1h-imidazo[4,5-c]naphthyridin-4-amines

136556/4 1 H-Imidazo [4,5-c] naphthy ridin-4-amines

Minnesota Mining and Manufacturing Company

The Inventors:

John F. Gerster Kyle J. Lindstrom Stephen L. Crooks Philip D. Heppner Gregory J. Marazalek Peter V. Maye Bryon A. Merrill John W. Mickelson Michael J. Rice C.125626 WO 99/29693 PCT/US98/26473 136556/2

Field of the Invention

This invention relates to imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds, processes for making these compounds and 10 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. 15

Background of the Invention

The first reliable report on the l//-iniidazo[4,5-c]quinoline ring system, Backman etal., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6- 20 methoxy-8-quinoIinyl)-2-methyl-17/-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 177-imidazo[4,5-c] quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound l-[2-(4-pipcridyI)ethyI]-l//-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 25 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J.

Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-cjquinolines.

Certain l//-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 30 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; 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 35 of cytokine biosynthesis or other mechanisms. - 1 - WO 99/29693 PCT/US98/26473

Summary of the Invention

We have found a new class of compounds that are useful in inducing cytokine 5 biosynthesis in animals. Accordingly, this invention provides imidazonaphthyridine compounds of Formula I:

<img img-format="tif" img-content="drawing" file="IL136556AD00021.tif" id="idf0001" />

10 wherein A, Ri and R2 are as defined hereinafter.

The invention also provides tetrahydroimidazonaphthyridine compounds of

Formula Π:

<img img-format="tif" img-content="drawing" file="IL136556AD00022.tif" id="idf0002" />

15 wherein B, Rj and R2 are as defined hereinafter.

The compounds of Formula I and Formula II are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune reponse when administered to animals. This ability makes the compounds useful 20 in the treatment of a variety of conditions, e.g. viral diseases and tumors that are responsive to such changes in the immune response. -2- WO 99/29693 136556/2 PCT/US98/26473

The invention further provides pharmaceutical compositions containing a compound of Formula I or Formula II and methods of inducing cytokine biosynthesis in an animal and/or treating a viral infection in an animal by administering a compound of Formula I or Fonnuia II to the animal. 5 In addition, methods of synthesizing compounds of Fonnuia I and Formula Π, 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 Formula I or Formula II in an amount effective to induce said interferon biosynthesis, and a method of 10 treating a viral infection m an animal comprising the step of administering to said animal a compound of Formula I or Formula Π in an amount effective to inhibit the viral infection.

Detailed Description of the Invention 15 As mentioned earlier, the invention provides compounds of Formula I:

<img img-format="tif" img-content="drawing" file="IL136556AD00023.tif" id="idf0003" />

I wherein A is =N-CR=CR-CR=; =CR-N=CR-CR=; =CR-CR=N-CR=; or 20 =CR-CR=CR-N=;

Ri is selected from the group consisting of: - hydrogen; -Ci-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: 25 -aryl; -heteroaryl; -heterocyclyl; -3- WO 99/29693 PCT/US98/26473 -O-Ci-20 alkyl, -0-(C].2oalkyl)o-i-aryl; -0-(Ci-2oalkyl)o-i-heteroaryl; -0-(Ci-2oalkyl)o-i-heterocyclyl; 5 -Ci-20 alkoxycarbonyl; -S(0)o-2-Ci-2o alkyl; -S(O)0-2-{Ci-20 alkyl)o-i-aryl; -S(0)o-2-&lt;Ci-2o alkyl)o-i -heteroaryi; -S(0)o-2 —{Ci-2o alkyl)o-i -heterocyclyl; 10 -N(R3)2; -N3; oxo; -halogen; -NO2; 15 -OH; and -SH; and -Cj-2o alkyl-NR3-Q-X-R4 or -C2-20 alkenyl-NR3-Q-X-R4 wherein Q is -CO- or-SO2-; X is a bond, -O- or -NR3- and R4 is aryl; heteroaryi; heterocyclyl; or -C1.20 alkyl or 20 C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryi; -heterocyclyl; 25 -O-C1-20 alkyl, -0-(Ci-2oalkyl)o.i-aryl; -0-(Ci-2oalkyl)o-i-heteroaryl; -0-(Ci-2oalkyl)o-i-heterocyclyl; -C1.20 alkoxycarbonyl; 30 -S(O)0-2-C,-20 alkyl; -S(0)o-2-(Ci-2o alkyl)o-i-aryl; -S(0)o-2-(Ci-2o alkyl)o.i-heteroaryi; -4- WO 99/29693 PCT/US98/26473 -S(0)o-2 - (Ci-20 alkyl)0-i -heterocyclyl; -N(R3)2; -NR3-C0-0-Ci.2oalkyl; -N3; oxo; -halogen; -NO2; -OH; and -SH; or R4 is 10

<img img-format="tif" img-content="drawing" file="IL136556AD00024.tif" id="idf0004" />

15 20 25 wherein Y is -N- or -CR-; R2 is selected from the group consisting of: -hydrogen; -Ci-to alkyl; -C2-10 alkenyl; -aryl; -Cmo alkyl-O-Cj-io-alkyl; -Cmo alkyl-0-C2-io alkenyl; and -Cmo alkyl or C2-10 alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R3)2; -CO-N(R3)2; -CO-Ci-10 alkyl; -N3; -aryl; -heteroaryl; -5- WO 99/29693 PCT/US98/26473 -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R3 is independently selected from the group consisting of hydrogen and Cuo 5 alkyl; and each R is independently selected from the group consisting of hydrogen,

Ci-io alkyl, Cuo alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.

10 This invention also provides compounds of Formula II

<img img-format="tif" img-content="drawing" file="IL136556AD00025.tif" id="idf0005" />

wherein 15 B is -NR-C(R&gt;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-;

Ri is selected from the group consisting of: - hydrogen; -Cuo alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more 20 substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; -O-C1-20 alkyl; 25 -0-(Ci-2oalkyl)0-i-aryI; -0-(Ci-2oalkyl)o-i-heteroaryl; -6- -0-(Cb2oaIkyl)0-i-heterocyclyl; -Ci.2o alkoxycaibonyl; -S(0)o-2 -Ci-20 alkyl; -S(0)o-2-(Ci-2o alkyl)o-i-aryl; 5 -S(O)0.2-(Ci-20 alkyl)o-i -heteroaryl; -S(0)o-2 -(C1.20 alkyl)o-i-heterocyclyl; -N(R3)2; -N3; oxo; 10 -halogen; -NO2; -OH; and -SH; and WO 99/29693 PCT/US98/26473 15 20 25 30 -Ci-2o alkyl-NR3-Q-X-R« or -C2-20 alkenyl-NR3-Q-X-R4 wherein Q is -CO- or-SO2-; X is a bond, -O- or -NR3- and R4 is aryl; heteroaryl; heterocyclyl; or -C1-20 alkyl or C2.20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; -O-C1.20 alkyl, -0-(Ci-20alkyl)o-i-aryl; -0-(Ci-2oalkyl)o-rheteroaryl; -0-(Ci-2oalkyl)o-i-heterocyclyl; -Ci-2o alkoxycaibonyl; -S(0)o-2-C,-20 alkyl; -S(0)o-2-(Ci-20 alkyl)0-i-aryl; -S(0)o-2-{Ci.2o alkyl)o-i-heteroaryl; -S(0)o-2 -(C1-20 alkyl)o-i-heterocyclyl; -N(R3)2; -NR3-CO-0-Ci-2oalkyl; -7- WO 99/29693 PCT/US98/26473 -N3; oxo; -halogen; -NO2; -OH; and -SH; or R4 is

<img img-format="tif" img-content="drawing" file="IL136556AD00026.tif" id="idf0006" />

10 15 20 25 wherein Y is -N- or -CR-; R2 is selected from the group consisting of: -hydrogen; -Ci-10 alkyl; -C2-10 alkenyl; -aryl -Ci-io alkyl -O-Ci.io-alkyl; -Cmo alkyl-0-C2.io alkenyl; and -C1-10 alkyl or C2.io alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R3)2; -CO-N(R3)2; -CO-Cmo alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; -8- WO 99/29693 136556/2 PCT/US98/26473 each R3 is independently selected from the group consisting of hydrogen and Cmo alkyl; and each R is independently selected from the group consisting of hydrogen,

Ci-10 alkyl, Cuo alkoxy, halogen and trifluoromethyl, 5 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 10 from 3 to 10 ring carbon'atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyi, 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 br ring systems that contain at least one ring 15 hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazoiyl, imidazo, and so on. “Heterocyclyl” includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N)· Exemplary heterocyclic groups include pyrrolidinyl, . tetrahydrofuranyl, morpholinyl, thiazolidinyl, and imidazolidinyl. 20 The aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of C1-20 alkyl, hydroxy, halogen, N(R3)2, NO2, Ci.2O alkoxy, Ci-2o alkylthio, trihalomethyl, Ci-2oacyl, arylcarbonyl, heteroarylcarbonyl, (Ci-ioalkyl)o-i-aryl, (Ci-ioalkyl)o-i-heteroaryl, cyano, Ci_2o alkoxycarbonyl, oxo, arylalkyl wherein the alkyl group has from 1 to 10 carbon atoms, and 25 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 PCT/US98/26473

Preparation of the Compounds

Compounds of Formulas I and II wherein A is =N-CR=CR-CR= or B is -NR-C(R)2-C(R)2-C(R)2- and R, Ri and R2 are as defined above can be prepared according 5 to Reaction Scheme I: -10- WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD00027.tif" id="idf0007" />

-11 - WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD00028.tif" id="idf0008" />

Many 2-aminonicotinic acids of Formula ΠΙ are known (see, for example, U.S. 5 3,917,624). The compound where R is hydrogen is commercially available. In step (1) of

Reaction Scheme I a 2-aminonicotinic acid of Formula III is reacted with acetic anhydride by heating to provide a 2-methyl-4//-pyrido[2,3-i/][l,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 10 herein by reference.

In step (2) 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 (3) of Reaction Scheme I an acid of Formula V is esterified to provide a 15 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 (4) of Reaction Scheme I a compound of Formula VI is cyclized to provide a tetrazolo[l,5-fl][l,8]naphthyridin-5-ol of Formula VII. The reaction may be carried out 20 by reacting the compound of Formula VI with an alkoxide in a suitable solvent, e.g., potassium ethoxide in Ν,Ν-dimethylformamide, at ambient conditions.

In step (5) 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[l,5-a][l,8]naphthyridin-5-ol of Formula VIII. 25 In step (6) 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, e.g., 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 5 connection with step (7).

In step (7) of Reaction Scheme I a compound of Formula IX is reacted with an amine of formula R1NH2 where Ri is as defined above to provide a 4-nitrotetrazolo[l,5-a][l,8]naphthyridin-5-amine of Formula X. The reaction can be carried out by adding the amine to the reaction mixture resulting from step (6). The reaction can also be carried out 10 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 (8) of Reaction Scheme I a compound of Formula X is reduced to provide a tetrazolo[l,5-a][l,8]naphthyridin-4,5-diamine ofFormula XI. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on 15 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 (9) of Reaction Scheme I a compound ofFormula XI is reacted with a carboxylic acid or an equivalent thereof to provide a 77/-tetrazolo[ 1,5-a]imidazo[4,5-c][l,8]naphthyridine ofFormula XII. Suitable equivalents to carboxylic acid include acid 20 halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound ofFormula XII. For example, diethoxymethylacetate will provide a compound where R2 is hydrogen and valeryl chloride will provide a compound where R2 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 25 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 ofFormula ΧΠ is reacted with triphenylphosphine to provide a N-triphenylphosphinyl-77/-imidazo[4,5-c][l,8]naphthyridin-4- amine ofFormula ΧΙΠ. The reaction can be carried out by 30 combining a compound ofFormula 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 XHI is hydrolyzed to provide a 7//-imidazo[4,5-c][l,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 5 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-77/-imidazo[4,5-c][l,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 10 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-777-imidazo[4,5-c][l,8]naphthyridin-4- amine of Formula XV can be prepared by 15 reduction of a compound of Formula XII. The reduction is carried out by suspending or dissolving a compound of Formula ΧΠ 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. 20 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, Ri and R2 are as defined above can be prepared according to Reaction Scheme Π.

Reaction Scheme Π 25

<img img-format="tif" img-content="drawing" file="IL136556AD00029.tif" id="idf0009" />

-14- WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD000210.tif" id="idf0010" />

<img img-format="tif" img-content="drawing" file="IL136556AD000211.tif" id="idf0011" />

<img img-format="tif" img-content="drawing" file="IL136556AD000212.tif" id="idf0012" />

<img img-format="tif" img-content="drawing" file="IL136556AD000213.tif" id="idf0013" />

<img img-format="tif" img-content="drawing" file="IL136556AD000214.tif" id="idf0014" />

<img img-format="tif" img-content="drawing" file="IL136556AD000215.tif" id="idf0015" />

J«

<img img-format="tif" img-content="drawing" file="IL136556AD000216.tif" id="idf0016" />

<img img-format="tif" img-content="drawing" file="IL136556AD000217.tif" id="idf0017" />

<img img-format="tif" img-content="drawing" file="IL136556AD000218.tif" id="idf0018" />

<img img-format="tif" img-content="drawing" file="IL136556AD000219.tif" id="idf0019" />

<img img-format="tif" img-content="drawing" file="IL136556AD000220.tif" id="idf0020" />

In step (1) of Reaction Scheme Π a 3-aminoisonicotinic acid of Formula XVI is reacted with acetic anhydride by heating to provide a 2-methyl-4/f-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 (2) 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 5 acid of Formula XVIII. The reaction conveniently may be run at ambient conditions.

In step (3) of Reaction Scheme II an acid of Formula XVIH 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 10 such as dichloromethane.

In step (4) of Reaction Scheme II a compound of Formula XIX is cyclized to provide a tetrazolo[ 1,5-α][ 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, e.g., potassium ethoxide in Ν,Ν-dimethylformamide, at ambient conditions. 15 In step (5) of Reaction Scheme Π 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[l,5-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 20 in neat phosphorus oxychloride with heating at about 90°C.

In step (6) of Reaction Scheme II a compound of Formula XXI is reacted with an amine of formula R1NH2 where Rj is as defined above to provide a tetrazolo[l,5- a][l ,7]naphthyridin-5-amine of Formula XXII. The reaction can be carried out by heating with an excess of the amine. 25 In step (7) of Reaction Scheme Π a compound of Formula XXII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[l,5-fl][l,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 (8) of Reaction Scheme II a compound of Formula XXIII is reduced to 30 provide a tetrazolo[l,5-fl][l,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 (9) of Reaction Scheme II a compound of Formula XXIV is reacted with a carboxylic acid or an equivalent thereof to provide a 777-tetrazolo[l,5-a]imidazo[4,5-c][l,7]naphthyridine of Formula XXV. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or 5 equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XXV. For example, diethoxymethylacetate will provide a compound where R2 is hydrogen and valeryl chloride will provide a compound where R2 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 10 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 N-triphenylphosphinyl-77i-imidazo[4,5-c][l,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 15 such as 1,2-dichlorobenzene and heating.

In step (11) of Reaction Scheme II a compound of Formula XXVI is hydrolyzed to provide a 777-imidazo[4,5-c][l,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 aikanol in the presence of an acid. The product or a 20 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-777-imidazo[4,5-c][l,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 25 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 6,7,8,9-tetrahydro-777-imidazo[4,5-c][l,7]naphthyridin-4-amine of Formula XXVIII can be 30 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 PCT/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 II wherein A is =CR-CR=CR-N= or B is -C(R)2-C(R)2-C(R)2-NR- and R, Ri and R2 are as defined above can be prepared according 5 to Reaction Scheme ΠΙ.

Reaction Scheme ΠΙ

<img img-format="tif" img-content="drawing" file="IL136556AD000221.tif" id="idf0021" />

<img img-format="tif" img-content="drawing" file="IL136556AD000222.tif" id="idf0022" />

<img img-format="tif" img-content="drawing" file="IL136556AD000223.tif" id="idf0023" />

<img img-format="tif" img-content="drawing" file="IL136556AD000224.tif" id="idf0024" />

N A.

<img img-format="tif" img-content="drawing" file="IL136556AD000225.tif" id="idf0025" />

<img img-format="tif" img-content="drawing" file="IL136556AD000226.tif" id="idf0026" />

<img img-format="tif" img-content="drawing" file="IL136556AD000227.tif" id="idf0027" />

<img img-format="tif" img-content="drawing" file="IL136556AD000228.tif" id="idf0028" />

In step (1) of Reaction Scheme III a 3-nitro[l,5]naphthyridin-4-ol of Formula XXIX is chlorinated using a suitable chlorinating agent such as phosphorus oxychloride to 15 provide a 4-chloro-3-nitro[l,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 Ν,Ν-dimethylformamide with mild heating (~55° C). The compound may be isolated by conventional methods or it can be carried on without isolation as described below in connection with step (2). The compound of Formula 5 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 (2) of Reaction Scheme ΠΙ a 4-chloro-3-nitro[l,5]naphthyridine of Formula XXX is reacted with an amine of Formula R1NH2 where Ri is as defined above to provide a 3-nitro[l,5]naphthyridin-4-amine of Formula XXXI. The reaction can be carried out by 10 adding water then excess amine to the reaction mixture resulting from step (1) 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 Rj is hydrogen is known and its preparation has been disclosed in Wozniak et al, J. R. Neth. Chem. Soc. 102 (12), 15 pp. 511-13 (1983).

In step (3) of Reaction Scheme ΠΙ a 3-nitro[l,5]naphthyridin-4-amine of Formula XXXI is reduced to provide a [l,5]naphthyridine-3,4-diamine of Formula ΧΧΧΠ. 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 20 be carried out on a Parr apparatus in a suitable solvent such as ethyl acetate.

In step (4) of Reaction Scheme ΙΠ a compound of Formula XXXII is reacted with a carboxylic acid or an equivalent thereof to provide a IH- imidazo[4,5-c][l,5)naphthyridine of Formula ΧΧΧΙΠ. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is 25 selected such that it will provide the desired R2 substituent in a compound of Formula ΧΧΧΠΙ. For example, diethoxymethylacetate will provide a compound where R2 is hydrogen and trimethylorthovalerate will provide a compound where R2 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 30 drive off any alcohol or water formed as a byproduct of the reaction.

Alternatively, step (4) may be carried out by (i) reacting a compound of Formula XXXII with an acylating agent; and then (ii) cyclizing the product. Part (i) involves -19- WO 99/29693 PCT/US98/26473 reacting a compound of Formula XXXII with an acyl halide of formula R2C(O)X wherein R2 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 (e.g. dropwise) to a solution of a compound of Formula XXXH in a suitable solvent such as dichloromethane at a reduced temperature 5 (e.g., 0°C). The resulting amide intermediate can be isolated by removal of the solvent.

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

In step (5) of Reaction Scheme III a compound of Formula ΧΧΧΠΙ is oxidized to provide a IH- imidazo[4,5-c][l,5]naphthyridine-5N-oxide of Formula XXXTV using a 10 conventional oxidizing agent that is capable of forming N-oxides. Preferred reaction conditions involve reacting a solution of a compound of Formula ΧΧΧΙΠ in chloroform with 3-chloroperoxybenzoic acid at ambient conditions.

In step (6) of Reaction Scheme ΙΠ a compound of Formula XXXTV is aminated to provide a IH- imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XXXV which is a

15 subgenus of Formula I. Step (6) involves (i) reacting a compound of formula XXXIV with an acylating agent; and then (ii) reacting the product with an aminating agent. Part (i) of step (6) involves reacting an N-oxide with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benzenesulfonyl chloride, methanesulfonyl choride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred, p- 20 Toluenesulfonyl chloride is most preferred. Part (ii) of step (6) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of 25 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 5°C during the addition of the acylating agent. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

Alternatively step (6) may be carried out by (i) reacting a compound of Formula 30 XXXTV with an isocyanate; and then (ii) hydrolyzing the product. Part (i) 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 -20- 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 5 (i). 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 (7) of Reaction Scheme HI a compound of Formula XXXV is reduced to provide a 6,7,8,9-tetrahydro-7//- imidazo[4,5-c][l,5jnaphthyridin-4-amine of Formula 10 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. 15 Certain functional groups recited in connection with Ri and R2 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-te/7-butyl dicarbonate. 20 Some compounds of Formula I or Formula II containing certain functional groups may be readily prepared from other compounds of Formula I or Formula Π. 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 Π wherein the Ri substituent contains a primary amine. Likewise, compounds wherein the Rj 25 substituent contains a urea group may be prepared by reacting an isocyanate with a compound of Formula I or Formula Π wherein the Ri substituent contains a primary amine. Further, compounds wherein the R] substituent contains a carbamate group may be prepared by reacting a chloroformate with a compound of Formula I or Formula II wherein the Ri substituent contains a primary amine. 30 Certain of the intermediate compounds useful in the preparation of compounds of

Formula I and Formula Π 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

<img img-format="tif" img-content="drawing" file="IL136556AD000229.tif" id="idf0029" />

wherein Ri, R2 and A are as defined above for compounds of Formula I and Formula II. 10

Intermediate Compound 2

<img img-format="tif" img-content="drawing" file="IL136556AD000230.tif" id="idf0030" />

wherein R, Ri, and R2 are as defined above for compounds of Formula I and Formula Π. -22- WO 99/29693 PCT/US98/26473

Intermediate Compound 3

<img img-format="tif" img-content="drawing" file="IL136556AD000231.tif" id="idf0031" />

wherein R, Ri and R2 are as defined above for compounds of Formula I and

Formula Π.

Intermediate Compound 4 10

<img img-format="tif" img-content="drawing" file="IL136556AD000232.tif" id="idf0032" />

wherein R7 is OH, halogen or NHRi (and A and Ri are as defined above for compounds of Formula I) and Re is Η, NO2 or NH2. -23- WO 99/29693 PCT/US98/26473

Intermediate Compound 5

<img img-format="tif" img-content="drawing" file="IL136556AD000233.tif" id="idf0033" />

wherein A is as defined above for compounds of Formula I and R$ is H or C|.1O alkyl.

Intermediate Compound 6

<img img-format="tif" img-content="drawing" file="IL136556AD000234.tif" id="idf0034" />

Ri wherein R and Ri are as defined above for compounds of Formula I and Formula Π with the proviso that Ri is other than hydrogen, and Rio is NO2 or NH2. 15

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 20 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 lOOng/kg to about 50mg/kg, preferably about 10pg/kg to about 5mg/kg of the compound to the subject. Any of the conventional dosage forms may be 5 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 10 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 compounds according to the invention generally include interferon (IFN) and tumor necrosis factor (TNF) as well as certain interleukins (IL). In particular, the compounds induce IFN-α, TNF-a, IL-1,6,10 15 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 20 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. 25 For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Thl) cytokine IFN-γ 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 Thl response and/or downregulation 30 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, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; as -25- 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 5 such as IFN-α and TNF-α, 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 Π, molluscum contagiosm, HIV, CMV, VZV, cervical intraepithelial 10 neoplasia, human papillomavirus and associated neoplasias; fungal diseases, e.g. Candida, aspergillus, cryptococcal meningitis; neoplastic diseases, e.g., 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 15 camii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis; bacterial infections, e.g., 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 20 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 Π 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, 25 macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, ENF-a, TNF-α, 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 lOOng/kg to about 50mg/kg, preferably about 10pg/kg to about 5mg/kg. The invention further provides a method of 30 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 lOOng/kg to about 50mg/kg, preferably about 10pg/kg to about 5mg/kg. 5 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 10 2-(5-Methyl-/Z/-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 5 15 gof 2-methyl-4//-pyrido[2,3-J][l,3]oxazin-4-one.

PartB:

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 2-(5- 20 methyl-///-tetrazol-l-yl)nicotinic acid as a white solid, m.p. 178-180°C (gas evolution).

Analysis: Calculated for C8H7N5O2: %C, 46.83; %H, 3.44; %N, 34.13; Found: %C, 46.38; %H, 3.36; %N, 34.01. -27- WO 99/29693 136556/2 PCT/US98/26473

Example 2

Compound of Fonnula VI Ethyl 2-(5-Methyl-77T-tetrazol-l-yl)nicotinate 2-(5-Methyl-777-tetrazol-l-yl)nicotinic acid (5.6 g, 27 mmole) was suspended in 5 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 dichioromethane. The dichioromethane layer was separated, dried, then concentrated under vacuum to provide 6.3 g of ethyl 2-(5-methyl-lH-tetrazol-l-yl)nicotinate. 10

Example 3

Compound of Formula VII Tetrazolo[l,5-a] [l,8]naphthyridin-5-oI

Ethyl 2-(5-methyl-77T-tetrazol-l-yl)nicotinate (6.3 g, 27 mmole) was covered with 15 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 of tetrazolo[l,5-a][l ,8]naphthyridm-5-ol as an off white solid, m.p. 236° (decomposition). Analysis: 20 Calculated for CgH5N5O: %C, 51.34; %H, 2.69; %N, 37.42; Found: %C, 51.23 ; %H, 2.77; %N, 37.25.

