 7.89 (dd, J=8.5, Hz, 1IH), 7.75 J=8 Hz, 2H), 7.40 (dd, 4.3 Hz, 1 6.94 (K J=8 Hz, 2H), 6.73 2H), 4.81 J=6 Hz, 2H), 4.00 J=7 H3C; Hz, 2H), 3.28 J=6 Hz, 2H), 2.91 J=7 HC Hz, 2H), 1.87 (mn, 2H), 1.78 (quintet, J=7 Hz, 2H). 1.71 (quintet, J=7 Hz, 2H), 1.60 (mn, 2H), 1.38 (sextet, J=7 Hz, 4H), 1.32 (mn, 2H), 1.28 (in, 4H), 0.91 J=7 Hz, 3H), 0.87 J=7 Hz, 3H) 124- WO 99/29693 PCT/US98/26473 Examples 191 212 Compounds of Formula I The compounds of Examples 191-212 shown in the table below were prepared according to the following method. 4-(4-Amino-2-butyl- 1H-imidazo[4,5-c][1,5]naphthyridin-1yl)ethaneamine (50 itmol) was dissolved in 5 mL of dichloromethane in a screw-capped test tube and a carboxylic acid (50 pmol) of formula RACOOH was added at ambient temperature. Within 3 minutes a light suspension typically formed. The coupling agent, 1-(3-dimethylaminopropyl)-3ethyl carbodiimide hydrochloride (-10.5 mg, 55 pmol) was added and the mixture was vortexed at 400 rpm for 1-2 h at ambient temperature, giving a clear solution in most cases. The mixture was applied to a short column (3 x 1 cm of silica gel conditioned with dichloromethane. The product was eluted with 10:1 dichloromethane:methanol, collecting -2 mL fractions. Thin layer chromatography of the fractions was performed, and fractions with the product spot were pooled and stripped to dryness in a Savant SpeedVac. Purity was checked by reversed phase-HPLC (HPLC conditions refer to using a Hewlett Packard HP 1090 system fitted with a C18 Rainin Microsorb MV column, 4.6 x 50 mm, particle size 3 microns, pore size 100 Angstroms.

Gradient elution: linear gradient from 100% water trifluoroacetic acid to 100% acetonitrile 0.1% trifluoroacetic acid over 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm). APCI-mass spectral data confirmed presence of the expected molecular ion, and proton nmr data supported the expected structure.