Example 4 5-Chlor otetrazolo ] 1,5-a] [1,8] naphthyridine 25 Tetrazolo[l,5-a][l,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) was suspended in phosphorus oxychloride (10 mL) and heated at reflux for 4 hours. The reaction mixture was concentrated under vacuum and the residue was poured into water. Dichioromethane was added and the aqueous layer was made basic with sodium bicarbonate. The dichioromethane layer was separated, dried over magnesium sulfate, filtered and then 30 concentrated under vacuum. The resulting solid was recrystallized from toluene to

provide 0.3 g of 5-chlorotetrazolo[l,5-a][l,8]naphthyridine as a solid, m.p. 229-230°C -28- WO 99/29693 PCT/US98/26473 (decomposition). Analysis: Calculated for CgHLClNs: %C, 46.73; %H, 1.96; %N, 34.06; Found: %C, 46.87; %H 1.54; %N, 33.93.

Example 5

5 Compound of Formula VIII 4-N itrotetrazolo [ 1,5-α] [1,8] naphthryidin-5-ol

Nitric acid (1.33 mL of 16M) was added to a suspension of tetrazolo[l,5-fl][l,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 10 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 of 4-nitrotetrazolo[l,5-a][l,8]naphthryidin-5-ol as a solid, m.p. 278°C (decomposition). Analysis: Calculated for C8H4N6O3 + 1.1 H2O: %C, 38.12; %H, 2.48; %N, 33.35; Found: %C, 37.99; %H, 2.41; %N, 32.82. 15

Example 6

Compound of Formula X

Ns-(2-Methylpropyl)-4-nitrotetrazolo[l,5-flni,8]naphthyridiii-5-amine 4-Nitrotetrazolo[l,5-a][l,8]naphthryidin-5-ol (3 g, 13 mmole) was suspended in 20 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 25 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 N5-(2-methylpropyl)-4-nitrotetrazolo[l,5-a][l,8]naphthyridine-5-amine as a yellow solid, m.p. 171°C (decomposition). Analysis: Calculated for C12H13N7O2: %C, 50.17; %H 4.56; %N, 34.13; Found: %C, 49.84; %H, 4.51; %N, 33.88. 30 -29- 136556/2

Example 7

Compound of Formula XI

Ns-(2-Methylpr opyl)tetrazolo [ 1,5-a] [i ,8] naphthyridin-4,5-diamine A catalytic amount of 5% platinum on carbon was added to a suspension of N3-(2- 5 methylpropyl)-4-nitrotetrazolo[l,5-a][l,8]naphthyridine-5-ainine (2.45 g, 8.5 mmoles) in ethanol (120 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide N5-(2-methyIpropyl)tetrazolo[l,5-a][l,8]naphthyridin-4,5-diamine as an oil. 10

Example 8

Compound of Formula ΧΠ l-(2-Methylpropyl)-77i-tetrazoIo [1,5-a] imidazo[4,5-c] [1,8] naphthyridine The N3-(2-methylpropyl)tetrazoIo[l,5-a][l,8]naphthyridin-4,5-diamine from 15 Example 7 was combined with diethoxymethyl acetate (2 mL) and heated on a steam bath for 3 hours. The reaction mixture was allowed to stand at ambient temperature overnight and then it was* diluted with dichloromethane 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 -(2- 20 methylpropyI)-7//'-tetrazolo[l,5-a]imidazo[4,5-c][l,8]naphthyridine as a solid, m.p. 248-250°C (decomposition). Analysis: Calculated for C13H13N7: %C, 58.42; %H, 4.90; %N, 36.68; Found: %C, 58.04; %H, 4.79; %N, 36.23. -30-

Example 9

Compound ofFormula I l-(2-Methylpropyl)-J^-imidazo[4,5-c]fl,8]naphthyridin-4-amine hydrate WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD000235.tif" id="idf0035" />

Part A:

Triphenylphosphine (1.0 g, 3.7 mmole) was added to a solution of 1-(2-methylpropyl)-7/7-tetrazolo[l,5-a]imidazo[4,5-c][l,8]naphthyridine (0.5 g, 1.87 mmole) 10 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 l-(2-methylpropyl)-N-triphenylphosphinyl-/J/-imidazo[4,5-c][l,8]naphthyridin-4- amine was isolated by filtration and dried. 15 PartB:

The 1 -(2-methylpropyl)-N-triphenylphosphinyl-///-imidazo[4,5-c][l,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 20 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 25 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 l-(2-methylpropyl)-//7-imidazo[4,5- -31 - WO 99/29693 PCT/US98/26473 c][l,8]naphthyridin-4-amine hydrate as a solid, m.p. 325-330°C (decomposition). Analysis: Calculated for C13H15N5 + % H2O: %C, 63.52; %H, 6.35; %N, 28.49; Found: %C, 64.02; %H, 5.87; %N, 28.23. 5 Example 10 .

Compound of Formula II 6,7,8,9-Tetrahydro-l-(2-methylpropyI)-777-imidazo[4,5-c] [l,8]naphthyridin-4- amine

<img img-format="tif" img-content="drawing" file="IL136556AD000236.tif" id="idf0036" />

Platinum oxide catalyst was added to a solution of 1-(2-methylpropyl )-7/7-tetrazolo[l,5-fl]imidazo[4,5-c][l,8]naphthyridine in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen 15 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 IN hydrochloric acid and charcoal filtered. The filtrate was treated with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from 20 ethyl acetate/methanol. The recrystallized material was dissolved in dichloromethane/methanol and placed on a silica gel column. The column was eluted with 10% 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-l-(2-methylpropyl)-7/7-imidazo[4&gt;5-c][l,8]naphthyridin-4-amine as a solid, m.p. 231- 25 233°C. Analysis: Calculated for Ci3H19N5: %C, 63.65; %H, 7.81; %N, 28.55; Found: %C, 62.99; %H, 7.74; %N, 28.33. -32- WO 99/29693 PCT/US98/26473

Example 11

Compound of Formula XII 2-Butyl-l-(2-methylpropyI)-7Z/-tetrazolo[l,5-a]imidazo[4,5-c][l,8]naphthyridine 5 A catalytic amount of 5% platinum on carbon was added to a suspension of N5-(2- methylpropyl)-4-nitrotetrazolo[l,5-a][l,8)naphthyridine-5-amine (5g, 17.4 mmoles) in ethanol (300 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide N5-(2-methylpropyl)tetrazolo[l,5- 10 a][l,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 dichioromethane, washed with sodium bicarbonate, dried over magnesium sulfate then 15 concentrated under vacuum. The residue was purified using flash chromatography (silica gel; eluting with 2-3% methanol in dichioromethane). The isolated product was purified further using preparatory high performance liquid chromatography eluting with 2% methanol in dichioromethane to provide 2-butyl-l-(2-methylpropyl)-///-tetrazolo[l,5-a]imidazo[4,5-c][l,8]naphthyridine as a solid, m.p. 182-184°C. Analysis: Calculated for 20 C17H21N7: %C, 63.14; %H, 6.55; %N, 30.32; Found: %C, 63.45; %H, 6.60; %N, 30.40. -33-

Example 12

Compound of Formula I 2-ButyH-(2-methylpropyl)-//f-imidazo[4,5-c]Il,81naphthyridin-4-amine WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD000237.tif" id="idf0037" />

Triphenylphosphine (0.9 g, 3.7 mmole) was added to a solution of2-butyl-l-(2-methylpropyl)-777-tetrazolo[l,5-fl]imidazo[4,5-c][l,8]naphthyridine (0.6 g, 1.8 mmole) in 10 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 dichloromethane and filtered through a layer of silica gel. The silica gel was eluted initially with dichloromethane to remove the 1,2-dichlorobenzene and then with 10% methanol in dichloromethane to recover 2-butyl-l-(2- 15 methylpropyl)-N-triphenylphosphinyl-/77-imidazo[4,5-c][ 1,8]naphthyridin-4- amine.

The 2-butyl-l-(2-methylpropyl)-N-triphenylphosphinyl-777-imidazo[4,5- c][l,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 20 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-l-(2-methylpropyl)-777-imidazo[4,5-c][l,8]naphthyridin-4-amine hemihydrate, m.p. 237-240°C. Analysis: 25 Calculated for C17H23N5 + % H2O: %C, 68.66; %H, 7.79; %N, 23.55; Found: %C, 66.80; %H, 7.62; %N, 23.46. -34- WO 99/29693 PCT/US98/26473

Example 13

Compound of Formula Π 2-Butyl-6,7,8,9-tetrahydro-l-(2-methylpropyl)-777-imidazo[4,5-c][l,8]naphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000238.tif" id="idf0038" />

A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyI)-/77-imidazo[4,5-c][l,8]naphthyridin-4-amine (2.0 g, 6.2 mmole) in 10 trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus under 50 psi (3.5 Kg/cm2) 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 15 (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)-777-imidazo[4,5-c][l,8]naphthyridin-4-amine hemihydrate as a solid, m.p. 81-84°C.

Calculated for C17H27N5 + /2¾O: %C, 65.77; %H, 9.09; %N, 22.56; Found: %C, 65.57; %H, 9.15; %N, 22.53. 20

Example 14

Compound of Formula XVIII 3-(5-Methyl-777-tetrazol-l-yl)pyridine-4-carboxylic acid 3-Aminopyridine-4-carboxylic acid (50.0 g, 0.36 mol) was suspended in acetic 25 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 50°C. The -35- WO 99/29693 136556/2 PCT/US98/26473 reaction mixture was stirred 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 5 resulting precipitate was isolated by filtration, washed with water and dried to provide 64.5 g of 3-(5-methyl-777-tetrazol-l-yl)pyridine-4-carboxylic acid as an off white solid, m.p. 214-215°C (decomposition).

Example 15

10 Compound of Formula XIX

Ethyl 3-(5-Methyl-/77-tetrazol-l-yI)pyridine-4-carboxyIate

Dimethylformamide diethyl acetal (46 mL) was added to a suspension of 3-(5-methyl-77/-tetrazol-l-yl)pyridine-4-carboxylic acid (36 g) in dichioromethane (800 mL). The reaction mixture was stirred at ambient temperature overnight then washed six times 15 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 3-(5-methyl-777-tetrazol-l-yl)pyridine-4-carboxylate as a solid.

Example 16

20 Compound of Formula XX

Tetrazolo[l,5-a]{l,7]naphthyridin-5-oI hydrate

Potassium ethoxide (20.2 g) was added to a mixture of ethyl 3-(5-methyl-7/7-tetrazol-l-yl)pyridine-4-carboxylate (28 g) and dimethylformamide (280 mL). The reaction mixture was stirred at ambient temperature overnight then poured into 25 cold dilute acetic acid. The resulting precipitate was collected, washed with water and dried to provide 22.4 g of tetrazolo[l,5-a][l,7]naphthyridin-5-ol hydrate as a solid, m.p. 247-248°C (decomposition). Analysis: Calculated for CgHsNsO: %C, 46.83; %H, 3.44; %N, 34.13; Found: %C, 46.48; %H, 3.42; %N, 34.03. -36- WO 99/29693 136556/2 PCT/US98/26473

Example 17

Compound of Formula XXI 5-Chlorotetrazolo [1 ,5-λ][1 ,7] naphthy ridine 5 A suspension of tetrazolo[l,5-a][l,7]naphthyridin-5-ol (3.5 g) in phosphorus oxychloride (15 mL) was heated at 90°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 10 magnesium sulfate then concentrated under vacuum to provide 3.8 g of 5- chlorotetrazolo[l,5-a][l,7]naphthyridine as a solid, m.p. 176-177°C. Analysis: Calculated for CgHLClNs: %C, 46.73; %H, 1.96; %N, 34.06; Found: %C, 46.80; %H, 2.16; %N, 34.45. 15 Example 18

Compound of Formula XXII N5-(2-Methylpropyl)tetrazoIo[l,5-a][l,7]naphthyridin-5-amine A suspension of 5-chlorotetrazolo[l,5-a][l,7]naphthyridine (20 g) in isobutylamine (100 mL) was heated at reflux for several hours. The reaction mixture was concentrated 20 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, 5-20% ethyl acetate in dichloromethane, and 10% methanol in dichloromethane. The 25 fractions with the slower moving material were concentrated to provide N5-(2- methylpropyl)tetrazolo[l,5-a][l,7]naphthyridin-5-amine as a solid,.m.p. 220-221°C. Analysis: Calculated for C12H14N6: %C, 59.49; %H, 5.82; %N, 34.69; Found: %C, 59.35; %H, 5.89; %N, 34.88. -37- WO 99/29693 PCT/US98/26473

Example 19

Compound of Formula XXIII

Ns-(2-MethylpropyI)-4-nitrotetrazolo[l,5-fllIl,7]naphthyridin-5-amine

Nitric acid (2 equivalents of 16M) was added to a solution of N5-(2- 5 methylpropyl)tetrazolo[l,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 10 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 15 of hexanes/ethyl acetate. The fractions containing the slower moving material were combined to provide about 0.3 g of Ns-(2-methylpropyl)-4-nitrotetrazolo[l,5-n][l,7]naphthyridin-5-amine as a yellow solid, m.p. 173-174°C. Analysis: Calculated for C12H13N7O2: %C, 50.17; %H, 4.56; %N, 34.13; Found: %C, 49.85; %H, 4.53; %N, 34.26. 20 Example 20

Compound of Formula XXIV N5-(2-MethyIpropyl)tetrazoloIl,5-a][l,7]naphthyridin-4,5-diamine N5-(2-Methylpropyl)-4-nitrotetrazolo[l,5-a][l,7]naphthyridin-5-amme (1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess of sodium hydrogen sulfide was 25 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 Ns-(2-methylpropyl)tetrazolo[l,5-a][l,7]naphthyridin-4,5-diamine as a light yellow solid, 30 m.p. 203-204.5°C. Analysis: Calculated for: C12H15N7: %C, 56.02; %H, 5.88; %N, 38.11; Found: %C, 55.68; %H, 5.81; %N, 37.74. -38- WO 99/29693 PCT/US98/26473

Example 21

Compound of Formula XXV l-(2-Methylpropyl)-7/7-tetrazolo[l,5-fl]imidazo[4,5-c][l,7]naphthyridme N5-(2-M ethylpropyl)tetrazolo [1,5-a] [l,7]naphthyri din-4,5-diamine (1.1 g, 4.3 5 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 l-(2-methylpropyl)-777-tetrazolo[l,5- 10 a]imidazo[4,5-c][l,7]naphthyridine as a solid, m.p. 181-182.5°C. Analysis: Calculated for C13H13N7: %C, 58.42; %H, 4.90; %N, 36.68; Found: %C, 58.87; %H, 5.04; %N, 36.13.

Example 22

Compound of Formula I 15 l-(2-Methylpropyl)-777-imidazol4,5-c] [l,7]naphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000239.tif" id="idf0039" />

Part A: 20 Triphenylphosphine (0.49 g, 1.8 mmol) was added to a suspension of 1-(2- methylpropyl)-7/7-tetrazolo[l,5-a]imidazo[4,5-c][l,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 1 -(2-methylpropyl)-N-triphenylphosphinyl-J7/-imidazo[4,5-c] [ 1,7]naphthyridin-4-amine 25 was isolated by filtration.

PartB: -39- WO 99/29693 PCT/US98/26473

The 1 -(2-methylpropyl)-N-triphenylphosphinyl-7H-imidazo[4,5-c][l,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 5 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 l-(2-methylpropyl)-777- imidazo[4,5-c][l,7]naphthyridin-4-amineas a solid, m.p. 306-307°C. Analysis: 10 Calculated for C,3Hi5N5: %C, 64.71; %H, 6.27; %N, 29.02; Found: %C, 65.10; %H, 6.28; « %N, 28.70.

Example 23

Compound of Formula Π 15 6,7,8,9-Tetrahydro-l-(2-methylpropyl)- 7/7-imidazo[4,5-c][l,7]naphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000240.tif" id="idf0040" />

20 A catalytic amount of platinum oxide was added to a solution of 1 -(2- methylpropyI)-777-imidazo[4,5-c][l,7]naphthyridm-4-amine (0.4 g, 1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The 25 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 -40- WO 99/29693 PCT/US98Z26473 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-l (2-methylpropyl)-7//-imidazo[4,5-c][l,7)naphthyridin-4-amine as a solid, m.p. 220-223°C. Analysis: Calculated for C13H19N5 + % H2O: %C, 62.50 %H, 7.87; %N, 28.03; 5 Found: %C, 62.50; %H, 7.72; %N, 27.46.

Example 24

Compound of Formula XX V 2-Methyl-l-(2-methylpropyl)-7jfir-tetrazolo[l,5-e]imidazo[4,5-c][l,7]naphthyridine 10 Acetic anhydride (2-3 mL) was added to a solution of N-(2- methylpropyl)tetrazolo[l,5-a][l,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 15 dichloromethane layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 2-5% methanol in dichloromethane) to provide 0.25 g of 2-methyl-l-(2-methylpropyl)-777-tetrazolo[l,5-a]imidazo[4,5-c][l,7]naphthyridine as a solid, m.p. 157-158°C. Analysis: Calculated for C14H15N7: %C, 59.77; %H, 5.37; %N, 34.85; Found: %C, 59.64; 20 %H, 5.48; %N, 34.98. -41 -

Example 25

Compound of Fonnula I 2-Methyl-l-(2-methylpropyl)-7B-imidazo[4,5-c][l,7]naphthyridin-4-amine WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD000241.tif" id="idf0041" />

Triphenylphosphine (2.5 g, 9.6 mmol) was added to a suspension of 2-methyl-l-(2-methylpropylj-7/f-tetrazolo[l,5-a]imidazo[4,5-c][l,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-1 -(2-methylpropyl)-N-triphenylphosphinyl-77/-imidazo[4,5-c][l,7]naphthyridin-4-amine was isolated by filtration.

PartB:

The 2-methyl-l-(2-methylpropyl)-N-triphenylphosphinyl-777-imidazo[4,5- 5 c][l,73naphthyridin-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 10 dichloromethane) to provide 2-methyl-l-(2-methylpropyl)-/7/-imidazo[4,5- c][l,7]naphthyridin-4-amine as a solid, m.p. 322-324°C. Analysis: Calculated for C14H17N5: %C, 65.86; %H, 6.71; %N, 27.43; Found: %C, 65.81; %H, 6.64; %N, 27.41.

Example 26

15 Compound of Formula II 6,7,8,9-Tetrahydro-2-methyH-(2-metliylpropyl)&gt; 777-imidazo{4,5-c] [1,7] naphthy ridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000242.tif" id="idf0042" />

<img img-format="tif" img-content="drawing" file="IL136556AD000243.tif" id="idf0043" />

20 A catalytic amount of platinum oxide was added to a solution of 2-methyl-l-(2- methylpropyl)-77/-imidazo[4,5-c][l,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 (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The 25 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 136556/2 PCT/US98/26473 vacuum. The resulting residue was recrystallized from toluene to provide 6,7,8,9-tetrahydro-2-methyl-1 -(2-methylpropyl)-/77-imidazo [4,5-c] [ 1,7]naphthyridin-4-amine as a solid, m.p. 226-230°C. Analysis: Calculated for C14H21N5 + 1.75 H2O: %C, 57.81; %H, 8.49; %N, 24.07; Found: %C, 57.89; %H, 8.04; %N, 23.45.

Example 27

Compound of Formula I 2-ButyI-l -(2-methylpropy 1)-/Lf-imidazo [4,5-c] 11,7] n aphthyridin-4-amin e

<img img-format="tif" img-content="drawing" file="IL136556AD000244.tif" id="idf0044" />

Part A:

Valeryl chloride (0.76 mL, 6.4 mmol) was added to a solution of N5-(2-methylpropyl)tetrazolo[l,5-a][l,7]naphthyridin-4,5-diamine (1.5 g, 5.8 mmol) in 15 acetonitrile (15 mL). ' The reaction mixture was stirred 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 20 dichloromethane extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to provide a mixture of 2-butyl -l-(2-methylpropyl)-7/7-tetrazolo[l,5-a]imidazo[4,5-c][l,7]naphthyridine and the acylated, but uncyclized intermediate.

Part B:

25 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-777-imidazo[4,5-c][l,7]naphthyridin-4-amine was isolated by filtration.

Part C:

The 2-butyl-l-(2-methylpropyl)-N-triphenylphosphinyl-777-imidazo[4,5- 5 c][l,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 10 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-butyi-l-(2-methylpropyl)-7//-imidazo[4,5-c][l,7]naphthyridin-4-amine as a solid, m.p 213-214°C. Analysis: Calculated for C17H23N5: %C, 68.66; %H, 7.80; %N, 23.55; Found: %C, 68.26; %H, 7.69; %N, 23.41. 15 20

Example 28

Compound of Formula II 2-Buty 1-6,7,8,9-tetrahydro -1 -(2-methyIpropyl)-777-imidazo [4,5-c] [ 1,7] naphthyridin-4-amine

HN A catalytic amount of platinum oxide was added to a solution of 2-butyl -1-(2-methylpropyl)-777-imidazo[4,5-c][l,7]naphthyridin-4-amine (0.5g, 1.68 mol)) in 25 trifluoroacetic acid (20 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) 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 -45- 136556/2 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 di chloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene then 5 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-2-butyl-1-(2-methylpropyl)-.///-imidazo[4,5-c][l,7]naphthyridin-4-amine as a solid, m.p. 164-166°C. Analysis: Calculated for Ci7H27N5 + 0.5 H2O: %C, 65.77; %H, 9.09; %N, 22.56; Found: %C, 65.99; %H, 8.71; %N, 22.23. 10

Example 29

Compound of Formula XXXI N4-(2-Methylp ropyl)-3-nitro [1,5] naphthyridin-4-amin e

Phosphorus oxychloride (0.6 mL, 6.44 mmol) was reacted with N,N-15 dimethylformamide then added to a solution of 3-nitro[l,5]naphthyridin-4-ol (1.0 g, 5.23 mmol) in N,N-dimethylfoimamide (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 20 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 25 concentrated to dryness to provide N4-(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine as a solid, m.p. 97-99°C. -46- WO 99/29693 136556/2

Example 30

Compound of Formula XXXIII 1 -(2-Methylpropy I)-lff-imidazo [4,5-c] [ 1,5] n aphthyridin e 5 Part A: A catalytic amount of 5% platinum on carbon was added to a solution of 1^-(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine (1.0 g, 4.1 mmol) in ethyl acetate (50 mL). The reaction mixture was reduced on a Pair apparatus at 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the 10 filtrate was concentrated under vacuum to provide N4-(2-methylpropyl)[ 1,5]naphthyridin- 3,4-diamine as a crude solid.

PartB:

The crude solid from Part A was combined with diethoxymethyl acetate (2 mL) then heated on a steam bath overnight. The reaction mixture was taken up in 15 dichioromethane, washed with water, dried over magnesium sulfate then filtered through a layer of silica gel. The silica gel was eluted with dichioromethane to remove excess diethoxymethyldcetate then with 5% methanol in dichioromethane 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 20 of l-(2-methylpropyI)-77T-imidazo[4,5-c][l,5]naphthyridine as a solid m.p. 82-84°C.

Analysis: Calculated for C13H14N4: %C, 69.00; %H, 6.24; %N, 24.76; Found: %C, 68.79; %H, 6.44; %N, 24.73.

Example 31

25 Compound of Fonnula XXXIV l-(2-MethylpropyI)-LS'-imidazo[4,5-c|[l,5]naphthyridnie-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 l-(2-methylpropyl)-//T-imidazo[4,5- c][l,5]naphthyridine (1.5 g) in chloroform at ambient temperature. After 3 hours the 30 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 PCT/US98/26473 methylpropyl)-777-imidazo[4,5-c][l,5]naphthyridine-5N-oxide as a solid, m.p. 183-185°C. Analysis: Calculated for C13H14N4O: %C, 64.45; %H, 5.82; %N, 23.12; Found: %C, 64.15; %H, 5.92; %N, 23.02. 5 Example 32

Compound of Formula I l-(2-Methylpropyl)-2jHr-imidazol4,5-c][l^]naphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000245.tif" id="idf0045" />

10 Ammonium hydroxide (10 mL) was added to a solution of 1-(2-methylpropyl)-7/7- imidazo[4,5-c][l,5]naphthyridine-5N-oxide (0.6 g) in dichioromethane (30mL). The reaction mixture was cooled in an ice bath then tosyl chloride (0.5 g) in dichioromethane was added while the reaction was being rapidly stirred. The reaction mixture was stirred at ambient temperature overnight. The dichioromethane layer was separated, washed with 15 aqueous sodium bicarbonate, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from ethyl acetate/hexane to provide 0.2 gofl-(2-methylpropyl)-777-imidazo[4,5-c][l,5]naphthyridin-4-amine as a solid, m.p. 230-231.5°C. Analysis: Calculated for C13H15N5: %C, 64.71; %H, 6.27; %N, 29.02; Found: %C, 64.70; %H, 6.01; %N, 29.08. -48- WO 99/29693 PCT/US98/26473

Example 33

Compound of Formula II 6,7,8,9-Tetrahydro-l-(2-methylpropyI)- 5 7//-imidazo[4,5-c][l,5]naphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000246.tif" id="idf0046" />

A catalytic amount of platinum oxide was added to a solution of 1-(2- 10 methylpropyl)-///-imidazo[4,5-c][l,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/cm2) 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. 15 The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under yacuum. 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 6,7,8,9- 20 tetrahydro-l-(2-methylpropyl)-/tf-imidazo[4,5-c][l,5]naphthyridin-4-amine as a solid, m.p. 222-226°C. Analysis: Calculated for C13H19N5: %C, 63.65; %H, 7.81; %N, 28.55; Found: %C, 63.07; %H, 7.51; %N, 28.00. -49- WO 99/29693 PCT/US98/26473

Example 34

Compound of Formula ΧΧΧΠΙ 2- Methyl-1 -(2-methy lpropyl)-7//-imidazo[4,5-c] [l,5]naphthyridine 5 Part A:

Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbon were added to a solution ofN4-(2-methylpropyl)-3-nitro[l,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 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove 10 the catalyst and the filtrate was concentrated under vacuum to provide 1^-(2-methylpropyl)[l,5]naphthyridin-3,4-diamine as a crude solid.