-125- WO 99/29693 WO 9929693PCT[US98/26473 NiE

RA

Example RA Fragment 'H NMR (500 MHz, solvent indicated) (00013) 58.47 (dd, J=4.4, 1.5 Hz, 1 8.10 191 (dd, J=8.5, 1.5 Hz, 1H), 7.45 (dd, J=8.5, 4.4 S Hz, 1IH), 7.15 (dd, J=5.0, 3.0 Hz, 1IH), 6.75 J=3 Hz, 1 6.64 (dd, J=5.0, 1.2 Hz, I 6.61 (br t, 1 6.3 (br s, 2H), 4.94 (t, ,J=6 Hz, 2H), 3.30 2H), 2.81 J=6 Hz, 2H), 2.89 J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, Hz, 3H) ~Br (CDC1 3 8 8.41 (dd, J=4.4, 1.5 Hz, 1IH), 8.04 192 (dd, J=8.5, 1.5 Hz, I 7.40 (dd, J=8.5, 4.4 Hz, 1IH), 7.34 (dd, J=8, 1.2 Hz, I 7.07 (dt, J=8, 2 Hz, 1IH), 7.00 (dt, J=8, 2 Hz, I H), 6.96 (dt, J=8,2 Hz, I 6.78 (br t, 1 5.72 (br s, 2H), 4.95 J=6 Hz, 2H), 3.85 J=6 Hz, 2H), 3.42 2H), 2.89 J=7 Hz, 2H), 1.83 (quintet, J=7 H, 2H), 1.50 (sextet, J=7 2H), 1.00 J=7 Hz, 3H) C1 (CDC 3 8 8.40 (dd, J=4.4, 1.5 Hz, 1IH), 8.07 193 (dd, J=8.5, 1.5 Hz, 1H), 7.43 (dd, J=8.5, Hz, I 7.14 J=2 Hz, 1IH), 7.06 (br t, C1 1 6.98 (dd, J=8, 2 Hz, 1IH), 6.85 J=8 H,1H), 5.75 (br s, 2H), 4.96 J=6 Hz, 2H), 3.86 J=6 Hz, 2H), 3.31 2H), 2.89 J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 J=7 Hz, 3H) 126- WO 99/29693 WO 9929693PCT1US98/26473 (COCl 3 68.59 (dd, J=4.5, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 1.8 Hz, 1 7.47 (dd, J=8.5, CI Hz, I1H), 7.19 (bt, 1 5.79 (bs, 2H), 4.96 (t, J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 3.36 (t, J.=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.91 (q, J=7 Hz, 2H), 1.87 J=7 Hz, 2H), 1.50 (in, 6H), 1.01 J=7Hz, 3H) (00013) 8.51 (dd, J 4.5, 1.8 Hz, 8.07 (in, 3H1), 7.42 (dd, J=4.5, 1IH), 7.31 (br I1H), 7.14 J=8 Hz, 5.8 2H), 4.95 J=6 Hz, 2H), 4.257 J=7 Hz, 2H), 3.80 NO 2 J=6 Hz, 2H), 2.94 J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H1), 1.83 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.34 (quintet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) (00013)5 8.60 (dd, J-4.5,,1.5 Hz, 1IH), 8.11 (dd, J 1.5 Hz, 141), 7.49 (dd, J N0 2 Hz, 1 7.24 (br s, 1 6.0 (br s, 2H), 4.95 J=6 Hz, 2H), 4.26 J=7 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.93 J=7Hz, 2H), 1.91 (quintet, J=7 Hz, 2H), 1.83 (in, 4H), 1.50 (sextet, J=7 Hz, 2H), 1.35 (quintet, J=7 Hz, 2H), 1.05 (in, 2H), 1.01 J=7 Hz, 3H) (CDC1 3 5 8.60 (dd, J=4.5, 1.5, 1H), 8.11 (dd, J=8.5, 1.5, 1IH), 7.49 (did, J=8.5, 4.5 Hz, 1H), 7.01 J=8 Hz, 2H) 6.76 J=8 Hz,

S-CH

3 2H), 6.59 (br s, 1 5.69 (br s, 2H), 4.93 (t, J=6 Hz, 2H), 3.80 J=6 Hz, 2H), 3.20 (s, 2H), 2.89 J=7 Hz, 2H), 2.44 3H), 1.90 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.0.1 Qt, J=7 Hz, 3H) H (COCl 3 8 8.58 (dd, J=4.4, 1.5 Hz, 1IH), 8.09 (dd, J=8.3, 1.5 Hz, I 7.48 (dd, J=8.3, 4.4 Hz, 1 7.30 (br t, 1 5.69 (br s, 2H), 5.01 0 (mn, 3H), 3.85 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.91 (quintet, J=7 Hz, 2H), 1.85 (in, I 1.79 (mn, I 1.60 (in, 211), 1.52 (sextet, J=7 Hz, 2H), 1.38 J=9 Hz, I H), 1.27 J=6 Hz, I 1.00 J=7 Hz, 3H) F F (CDCI 3 6 8.59 (did, J=4.5, 1.5 Hz, 1IH), 8.11 (dd, J=8.5, 1.5 Hz, 1H), 7.48 (dd, J=8.5, 4.4 F Hz, 1IH), 7.48 (br s, 1 6.11 (br s, 2H), 4.94 J=6 Hz, 2H), 3.83 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 2.28 (mn, 2H), 2.08 (t.

J=7 Hz, 2H), 1.90 (quintet, J=7 Hz. 2H), 1.52 (sextet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) 127 WO 99/29693 WO 9929693PCT[US98/26473 (CDC1 3 68.54 (dd, J-4.4, 1.5 Hz, IH), 8.10 200 (dd, J=8.4, 1.5 Hz, 1 7.46 (dd, 4.4 Hz, 1 7.19 (br t, 1 7.12 J=8 Hz, 2H), 6.88 J=8 Hz, 2H), 5.94 (br s, 2H), 4.91 J=6 Hz, 2H), 3.78 J=6 Hz, 2H), 2.90 J=7 Hz, 2H), 2.65 J=7 Hz, 2H), 2.12 J=7 Hz, 2H), 1.86 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.02 J=7 Hz, 3H) 3

(ODC

3 858.60 (dd, J=4.4, 1.5 Hz, 1 8.12 201 (dd, J=8, 1.5 Hz, 1IH), 7.47 (dd, J=8.0, 4.4 Hz, 1 6.86 (br s, I 6.20 (br s, 2H), 4.96 J=6 Hz, 2H), 3.81 J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 1.90 (in, 4H), 1.51 (sextet, J=7 Hz, 1.33 (quintet, J=7 Hz, 2H), 1.23 (in, 16H), 1.01 J=7 Hz, 3H), 0.87 J=7 Hz, 3H)- 0 H 3 (CD013) 5 8.58 (dd, J=4.3, 1.5 Hz, I 8.04 202 ll x 3(dd, J=8.0, 1.5 Hz, I 7.56 (br s, 1IH), 7.43 H (dd, J=8.0, 4.3 Hz, 1 5.84 (br s, 2H), 4.94 J=6 Hz, 2H), 4.89 (br s, 1 3.85 J=6 Hz, 2H), 3.54 J=6 Hz, 2H1), 2.92 J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.41 9H), 1.00 (t, J=7 Hz, 3H) J 'V3

(C~DC

3 8 8.60 J-4.4 Hz, 1 8.07 (dd, 203 3C'N H J=8.0, 1.5 Hz, I 7.59 (br s, I 7.45 (dd, H J=8.5, 4.4 Hz, I 5.88 (br s, 2H), 4.94 (in, 2H1), 4.77 1IH), 3.93 (in, 1 3.84 (in.

2H), 2.94 J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.40 (s, 9H1), 1.01 J=7 Hz, 0.99 J=7 Hz, 3H) S Br (d 6 -DMSO at 801C) 8 8.53 (dd, J=4.4, 204 LiHz, 1 8.53 J=6 Hz, 1 7.96 (dd, J=8.3, 1.5 Hz, 1H), 7.45 (dd, J=8.3, 4.4 Hz, 1H), 7.32 J-4 Hz, 1IH), 7.16 J=4 Hz, 1 6.81 (br s, 2H), 4.91 J=6 Hz, 3.78 J=6 Hz, 2H1), 2.85 J=7 Hz, 2H), 1.77 (quintet, J=7 Hz, 2H), 1.37 (sextet, J=7 Hz, 2H), 0.87 J=7 Hz, 311) N ~(C~dC 3 8 9.16 J=1.4 Hz, 1IH). 8.66 (dd, 205 H3 J=4.4. 1.5 Hz, I 8.44 J=6 Hz, I H), N 8.11 J=1.4 Hz, 1H), 8.09 (dd, J=8.4, IH) ,7.47 (dd, J=8.5, 4.4 Hz, IH) ,6.10 128 WO 99/29693 WO 9929693PCT1UJS98/26473 (br s, 2H), 5.11 J=6 Hz, 2H), 4.05,(q, J=6 Hz, 2H), 2.92 J=7 Hz, 2H), 2.59 3H), 1.87 (quintet, J=7 Hz, 2H), 1.46 (sextet, J=7 2H), 0.95 J=7 Hz, 3H) 0 Br (CDC 3 8.73 (dd, J4.4, 1.5 Hz, 1 8.12 206 (dd, J=8.4, 1.5 Hz, 1 7.95 (br s, 1 7.52 (dd, J=8.4, 4.4 Hz, 1 6.91 J=3.4 Hz, I 6.31 J=3.4 Hz, 1 6.04 (br s, 2H), 5.07 J=6 Hz, 2H), 3.99 J=6 Hz, 2H), 2.93 J=7 Hz, 2H), 1.91 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 0.99 J=7 Hz, 3H)