PartB:

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 15 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-l-(2-methylpropyl)-7/7-imidazo[4,5-c][l,5]naphthyridine as off-white needles, m.p. 118-119°C. Analysis: 20 Calculated for C,4H16N4: %C, 69.97; %H, 6.71; %N, 23.31; Found: %C, 69.24; %H, 6.67; %N, 23.23.

Example 35

Compound of Formula XXXIV 25 2-Methyl-l-(2-methylpropyl)-7/i-imidazo[4,5-c][l,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-l-(2-methylpropyl)-7/7-imidazo[4,5-c][l,5]naphthyridine (2.1 g, 8.7 mmole) in chloroform at ambient temperature. After 3 hours the reaction mixture was diluted with chloroform, washed 30 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- -50- WO 99/29693 PCT/US98/26473 methyl-l-(2-methylpropyl)-///-imidazo[4,5-c][l,5]naphthyridine-5N-oxide as a solid, m.p. 228-230°C. Analysis: Calculated for C14H16N4O: %C, 65.61; %H, 6.29; %N, 21.86; Found: %C, 65.73; %H, 6.31; %N, 21.95. 5 Example 36

Compound of Formula I 2-Methyl-l-(2-methylpropyl)-7/ir-imidazof4,5-c][l,5Jnaphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000247.tif" id="idf0047" />

10

Ammonium hydroxide (10 mL) was added to a solution of 2-methyl-1-(2-methylpropyl)-//7-imidazo[4,5-c][l,5]naphthyridine-5N-oxide (1.1 g, 4.29 mmol) in dichloromethane (50mL). 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 15 about 30°C while being rapidly stirred. The reaction mixture was stirred at ambient temperature overnight. The dichloromethane layer was separated, washed with 10% 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 of2-methyl-l-(2-methylpropyl)-///-imidazo[4,5-c][l,5]naphthyridin-4-amine as a solid, m.p. 228- 20 230°C. Analysis: Calculated for C,4H,7N5: %C, 65.86; %H, 6.71; %N, 27.43; Found: %C, 65.65; %H, 6.69; %N, 27.59. -51 - WO 99/29693 PCT/US98/26473

Example 37

Compound of Formula XXXIII 2- Butyl-l-(2-methylpropyI)-777-imidazo[4,5-c] [l,5Jnaphthyridine

Part A:

Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbon were added to a solution of N4-(2-methylpropyl)-3-nitro[l,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 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide 1^-(2-methylpropyl)[l,5]naphthyridin-3,4-diamine as a crude solid.

PartB:

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 N-(4-(2- methylpropylamino)[l,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 dichioromethane and aqueous sodium bicarbonate. The dichioromethane layer was separated, dried over magnesium sulfate and concentrated under vacuum to provide 2.3 g of 2-butyl-l-(2-methylpropyl)-777-imidazo[4,5-c][l,5]naphthyridine as an oil. -52 - WO 99/29693 PCT/US98/26473

Example 38

Compound ofFormula XXXTV 2-Butyl-l-(2-methylpropyl)-Iff-imidazo[4,5-c] [1,5] naphthyridine-5N-oxide 5 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)-7Zf-imidazo[4,5-c][l,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 10 magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 2-butyl-l-(2-methylpropyl)-777'-imidazo[4,5-c][l,5]naphthyridine-5N-oxide. Analysis: Calculated for C17H22N4O: %C, 68.43; %H, 7.43; %N, 18.78; Found: %C, 67.67; %H, 6.73; %N, 18.13 15

Example 39

Compound ofFormula I 2-Butyl-l-(2-methylpropyI)-7/7-iinidazo[4,5-c][l,5]naphthyridin-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000248.tif" id="idf0048" />

20

Ammonium hydroxide (25 mL) was added to a solution of 2-butyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine-5N-oxide (2.0 g, 6.7 mmol) in dichloromethane (lOOmL). The reaction mixture was cooled in an ice bath then tosyl 25 chloride (1.3 g, 6.7 mmol) in dichloromethane was added. The reaction was wanned to about 30°C while being rapidly stirred. The reaction mixture was stirred at ambient temperature overnight. The dichloromethane layer was separated, washed with 10% sodium hydroxide, water and brine, dried over magnesium sulfate then concentrated under -53- WO 99/29693 PCT/US98/26473 vacuum. The residue was recrystallized from hexane to provide 1.55 g of2-butyl-l-(2-methylpropyl)-777-imidazo[4,5-c][l,5]naphthyridin-4-amine as a solid, m.p. 115-116°C. Analysis: Calculated for C17H23N5: %C, 68.66; %H, 7.80; %N, 23.55; Found: %C, 69.52; %H, 7.72; %N, 21.72 5

Example 40

Compound of Formula Π J 6,7,8,9-Tetrahydro-2-butyl-l-(2-methylpropyl)- 7Z7-imidazo[4,5-c] [l,5]naphthyridin-4-amine 10

<img img-format="tif" img-content="drawing" file="IL136556AD000249.tif" id="idf0049" />

A catalytic amount of platinum oxide was added to a solution of2-butyl-l-(2-m ethylprop yl)-777-imidazo [4,5-c][l, 5 ]naphthyri din-4-amine (0.5 g) in trifluoroacetic acid 15 (15 mL). The reaction mixture was reduced on a Parr apparatus under 50 psi (3.5 Kg/cm2) 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 20 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-l-(2-methylpropyl)-777-imidazo[4,5-c][l,5]naphthyridin-4- 25 amine as a solid, m.p. 143-147°C. Analysis: Calculated for C17H27N5: %C, 67.74; %H, 9.03; %N, 23.23; Found: %C, 61.90; %H, 7.51; %N, 19.91. -54- WO 99/29693 PCT/US98/26473

Example 41

Compound of Formula XXXI 1,1-Dimethylethyl 5 N-{4-[(3-Nitro[l,5]naphthyridin~4-yl)amino]butyI}carbamate

Phosphorus oxychloride (4 mL, 0.31 mole) was combined with N,N- dimethylformamide (100 mL) while cooling in an ice bath. The resulting mixture was added to a solution of 3-nitro[l,5]naphthyridin-4-ol (50 g, 0.26 mole) in N,N-dimethylfoimamide (500 mL). The reaction mixture was stirred at ambient temperature 10 for 6 hours. The reaction mixture was poured into ice water and then extracted with 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 15 filtration, washed with water and dried to provide 76 g of 1,1 -dimethylethyl N- {4-[(3- nitro[l,5]naphthyridin-4-yl)arnino]butyl} carbamate as a solid. A small sample was recrystallized from isopropyl alcohol to provide a pure sample, m.p. 137-138°C. Analysis: Calculated for C17H23N5O4: %C, 56.50; %H, 6.41; %N, 19.38; Found: %C, 56.26; %H, 6.30; %N, 19.53. 20

Example 42

Compound of Formula XXXII 1,1-Dimethylethyl N-{4-[(3-Amino[l,5]naphthyridin-4-yl)amino]butyl}carbamate 25 1,1-Dimethylethyl N-{4-[(3-nitro[l,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/cm2) 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 N-{4-[(3- 30 amino[ 1,5]naphthyridin-4-yl)amino]butyl} carbamate as a bright yellow-orange solid. -55- WO 99/29693 136556/2 PCT/US98/26473

Example 43

Compound of Formula ΧΧΧΠΙ 1,1-Dimethylethyl 5 N-[4-(2-Butyl-l/f-imidazo[4,5-c] [l,5]naphthyridin-l-yl)butyl]carbamate

Freshly distilled trimethyl orthovalerate (41 mL, 0.24 mole) was added to a mixture of 1,1-dimethylethyl N-{4-[(3-amino[l,5)naphthyridin-4- yl)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 10 half of the starting material was still present p-Toluenesulfonic anhydride monohydrate (6 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 15 triturated with hexane to provide a dark pink solid. This solid was recrystallized from acetonitrile to provide 1,1-dimethylethyl N-[4-(2-butyl-l#-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl] carbamate as a pale peach solid, m.p. 96.0-98.0°C. Analysis: Calculated for C22H31N5O2: %C, 66.47; %H, 7.86; %N, 17.62; Found: %C, 66.29; %H, 7.78; %N, 17.76. 20

Example 44

Compound of Formula XXXIV l-{4-[(l,l-Dimethylethylcarbonyl)amino]butyl}-2-butyl- lZf-imidazo [4,5-c] [1,5] π aphthyridine-5N-oxide 25 3-Chloroperbenzoic acid (1 eq at 57%) was added in portions to a solution of 1,1- dimethylethyl N-[4-(2-butyl-l/7-imidazo[4,5-c][ 1,5]naphthyridin-1 -yl)butyl] carbamate in chloroform (50 mL). The reaction mixture was stirred 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 30 with IM sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under vacuum to provide 1- {4-((1,1- -56- WO 99/29693 PCT/US98/26473 dimethylethylcarbonyl)amino]butyl}-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridine~5N-oxide as an orange oil which solidified on standing.

Example 45

5 Compound of Formula I 1,1 -Dimethylethy 1 N-|4-(4-Amin o-2-butyl-l /7-imidazo [4,5-c] [1,5] naphthyridin-1 -yl)butyl]carbamate

<img img-format="tif" img-content="drawing" file="IL136556AD000250.tif" id="idf0050" />

10

Ammonium hydroxide (20 mL) was added to a solution of 1-(4-((1,1-dimethylethylcarbonyl)amino]butyl} -2-butyl-1 H-imidazo [4,5-c] [ 1,5]naphthyridine-5N-oxide (19.4 g) in chloroform. Tosyl chloride (9 g) was slowly added. Thin layer chromatography indicated that the reaction was proceeding slowly. Additional tosyl 15 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 20 filtration, washed with hexane and then dried to provide 15.1 g of 1,1-dimethylethyl N-[4-(4-amino-2-hutyl-177-imidazo[4,5-c][l ,5]naphthyridin-l-yl)butyl]carbamate, m.p. 148.5-149.5°C. Analysis: Calculated for C22H32N6O2: %C, 64.05; %H, 7.82; %N, 20.37; Found: %C, 64.15; %H, 7.82; %N, 20.55. -57- WO 99/29693 PCT/US98/26473

Example 46

Compound of Formula I 4-(4- Amino-2-butyl-127-imidazo[4,5-c] [1,5] naphthyridin-l-yl)butaneamine

<img img-format="tif" img-content="drawing" file="IL136556AD000251.tif" id="idf0051" />

A suspension of 1,1-dimethylethyl N-[4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate (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 10 temperature and then it was made basic (ρΗ&gt;11) with 50% sodium hydroxide. The resulting precipitate was isolated by filtration, washed with water and then dried to provide 9.5g of 4-(4-arnino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine as a white solid, m.p. 212-213°C. Analysis: Calculated for C17H24N6: %C, 65.36; %H, 7.74; %N, 26.90; Found: %C, 65.16; %H, 7.65; %N, 27.29. 15

Example 47

Compound of Formula I N-{4-(4-Amino-2-butyl-lJ7-imidazo [4,5-c] [1,5]naphthyridin-l-yl)butyl]-N*-phenylurea 20

<img img-format="tif" img-content="drawing" file="IL136556AD000252.tif" id="idf0052" />

<img img-format="tif" img-content="drawing" file="IL136556AD000253.tif" id="idf0053" />

Under a nitrogen atmosphere, phenyl isocyanate (52 pL, 0.48 mmol) was added to a suspension of 4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine -58- 136556/2 WO 99/29693 PCT/US98/26473 (0.15 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 5 added and the reaction mixture was stirred for 0.5hr. 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 ofN-[4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridm-l-yl)butyl]-N’-phenylurea. Analysis: Calculated for 10 C24H29N7O + 1/5 H2O: %C, 66.25; %H, 6.81; %N, 22.53; Found: %C, 66.27; %H, 6.63; %N, 22.83

Example 48

Compound of Formula I 15 N-[4-(4-Amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- N’-cyclohexylurea

<img img-format="tif" img-content="drawing" file="IL136556AD000254.tif" id="idf0054" />

Using the general method of Example 47, cyclohexyl isocyanate (61 pL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-177-iniidazo[4,5-c][l,5]naphthyridin-l- 20 yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.14 g of N-[4-(4-amino-2-butyl-l/7- imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- Ν’- cyclohexylurea as a white solid.

Analysis: Calculated for C24H35N7O: %C, 65.88; %H, 8.06; %N, 22.41. ’H NMR (300 MHz, CDCI3) δ 8.60 (dd, J = 4.4,1.4 Hz, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 7.44 (dd, J = 8.5, 4.4 Hz, 1 H), 5.55 (br s, 2 H), 4.92 (t, J = 5.8 Hz, 1 H), 4.82 (apparent t, J = 7.8 Hz, 2 H), 25 4.13 (d, J = 8.6 Hz, 1 H), 3.48 (m, 1 H), 3.35 (apparent q, J = 6.4 Hz, 2 H), 2.93 (apparent t, J = 7.8 Hz, 2 H), 1.80-2.05 (m, 4 H), 1.45-1.75 (m, 6 H), 12-1.4 (m 2 H), 1.0-1.2 (m, 2 -59- WO 99/29693 PCT/US98/26473 Η), 1.03 (t, 7.4 Hz, 3 H); HRMS (El) calcd for C24H35N7O (M+) 437.2903, found 437.2903.

Example 49

Compound of Formula I N-[4-(4-Amino-2-butyI-17/-imidazo[4^-c][l,5]naphthyridin-l-yl)butyI]- N’-butylurea

<img img-format="tif" img-content="drawing" file="IL136556AD000255.tif" id="idf0055" />

10

Using the general method of Example 47, butyl isocyanate (54 pL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-17/-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.13 g of N-[4-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- N’-butylurea as a white solid. Analysis: Calculated for C22H33N7O: %C, 64.21; %H, 8.08; %N, 23.82; Found: %C, 64.05; %H, 7.97; %N, 24.00. 15

Example 50

Compound of Formula I Phenyl N-[4-(4-Amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate

<img img-format="tif" img-content="drawing" file="IL136556AD000256.tif" id="idf0056" />

20 -60- WO 99/29693 PCT/US98/26473

Using the general method of Example 47, phenyl chloroformate (61 pL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-l//'-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.12 g of phenyl N-[4-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate as a solid. Analysis: Calculated 5 for C24H28N6O2: %C, 66.65; %H, 6.53; %N, 19.43; Found: %C, 66.49; %H, 6.59; %N, 19.32.

Example 51

Compound of Formula I 10 N-]4-(4-Amino-2-butyHJy-innidazoI4^-c]Il^]naphthyridin-l-yl)butyl]- 2-furamide

<img img-format="tif" img-content="drawing" file="IL136556AD000257.tif" id="idf0057" />

Using the general method of Example 47, furoyl chloride (15.8 pL, 0.16 mmol) was reacted with 4-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l- 15 yl)butaneamine (0.05 g, 0.16 mmole) to provide 0.019 g of N-[4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5)naphthyridin-l-yl)butyl]-2-furamide as a white solid. *H NMR (300 MHz, CDClj) δ 8.58 (dd, J = 4.4,1.5 Hz, 1 H), 8.06 (dd, J = 8.6,1.6 Hz, 1 H), 7.41 (dd, J = 8.5,4.4 Hz, 1 H), 7.33 (m, 1 H), 7.08 (dd, J = 3.5,0.6 Hz, 1 H), 6.84 (m, 1 H), 6.47 (dd, J = 3.5,1.7 Hz, 1 H), 4.86 (apparent t, J = 7.7 Hz, 2 H), 3.59 (apparent q, J = 6.5 Hz, 2 H), 20 2.92 (apparent t, J = 7.8 Hz, 2 H), 1.7-2.1(m, 6 H), 1.51 (m, 2 H); 1.00 (t, J = 7.3 Hz, 3 H); HRMS (El) calcd for C22H26N6O2 (M+) 406.2117, found 406.2121. -61- WO 99/29693 PCT/US98/26473

Example 52

Compound of Formula I N-[4-(4-Amino-2-butyl- l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyI]benzamide

<img img-format="tif" img-content="drawing" file="IL136556AD000258.tif" id="idf0058" />

Using the general method of Example 47, benzoyl chloride (56 pL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.11 g of N-[4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]benzamide as a white solid. Analysis: 10 Calculated for Ci^gNeO + % H2O: %C, 68.47; %H, 6.82; %N, 19.96: Found: %C, 68.24; %H, 6.76; %N, 19.90. 15

Example 53

Compound of Formula I N-[4-(4-Amino-2-butyl-l^-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- N’-benzylurea

<img img-format="tif" img-content="drawing" file="IL136556AD000259.tif" id="idf0059" />

O

Benzyl isocyanate (59 pL, 0.48 mmol) was added at ambient temperature to a suspension of4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-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 30 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 5 removed under vacuum. The residue was purified by column chromatography to provide 0.16 g of N-[4-(4-amino-2-butyl-17/-imidazo[4,5-c][ 1,5]naphthyridin-l -yl)butyl]-N’-benzylurea as a white solid. Analysis: Calculated for C25H31N7O: %C, 67.39; %H, 7.01; %N, 22.00; Found: %C, 67.43; %H, 6.92; %N, 22.02. 10 Example 54

Compound of Formula I N3-[4-(4-Amino-2-butyl- l//-imidazo[4,5-c][l,5jnaphthyridin-l-yl)butyl]nicotinamide

<img img-format="tif" img-content="drawing" file="IL136556AD000260.tif" id="idf0060" />

15 4-(4-Amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.050 g, 0.16 mmol) was suspended in tetrahydrofuran (30 mL). N,N-diisopropylethylamine (28 pL, 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 20 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 25 were combined and then concentrated under vacuum to provide N3-[4-(4-amino-2-butyl- -63- WO 99/29693 136556/2 PCT/US98/26473 177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]nicotinamide as a white powder. !H NMR (300 MHz, CDClj) δ 8.91 (m, 1 H), 8.68 (d, J = 4.5 Hz, 1 H), 8.45 (d, J = 4.3 Hz, 1 H), 8.03 (m, 2 H), 7.30-7.40 (m, 2 H), 6.98 (s, 2 H), 5.51 (s, 1 H), 4.86 (apparent t, J = 7.9 Hz, 2 H), 3.66 (q, J = 6.5 Hz, 2 H), 2.92 (apparent t, J = 7.7 Hz, 2 H), 2.05 (m, 2 Η), 1.75-1.95 5 (m, 4 H), 1.51 (m, 2 H), 1.00 (t, J = 7.3 Hz, 3 H); HRMS (EI) calcd for C23H27N7O (M4) 417.2277, found 417.2276.

Example 55

Compound of Formula I 10 " N-[4-(4-Amino-2-butyl- 127-imidazo[4,5-c] (l,5]naphthyridin-l-yl)butyl]phenylaceatarnide

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Phenylacetyl chloride (21 pL, 0.16 mmol) was added to a suspension of 4-(4-amino-2-butyl-17i-imidazo[4,5-c][l,5]naphthyridm-l-yl)butaneamme (0.050 g, 0.16 15 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 20 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 N-[4-(4- 25 ’ amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]phenylacetamide as a white powder. Analysis: Calculated for C2sH3oN60; %C, 67.24; %H, 6.77; %N, 18.82; Found: -64- WO 99/29693 PCT/US98/26473 %C, 67.52; %H, 6.85; %N, 18.38. *H NMR (300 MHz, CDC13) δ 8.51 (dd, J = 4.4,1.5 Hz, 1 H), 8.11 (dd, J = 8.4,1.4 Hz, 1 H), 7.43 (dd, J = 8.4,4.4 Hz, 1 H), 7.10-7.20 (m, 5 H), 6.30 (br s, 2 H), 5.83 (m, 1 H), 4.72 (apparent t, J = 7.8 Hz, 2 H), 3.54 (s, 2 H), 3.35 (apparent q, J = 6.5 Hz, 2 H), 2.88 (apparent ζ J = 7.8 Hz, 2 H), 1.80-1.90 (m, 4 H), 1.45- 5 1.65 (m, 4 Η), 1.00 (t, J = 7.3 Hz, 3 H); HRMS (EI) calcd for C25H3oN60 (M+) 430.2481, found 430.2490.

Example 56

Compound of Formula I 10 Benzyl N-[4-(4-Amino-2-butyl- l/f-imidazo[4^-c][l,5]naphthyridin-l-yl)butyl]carbamate

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Using the general method ofExample 55, benzyl chloroformate (83 gL, 0.58 mmol) was reacted with 4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l- 15 yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.18 g of benzyl N-[4-(4-amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate as a white powder. -65- WO 99/29693 PCT/US98/26473

Example 57

Compound ofFormula I 9H-9-FluorenyImethylN-[4-(4-Amino-2-butyl- 177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate NH2

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O

Using the general method of Example 55,9-fluorenylmethyl chloro formate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-l//-irnidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethyl N-[4- 10 (4-amino-2-butyl-17/-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate as a white powder. Analysis: Calculated for C32H34N6O2 + % H2O: %C, 71.29; %H, 6.45; %N, 15.59; Found: %C, 70.99; %H, 6.35; %N, 15.55. 15

Example 58

Compound ofFormula I Ethyl N-[4-(4-Amin o-2-butyl-l/f-imidazo[4,5-c][l^]naphthyridin-l-yl)butyl]carbamate NH2 o

Using tiie general method of Example 55, ethyl chloroformate (46 pL, 0.48 mmol) 20 was reacted with 4-(4-amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l- yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.15 g of ethyl N-[4-(4-amino-2-butyI-l/7- -66- WO 99/29693 PCT/US98/26473 imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate as a white powder. Analysis: Calculated for C2oH28N602: %C, 62.48; %H, 7.34; %N, 21.86; Found: %C, 61.73; %H, 7.28; %N, 21.62. 5 Example 59

Compound of Formula XXXI l,l-Dimethyl-2-I(3-nitro[l,5]naphthyridin-4-yl)amino]ethanol Phosphorus oxychloride (4 mL, 43 mmol) was reacted with N,N- dimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a 10 solution of 3-nitro[l,5]naphthyridin-4-ol (6.9 g, 36.1 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was wanned in an oil bath to 60°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[l,5]naphthyridine was suspended in dichloromethane (150 mL). Diisopropylethylamine was added followed 15 bytheslowadditionofhydroxyisobutylamine(3.4g,40mmol). 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 l,l-dimethyl-2-[(3-nitro[l,5]naphthyridin-4-yl)amino]ethanol. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 184.5-186°C. Analysis: Calculated for C12H14N4O3: %C, 54.96; %H, 5.38; 20 %N, 21.36; Found: %C, 54.63; %H, 5.36: %N, 21.51. -67- 972 5 7109411 09/21 ‘06 09:12 NO.164 02/02 136556/3

Example 60

Compound of Formula XXXJII l,l-Dinjethyl-2-(2’butyl-ie'-imidazo[4,5-cl[l,5]jiaphthyridin-l-yl) ethanol

Part A . , A catalytic amount of 5% platinum on carbon was added to a suspension of 1,1 r dimethyl-2-[(3-nitrol[l,5]napbthyridin-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/cm2) hydrogen pressure for 3 hours. The reaction mixture was filtered 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] naphthyndin-4-yI) amino] ethanol.

PartB

Trimethylorthovalerate (3.6 mL, 20 mmol) was added to a suspension of 1,1 dimethyl-2- ((3-araino [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° 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 -I//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethanol as a solid, m. p. 85-88.5° C. Analysis Calculated for C.iHaNaO: % C, 68.43; % H, 7.43; % N, 18.78; found: % C, 68.04; % H,7.18;%N, 19.09.

Example 61

Compound of Formula XXXFV 2-ButyM-{2-hydroxy-2-methylpropyf)-IZr-/midazo [4^-c}(LS] naphthyridin-5N-oxide 3-Cbloroperbenzoic acid (2.6 g, 9.5 mmol) was added in 3 portions to a solution of 1,1-dimeth.yl-2- (2-butyl -IH-imidazo [4,5-c](l,5]naphthyridine-l-yl) ethanol (2.6 g, 8.7 mmol) in chloroform (50mL) 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- 136556/2

The residue was recrystallized from methyl acetate to provide 2.25 g of 2-butyl-1-(2-hydroxy-2-methylpropyl)-17i-imidazo [4,5-c] [1,5] naphthyridine-5N-oxide, m. p. 156-158° C. Analysis: Calculated for: C17H22N4O2 + 1/4H2O: % C, 64.03; % H, 7.11; % N, 17.57; Found: % C, 63.96; % H, 6.84; % N, 17.71.

Example 62

Compound of Formula I l,l-Dimethyl-2- (4-amino-2-butyl -lH-imidazo-[4,5-c][l,5]naphthyridin-l-yl) ethanol

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Ammonium hydroxide (15 mL) was added to .a solution of 2-butyl-1- (2-hydroxy-2- methylpropyl)-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 -lH-imidazo-[4,5-c][l,5]naphthyridin-l-yl) ethanol m. p. 177-179° C. Analysis: Calculated for C17H23N5O: % C, 65.15; % H, 7.40; % N, 22.35; Found: % C, 64.97; % H, 7.33; % N, 22.71. -69- 136556/2

Example 63

Compound of Formula XXXIII l,l-Dimethyl-2- (2-phenyImethyI -lH-imidazo[4,5-c][l,5] naphthyridin-l-yl)ethanol

Part A

Phenylacetyl chloride (2.0 mL, 20 mmol) was added to a suspension of 1,1 dimethyl-2- [ (3-amino [1,5] naphthyridin-4-yl) amino] ethanol 3.5 g, 13 mmol) in dichioromethane (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 dichioromethane (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 l,l-dimethyI-2- (2- phenylmethyl -IH-imidazo [4,5-c][l,5] naphthyridin-1-yl)ethanol as a solid, m.p 150-152° C. Analysis: Calculated for C2oH2oN40: % C, 72.27; % H, 6.06; % N, 16.85; Found: % C, 72.11,%H, 6.01; %N, 17.00.

Example 64

Compound of Formula XXXIV 2-PhenylmethyI-l-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-cl[l,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-phenyImethyi -lH-imidazo[4,5-c][l,5]:naphthyridin-l-yl) ethanol (2g, 6 mmol) in · chloroform (50 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 2.25g of 2-phenylmethyl-l-(2-hydroxy-2-methylpropyl)-L/7-imidazo [4,5-c] [1,5] naphthyridin-5N-. -70- 136556/2 oxide, m. p. 204-206 C_..-Analysis: Calculated for: C2o H2oN402 + 1AH2O. %~C, 67.21; % H, 5.92; % N, 15.68; Found: % C, 67.05; % H, 5.65; % N, 15.39.

Example 65

Compound of Formula I l,l-Dimethyl-2-(4-amino-2-phenylmethyl-lH-imidazo-[4,5-c][l,5]naphthyridin-l-yI) ethanol nh2

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Ammonium hydroxide (10 mL) was added to a solution of 2-phenylmethyl-l- (2- hydroxy-2-methylpropyl)-lH-imidazo-[4,5-0][1,5] naphthyridint -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

I 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 mT.) was added and the mixture was allowed to stand overnight. The resulting crystalline solid was isolated by filtration to provide 1, l-dimethyl-2- (4-amino-2-phenylmethyl -lH-imidazo-[4,5-c][l,5]naphthyridin-l-yl) ethanol, m. p. 211-213° C. Analysis: Calculated for C20H21N5O: °/o C, 69.14; % H, 6.09; % N, 20.16; Found: % C, 69.10; % H, 6.12; % N, 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, N-dimethylformamide (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 (60 mL).

The reaction mixture was warmed in an oil bath to 60° C. After 3 hours the -71 - WO 99/29693 136556/2 reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water. The-wet cnide4&gt;-chloro-3-nitro[l,5]naphthyridine was suspended in dichioromethane (150 mL). Diisopropylethylamine (1.2 eq) was added followed by the slow addition of benzylamine (4.7 mL g, 40 mmol). The reaction mixture 5 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 N-phenylmethyl-3-nitro[l,5]naphthyridin-4-amine. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 127-129°C. Analysis: Calculated for C15H12N4O2: %C, 64.28; %H, 4.32; %N, 19.99; Found: %C, 63.89; %H, 4.40: %N, 20.35. 10

Example 67 N-(4-Phenylmethylamino[l^lnapIithyridin-3-yI)-ethoxyacetamideH[ydrochlQride A catalytic amount of platinum on carbon was added to a suspension of N- phenylmethyl-3-nitro[l,5]naphthyridin-4-amine (5.1 g, 18.2 mmol) in toluene (300 mL). 15 The reaction mixture was hydrogenated on a Parr apparatus under a hydrogen pressure of 50 psi (3.5Kg/cm2).for 1 hour. The reaction mixture was filtered to remove the catalyst. k

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 20 N-(4-phenyImethylamino[ 1,5]naphthyridin-3-yl) ethoxyacetamide hydrochloride, m.p. 205-212°C. Analysis: Calculated for C19H20N4O2 HCI: %C, 61.21; %H, 5.68; %N, 15.03; Found: %C, 60.90; %H, 5.38; %N, 15.38.

Example 68 25 Compound of Formula ΧΧΧΠΙ 2-Ethoxymethyl-l-phenyImethyI-177-imida;zo[4,5-c][l,5]naphthyridjne 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 30 was concentrated under vacuum. The residue was partitioned between water and dichioromethane. The dichioromethane 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-l-phenylmethyl-l/f-imidazo[4,5-c][l,5]naphthyridine, m.p. 118-119°C. Analysis: Calculated for Ci9Hl8N4O: %C, 71.68; %H, 5.70; %N, 17.60; Found: %C, 71.44; %H, 5.60; %N, 17.66. 5 Example 69

Compound of Formula XXXIV 2-Ethoxy methyl-1 -ph eny Imethy 1-17/-imidazo[4,5-c] [ 1,5] naphthyridin e-5N-oxide 3-Chloroperbenzoic acid (3.7 g, 13.4 mmol) was added in 3 portions to a solution 10 of 2-ethoxymethyl-l-phenylmethyl-177-imidazo[4,5-c][l,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 15 portion was concentrated under vacuum. The residue was recrystallized from isopropyl alcohol to provide 2-ethoxymethyl-l-phenylmethyl-177-imidazo[4,5-c][l,5]naphthyridine 5N-oxide as a solid, m.p. 187.5-189°C. Analysis: Calculated for Ci9Hi8N4O2 + ’Λ H2O: %C, 67.52; %H, 5.49; %N, 16.58; Found: %C, 67.56; %H, 5.36; %N, 16.77. 20

Example 70

Compound of Formula I 2-EthoxymethyI-l-phenyImethyl-l/7-imidazoI4,5-cl{l,5]naphthyridin-4-amine NH2

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25

Ammonium hydroxide (20 mL) was added to the chloroform solution of 2-ethoxymethyl-1 -phenylmethyl-177-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 5 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 2-ethoxymethyl-l-phenylmethyl-l//-imidazo[4,5-c][l,5]naphthyridin-4-amine, m.p. 173-174°C. Analysis: Calculated for C19H19N5O: %C, 68.45; %H, 5.74; %N, 21.01; Found: %C, 68.35; %H, 5.83; %N, 21.27. 10

Example 71

Compound of Formula XXXI N4-(3-Isopropoxypropyl)-3-nitro[l^]naphthyridin-4-amine

Part A 15 Phosphorus oxychloride (3.4 mL, 30 mmol) was added to chilled (ice bath) N,N- dimethylformamide (15 mL). The resulting solution was added dropwise to a solution of 3-nitro[l,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 20 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[l,5]naphthyridine.

PartB 4-Chloro-3-nitro[l,5]naphthyridine (4.1 g), dichloromethane (150 mL), 25 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 (lOOmL). 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 30 oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 4.8 g of N4-(3-isopropoxypropyl)-3-nitro[l,5]naphthyridin-4-amine as a yellow powder, m.p. 62.5-63.5°C. Analysis: Calculated for C14H18N4O3: %C, -74- WO 99/29693 PCT/US98/26473 57.92; %H, 6.25; %N, 19.30; Found: %C, 57.96; %H, 6.19; %N, 19.51. *H NMR (300 MHz. CDCb): δ 10.08 (broad s, IH), 9.38 (broad s, IH), 8.78 (m, IH), 8.21 (dd, J=8.4,1.6 Hz, IH), 7.64 (dd, &gt;8.4,4.1 Hz, IH), 4.57 (broad s, 2H), 3.65-3.57 (m, 3H), 2.05 (t, J=5.6 Hz, 2H), 1.19 (d, &gt;6.0 Hz, 6H); MS (EI): m/e 290.1366 (290.1378 calc’d for 5 C14H18N4O3).

Example 72

Compound of Formula XXXII N4-(3-Isopropoxypropyl)[l,5]naphthyriduie-3,4-diamine 10 ^-(S-Isopropoxypropylj-S-nitrotl.Sjnaphthyridin^-amine (4.2 g, 14.5 mmol), platinum on carbon (1.1 g of 5%), and ethyl acetate (100 mL) were placed in a hydrogenation flask. The mixture was shaken under a hydrogen pressure of 50 psi (3.5 Kg/cm2) 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 15 concentrated under vacuum to provide 3.6 g of ^-(3- isopropoxypropyl)[l,5]naphthyridine-3,4-diamine as a bright yellow oil. *H NMR (300 MHz, CDCb): δ 8.70 (dd, J=4.1,1.6 Hz, IH), 8.39 (s, IH), 8.17 (dd, &gt;8.4,1.6 Hz, IH), 7.37 (dd, &gt;8.4,4.1 Hz, IH), 5.99 (broad s, IH), 3.98 (broad s, 2H),3.63-3.55 (m, 5H), 1.87 (pentet, &gt;6.2 Hz, 2H), 1.17 (d, &gt;6.1 Hz, 6H); MS (EI): m/e 260.1630 (260.1637 calc’d 20 for C14H20N4O).

Example 73

Compound of Formula XXXHI 2-ButyI-l-(3-isopropoxypropyl)-l/7-imidazo]4,5-c][l,5]naphthyridine

25 Part A

Valeryl chloride (1.53 mL, 12.9 mmol) was added dropwise over a 15 minute period to a chilled (ice bath) solution of N4-(3-isopropoxypropyl)[l,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 1 hour. The solvent 30 was removed trader 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 150°C for 6 hours. After the mixture was cooled to ambient temperature it was concentrated under 5 vacuum. The residue was partitioned between dichioromethane (150 mL) and water (150 mL). The fractions were separated and the aqueous fraction was extracted with dichioromethane (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 10 2-butyl-l-(3-isopropoxypropyl)-l/i-imidazo[4,5-c][l,5]naphthyridine as a colorless oil. *H NMR (300 MHz. CDCh): δ 9.32 (s, IH), 8.90 (dd, J=4.3,1.7 Hz, IH), 8.49 (dd, J=8.5,1.7 Hz, IH), 7.57 (dd, J=8.5,4.3 Hz, IH), 4.94 (t, J=7.0 Hz, 2H), 3.56 (pentet, J=6.1 Hz, IH), 3.44 (t, J=5.7 Hz, 2H), 3.05 (t, J=7.9 Hz, 2H), 2.29-2.20 (m, 2H), 2.01-1.90 (m, 2H), 1.60-1.48 (m, 2H), 1.15 (d, J=6.1 Hz, 6H), 1.03 (t, J=7.3 Hz, 3H); MS (El): m/e 326.2104 15 (326.2106 calc’d for Ci9H26N4O).

Example 74

Compound of Formula XXXIV 2- ButyI-l-(3-isopropoxypropyI)-17(-imidazo[4,5-c][l,5]naphthyridine- 20 5N-oxide 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)-lZ/-imidazo[4,5-c][l,5]naphthyridine (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 25 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)-lH-imidazo[4,5-c][I,5]naphthyridine-5N-oxide as a yellow solid, m.p. 92.0-93.0°C. Analysis: Calculated 30 for Ci9H26N4O2: %C, 66.64; %H, 7.65; %N, 16.36; Found: %C, 66.18; %H, 7.39; %N, 16.26. ]H NMR (300 MHz. CDCb): δ 9.24 (dd, J=8.8,l.6 Hz, IH), 9.05 (s, IH), 8.98 (dd, J=4.3,l .6 Hz, IH), 7.65 (dd, J=8.8,4.3 Hz, IH), 4.89 (t, J=7.0 Hz, 2H), 3.56 (pentet, &gt;6.1 -76- WO 99/29693 PCT/US98/26473

Hz, 1H), 3.44 (t, J=5.7 Hz, 2H), 3.02 (t, J=7.9 Hz, 2H), 2.27-2.18 (m, 2H), 1.97-1.87 (m, 2H), 1.59-1.47 (m, 2H), 1.15 (d, &gt;6.1 Hz, 6H), 1.02 (t, &gt;7.3 Hz, 3H).

Example 75

5 Compound of Formula I 2-Butyl-l-(3-isopropoxypropyI)-l/r-imidazo[4^-c][l^]naplithyridine-4-amine

<img img-format="tif" img-content="drawing" file="IL136556AD000267.tif" id="idf0067" />

Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.42 mL, 3.5 mmol) was added dropwise to a solution of 2-butyl-l-(3-isopropoxypropyl)-l/7-imidazo[4,5- 10 c][ 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 mmol) was slowly added. The reaction was maintained at ambient temperature overnight. The resulting precipitate was 15 isolated by filtration and then recrystallized from methyl acetate to provide 0.47 g of 2-butyl-l-(3-isopropoxypropyl)-l//-imidazo[4,5-c][l,5]naphthyridine-4-amine as a white crystalline solid, m.p. 174-175°C. Analysis: Calculated for C19H27N5O: %C, 66.83; %H, 7.97; %N, 20.51; Found: %C, 66.70; %H, 7.81; %N, 20.75. *H NMR (300 MHz, CDCb): δ 8.50 (dd, J=4.3,1.5 Hz, 1H), 7.90 (dd, 1=8.4,1.5 Hz, 1H), 7.42 (dd, J=8.4,4.3 Hz, 1Ή), 20 6.75 (s, 2H), 4.77 (t, J=6.8 Hz, 2H), 3.50 (pentet, J=6.1 Hz, 1H), 3.35 (m, 2H), 2.95 (t, &gt;7.8 Hz, 2H), 2.13-2.04 (m, 2H), 1.86-1.76 (m, 2H), 1.52-1.40 (m, 2H), 1.05 (d, &gt;6.1 Hz, 6H), 0.97 (t, &gt;7.3 Hz, 3H). -77- WO 99/29693 PCT/US98/26473

Example 76

Compound of Formula XXXI N4-(3-Butoxypropyl)-3-nitro[l,5]naphthyridin-4-amine 5 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[l,5]naphthyridine (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 10 dichloromethane (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 gof N4-(3-butoxypropyl)-3-nitro[l,5]naphthyridin-4-amine as a colorless oil. ]H NMR (300 MHz. CDCh): 6 10.08 (broad s, IH), 9.38 (broad s, IH), 8.78 (m, IH), 8.22 15 (dd, J=8.4,1.6 Hz, IH), 7.64 (dd, J=8.4,4.1 Hz, IH), 4.57 (broad s, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.10-2.03 (m, 2H), 1.65-1.55 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (EI): m/e 304.1535 (304.1535 calc’d for C15H20N4O3).

Example 77 20 Compound of Formula ΧΧΧΠ N4-(3-Butoxypropyl)[l,5]naphthyridine-3,4-diamine

Using the method of Example 72, N4-(3-butoxypropyl)-3-nitro[l,5]naphthyridin-4-amine (4.9 g, 16 mmol) was reduced to provide 4.3 g ofN4-^- butoxypropyl)[l,5]naphthyridine-3,4-diamine as a bright yellow oil. Analysis: Calculated 25 for C15H22N4O: %C, 65.67; %H, 8.08; %N, 20.42; Found: %C, 65.48; %H, 8.07; %N, 20.41. *H NMR (300 MHz. CDCh): δ 8.70 (dd, J=4.1,1.6 Hz, IH), 8.39 (s, IH), 8.18 (dd, J=8.4,1.6 Hz, IH), 7.37 (dd, J=8.4,4.1 Hz, IH), 5.97 (broad s, IH), 3.96 (broad s, 2H), 3.63-3.56 (m, 4H), 3.44 (t, 1=6.7 Hz, 2H), 1.89 (pentet, 3=6.2 Hz, 2H), 1.63-1.53 (m, 2H), 1.44-1.32 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); MS (EI): m/e 274.1799 (274.1793 calc’d for 30 C15H22N4O). -78- WO 99/29693 PCT/US98/26473

Example 78

Compound ofFormula ΧΧΧΙΠ l-(3-Butoxypropyl)-2-butyl-l//-imidazo[4,5-c]il,51naphthyridine

Using the general method of Example 73 Part A and Part B, 1^-(3- 5 butoxypropyl)[l,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-17/-imidazo[4,5-c][l,5]naphthyridine 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. 10 Analysis: Calculated for C20H28N4O: %C, 70.56; %H, 8.29; %N, 16.46; Found: %C, 70.48; %H, 8.25; %N, 16.61. ]H NMR (300 MHz. CDCh): δ 9.32 (s, IH), 8.90 (dd, J=4.3,l.6 Hz, IH), 8.49 (dd, &gt;8.5,1.6 Hz, IH), 7.57 (dd, &gt;8.5,4.3 Hz, IH), 4.94 (t, &gt;7.0 Hz, 2H), 3.45-3.39 (m, 4H), 3.04 (t, &gt;7.9 Hz, 2H), 2.26 (pentet, J=6.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.62-1.48 (m, 4H), 1.45-1.33 (m, 2H), 1.03 (t, &gt;7.3 Hz, 3H), 0.94 (t, &gt;7.3 Hz, 15 3H).

Example 79

Compound ofFormula XXXIV l-(3-Butoxypropyl)-2-butyl-lH-imidazo[4,5-c][l,51naphthyridine-5N-oxide 20 Using the general method of Example 74, l-(3-butoxypropyl)-2-butyl-l/f- imidazo[4,5-c][l,5]naphthyridine (2.2 g, 6.47 mmol) was oxidized to provide 1.6 g of 1-(3-butoxypropyl)-2-butyl-l#-imidazo[4,5-c][l,5]naphthyridine-5N-oxide as a yellow powder, m.p. 126.5-127.5°C. Analysis: Calculated for C20H28N4O2: %C, 67.39; %H, 7.92; %N, 15.72; Found: %C, 67.13; %H, 7.69; %N, 15.82.*H NMR (300 MHz, CDCh): δ 9.22 25 (dd, &gt;8.8,1.5 Hz, IH), 9.04 (s, IH), 8.99 (dd, J=4.3,1.5 Hz, IH), 7.65 (dd, &gt;8.8,4.3 Hz, IH), 4.89 (t, &gt;7.0 Hz, 2H), 3.46-3.39 (m, 4H), 3.01 (t, &gt;7.9 Hz, 2H), 2.28-2.20 (m, 2H), 1.97-1.87 (m, 2H), 1.62-1.46 (m, 4H), 1.45-1.33 (m, 2H), 1.03 (t, &gt;7.3 Hz, 3H), 0.94 (t, &gt;7.3 Hz, 3H). -79- WO 99/29693 PCT/US98/26473

Example 80

Compound of Formula I 1 -(3-ButoxypropyI)-2-buty I-177-imidazo [4,5-c] [1,5] naphthyridin-4-amin e

<img img-format="tif" img-content="drawing" file="IL136556AD000268.tif" id="idf0068" />

Using the general method ofExample 75, l-(3-butoxypropyl)-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridine-5N-oxide (1.2 g, 3.4 mmol) was reacted with trichloroacetyl isocyanate (0.6 mL, 5.0 mmol) and the resulting intermediate was hydrolyzed to provide 0.86 g of l-(3-butoxypropyl)-2-butyl-l//-imidazo[4,5- 10 c][l,5]naphthyridin-4-amine as a white powder, m.p. 101.0-101.5°C. Analysis: Calculated for C20H29N5O: %C, 67.58; %H, 8.22; %N, 19.70; Found: %C, 67.55; %H, 7.96; %N, 20.10. *H NMR (300 MHz. DMSO): δ 8.50 (dd, J=4.4,1.5 Hz, IH), 7.91 (dd, &gt;8.4,1.6 Hz, IH), 7.42 (dd, J=8.4,4.4 Hz, IH), 6.77 (s, 2H), 4.78 (t, J=6.9 Hz, 2H), 3.38-3.30 (m, 4H), 2.93 (t, &gt;7.8 Hz, 2H), 2.11 (pentet, &gt;6.1 Hz, 2H), 1.82 (pentet, J=7.6 Hz, 2H), 1.51- 15 1.39 (m, 4H), 1.37-1.25 (m, 2H), 0.96 (t, &gt;7.3 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).

Example 81

Compound of Formula XXXI N4-(2-Phenoxyethyl)-3-nitro[l ,5] naphthyridin-4-amine 20 Using the general method ofExample 76,4-chloro-3-nitro[l,5]naphthyridine (5.0 g, 24 mmol) was reacted with 2-phenoxyethylamine (3.5 mL, 27 mmol) to provide 6.6 g of N4-(2-phenoxyethyI)-3-nitro[l,5]naphthyridin-4-ainine as a yellow solid, m.p. 107-108°C. Analysis: Calculated for C16H14N4O3: %C, 61.93; %H, 4.55; %N, 18.05; Found: %C, 61.99; %H, 4.58; %N, 18.42. *H NMR (300 MHz, DMSO): δ 10.25 (broad s, IH), 9.39 25 (broad s, IH), 8.81 (dd, J=4.1,1.7 Hz, IH), 8.25 (dd, &gt;8.5,1.7 Hz, IH), 7.67 (dd, &gt;8.5,4.1 Hz, IH), 7.34-7.26 (m, 2H), 7.01-6.96 (m, 3H), 4.89 (broad s, 2H), 4.35 (ζ &gt;5.1 Hz, 2H); MS (EI): m/e 310.1065 (310.1065 calc’d for Ci6H14N4O3). -80- WO 99/29693 PCT/US98/26473

Example 82

Compound of Formula XXXII N4-(2-Phenoxyethyl)[l,5]naphthyridine-3,4-diamine 5 Using the general method of Example 77, N4-(2-phenoxyethyl)-3- nitro[l,5]naphthyridin-4-amine (5.4 g, 17.4 mmol) was reduced to provide 4.6 g ofN4-(2-phenoxyethyl)[l,5]naphthyridine-3,4-diamine as a bright yellow oil. 1H NMR (300 MHz, DMSO): δ 8.68 (dd, J=4.1,1.7 Hz, 1H), 8.40 (s, 1H), 8.10 (dd, &gt;8.4,1.7 Hz, 1H), 7.39 (dd, &gt;8.4,4.1 Hz, 1H), 7.28-7.22 (m, 2H), 6.94-6.90 (m, 3H), 6.12 (t, J=7.0 Hz, 1H), 5.15 (s, 10 2H), 4.13 (t, &gt;5.5 Hz, 2H), 3.93-3.87 (m, 2H); MS (CI): m/e 281 (M+H).

Example 83

Compound of Formula XXXHI 2-(2-Butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl Phenyl Ether 15 Using the general method of Example 73 Part A and Part B, ^-(2- phenoxyethyl)[l,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) was reacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resulting amide intermediate was cyclized to provide 4.0 g of 2-(2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl phenyl ether as a white solid, m.p. 150-150.5°C. Analysis: Calculated for C21H22N4O: %C, 72.81; %H, 20 6.40; %N, 16.17; Found: %C, 72.78; %H, 6.40; %N, 16.31. *H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3,1.7 Hz, 1H), 8.52 (dd, &gt;8.4,1.7 Hz, 1H), 7.74 (dd, &gt;8.4,43 Hz, 1H), 7.25-7.20 (m, 2H), 6.91-6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t, &gt;5.2 Hz, 2H), 3.09 (t, &gt;7.7 Hz, 2H), 1.91 (pentet, &gt;7.6 Hz, 2H), 1.55-1.43 (m, 2H), 0.97 (t, &gt;7.3 Hz, 3H); MS (EI): m/e 346.1794 (346.1793 calc’d for C21H22N4O). 25

Example 84

Compound of Formula XXXIV 2-Butyl-l-(2-phenoxyethyl)-lir-imidazo[4,5-c][l^]naphthyridine-5N-oxide Using the general method of Example 74,2-(2-butyl- ltf-imidazo[4,5- 30 c][l,5]naphthyridin-l-yl)ethyl phenyl ether (0.6 g, 1.7 mmol) was oxidized to provide 0.44 g of 2-butyl-l-(2-phenoxyethyl)-l/f-imidazo[4,5-c][l,5]naphthyridine-5N-oxide as a yellow powder. ]H NMR (300 MHz, CDClri: δ 9.10-9.03 (m, 3H), 7.81 (dd, &gt;8.7,43 Hz, -81 - WO 99/29693 PCT/US98/26473 IH), 7.25-7.20 (m, 2H), 6.92-6.83 (m, 3H), 5.16 (t, J=4.9 Hz, 2H), 4.51 (t, J=4.9 Hz, 2H), 3.06 (t, J=7.7 Hz, 2H), 1.93-1.83 (m, 2H), 1.54-1.41 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (CI): m/e 363 (M+H). 5 Example 85

Compound of Formula I 2-Butyl-l-(2-phenoxyethyl)-l//-imidazo[4,5-c][l,5]naphthyridin-4-ainine

<img img-format="tif" img-content="drawing" file="IL136556AD000269.tif" id="idf0069" />

Using the general method of Example 75,2-butyl-l-(2-phenoxyethyl)-l//- 10 imidazo[4,5-c][l,5]naphthyridine-5N-oxide (0.38 g, 1.05 mmol) was reacted with trichloroacetyl isocyanate (0.19 mL, 1.6 mmol) and the resulting intermediate was hydrolyzed to provide 0.23 g of 2-butyl-l-(2-phenoxyethyl)-l/7-imidazo[4,5-c][l,5]naphthyridin-4-amine as a white powder, m.p. 159.0-159.2°C. ]H NMR (300 MHz. DMSO): δ 8.52 (dd, J=4.4,1.5 Hz, IH), 7.92 (dd, J=8.4,1.5 Hz, IH), 7.45 (dd, J=8.4,4.4 15 Hz, IH), 7.26-7.21 (m, 2H), 6.92-6.86 (m, 3H), 6.79 (s, 2H) 5.13 (t, J=5.2 Hz, 2H), 4.48 (t, J=5.2 Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 1.91-1.81 (pentet, J=7.4 Hz, 2H), 1.52-1.40 (m, 2H), 0.95 (t, &gt;7.3 Hz, 3H); MS (El): m/e 361.1899 (361.1902 calc’d for C21H23N5O).