(CDCI

3 8 8.50 (dd, J=4.4, 1.5 Hz, I 8.42 207 ,3t\N J=4 Hz, I 8.19 J=1.5 Hz, 1IH), 8.09 (dd, J=8.2, 1.5 Hz, 1IH), 7.47 (dd, J=8.3, 4.4 Hz, I 7.26 (br s, 1 7.23 J=8 Hz, I 7.07 (dd, J=8.5, 5 Hz, I 6.06 (br s, 2H), 3.95 J=6 Hz, 2H), 3.84 J=6 Hz, 2H), 3.21 2H), 2.87 J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 1.00 J=7 Hz, 3H)

(CDCI

3 8 8.54 (dd, J=4.4, 1.5 Hz, 1 8.37 208 J=4Hz, I1H), 8.24 (br s, I 8.09 (dd, Ilk J=8.5, 1.5 Hz, 1 7.46 (dd, J=8.5, 4.4 Hz, N 1 1H), 7.35 (br t, 1IH), 7.27 (td, J=8, 2 Hz, I H), 7.08 (dd, J=8, 5 Hz, 1 5.98 (br s, 2H), 4.91 J=6 Hz, 2H), 3.79 J=6 Hz, 2H), 2.90 J=7 Hz, 2H), 2.69 J=7 Hz, 2H), 2.14 J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.01 J=7 Hz, 3H) 209 -000 (d 6 -DMSO) 8 8.52 J=8.3 Hz, 1 8.37 N CH(in, 2H), 7.96 J=8.3 Hz, 1IH), 7.48 (dd.

J=8.3, 4.5 Hz, I 7.14 (br s, 2H), 4.72 (t, NOI J=6 Hz, 2H), 4.1 J=6 Hz, 2H), 3.56 (q, 2H), 2.33 3H), 1.75 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.94 J=7 Hz, -129- WO 99129693 WO 9929693PCT/US98/26473 3H) 0 (C~DC 3 858.52 (dd, J=4.4, 1.5 Hz, 1 8.05 210 CfN(dd, J=8.4, 1.5 Hz, I 7.76 J=6 Hz, 1IH), 7.43 (dd, J=8.5, 4.4 Hz, I1H), 7.27 J=8 Hz, 2H), 7.06 J=8 Hz, 2H), 5.82 (br s, 2H), 5.06 4.83 (in, 2H), 3.88 3.79 (in, 2H), 3.03 (in, 1H), 2.89 J=7 Hz, 2H), 2.79 ci (in, 1IH), 2.5 (in, 3H), 2.25 (in, 1 1.90 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.00 J=7 Hz, 3H) 211 (d 6 -DMSO) 858.53 (dd, J=4.4, 1.5 Hz, 1IH), 21N 8.24 J =6 Hz, I 7.96 (dd, J 1.5 Hz, 0 1 IH), 7.84 (in, 4H), 7.48 (dd, J=4.4, 8.4 Hz, 1H), 7.18 (br s, 2H), 4.75 J=6 Hz, 2H), 3.73 J=7 Hz, 2H), 3.52 J=6 Hz, 2H), 2.86 J=7 Hz, 2H), 2.34 J=7 Hz, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 2H), 0.92 J=7 Hz, 3H)

(CDCI

3 858.60 (dd, J=4.4, 1.5 Hz, 1IH), 8.04 212 (dd, J=8.5, 1.5 Hz, 1H), 7.68 (dd, J=3.5, 1.2 s Hz, I1H), 7.61 (dd, J=3.5, 1.2 Hz, 1IH), 7.43 (dd, J=8.5, 4.4 Hz, 1IH), 7.39 J=6 Hz, 1IH), 7.10 (dd, J=5, 3.5 Hz, 1 5.79 (br s, 2H), 4.93 J=6 Hz, 2H), 3.82 J=6 Hz, 2H), 3.12 J=7 Hz, 2H), 2.92 J=7 Hz, 2H), 2.32 J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.49 (sextet, J=7 Hz, 2H), 0.99 J=7 Hz, 3H) -130- WO 99129693 WO 9929693PCT/IJS98/26473 Example 213 Compound of formula 11 N-12-(4-Amino -2-butyl-1 H-imidazol4,5-cI 11,5] naphthyridin-1 -yl)ethylj- 5-oxo-2-pyrrolinecarboxamide NH 2

N

N 0 H

N

Using the general method of Example 97 L-pyroglutamic acid (0.23 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl- 1H-imidazo[4,5-c] [1 ,5]naphthyridin- 1yl)ethaneamnine (0.5 g, 1.7 mmole) to provide 0. 10 g of N-[2-(4-amino-2-butyl- IH- [1 ,5]naphthyridin-1I-yl)ethyl]-5-oxo-2-pyrrolinecarboxaniide as a white powder, m.p. 13 5-138 0 C. Analysis: Calculated for C 20

H

25

N

7 0 2 1 2

CH

3 CN: 60.63; 6.42; 25.25; Found: 60.14; 6.41; 25.20. HR.MS (EL) calcd for

C

2 oH 2 5N 7

O

2 396.2103 found 396.2112 TEST METHODS CYTOKINE INDUCTION IN HUMAN CELLS An in vitro human blood cell system was used to assess cytokine induction by compounds of the invention. Activity is based on the measurement of interferon and tumor necrosis factor (oc) (LFN and TNF, respectively) secreted into culture media as described by Testerman et. In "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture Whole blood is collected by venipuncture into EDTA vacutainer tubes from healthy human donors. Peripheral blood mononuclear cells (PBMCs) are separated from.

whole blood by Histopaque®- 1077 (Sigma Chemicals, St. Louis, MO) density gradient centrifugation. The PBMCs are suspended at 1.5-2 x 106 cells/mL in RPMI 1640 mediumcontaining 10 fetal bovine serum, 2 miM L-glutamine and 1% penicillin/streptomycin 131 WO 99/29693 PCT/US98/26473 solution (RPMI complete). 1 mL portions of PBMC suspension are added to 24 well flat bottom sterile tissue culture plates.

Compound Preparation 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 in a concentration range of from 0.1 to 100

.M.

Incubation The solution of test compound is added to the wells containing 1 mL of PBMCs in media. The plates are covered with plastic lids, mixed gently and then incubated for 18 to 24 hours at 37 0 C with a 5% carbon dioxide atmosphere.

Separation Following incubation the plates are centrifuged for 5-10 minutes at 1000 rpm (-200 x g) at 4°C. The cell culture supernatant is removed with a sterile polypropylene pipet and transferred to a 2 mL sterile cryotube. Samples are maintained at -70 0 C until analysis.

Interferon Analysis/Calculation Interferon is determined by bioassay using A549 human lung carcinoma cells challenged with encephalomyocarditis. The details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in "Automated Bioassay of Interferons.

in Micro-test Plates", Biotechniques, June/July, 78, 1983, incorporated herein by reference. Briefly stated the method is as follows: A549 cells are incubated with samples and standard interferon dilutions at 37 0 C for 24 hours. The incubated cells are then infected with an inoculum of encephalomyocarditis virus. The infected cells are incubated for an additional 24 hours at 37 0 C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining followed by visual scoring of the plates. Results are expressed as alpha reference units/mL based on the value obtained for NIH Human Leukocyte IFN standard.