Example 86

20 Compound of Formula XXXI 1,1-DimethyIethyl N-{2-[(3-Nitroll,5]naphthyridin-4-yl)amino]ethyI}carbamate A solution of diisopropylethylamine (13.47 g, 0.10 mole) in dichloromethane (25 mL) was added to a solution of 5-chloro-3-nitro[l,5]naphthyridine (18.2 g, 0.086 mol) in 25 dichloromethane (250 mL). A solution of ieri-butyl N-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL) was slowly added to the reaction mixture. The reaction mixture was heated at reflux overnight. Additional ieri-butyl N-(2- -82- 136556/2 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 5 purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1-dimethylethyl N-{2-[(3-nitro[l,5Jnaphthyridin-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 C15H19N5O4: %C, 54.05; %H, 5.75; %N, 21.01; Found: %C, 54.17; %H, 10 5.73; %N, 20.90.

Example 87

Compound of Formula XXXH 1.1- Dimethylethyl 15 N-{2-[(3-AminoIl,5]naphthyridin-4-yl)amino]ethyl}carbamate 1,1-Dimethylethyl N-{2-[(3-nitro[l ,5]naphthyridin-4-yl)amino]ethyl} carbamate (10 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 20 9.1 g of 1,1-dimethylethyl N-{2-[(3-amino[l,5]naphthyridin-4-yl)aminoJethyl}carbamate as a yellow syrup. Analysis: Calculated for C15H21N5O2 + 0.1 CH3CO2C2H5: %C, 59.25; %H, 7.04; %N, 22.43; Found: %C, 58.96; %H, 6.87; %N, 22.46.

Example 88

25 Compound of Formula XXXHI 1.1- Bismethylethyl N-[2-(2-butyl-l//-imizado[4,5-c]l,5]naphthyridin-l-yI)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 30 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 PCT/US98/26473 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-lH-imidazo[4,5-c]l,5]naphthyridin-l-yl)ethyl]carbamate as an ivory powder, m.p. 198-199°C. Analysis: 5 Calculated for C20H27N5O2: %C, 65.01; %H, 7.36; %N, 18.95; Found: %C, 64.75; %N, 7.57; %N, 19.09.

Example 89

Compound of Formula XXXIII 10 l-{2-[(l, l-dimethylethoxycarbonyl)anaino]ethyl}-2-butyl- 177-imidazo[4,5-c][l,5]naphthyridine-5N-oxide 3-Chloroperbenzoic acid (0.7 g of57-86%) was dissolved in chloroform (10 mL). One half of this solution was added to a solution of 1,1 -dimethylethyl N-[2-(2-butyl-1/7-imidazo[4,5-c]l,5]naphthyridin-l-yl)ethyl)carbamate (1.0 g, 2.7 mmol) in chloroform (10 15 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 10% sodium hydroxide, with water, and with brine; dried and concentrated under vacuum 20 to provide 1.1 g of a yellow solid. This material was recrystallized twice from acetonitrile to provide 1.0gofl-{2-[(l,l-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-lJY-imidazo[4,5-c][l,5]naphthyridine-5N-oxide. Analysis: Calculated for C20H27N5O3: %C, 62.32; %H, 7.06; %N, 18.17; Found; %C, 62.03; %H, 6.73; %N, 18.10. -84- WO 99/29693 PCT/US98/26473

Example 90 Compound of Formula I 1,1 -Dimethy lethyl N-[2-(4-Amino-2-butyl-l/f-imidazol4,5-c][l,5]naphthyridin-l-yl)ethyl]carbamate

<img img-format="tif" img-content="drawing" file="IL136556AD000270.tif" id="idf0070" />

10 15 20

Trichloroacetyl isocyanate (4.8 mL, 40 mmol) was added via a syringe to a solution of l-{2-[(l,l-dimethylethoxycarbonyl)aminoJethyl}-2-butyl-l//-imidazo[4,5-c][l,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 caibonate, 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 6.0 g of 1,1-dimethylethyl N-[2-(4-amino-2-butyl-l //-imidazo [4,5 -c][ 1,5 ]naphthyridin-l -yl)ethyl]carbamate as ivory crystals, m.p. 118-120°C. Analysis: Calculated for C2oH28N602: %C, 62.48; %H, 7.34; %N, 21.85; Found: %C, 62.31; %H, 7.23; %N, 22.13. HRMS (EI) calcd for C2oH28N602 (M+) 384.2273, found 384.2273 -85- WO 99/29693 PCT/US98/26473

Example 91

Compound of Formula I 2-(4-Amino-2-butyl-lZf-imidazo[43-cni,5Jnaphthyridin-l-yI)ethaneamine

<img img-format="tif" img-content="drawing" file="IL136556AD000271.tif" id="idf0071" />

Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethyl N-[2-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]carbamate (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 dichloromethane and then extracted with 10 10% hydrochloric acid. The hydrochloric acid extract was washed twice with dichloromethane and then it was made basic with ammonium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 3.7 g of 2-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine as a white powder, m.p. 175-176°C. Analysis: Calculated for C15H20N6.· %C, 63.36; %H, 7.09; %N, 29.55; Found: %C, 62.98; 15 %H, 6.92; %N, 29.89. HRMS (EI) caicd for C15H2oN6 (M+) 284.1749, found 284.1748.

Example 92

Compound of Formula I N’-[2-(4-Anaino-2-butyl- 20 l//-imidazo[4,5-c] [ 1,5] n aph thy ridin-l-yl)ethy IJ acetamide

<img img-format="tif" img-content="drawing" file="IL136556AD000272.tif" id="idf0072" />

-86- WO 99/29693 PCT/US98/26473

Under a nitrogen atmosphere, acetyl chloride (50 pL, 0.7 mmole) in dichloromethane (25 mL) was added dropwise to a cooled (ice bath) solution of 2-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (0.2 g, 0.7 mmol) in dichloromethane (50 mL). After the addition was complete, the reaction mixture was 5 allowed to warm to ambient temperature. After 30 minutes thin layer chromatography indicated that the reaction was complete. The reaction mixture was washed with 10% 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 dichloromethane) to provide 0.2 g of a solid. This solid was recrystallized 10 from acetonitrile (30 mL) to provide 0.18 g of N1-[2-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]acetamide as a white powder, m.p.228-230°C. Analysis: Calculated for CnHzjNeO: %C, 62.56; %H, 6.79; %N, 25.75; Found: %C, 62.50; %H, 6.59; %N, 26.04. HRMS (El) calcd for CzaHzsNsOz (M+) 326.1855, found 326.1846 15 Example 93

Compound of Formula I N’-(2-(4-Amino-2-butyl- l//-imidazo[4,5-c] [1,5] naphthyridin-1 -yl)ethyl]-(E)-2-butenamide

<img img-format="tif" img-content="drawing" file="IL136556AD000273.tif" id="idf0073" />

20 Using the general method of Example 92, crotonyl chloride (68 pL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-17/-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1 -[2-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)efhyl]-(E)-2-butenamide as a white powder, m.p. 198-200°C. Analysis: Calculated for C19H24N6O: %C, 64.75; %H, 6.86; %N, 23.85; Found: %C, 25 64.25; %H, 6.68; %N, 23.99. HRMS (El) calcd for C,9H24N6O (M+) 352.2011 found 352.1996 -87-

Example 94

Compound of Formula I N’-[2-(4-Amino-2-butyl-ljHr-imidazo[4,5-c][l,5]naphthyridin-l-yI)ethyl]- 1 -cyclohexanecarboxamide WO 99/29693 PCT/US98/26473 NH,

<img img-format="tif" img-content="drawing" file="IL136556AD000274.tif" id="idf0074" />

0 10

Using the general method of Example 92, cyclohexanecarbonyl chloride (94 pL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-l/7-imidazo[4,5-c] [1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g ofN1-[2-(4-amino-2-butyl-l/f-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-l-cyclohexanecarboxamide as a white powder, m.p. 188-190°C. Analysis: Calculated for C22H30N6O: %C, 66.98; %H, 7.66; %N, 21.30; Found: %C, 66.72; %H, 7.57; %N, 21.48. HRMS (El) calcd for C22H30N6O (M+) 394.2481 found 394.2475.

Example 95

15 Compound of Fonnula I N1-[2-(4-amino-2-butyl-lZf-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethylJ- 3,5-di-(l,l-dimethyIethyl)-4-hydroxybenzamide NH,

<img img-format="tif" img-content="drawing" file="IL136556AD000275.tif" id="idf0075" />

-88- 136556/2 WO 99/29693 PCT/US98/26473

Using the general method of Example 92, 3,5-bis-(l,l-dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reacted with 2-(4-amino-2-butyl- 1H-imidazo[4,5-c][lJ5]naphthyridin-l-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1 -[2-(4-amino-2-butyl-l//-imidazo[4,5-c][ 1,5]naphthyridin-l-yl)ethyl] -3,5-bis-( 1,1 - 5 dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 248-250°C. Analysis:

Calculated for C30H4oN602: %C, 69.74; %H, 7.80; %N, 16.27; Found: %C, 69.65 %H, 7.69; %N, 16.42. HRMS (EI) calcd for C30H4oN602 (M+) 516.3212 found 516.3226

Example 96

10 - Compound of Formula I N1-I2-(4-Amino-2-butyl-lfl'-imidazo[4,5-c][l^]naphthyridm-l-yI)ethyl]-

<img img-format="tif" img-content="drawing" file="IL136556AD000276.tif" id="idf0076" />

Using the general method of Example 92, hydrocinnamoyl chloride (0.1 g, 0.7 15 mmol) was reacted with 2-(4-amino-2-butyl- l//-imidazo[4,5-c] [ 1,5]naphthyridin-1 - yl)ethaneamine (0.2 g, 0.7 mmol). After one hour the reaction mixture was poured directly onto a silica gel column and eluted with di chloromethane at first, then 15% methanol / dichloromethane to provide 0.2 g of a solid. This solid was recrystallized from toluene to provide 0.2 g ofN1-[2-(4-amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]- 20 3-phenylpropanamide hydrochloride as a white powder, m.p. 183-185°C. Analysis:

Calculated for C24H28N6O HCI: %C, 63.64; %H, 6.45; %N, 18.55; Found: %C, 63.68; %H, 6.43; %N, 18.55. -89- WO 99/29693 PCT/US98/26473

Example 97

Compound of Formula I N-[2-(4-Amino-2-butyI-l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-5 5-oxotetrahydro-2-furancarboxamide

<img img-format="tif" img-content="drawing" file="IL136556AD000277.tif" id="idf0077" />

A solution of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (0.23 g, 1.7 mmole in anhydrous dichloromethane (30 mL) was slowly added to a solution of2-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (0.5 g, 1.7 mmol) in 10 anhydrous dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then a solution of l-[3-(dimethoxyamino)propyl]-3-ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 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 10% 15 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 with dichloromethane) followed by recrystallization from acetonitrile to provide 0.1 g ofN-[2-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l~yl)ethyl]-5-oxotetrahydro-2-furancarboxamide as a white powder, m.p. 153-154°C. Analysis: 20 Calculated for C20H24N6O3: %C, 60.59; %H, 6.10; %N, 21.19; Found: %C, 60.34; %H, 6.14; %N, 21.13. HRMS (EI) calcd for C2oH24N603 (M+) 396.1909 found 396.1905 -90- WO 99/29693 PCT/US98/26473

Example 98

Compound of Formula I

Amino-2-buty 1-1 77-imidazo [4,5-c] [ 1,5] naph thyridin-1 -y l)ethy 1]-5 2-(3-hydroxyphenyl)acetamide

<img img-format="tif" img-content="drawing" file="IL136556AD000278.tif" id="idf0078" />

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-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.13 g of N1-[2-(4-amino-2-butyl-l//- 10 imidazo[4,5-c][l ,5]naphthyridin-l-yl)ethyl]-2-(3-hydroxyphenyl)acetamide as a white powder, m.p. 208-210°C. Analysis: Calculated for C23H26N6O2: %C, 66.01; %H, 6.26; %N, 20.08; Found: %C, 65.63; %H, 6.11; %N, 20.30. HRMS (El) calcd for C23H26N6O2 (M+) 418.2117 found 418.2109. 15 Example 99

Compound of Formula I N-I2-(4-Amino-2-butyl-17r-imidazo[4,5-c][l,5]naphtliyridin-l-yl)ethyl]- 6-hydroxy-2~pyridinecarboxamide

<img img-format="tif" img-content="drawing" file="IL136556AD000279.tif" id="idf0079" />

20 Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-l/Z-imidazo [4,5-c] [1,5] naphthyri din-1- -91- WO 99/29693 PCT/US98/26473 yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.15 g ofN-[2-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide as a white powder, m.p. 258-260°C. Analysis: Calculated for C21H23N7O2 + ’/2 CH3CN: %C, 62.03; %H, 5.80; %N, 24.66; Found: %C, 61.87; %H, 5.70; %N, 24.60.

Example 100 Compound of Formula I N1-[2-(4-Ainino-2-butyI-lZ/-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]- 3,7-dimethyl-6-octenamide

<img img-format="tif" img-content="drawing" file="IL136556AD000280.tif" id="idf0080" />

Using the general method ofExample 97 citronellic acid (0.3 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl- l//-imidazo[4,5-c][ 1,5]naphthyridin-1 -yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N!-[2-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-3,7-dimethyl-6-octenamide as a white whispy solid, m.p. 15 163-164°C. Analysis: Calculated for C25H36N6O: %C, 68.77; %H, 8.31; %N, 19.25;

Found: %C, 68.84; %H, 8.14; %N, 19.58. HRMS (EI) calcd for C25H36N6O (M+) 436.2950 found 4362952. -92- WO 99/29693 PCT/US98/26473

Example 101 Compound of Formula I 1,1-Dimethylethyl N-[l-({[2-(4-Amino-2-butyl-l//-imidazo[4,5-c] [ 1,5] naphthyridin-1 -yl)ethy 1] amino} carbonyl)-3-methylbu tyl] carb amate

<img img-format="tif" img-content="drawing" file="IL136556AD000281.tif" id="idf0081" />

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-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of 1,1-dimethylethyl N-[l-({[2-(4- 10 amino-2-butyl- l/f-imidazo[4,5-c] [ 1,5]naphthyridin-1 -yl)ethyl]amino} carbonyl)-3- methylbutyl]carbamate as a white solid, m.p. 184-185°C. HRMS (EI) caicd for C26H39N7O3 (M+) 497.3114 found 497.3093. 15

Example 102 Compound of Formula I N’-[2-(4-Amino-2-butyl-l/7-imidazo [4,5-c] [1,5) naphthyridin-1 -yl)ethyl]-2-amino-4-methylpentanamide NH2 1,1 -Dimethylethyl N-[ 1 -({[2-(4-amino-2-butyI- l/7-imidazo[4,5-20 c][l,5]naphthyridin-l-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate (0.35 g, 0.7 mmol) was combined with 1 N hydrochloric acid (40 mL) and heated on a steam bath for -93- WO 99/29693 PCT/US98/26473 30 minutes. The reaction mixture was allowed to cool and then it was made basic with 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.15 g ofN’-[2-(4-amino-2-butyl-17/-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-2-amino-4-methylpentamide as a white solid, m.p.60-65°C. Analysis: Calculated for 5 C21H31N7O: %C, 63.27; %H, 7.86; %N, 24.66; Found: %C, 62.27; %H, 7.67; %N, 24.77. HRMS (El) calcd for C2iH3,N7O (M+) 397.2590 found 397.2582. 10 15 20

Example 103 Compound of Formula I N-(2-(4-Amino-2-butyl-177-imidazo[4,5-c]Il,5]naphthyridin-l-yl)ethyl]- 3,5-dimethyl-4-isoxazolecarboxamide NH2

<img img-format="tif" img-content="drawing" file="IL136556AD000282.tif" id="idf0082" />

Using the general method of Example 97 3,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.23 g ofN-[2-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide as a white powder, m.p. 188-189°C. Analysis: Calculated for C21H25N7O2: %C, 61.90; %H, 6.18; %N, 24.06; Found: %C, 61.92; %H, 6.15; %N, 24.28. HRMS (El) calcd for C21H25N7O2 (M+) 407.2069 found 407.2068 -94- WO 99/29693 PCT/US98/26473

Example 104 Compound of Formula II N1-[2-(4-Amino-2-butyl-6,7,8,9-tetrahydro-l/f-imidazo[4,5-c] [l,5]naphthyridin-l-yI)ethyI]-3^-di-(l,l-diniethylethyl)-4-hydroxybenzamide

<img img-format="tif" img-content="drawing" file="IL136556AD000283.tif" id="idf0083" />

NH2

<img img-format="tif" img-content="drawing" file="IL136556AD000284.tif" id="idf0084" />

A solution of N*-[2-(4-amino-2-butyl- l/f-imidazo[4,5-c][ 1,5]naphthyridin-1 -yl)ethyl)-3,5-di-(l,l-dimethylethyl)-4-hydroxybenzamide (0.1 g, 0.19 mmol) in trifluoroacetic acid (15 mL) and platinum oxide (0.1 g) were combined and hydrogenated overnight on a Parr apparatus. The reaction mixture was filtered to remove the catalyst. 10 The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane. The dichloromethane 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 dichloromethane. The resulting oil was triturated with acetonitrile to provide 0.05 g of N1 15 [2-(4-amino-2-butyl-6,7,8,9-tetrahydro-17/-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]- 3,5-di-(l,l-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 208-210°C. Analysis: Calculated for C30H44N6O2 + 0.1 CF3CO2H: %C, 68.17; %H, 8.35; %N, 15.79; Found: %C, 68.48; %H, 8.29; %N, 16.08. -95- WO 99/29693 136556/2 PCT/US98/26473

Example 105 Compound of Formula I N1-[4-(4-Amino-2-butyl-lTi-imidazo[4,5-c][l^]naphthyridin-l-yl)butyl]-5 5-(l,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-l H-purinyl)pentamide

<img img-format="tif" img-content="drawing" file="IL136556AD000285.tif" id="idf0085" />

4-(4-Amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l -yl)butaneamine (0.2 g), 5-(l,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-lH-purinyl)pentanoic acid (0.18 g) and dichioromethane (100 mL) were combined and stirred at ambient temperature for 30 10 minutes. l-[3-(Dimethylamino)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-amino-2-butyl -17/-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- 5-(l,3-dimethyl-2,6-oxo-2,3,6,7-tetrahy4ro-lH-purinyl)pentamide, m.p. 153.5-155°C. 15 Analysis: Calculated for C28H36N10O3: %C, 60.61; %H, 6.66; %N, 24.37; Found: %C, 60.65; %H, 6.66; %N, 24.32. -96-

Example 106

Compound of Formula I N’-[4-(4-Amino-2-butyl -l/7-imidazo[4,5-c][lr5]naphthyridin-l-yl)butyl}- WO 99/29693 136556/2

<img img-format="tif" img-content="drawing" file="IL136556AD000286.tif" id="idf0086" />

10

Using the general method of Example 105 6-moipholinonicotinic acid (0.12 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-17?-imidazo[4,5-c][lJ5]naphthyridin-l-yl)butaneamine (0.2 g, 0.64 mmol) to provide N’-[4-(4-amino-2-butyl -177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]-6-morpholinonicotinamide as a white solid, m.p. 95-100°C. Calculated for C27H34N8O2 + ΆΗιΟ: %C, 63.39; %H, 6.90: %N, 21.90; Found: %C, 63.69; %H, 6.95; %N, 21.52.

Example 107 Compound of Formula I 15 N1-[4-(4-Amino-2-butyl -lJ7-imidazo[4,5-c] {l,5]naphthyridin-l-yl)butyl]-

<img img-format="tif" img-content="drawing" file="IL136556AD000287.tif" id="idf0087" />

Using the general method of Example 105 6-quinolinecarboxyliG acid (0.11 g, 64 mmol) was reacted with 4-(4-an±io-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l- -97- WO 99/29693 PCT/US98/26473 yl)butaneamine (0.2 g, 0.64 mmol) to provide N’-[4-(4-amino-2-butyl -l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]-6-quinolinecarboxamide as a white solid, m.p. 190-191°C. Analysis: Calculated for C27H29N7O + V4H2O: %C, 68.70; %H, 6.30; %N, 20.77; Found: %C, 68.54; %H, 6.21; %N, 20.93.

Example 108 Compound of Formula I N’-[4-(4-Amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l-yI)butyl]-2-(4-hydroxy-5-methyI-2-oxo-l ,2-dihydro-l -pyrimidinyl)acetamide

<img img-format="tif" img-content="drawing" file="IL136556AD000288.tif" id="idf0088" />

Using the general method of Example 105 2-(4-hydroxy-5-methyl-2-oxo-l,2-dihydro-l-pyrimidinyl)acetic acid (0.12 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.06 g of N1 -[4-(4-amino-2-butyl - ltf-imidazo[4,5-c][ 1,5]naphthyridin-1 -yl)butyl]-2-(4- 15 hydroxy-5-methyl-2-oxo-l ,2-dihydro-l -pyrimidinyl)acetamide as a solid, m.p. 242-244°C. -98-

Example 109

Compound of Formula I N’-[4-(4-Amino-2-butyl -l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- 2-(2-pyrimidinylsulfanyl)acetamide WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD000289.tif" id="idf0089" />

Using the general method of Example 105 (2-pyrimidinylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-ltf-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.2 g, 0.64 mmol) to provide N’-[4-(4-amino-2-butyl -l//-imidazo[4,5- 10 c][l,5]naphthyridin-l-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide as a white solid, m.p 156-160’C (dec.).

Example 110 Compound of Formula I 15 N1-[4-(4-Amino-2-butyl -1/7-imid azo [4,5-c] [l,5]naphthyridin-l-yl)butyl]-

<img img-format="tif" img-content="drawing" file="IL136556AD000290.tif" id="idf0090" />

Using the general method of Example 105 (4-pyridylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l- 20 yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.1 g of N1-[4-(4-amino-2-butyl -1H- -99- WO 99/29693 PCT/US98/26473 imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]-2-(4-pyridyIsulfanyl)acetamide as a solid, m.p. 127.5-129°C.

Example 111 Compound of Formula I 4-(4-amino-17¥-imidazo[4,5-c][ 1,53naphthyridin-1 -yl)butaneamine

<img img-format="tif" img-content="drawing" file="IL136556AD000291.tif" id="idf0091" />

NH2

Part A 10 Triethylorthofoimate (2.8 mL, 16.6 mmol) was added to a solution of 1,1- dimethylethylN-{4-[(3-amino[l,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 15 reaction was refluxed overnight. A dark orange/brown oil had formed. The toluene supernatant was decanted off and concentrated under vacuum to provide 1.1 g of 1,1-dimethylethyl N-[4-(l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate. The oil was identified as 4-(l/f-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine. This material was reacted with 1,1-dimethylethyl-dicarbonate to provide an additional 1 g of 1,1- 20 dimethylethyl N-[4-(l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate. The two lots were combined and carried on to the next step.

PartB 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 25 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 {4- [(1,1 -dimethylethylcarbonyl)amino]butyl}-l//-imidazo[4,5-c] [ 1,5]naphthyridine-5N-oxide.

Part C

Tosyl chloride (0.64 g, 3.37 mmol) was slowly added in small portions to a 5 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 10 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/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate.

PartD A mixture of the material from Part C and 1 N hydrochloric acid (25 mL) was 15 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 of 4-(4-amino-l//-imidazo[4,5- c][l,5]naphthyridin-l-yl)butaneamine as a pale yellow solid, m.p. 161-163°C. Mass spec (M+1) = 257.09. 20 -101- WO 99/29693 136556/2 PCT/US98/26473

Example 112 Compound of Formula I ^-(4-(4-Amin o-2-butyl-12F-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- 4-{{2-(dimethylamino)ethoxyl(phenyl)methyl}benzamide

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Part A

Under a nitrogen atmosphere phenyl magnesium bromide (39 mL of 3 M in ether) 10 was added via a syringe over a period of 30 minutes to a solution of methyl 4-formylbenzoate (19.2 g, 117 mmol). The mixture was stirred for an additional 10 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 15 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 (~1 mL) was collected 20 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,N-dimethylethanolamine (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 25 bicarbonate (the aqueous layer was basic). The aqueous layer was extracted with an -102- WO 99/29693 PCT/US98/26473 additional lOOmL 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 5%, then 10% methanol in dichioromethane) to provide 2.49 g of methyl 4-[a-(2-N,N-dimethylaminoethoxy)benzyl]benzoate as a colorless oil. 5 IN Sodium hydroxide (2.54 mL) was added to a solution of methyl 4-[a-(2-N,N- 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 45°C). The resulting residue was extracted into a mixture of 10 dichioromethane (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 of diethyl ether provided 0.39 g of 4-[ct-(2-N,N- dimethylaminoethoxy)benzyl]benzoic acid as a white powder.