Tumor NecrosisFactor Analysis Tumor necrosis factor (oc) (TNF)concentration is determined using an ELISA kit available from Genzyme, Cambridge, MA. The results are expressed as pg/mL.

-132- WO 99/29693 PCT/US98/26473 In the table below, a indicates that the compound induced the indicated cytokine at that particular concentration, a indicates that the compound did not induce the indicated cytokine at that particular concentration, and a indicates that the results were equivocal at that particular concentration.

133- Induction in Human Cells

TNF

Example Concentration Dose Concentration (jiM) 1 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 9 12 Not run Not run 13 Not run Not run 22 Not run Notninun 23 Not run -Not run Not run Notnirun 26 Not run Not run 27 Not run Not run 28 Not run Not run 32 Not run Not run 33 Not run Not run 36 Not run Not run 39 Notruin Not run +4 Not run Not run 46 46 Not run Not run 47 48 49 Not run -Not run 51 Not run Not run 52 Not run I Not run Induction in Human Cells IFN

TNF

Example Dose Concentration (jiM) Concentration 0.1 1.0 10.0 100.0 .0.1 1.0 10.0 100.0 53 54 Not run Not run Not run Not run 56 57 58 62 +4 91 91 923 +4 94 96 97 +4 98 99 100 101 1.02 -1 i i I j I I

J

0 ICytokine Induction in Human Cells IFN TNF Example Dose Conce tain (jfy Dose Concentration 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 103 104 105 106 107 I 108 109 110 III11 112 113 114 115 116 j 117 1 I Cytokine Induction in Human Cells IFN

TNF

Example Concentration (jiM) Concentration (jiM) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 118 Not run Not run 119 Not run Not run- 120 Not run Not run 121 Not run Not run 122 Not run Not run 123 Notruin Not run 124 Not run Not run 125 Not run Not run 126 Not run Not run 127 Not run Not run 128 Not run Not run 129 Not run Not run 130 Not run T+ Not run 131 Not run Not run 132 Not run Not run 133 Not run +Not run 134 Notu Not run

+-A

135 136 137 138 139 140 141 Not run Not run Not run Not run Not run I Nt rn I

L

J Not run- II N t runf I -a- 00 i-3 Not run .1.

Not run Not run Not run -i 1"JA$ nin i -1r o run___ _i Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (VM) Concentration (jiM) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 142 Not run Not run 143 Not run Not run-± 144 145 146 147 148 149 150 151 152 +I 153 155 156 157 158 159 160 161 162 163 164 165 166 167 Cytokine Induction in Human Cells0 LFN

TNF

Example Dose Concentration Concentration 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183- 183 184 185 +4 186 187 188 189 190 191 Not run Not run Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (tiM) Dose Concentration (jiM) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 208 209 210 211 212 WO 99/29693 PCT/US98/26473 INTERFERON INDUCTION IN HUMAN CELLS An in vitro human blood cell system was used to assess interferon induction by compounds of the invention. Activity is based on the measurement of interferon secreted into culture media. Interferon is measured by bioassay.

Blood Cell Preparation for Culture Whole blood was collected by venipuncture into EDTA vacutainer tubes.

Peripheral blood mononuclear cells (PBM's) were separated from whole blood by using either LeucoPREP T Brand Cell Separation Tubes (available from Becton Dickinson) or Ficoll-Paque® solution (available from Pharmacia LKB Biotechnology Inc, Piscataway, NJ). The PBM's were suspended at 1 x 10 /mL in RPMI 1640 media (available from GIBCO, Grand Island, NY) containing 25 mM HEPES (N-2-hydroxyethylpiperazine-N'-2ethanesulfonic acid) and L-glutamine penicillin-streptomycin solution added) with heat inactivated (56 0 C for 30 minutes) autologous serum added. 200 L portions of PBM suspension were added to 96 well (flat bottom) MicroTest III sterile tissue culture plates.

Compound Preparation The compounds were solubilized in ethanol, dimethyl sulfoxide or tissue culture water then diluted with tissue culture water, 0.01N sodium hydroxide or 0.01N hydrochloric acid (The choice of solvent will depend on the chemical characteristics of the compound being tested.). Ethanol or DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. Compounds were initially tested in a concentration range of from about 0.1 pg/mL to about 5 gg/mL. Compounds which show induction at a concentration of 0.5 pig/mL were then tested in a wider concentration range.

Incubation The solution of test compound was added in a volume (less than or equal to 50 uL) to the wells containing 200 1L of diluted whole blood or of PBM's in media. Solvent and/or media was added to control wells (wells with no test compound) and as needed to adjust the final volume of each well to 250 gL. The plates were covered with plastic lids, -141- WO 99/29693 PCT/US98/26473 vortexed gently, and then incubated for 48 hours at 37 0 C with a 5% carbon dioxide atmosphere.

Separation Following incubation, the plates were covered with parafilm and then centrifuged at 1000 rpm for 10 to 15 minutes at 4 0 C in a Damon IEC Model CRU-5000 centrifuge.

Media (about 200 gL) was removed from 4 to 8 wells and pooled into 2 mL sterile freezing vials. Samples were maintained at -70 0 C until analysis.

Interferon Analysis/Calculation Interferon was determined by bioassay using A549 human lung carcinoma cells challenged with encephalomyocarditis. The details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in "Automated Bioassay of Interferons in Micro-test Plates", Biotechniques, June/July, 78, 1983, incorporated herein by reference. Briefly stated the method is as follows: interferon dilutions and A549 cells are incubated at 37 0 C for 12 to 24 hours. The incubated cells are infected with an inoculum of encephalomyocarditis virus. The infected cells are incubated for an additional period at 37 0 C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining followed by spectrophotometric absorbance measurements. Results are expressed as alpha reference units/mL based on the value obtained for NIH HU IF-L standard. The interferon was identified as essentially all interferon alpha by testing in checkerboard neutralization assays against rabbit anti-human interferon (beta) and goat anti-human interferon (alpha) using A549 cell monolayers challenged with encephalomyocarditis virus.

In the table below, a indicates that the compound induced interferon a at that particular concentration, a indicates that the compound did not induce interferon a at that particular concentration, and a indicates that the results were equivocal at that particular concentration.

P

-142-

I

0 Interferon Induction in Human Cells Example Dose Concentration tg/mL) 0.01 0.05 0.10 0.50 1.0 5.0 10.0 25.0 50.0 12 13 22 not run not run not run not run not run 23 not run not run not run not run not run not run 26 not run 27 not run 28 not run 32 33 36 39 0 '0 '0 0' '0 c-J

C,)

'0 0' -a c-h WO 99/29693 PCTIUS98/26473 The present invention has been described with reference to several embodiments thereof. The foregoing detailed description and examples have been provided for clarity of understanding only, and no unnecessary limitations are to be understood therefrom. It will be apparent to those skilled in the art that many changes can be made to the described embodiments without departing from the spirit and scope of the invention. Thus, the scope of the invention should not be limited to the exact details of the compositions and structures described herein, but rather by the language of the claims that follow.