PartB 15 4-(4-Amino-2-butyl- l#-imidazo[4,5-c][ 1,5]naphthyridin-l -yl)butaneamine (0.13 0 g, 0.4175 mmol) and 4-[a-(2-N,N-dimethylaminoethoxy)benzyl]benzoic acid (0.125 g, 0.4175 mmol) were combined in dichioromethane (150 mL) and stirred at ambient temperature until a clear solution was obtained. l-[3-(Dimethylamino)propy]-3-ethylcarbodiimide hydrochloride (0.088 g, 0.46 mmol) was added and the reaction was 20 maintained at ambient temperature for 2 days. The volume of dichioromethane was reduced and the concentrate was purified by flash chromatography (silica gel eluting with 10% methanol in dichioromethane) to provide 0.085 g of N1-[4-(4-amino-2-butyl-liZ-imidazo[4,5-c] [ 1,5]naphthyridin-1 -yl)butyl]-4- {[2- (dimethylamino)ethoxy](phenyl)methyl}benzamide as a solid, m.p. 105-108°C. Mass 25 spec (M + 1) = 594.30. -103- WO 99/29693 PCT/US98/26473

Example 113 Compound of Formula I N1-I4-(4-Amino-2-butyI-l/f-imidazol4,5-c][l,51naphthyridin-l-yl)butyl]-

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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-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (100 mg, 0.32 mmol) to provide 30 mg ofN1-[4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]-4-benzoylbenzamide as a white solid. Mass- 10 spec (M+1=521.31).

Example 114 Compound of Formula I N’-[4-(4-Amino-2-butyl-l/f-imidazol4,5-c] (1 naphthyridin-1-yl)ethyl]-15 2-(5-methyl-2,4-dioxo-l ,2,3,4-tetrahy dro-1 -pyrimidinyl)acetamide

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Using the general method of Example 112 Part B, thymine-1-acetic acid (130 mg, 0.70 mmole) was reacted with 4-(4-amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l yl)ethaneamine (200 mg, 0.70 mmol) to provide 68 mg of N’-[4-(4-amino-2-butyl-17/- -104- WO 99/29693 PCT/US98/26473 imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]-2-(5-methyl-2,4-dioxo-l,2,3,4-tetrahydro-l-pyrimidinyl)acetamide as a white solid, m.p. 241-242°C. Mass-spec (M + 1 = 451.24).

Example 115

5 Compound of Formula I NI-[4-(4-Amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]- 6-(5-methyl-2-oxo-4-imidazoIidinyI)hexamide

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Using the general method ofExample 112 Part B, D-desthiobiotin (151 mg, 0.70 10 mmole) was reacted with 4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l- yl)ethaneamine (200 mg, 0.70 mmol) to provide 231 mg of N'-[4-(4-amino-2-butyl-1//-imidazo[4,5-c] [ 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-

Example 116

Compound of Formula I N1-[4-(4-Amino-2-butyl-lH-imidazo[4,5-c] [l,5]naphthyridin-l-yl)ethyl]methanesulfonamide WO 99/29693 PCT/US98/26473

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Using the method of Examples below, 4-(4-amino-2-butyl-l/7-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (14 mg, 50 pmol) was reacted with methanesulfonyl chloride (4 pL, 50 pmol) to provide 5.3 mg of N’-[4-(4-amino-2-butyl-l//-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]methanesulfonamide. IH NMR (500 MHz, d6-DMSO) 6 = 10 8.49 (dd, J=4.3; 1.5 Hz, 1 H), 7.92 (dd, J=8.0; 1.5 Hz, 1 H), 7.44 (dd, J=8.0; 4.3 Hz, 1 H), 7.30 (t, J=6 Hz, 1 H), 6.76 (s, 2H), 4.77 (t, J=6 Hz, 2 H), 3.50 (q, J=6 Hz, 2 H), 2.98 (t, J=7 Hz, 2 H), 2.85 (s, 3H), 1.82 (quintet, J=7 Hz, 2 H), 1.46 (m, 2 H), 0.96 (t, J=7 Hz, 3 H). Mass spec by APCI (+/-) plug injection gave desired MW. -106-

Example 117

Compound of Formula I N1-[4-(4-Amino-2-butyl-l//-imidazo[4,5-c] [l^]naphthyridin-l-yl)ethyl]benzenesulfonamide WO 99/29693 PCT/US98/26473

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Using the method of Examples 118-152 below, 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethaneamine (14 mg, 50 pmol) was reacted with benzenesulfonyl chloride (6 pL, 50 pmol) to provide 10.9 mg of N’-[4-(4-amino-2-butyl-l//-imidazo[4,5-c][ 1,5]naphthyridin-1 -yl)ethyl]benzenesulfonamide. 1H NMR (500 MHz, 10 d6-DMSO) δ = 8.43 (dd, &gt;4.4; 1.5 Hz, 1 H), 7.94 (t, J=6 Hz, 1 H), 7.89 (dd, &gt;8.4; 1.5 Hz, 1 H), 7.68 (d, &gt;8 Hz, 2 H), 7.58 (t, &gt;8 Hz, 1 H), 7.50 (t, J=8Hz, 2H), 7.41 (dd, J=8.4; 4.4 Hz, 1 H), 4.72 (t, &gt;6 Hz, 2 H), 3.34 (m, 2 H), 2.97 (t, &gt;7 Hz, 2 H), 1.81 (quintet, J=7 Hz, 2 H), 1.45 (sextet, &gt;7 Hz, 2 H), 0.97 (ζ &gt;7 Hz, 3 H). Mass spec by APCI (+/-) plug injection gave desired MW. 15

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-Amino-2-butyl-l//-imidazo[4,5- 20 c][l,5]naphthyridin-l-yl)ethaneamine (50 pmol) was dissolved in dichloromethane (5 mL) in a screw-capped test tube and the solution was cooled in an ice-water bath. An acid chloride (50 pmol) of the formula RACOC1 was added as a solution in 100 pL of dichloromethane (Acid chlorides that are solids were either dissolved or suspended in -400 pL of dichloromethane and then added). The mixture was vortexed for 15 seconds 25 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 χ 1 cm) of silica gel conditioned with dichloromethane. The product was eluted with 10:1 dichloromethane:methanol, collecting ~2 mL fractions. Thin layer 5 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 Cl 8 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% 10 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 PCT/US98/26473

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Ra

Example # Ra Fragment ‘H NMR (500 MHz, solvent indicated) 118 A H (de-DMSO) δ 8.51 (dd, J=4.4,1.5 Hz, 1H), 7.91 (dd, J=8.3,1.5 Hz, 1H), 7.46 (t, J=6 Hz, 1H), 7.44 (dd, J=8.3, 4.4 Hz, 1H), 6.73 (br s, 2H), 4.80 (t, J=6 Hz, 2H), 3.60 (q, J=6 Hz, 2H), 2.87 (t, J=7 Hz, 2H), 2.0-1.8 (m, 17H), 1.43 (sextet, J=7 Hz, 2H), 0.96 (t, J=7 Hz, 3H) 119 a (de-DMSO) δ 8.49 (d, J=4.5 Hz, 1H), 7.93 (d, J=8 Hz, 1H), 7.65 (t, J=6 Hz, 1H), 7.45 (dd, J=4.5, 8 Hz, 1H), 7.29 (d, J=8 Hz, 2H), 7.17 (d, J=8 Hz, 2H), 6.92 (br s, 2H), 4.69 (t, J=6 Hz, 2H), 3.59 (q, J=6 Hz, 2H), 2.60 (t, J=7 Hz, 2H), 2.28 (m, 2H), 1.67 (m, 4H), 1.5-1.3 (m, 6H), 0.92 (t, J=7 Hz, 3H) 120 Cl (de-DMSO) δ 8.96 (t, J=6 Hz, 1H), 8.49 (dd, J=4.0,1.5,1H), 7.92 (dd, J=8,1.5 Hz, 1H), 7.50 (d, J=8 Hz, 2H), 7.44 (dd, J=8,4.0 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 6.76 (s, 2H), 4.85 (t, J=6 Hz, 2H), 3.88 (q, 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 (t, J=7 Hz, 3H) 121 - (de-DMSO) δ 8.52 (dd, J=4.2,1.5 Hz, 1H), 8.04 (t, J=6 Hz, 1H), 7.95 (dd, J=8.5,1.5 Hz, 1H), 7.45 (dd, J=8.5,4.2 Hz, 1H), 7.4-7.2 (m, 5H), 7.00 (br s, 2H), 4.84 (t, J=6 Hz, 2H), 4.37 (s, 2H), 3.74 (s, 2H), 3.65 (q, J=6 Hz, 2H), 2.87 (t, J=7 Hz, 2H), 1.77 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.94 (t, J=7 Hz. 3H) -109- WO 99/29693 PCT/US98/26473 122 CH3 (de-DMSO) δ 8.50 (dd, J=4.4,1.5 Hz, 1H), 7.97 (t, J=6 Hz, 1H), 7.92 (dd, J=8.4,1.5 Hz, 1H), 7.45 (dd, J=8.4,1.5 Hz, 1H), 6.75 (br s, 2H), 4.762 (t, J=6 Hz, 2H), 3.57 (s, 3H), 2.88 (t, J=7 Hz, 2H), 2.27 (t, J=7 Hz, 4H), 2.18 (t, J=7 Hz, 2H), 1.93 (t, J=7 Hz, 2H), 1.80 (quintet, J=7Hz, 2H), 2.6-1.1 (m, 12H), 0.96 (t, J=7 Hz. 3H) 123 (de-DMSO) δ 8.52 (dd, J=4.4,1.5 Hz, 1H), 7.97 (t, J=6 Hz, 1H), 7.95 (dd, J=8.3,1.5 Hz, 1H), 7.45 (dd, J=8.3,4.4 Hz. 1H), 6.88 (br s. 2H). 5.79 (m, 1H), 4.98 (d. J=15 Hz. 1H). 4.91 (d, J=13 Hz, 1H), 4.76 (t, J=6 Hz, 2H), 3.57 (q, J=6 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 2.00 (q, J=7 Hz, 2H), 1.93 (t, J=6 Hz, 2H), 1.80 (quintet, J=7 Hz, 2H), 1.44 (sextet, 3-7 Hz, 2H), 1.5-1.1 (m, 12H), 0.96 (t, J=6 Hz, 3H) 124 (de-DMSO) δ 8.51 (dd, J=4.4,1.7 Hz, 1H), 7.96 (t, J=6Hz, 1H), 7.92 (dd, J=8.3,1.5 Hz, 1H), 7.44 (dd, J=8.3,4.4 Hz, 1H), 6.81 (br s, 2H), 3.76 (t, J=6 Hz, 2H), 3.59 (q, J=6 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 1.94 (m, 3H), 1.80 (quintet, J=7 Hz, 2H), 1.58 (m, 2H), 1.55-1.40 (m, 6H), 0.96 (m, 5H) 125 \-F F F (de-DMSO) δ 9.32 (t, J=6 Hz, 1H), 8.51 (dd, J=4.4,1.5 Hz, 1H), 8.29 (br s, 1H), 8.26 (br s, 2H), 7.97 (d, J=8 Hz, 1H), 7.44 (dd, J=8, 4.4 Hz, 1H), 7.42 (br s, 2H), 4.97 (t, J=6 Hz, 2H), 3.88 (q, J=6 Hz, 2H), 2.86 (t, J=7 Hz, 2H), 1.73 (quintet, J=7 Hz, 2H), 1.30 (sextet, J=7 Hz, 2H), 0.80 (t, J=7 Hz, 3H) 126 Cl (de-DMSO) δ 8.68 (d, J=4.5 Hz, 1H), 8.61 (t, J=6 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 8.1 (br s, 2H), 7.62 (dd, J=8.0,4.5 Hz, 1H), 7.44 (dd, J=7.5, 2 Hz, 1H), 7.41 (dt, J=7.5, 2.0 Hz, 1H), 7.31 (dt, J=7.5,2.0 Hz, 1H), 7.12 (dd, J=7.5,2 Hz, 1H), 4.91 (t, J=6 Hz, 2H), 3.83 (q, J=6 Hz, 2H), 3.00 (t, J=7 Hz, 2H), 1.83 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.94 (t, J=7 Hz, 3H) -110- WO 99/29693 PCT/US98/26473 127 —Cl Cl (de-DMSO) δ 8.69 (t, J=6 Hz, 1H), 8.63 (dd, J=4, 1.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.80 (br s, 2H), 7.65 (d, J=2 Hz, 1H), 7.57 (dd, J=8.5,4.5 Hz, 1H), 7.42 (dd, J=8, 2 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 4.91 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.98 (t, J=7 Hz, 2H), 1.82 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.94 (t, J=7 Hz, 3H) 128 h3c-o Φ θχ CH3 (de-DMSO) δ 8.48 (dd, J=4.3,1.5 Hz, 1H), 8.25 (t, J=6 Hz, 1H), 7.91 (dd, J=8.5, 1.5 Hz, 1H), 7.42 (dd, J=8.5,4.3 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 6.74 (br s, 2H), 6.61 (d, J=8 Hz, 2H), 4.80 (t, J=6 Hz, 2H), 3.76 (q, J=6 Hz, 2H), 3.33 (s, 6H), 3.00 (t, J=7 Hz, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.95 (t, J=7 Hz, 3H) 129 -O" (de-DMSO) δ 8.66 (t, J=6 Hz, 1H), 8.57 (dd, J=4.3, 1.2 Hz, 1H), 8.00 (dd, J=8.5,1.2 Hz, 1H), 7.69 (dd, J=9, 5.8 Hz, 2H), 7.50 (dd, J=8.4, 4.3 Hz, 1H), 7.30 (br s, 2H), 7.25 (t, J=9 Hz, 2H), 4.91 (t, J=6 Hz, 2H), 3.81 (q, J=6 Hz, 2H), 2.81 (t, J=7 Hz, 2H), 1.70 (quintet, J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.81 (t, J=7 Hz, 3H) 130 (de-DMSO) δ 8.72 (t, J=6 Hz, 1H), 8.52 (dd, J=4.3,1.5 Hz, 1H), 7.93 (dd, J=8.0,1.5 Hz, 1H), 7.72 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 7.44 (dd, J=8,4.3 Hz, 1H), 6.80 (br s, 2H), 4.90 (t, J=6 Hz, 2H). 3.81 (q, J=6 Hz, 2H), 2.79 (t, J=7 Hz, 2H), 1.70 (quintet, J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.81 (t, J=7 Hz, 3H) 131 (de-DMSO) δ 8.55 (dd, J=4.3,1.5 Hz, 1H), 8.49 (t, J=6 Hz, 1H), 7.95 (dd, J=8.4,1.5 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 7.46 (dd, J=8.4, 4.3 Hz, 1H), 6.93 (d, J=8 Hz, 2H), 6.91 (br s, 2H), 4.90 (t, J=6 Hz, 2H), 3.8 (q, J«6 Hz, 2H), 3.79 (s, 3H), 2.79 (t, J=7 Hz, 2H), 1.69 (quintet, J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.80 (t, J=7 Hz, 3H) 132 -d' (de-DMSO) δ 8.76 (t, J=6 Hz, 1H), 8.53 (dd, J=4.3,1.5 Hz, 1H), 7.95 (dd, J=8.5,1.5 Hz, 1H), 7.67 (brs, 1H), 7.65 (d, J=8 Hz, 1H), - Ill - WO 99/29693 PCT/US98/26473 7.57 (m, 1H), 7.48-7.43 (m, 2H), 7.02 (br s. 2H), 4.91 (t. J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.81 (t, 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) 133 -o-e (de-DMSO) δ 8.69 (dd, J=4.4,1.2 Hz, 1H), 8.57 (t, J=6 Hz, 1H), 8.22 (br s, 2H). 8.12 (dd, J=8.0,1.2 Hz, 1H), 7.61 (m, 3H), 7.41 (d, J=9 Hz, 2H), 4.92 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.84 (t, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 1.27 (sextet, J=7 Hz, 2H), 1.27 (s, 9H), 0.78 (t, J=7 Hz, 3H) 134 (de-DMSO) δ 8.55 (t, J=6 Hz, 1H), 8.54 (dd, J=4.5,1.5 Hz, 1H), 7.94 (dd, J=8.5,1.5 Hz, 1H), 7.60 (d, J=8 Hz, 2H), 7.46 (dd, J=8.2, 4.5 Hz, 1H), 7.21 (d, J=8 Hz, 2H), 6.87 (brs, 2H), 4.90 (t, J=6 Hz, 2H), 3.80 (q, J=6 Hz, 2H), 2.80 (t, J=7 Hz. 2H), 2.32 (s, 3H), 1.69 (quintet J=7 Hz, 2H), 1.29 (sextet, J=7 Hz, 2H), 0.81 (t, J=7 Hz, 3H) 135 H3C CH3 (de-DMSO) δ 8.58 (dd, J=4.4,1.5 Hz, 1H), 8.00 (dd, J=8.4,1.5 Hz, 1H), 7.97 (t, J=6 Hz, 1H), 7.52 (dd, J=8.4,4.4 Hz, 1H), 7.35 (br s, 2H), 4.77 (t, J=6 Hz, 2H), 3.58 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 1.85 (s, 2H), 1.81 (quintet, J=7 Hz, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.96 (t, J=7 Hz, 3H), 0.87 (s, 9H) 136 (CDCb at 60°C) δ 8.56 (dd, J=4.0,1.5 Hz, 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 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 0.99 (m, 1H), 0.99 (t, J=7 Hz, 3H), 0.79 (m, 2H), 0.54 (m, 2H) 137 -Ό (CDCb) δ 8.59 (dd, J=4.5,1.5 Hz, 1H), 8.10 (dd, J=8.3, 1.5 Hz, 1H), 7.46 (dd, J=8.5, 4.5 Hz, 1H), 6.79 (br s, 1H), 6.02 (br s, 2H), 4.96 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 2.18 (quintet, J=7 Hz, 1H), 1.90 (quintet, J=7 Hz, 2H), 1.65-1.35 (m, 10H), 1.00 (t, J=7 Hz, 3H) 138 (CDCb) δ 8.58 (dd, J=4.4,1.5 Hz, 1H), 8.09 (dd, J=8.0,1.5 Hz, 1H), 7.46 (dd, J=8.3, 4.4 Hz, 1H), 7.00 (brs, 1H), 5.85 (brs, 2H), - 112- WO 99/29693 PCT/US98/26473 4.96 (t, J=6 Hz, 2H), 3.81 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.88 (m. 3H), 1.52 (m, 6H), 1.50 (m, 2H), 1.49 (m, 2H), 1.291 (q, 2H), 1.01 (t, J=7 Hz, 3H), 0.85 (m, 2H) 139 (CDCI3) δ 8.52 (dd, J=4.4,1.5 Hz, 1H), 8.26 (brt, 1H), 8.09 (dd, J=8.5,1.5 Hz, 1H), 7.47 (d, J=8 Hz, 2H), 7.46 (dd, J=8.5,4.4 Hz, 1H), 7.34 (d, J=8 Hz, 2H), 5.92 (br s, 2H), 5.12 (t, J=6 Hz, 2H), 4.04 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 1.92 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 140 (CDCI3) δ 8.65 (dd, J=4.4,1.5 Hz, 1H), 8.03 (dd, J=8.5, 1.5 Hz, 1H), 7.59 (brt, 1H), 7.45 (dd, J=8.5,4.4 Hz, 1H), 7.35 (dd, J=5,1.2 Hz, 1H), 7.10 (d, J=3 Hz, 1H), 6.89 (dd, J=5, 3 Hz, 1H), 6.32 (br s, 2H), 5.08 (t, J=6 Hz, 2H), 4.02 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.47 (sextet, J=7 Hz, 2H), 0.96 (t, J=7 Hz, 3H) 141 (CDCI3) δ 8.45 (dd, J=4.4, 1.5 Hz, 1H), 8.08 (dd, J=8.4,1.5 Hz, 1H), 7.43 (dd, J=8.3,4.4 Hz, 1H), 7.07 (dd, J=5,1.6 Hz, 1H), 6.84 ( br t, 1H), 6.78 (dd, J=5, 3.4 Hz, 1H), 6.51 (dd, J=3, 1 Hz, 1H), 6.05 (br s, 2H), 4.94 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 3.49 (s, 2H), 2.89 (t, J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 142 ~O~n°! (CDCI3) δ 8.52 (dd, J=4.4, 1.5 Hz, 1H), 8.42 (brt, 1H), 8.08 (dd, J=8.3,1.5 Hz, 1H), 8.01 (d, J=9 Hz, 2H), 7.48 (dd, J=8.4,4.4 Hz, 1H), 7.39 (d, J=9 Hz, 2H), 5.80 (br s, 2H), 5.12 (t, J=6 Hz, 2H). 4.05 (q, J=6 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) 143 h3c -0-CH3. HjC (CDCb) δ 8.21 (dd, J=4.4,1.5 Hz, 1H), 8.05 (dd, J=8.4,1.5 Hz, 1H), 7.53 (brt, 1H), 7.28 (dd, J=8.3,4.4 Hz, 1H), 6.68 (s, 2H), 6.23 (brs, 2H), 5.02 (t, J=6 Hz, 2H), 4.00 (q, J=6 Hz, 2H), 3.03 (t, J=7 Hz, 2H), 2.21 (s, 3H), 1.99 (s, 6H), 1.94 (quintet, J=7 Hz, 2H), 1.59 (sextet, J=7 Hz, 2H), 1.03 (t, J=7 Hz, 3H) -113- WO 99/29693 PCT/US98/26473 144 ov CH3 (CDCb at 29°C) δ 8.59 (dd, J=4.0,1.5 Hz, 1H), 8.14 (dd, J=8.0, 1.5 Hz, 1H), 8.09 (dd, J=8,1.5 Hz, 1H), 7.87 (t, J=6 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 7.42 (dd, J=8.0,4.0 Hz, 1H), 7.06 (t, J=8 Hz, 1H). 6.87 (d, J=8 Hz, 1H), 6.19 (br s, 2H), 5.07 (t, J=6 Hz, 2H), 4.04 (q, J=6 Hz, 2H),.3.68 (s, 3H), 2.89 (t, J=7 Hz, 2H), 1.80 (quintet, J=7 Hz, 2H), 1.39 (sextet, J=7 Hz, 2H). 0.88 (t, J=7 Hz, 3H) 145 t° 0—CHj (CDCb) δ 8.60 (dd, J=4.4,1.5 Hz, 1H), 8.11 (dd, J=8.5,1.5 Hz, 1H), 7.47 (dd, J=8.5,4.4 Hz. 1H), 7.01 (brt, 1H), 6.43 (br s, 2H), 4.95 (t, J=6 Hz, 2H), 3.81 (q, J=6 Hz, 2H), 3.63 (s, 3H), 2.93 (t, J=7 Hz, 2H), 2.19 (t, J=7 Hz, 2H), 1.92 (m, 4H), 1.51 (sextet, J=7 Hz, 2H), 1.42 (m, 4H), 1.00 (t, J=7 Hz, 3H) 146 O^NO, XT (CDCb) δ 8.23 (dd, J=4.4,1.5 Hz, 1H), 8.52 (brs, 1H), 8.10 (dd, J=8.5,1.5 Hz, 1H), 7.53 (dd, J=8.3,4.4 Hz, 1H), 7.21 (d, J=4 Hz, 1H), 7.06 (d, J=4 Hz, 1H), 6.1 (brs, 2H), 5.11 (t, J=6 Hz, 2H), 4.04 (q, J=6 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H). 1.53 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz. 3H) 147 c,\_ (CDCb) δ 8.39 (dd, J=4.4,1.5 Hz, 1H), 8.31 (dd, J=5.0, 2 Hz, 1H), 8.21 (brt, J=6 Hz, 1H), 8.00 (dd, J=8.4,1.5 Hz, 1H), 7.42 (dd, J=5,8 Hz, 1H), 7.33 (dd, J=8.5,4.4 Hz, 1H), 7.07 (dd, J=8, 5 Hz, 1H), 5.84 (br s, 2H), 5.06 (t, J=6 Hz, 2H), 4.05 (q, J=6 Hz, 2H), 2.97 (t, J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.53 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) 148 /SSN -Q-0 (CDCI3 at 60°C) δ 8.54 (dd, J=4.4,1.5 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 8.06 (dd, J=8.4, 1.5 Hz, 1H), 8.06 (brs, 1H), 7.56 (dd, 8.5, 2 Hz, 1H), 7.45 (dd, J=8.4,4.4 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 5.72 (brs, 2H), 5.08 (t, J=6 - 114- WO 99/29693 PCT/US98/26473