-144-

Claims

1. A compound of formula (IA): NH 2 N N N (R)n IN R (lA) wherein R, is selected from the group consisting of: -C1..20 alkyl-NR 3 -Q-X-R 4 and -C 220 alkenyl-NR 3 -Q-X-R 4 wherein Q is X is NR 3 and R 4 is aryl, or -01-20 alkyl or C 220 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -0-Cl120 alkyl; -O-(C1 2 oalkyI)o 1 -aryl; alkoxycarbonyl; alkyl; -S(O)o-2-(C1-2o alkyl)o- 1 -aryl; -(32 -NR 3 -CO-O-Cl- 20 alkyl; -N 3 oxo; -halogen; -NO 2 -OH; and R 2 is selected from the group consisting of: -hydrogen; -Cl-1oalkyl; -C2-10 alkenyl; -aryl; W.%dska'akI~species0flVS1ONAL OF 19123.90.dc 146 -C1-1 0 alkyl -O-Cl-io-alkyl; -C1-o alkyl-O-C2-o alkenyl; and -C1-10 alkyl or C2-10 alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R3)2; -CO-N(R 3 2 -CO-Ci.io alkyl; -N 3 -aryl; and -CO-aryl; each R 3 is independently selected from the group consisting of hydrogen and C1- 10 alkyl; each R is independently selected from the group consisting of hydrogen, Ci-1o alkyl, C1. 1 o alkoxy, halogen and trifluoromethyl; and n is 3; or a pharmaceutically acceptable salt thereof

2. A compound or salt of claim 1 wherein each R is hydrogen.

3. A compound or salt of claim 1 wherein R 1 is -C1-6 alkyl-NR 3 -Q-X-R 4 and R 4 is aryl, -C 1 20 alkyl, or -C1-20 alkyl-aryl.

4. A compound or salt of claim 3 wherein R 1 is -n-butyl-NR 3 -Q-X-R 4 R 3 is hydrogen, and R 4 is phenyl, cyclohexyl, n-butyl, or benzyl.

A compound or salt of claim 1 wherein R 2 is -Ci-1o alkyl.

6. A compound or salt of claim 3 wherein R 2 is -Ci-io alkyl.

7. A compound or salt of claim 6 wherein R 2 is butyl.

8. A compound or salt of claim 4 wherein R 2 is -Ci-10 alkyl. W:\ciskanki\species\DIVISIONAL OF 19123-99.doc I II 147

9. A compound or salt of claim 2 wherein R 1 is -C1-6 alkyl-NR 3 -Q-X-R 4 and R 4 is aryl, C1-20 alkyl, or -C1-20 alkyl-aryl.

A compound or salt of claim 9 wherein R 2 is -C1-10 alkyl.

11. A compound or salt of claim 10 wherein R 1 is -n-butyl-NR 3 -Q-X-R 4 and R 4 is phenyl, cyclohexyl, n-butyl, or benzyl.

12. A compound selected from the group consisting of N-[4-(4-amino-2-butyl-1H- imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-phenylurea, N-[4-(4-amino-2-butyl-1H- imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-cyclohexylurea, N-[4-(4-amino-2-butyl-1H- imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-butylurea, and N-[4-(4-amino-2-butyl-1H- imidazo[4,5-c][1,5]naphthyridin-1 -yl)butyl]-N'-benzylurea; and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 3 and a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 12 and a pharmaceutically acceptable carrier.

16. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

17. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 3 to the animal.

18. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 12 to the animal.

19. A method of treating a viral infection in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

W cVskaUnkipeaes\DIVISIONAL OF 19123-99.doc 148 A method of treating a viral infection in an animal comprising administering an effective amount of a compound or salt of claim 3 to the animal.

21. A method of treating a viral infection in an animal comprising administering an effective amount of a compound or salt of claim 12 to the animal.

22. A method of treating neoplastic diseases in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

23. A method of treating neoplastic diseases in an animal comprising administering an effective amount of a compound or salt of claim 3 to the animal.

24. A method of treating neoplastic diseases in an animal comprising administering an effective amount of a compound or salt of claim 12 to the animal. DATED: 2 September, 2002 PHILLIPS ORMONDE FITZPATRICK Attorneys for: MINNESOTA MINING AND MANUFACTURING COMPANY At/ep W:\ciskankt\speciesDIVISIONAL OF 19123-99.doc