Hz, 2H), 4.03 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 149 HjC—' (CDCI3) δ 8.61 (dd, J=4.4, 1.5 Hz, 1H), 8.03 (dd, J=8.3, 1.5 Hz, 1H), 7.50 (t, J=6 Hz, 1H), 7.44 (dd, J=8.3,4.4 Hz, 1H), 7.42 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 6.45 (br s, 2H), 5.06 (V J=6 Hz, 2H), 4.00 (q, J=6 Hz, 2H), 3.90 (t, J=7 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 1.84 (quintet, J=7 Hz, 2H), 1.74 (quintet, J=7 Hz, 2H). 1.42, m, 4H), 1.28 (m, 6H), 0.93 (t, J=7 Hz, 3H), 0.87 (t, 3H) 150 HjC (CDCI3) δ 8.61 (dd, J=4.4,1.5 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.90 (d, J=8 Hz, 2H), 7.84 (br s, 1H), 7.48 (dd, J=8.5, 4.4 Hz, 1H), 7.44 (d, J=8 Hz, 2H), 6.4 (br s, 2H), 5.12 (t, J=6 Hz, 2H), 3.94 (t, J=7 Hz, 2H), 3.91 (s, 3H), 2.94 (t, J=7 Hz, 2H), 1.91 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 0.99 (t, J=7 Hz, 3H) 151 Cl (CDCb) δ 8.48 (br s, 1H), 8.22 (dd, J=4.5, 1.5 Hz, 1H), 8.04 (dd, J=8.4,1.5 Hz, 1H), 7.33 (s, 2H), 7.30 (dd, J=8.4, 4.4 Hz, 1H), 5.96 (br s, 2H), 5.00 (t, J=6 Hz, 2H), 4.03 (q, J=6 Hz, 2H), 2.99 (t. J=7 Hz, 2H), 1.93 (quintet, J=7 Hz, 2H), 1.54 (sextet, J=7 Hz, 2H), 1.03 (t, J=7 Hz, 3H) 152 O-CHj (CDCb) δ 8.41 (dd, J=4.4,1.5 Hz, 1H), 8.06 (dd, J=8.3,1.5 Hz, 1H), 7.41 (dd, J=8.5,4.4 Hz, 1H), 6.75 (d. J=8 Hz, 2H), 6.64 (d, &gt;8 Hz, 2H), 6.60 (br t, 1H), 6.02 (br s, 2H), 4.92 (t, J=6 Hz, 2H), 3.80 (q, J=4.6 Hz, 2H), 3.76 (s, 3H), 3.22 (s, 2H), 2.88 (t, J=7 Hz, 2H), 1.87 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) -115- WO 99/29693 PCT/US98/26473

Examples 153-190

Compounds of Formula I

The compounds of Examples 153-190 shown in the table below were prepared 5 according to the following method. 4-(4-Amino-2-butyl-l/f-imidazo[4,5- c][l,5]naphthyridin-l-yl)butaneamine (25 pmol) was dissolved in dichioromethane (10 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 RACOC1 was added as a solution in 100 pL of dichioromethane (Acid chlorides that are solids were added directly.). The mixture was 10 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 (3x1 cm ) of silica gel conditioned with dichioromethane. The product was eluted with 10:1 dichloromethane:methanol, collecting 15 ~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 20 100% 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. -116- WO 99/29693 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD000299.tif" id="idf0099" />

Example # Ra Fragment 2H NMR (500 MHz, solvent indicated) 153 -5 (CDCI3 at 29°C) δ 8.53 (dd, J=4.4,1.5 Hz, 1H), 8.12 (dd, J=8.5,1.5 Hz, 1H), 7.83 (t, J=2 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.42 (dd, J=8.5, 4.4 Hz, 1H), 7.23 (t, J=8 Hz, 1H), 6.73 (t, J=6 Hz, 1H), 6.50 (brs, 2H), 4.84 (t, J=6 Hz. 2H), 3.60 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 2.04 (quintet, J=7 Hz, 2H). 1.88 (quintet, J=7 Hz, 2H), 1.80 (m, J=7 Hz, 2H), 1.48 (m, 2H), 0.99 (t, J=7 Hz. 3H) 154 h^H H (CDCb at 29°C) δ 8.60 (dd, J=4.4,1.5 Hz, 1H), 8.09 (dd, J=8.5,1.5 Hz, 1H), 7.43 (dd, J=8.5, 4.4 Hz, 1H), 6.32 (br s, 2H), 5.75 (t, J=6 Hz, 1H), 4.81 (t, J=6 Hz, 2H), 3.35 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 2.1-1.6 (m, ca. 21H), 1.51 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) 155 a (CDCI3 at 60°C) δ 8.44 (dd, J=4.4,1.5 Hz, 1H), 8.10 (dd, J=8.5,1.5 Hz, 1H) 7.43 (dd, J=8.5,4.4 Hz, 1H), 7.10 (s, 4H), 6.00 (br s, 2H), 5.60 (t, J=6 Hz, 1H), 4.63 (t, J=6 Hz, 2H), 3.30 (q, J=6 Hz, 2H), 2.86 (t, J=7 Hz, 2H), 2.37 (m, 2H), 2.0-1.4 (m, 14H), 1.01 (t, J=7 Hz, 3H) 156 Cl (CDCI3 at 60°C) δ 8.33 (d, J=4.4 Hz, 1H), 8.08 (dd, J=8.5,1.5 Hz, 1H), 7.5-7.0 (m, 4H), 6.70 (br s, 1H), 6.25 (br s, 2H), 4.85 (t, J=6 Hz, 2H), 3.67 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 2.08 (quintet, J=7 Hz, 2H), 1.89 (m, 4H), 1.53 (sextet, J=7 Hz, 2H), 1.02 (t, J=7 - 117- WO 99/29693 PCT/US98/26473

Hz, 3H) 157 8 (CDCI3 at 60°C) δ 8.59 (dd. J=4.4,1.5 Hz, 1H), 8.10 (dd, J=8.5, 1.5 Hz, 1H), 7.40 (dd, J=8.5,4.4 Hz, 1H). 7.28 (m, 3H), 7.21 (m, 2H), 6.84 (t, J=6 Hz, 1H), 6.4 (br s, 2H), 4.81 (t, J=6 Hz, 2H), 4.49 (s, 2H), 3.96 (s, 2H), 3.42 (q, J=6 Hz, 2H), 2.91 (t, 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 (t, J=7 Hz, 3H) 158 CHj (de-DMSO at 29°C) δ 8.50 (dd, J=4.4,1.5 Hz, 1H), 7.91 (dd, J=8,1.5 Hz, 1H), 7.71 (t, J=6 Hz, 1H), 7.43 (dd, J=8.4, 4,4 Hz, 1H), 6.80 (br s, 2H), 4.79 (t, J=6 Hz, 2H), 3.57 (s, 3H), 3.05 (q, J=6 Hz, 2H), 2.28 (q, J=7 Hz, 4H), 2.20 (t, J=7 Hz, 2H), 1.98 (t, J=7 Hz, 2H), 1.80 (m, 4H), 1.6-1.1 (m, 14H), 0.96 (t, J=7 Hz, 3H) 159 (de-DMSO at 29OC) δ 8.51 (dd, J=4.4,1.5 Hz, 1H), 7.92 (dd, J=8.5,4.4 Hz, 1H), 7.72 (t, J=6 Hz, 1H), 7.43 (dd, J=8.5,4.4 Hz, 1H), 6.86 (br s, 2H), 5.77 (m, 1H), 4.98 (dd, J=2 Hz, 1H), 4.92 (m, 1H), 4.79 (t, J=6 Hz, 2H), 3.08 (q, J=6 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.98 (quintet, J=7 Hz, 2H), 1.80 (m, 2H). 1.55-1.1 (m, 20 H), 0.96 (t, J=7 Hz, 3H) 160 X (de-DMSO at 29°C) δ 8.49 (dd, J=4.4,1.5 Hz, 1H), 7.90 (dd, J=8.2,1.5 Hz, 1H), 7.71 (t, J=6 Hz, 1H), 7.42 (dd, J=8.2,4.4 Hz, 1H), 6.74 (br s, 2H), 4.79 (t, J=6 Hz, 2H), 3.06 (q, J=6 Hz, 2H), 2.92 (t. J=7 Hz, 2H), 2.04 (m, 1H), 1.96 (m, 2H), 1.82 (m, 4H), 1.6-1.3 (m, 10H), 1.04 (m, 2H), 0.96 (t, J=7 Hz, 3H) 161 F F 4 F F (de-DMSO at 29°C) δ 8.95 (t, J=6 Hz, 1H), 8.44 (m, 3H), 8.31 (s, 1H), 7.88 (dd, J=8.5, 1.5 Hz, 1H). 7.37 (dd, J=8.5,4.4 Hz, 1H), 6.76 (s, 2H), 4.82 (t, J=6 Hz, 2H), 3.38 (m, 2H), 2.91 (t, J=7 Hz, 2H), 1.90 (m, 2H), 1.76 (m, 2H), 1.64 (m, 2H), 1.,39 (m, 2H), 0.86 (t, J=7 Hz, 3H) 162 HA P /=&lt;_ ZCH3 O-CHj (de-DMSO at 29°C) δ 8.44 (dd, J=4.4,1.5 Hz, 1H), 8.39 (t, J=6 Hz, 1H), 7.89 (dd, J=8.2,1.5 Hz, 1H), 7.39 (dd, J=8.2, 4.4 Hz, 1H), 7.12 (s, 2H), 6.75 (br s, 2H), 4.81 (t, J=6 Hz, 2H), 3.78 (s, 6H), 3.68 (s, 3H), 3.32 (m, 2H), 2.92 (m, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.91 (t, J=7 -118- WO 99/29693 PCT/US98/26473

Hz, 3H) 163 ^F F F (de-DMSO at 29°C) δ 8.89 (t, J=6 Hz, 1H), 8.51 (dd, J=4.4,1.5 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.44 (dd, J=8.5, 4.4 Hz, 1H), 6.95 (br s, 2H), 4.83 (t, J=6 Hz, 2H), 3.34 (m, 2H), 2.95 (t, J=7 Hz, 2H), 2.90 (m, 2H), 2.85 (m, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.45 (m, 2H), 0.96 (t, J=7 Hz, 3H) 164 -v Cl (de-DMSO at 29°C) δ 8.50 (dd, J=4.3,1.5 Hz, 1H), 8.38 (t, J=6 Hz, 1H), 7.91 (dd, J=8.4,1.5 Hz, 1H), 7.44 (dd, J=8,1 Hz, 1H), 7.39 (dt, J=8,1 Hz, 1H), 7.43 (dd, J=8.4,4.3 Hz, 1H), 7.31 (dt (J=8,1 Hz, 1H), 7.27 (dd, J=8,1 Hz, 1H), 6.74 (s, 2H), 4.83 (t, J=6 Hz, 2H), 3.26 (q, J=6 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.95 (m, 2H), 1.83 (m, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.45 (m, 2H), 0.95 (t, J=7 Hz, 3H) 165 -Q-c Cl (de-DMSO at 29°C) δ 8.49 (dd, J=4.3,1.5 Hz, 1H), 8.44 (t, J=6 Hz, 1H), 7.91 (dd, J=8.2,1.5 Hz, 1H), 7.64 (d, J=2 Hz, 1H), 7.43 (dd, J=8.2,4.3 Hz, 1H), 7.42 (dd, J=8,2 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 6.75 (br s, 2H), 4.82 (t, J=6 Hz, 2H), 3.25 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 1.90 (m, 2H), 1.82 (m, 2H), 1.60 (m, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.95 (t, J=7 Hz, 3H) 166 “O' (de-DMSO at 29°C) δ 8.46 (dd, J=4.3,1.5 Hz. 1H), 8.46 (m, 1H), 7.89 (dd, J=8.5,1.5 Hz, 1H), 7.84 (dd, J=8, 5 Hz, 2H), 7.40 (dd, J=8.5, 4.3 Hz, 1H), 7.26 (t, J=9 Hz, 2H), 6.74 (br s, 2H), 4.81 (t, J=6 Hz, 2H), 3.31 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.88 (m, 2H), 1.79 (m, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.45 (m, 2H), 0.91 (t, J=7 Hz, 3H) 167 —Cl (de-DMSO at 29°C) δ 8.53 (t, J=6 Hz, 1H), 8.46 (dd, J=4.4,1.5 Hz, 1H), 7.89 (dd, J=8.5, 1.5 Hz, 1H), 7.79 (d, J=8 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.40 (dd, J=8.5,4.3 Hz, 1H), 6.74 (s, 2H), 4.81 (t, J=6 Hz, 2H), 3.30 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.92 (m, 2H), 1.78 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.90 (t, J=7 Hz, 3H) - 119- WO 99/29693 PCT/US98/26473 168 -q-/8· (d6-DMSO at 29°C) δ 8.47 (dd, J=4.3,1.5 Hz, 1H), 8.29 (t, J=6 Hz, 1H), 7.89 (dd, J=8.5,1.5 Hz, 1H), 7.76 (d, J=8 Hz, 2H), 7.40 (dd, J=8.5, 4.3 Hz, 1H), 6.96 (d, J=8 Hz, 2H), 6.74 (s, 2H), 4.81 (t, J=6 Hz, 2H), 3.79 (s, 3H), 3.39 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.86 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.41 (sextet, J=7 Hz, 2H), 0.91 (t, J=7 Hz, 3H) 169 (de-DMSO at 29°C) δ 8.67 (t, J=6 Hz, 1H), 8.46 (dd, J=4.0,1.5 Hz, 1H), 7.97 (d, J=8 Hz, 2H), 7.89 (dd, J=8,1.5 Hz, 1H), 7.39 (dd, J=8,1.5 Hz, 1H), 7.38 (d, J=8 Hz, 2H), 6.74 (s, 2H), 4.82 (t, J=6 Hz, 2H), 3.32 (m, 2H), 2.91 (t, J=7 Hz, 2H), 1.89 (m, 2H), 1.78 (quintet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.89 (t, J=7 Hz, 3H) 170 (de-DMSO at 29°C) δ 8.46 (dd, J=4.0,1.5 Hz, 1H), 8.35 (t, J=6 Hz, 1H), 7.89 (dd, J=8.5,1.5 Hz, 1H), 7.71 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H), 7.40 (dd, J=8,4.0 Hz, 1H), 6.73 (s, 2H), 4.80 (t, J=6 Hz, 2H), 3.30 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 2.80 (quintet, J=7 Hz, 2H), 1.60 (m, 2H), 1.39 (sextet, J=7 Hz, 2H), 1.29 (s, 9H), 0.90 (t, J=7 Hz, 3H) 171 —θ-&lt;»&gt; (de-DMSO at 29°C) δ 8.47 (dd, J=4.0,1.5 Hz, 1H), 8.35 (t, J=6 Hz, 1H), 7.89 (dd, J=8.0,1.5 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 7.40 (dd, J=8.0, 4.0 Hz, 1H). 7.23 (d, J=8 Hz, 2H), 6.74 (s, 2H). 4.81 (t, J=6 Hz, 2H), 3.28 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz. 2H), 2.34 (s, 3H), 2.90 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.41 (sextet, J=7 Hz, 2H), 0.91 (t, J=7 Hz, 3H) - 120- WO 99/29693 PCT/US98/26473 172 \-ch3 h3c ch3 (de-DMSO at 29°C) δ 8.49 (dd, J=4.5, 1.5 Hz, 1H), 7.90 (dd, J=8.5, 1.5 Hz, 1H), 7.67 (t, J=6 Hz, 1H), 7.42 (dd, J=8.5,4.5 Hz, 1H), 6.74 (s, 2H), 4.79 (t, J=6 Hz, 2H), 3.06 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz2H), 1.87 (s, 2H), 1.82 (quintet, J=7 Hz, 4H), 1.46 (sextet, J=7 Hz, 4H), 0.96 (t, J=7 Hz, 3H), 0.86 (s, 9H) 173 (de-DMSO at 29°C) δ 8.50 (dd, J=4.5,1.5 Hz, 1H), 8.00 (t, J=6 Hz, 1H), 7.90 (dd, J=8.5,1.5 Hz, 1H), 7.43 (dd, J=8.5, 4.5 Hz, 1H), 6.75 (s, 2H). 4.79 (t, J=6 Hz, 2H), 3.10 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.82 (m, 4H), 1.45 (m, 5H), 0.94 (t, J=7 Hz, 3H), 0.60 (m, 4H) 174 &lt;1 (de-DMSO at 29°C) δ 8.49 (dd, J=4.3,1.5 Hz, 1H), 7.90 (dd, J=8.4,1.5 Hz, 1H), 7.68 (t, J=6 Hz, 1H), 7.42 (dd, J=8.4,4.3 Hz, 1H), 6.73 (br s, 2H), 4.80 (t, J=6 Hz, 2H), 3.06 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 2.44 (m, 1H), 1.81 (m, 4H), 1.70-1.30 (m, 12H), 0.96 (t, J=7 Hz, 3H) 175 (de-DMSO at 29°C) δ 8.50 (dd, J=4.5,1.5 Hz, 1H), 7.90 (dd, J=8.0,1.5 Hz, 1H), 7.73 (t, J=6 Hz, 1H), 7.42 (dd, J=8.0,4.5 Hz, 1H), 6.75 (s, 2H), 4.78 (t, J=6 Hz, 2H), 3.06 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.99 (t, J=7 Hz, 2H), 1.81 (m, 4H), 1.63 (m, 3H), 1.6-1.3 (m, 10H), 1.00 (m, 2H), 0.97 (t, J=7 Hz, 3H) 176 (de-DMSO at 29°C) δ 8.69 (t, J=6 Hz, 1H), 8.45 (dd, J=4.3,1.5 Hz, 1H), 7.91 (m, 4H), 7.89 (dd, J=8.3,1.5 Hz, 1H), 7.40 (dd, J=8.3, 4.3 Hz, 1H), 6.74 (s, 2H), 4.81 (t, J=6 Hz, 2H), 3.31 (m, 2H). 2.91 (t, J=7 Hz, 2H), 1.90 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (m, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.90 (t, J=7 Hz, 3H) -121 - WO 99/29693 PCT/US98/26473 177 (de-DMSO at 29°C) δ 8.46 (dd, J=4.3, 1.5 Hz, 1H), 8.45 (t, J=6 Hz, 1H), 7.89 (dd, J=8.4,1.5 Hz, 1H), 7.72 (dd, J=5, 1 Hz, 1H), 7.67 (dd, J=3,1 Hz, 1H), 7.40 (dd, J=8.4, 4.3 Hz, 1H), 7.11 (dd, J=5, 3 Hz, 1H), 6.74 (s, 2H), 4.82 (t, J=6 Hz, 2H), 3.28 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.87 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 1.42 (sextet, J=7 Hz, 2H), 0.91 (t, J=7 Hz, 3H) 178 (de-DMSO at 29°C) δ 8.49 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (t, J=6 Hz, 1H), 7.91 (dd, J=8.2,1.5 Hz, 1H), 7.43 (dd, J=8.2, 4.3 Hz, 1H), 7.29 (dd, J=5,1 Hz, 1H), 6.89 (dd, J=5, 3 Hz, 1H), 6.82 (dd, J=3,1 Hz, 1H), 6.77 (br s, 2H), 4.79 (t, J=6 Hz, 2H), 3.56 (s, 2H), 3.09 (q, J=6 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 1.75 (m, 4H), 1.45 (m, 4H), 0.95 (t, J=7 Hz, 3H) 179 ~θ“Νθ! (de-DMSO at 29°C) δ 8.77 (t, J=6 Hz, 1H), 8.46 (dd, J=4.4,1.5 Hz, 1H), 8.28 (dd, J=8.5, 2.5 Hz, 2H), 8.00 (dd, J=8.5 2.5 Hz, 2H), 7.89 (dd, J=8.3,1.5 Hz, 1H), 7.39 (dd, J=8.3, 4.4 Hz, 1H), 6.75 (s, 2H), 4.82 (t, J=6 Hz, 2H), 3.32 (m, 2H), 2.92 (t, J=7 Hz, 2H), 1.90 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.63 (m, 2H), 1.42 (sextet, J=7 Hz, 2H), 0.91 (t, J=7 Hz, 3H) 180 h3c ^Q“CH3 HjC (de-DMSO at 29°C) δ 8.48 (dd, J=4.3,1.5 Hz, 1H), 8.14 (t, J=6 Hz, 1H), 7.91 (dd, J=8.4,1.5 Hz, 1H), 7.42 (dd, J=8.4, 4.3 Hz, 1H), 6.78 (s, 2H), 6.75 (br s, 2H), 4.82 (t, J=6 Hz, 2H), 3.22 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 2.50 (s, 3H), 2.03 (s, 6H), 1.90 (m, 2H), 1.85 (quintet, J=7 Hz, 2H), 1.58 (m, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.96 (t, J=7 Hz, 3H) -122- WO 99/29693 PCT/US98/26473 181 _ F FfH-F / F F Λ— F F F (de-DMSO at 29°C) δ 9.48 (t, J=6 Hz, 1H), 8.52 (d, J=4.3 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 7.45 (dd, J=8.0, 4.3 Hz, 1H), 7.09 (br s, 2H), 4.80 (t, J=6 Hz, 2H), 3.25 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.81 (m, 4H), 1.58 (m, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.95 (t, J=7 Hz, 3H) 182 CH3 (de-DMSO at29°C) δ 8.50 (dd, J=4.3,1.5 Hz, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.75 (t, J=6 Hz, 1H), 7.42 (dd, J=8.0,4.3 Hz, 1H), 6.77 (br s, 2H). 4.78 (t, J=6 Hz, 2H), 3.56 (s, 3H), 3.06 (q, J=6 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 2.25 (m, 2H), 2.00 (m, 2H), 1.81 (m, 4H), 1.44 (m, 8H), 0.96 (t. J=7 Hz, 3H) 183 &lt;\ (de-DMSO at 29°C) δ 8.55 (t, J=6 Hz, ΪΗ), 8.50 (dd, J=4.3,1.5 Hz, 1H), 8.43 (dd. J=5, 2 Hz, 1H), 7.91 (dd, J=8.4,1.5 Hz, 1H), 7.74 (d, J=8.0, 2 Hz, 1H), 7.43 (dd, J=8,4.3 Hz, 1H), 7.42 (dd, J=8, 5 Hz, 1H), 6.75 (br s, 2H), 4.83 (t, J=6 Hz, 2H), 3.27 (q, J=6 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.92 (m, 2H), 1.83 (quintet, J=7 Hz, 2H), 1.60 (m, 2H), 1.46 (sextet, J=7 Hz, 2H), 0.95 (t, J=7 Hz, 3H) 184 (de-DMSO at 29°C) δ 8.77 (dd, J=2.5, 0.5 Hz, 1H), 8.70 (t, J=6 Hz, 1H), 8.46 (dd, J=4.3,1.5 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, 1H), 7.43 (dd, J=8.4,1.5 Hz, 1H), 6.76 (br s, 2H), 4.81 (t. J=6 Hz, 2H), 3.31 (m, 2H), 2.92 (t, J=7 Hz, 2H), 1.89 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.61 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.91 (t, J=7 Hz, 3H) 185 /=v FA (de-DMSO at 29°C) δ 8.55 (t, J=6 Hz, 1H), 8.45 (dd, J=4.3,1.5 Hz, 1H), 7.90 (d, J=8 Hz, 2H), 7.89 (dd, J=8,1.5 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.39 (dd, J=8, 4.3 Hz, 1H), 6.74 (br s, 2H), 4.81 (t, J=6 Hz, 2H), 3.30 (m, 2H), 2.91 (t, J=7 Hz, 2H), 1.88 (m, 2H), 1.78 (quintet, J=7 Hz, 2H), 1.63 (m, 2H), 1.34 (sextet, J=7 Hz, 2H), 0.89 (t, J=7 Hz, 3H) 186 F~° Cl (de-DMSO at 29°C) δ 8.64 (t, J=6 Hz, 1H), 8.49 (dd, J=4.4,1.5 Hz, 1H), 7.90 (dd, J=8.5, 1.5 Hz, 1H), 7.69 (s, 2H), 7.42 (dd, J=8.5,4.3 Hz, 1H), 6.74 (s, 2H), 4.84 (t. J=6 Hz, 2H), - 123- WO 99/29693 PCT/US98/26473 3.26 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H). 1.90 (m, 2H), 1.83 (quintet, J=7 Hz, 2H), 1.60 (m. 2H), 1.46 (sextet, J=7 Hz, 2H), 0.96 (t, J=7 Hz, 3H) 187 o-ch3 (de-DMSO at 29°C) δ 8.49 (dd, J=4.3,1.5 Hz, 1H), 7.92 (t, J=6 Hz, 1H), 7.90 (dd, J=8.5, 1.5 Hz. 1H), 7.42 (dd, J=8.5,4.3 Hz, 1H), 7.07 (d, J=8 Hz, 2H), 6.76 (d, J=8 Hz, 2H), 6.74 (br s, 2H), 4.79 (t, J=6 Hz, 2H), 3.70 (s, 3H), 3.25 (s, 2H), 3.08 (q, J=6 Hz, 2H), 2.89 (t, J=7 Hz, 2H), 1.80 (m, 4H), 1.46 (m, 2H), 1.44 (sextet, J=7 Hz, 2H), 0.95 (t. J=7 Hz, 3H) 188 q CHj (de-DMSO at 29°C) δ 8.47 (dd, J=4.3,1.5 Hz, 1H), 8.15 (t, J=6 Hz, 1H), 7.90 (dd, J=8.4,1.5 Hz, 1H), 7.64 (dd, J=8, 2 Hz, 1H), 7.41 (dt, J=8,2 Hz, 1H), 7.40 (dd, J=8.4,4.3 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 6.98 (dt, J=8,2 Hz, 1H), 6.74 (s, 2H), 4.82 (t, J=6 Hz, 2H), 3.70 (s, 3H), 3.33 (m, 2H), 2.92 (t, J=7 Hz, 2H), 1.90 (m. 2H), 1.80 (quintet, J=7 Hz, 2H), 1.60 (m, 2H), 1.43 (sextet, J=7 Hz, 2H), 0.92 (t, J=7 Hz, 3H) 189 (de-DMSO at 29°C) δ 8.56 (t, J=6 Hz, 1H), 8.46 (dd, J=4.4,1.5 Hz, 1H), 7.89 (dd, J=8.4, 1.5 Hz, 1H), 7.82 (t, J=2 Hz, 1H), 7.74 (td, J=8,2 Hz, 1H), 7.58 (td, J=8,2 Hz, 1H), 7.47 (t, J=8 Hz, 1H), 7.39 (dd, J=8.4,4.4 Hz, 1H). 6.74 (s, 2H), 4.81 (t, J=6 Hz, 2H), 3.31 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.88 (m, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.61 (m, 2H), 1.36 (sextet, J=7 Hz, 2H), 0.90 (t, J=7 Hz, 3H) 190 -CX\ h3c^ (de-DMSO at 29°C) δ 8.46 (dd, J=4.3,1.5 Hz, 1H), 8.27 (t, J=6 Hz, 1H), 7.89 (dd, J=8.5,1.5 Hz, 1H), 7.75 (d. J=8 Hz. 2H), 7.40 (dd, J=8.5, 4.3 Hz, 1H), 6.94 (d, J=8 Hz, 2H), 6.73 (s, 2H), 4.81 (t, J=6 Hz, 2H), 4.00 (t, J=7 Hz, 2H), 3.28 (q, J=6 Hz, 2H), 2.91 (t, J=7 Hz, 2H), 1.87 (m, 2H), 1.78 (quintet, J=7 Hz, 2H), 1.71 (quintet, J=7 Hz, 2H), 1.60 (m, 2H), 1.38 (sextet, J=7 Hz, 4H), 1.32 (m, 2H), 1.28 (m, 4H), 0.91 (t, J=7 Hz, 3H), 0.87 (t, J=7 Hz, 3H) -124- WO 99/29693 PCT/US98/26473

Examples 191 -212

Compounds of Formula I 5 The compounds of Examples 191-212 shown in the table below were prepared according to the following method. 4-(4-Amino-2-butyl-l/7-imidazo[4.5-c][l,5]naphthyridin-l-yl)ethaneamine (50 pmol) was dissolved in 5 mL of dichloromethane in a screw-capped test tube and a carboxylic acid (50 μχηοΐ) of formula RaCOOH was added at ambient temperature. Within 3 minutes a light suspension typically formed. The coupling agent, l-(3-dimethylaminopropyl)-3- 10 ethyl 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 χ 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 15 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 Cl 8 Ramin 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 20 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 PCT/US98/26473

<img img-format="tif" img-content="drawing" file="IL136556AD0002100.tif" id="idf0100" />

Example # Ra Fragment lH NMR (500 MHz, solvent indicated) 191 "Vi s (CDCb) δ 8.47 (dd, J=4.4,1.5 Hz, 1H), 8.10 (dd, J=8.5,1.5 Hz, 1H), 7.45 (dd, J=8.5,4.4 Hz, 1H), 7.15 (dd, J=5.0, 3.0 Hz, 1H), 6.75 (d, J=3 Hz, 1H), 6.64 (dd, J=5.0,1.2 Hz, 1H), 6.61 (brt, 1H), 6.3 (br s, 2H), 4.94 (t, J=6 Hz, 2H), 3.30 (s, 2H), 2.81 (q, J=6 Hz, 2H), 2.89 (t, J=7 Hz, 2H), 1.88 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 192 (CDCb) δ 8.41 (dd, J=4.4,1.5 Hz, 1H), 8.04 (dd, J=8.5,1.5 Hz, 1H), 7.40 (dd, J=8.5,4.4 Hz, 1H), 7.34 (dd, J=8,1.2 Hz, 1H), 7.07 (dt, J=8, 2 Hz, 1H), 7.00 (dt, J=8,2 Hz, 1H), 6.96 (dt, J=8,2 Hz, 1H), 6.78 (br t, 1H), 5.72 (br s, 2H), 4.95 (t, J=6 Hz, 2H), 3.85 (q, J=6 Hz, 2H), 3.42 (s, 2H), 2.89 (t, J=7 Hz, 2H), 1.83 (quintet, J=7 Η, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 193 If Cl (CDCb) δ 8.40 (dd, J=4.4,1.5 Hz, 1H), 8.07 (dd, J=8.5,1.5 Hz, 1H), 7.43 (dd, J=8.5,4.5 Hz, 1H), 7.14 (d, J=2 Hz, 1H), 7.06 (brt, 1H), 6.98 (dd, J=8,2 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 5.75 (br s, 2H), 4.96 (t, J=6 Hz, 2H), 3.86 (q, J=6 Hz, 2H), 3.31 (s, 2H), 2.89 (t, J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) -126- WO 99/29693 PCT/US98/26473 194 Cl (CDCI3) δ 8.59 (dd, J=4.5,1.8 Hz, 1H), 8.09 (dd, J=8.5, 1.8 Hz, 1H), 7.47 (dd, J=8.5,4.5 Hz, 1H), 7.19 (bt, 1H), 5.79 (bs, 2H), 4.96 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 3.36 (t, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.91 (q, J=7 Hz, 2H), 1.87 (q, J=7 Hz, 2H), 1.50 (m, 6H), 1.01 (t, J=7Hz,3H) 195 no2 (CDCI3) δ 8.51 (dd, J=4.5,1.8 Hz, 1H), 8.07 (m, 3H), 7.42 (dd, J=4.5, 8.5), 1H), 7.31 (br t, 1H), 7.14 (d, J=8 Hz, 2H), 5.8 (s, 2H), 4.95 (t, J=6 Hz, 2H), 4.257 (t, J=7 Hz, 2H), 3.80 (q, J=6 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H), 1.83 (quintet, j=7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.34 (quintet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) 196 (CDCI3) δ 8.60 (dd, J=4.5,1.5 Hz, 1H), 8.11 (dd, J=8.5,1.5 Hz, 1H), 7.49 (dd, J=8.5,4.5 Hz, 1H), 7.24 (br s, 1H), 6.0 (br s, 2H), 4.95 (t, J=6 Hz, 2H), 4.26 (t, J=7 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 2.93 (t, J=7Hz, 2H). 1.91 (quintet, J=7 Hz, 2H), 1.83 (m, 4H), 1.50 (sextet, J=7 Hz, 2H), 1.35 (quintet, J=7 Hz, 2H), 1.05 (m, 2H), 1.01 (t, J=7 Hz, 3H) 197 S-CHj (CDCI3) δ 8.60 (dd, J=4.5,1.5,1H), 8.11 (dd, J=8.5,1.5,1H), 7.49 (dd, J=8.5,4.5 Hz, 1H), 7.01 (d, J=8 Hz, 2H), 6.76 (d, J=8 Hz, 2H), 6.59 (br s, 1H), 5.69 (br s, 2H), 4.93 (t. J=6 Hz, 2H), 3.80 (q, J=6 Hz, 2H), 3.20 (s, 2H), 2.89 (t, J=7 Hz, 2H), 2.44 (s, 3H), 1.90 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) 198 X 0 (CDCI3) δ 8.58 (dd, J=4.4,1.5 Hz. 1H), 8.09 (dd, J=8.3,1.5 Hz, 1H), 7.48 (dd, J=8.3,4.4 Hz, 1H), 7.30 (br t, 1H), 5.69 (br s, 2H), 5.01 (m, 3H), 3.85 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.91 (quintet, J=7 Hz, 2H), 1.85 (m, 1H), 1.79 (m, 1H), 1.60 (m, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.38 (d, J=9 Hz, 1H), 1.27 (t, J=6 Hz, 1H), 1.00 (t, J=7 Hz, 3H) 199 F (CDCI3) δ 8.59 (dd, J=4.5,1.5 Hz, 1H), 8.11 (dd, J=8.5,1.5 Hz, 1H), 7.48 (dd, J=8.5,4.4 Hz, 1H), 7.48 (brs, 1H), 6.11 (brs, 2H), 4.94 (t, J=6 Hz, 2H), 3.83 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 2.28 (m, 2H), 2.08 (t, J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) -127- WO 99/29693 PCT/US98/26473 200 (CDCb) δ 8.54 (dd, J=4.4, 1.5 Hz, 1H), 8.10 (dd, J=8.4, 1.5 Hz, 1H), 7.46 (dd, J=8.4, 4.4 Hz, 1H), 7.19 (brt, 1H), 7.12 (d, J=8 Hz, 2H), 6.88 (d, J=8 Hz, 2H), 5.94 (br s, 2H), 4.91 (t, J=6 Hz, 2H), 3.78 (q, J=6 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 2.65 (t, J=7 Hz, 2H), 2.12 (t, J=7 Hz, 2H), 1.86 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.02 (t, J=7 Hz, 3H) 201 (CDCb) δ 8.60 (dd, J=4.4, 1.5 Hz, 1H), 8.12 (dd, J=8, 1.5 Hz, 1H), 7.47 (dd, J=8.0,4.4 Hz, 1H), 6.86 (br s, 1H). 6.20 (br s, 2H), 4.96 (t, J=6 Hz, 2H), 3.81 (q, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H). 1.90 (m, 4H), 1.51 (sextet, J=7 Hz, 2H), 1.33 (quintet, J=7 Hz, 2H), 1.23 (m, 16H), 1.01 (t, J=7 Hz, 3H), 0.87 (t, J=7 Hz, 3H) 202 (CDCb) δ 8.58 (dd, J=4.3,1.5 Hz, 1H), 8.04 (dd, J=8.0,1.5 Hz, 1H), 7.56 (br s, 1H). 7.43 (dd, J=8.0,4.3 Hz, 1H), 5.84 (br s, 2H), 4.94 (t, J=6 Hz, 2H), 4.89 (br s, 1H), 3.85 (q. J=6 Hz, 2H), 3.54 (d, J=6 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.41 (s, 9H), 1.00 (t, J=7 Hz, 3H) 203 H&gt;C S °ΧΗ, (CDCb) δ 8.60 (d, J=4.4 Hz, 1H), 8.07 (dd, J=8.0,1.5 Hz, 1H), 7.59 (br s, 1H), 7.45 (dd, J=8.5,4.4 Hz, 1H), 5.88 (br s, 2H), 4.94 (m, 2H), 4.77 (s, 1H), 3.93 (m, 1H), 3.84 (m. 2H), 2.94 (t, J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.40 (s, 9H), 1.01 (d, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H) 204 ΧτΒ' (de-DMSO at 80°C) δ 8.53 (dd, J=4.4, T.5 Hz, 1H), 8.53 (t, J=6 Hz, 1H), 7.96 (dd, J=8.3,1.5 Hz, 1H), 7.45 (dd, J=8.3,4.4 Hz, 1H), 7.32 (d, J=4 Hz, 1H), 7.16 (d, J=4 Hz, 1H), 6.81 (br s, 2H), 4.91 (t, J=6 Hz, 2H), 3.78 (q, J=6 Hz, 2H), 2.85 (t, J=7 Hz, 2H). 1.77 (quintet, J=7 Hz, 2H), 1.37 (sextet, J=7 Hz, 2H), 0.87 (t, J=7 Hz, 3H) 205 —ζΧεπ. (CDCb) δ 9.16 (d, J=1.4 Hz, 1H), 8.66 (dd, J=4.4,1.5 Hz, 1H), 8.44 (t, J=6 Hz, 1H), 8.11 (d, J=1.4 Hz, 1H), 8.09 (dd, J=8.4,1.5 Hz, 1H), 7.47 (dd, J=8.5, 4.4 Hz, 1H), 6.10 -128- WO 99/29693 PCT/US98/26473 (br s, 2H), 5.11 (t, J=6 Hz, 2H), 4.05 (q, J=6 - Hz, 2H), 2.92 (t, J=7 Hz, 2H). 2.59 (s, 3H), 1.87 (quintet, J=7 Hz, 2H), 1.46 (sextet, J=7 Hz, 2H), 0.95 (t, J=7 Hz, 3H) 206 ΊΰΓ* (CDCb) δ 8.73 (dd, J=4.4,1.5 Hz, 1H), 8.12 (dd, J=8.4,1.5 Hz, 1H), 7.95 (brs, 1H), 7.52 (dd, J=8.4,4.4 Hz, 1H), 6.91 (d, J=3.4 Hz, 1H), 6.31 (d, J=3.4 Hz, 1H), 6.04 (brs, 2H), 5.07 (t, J=6 Hz, 2H), 3.99 (q, J=6 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 1.91 (quintet, J=7 Hz, 2H). 1.50 (sextet, J=7 Hz, 2H), 0.99 (t, J=7 Hz, 3H) 207 (CDCb) δ 8.50 (dd, J=4.4,1.5 Hz, 1H), 8.42 (d, J=4 Hz. 1H), 8.19 (d, J=1.5 Hz, 1H), 8.09 (dd, J=8.2,1.5 Hz, 1H), 7.47 (dd, J=8.3,4.4 Hz, 1H), 7.26 (br s, 1H), 7.23 (d, J=8 Hz, 1H), 7.07 (dd, J=8.5, 5 Hz, 1H), 6.06 (br s, 2H), 3.95 (t, J=6 Hz. 2H), 3.84 (q, J=6 Hz, 2H), 3.21 (s, 2H), 2.87 (t, J=7 Hz, 2H). 1.88 (quintet, J-7 Hz, 2H), 1.50 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 208 (CDCb) δ 8.54 (dd, J=4.4,1.5 Hz, 1H), 8.37 (d, J=4Hz, 1H), 8.24 (br s, 1H), 8.09 (dd, J=8.5,1.5 Hz, 1H), 7.46 (dd, J=8.5,4.4 Hz, 1H), 7.35 (br t, 1H), 7.27 (td, J=8,2 Hz, 1H), 7.08 (dd, J=8, 5 Hz, 1H), 5.98 (brs, 2H), 4.91 (t, J=6 Hz, 2H), 3.79 (q, J=6 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 2.69 (t, J=7 Hz, 2H), 2.14 (t, J=7 Hz, 2H), 1.90 (quintet, J=7 Hz, 2H), 1.52 (sextet, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H) 209 cr· NOf (de-DMSO) δ 8.52 (d, J=8.3 Hz, 1H), 8.37 (m, 2H), 7.96 (d, J=8.3 Hz, 1H), 7.48 (dd, J=8.3,4.5 Hz, 1H), 7.14 (br s, 2H), 4.72 (t, J=6 Hz, 2H), 4.12 (t, J=6 Hz, 2H), 3.56 (q, J=6 Hz, 2H), 2.81 (t, J=7 Hz, 2H), 2.52 (m, 2H), 2.33 (s, 3H), 1.75 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.94 (t, J=7 Hz, -129- WO 99/29693 PCT/US98/26473 3H) 210 φ Cl (CDC13) δ 8.52 (dd, J=4.4,1.5 Hz, 1H), 8.05 (dd, J=8.4, 1.5 Hz, 1H), 7.76 (t, J=6 Hz, 1H), 7.43 (dd, J=8.5,4.4 Hz, 1H), 7.27 (d, J=8 Hz, 2H), 7.06 (d, J=8 Hz, 2H), 5.82 (br s, 2H), 5.06 &amp;amp; 4.83 (m, 2H), 3.88 &amp;amp; 3.79 (m, 2H), 3.03 (m, 1H), 2.89 (t, J=7 Hz, 2H), 2.79 (m, 1H), 2.5 (m, 3H), 2.25 (m, 1H), 1.90 (quintet, J=7 Hz, 2H), 1.51 (sextet, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H) 211 (d6-DMSO) δ 8.53 (dd, J=4.4, 1.5 Hz, 1H), 8.24 (t, J=6 Hz. 1H), 7.96 (dd, J=8.4,1.5 Hz, 1H), 7.84 (m, 4H), 7.48 (dd, J=4.4, 8.4 Hz, 1H), 7.18 (br s, 2H), 4.75 (t, J=6 Hz, 2H), 3.73 (t, J=7 Hz, 2H), 3.52 (q, J=6 Hz, 2H), 2.86 (t, J=7 Hz, 2H), 2.34 (t, J=7 Hz, 2H), 1.79 (quintet, J=7 Hz, 2H), 1.40 (sextet, J=7 Hz, 2H), 0.92 (t, J=7 Hz, 3H) 212 (CDCI3) δ 8.60 (dd, J=4.4,1.5 Hz, 1H), 8.04 (dd. J=8.5,1.5 Hz, 1H), 7.68 (dd, J=3.5,1.2 Hz, 1H). 7.61 (dd, J=3.5,1.2 Hz, 1H), 7.43 (dd, J=8.5,4.4 Hz, 1H), 7.39 (t, J=6 Hz, 1H), 7.10 (dd, J=5, 3.5 Hz, 1H), 5.79 (br s, 2H), 4.93 (t, J=6 Hz, 2H), 3.82 (q, J=6 Hz, 2H), 3.12 (t, J=7 Hz, 2H), 2.92 (t, J=7 Hz, 2H), 2.32 (t, J=7 Hz, 2H), 1.89 (quintet, J=7 Hz, 2H), 1.49 (sextet, J=7 Hz, 2H), 0.99 (t, J=7 Hz, 3H) -130- 136556/2

Example 213

Compound of formula I N- [2- (4-Amino-2-butyl-lH-imidazo [4,5-c] [1,5] naphthyridin-l-yl) ethyl]-5-oxo-2- pyrrolidinecarboxamide

<img img-format="tif" img-content="drawing" file="IL136556AD0002101.tif" id="idf0101" />

Using the general method of Example 97 L-pyroglutamic acid (0.23 g, 1.7 mmole) was reacted with 2- (4-amino-2-butyl-lH-imidazo [4, 5-c] [1,5] naphthyridin-l-yl) ethaneamine (0.5 g, 1.7 mmole) to provide 0.10 g of N-[2-(4-amino-2-butyl-lH- imidazo [4,5-c] [1,5] naphthyridin-l-yl) ethyl]- 5-oxo-2-pyrrolidinecarboxamide as a white powder, m. p. 135-138° C. Analysis: Calculated for C20H25N7O2 ’ACHsCN: % C, 60.63; % H, 6.42; % N, 25.25; Found: % C, 60.14; % H, 6.41; % N, 25.20. HRMS (EI) caicd for C2oH25N702 (M+) 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 (^(IFN and TNF, respectively) secreted into culture media as described by Testerman et. al..

In "Cytokine Induction by the Immunomodulators Imiquimod and S-27609",

Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

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 medium containing 10 % fetal bovine serum, 2 mM 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 5 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 μΜ.

Incubation

The solution of test compound is added to the wells containing 1 mL of PBMCs in 10 media. The plates are covered with plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°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 15 pipet and transferred to a 2 mL sterile cryotube. Samples are maintained at -70°C until analysis.

Interferon Analvsis/Calculation

Interferon is determined by bioassay using A549 human lung carcinoma cells challenged with encephalomyocarditis. The details of the bioassay method have been 20 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°C for 24 hours. The incubated cells are then infected with an inoculum of encephalomyocarditis virus. The infected cells are incubated 25 for an additional 24 hours at 37°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 Necrosis Factor («) Analysis 30 Tumor necrosis factor («) (TNF)concentration is determined using an ELISA kit available from Genzyme, Cambridge, MA. The results are expressed as pg/mL. -132-

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. WO 99/29693 PCT/US98/26473 -133- -134-

Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 9 ± - + - - - - - 10 + + + + - - - + 12 Not run + + + Not run + + + 13 Not run + + + Not run 4* + + 22 Not run - - - Not run - ± + 23 Not run + + - Not nm - + - 25 Not run - + Not run - ± - 26 Not run + - + Not run + + - 27 Not run 4" + + Not run + + + 28 Not run + + + Not run - + + 32 Not run + + + Not run - - - .. 33 Not run + + 4- Not run - - - 36 Not run + + + Not run - + - 39 Not run + + - Not run + + - 40 Not run + + ± Not run + + + 45 + + - - + 4* - 46 + + + 4" + + + + 46 Not run + + + Not run 4- + + 47 - + + ± - + + + 48 + + + - - + + - 49 + + + + - + + + 50 Not run + + - Not run + + - 51 Not run + + 4* Not run + + - 52 Not run + + - Not run + + - 99/29693 PCT/US98/26473

Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 53 + + + + - + + - 54 Not run + + ' + Not run + + + 55 Not run + + Not run 4- + - 56 - + + - - - + - 57 t + + + - - + + 58 + + - - + + - 62 + + + + + + + 65 + + + + - + + + 70 + + + - - + + - 75 - + + + - - + - 80 - + + - - - + - 85 + + + - - + + - 90 + + + + &gt; - + + 91 + + + + + + + + 92 ± + + + - + + + 93 - + + + - + + + 94 - + + + - + + + 95 ± + + + - - + + 96 - ± + + - - + + 97 - - + + - - + 98 - + + + - + + 99 - - + + - - + + 100 * - + + - - + + 101 - - + + - - + + 101 - - + + - - - + 102 + + + + + + + + WO 99/29693 PCT/US98/26473 -136-

Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 103 - - + + - - + + 104 - + + - - - + - 105 + + + + - - + + 106 + + + - - + + - 107 ' + + + - - + + - 108 + + + ± - + + 109 + + + - ± + + 110 + + + + - + + + 111 - - + + - - + + 112 + + + ± + + - - 113 - + + + - + + + 114 - - + + - - + + 115 • - + + - - + + 116 - + 4“ - + + 3 + 117 - - + + - - + WO 99/29693 PCT/US98/26473 -137-

Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 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 Not run i - - 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 + + + Not run + + ’ + 131 Not run + + + Not run + + + 132 Not run + + + Not run + + + 133 Not run + + + Not run + + + 134 Not run + + + Not run + + + 135 Not run - + + Not run - + + 136 Not run + + + Not run - + + 137 Not run + + + Not run - + + 138 Not run + + + Not run 4- + + 139 Not run + + + Not run - + + 140 Not run + + + Not run + + + 141 Not run + + + Not run - + + 99/29693 PCT/US98/26473 -138-

Cytokine Induction in Human Cells IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 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 ί - + + - + + + 146 + + + - + + + + 147 - + + + - - + + 148 - + + - - + + 149 - - - - - - - - 150 - - + - - + + 151 - + - - + + 152 - - + + - - + + 153 - + + - - + + 155 - + + - - + + 156 + + + + - + + - 157 + + + - - - + - 158 - + + + - - + - 159 + + + - + . + + + 160 + + + - - + - 161 ± + + + - - + + 162 + + + + ' - + + + 163 + + + - + + - 164 + + + - - + + - 165 + + + + - + + + 166 - + + - - + + - 167 - + + - - - + WO 99Z29693 PCT/US98/26473 -139-

Cytokine Induction in Human Ceils IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 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 - - ± + - - i + 182 - + - + + - 183 - - - - - - - - 183 + + + - 184 + + + - + + + - 185 - + + ± - ± + - 186 + + + + - + + + 187 - + + + - + + - 188 +. + + - - + +, - 189 - + + - - ± + - 190 + + + - - + + - 191 Not run + + + Not run - + + WO 99/29693 PCT/US98/26473

Cytokine Induction in Human Celis IFN TNF Example Dose Concentration (μΜ) Dose Concentration (μΜ) 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 192 - - + + - - + + 193 - - + + - - + + 194 - + + - + + + 195 &lt; · - + - - + + + 196 - - + + - - + + 197 - - + + - + + + 198 - - + + - + + 199 4- - + - - + + 200 - - + + - - + + 201 - - - - - - - 202 - - + + - - + + 203 - - + + - - + + 204 + + + + - + + + 205 + + + + - + 3 + + 206 • + + + + - + + 207 - - + + - - + 208 - - + + - - - - 208 - + + + 209 - - + + -. - + + 210 - - + + + + + + 211 - . - + + - - + + 212 - + + + - + + + WO 99/29693 PCT/US98/26473 136556/2

INTERFERON (a) 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™ 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 106/mL in RPMI 1640 media (available from GIBCO, Grand Island, NY) containing 25 mM HEPES (N-2-hydroxyethylpiperazine-N'-2ethanesulfonic acid) and L-glutamine (1% penicillin-streptomycin solution added) with 10% heat inactivated (56° C for 30 minutes) autologous serum added. 200 pL 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, 0.0 IN 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 pg/mL. Compounds which show induction at a concentration of 0.5 pg/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 pL) to the wells containing 200 pL 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 pL. The plates were covered with plastic lids, -141 - WO 99/29693 PCT/US98/26473 vortexed gently and then incubated for 48 hours at 37°C with a 5% carbon dioxide atmosphere.

Separation 5 Following incubation, the plates were covered, with parafilm and then centrifuged at 1000 rpm for 10 to 15 minutes at 4°C in a Damon IEC Model CRU-5000 centrifuge. Media (about 200 pL) was removed from 4 to 8 wells and pooled into 2 mL sterile freezing vials. Samples were maintained at -70°C until analysis. 10 Interferon Analvsis/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 15 reference. Briefly stated the method is as follows: interferon dilutions and A549 cells are incubated at 37°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°C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining followed by spectrophotometric absorbance measurements. Results 20 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. 25 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. - -142- - 143-

Interferon (a) Induction in Human Cells Example Dose Concentration (pg/mL) 0.01 0.05 0.10 0.50 1.0 5.0 10.0 25.0 50.0 9 - - - - - - - - 10 - - - - + + + + + 12 t “ - + + + + + + + 13 - + + + + + + + + 22 not run not run not run not run - - - + not run 23 not run not run not run not run - - - - not run 25 • - - - - - + + + not run 26 - - - - - ± + + not run 27 - - + + + + + + t not run 28 - ± + + + + + + not run 32 - - - - + + .- + + + 33 - - - - - + + + + 36 - + + + + + + + + 39 - - + + + + + + + 40 - + + + + + + + + WO 99/29693 PCT/US98/26473 136556/2 WO 99/29693 PCT/US98/26473

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 5 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. ***************'*******************************

All passages of the description, which are not within the scope of the claims, do not form part of the invention. -144-